JPS61145167A - 1,3-disubstituted-5-fluoro-6-chlorouracil derivative and antitumor agent - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R<1> and R<2> are alkyl, alkenyl, aralkyl or oxygen-containing heterocyclic group). EXAMPLE:1-Methyl-3-benzyl-5-fluoro-6-chlorouracil. USE:An antitumor agent having decreased toxicity of 5-fluorouracil with lowering its activity to suppress the proliferation of malignant tumor. PREPARATION:The compound of formula I can be produced economically without using hazardous fluorine agent, by (1) reacting the compound of formula II with phosphorus oxychloride in the absence of solvent, preferably in the presence of a tert-amine such as dimethyl-aniline, at room temperature-150 deg.C, or (2) reacting the compound of formula IV with the compound of formula V (X is halogen) in an aprotic solvent, preferably in the presence of an acid acceptor under cooling or at <=150 deg.C, and (3) reacting the resultant compound of formula III with the compound of formula VI (Y is halogen) under the condi tion similar to that of the step (2).

Description

DETAILED DESCRIPTION OF THE INVENTION [Object of the invention and industrial field of application] The present invention is based on the general formula (wherein R1 and HI2 are an alkyl group, an alkenyl group,
It is an aralkyl group or an oxygen-containing heterocyclic group. ) and an antitumor agent containing the same as a main component.

[Conventional technology]

5-Fluorouracil is a widely used antitumor agent, but it has drawbacks such as being highly toxic, its range of application is limited, its long-term use is difficult, and it is difficult to administer orally. There is.

In recent years, much research has been conducted to chemically modify 5-fluorouracil to overcome the above drawbacks, and compounds with substituents introduced at the 1- and 3-positions are attracting attention.

However, although the above-mentioned drawbacks can be overcome to some extent by chemical modification, there is a drawback that the inhibition rate of malignant tumor cell proliferation is reduced.Furthermore, in order to synthesize these 5-fluorouracil derivatives, fluorine is required. Another drawback is that dangerous fluorinating agents such as gases must be used.

[Problems solved by the invention]

In order to overcome the drawbacks of the conventional methods, the inventors have conducted extensive research into developing an antitumor agent that chemically modifies the 1st and 3rd positions of 5-fluorouracil and has a higher rate of inhibiting malignant tumor growth. The present invention was completed by discovering that the compound represented by the general formula (I) of the invention can fully achieve the object.

[Summary of the invention]

1,3-disubstituted-5 represented by the general formula (1) of the present invention
-Fluoro-6-Chlorouracil Derivatives Co., Ltd. It can be produced, for example, according to the following reaction acid.

[Second process]

In the present invention, X and Y in the formula are each halogen, R'' and R2 are alkyl groups, alkenyl M, 79 A.

It is a kill group or an oxygen-containing heterocyclic group. Specifically, the alkyl group is an unsubstituted or substituted alkyl group, the alkenyl group is an unsubstituted or substituted alkenyl group, the aralkyl group is an unsubstituted or substituted aralkyl group, and the oxygen-containing heterocyclic group is an unsubstituted or substituted aralkyl group. It is an oxygen-containing heterocyclic group that may be present.

Furthermore, to specifically describe the definitions of each of the above symbols, examples of halogen include fluoro, chloro, fluoro, iodo, etc., and halogens represented by X and Y include chloro,
I like bromo and iodine.

The unsubstituted alkyl group includes lower alkyl, specifically an alkyl group having 1 to 8 carbon atoms, including methyl, ethyl, propyl, inglovil, butyl, 5ec-butyl, t-butyl, pentyl, neopentyl, octyl, and the like.

Substituted alkyl groups include halogens such as fluoro, chloro, bromo, and iodo, alcoquine, alkylthio, trialkylsilyloxy, nitro, cyano, acyl, acyloxy, and phenyloxy which may have halokene, nitro, etc. in the benzene nucleus. , phenylthio, aroyloxy fx, etc. refers to the above alkyl group having 1 to 3 substituents, and unsubstituted aralkyl group refers to benzyl, phenethyl, etc., and substituted aralkyl group and monoalkyl,
Substituted by halokene, nitroalkoxy, etc. means fp-1 aralkyl group.

An unsubstituted alkenyl group means a lower alkenyl group, specifically an alkenyl group having 3 to 5 carbon atoms, and includes allyl, isopropenyl, phthynyl, and pentenylnato. The substituted alkenyl group means an alkenyl group substituted with I.rogen, alkoxy, or the like.

