JPS6092217A - Antitumor agent containing fluorodeoxyuridine derivative and thymidine - Google Patents

Abstract

PURPOSE:An antitumor agent containing a fluorodeoxyuridine derivative and thymidine together, having reduced toxicity and side effects, particularly effect on digestive tracts, body weight and leukocytes. CONSTITUTION:An antitumor agent containing a compound expressed by the formula (R<1> is unsubstituted or substituted phenylcarbonyl; R<2> is H, alkyl, alkylcarbonyl or unsubstituted or substituted phenoxycarbonyl) and thymidine together. The fluorodeoxyuridine derivative expressed by the formula (R<2> is unsubstituted or substituted phenoxycarbonyl) is a novel substance, and obtained by reacting 2'-deoxy-5-fluorouridine with an unsubstituted or substituted phenoxycarbonyl chloride, etc.

Description

Detailed Description of the Invention The present invention relates to the general formula (I) 20 (wherein, R1 is an unsubstituted or substituted phenylcarbonyl group, and R2 is a hydrogen atom, an alkyl group, an alkylcarbonyl group, or an unsubstituted or substituted phenoxycarbonyl group). The present invention relates to an antitumor agent containing a fluorodeoxyuridine derivative represented by the following formula and thymidine.

BACKGROUND ART Numerous compounds having antitumor effects have been studied for the purpose of treating cancer diseases, and among them, many compounds having nucleic acid antimetabolite effects have been applied in actual treatments.

The reason why these compounds exhibit antitumor effects is often the result of the compound's inherent cell-killing effect acting on cancer cells.

However, since this cell-killing effect acts not only on cancer cells but also on normal cells, in actual therapeutic applications of such compounds, the occurrence of strong toxicity or side effects is inevitable as a result of this action. However, it is extremely difficult to avoid this because the essential action of these compounds is cell-killing action.

Therefore, in research into compounds having antitumor effects, it is not only important to enhance the antitumor effects but also to reduce the toxicity or side effects of these compounds. In order to solve this problem, attempts have also been made to use thymidine in combination, for example. However, it has been reported that increased toxicity must be taken into account when such nucleic acid antimetabolites are used in combination with nucleobase substances such as thymidine (Clinical Pharmacology, Vol. 12, No. 2, 73- 78 pages, 1981).

The present inventors conducted research with the aim of reducing the toxicity or side effects of compounds that have antitumor effects, and by using the fluorodeoxyuridine derivative represented by the general formula ('r) in combination with thymidine, We have completed the present invention by discovering that toxicity or side effects, particularly the effects on the gastrointestinal tract, body weight, and white blood cells, are reduced.

The antitumor agent of the present invention is characterized in that it contains a fluorodeoxyuridine derivative represented by the general formula (1) and thymidine. , for example an alkyl group having a straight chain or a side chain, preferably methyl,
Ethyl 11-Lower alkyl group such as furobil, isopropyl, n-butyl, isobutyl, linear or side chain alkoxy group, preferably 4-methoxy, ethoxy, n-propoxy, impropoxy, n-butoxy, inpropoxy Lower alkoxy groups such as butoxy, alkylene dioxy groups, preferably lower alkylene dioxy groups such as methylene dioxy, ethylene dioxy, propylene dioxy, halogen atoms such as chlorine, bromine, fluorine, iodine, hydroxy groups, Examples of the alkyl group and alkylcarbonyl group represented by R2 include a benzyloxy group, and examples of the alkyl group represented by R2 include linear or side chain alkyl groups, preferably methyl, ethyl, n-propyl, isoflovir, Alkyl groups such as n-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonanyl, etc. are the same groups and atoms as mentioned as substituents for the substituted phenylcarbonyl group represented by R1 above as substituents for the substituted phenoxycarbonyl group. can be mentioned.

Further, in the present invention, a fluorodeoxyuridine derivative in which R2 in general formula (I) is an unsubstituted or substituted phenoxycarbonyl group is a new compound.

These compounds are free from the products obtained by, for example, reacting 2'-deoxy-5-fluorouridine with unsubstituted or substituted phenoxycarbonyl chlorides, or reacting 2'-deoxy-5-fluorouridine with phosgene. This is carried out by reacting substituted or substituted phenols or by reacting the product thus obtained with unsubstituted or substituted phenyl carbonyl halides.

A specific method for producing the new compound is shown below as a reference example.

Reference example 1 2'-deoxy-5-fluorouridine 2. ．． 00f was dissolved in 40 w/dry pyridine, and then 3.81 f of 4-methoxyphenylchloroforme was added dropwise thereto.

This was left at 70°C for 4 hours and then concentrated under reduced pressure.

