WO2000049030A1 - 5-fluorouridine derivatives and anticancer agents containing the same as the active ingredient - Google Patents
5-fluorouridine derivatives and anticancer agents containing the same as the active ingredient Download PDFInfo
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- WO2000049030A1 WO2000049030A1 PCT/JP1999/000705 JP9900705W WO0049030A1 WO 2000049030 A1 WO2000049030 A1 WO 2000049030A1 JP 9900705 W JP9900705 W JP 9900705W WO 0049030 A1 WO0049030 A1 WO 0049030A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
Definitions
- 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.
- 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.
- 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.
- 5'-deoxy 5-fluorouridine 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.
- 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.
- R 1 represents a C 3 -C 13 linear or branched alkyl group
- 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 .
- 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.
- the present invention provides a compound represented by the following formula (II):
- R 2 represents a C 4 -C 13 linear or branched alkyl group
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- oils 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.
- 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.
- 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.
- the active ingredient content is preferably in the range of 0.01 to 60 (w / v)%, more preferably 1 to 50 (w / v)%.
- 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).
- 5'-DFUR 5'-deoxy-5-fluorouridine
- 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.
- 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.
- 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
- 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 ⁇ ⁇ ⁇ ⁇ 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.
- 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.
- 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.
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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
明 細 書 Specification
5—フルォロゥリジン誘導体及び該誘導体を有効成分とする抗癌剤 技術分野 TECHNICAL FIELD The present invention relates to a 5-fluoroperidine derivative and an anticancer agent containing the derivative as an active ingredient.
本発明は、 新規な 5—フルォロウリジン誘導体、 及び該誘導体を有効成分とし て含む抗癌剤に関するものである。 背景技術 The present invention relates to a novel 5-fluorouridine derivative and an anticancer agent containing the derivative as an active ingredient. Background art
癌のリンパ節への転移が頻繁にみられることから、 転移予防のために、 外科手 術の際に腫瘍巣周辺リンパ節の廓清が行われる。 その場合、 患者への負担も大き くなるが、 それにもかかわらず手術が完全でない場合も多く、 しばしば癌の再発 転移がみられる。 このように、 外科手術の予後はリンパへの癌転移及びリンパ系 を介した他の組織への癌転移の有無に大きく左右されることから、 抗癌剤をリン パ系へ高濃度に分布できれば、 化学療法剤として極めて有効と考えられている。 従来から、 種々の薬剤学的手法により抗癌剤をリンパ系に選択的に分布させる 試みがなされている。 例えば、 油中水型ェマルジヨン [特公昭 63-46043号公報]、 キトサンを用いた製剤 [特開昭 64-61429号公報]、 マイ 卜マイシン類と多糖体と の結合体 [特公平 3-70690号公報] 等の手法が知られている。 しかし、 これらの 製剤は 、ずれも注射剤に限られている。 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.
一方、 5'-デォキシ 5-フルォロウリジン (5'- DFUR) は、 臨床の場において抗癌 剤として経口的に広く使用されている。 この抗癌剤は 5-フルォロウラシル (5 - FU) のプロ ドラッグであり、 この薬物自体は作用を示さないが、 投与後、 癌部位 で特異的に活性の高いピリミジンヌクレオシドホスホリラーゼにより 5-FU に変 換されて効果を発揮するため、 他のフッ化ピリミジン系抗癌剤に比べて副作用が 少なく安全性が高いと評価されている。 しかしながら、 この抗癌剤は水溶性が高 いために、 リンパ系への薬物移行が少ない。 なお、 特公昭 63-2960 号公報には
本発明化合物の具体例は示されていないが 5' デォキシ -5-フルォロゥリジンの脂 肪酸エステル誘導体が開示されている。 発明の開示 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
本発明者らは、 経口投与により 5'- DFURをリンパ系へ高濃度に移行させること ができれば、 癌の転移予防又は治療を目的とした副作用の少ない化学療法剤が得 られると考え、 この課題を解決すべく鋭意研究を行った。 その結果、 水溶性の 5'- DFUR の 2', 3'位の 0H 基を特定の脂肪酸でエステル化することにより脂溶性の 高いジエステル誘導体とし、 この誘導体を油と界面活性剤中に混合した油性製剤 として、 又はその油性製剤に水を加えた乳剤として経口投与すると、 薬物がリン パ系に高濃度に移行することを見いだした。 また、 このジエステル誘導体は、 生 体内に広く分布するエステラーゼにより生体内で 5'-DFURに変換され、 高い抗癌 活性と癌転移予防効果を達成できることも見出した。 本発明はこれらの知見を基 にして完成されたものである。 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.