Unsubstituted oxygen-containing heterocyclic groups include tetrahydrofuryl, tetrahydropyranyl, 5-oxo-2,3,4,5-tetrahydro-2-furyl, 2-oxo-2,3,4゜5-tetrahydro-3- It means a 5- or 6-membered heterocyclic group containing an oxygen atom such as furyl, 3-oxo-1°3-dihydro-1-isope/zofuranyl, and 2-oxo-tetrahydro-2-pyranyl. Substituted oxygen-containing hetero JR group refers to the above oxygen-containing ' substituted with hydroxy, lower alkyl, alkoxy, trialkylsilyloxy, amino, alkoxycarbonylamino, haloalkoxycarbonylamino, nitro, cyano, carboxy, or carboxyalkyl, etc.
! M means a ring group and may have 1 to 2 substituents. Alkoxy is alkoxy having carbon a1 to a5, such as methoxy, ethoxy, globoxy, imbutoxy, butoxy, imbutoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy,
t-pentyloxy and the like. Trialkylsilyloxy refers to silyloxy, silyloxy, trimethylsilyloxy, triethylsilyloxy, tripropylsilyloxy, dimethylethylsilyloxy, and 9 having three same or different alkyl groups having 1 to 4 carbon atoms.

It means diethylmethylsilyloxy, diethylmethylsilyloxy, methylethylclobylsilyloxy, dimethylbutyl7lyloxy, dimethyl t-butylsilyloxy, and the like. Alkoxycarbonylamino is carbonylamino having the above-mentioned alkoxy group, and haloalkoxycarbonylamino means alkoxycarbonylamino having a halogen t-substituent such as chloro, bromo, or iodo on the alkyl moiety.

Each trap process will be explained below.

[First step]

In this step, the 5-fluorobarbylic acid salt conductor represented by the general formula (2) is reacted with phosphorus oxychloride, and the 3-substituted-5-fluoro-
6-Chlorouracil visiting conductor is manufactured.

The 5-fluoroparbituric acid derivative represented by the general formula (2) used in this step can be easily produced from a fluoromalonic acid diester and ureas (see the reference side below).

This step usually involves adding phosphorus oxychloride to the general formula (■) without a solvent.
The amount of the compound to be added is from 11 equivalents to 11 equivalents, preferably 5 to 30 equivalents.

The reaction is usually carried out in the range of base base to 150c. It is also desirable to add a tertiary amine such as dimethylaniline or triethylamine to the reaction system.

[Second process]

This step is a substitution reaction of 5-fluoro-a-5-chloro(9cybW) using a halide represented by the general formula (7). 5-Fluoro-6-9a louracil (transformation)
can be easily produced by subjecting it to a reaction similar to the first step of 5-fluorobarbic acid tg (see reference side below).

The amount of halide soda used varies depending on the type of halide used, but usually 1 to 5 equivalents are used.

This step is usually carried out in an aprotic solvent such as tetrahydrofuran, acetonitrile, dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, or a mixture thereof at a temperature of 150° C. under cooling. In addition, in order to remove hydrogen halogenide produced as a result of this reaction, a base such as triethylamine, tri-t-butylamine, pyridine, sodium carbonate, potassium carbonate, etc. may be added to the reaction system as a deoxidizing agent. desirable.

[Third step]

Synopsis of this process The 3-substituted-5-fluoro-6-rita laurasil spinner represented by the above general formula (2) obtained in the first step or the second step and the above general formula (2) The 1,3-disubstituted-5-fluoro-6-chlorouracil visiting conductor represented by the above general formula is produced by reacting the compound with a halide.

The amount of halide (b) to be used is from normal to excessive. This step proceeds under the same reaction conditions as the second step, in the same normal aprotic solvent as the second step, under cooling at ~150 tll.
' and the reaction proceeds smoothly. In order to carry out the reaction with good yield, it is desirable to add a deoxidizer as in the second step.

The 1,3-disubstituted-5-fluoro-6-V-louracil derivatives obtained as described above can be used as antitumor agents.

The usefulness as an antitumor agent was confirmed by conducting a malignant tumor cell growth inhibition test. The test was conducted by a well-known method using mouse lymphocytic leukemia cells (p388), and the inhibition rate relative to the control was determined (see Test Example below).

The antitumor agent according to the present invention may be administered as the 1,3-disubstituted-5-fluoro-6-chlorouracil derivative itself, but
Orally or in the form of powder, granules, tablets, capsules, whole tablets, injections, etc., using physiologically measured carriers, excipients, diluents, etc., according to commonly used methods. Can be administered parenterally.