The residue thus obtained was dissolved in ethyl acetate, washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was fractionated by silica gel column chromatography (solvent = 2% methanol-chloroform), and both fractions were concentrated under reduced pressure to obtain a/
, s/-di0-(4-methoxyphenoxycarbonyl)2/-deoxy-5-fluorouridine was obtained as white crystals.

Yield near 3.3%, melting point: 189.5-191℃tOH UV λ nm: 22L5.269, ax NMRδ (ppm, DMSO-da): uridine moiety, 2,44 2.65 (2H, m, C2 '
-H), 439-4.64 (3H, m, C4', s'
-H), N24-N45 (IH, m, C3'-H), 6
．． 2+ (IH, bt, J=7Hz, C1'-H),
N02 (IH, d, J=7H2°C6-H), 1188
(IH, bs, D, disappeared by addition of O, -NH-); substituent part at a' and 5' positions, 3.79 (6H, s, C
HsO-X2), 6.86 Fu-7.15 (sH, m, phenyl-H), elemental analyzer C25H23F N20. Calculated value % as I:
C, 54,95iH, 4,24-N, 5.13 actual value e
/e: C, 5a07iH, 4,22BN, 4.94 40 g of 3',5'-di〇-(4-methoxyphenoxycarbonyl)2/-deoxy-5-fluorouridine thus obtained was mixed with 300 g of dioxane. dissolved in soap,
Add to this 22g of 4-n-propoxybenzoyl chlorite
and 50 g/triethylamine were added. 80°
After being left under stirring for 6 hours at C, it was concentrated under reduced pressure. The obtained residue was dissolved in 200 ml of ethyl acetate, washed three times with 50 ml of saturated brine, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was washed with hot n-hexane and then recrystallized from ethyl acetate-ether-ethanol to give 42f a-(4-n-propoxybenzoyl)-3',5'-di0-(4- methoxyphenoxycarbonyl)-2'-deoxy-5-fluorouridine was obtained.

8- Yield: 81%, melting point: 93-95°C, UVλ"': ?," nm: 222.5.278 (
8h), 283.291 (sh), NMRδ (ppm, CDC/3): Uridine moiety, around 2.4 (2H, m, C2'-H), 4.30-4
．． 58 (3H.

m, C, , ”-H), at6-raas (1, m.

Cs'-H), N32 (IH, bt, J=7Hz.

C1'-, -H), 7.77 (IH, d, J=6Hz.

Cs -H); 3' and 5' substituent moieties, 3.
72 (6H, s, CHsO-X2), 6.8
s (4H.

d, J=9Hz, Cs, 5-HX2),
7.08(4)1゜d, J=ghHz, C2,6
-HX2) ; 3rd-position substituent part, 0.99(3)1
．． t, J=7Hz.

CH, CH2CH2O-), 1.50-1.96 (2H
, m.

CH3CH, H2O-), 3.93(2H,t,
J=7Hz.

CH3CH2C)120-), 6.90 (2H, d
, J=9Hz.

Cs, s-H), 7.88 (2H, d, J=9H
z.

C2, a -H), elemental analysis value C35H311F N2013, calculated value e/a: C, 59,326H, 4,69; N, 3
．． 95 actual measurement value (to): c, 59.54i) (,4,7
5iJ3.77 The content ratio of the fluorodeoxyuridine derivative represented by the general formula (1) used in the present invention and thymidine is 0 thymidine per mol of the compound of the general formula α),
It may be at least 25 times the molar amount, and preferably 1 to 4 times the molar amount.

The daily dosage of the fluorodeoxyuridine derivative represented by the general formula (1) used in the present invention was 100
A range of 1 to 1000 If is preferred.

In the present invention, the fluorodeoxyuridine derivative represented by general formula (I) and thymidine can be administered simultaneously or separately, and when they are administered simultaneously, these two complexes are blended in advance, and then It is preferable to administer.

The route of administration varies depending on the therapeutic purpose, but usually includes intravenous administration, intraperitoneal administration, parenteral administration such as intrarectal administration using suppositories, or oral administration.

The dosage form for administration is 25 to 300q and 10 to 100011g of each unit of the fluorodeoxyuridine derivative represented by general formula (I) and thymidine.
Examples include tablets, capsules, injections, etc. containing as an ingredient.

Experiments were conducted to measure the antitumor activity and toxicity of the antitumor agent obtained by the present invention as described below, and the therapeutic coefficient of the antitumor agent of the present invention was determined based on the results of these experiments.

