WO2000049030A1

WO2000049030A1 - 5-fluorouridine derivatives and anticancer agents containing the same as the active ingredient

Info

Publication number: WO2000049030A1
Application number: PCT/JP1999/000705
Authority: WO
Inventors: Hirotaka Endoh; Katsuyori Kumakura; Hiromasa Omori
Original assignee: Nikken Chemicals Co., Ltd.
Priority date: 1997-09-17
Filing date: 1999-02-18
Publication date: 2000-08-24
Also published as: JPH1192386A

Abstract

Anticancer agents containing as the active ingredient 5-fluorouridine derivatives represented by general formula (I) or physiologically acceptable salts thereof or hydrates or solvates of the same and being excellent in the ability to migrate into lymph wherein R1 represents linear or branched C¿3-13? alkyl.

Description

Specification

TECHNICAL FIELD The present invention relates to a 5-fluoroperidine derivative and an anticancer agent containing the derivative as an active ingredient.

The present invention relates to a novel 5-fluorouridine derivative and an anticancer agent containing the derivative as an active ingredient. Background art

Because of the frequent spread of cancer to the lymph nodes, lymph nodes around the tumor are dissected during surgery to prevent metastasis. In this case, the burden on the patient is increased, but the operation is often not complete, and the cancer often recurs and spreads. As described above, the prognosis of a surgical operation is largely determined by the presence or absence of cancer metastasis to the lymph and to other tissues via the lymphatic system. It is considered to be extremely effective as a therapeutic agent. Conventionally, attempts have been made to selectively distribute anticancer drugs to the lymphatic system by various pharmacological techniques. For example, a water-in-oil emulsion (Japanese Patent Publication No. 63-46043), a preparation using chitosan [Japanese Patent Application Laid-Open No. 64-61429], a conjugate of mitomycins and a polysaccharide [Japanese Patent Publication No. 3-70690] No. Gazette] is known. However, these preparations are limited to injections.

On the other hand, 5'-deoxy 5-fluorouridine (5'-DFUR) is widely used orally in clinical settings as an anticancer drug. This anticancer drug is a prodrug of 5-fluorouracil (5-FU), which has no effect, but is converted to 5-FU by pyrimidine nucleoside phosphorylase, which is specifically active at the cancer site after administration. It is evaluated as having high safety with few side effects compared to other fluorinated pyrimidine-based anticancer drugs. However, because this anticancer drug is highly water-soluble, drug transfer to the lymphatic system is small. In addition, Japanese Patent Publication No. 63-2960 Although no specific example of the compound of the present invention is shown, a fatty acid ester derivative of 5'-deoxy-5-fluoroperidine is disclosed. Disclosure of the invention

The present inventors thought that if 5'-DFUR could be transferred to the lymphatic system at a high concentration by oral administration, a chemotherapeutic agent with less side effects for the purpose of preventing or treating cancer metastasis would be obtained. Intensive research to solve the problem. As a result, the 2H and 3H 0H groups of water-soluble 5'-DFUR were esterified with a specific fatty acid to form a highly fat-soluble diester derivative, and this derivative was mixed with oil and a surfactant. It was found that when administered orally as an oily preparation or as an emulsion containing water in the oily preparation, the drug was transferred to the lymphatic system at a high concentration. They have also found that this diester derivative is converted into 5'-DFUR in vivo by esterases widely distributed in the living body, and can achieve high anticancer activity and cancer metastasis preventing effect. The present invention has been completed based on these findings.

That is, the present invention provides the following formula (I):

[Wherein, R ¹ represents a C ₃ -C ₁₃ linear or branched alkyl group] or a physiologically acceptable salt thereof, or a hydrate or a hydrate thereof. It is intended to provide a medicine containing a solvate as an active ingredient. This medicament can be used as an anticancer agent. According to a preferred embodiment of the present invention, there is provided the above medicament, which is a linear or branched alkyl group of R 4; C _{4 to} C ₁₃ . According to a further preferred embodiment, the above-mentioned medicament in the form of an oily preparation or an emulsion; the above-mentioned medicament which is an oral lymph-translocating anticancer agent having increased lymphatic translocation; and the above-mentioned medicament which is an agent for preventing lymph-mediated cancer metastasis. A medicament is provided.

