JPS6058204B2 - Solid tumor treatment agent - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a homologous tumor therapeutic agent containing N,- or No-phthalidyl-5-fluorouracil as an active ingredient.

During cancer chemotherapy, 5-fluorouracil (5-F
5-FU (sometimes abbreviated as U) and its derivatives account for a large portion, and new 5-FU derivatives are being actively researched with the aim of developing even better antitumor agents. More than 90% of human cancers are homogeneous tumors, including gastric cancer, lung cancer, liver cancer, pancreatic cancer, colorectal cancer,
Common cancers include breast cancer, uterine cancer, and bladder cancer. These homogeneous tumors grow more slowly than leukemia, which is a non-solid tumor, and therefore require the long-term use of chemotherapeutic agents. There are already several excellent therapeutic agents for leukemia, and by using these in combination, the survival period of leukemia patients has recently been significantly extended. In contrast, despite the high incidence of homotypic tumors in humans, no satisfactory therapeutic agent with strong action and low toxicity has yet been obtained.
5-FU is highly toxic, rapidly metabolized, and rapidly inactivated, making it difficult to administer for a long period of time. In order to overcome this drawback, many 5-FU derivatives were studied, and tegafur (FT-207) was the first to appear.
It is administered orally or as a suppository, and as it is gradually converted into 5-FU mainly in the liver, the blood concentration of 5-FU is maintained for a relatively long period of time, making it a time-dependent drug. −
Provides conditions for favorable chemical modification of FU. Although it is effective, the blood concentration of 5-FU derived from tegafur is actually extremely low, so the antitumor effect is not sufficient. In order to improve these drawbacks of decapole, further research has been conducted on derivatives that increase the blood concentration of 5-FU, and N2,3-bis(
2-tetrahydrofuryl)-5-fluorouracil (F
D-1), carmofur HCFU
) and TAC-278 were used clinically as drugs that yield high blood concentrations of 5-FU. In reality, these drugs have side effects such as central nervous system disorders, which are thought to be due to the excessively high 5-FU blood concentration and the nature of the functional groups introduced through chemical modification. , fever sensation and frequent urination due to central effects occur at a high rate, and they are also highly toxic. Some L-121 and P-388 exhibit strong antitumor effects, but are not sufficient against solid tumors.

The present inventors found that when compared with the conventional 5-FU and its derivatives, the blood concentration of 5-FU is moderate, it exhibits a particularly strong effect on solid tumors, and it has low toxicity. As a result of intensive research to find -FU derivatives, the present invention has been completed.

N1- and N3-phthalidyl-5 used in the present invention
-Fluorouracil (hereinafter 1-PFU and 3-PFU, respectively)
(sometimes abbreviated as PFU) is a compound (1) having the structure shown in formula 1, and this compound is, for example, a combination of 5-FU and 3
- produced by reacting halogenophthalides in the presence of a base. Formula 1 R1-['':0? R2=H: N1-phthalidyl-5-fluorouracil (1-PFU) R1=H. l2=
[． UL/013-phthalidyl-5-fluorouracil (3-PFU) antitumor agent may or may not be effective depending on the type of cancer.

Just because a drug is effective against non-solid tumors does not necessarily mean it will be effective against solid tumors. Even if the type of cancer is the same, if the type of compound is even slightly different, the effects will be different. Publicly known literature (Unexamined Japanese Patent Publication No. 1983)
-16881) contains the compound 1-(3-oxo-6-cyano1●3-dihydro-1-isobenzofuranyl)-5
-FU (hereinafter abbreviated as compound A), 3-(3-oxo 6
-Cyano1●3-dihydro1-isobenzofuranyl)-5-FU (hereinafter abbreviated as compound B) and 1,3-bis(3-oxo6-cyano1,3-dihydro1-
Isopenzofuranyl)-5-FU (hereinafter abbreviated as Compound C) has been specifically shown to have an antitumor effect, but its target is only non-solid tumors.

Therefore, the same compounds A, B. ．． Even if it is C, it is completely impossible to predict whether it will be effective against solid tumors. Moreover, the compound AlB. ．． Regarding compounds other than C, even if they are very closely related, it is not possible to predict whether they will have antitumor effects. moreover,
Regarding the present compound 1-PFU, it is only obtained in small amounts as a by-product in known literature.

Therefore, no one can predict that 1-PFU, which is just a by-product, will be effective against a specific solid tumor. 3-P
Similarly, it is not possible to predict whether FU will be effective against solid tumors.

