JPS6178724A - Antitumor agent - Google Patents

Abstract

PURPOSE:To provide an antitumor agent composed of a specific nitrosourea derivative having 2-fluoroethyl group, acting as an alkylation agent similar to a compound having 2-chloroethyl group, and having widened applicable therapeutic field. CONSTITUTION:The nitrosourea derivative of formula A or its salt is used as an antitumor agent. It has been found newly that the compound of formula A acts as an alkylation agent similar to the compound having 2-chloroethyl group. It has wider therapeutic range as an antitumor agent than compound having 2-chloroethyl group, and is applicable to wide variety of diseases. The compound of formula A can be prepared by reacting the compound of formula B with the compound of formula C.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a new antitumor agent comprising a nitrosourea derivative.

Compounds called alkylating agents are known as antitumor agents due to their mechanism of action. One typical example of an alkylating agent is >NcH represented by nitrogen mustard.
It is a compound with 2cH2C1 group, and what is its effect? −
It is believed that the gloloethyl group alkylates functional groups such as tertiary nitrogen atoms and amide 7 groups in nucleic acids and proteins. Since nitrogen mustard itself is highly toxic to living organisms and difficult to use as an antitumor agent, titrogien mustard-N-oxide and >NGONC)I2c) are recommended as antitumor agents.
A nitrosourea derivative having a 2-chloroO a ethyl group represented by 12CI is used. These compounds decompose in vivo and become CH2cH2at
Generates (chloroethyl cation) and alkyl/l,=
It is thought that it acts as a curing agent.

The present inventor has been researching and examining antitumor agents comprising nitrosourea derivatives for many years. One problem with antitumor agents comprising nitrosourea derivatives is that they have a narrow therapeutic range. That is, the problem is that the effective dose at which antitumor activity is exhibited is close to the lower limit of the acute toxicity level. A narrow therapeutic range requires strict adjustment of the dosage and is difficult to apply to treated organisms under various conditions or states.One way to expand the therapeutic range is to use drugs without reducing antitumor activity. This is the development of antitumor agents with reduced toxicity. However, although this method is the best, in many cases it is not easy to develop such antitumor agents.On the other hand, even if the antitumor activity is reduced, if the toxicity is further reduced, the therapeutic range will expand. it is conceivable that. In other words, if the effective dose of the antitumor agent is increased compared to the conventional one and the amount of acute toxicity is increased by more than the increased amount, the therapeutic range will be expanded, and as a result, the range of application of the antitumor agent will be widened. Based on this basic idea, the inventor conducted various research studies to expand the therapeutic range of antitumor agents made from conventional nitrosourea derivatives, and as a result, the 2-chloroethyl group of a specific nitrosourea derivative was It has been discovered that this object can be achieved by replacing the 2-fluoroethyl group with a fluoroethyl group.The present invention relates to an antitumor agent comprising a specific nitrosourea derivative having the 2-fluoroethyl group, that is, an antitumor agent having the following formula: Anti-l consisting of a nitrosourea derivative represented by (1) or a salt thereof
14i agent.

A compound having a 2-chloroethyl group corresponding to the compound represented by formula (1) of the present invention is known, and is described, for example, in the following literature published by the present inventors.

N1trasoureas Ca5cer Treat
eer+t INsERMSytnpasultm
No. 19, 37-101 (1981) Compared to these known nitrosourea derivatives having a 2-chloroethyl group, the nitronurea, A conductor having a 2-fluoroethyl group of the present invention usually has anti-Il! Tumor activity is often reduced.

However, acute toxicity has been further reduced, thus expanding the therapeutic window. It should be noted that among conventional antitumor agents that act as alkylating agents such as nitrosourea derivatives and other nitrogen mustards and their derivatives, it is known that compounds having a 2-fluoroethyl group can act as alkylating agents +2. The basic idea that a compound having a 2-fluoroethyl group can act as an alkylating agent in the same way as a compound having a 2-chloroethyl group was newly discovered by the present inventor.

The method for producing the compound represented by formula (1) in the present invention is not particularly limited, but preferably, as shown in the reference example, the corresponding 2,6-hydroxycyclohexylamine and 2-fluorocarbon The compound represented by formula (1), which is produced by nitrosating the urea jA conductor obtained by reacting it with ethyl isocyanate with nitrous salt, etc., can also be used as a salt, such as salt f9 salt, sulfate salt, etc. , acetate, etc. can be used.

Below, reference examples will explain the production of the compound represented by formula (1), and Examples will explain the antitumor test results of the compound and the corresponding compound having a 2-chloroethyl group.

Reference Example 1 Compound A [1-(2-fluoroethyl)-3-(1,3/2N-dihydra-xysiglohequinyl)-1-nitronurea] was produced through the following reaction steps.

0HOH Compound (8) Compound (C) OH Compound A Compound (B) 1.543.4 mg (4.14 mmol
) was dissolved in methanol 15+oJ2 and stirred with water cooling.
- 0.83a+g of fluoroethyl isocyanate was added. After 30 minutes, the precipitated liquid crystal was separated in a furnace and washed with methanol to obtain 240.1 mg of white crystals of compound (C). Uta. v5R was dried under reduced pressure, and the precipitated crystals were washed with isopropyl alcohol to obtain 539.9 mg of secondary crystals (total yield 85.5%). The physical property data of the obtained compound (C) are shown below. .

mp17? -178℃ IR (KBr) y 3350(0)1), 182
5 ((:=0).