In another aspect, the present invention provides a compound represented by the following formula (II):

(II)

[Wherein R ² represents a C ₄ -C ₁₃ linear or branched alkyl group], a 5-fluorouridine derivative or a salt thereof, or a hydrate or a solvate thereof. Is done.

From still another viewpoint, use of a 5-fluoroperidine derivative represented by the above formula (I), a physiologically acceptable salt thereof, a hydrate or a solvate thereof for the manufacture of the above-mentioned medicament is described. A method for treating cancer, which is selected from the group consisting of a 5-fluoroperidine derivative represented by the above formula (I), a physiologically acceptable salt thereof, and a hydrate and a solvate thereof. A method comprising the step of administering a therapeutically effective amount of a substance to a patient; a method for preventing lymph-mediated cancer metastasis, which comprises a 5-fluorouridine derivative represented by the above formula (I) and a physiologically acceptable salt thereof. And a method comprising administering to a cancer patient a prophylactically effective amount of a substance selected from the group consisting of hydrates and solvates thereof. BEST MODE FOR CARRYING OUT THE INVENTION

The 5-fluoroperidine derivative represented by the formula (I) of the present invention can be produced according to the method described in JP-B-63-2960. For example, it can be synthesized by reacting 5′-DFUR with a fatty acid mouth ride or a fatty acid anhydride by a conventional method.

As an active ingredient of the medicament of the present invention, a 5-hydrate of a 5-fluorouridine derivative represented by the formula (I) or a physiologically acceptable salt thereof, a hydrate or a solvate thereof may be used. As the active ingredient of the medicament of the present invention, among the 5-fluorouridine derivatives represented by the formula (I), R ¹ is a linear alkyl group of C _{5 to} C _U , particularly a linear alkyl group of C _{7 to} C _9. Compounds that are groups are preferred.

The medicament of the present invention can be used as an anticancer agent for the treatment of various solid or non-solid cancers.However, the medicament of the present invention is characterized by being particularly excellent in the ability to transfer to the lymphatic system. It is particularly useful for preventing lymph-mediated cancer metastasis. The anticancer agent of the present invention is preferably used as an oily preparation or an emulsion. The oil-based preparation has the ability to dissolve the active ingredient such as a 5-fluorouridine derivative represented by the formula (I) or a physiologically acceptable salt thereof in an oily base and a surfactant, or to dissolve the active ingredient. It can be manufactured by dispersing in The emulsion can be produced by a usual method for producing an oil-in-water emulsion. For example, an active ingredient such as a 5-fluorouridine derivative represented by the formula (I) or a physiologically acceptable salt thereof is dissolved in a mixture of an oil base and a surfactant, and water is added to the obtained mixture. It is produced by homogenization.

Examples of the oil base include fats and oils that can dissolve or uniformly disperse an active ingredient such as a 5-fluorouridine derivative represented by the formula (I) or a physiologically acceptable salt thereof, and are physiologically acceptable. Can be used. Specific examples include vegetable oils such as soybean oil, cottonseed oil, sesame oil, and olive oil. In addition, a solvent may be used together with fats and oils to help dissolve the drug. Examples of such a solvent include ethanol and medium-chain fatty acid triglycerides. Phosphate is a surfactant And phospholipids such as atidylcholine, phosphatidylserine and sphingomyelin. Further, if necessary, sugars such as glucose, maltose and trehalose, glycerin, nonionic surfactants, and emulsifying aids such as gelatin can be added to the emulsion. The medicament of the present invention can be produced using various pharmaceutical additives. For example, a flavoring agent, a flavor, and the like can be added.