すなわち、 本発明は、 下記の式 (I ) : That is, the present invention provides the following formula (I):
[式中、 R 1は C 3〜C 13の直鎖又は分岐鎖のアルキル基を示す] で表される 5- フルォロゥリジン誘導体若しくは生理学的に許容されるその塩又はそれらの水和 物若しくはそれらの溶媒和物を有効成分として含む医薬を提供するものである。
この医薬は抗癌剤として用いることができ、 この発明の好ましい態様によれば、 R 4; C 4〜C 13の直鎖又は分岐鎖のアルキル基である上記医薬が提供される。 ま た、 さらに好ましい態様によれば、 油性製剤又は乳剤の形態の上記医薬; リンパ 移行を増大させた経口用リンパ移行性抗癌剤である上記医薬;及びリンパを介し た癌転移の予防剤である上記医薬が提供される。 [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.
別の観点からは、 本発明により、 下記の式 (Π) : In another aspect, the present invention provides a compound represented by the following formula (II):
[式中、 R 2は C 4〜C 13の直鎖又は分岐鎖のアルキル基を示す] で表される 5- フルォロウリジン誘導体若しくはその塩、 又はそれらの水和物若しくはそれらの 溶媒和物が提供される。 [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.
さらに別の観点からは、 上記医薬の製造のための上記式 ( I ) で表される 5- フルォロゥリジン誘導体若しくは生理学的に許容されるその塩又はそれらの水和 物若しくはそれらの溶媒和物の使用 ;癌の治療方法であって、 上記式 ( I ) で表 される 5-フルォロゥリジン誘導体及び生理学的に許容されるその塩並びにそれ らの水和物及びそれらの溶媒和物からなる群から選ばれる物質の治療有効量を患 者に投与する工程を含む方法; リンパを介した癌転移の予防方法であって、 上記 式 ( I ) で表される 5 フルォロウリジン誘導体及び生理学的に許容されるその 塩並びにそれらの水和物及びそれらの溶媒和物からなる群から選ばれる物質の予 防有効量を癌患者に投与する工程を含む方法が提供される。
発明を実施するための最良の形態 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
本発明の式( I )で表される 5 —フルォロゥリジン誘導体は、特公昭 63-2960号 公報に記載の方法に準じて製造することができる。 例えば、 5 '- DFURに脂肪酸ク 口ライ ド又は脂肪酸無水物等を常法により反応させることによって合成すること ができる。 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.
本発明の医薬の有効成分としては、 式 ( I ) で表される 5—フルォロウリジン 誘導体又は生理学的に許容されるその塩のほ力 \ それらの水和物又は溶媒和物を 用いてもよい。 本発明の医薬の有効成分としては、 式 (I ) で表される 5—フル ォロウリジン誘導体のうち、 R 1が C5〜C Uの直鎖アルキル基、 特に C 7〜C9の 直鎖アルキル基である化合物が好ましい。 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.
本発明の医薬は、 抗癌剤として種々の固形癌又は非固形癌の治療に用いること ができるが、 本発明の医薬は特にリンパ系への移行性に優れるという特徴がある ので、 悪性リンパ腫の治療や、 リンパを介した癌転移の予防に特に有用である。 本発明の抗癌剤は、 油性製剤又は乳剤として用いることが好ましい。 油性製剤 は式 (I ) で表される 5—フルォロウリジン誘導体又は生理学的に許容されるそ の塩などの有効成分を油性基剤及び界面活性剤に混合して溶解させる力、、 あるい は均一に分散させることによって製造できる。 また、 乳剤は、 通常の水中油型乳 剤の製造法によって製造することができる。 例えば、 式 ( I ) で表される 5—フ ルォロウリジン誘導体又は生理学的に許容されるその塩などの有効成分を油性基 剤及び界面活性剤の混合物に溶解し、 得られた混合物に水を加えてホモジナイズ することにより製造される。 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.
油性基剤としては、 式 (I ) で表される 5—フルォロウリジン誘導体又は生理 学的に許容されるその塩などの有効成分を溶解または均一に分散でき、 かつ生理 学的に許容し得る油脂類を用いることができる。 具体的には、 大豆油、 綿実油、 ゴマ油、 ォリーブ油等の植物油等が挙げられる。 また、 薬物の溶解を助けるため に油脂類とともに溶媒を用いてもよい。 このような溶媒としてエタノール又は中 鎖脂肪酸トリグリセリ ド等を挙げることができる。 界面活十生剤としては、 ホスフ
ァチジルコリン、 ホスファチジルセリン、 スフインゴミエリン等のリン脂質等が 挙げられる。 さらに、 乳剤には、 必要に応じてグルコース、 マルトース、 トレハ ロース等の糖類、 グリセリン、 非イオン界面活性剤、 ゼラチン等の乳化補助剤を 添加することができる。 本発明の医薬は、 種々の製剤用添加物を用いて製造する ことができるが、 例えば、 矯味剤や香料等を添加することもできる。 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.