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

Reference example 1 Sodium methoxide (1.63 g, 30 mmol) K
After adding and dissolving ethanol (32d), add urea (1
, 4tge 24mmol) and completely dissolved.

To this solution was added diethyl fluoromalonate (3.56 g).

29 mmol) was added dropwise and stirred for 10 minutes at 80C.
The mixture was heated and stirred for 14 hours. The solvent was distilled off under reduced pressure, and the residue was adjusted to pH 1 by adding water (8IRt) and 3N salt-brewed water and cooled. Ruic acid 2.
67 g (yield: 91 g) was obtained.

Further, 146q (yield: 5%) of t- was further obtained by recrystallizing solution F from water-ethanol, and the total yield of 5-fluorobarbic acid was 97%.

mp: 300C or more IHNM le (CD, 8UCD, :TM8): δ3.4
(bs.

2H) 19.4 (bs, IH) -I-F NMR
(CD, 80CD, :CFCI ship): δ-205,5(
S)・IR(KBr): 1710= 1675.16353
-'.

('C=O) Mass: m/e (rel・int, ) M”1
46 (15) +'103 (51), 60 (10
0), 44 (68).

43 (100) + 28 (34), 20 (
98).

-Example 2 Sodium methoxide (810Iq, 15.0mmo+
) was added and dissolved in ethanol (12d), then methylurea (667"F-9,0 mmol) was added and completely dissolved. Diethyl fluoromalonate (1,3
4g, 7.5mmo I)'fI: Dropped and stirred for 10 minutes, then heated and stirred at 80C for 16 hours. The solvent was distilled off under reduced pressure, and water C31R1> and a 3N aqueous hydrochloric acid solution were added to the residue to adjust the pH to 1, followed by cooling. By removing the precipitated solid and washing it with water, l-methyl-5-fluorobarbyl #! 591av (yield: 49cm) was obtained. Also P
By recrystallizing the liquid with water-ethanol, 27
A total yield of 1-/l thi-5-fluorobarbic acid of 72% was obtained.

mp: 300L or more (decomposition) Snow) I NMR<cD, 5oCo, -cD, oD:TM
8): δ2.9B (st 3H) = 3.9 (bs
, 2H).

19F NMI(, (CI), 80CD, :CFC
I,) 2 δ-203,3<s> IR(KBr): 1715,1695,1670,1
615crIIt.

Mass = m/e (reL int, ) M”1
60 (16L 103"1 (22), 60 (78), 44 (100), 28 Reference Example 3 After adding and dissolving ethanol (20xl) in sodium methoxide (1.03g, 19mmof), benzyl urea (2 , 25gy 15mmol) was added and completely dissolved.To this solution was added diethyl fluoromalonate (2,2
3 g = 12.5 mmol) was added dropwise, stirred for 10 minutes, and then heated and stirred at 80C for 16 hours. The solvent was distilled off under reduced pressure, and the residue was diluted with water (10 μl and 3 N aqueous hydrochloric acid solution added to make H1), and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, ethyl acetate was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-chloroporm to give 1-benzyl-5-fluorohalhylic acid 923w.
(yield EK 31%). Furthermore, by purifying the P solution by silica gel column chromatography (ethyl acetate), 793 ~ (yield 27%) was obtained, and the total yield of 1-benzyl-5-fluorobarbic acid was 58%. there were.

mp: 182-183C.

'HNMR (CD, C0CD, : TMS) : a
4.95 (s.

2H), 6.00 (d, J=22Hz, IH).

7.27 (m, 5H), 10.4 (bs, I
H).

1'F NMR (CD, COCD,: CFCI: J-209,3 (d, J=1.4Hz).

IR (KHr) 2 1780, 1755, 17
30+ 1705□-1 (W c = Q) Mass: m/e (tel, int, ) M
+236 (78)+ 165C36)t 132 (
100L 122 (49).

104 (25), 91 (52), 77 C34
).

65 (25), 51 (20) - Reference Example 4 5-Fluorobarbyl fR (730'9. 5
mmol) was added thereto, and the mixture was heated and stirred at 80C for 15 minutes. After cooling, excess phosphorus oxychloride was distilled off under reduced pressure, ice was added to the residue, and the mixture was extracted with ether (30 mt x 4 times). anhydrous ff
After drying over sodium chloride, the ether was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:chloroform=1:1) to obtain 5-fluoro-6-chloro'flsil 403q (yield 49%).
) was obtained.

