JP2001064179A - Anticancer agent including carbamoyl derivative as active ingredient - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an anticancer agent, a therapeutic agent for autoimmune diseases, and for therapeutic agent for infections and the like with high safety causing no or hardly side-effects by using a specific carbamoyl derivative as an active ingredient. SOLUTION: This carbamoyl derivative is represented by the formula [R1 and R2 are each H, a 1-4C alkyl; R3 is H, a 1-20C alkyl, alkynyl, a (substituted) cycloalkyl or the like], typically 1-(n-hexylcarbamoyl)uracil or the like, or their pharmaceutically acceptable salt is used as an active ingredient. This compound is prepared by subjecting pyrimidine to the condensation reaction with an alkyl isocyanate. This active component is encapsulated and the capsules are orally administered in a dose of 10 mg-2 g/day in the single or several portions in usual.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a highly safe drug containing a carbamoyl derivative as an active ingredient, particularly to an anticancer drug with reduced side effects, a remedy for autoimmune diseases, and a remedy for infectious diseases. .

[0002]

2. Description of the Related Art The field of application of compounds having a cell growth inhibitory activity to pharmaceuticals is mainly for the treatment of autoimmune diseases such as cancer, rheumatism, nephritis and diabetes, and infectious diseases. The most promising is the field of cancer. Development of effective treatments for cancer is one of the most important medical issues. Many anti-cancer drugs have been developed for treatment. Among them, 5-fluorouracil (2,4-dioxo-5-fluoropyrimidi
ne, 5-FU) and its derivatives are effective for many carcinomas and widely used in clinical treatment.

However, 5-FU shows side effects such as myelosuppression, diarrhea, liver dysfunction, vomiting, and nausea by continuous administration. From the viewpoint of QOL of patients, anticancer drugs with reduced side effects are required. Was.

Therefore, a mask type compound of 5-FU was synthesized and developed for the purpose of improving the pharmacokinetics of 5-FU and reducing side effects. Tegafur, 1- (2-t
etrahydrofuryl) -5-fluorouracil, FT-207), 5
N-hexylcarb at position 1 of uracil of FU
Carmofur with amoyl side chain (Carmofu
r, 1- (n-hexylcarbamoyl) -5-fluorouracil, HCF
U) and the like are typical compounds thereof (JP-A-54-1).
No. 29131). They are currently widely used in clinical cancer treatment.

[0005] However, even with these 5-FU mask-type compounds, blood injury such as leukopenia, erythrocytopenia, and thrombocytopenia derived from 5-FU sometimes occur, anorexia, nausea / vomiting, and digestive system injury such as diarrhea. And neurological symptoms, impaired consciousness,
Psycho-nervous system injuries such as sensory injuries have been observed, and these side effects have often been obstacles to treatment. That is, 5
Even reduction of side effects of the FU mask type compound is not sufficient from the viewpoint of treatment and QOL of patients, and anticancer agents having no or reduced side effects have been required.

In the field of anti-rheumatic drugs, the effects of non-steroidal anti-inflammatory drugs are not sufficient, and steroid drugs have side effects, and disease-modifying anti-rheumatic drugs have a long lasting effect. There is a problem, and in these fields, anti-rheumatic drugs with no or reduced side effects have been required.

[0007]

Means for Solving the Problems In order to find a drug which is highly effective in the above-mentioned disease fields and has few side effects, the present inventors have developed the above-mentioned 5-FU by using cell growth inhibitory action and acute toxicity as indices. Formula (2) which is a mask type derivative

[0008]

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Various changes were made to the chemical structure of HCFU represented by

Many studies have been made on 5-FU derivatives so far, and anticancer agents such as HCFU, FT-20 and FH have been developed. However, in order to maintain the activity of 5-FU, a fluorine atom at the 5-position of the uracil group was added. No replacement attempt was made. The present inventors have come to believe that HCFU has a cell growth inhibitory ability by a different mechanism of action from 5-FU, because HCFU exhibits an ability to inhibit cell growth against 5-FU-resistant cells. If HCFU, which is a 5-FU mask type compound, has the same or similar mechanism of action as 5-FU in suppressing cell growth, it is considered that HCFU has the ability to suppress cell growth against 5-FU-resistant cells. Because there is no. As a result, the formula (1) wherein the fluorine of HCFU is replaced by hydrogen is

[0011]

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It has been found that the carbamoyl derivative represented by the formula (1) has a cell growth inhibitory effect and an anticancer effect, while having extremely high safety.