L Test for measuring antitumor activity and toxicity in Sarcoma 180 (1) Test in a system in which the compound represented by general formula (I) and thymidine were simultaneously administered (a) Test for measuring antitumor activity Sarcoma 180 tumor cells (ICR system) Approximately 10 million cells (subcultured in the peritoneal cavity of male mice) were subcutaneously transplanted into the inguinal region of 5-week-old male ICR mice.

After 24 hours, a mixture of the compound represented by general formula (1) and 11-thymidine in the proportions shown in Tables 1 and 2 below was suspended in a 5% Akasha aqueous solution, and the control group Only 5% Akasha aqueous solution,
Once a day at the same volume of 0.1 ton/1o1 for each animal,
The animals were administered by oral probe for 7 days, and the weight of each animal was measured every day immediately before administration. The dosage of the compound represented by general formula (I) varies depending on the individual compound, but is generally 8
Misaki/kti to 256111/kq, and when thymidine is blended only with the compound represented by the general formula σ) or the compound represented by the general formula (I), the blending molar ratio is 1:0.25 to 256111/kq. The same compound was dosed 1:4 over 1 to 4 steps, and one group of mice (consisting of 6 mice) was administered at each dose step. still,
Eighteen mice were used in the paired fish group.

On the 8th day after transplantation, the mouse was sacrificed by exsanguination under ether anesthesia, the tumor tissue was excised, and the tumor weight (12-) was immediately measured. For each compound, for each dose, the average tumor weight (this is referred to as T) and the average value of tumor weight in the control group (this is referred to as C) are calculated from the dose-response curve, respectively, and the C value is determined. The values were read as 0.70 and 0.50.

(b) Test for measuring toxicity Toxicity was measured by measuring the degree of weight loss and decrease in white blood cell count of the mice in the experiment (1)-(a) above, and observing the contents of the gastrointestinal tract.

(i) Effect on body weight The body weight of the animals was measured every day from before the first administration until just before stratification on the 8th day. As a toxicity index, the ratio of the average body weight immediately before stratification on day 8 to the average body weight before administration was calculated for each group, and the relative value to the ratio of the control group was calculated for each dose, and if this relative value was 0. 31 (BWao) to reach 90 was determined from a dose-response curve.

Furthermore, in order to understand the relationship between antitumor activity and toxicity, the therapeutic coefficients were BWo, 9 and T/C: 0.
．． 70 and T/C: Ratio of 0.50 (BW, 9/T
/C: 0.70, BWo, 9/T/C:O,S
I met O).

If the dose-response curve is not determined, calculate the ratio of the average body weight immediately before stratification on day 8 to the average body weight before administration for each group, and calculate the relative value (BW) to the ratio of the control group as T/ The value divided by the value of C (BW/T/C) was determined as the therapeutic coefficient.

(ii) Effect on the number of white blood cells The number of white blood cells in the blood collected at the time of stratification on day 8 was measured using a TOA automatic hematology analyzer model CC-108, and the dose showed 30% of the number of white blood cells in the control group. (L/C:O, aO) was determined from a dose-effect curve.

Furthermore, in order to understand the relationship between antitumor activity and toxicity to bone marrow, the therapeutic coefficients were L/C: o, 30, T/C: 0.70, and T/C:
Ratio with 0.50 (L/C: o, 30 /T/C: 0
,70゜L/C: 0.30 / T/C: 0.50
).

In addition, when the dose-response curve was not used, the value obtained by dividing the ratio (L/C) to the number of white blood cells in the control group by T/C (L/C/T/C) was determined as the therapeutic coefficient.

(e) Effect on the gastrointestinal tract Animals were opened on day 8 after tumor removal. Abdomen and visually observe disorders of the gastrointestinal tract. Digestion according to the criteria below. The effect on the tube was measured.

Criteria for gastrointestinal disorder index small intestine contents; Watery but mild case: 1 point Condition of cecal stool; Case 2 points 15- Condition of the colon/rectum side; Soft stool (feces just before defecation) 1 point If the stool contains diarrhea, 2 points Watery stool with almost no contents If yes, 3 points Small intestine, caecum, colon and The sum of the indices related to the is the disability index of the individual. Therefore the most In individuals with severe impairment, the finger The number will be 7 points.

Gastrointestinal disturbance index scores of 2 and 3 The doses (G2 and Ga) were determined from a dose-response curve.

Furthermore, in order to understand the relationship between antitumor activity and damage to the gastrointestinal tract, the therapeutic coefficients were G2 and T/C: 0.70 and T/C: 0.5.
0 ratio (G2/T/C: 0.70, G2/
T/C: 0,50) and G3 and T/C: 0.70
and T/CQ, ratio of 50 (G3/T/C: 0.7
0.

a/　T/C:　o,　s　o　).