Sublimation point 247-249C 19F NMR (C1), C0CD, :CFCI,)
:δ-1664<s>・I几(KHr): 1735. 1690.16
70aπ-凰('c=o) Mass: m/e (rel, int, ) M
”166 (24) +164 (71), 123 (
23), 121 (66), 86 (100), 58 (
25).

Reference example 5) 7=') (2,36gw 19.5mm
ol) and oxychloride 7 (23g v 15Qm
Add 1-methyl-5-fluorobarbic acid ('2.4 g + 15 mmol) to the mixture of
The mixture was heated and stirred at 0C for 15 minutes. After cooling, excess phosphorus oxychloride was distilled off under reduced pressure, ice was added to the residue, and the mixture was extracted with ether. After drying over anhydrous sodium sulfate, the ether was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:chloroform = 11) to obtain 3-methyl-5-fluoro-6-chlorouracil 1.
．． 93 g (yield 72%) of t- was obtained.

Sublimation point 205-207C'HNMR (CD, C0CD3:TMS): δ3.21
(S.

CH,) ”F NMR (CD, C0(1),: CFCI,)
:δ-164,9(S) IN, (KHr): 1725,1670,1650c
rn'('c=o) Mass: m/e (rel, int,
)M”180 (27)+178(82), 123
(28), 121 (81).

86 (100), 58 (35)・Reference Example 6 1-Benzyl-5-fluorobarbylic acid (
354W, 1.5 mmol) was added, and the mixture was heated and stirred at 80 U for 15 minutes. After cooling, excess phosphorus oxychloride was distilled off under reduced pressure, ice was added to the residue, and the mixture was extracted with ether.

After drying over anhydrous sodium sulfate, the ether was distilled off under reduced pressure.

The residue was purified by silica gel column chromatography (ethyl acetate:chloroform = 1:3) to give 358 kg of di-3-benzy-5-fluoro-6-chlorouracil (yield 94%)'5r: Obtained O Melting point 197-198C IHNM 几(CDCI 3-CD3UD: To T(S)
: δ4.2 (b S, NH), 5.19 (S+ C
H2) +7.1~7.6 (m, C,)l,).

"F NMl((CDCI, -CD3(JD: CFC
I3): δ-163,5(s)・IR(KHr): 1720,1650Crn' (
'c=o) Example 7 5-Fluoro-6-chlorouracil (70■.

0.43 mmol1) of THE' (2/nj solution,
A solution of α-chlorotetrahydrofuran prepared from tetrahydrofuran (2,4/d) and sulfuryl chloride (1081′IF, 0.80 mmol) and triethylamine (218% 2.16 mmol) in THF (
1,21d) The solution was poured down at the same time. After stirring at room temperature for 15 hours, the solvent was distilled off under reduced pressure. The residue was acidified with dilute hydrochloric acid and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. By purifying the residue by silica gel column chromatography (ethyl acetate:chloroform-2:3), 20.9 ~ of 5-fluoro-6-chlorouracil was recovered, and 3
-(2-tetrahydrofuryl)-5-91%).

Melting point: 12FI: It starts to soften around 240C, but it does not change to 1IHNMII (CD3COCD32 TMS)
δ 1.7~2.7 (m, 4t-1) 13.7~4
．． 4 (m, 3H).

6.5 (In, IH).

! 9F NM)L (CD3CUCD3:CFCI3)
: δ-164,8 (d, J=lHz).

IR (KBr): 1750, 1680, 1670.1
625cm-” ('C=O) Mass: m/e (rel, int, )M+
236 (2) + 234 (4), 105 (12
), 71 (100).

70 (12), 43 (43), 41 (40)
.

Example 1 3-h/cyl-5-fluoro-6-chlorouracil (5
20n! , 2.04 mmol) in dimethylformamide (3 m/), potassium carbonate (1.38 g, 10
mmol) followed by methyl iodide (2.84 g,
20 mmol) was added. After heating and stirring in a 100C oil bath for 2 hours, the mixture was made acidic by adding gold hydrochloric acid and extracted with ether.

The ether layer was washed with an aqueous sodium thiosulfate solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to obtain 1-methyl-3-benzyl-
5-fluoro-6-chlorouracil 468'9 (yield 8
6%).

Melting point 87-88C IHNMR (C3)C13: TMS): δ3.51
(s, 3H).

5.10 (s, 2H),'! , 1 to 7.6 (r
n.