Next, 1-PFU and 3-PFU used in the present invention
We will specifically discuss the biological activity test of

(4) Acute toxicity Each sample was orally administered to 6-7 week old ICR mice (female, 10 mice per group), and the presence or absence of death was observed for 3 weeks.
D5.

I found the value. 1-PFU and 3-PFU have extremely low toxicity.

(B) Blood concentration 1 TrLm011k9 of each sample was orally administered to 6-week-old BDFl mice (female, 3 to 4 mice per group), blood was collected over time, serum was separated, and unchanged drug and metabolites ( 5-FU)
was fractionated.

Concentration measurement of 5-FU and tegafur is performed using a sensitive disk.
StaphylOcOcusau on medium (Eiken Chemical)
The measurement was carried out by the thin layer cup method using the reus2O9P strain, and other unchanged substances were determined by high performance liquid chromatography.

Tables 2 and 3 show the average values. (C) Antitumor effect against solid tumors (1) MH-134 (1 x 1 Cf' pieces) was added to C3H/He
It was inoculated subcutaneously into the flank of mice (5 to 6 mice per group), and 0.3
% CMC aqueous solution was orally administered twice a day for 20 days starting from the day after inoculation, and the weight of the tumor 2 days after inoculation was measured.

The efficacy was determined by comparing the tumor weights of the sample administration group and the control group to determine the inhibition rate (IR). CarmOfur's 150
At the dose of m9'K9, all mice died due to its toxicity, and no antitumor effect was observed at doses of 25TrL91kg and 50m91k9.

The amount of 25TfLg'K9 in Tegafur' does not show any antitumor effect. On the other hand, 1-PFU and 3-PF
U also has an antitumor effect on 25TngIk9.

(2) GardnerlynlphOma(5×l(1
y′) were transferred to 9-week-old C3H/HeN mice (female, 6 per group).
The sample suspension was administered orally once a day for 5 days from the next day, and the tumor weight after 14 days was compared with that of the control group to determine the inhibition rate (IR). .

Complete tumor regression was observed in 2 animals at a dose of 27TLm011 kg of 3-PFU.

(3) L-5178Y (5.35 x 103 mice) was subcutaneously inoculated into the flank of 7-week-old CDFl mice (male, 6 mice per group), and the sample suspension was injected once a day from the next day. The tumor weight was orally administered for 10 days, and the tumor weight after 14 days was compared with that of the control group to determine the inhibition rate (IR).

1.0 n1. of 1-PFU and 3-PFU. m0IIk
Complete regression of the tumor is observed at g.

(4) MethA (5 × 1σ pieces) to 8-week-old BALB/
Inoculated subcutaneously into the flank of CCr mice (female, 6 mice per group),
From the next day, the sample suspension was orally administered once a day for 5 days, and the tumor weight after 14 days was compared with that of the control group.
IR).

(5) SarcOmal8O (5 x 1σ pieces) was subcutaneously inoculated into the flank of a 5-week-old ICR mouse (female, 5 weeks old), and from the next day, the sample suspension was orally administered once a day for 7 days. ,
The tumor weight after 10 days was compared with that of the control group, and the inhibition rate (I
R) was determined.

In the present invention, the active ingredients N1- and N3-
Phthalidyl-5-fluorouracil can be administered either internally or externally, and can be administered in solid forms such as capsules, tablets, powders, granules, and fine granules, or as liquid syrups (dry syrup, etc.). ), administered orally in the form of a suspension, etc.

In addition to pharmaceutical preparations, examples include parenterally administered suppositories, injections, and ointments. Tablets, a typical dosage form among these, are manufactured using a mixture of the active ingredient and a powdered carrier (lactose, sucrose, mannitol, starch, cellulose derivatives, stearic acid, etc.).

A similar formulation is made into granules, powders, etc. and encapsulated in gelatin capsules to obtain capsules. Of course, a sugar or film coating may be applied during tablet manufacture to mask unpleasant taste and protection from the elements, or an enteric coating for selective absorption in the gastrointestinal tract.
Syrup can contain colorants and aromatics for ease of drinking. Further, suppositories are manufactured using active ingredients and known base ingredients (isococoa butter, glycerin esters of fatty acids, polyalkylene glycols, gelatin, nonionic surfactants, liquid paraffin vegetable oil, etc.). Next, the present invention will be explained in more detail by describing the preparation of the present invention and synthesis examples of the compounds used in the present invention.

Synthesis Example 1 52.0y (0.4 mol) of 5-fluorouracil and 85.2y (0.4 mol) of 3-bromophthalide were mixed with 7
The solution was dissolved in 700 ml of chillformamide (DMF), and 27.6 y (0.2 mol) of potassium carbonate was added thereto in 5 portions approximately every 3 portions while stirring at room temperature.