The amount of the active ingredient contained in the medicament of the present invention can be appropriately increased or decreased. In the case of oily preparations, the active ingredient content is preferably in the range of 0.01 to 60 (w / v)%, more preferably 1 to 50 (w / v)%. In the emulsion, the content is preferably in the range of 0.001 to 20 (w / v)%, more preferably in the range of 0.1 to 10 (w / v)%. Oral administration is suitable as the method for administering the medicament of the present invention, but it is also possible to select a non-oral administration method such as rectal administration or intravascular administration. The administration frequency, dosage, and administration period of the medicament of the present invention can be appropriately selected depending on the purpose of treatment or prevention, the age and weight of the patient, the type and severity of the disease, and the like. Specifically, desired treatment or prevention can be performed with reference to the dose and the number of times of administration of 5'-deoxy-5-fluorouridine (5'-DFUR).

The novel compound represented by the formula (II) provided by the present invention can be produced by the same method as in the formula (I). The 5-fluorouridine derivative represented by the formula (II) or a salt thereof, or a hydrate or a solvate thereof, is included in the scope of the present invention. The use of the compound of the present invention represented by the formula (II) is not particularly limited, but the above-mentioned use as a medicine is a preferable use. Example

Hereinafter, the present invention will be described more specifically with reference to Examples, but the scope of the present invention is not limited to the following Examples. Synthesis Example 1: Synthesis of 2 ', 3, -didecanol-5'-DFUR

5'-DFUR (60.5 g, 232.4 ol) was added to pyridine (900 ml) and benzene (600 ml) At 0 ° C., a solution of n-decanoic acid chloride (110.8 g, 581.1 mmol) in benzene (750 ml) was added dropwise to the solution dissolved in the mixed solvent over 4 hours. The mixture was returned to room temperature and stirred for 20 hours. The reaction mixture was cooled to 0 ° C, methanol (50 ml) was added, and the mixture was stirred for 30 minutes to decompose excess acid chloride. Most of the solvent was distilled off under reduced pressure, and the residue was dispersed in a large amount of water. The mixture was extracted with ethyl acetate, and the extract was washed with water, 10% hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate, and a saturated saline solution, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain an oil. This oil was purified by column chromatography on silica gel (n-hexane: ethyl acetate = 5: 1), recrystallized from a mixed solvent of n-hexane and ethyl acetate, and the target compound was converted to a white plate. 101.5 g (183.0 mmol) were obtained as crystalline crystals. Further, 14.1 g of crude crystals were obtained from the mother liquor.

_{^ -NMR (CDC1 3, ppm)} ; 0.88 (6H, t, J = 6.3Hz), 1.10-1.35 (24H, m), 1.45 (3H, d, J = 6.3Hz), 1.56-1.68 (4H, m ), 2.30-2.38 (4H, m), 4.22 (1H, dq, J = 6.3, 5.4Hz) 5.00 (1H, dd, 5.4, 5.4Hz), 5.27 (1H, dd, 5.4, 5.4Hz), 5.92 ( 1H, dd, 5.4, 1.5Hz), 7.33 (1H, d, J = 5.9Hz), 8.50 (1H, br) Synthesis Example 2: Synthesis of 2,3, dioctanoyl-5'-DFUR

2 ′, 3′-Dioctanoyl-5′-DFUR was synthesized in the same manner as in Synthesis Example 1 except that n-octanoic acid chloride was used instead of n-decanoic acid lid.

_{Ή-NMR (CDC1 3, ppm} ); 0.85-0.90 (6H, in), 1.20-1.35 (20H, m), 1.46 (3H, d, J = 6.3Hz), 1.56-1.68 (4H, m), 2.30 -2.38 (4H, m), 4.22 (1H, dq, J = 6.3, 5.4Hz) 5.00 (1H, dd, 5.4, 5.4Hz), 5.28 (1H, dd, 5.4, 5.4Hz), 5.92 (1H, dd , 5.4, 1.5Hz), 7.33 (1H, d, J = 5.9Hz), 8.68 (1H, br) Formulation example 1

Add 1.2 g of egg yolk lecithin, 2 ', 3, didecanyl-5'-0-1¾3 g to soybean oil80. After mixing and dissolving with C, an oil-based preparation was prepared with soybean oil in a total volume of 10 ml. Formulation Example 2

Add 1.2 g of egg yolk lecithin and 2.7 g of 2,2,3, -dioctanoyl-5'-DFUR to soybean oil80. After mixing with C, an oil-based formulation was made up to 10 ml with soybean oil. Formulation Example 3