16-G2. If G3 is not achieved, calculate the difference between the index 7 indicating the most severe disorder and the actual gastrointestinal disorder index (G) divided by T/C (7
-G/T/C) was taken as the therapeutic index.

The results of antitumor activity and toxicity are shown in Table 1 and Table 2 shows the treatment coefficients based on these factors. It is shown in Table 3 and Table 4.

The following margins are JP-A-92217 (6) JP-A-92217 (7) <m> Test in a system in which the compound represented by general formula (I) and thymidine were separately administered (a) Antitumor activity measurement Test (1) - (a) by changing the simultaneous administration of the compound represented by the general formula (I) and thymidine in (1) - (a) to a system in which they are administered separately at fixed time intervals; A test for measuring antitumor activity was conducted in the same manner as above. In addition, when administering approximately one dose of thymidine continuously, thymidine was dissolved in drinking water and administered, and the test was conducted in the same manner as above.

(b) Toxicity measurement test The degree of weight loss, decrease in white blood cell count, and degree of gastrointestinal disorder of mice in the experiment of (2)-(a) above was determined by (1)-(b).
A toxicity measurement test was conducted by measuring in the same manner as in ), and the therapeutic index was determined.

The results of antitumor activity and toxicity measurements are shown in Table 5, and the therapeutic coefficients calculated from these are shown in Table 6.

21- JP-A Sho GO-92217 (8) JP-A Sho GO-92217 (9) (3) Test in a system in which the administration route of the compound represented by general formula (1) and thymidine was changed (a) Antitumor activity Measurement Test In the experiment of (1)-(a), the oral administration of the compound represented by the general formula α) and thymidine was changed to oral and intraperitoneal administration, and subcutaneous and oral administration, respectively.
A test for measuring antitumor activity was conducted in the same manner as in 1-(a).

0) Toxicity measurement test The degree of weight loss, decrease in white blood cell count, and degree of gastrointestinal disorder of the mouse in the experiment (3)-(a) above was conducted in the same manner as in the method of 1-Mountain). The therapeutic coefficient was determined.

Table 7 shows the results of antitumor activity and toxicity measurements, and Table 8 shows the therapeutic coefficient based on these results.

Below in the margin 23-2, General formula (1) in Ehrlich carcinoma
) Test for measuring antitumor activity and toxicity in a system in which the compound represented by 6 and thymidine were administered simultaneously (,L) Test for measuring antitumor activity
180 tumor cells to Ehrlich carcinoma, the dosage of the compound represented by general formula (1) varies depending on the individual compound, 64 m19/- and 128 q/-
Next, the molar ratio of the compound represented by the general formula (1) and thymidine was changed to 1:0 and 1:1, and 1-(1
An experiment similar to )-1) and -1 was conducted to test for anti-tumor oil properties.

(b) Toxicity measurement test The degree of gastrointestinal disorder in the experiment of 2-(a) above was 1-
A toxicity measurement test was carried out in the same manner as in (1) - (b) - (ill), and the therapeutic coefficient was determined.

26- The results of the antitumor activity and toxicity measurements are shown in Table 9, and the results of the therapeutic index calculated therefrom are shown in Table 10.

Margin 26 below - JP-A-92217 (13) From the test results in Tables 1 to 10, it is clear that the antitumor agent of the present invention, compared to single agent administration of the fluorodeoxyuridine derivative represented by the general formula α), It reduces toxicity or side effects such as gastrointestinal disorders, decrease in white blood cell count and body weight without reducing antitumor activity, provides a high therapeutic index value, and has excellent utility in the actual treatment of cancer. it is obvious.

28-

Claims (1)

[Claims] (1) General formula (1) (In the formula, R1 represents an unsubstituted or substituted phenylcarbonyl group, and R2 represents a hydrogen atom, an alkyl group, an alkylcarbonyl group, or an unsubstituted or substituted) dicarbonyl group. . ) An antitumor agent characterized by containing a fluorodeoxyuridine derivative represented by the following formula and thymidine. (2) Special # where R is an alkyl group! Anti-1 fltf9 agent according to item 1. (3) The antitumor drug according to claim 1, wherein r is an alkylcarbonyl group. (4) The antitumor drug according to claim 1, wherein R is an unsubstituted or substituted phenoxycarbonyl group. (6) The anti-noodle agent according to item 1, wherein R is a water atom. (R' is a hydroxy group, an alkyl group, an alkoxy group,
Claims 2 to 6 are substituted phenylcarbonyl groups substituted with one or more atoms or groups of an alkylenedioxy group,) 10 gene atoms or a benzyloxy group.
An anti-glandular drug 1 sold by Nihon Hpi.