The compound represented by the formula (1) is predicted from conventional knowledge to have no activity as 5-FU since it does not have a fluorine atom at the 5-position of uracil. Surprisingly, it has been found that the compound has a cell growth effect and exhibits an anticancer effect. in addition,
The present compound was found to have extremely high safety without showing toxicity derived from 5-FU, and completed the present invention. Actually, the compound of the present invention represented by the formula (1) has been used as a raw material compound of a mask type compound of 5-FU used as an anticancer agent, but is a compound having no use example as an anticancer agent itself. (JP-A-52-1
No. 4808). That is, the present invention relates to [1] Formula (1)

[0014]

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(Wherein R1 and R2 represent hydrogen or an alkyl group having 1 to 4 carbon atoms, and R3 represents hydrogen, 1 to 4 carbon atoms.
An alkyl group of 20; an alkynyl group of 1 to 20 carbon atoms; a halogen atom or an alkyl group of 1 to 4 carbon atoms; a cycloalkyl group optionally substituted by an alkyl group; or a halogen atom or an alkyl of 1 to 4 carbon atoms Represents an aryl group which may be substituted with a group or an alkyl group. A) a carbamoyl derivative or a pharmaceutically acceptable salt thereof as an active ingredient, [2]
R1 and R2 are hydrogen or an alkyl group having 1 to 4 carbon atoms, and R3 is hydrogen, an alkyl group having 1 to 20 carbon atoms, an alkynyl group having 1 to 20 carbon atoms, a cycloalkyl group or an aryl group. [3] R
1 is hydrogen, R2 is hydrogen or an alkyl group having 1 to 4 carbon atoms, R3 is hydrogen, an alkyl group having 1 to 16 carbon atoms, an alkynyl group having 1 to 16 carbon atoms, a cycloalkyl group or an aryl group [1] [4] R is an anticancer agent described in
1 and R2 are hydrogen and R3 is n-hexyl [1]
[5] The carbamoyl derivative according to [1] to [4], which comprises at least one carbamoyl derivative according to [1] to [4] as an active ingredient. A therapeutic agent for an autoimmune disease comprising at least one active ingredient, [7]
A therapeutic agent for infectious diseases, which comprises at least one carbamoyl derivative according to any one of [1] to [4] as an active ingredient.

[0016]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail.

In the compound represented by the formula (1), R1
And the alkyl group represented by R2 includes a methyl group, an ethyl group, a propyl group and a butyl group.

In the compound represented by the formula (1), R3
The alkyl group represented by is a methyl group, propyl group, hexyl group, dodecyl group, hexadecyl group, icosyl group, 2-
Examples include a methylhexyl group and the like, and an alkynyl group includes 2-
Examples include a propynyl group and a 3-hexenyl group, a cycloalkyl group includes a cyclohexyl group and a cyclopentyl group, and an aryl group includes a phenyl group and a tolyl group.

Among the compounds represented by the formula (1), R 1 and R 2 are preferably hydrogen and R 3 is preferably one having 1 carbon atom.
A carbamoyl derivative which is an alkyl group of -20,
A particularly preferred compound is 1- (n-hexylcarbamoyl) uracil, wherein R1 and R2 are hydrogen and R3 is n-hexyl.

The salt is not particularly limited, and examples thereof include salts with inorganic acids such as hydrochloric acid and sulfuric acid and organic acids such as acetic acid, oxalic acid, fumaric acid, maleic acid and tartaric acid.

The pyrimidine carbamoyl derivative represented by the formula (1) of the present invention can be easily prepared from a pyrimidine and an alkyl isocyanate by a condensation reaction.

The method for administering the product of the present invention is preferably an oral preparation, but is not particularly limited. The formulation is a formulation containing commonly used excipients and other additives, such as crystalline cellulose, light silicic anhydride, corn starch, lactose, calcium phosphate, magnesium stearate, etc., tablets, granules, powders , Capsules, suspensions and the like.

[0023] The dosage may also vary according to symptoms, usage, patient condition, age,
Of course, it is appropriately selected according to gender and the like.
10 mg to 2 g per day can be administered once or in several divided doses.

The treatment in the field of cancer can be applied to breast cancer, small cell lung cancer, non-small cell lung cancer, ovarian cancer, stomach cancer, colorectal cancer, liver cancer, prostate cancer, etc., but is not particularly limited.

In the field of autoimmune diseases, rheumatism, nephritis,
It can be applied to diabetes, various allergic diseases and the like. In addition, the present invention can be applied to various diseases that can be expected to have a therapeutic effect by suppressing cell growth that is inconvenient to the human body, such as infectious diseases and skin diseases.