To 60 g of soybean oil, 7.2 g of egg yolk lecithin and 20 g of 2 ', 3, -didecanyl-5'-DFUR were added and dissolved by heating at 80 ° C. Further, the total volume was adjusted to 700 ml with a 2.5% glycerin aqueous solution, coarsely emulsified by a homogenizer, emulsified by a high-pressure homogenizer (Gaulin Co., Ltd.) at a preload of 1000 psi and a main pressure of 8000 psi for about 30 minutes, and the average particle diameter was 200 nm ( (Coulter N4 type). Formulation Example 4

To 35 g of soybean oil, 7.2 g of egg yolk lecithin and 0.7 g of 2 ′, 3, -dioctanoyl-5′-DFUR were added, and a uniform emulsion was obtained in the same manner as in Preparation Example 3. In the test examples shown below (Test Examples 1 to 4), the formulation obtained in Formulation Example 1 (Formulation A), the formulation obtained in Formulation Example 3 (Formulation B), and a 5'-DFUR aqueous solution as a control drug were used. Using. All doses were 0.406 mmol / kg as drug (100 mg / kg as 5'-DFUR) for comparison with control drug. Test Example 1: In vivo drug concentration measurement in rat lymph fluid (control drug administration)

A control drug was orally administered to rats ( _n = 4) that had been subjected to a force neuration in the thoracic lymph, and thoracic lymph was continuously collected for 24 hours. Lymph fluid collected at 0 to 1 hour, 1 to 2 hours, 2 to 3 hours, 3 to 5 hours, 5 to 7 hours, 7 to 9 hours, and 9 to 24 hours after oral administration was used as a lymph fluid sample. The 5'-DFUR concentration in the sample was measured by HPLC. Table 1 shows the results. Test Example 2: In vivo rat lymphocyte drug concentration measurement test (administration of A and B preparations) A and B preparations were applied to rats (n = 3) in which thoracic lymph was force-neutralized under anesthesia, respectively. After oral administration, a lymph fluid sample was collected in the same manner as in Test Example 1. The drug concentration in the sample was determined by subjecting the sample to esterase treatment and converting the unchanged 2,2'-didecanyl-5'-DFUR (10-57% of the total drug concentration) partially contained in the sample to 5'- After conversion to DFUR, the 5'-DFUR concentration was measured by HPLC. Table 1 shows the results. Table 1 Lymph drug concentration

As shown in Table 1, the 5'-DFUR concentration in the lymph fluid of the control drug-administered group rapidly disappeared without persisting, and was below the detection limit after 9 hours. On the other hand, it was found that the drug concentration in the lymph fluid of the groups administered with Preparations A and B was high and lasted for a long time. Test Example 3: In vivo rat plasma drug concentration measurement test (control drug administration)

Oral administration of a control drug to rats with carotid arterial force under anesthesia, 0.33 hours, 0.67 hours, 1 hour, 1.5 hours, 3 hours, 5 hours, 7 hours, 9 hours Blood was collected at time, 24 hours, and over time, and plasma after deproteinization was used as a sample. The 5'-DFUR concentration in the sample was measured by HPLC. Table 2 shows the results. Test Example 4: In vivo rat plasma drug concentration measurement test (administration of formulation A and formulation B) Oral administration of formulation A and formulation B, respectively, to rats ( _n = 3) with carotid arterial forceneurism under anesthesia After that, a plasma sample was obtained in the same manner as in Test Example 3. The 5'-DFUR concentration in the sample was measured by HPLC. Table 2 shows the results. Table 2 Plasma drug concentrations

As is clear from the results in Table 2, the 5'-DFUR concentration in the plasma of the control drug rapidly disappeared without persisting, and was below the detection limit after 7 hours. On the other hand, with respect to the time course of plasma drug concentration in the A and B formulation administration groups, the maximum plasma concentration was low, but a clear persistence of the plasma drug concentration was observed compared to the control drug. Table 1 and the area under the curve elapsed drug concentration time table 2 (AU:,) and is indicative of retention of the drug Drug mean residence time _(MRT,:.:) Are summarized in Table 3. Table 3. AU C after drug administration. ： (Nmole-hr / ml), MR T _∞ (hr)

