JPS58150507A - Agent for curing solid tumor - Google Patents

Abstract

PURPOSE:An agent for curing solid tumors that contains N1- or N3-phthalidyl-5- fluorouracyl as an active ingredient, thus showing strong effect against solid tumors, because the concentration of 5-fluorouracil is kept adequate in blood. CONSTITUTION:The objective agent for curing solid tumors is obtained by using N1- or N3-phthalidyl-5-fluorouracil (in formulaI, the former uracil has a group of formula II as R1 and H as R2, while the latter one has H as R1 and group of formula II as R2) as an active ingredient. The resultant curing agent has a good effect to keep the concentration of 5-fluorouracil adequate in blood and furthr, causes no undersirable side-effects due to high concentration in boold. The agent is given orally in the solid form of capsules, tablets, a powder, granules or fine particles or in the liquid form of syrup, as well as parenterally in the form of suppository, injection solutions and ointments.

Description

DETAILED DESCRIPTION OF THE INVENTION Miscellaneous #) 1 relates to a treatment system for solid P4 tumors containing N,- or N-7talidyl-5-fluorouracil as an active ingredient.

5-fluorouracil (hereinafter referred to as 5-1')
(sometimes abbreviated as "U") and its derivatives occupy a large portion, and are also being used for the purpose of developing more intensive anti-cotton drugs. A lot of research is being conducted on U derivatives. Solid matter accounts for more than 90% of human learning! It's a crow.

Thank you for your support! h, pancreatic axis 1 person 11 breasts, child M
ll! 1. This is the case with many commonly seen spiders, such as the common spider.

These solid* tumors grow more slowly than leukemia, which is a non-solid mA tumor, and therefore require 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. On the other hand, despite the high frequency of this disease in humans, there has not yet been a satisfactory therapeutic agent with strong action and low toxicity for solid palsy.

5-FU is highly toxic, rapidly metabolized, and rapidly inactivated, making long-term use difficult. In order to overcome this drawback, many 5-pu derivatives have been researched, and Tegafu Jl/
(t@gafur, FT 207) first appeared. It is administered orally or as a suppository.

5-FU mainly because it is gradually converted to 5-PU in the liver.
The blood concentration of is maintained for a relatively long time and is continuous, and is time-dependent8! It has conditions for favorable chemical modification of the drug 5-PU. However, since the amount of 5-FU derived from tegafur is actually extremely low, the anti-farming effect is not sufficient. In order to improve these shortcomings of Tegafur,
Derivatives that increase the blood penetration of 5-FU have been further studied, N.

, -bis(2-tetrahydrofuryl)-5-fluorouracil (FD-1), carmofa
+, HeFD) and TAe-278 were used clinically as agents that yielded high 5-FU infiltration. These drugs actually have too high 5-FU blood concentration and chemical modification (2) of the functional disorders introduced from 2. Cal-7fur C2 has a high incidence of central effects (feeling of heat and frequent urination) and is highly toxic.5
-These drugs that cause high blood concentrations of PU are L-1210,P-
388 Kami 2 shows a strong anti-embroidery effect, but it is solid 1t! I
Not enough for M.

The present inventors found that when compared with the conventional 5-FU and its derivatives as described above, the blood production of 5-FU is appropriate, and the special electric potential is strong (1 action As a result of intensive research to find a 5-PU derivative with low toxicity and a low toxicity, the present invention was completed. -PFU and 3-PPU) is a compound (sometimes abbreviated as 3-PPU) having the structure shown in formula 1 (
The compound 1) is produced, for example, by reacting 5-FU and 3-10genophthalide in the presence of a base.

Fluorouracil (1-PFU) Fluorouracil (3-pyu) Antitumor agents may or may not be effective depending on the type of -. Just because it was effective against non-solid tumors.

It is not necessarily effective against solid malignancies. Even if the type of cancer is the same, if the type of compound is even slightly different, the action and effect will be different.A known document (Japanese Patent Application Laid-open No. 16881-1981) describes the compound 1-(
3-oxo-6-diatu-1,3-dihydro-1-inbenzofuranyl)-5-FU (hereinafter abbreviated as compound),
3-(3-oxo-6-diatu-1,3-dihydro-1
-inbenzofuranyl)-5-PU (hereinafter abbreviated as compound B) and 1゜3-bis(3-oxo-6-dia2-1,3-dihydro-1-inbenzofuranyl)-5-F
U (hereinafter abbreviated as compound C) has been shown to have a specific anti-M tumor effect, but its target is non-solid I1.
1! Only intimidation. Therefore, the same compounds A, B, e
Even so, it is completely impossible to predict whether or not it will be effective against the same type of abscess. Furthermore, with respect to compounds other than Compounds A and B%C, even if they are very closely related to these compounds, it is impossible to predict whether they will have anti-a*-effects or not.