[0026]

EXAMPLES Hereinafter, the present invention will be described in more detail by reference examples and examples, but the present invention is not limited to these examples. Reference Example 1 Synthesis Example of 1- (n-hexylcarbamoyl) uracil [MS-2917] 5.6 g of uracil and 9.5 of n-hexyl isocyanate
4 g was added to 40 ml of pyridine and heated at 90 ° C. for 6 hours. The reaction solution was concentrated under reduced pressure, 50 ml of ethanol heated to 50 ° C. was added to the residue, and the mixture was ice-cooled with stirring. The precipitated solid was collected by filtration, washed with ethanol, and dried under reduced pressure to obtain 1.06 g.
Was obtained. Example 1 Preparation Example of Formulation of MS-2917 MS-2917 (300 g), lactose (36.9 g), corn starch (15.9 g) were mixed well, and wet method using aqueous solution of hydroxypropylcellulose (11.7 g / 20 ml). It was granulated by a granulation method and dried to obtain granules. Next, carmellose calcium (19.5 g) and magnesium stearate (6 g) were sequentially added and mixed well, and the mixture was tableted using a tableting machine at a weight of 390 mg per tablet to obtain tablets. In addition, this drug is MS-2917 in one tablet 300m
g-containing tablets. Example 2 In Vitro Cancer Cell Growth Inhibitory Effect The in vitro cancer cell growth inhibitory effect of the compound of the present invention was examined using human colon cancer cell DLD-1. That is, a human colon cancer cell line DLD-1 human small cell lung cancer line (S
BC-3) was placed in a 96-well microplate at 3 × 103.
６6 × 103 cells / 0.2 ml / well. Next, each compound was added to each well so that the compound of the present invention had a final concentration of 0.001 to 1000 μg / ml. After culturing for 3 hours, the concentration of the 50% inhibitory compound (IC50 value) for the cell growth of the control well was determined by MTT.
Determined by assay. The results are shown in Table 1 [Table 1].

[0027]

[Table 1]

Comparative Example 1 In vitro cancer cell growth inhibitory effect of 1- (N, N-dimethylcarbamoyl) uracil, a compound similar to the compound of the present invention, was determined in the same manner as in Example 2. The results are shown in Table 2 [Table 2].

[0029]

[Table 2]

Example 3 In Vitro Cell Growth Inhibitory Effect of MS-2917 on Various Human Cancer Cells Human Colorectal Cancer Cell Line DLD-1 Human Small Cell Lung Cancer Line (SBC
-3), a human non-small cell lung cancer (PC-14) and a human colon cancer cell line (WiDR) were seeded on a 96-well microplate at 3 × 103 to 6 × 103 cells / 0.2 ml / well. Next, each compound was added to each well with M
S-2917 final concentration 0.001-1000 μg / ml
Was added so that After 3 hours of culture, the concentration of 50% inhibitory compound (IC50
Value) was determined by the MTT assay. The results are shown in Table 3 [Table 3]. MS-2917 showed an IC50 value of 10 to 30 μg / ml against any human cancer cell lines.

[0031]

[Table 3]

Example 4 In vivo of MS-2917
o Anticancer activity Human colon cancer cell line (DLD-
1) was implanted subcutaneously on the side of BALB / C nude mice. Twelve days after transplantation, success or failure of engraftment was confirmed, and the mice were divided into groups of 5 animals. MS-2917 and HCFU suspended in a 0.05 M acid buffer containing 0.5% methylcellulose were orally administered. The administration schedule was continuous administration for 5 days, and administration was continued for 30 days in a 2-day washout cycle. During that time, the diameter of the tumor was measured over time to determine the volume, which was used as an index of the anticancer effect.

The results are shown in FIG. 1 [FIG. 1]. MS-291
7 showed antitumor activity in a dose-dependent manner at the dose and 400 mg / kg group. The degree of activity is 40 of MS-2917.
0 mg / kg was almost equivalent to the HCFU 100 mg / kg administration group. On the other hand, in the HCFU group, two deaths were observed on day 21 after administration, which were considered to be due to the occurrence of side effects. On the other hand, MS-2917 did not show any signs even in the 400 mg / kg group, suggesting low toxicity. Was. Example 5 Acute toxicity test of MS-2917 Male Wistar rats (6 weeks of age) were treated with 5 mice per group.
S-2917, HCFU and 5-FU were given a single oral dose. For 21 days after administration, the presence or absence of death was observed, and LD5
The 0 value was calculated by the Van der Waerden method. Table 4 shows the acute toxicity of MS-2917 in HC.
The result compared with FU and 5-FU is shown.