The AUC _∞ of lymph, about 7 times compared to A formulation control drug, about 3.6 times and clearly large in B formulation, it was shown to migrate to lymph is increased. Furthermore, it was shown that MRT 明_らか_に was clearly longer and the drug concentration in the lymph persisted. On the other hand, the AUC _∞ in plasma, about 74% in A formulation as compared to the control drug, and about 63% in B formulation, that there is no migration is despite marked reduction increased to lymph It could be confirmed. Also, A formulation for MRT _∞, sustained long become plasma drug concentration than the control drug with B formulation were observed. Test Example 5: Release of 5-FU in the intestinal tract

5'-DFUR is highly toxic to the intestinal tract, causing side effects such as nausea, vomiting, diarrhea, and anorexia. This is thought to be due to 5-FU produced by enzymes in the intestinal tract. For the medicament of the present invention, the release of 5-FU in the intestinal tract was examined. Oral administration of 2 ', 3'-dibutyryl-5'-DFUR (pharmaceutical of the present invention) and 5'-DFUR (control) was performed in rats, and the AU of 5'-DFUR in plasma and intestinal membrane of small intestine were observed. the AUC _∞ of 5-FU was measured of, AU of 5'-DFUR in the pharmaceutical as compared to controls in the plasma of the present invention. Power: 1. Despite a 3-fold increase, the AU of 5-FU in the small intestinal tract was reduced to 60%. this As described above, since the amount of 5-FU converted by the enzyme in the intestinal tract is smaller than that of 5'-DFUR, the medicament of the present invention can reduce intestinal side effects. Industrial applications

The medicament of the present invention can transfer to the lymph as a prodrug after oral administration, and is characterized by being retained in the lymph for a longer period of time at a higher concentration than conventional 5'-DFUR. Accordingly, the medicament of the present invention is useful for treating cancer of the lymph system such as malignant lymphoma, preventing cancer metastasis to the lymph system and preventing cancer metastasis to other tissues via the lymph, or treating cancer metastasized to the lymph system. Suitable for chemotherapy.

Claims

Scope of Claim Formula (I) below:

[In the formula, R ¹ is C ₃ to -C ₁₃ straight or branched chain alkyl group shows a] represented by 5-Furuorourijin derivative or physiologically acceptable salt thereof or their hydrated product or their being A medicament comprising a solvate as an active ingredient.

2. The medicament according to claim 1, which is used as an anticancer agent.

3. The medicament according to claim ^{1, wherein} R ¹ is a C ₅ -C ii linear alkyl group.

4. The medicament according to claim ^{1, wherein} R ¹ is a C _{7 to} C ₉ linear alkyl group.

5. The medicament according to claims 1 to 4 in the form of an oily preparation or an emulsion.

6. The medicament according to claim 5, which is in the form of an emulsion containing physiologically acceptable oils, water, and a surfactant.

7. The medicament according to any one of claims 1 to 6, which is an agent for preventing cancer metastasis via lymph.

8. The following formula (II):

[Wherein, R ² represents a C _{4 to} C ₁₃ linear or branched alkyl group], a 5-fluoroperidine derivative or a salt thereof, or a hydrate or a solvate thereof.

9. A 5-fluorouridine derivative represented by the formula (I) according to claim 1 or a physiologically acceptable derivative thereof for the production of a medicament according to claims 1 to 7. Use of salts or hydrates or solvates thereof.

10. A method for treating cancer, comprising a 5-fluoroperidine derivative represented by the formula (I) according to claim 1, a physiologically acceptable salt thereof, a hydrate thereof, and a solvent thereof. Administering to the patient a therapeutically effective amount of a substance selected from the group consisting of Japanese citrates.

11. A method for preventing cancer metastasis via lymph, comprising a 5-fluorourizine derivative represented by the formula (I) according to claim 1, a physiologically acceptable salt thereof, and a hydration thereof. Administering a prophylactically effective amount of a substance selected from the group consisting of a substance and a solvate thereof to a cancer patient.