1590c+a-' (CON-H) NMR (0211) 61.10-1.80 (3) 1. m,C,-HaKC5
-Ham C, -Hag)1, fiO-2, IQ(3
H4, Ca -Heq C5-H[! q CG -
Heq) 2.32 (IH, t, C2-H, JJ
Hz)3.17-3.50 (2H,m, Cr-
HC3-H)3.45 (2)1. dt, NO flattened JH9F = 27Hz.

J H, H=6H2) 4.53 (2)1. dt, Fdanz, JH,
(gem)"48.5Hz'H, h= [()Iz) Elemental analysis value Cq HI3 N2 03 F (MW
Calculated as 220.24) Ca1cd, C: 49.08%, H near, 78%,
N: 12.72% Found, C: 43.09
%, l (near, 59L N: 12.70% Compound (G) obtained above 420.0 mg (1,9a + mo
1) was dissolved in 99% phosphoric acid 3I, and 238.0 mg (1.8 equivalents) of sodium nitrite was added over about 10 minutes while stirring under water cooling. After 1 hour, Rf = 0. 54(
After confirming a spot with UV absorption in the developing system (toluene/ethanol = 3/l), dilute the reaction solution with 101 m of ice water and add cation exchange resin [IR-120 (H").
)] was added and stirred for 30 minutes to remove the sodium ions. After the resin was separated from the furnace, it was concentrated under reduced pressure, and crystallized by azeotropic distillation with ethanol.

The obtained crystals were washed with ether/ethanol=1/1 and ether/ethanol=3/1 to obtain 1139.2a+g of yellow crystals of compound A (yield Ei 35.[1%).

Physical property data etc. of Compound A are shown below.

mp 132-133℃ (dec) IR (KBr) p 3430 (OH), 1890
(Cm0).

1550(CON-H), 1500cm-'(N
G) NMR (Acetone-d6) 61.13-1.83 (31(,a, Cm-Ha
tC5-Hat CG-! (ax) 1.83 = 2.13 (3H, a+, Ca-Heq
Cs -Heq CG-Heq) 3.07-3.50 (3H, m, C2-H, Cr
-0HC4-1)H> 3.50-3.82 (2)1. Country, C, -)1.
C3-H)4.18 (2H, dt, N(NO)
Chz.

JH,=19.5Hz JH,=8)12)4.43
(2H, dt, FCIh, J,, (gem>=
48.58zJH,)l=8Hz) Elemental analysis value 09 HIG H30a F (MW
Calculated as 249.24) Ca1cd, C: 43.37L H: 8.47%,
N: 18.88% Found, C: 43.12
L H: 8.28%, N: l [3, H% Example 1 Compound A prepared in Reference Example 1 and the following compound The effect of intraperitoneal injection was investigated.

OH Test animal: C57BL mouse (approximately 7 weeks old, female).

8 animals per group) Ham: LLC (muew:s muar+g Car
cinama).

A 1-2 mm square tissue section was subcutaneously transplanted on Day O.

Administration of compounds A and X: 0.2 m of physiological saline solution
y l, 3 littermate intravaginal injections of 5.9.

Dose 1 Physiological saline only -8 2 compounds X 28 4 〃 8 85 /
/ 18 8 Note (1) 6 Compound A 28 ? // 4 138
〃 8 89 t
t I8 81o ti
'・: 12 g test result Physiological saline only -31,3±5.49 100
0/8 Compound X 2 >31.5
>99 1/8// 4 >41
．． ．． 8 >130 1/8//8
>57.5 >180 8/8//
18 (Toxicity expression) 1/8 Note (2
) Compound A 2 32.9±8.88 1
03 0/8// 4 30.8±5.
80 97 0/8/Door 8>54.3>17067
8 /l 18 >59.8 >18
7 7/8/l 32 >43.3
>136 3/8 Note (2) Day 1 administration comment: Both Compound X and Compound A showed significant therapeutic effects on LLC.

Compound X cured 678 cases at 8 mg/kg, but 16 m
g/kg, toxicity occurred and the 2nd and 3rd administrations could not be administered. At 6.32 mg/kg of Compound AI, 8/8.7/8 cases were cured, and no toxicity was observed. Therefore, Compound A shows the same anti-I14 tumor activity as Compound X when administered twice as often as Compound X, and it is considered that the therapeutic range is wider than that of Compound X.

Example 2 The anti-1t4gA effect of intravenous administration of the same compounds A and X as in Example 1 on intravaginally implanted L1210 was investigated.

Test animal: CDF, mouse (approximately 7 weeks old, female).

5 animals per group) Tumor 20 Loukemia L 121
Inject the amount of 0IXIO' cells/mouse into the DayO MI vagina.

Administration of compounds A and X, 0.2 mJl of physiological saline solution D
Intravenous injection into a71.

Result Physiological saline only -8,8±0.88100 0/
8 Note (]) Compound X 2 9. B±0.8
4 112 015// 4 >23.0
)283 115/l 8 >51.8 >
530 415// Is >60.0 >8
88 515// 32 5.4±0.5
5 82 015 Note (4) (Hicompound A
4 9. B±0.55 1i0 015//
8 >22.2 ) 254 115tt
1B >so, o >886 515/l
32 N B0.0 :)688 515/
/ 64 >80.0 >US 515 Note (
j) 8 animals per group were used Note 0) Amendment of procedure for death due to toxicity November 7, 1980

Claims (1)

[Claims] 1. An antitumor agent comprising a nitrosourea derivative represented by the following formula (1) or a salt thereof. ▲Contains mathematical formulas, chemical formulas, tables, etc.▼