After continuing stirring for an additional 1.5 hours, the mixture was concentrated under reduced pressure and the concentrated solution was poured into 1.5 e of water. The precipitated crystals are collected,
After washing with water and drying, it was treated with 500 ml of hot chloroform for 30 minutes, and the crystals that were insoluble during heating were collected.
%) was obtained. Colorless needle crystals recrystallized from dimethyl sulfoxide-methanol, melting point 292-296°C (decomposition) 8
1.7y (78%) was obtained. Elemental analysis value Cl.

H7FN2O4 calculated value Cl54.97; Hl2.69;
NlllO. 68 Experimental value Cl55. O9; Hl2.89;
N. ．． lO. 55 Infrared Absorption Svector Cm-1 (K
Br) 17901170011660 (C=0, C=C
) Nuclear magnetic resonance vector diδ(CDCl3+D6-DM
SO) 7.43-8.17 (6F[, M.., Ar-H
and Ar-C) Synthesis Example 2 1-acetyl-5-fluorouracil 3.44fI is D
Dissolved in 8 ml of MF, added 0.80 f of sodium hydride (content 60%) under ice-cooling and stirring, and then added dropwise 4.69 y of 3-bromophthalide dissolved in 7 ml of DMF.

After dropping, stir at room temperature for 3.5118 minutes, then add 100ml of water.
and extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue is washed twice with 25 mt of n-hexane to obtain crude N1-acetyl-N3-phthalidyl-5-fluorouracil. Add 50 mL of 0.05N hydrochloric acid and 50 ml of ethanol to this product and reflux for a minute. The solvent was distilled off, water was added to the residue, and the colorless crystals formed were collected. After washing with water and drying, the mixture was refluxed in 15 mι of chloroform for 3 minutes and then taken out in a hot oven to give N as colorless crystals. -phthalidyl-5-fluorouracil (3-PU
F) Obtained 2.65y (50%). This was recrystallized from methanol to obtain colorless needle crystals with a melting point of 234-237°.
Elemental analysis value C.

H,FN. O. Calculated value C) 54.97; H) 2.69;
N) 10.68 experimental value C) 55.21; H) 2.96;
N) 10.42 Infrared absorption vector Cm-1 (K
Br) 1780, 172ゝ1675 (C=0 and C=
C) Nuclear magnetic resonance vector diδ (CDCI).

+D. -DMSO)7.38-8.05(m)6-H
) Ar-H and N-CH) Example 1 (Granules) 1-PFU- (or 3-PFU) 1 part Lactose 268 parts Starch 12 parts Hydroxypropylcellulose (℃) Part 1-PFU according to the above recipe (or 31 PFU), a mixture of lactose and starch was granulated with an aqueous hydroxypropylcellulose solution, dried and sieved to obtain granules containing about 100 m9 of active ingredient in 500 m9 of the preparation.

Example 2 (tablet) 1-PFU (or 3-PFU) 1 part Crystalline cellulose 3 parts Sacral starch 27 parts Lactose 2 parts HPC 1 part Magnesium stearate According to the above recipe, 1-PFU (or 3-PFU), crystalline Granules were prepared using cellulose, starch, lactose and an aqueous HPU solution, to which magnesium stearate was added and then compressed to obtain tablets containing approximately 100 m9 of active ingredient per tablet.

This uncoated tablet can also be sugar-coated or film-coated by a known method. Example 3 (Capsules) 1-PFU (or 3-PFU) 10 parts Microcrystalline cellulose 3 parts Starch 28 parts Lactose 4 parts Magnesium stearate 2 parts The mixture obtained according to the above recipe was packed into gelatin capsules using a capsule filling machine. Approximately 100m per capsule
Capsules containing 9 active ingredients were obtained.

Example 4 (Suppositories) 1-PFU (or 3-PFU) 1-PFU (or 3-PFU) A mixture of the above formulation was heated and made uniform, and then heated to about 40°C.
The suppositories were cooled to 15° C., filled into plastic containers using a suppository filling machine, and cooled to about 15° C. to obtain suppositories containing about 200 mg of active ingredient per suppository.

Example 5 (Suppositories) 1-PFU (or 3-PFU) 250 Witepzol H-15120W, Polysorbate 805 Suppositories Approximately 250 m9 of the active ingredient per suppository was prepared in the same manner as in Example 4 using a mixture consisting of the above formulation. A suppository containing the following was obtained.

Claims (1)

[Claims] 1 A homologous tumor therapeutic agent containing N_1- or N_3-phthalidyl-5-fluorouracil as an active ingredient.