5) 1)・1'F NMR (CDCI 3: CFCl 3): δ-
157,1(S)・IR(KBr): 1720,1670,1660cr
r1'('c=o) Mass :m/e (rel, int, ) M"
270 (6) + 268 (17), 91 (100
)・Example 2 3-(2-tetrahydrofuryl)-5-fluoro-6-
rioourashi/'(105"Pt O, 43mmo
Add potassium carbonate (138”P+ 1.0 mmol) ft to dimethylformamide (24 solution) of l),
Subsequently, methyl iodide (142"F, 1.0 mmol) was added and the cap was sealed. After heating and stirring in a 100 C oil bath for 10 minutes, diluted hydrochloric acid was added to acidify and extract with ether. The ether layer was washed with an aqueous sodium thiosulfate solution, then anhydrous. It was dried over sodium sulfate and the solvent was distilled off under reduced pressure.The residue was purified by silica gel column chromatography (chloroform) to give 1-methyl-3-(2-tetrahydrofuryl).
-5-fluoro-6-chloro-2-sil 87~ (yield 81
%) was obtained.

Melting point 122.5-123C'HNM)L (CDel 3:TMS): δ1.7-2
．． 7 (m.

4H), 3.50 (s, 3H) - 3,9 (m.

IH), 4.3 (m, IH), 6.60 (d
,d.

J=7.7Hz, 5.7Hz, IH)-”9F NMR
(CDCI 3: CFCI,): δ-157,9(b
s)・■几(KBr): 1720,1660crn-1('
c=o)Mass: m/e (rel, int,
) M+250 (1,2) v248 (3,9),
179 (14), 100 (11), 71 (100
), 70 (11)? 43 (41), 41 (1
5)・Example 3 3-methyl-5-fluoro-6-chlorouracil (80
Potassium carbonate (300 ~, 2.17
mmol) f followed by methyl iodide (6841rl
i.

4.82 mmol) was added. It takes 1 hour in a 100C oil bath. The ether layer was washed with an aqueous sodium thiosulfate solution and dried over anhydrous sodium 4A acid. After removing the bath medium under reduced pressure,
The residue was purified by silica gel column chromatography (chloroform) to obtain 1,3-dimethyl-5-
Fluoro-6-chlorouracil 82~ (yield 95%) was obtained.

Melting point 100-100.5 tl; IHNM 几(CDCI 3:TMS): a 3.
40 (s, 3) 1).

3.57 (s, 3H).

19F NMR (CDCI3:CFCl3): δ
-157,9(s)IR(KBr): 1720,16
70,1655crR'('c=o) Mass: m/e (rel, 1nt) M+1
94 (12) p192 (35), 135 (33
), 100 (100), 72 (26).

Example 4 3-Methyl-5-fluoro-6-chlorouracil (50
Potassium carbonate (58 capes, 0.4
2 mmol) and then benzyl bromide (72HI+0
．． 42 mmol) was added. The mixture was heated and stirred in a 100C oil bath for 2 hours, acidified with dilute hydrochloric acid, and extracted with ether. The ether layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane ether=3
: 2) to refine it! , 91-benzyl-3-methyl-5-fluoro-''6-chlorouracil 44.7
~(yield 59%) was obtained.

Melting point 98C 1) (NM几(CL)C13:TMS): δ3.38
(S, 3)1).

5.25 (s, 2H), 7.32 (s,
5H).

"F NMR (CDCI 3: CFCIs): δ-
156,4(S)・IRCKBr): 1720,1675.1650t
M-"('c=o)・Mass: m/e (rel, int, ) M
” 270 (12L268 (33), 92 (4
4), 91 (Zoo), 65 (60).

Test Example: The proliferation inhibition test was performed using mouse lymphocytic leukemia cells (p38
8) with RPMI-1640 containing 10% calf fat serum.
In addition to the culture medium, the number of cultured cells was adjusted to t-5, 4X10' cells/l, and an aqueous solution of the compound of the present invention was added at 1X10' pmol/l.
m, I
Received the Time Relief Award. The measurement was carried out using a Coulter counter, and the number of floating cells was counted to determine the inhibition rate relative to the control. The results are shown in the table.

Handbook continuation supplementary text (self-published) February 28, 1985

Claims (2)

[Claims] (1) A 1,3-disubstituted-5-fluoro-6-chlorouracil derivative represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (wherein R^1 and R^2 are alkyl groups, alkenyl group, aralkyl group, or oxygen-containing heterocyclic group). (2) An antitumor agent whose main component is a 1,3-disubstituted-5-fluoro-6 chlorouracil derivative represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (in the formula, R^
1 and R^2 are an alkyl group, an alkenyl group, an aralkyl group, or an oxygen-containing heterocyclic group. ).