[0034]

[Table 4]

No death was observed in the highest dose group of MS-2917 at 3200 mg / kg. On the other hand, in the case of HCFU, deaths were observed at 62.5 mg / kg.
Of the compound according to the present invention is significantly lower than that of the control compound. Example 6 Cancer cell growth inhibitory effect of MS-2917 The cancer cell growth inhibitory effect of MS-2917 was compared with that of 5-FU and HCFU. 5-FU resistant human gastric cancer cell line NU
GC-3 / 5-FU / L and its parent strain NUGC were added to Dulbecco's modified Eagle medium (10% fetal calf serum, 100 μl).
M streptomycin), and 3 × 103 to 6 × 103 cells in a 96-well microplate.
s / 0.2 ml / well. Next, each compound was added to each well at a final concentration of 0.001 to 1000 μg /
ml. After 3 hours of culture, the concentration of 50% inhibitory compound (IC
50 values) were determined by the MTT assay. The results are shown in Table 5 [Table 5].

[0036]

[Table 5]

MS-2917 is NUGC-3 / 5-FU
/ L and its parent strain NUGC-3 showed almost the same IC50 value as HCFU. On the other hand, 5-FU is NU
GC-3 has about half the growth inhibitory activity of MS-2917, and 1000 μg / ml against the 5-FU resistant strain.
However, it did not show any activity. From these results, MS-29
17 has a cancer cell growth inhibitory activity equivalent to that of HCFU which is a representative compound of the above-mentioned publication, but has extremely low toxicity.
It can be seen that this is an excellent anticancer agent having an extremely wide safety margin as compared with HCFU.

[0038]

EFFECTS OF THE INVENTION The anticancer agent, therapeutic agent for autoimmune disease and therapeutic agent for infection containing the carbamoyl derivative of the present invention as an active ingredient have few side effects, are highly effective, and are effective as a drug having improved QOL.

[Brief description of the drawings]

FIG. 1 shows the in vivo antitumor effect of MS-2917 in a human colon cancer cell line (DLD-1) tumor-bearing nude mouse as a change in tumor volume over time using HCFU as a control. In FIG. S. Indicates no significant difference from the control in the t-test. D. Indicates that there is a significant difference of 5% from the control in the t test.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Tsutomu Ueyama 1900-1 Togo, Mobara-shi, Chiba Mitsui Pharmaceutical Industry Co., Ltd. (72) Inventor Hideo Fukui 1900-1 Togo, Togo, Mobara-shi, Chiba Mitsui Pharmaceutical Co., Ltd. F term (reference) 4C086 AA01 AA02 BC43 MA01 MA04 NA06 NA14 ZB07 ZB21 ZB26 ZB35

Claims (7)

[Claims] 1. A compound of the formula (1) (Wherein, R1 and R2 represent hydrogen or an alkyl group having 1 to 4 carbon atoms, and R3 represents hydrogen, an alkyl group having 1 to 20 carbon atoms, an alkynyl group having 1 to 20 carbon atoms, a halogen atom or 1 to 4 carbon atoms. A cycloalkyl group optionally substituted by an alkyl group of 4 or a halogen atom or an aryl group optionally substituted by an alkyl group having 1 to 4 carbon atoms) or a pharmaceutically acceptable salt thereof. An anticancer agent comprising a salt as an active ingredient. 2. R1 and R2 are hydrogen or C1 to C4.
The anticancer agent according to claim 1, wherein R 3 is hydrogen, an alkyl group having 1 to 20 carbon atoms, an alkynyl group having 1 to 20 carbon atoms, a cycloalkyl group or an aryl group. (3) R1 is hydrogen, R2 is hydrogen or a compound having 1 to 1 carbon atoms;
The anticancer agent according to claim 1, wherein the alkyl group of 4 and R3 are hydrogen, an alkyl group of 1 to 16 carbon atoms, an alkynyl group of 1 to 16 carbon atoms, a cycloalkyl group or an aryl group. 4. The anticancer agent according to claim 1, wherein R1 and R2 are hydrogen and R3 is an n-hexyl group. 5. An anticancer agent comprising at least one carbamoyl derivative according to claim 1 as an active ingredient. 6. A therapeutic agent for an autoimmune disease, comprising at least one carbamoyl derivative according to claim 1 as an active ingredient. 7. A therapeutic agent for infectious diseases comprising at least one carbamoyl derivative according to claim 1 as an active ingredient.