Furthermore, regarding the subject compound 1-PFU.

In known literature, 1-
No one can predict that PFU will be effective against a specific solid tumor. 3
- It is similarly unpredictable that PFU will be effective against umm.

Next, 1-Pi'U and 3-PF used in the present invention
The biological activity test for U will be specifically described.

A) 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.
D. The value was calculated.

Table 1: LD, value (q/kl) 1-PFU and 3-PFU have extremely low toxicity.

B) Blood concentration: 1 mmol of each sample was orally administered to 6-week-old BDF mice (female, 3 to 4 mice per group), blood samples were collected over time, serum was separated, and untreated Variants and metabolites (S-VU
) was fractionated. A degree measurement of 5-IFU and tegafur was performed using 5lapbylo on sensitive dia Shiji (Eiken Chemical).
Cocua auress 2'09 P strain was carried out by the thin layer cup method, and other unchanged substances were measured by high performance liquid chromatography. Tables 2 and 3 show the average values.

Table 2: Blood concentration of metabolite (5-1?U) (mmoJ/s
g) Table 3: Blood concentration of unchanged drug (n mol ~) C) Antitumor effect on solid tumors tl) MH-1j4 (1x 10" pieces) was added to C3H
Flank skin F1 of /H@ mice (5 to 6 mice per group): Grafted.

From the day after inoculation, the specimen suspended in 0.3% CMC water bath solution was
Orally administered twice a day for 20 days, 21 days after vaccination, directly in mm.
was measured. The effect was determined by comparing the S tumor device in the sample administration group and the control group to determine the inhibition rate (IR). Table 4: Anti-1llI side effect on MH-134 (IR,
%) carmofs+r at 1509/# caused the mice to die due to its toxicity, and at 25/il and 50~/# of carmofs+r, no anti-armpit effect was observed.

No antitumor effect was observed at a dose of 25 caps/hour of 1@gafor. - 10,000, 1-PPU and 3-PF [J is 25■
Anti-1m1 effects were also observed in / and #.

(2) Gardner lymphoma (5X
10@pcs) were added to 9-week-old C31(/HeN mice (female,
The sample suspension was inoculated subcutaneously into the flank of 6 animals per group, and from the next day, the sample suspension was orally administered once a day for 5 days, and after 14 days, the -polarized device was compared with that of the control group to determine the inhibition rate (IR). I asked for

55: Anticancer effect (IR, %) on Gardner lyasphoma 3-Pl? 2 m mollkl of υ and MW to 2 fish
complete regression can be seen.

(31L-5178Y (5,35xlO@pcs) was administered subcutaneously to the flank of 7-week-old CDF mice (male, 6 mice per group).
From the next day, the sample suspension was orally administered once a day for XIO days, and the tumor weight after 14 days was compared with that of the control group to determine the inhibition rate (IR).

Table 6: Anti-vaginal ulcer effect on L-5178Y (III
,%) of 1-PiFU and 3-PFU. Q @
Complete tumor regression is observed at mol/l#.

14) M@thum (5 x 10' pieces) to 8 week old BALB
/Include subcutaneously into the flank of CCr mice (female, 6 mice per group), and sample from the next day! v! L1li solution was orally administered once a day for 5 days, and the pupil hemorrhage after 14 days was compared with that of the control group to determine the inhibition rate (IR).

Table 7: Anti-II against Mesh A6! Tumor effect (I
R,%) (5)8ircomal 80 (5X 1
4 units of ICR mice (female, 5 weeks old) were subcutaneously injected into the flanks of 5-week-old ICR mice, and from the next day, the sample suspension was orally administered once a day for 7 days, and after 10 days, all ml of The inhibition rate (IR) was determined by comparing with that of the control group.

In the present invention, the active ingredients N,- and N,-
7 Talidyl-5-fluorouracil can be administered either internally or externally, and therefore can be administered in solid forms such as capsules, tablets, powders, granules, or fine granules, or as liquid syrups (dry syrup, syrup, etc.). In addition to formulations that are administered orally, such as suspensions and suspensions, examples include suppositories, injections, ointments, and the like that are administered parenterally.

Tablets, a typical dosage form among these, are manufactured using a mixture of the active ingredient and powdered carriers (lactose, sucrose, mannitol, starch, cellulose derivatives, stearic acid, etc.). , as a tablet, etc., and encapsulated in gelatin capsules to obtain capsules. Of course, when manufacturing one tablet, sugar coating or film coating is applied to mask the taste and protect it from the outside air, or it can be placed in an intestine tube. Suppositories may contain enteric coatings/gums for selective absorption.Syrups may contain coloring agents and fragrances for ease of drinking, etc.Suppositories may contain active ingredients and known ingredients. Manufactured using base ingredients (cacao butter, glycerin esters of fatty acids, polyalkylene glycol activators, liquid paraffin vegetable oil, etc.).

Next, the present invention will be explained in more detail by describing synthesis examples of the formulation of the present invention and the compounds used in the present invention.

Synthesis example 1.

5-Fluorouracil 52.0P (04 Morph 1 and 3-Bit Mo7 Talide 85,2) (0.4 Morph 1
Dimethylformamide (DMF) was dissolved in 700% of dimethylformamide (DMF), and 27.6% of potassium carbonate was added with stirring at room temperature. (0.2 mol) was added in five portions approximately every 30 minutes.

After stirring was continued for an additional 1.5 hours, the mixture was placed in a vacuum chamber and the concentrated liquid was poured into the bottle. One harvest of precipitated crystals was obtained,
After washing with water and drying, it was treated with hot chloroform at 500°C for 30 minutes, and small-sized crystals were collected when heated. NI-7 Tarijiro 5
-Fluoroura tulle (1-PFU) 85.1P (8
2%). Recrystallized from dimethyl sulfoxide-methanol to give colorless needle-like crystals, melting point 292-296°C (decomposed) 81.7. P (78%) was obtained.

Elemental analysis value G It H-P N* 0° Calculated value c
, 54.97; H, 2,69; N, 10.68 experimental value c, 55.09; H, 2,89: N, 10.
55 Infrared absorption spectrum, cm (KBr) 179
0.1700,1660 (C=0.C=C) nuclear magnetic resonance spectrum: J (CDel・+d, -DM80
) 7゜43~8.17 (6H,m, Ar -H and Ar -C synthesis example 2゜l-acetyl-5-fluorouracil 3.44P Dissolve ice in DMF8-, and add hydrogen under cold stirring. Sodium (
content 60%) 0.80/-, then 3-boo-77
Drop F of thalide 4.691P dissolved in l)liJp7m. After stirring at room temperature for 3.5 hours, %
100- was added and extracted with chloroform, the chloroform layer was washed with water, dried with anhydrous sodium sulfate, the #L bath medium was distilled off, the residue was washed twice with n-hexane 25-, and the crude N,-acetyl-N1-7 Talijyl-5-fluorouracil is obtained. 0.05N hydrochloric acid 50- and ethanol 50- on the main island
- was added and refluxed for 15 minutes.

The solvent was distilled off and water was added to the residue to form a colorless crystalline product. After washing with water and drying, the product was refluxed in 15-chloroform for 3 minutes and then filtered while hot to form colorless crystals of N,-7 talidi-5-fluorouracil (3-PFU) 2.65ν (5
0%), which was recrystallized from methanol and had a melting point of 23
Colorless needles of 4-237° were obtained.

Elemental analysis value C+tHv FN@0゜Calculated value C,5
4,97iH, 2,69;N, 10.68 experimental value C
, 55, 21 H, 2, 96; N, 10.42 Infrared absorption spectrum, am (KBυ1780.1725
, 1675 (C=0 and C-C) nuclear magnetic resonance spectrum: ' (CDels +d@DM80)7.
38-8.05 (m, 6H, Ar-H and A
t-C■) Example 1 (M granules) According to the recipe E, a mixture of 1-PFU (or 3-PFU), lactose and starch was granulated with a hydroquinepropylcellulose water bath solution and then Q'L dried. , to obtain pellets containing #J 100 Nf active ingredient in formulation 50011i11.

Example 2 (Tablet) According to the above formulation, 1-PFU (or 3-Pli'U)
, using microcrystalline cellulose, starch, lactose and HPC water bath liquid to make granules, add stearic acid/magnesium acid and then tablet, to obtain tablets containing about 100 capes of active ingredient per tablet. This uncoated tablet can also be sugar coated or film coated by a known method.

Example 3 (Capsules) The mixture obtained according to the above recipe was filled into gelatin capsules by a capsule filling machine, and about 100 g per 1 capsule.
Capsules containing 1 g of active ingredient were obtained.

Example 4 (half-open) After heating the mixture according to the above recipe and making it homogeneous, the mixture was heated to about 40°
The mixture was cooled to C and filled into plastic containers using a half-open filling machine, and cooled to about 15'e to obtain half-open containers containing about 200 ml of active ingredient each.

Example 5 (Half-opens) Using a mixture consisting of the above formulation and in the same manner as in Example 4, half-opens containing approximately 2501% l of active ingredient per piece were obtained. In addition, one prescription contains 10% culm macrogol 400.
'! 'm may be added.

Claims (1)

[Claims] Ns * Ri is Ns-7 Talysil-5-71 solid I11 containing rheochloride as an active ingredient! Liao treatment agent