本発明の医薬に含有される有効成分の量は適宜増減することができる。 油性製 剤の場合は、 有効成分含量が 0. 01〜60 (w/v) %の範囲であることが好ましく、 1 〜50 (w/v) %の範囲がより好ましい。 また、 乳剤では、 0. 001〜20 (w/v) %の範囲 であることが好ましく、 0. l〜10 (w/v) %の範囲がより好ましい。 本発明の医薬の 投与方法としては経口投与が好適であるが、 直腸内投与や血管内投与などの非経 口投与方法を選択することも可能である。 本発明の医薬の投与回数、 投与量、 及 び投与期間などは、 治療又は予防の目的、 患者の年齢や体重、 疾患の種類及び重 篤度などに応じて適宜選択することができるが、 一般的には、 5'-デォキシ- 5-フ ルォロウリジン (5'-DFUR) の投与量及び投与回数を参考にして所望の治療又は 予防を行なうことが可能である。 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).
本発明により提供される式 (II) で表される新規化合物は、 式 ( I ) と同様の 方法により製造可能である。 式 (II) で表される 5—フルォロウリジン誘導体若 しくはその塩、 又はそれらの水和物若しくはそれらの溶媒和物はいずれも本発明 の範囲に包含される。 式 (I I) で表される本発明の化合物の用途は特に限定され ないが、 上記の医薬としての用途は好ましい用途である。 実施例 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
以下、 実施例により本発明をさらに具体的に説明するが、 本発明の範囲は下記 の実施例に限定されることはない。 合成例 1 : 2 ', 3,-ジデカノィル- 5'-DFURの合成 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 匪 ol)をピリジン (900 ml)とベンゼン (600 ml)の δ
混合溶媒に溶かした溶液に、 0°Cにおいて n-デカン酸クロリ ド (110.8 g, 581.1 mmol)をベンゼン (750 ml)に溶かした溶液を 4時間かけて滴下した。 この混合物 を室温に戻し、 20時間攪拌した。反応混合物を 0°Cに冷却し、メタノール (50 ml) を加えて 30 分攪拌し、 過剰の酸クロリ ドを分解した。 減圧下に大部分の溶媒を 留去し、 大量の水に分散した。 この混合物を酢酸ェチルで抽出し、 抽出液を水、 10%塩酸、 飽和炭酸水素ナトリウム水溶液、 飽和食塩水にて洗浄し、 無水硫酸マ グネシゥムで乾燥した。 濾過後、 溶媒を減圧下に留去してオイルを得た。 このォ ィルをシリカゲルによるカラムクロマ卜グラフィー (n -へキサン:酢酸ェチル =5:1) にて精製し、 n -へキサンと酢酸ェチル混合溶媒から再結晶を行い、 目的化 合物を白色板状晶として 101.5 g (183.0 mmol)得た。 さらに母液からも粗結晶 が 14.1 g得られた。 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 (CDC13 , 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) 合成例 2 : 2,, 3, ジォクタノィル- 5' - DFURの合成 ^ -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
n -デカン酸ク口リ ドの代わりに n-ォクタン酸ク口リ ドを用いる以外は合成例 1と同様にして 2', 3'-ジォクタノィル- 5' - DFURを合成した。 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 (CDC13, 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) 製剤例 1 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
大豆油に卵黄レシチン 1.2 g、 2',3, ジデカノィル-5'-0?1¾ 3 g を加え 80。Cで 混合溶解させた後、 大豆油で全量を 10 ml とした油性製剤を得た。
製剤例 2 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
大豆油に卵黄レシチン 1. 2 g、 2,,3,-ジォクタノィル- 5'-DFUR 2. 7 gを加え 80。C で混合させた後、 大豆油で全量を 10 mlとした油性製剤を得た。 製剤例 3 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
大豆油 60 g に卵黄レシチン 7. 2 g、 2', 3, -ジデカノィル- 5'-DFUR 20 g を加え て 80°Cにて加温溶解させた。 さらに、 2. 5% グリセリン水溶液で全量 700 ml と し、 ホモジナイザーにより粗乳化後、 高圧ホモジナイザー (ゴーリン社) により 予圧 1000 psi、 本圧 8000 psiで約 30分乳化を行ない、 平均粒子径 200 nm (コ 一ルター N4型) の均一乳剤を得た。 製剤例 4 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
大豆油 35 gに卵黄レシチン 7. 2 g、 2', 3,-ジォクタノィル- 5' - DFUR 0. 7 gを加 え、 製剤例 3と同様の方法により均一乳剤を得た。 以下に示す試験例 (試験例 1〜試験例 4 ) では、製剤例 1で得た製剤( A製剤)、 製剤例 3で得た製剤(B製剤)、 及び対照薬として 5'- DFUR水溶液を用いた。 対照 薬と比較するため、 投与量は全て薬物として 0. 406 mmol/kg (5'-DFUR として 100mg/kg)と 試験例 1 : in vivoラットリンパ液中薬物濃度測定試験 (対照薬投与) 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)
胸管リンパに力ニューレを施したラット (n=4)に無麻酔下、 対照薬を経口投与 した後、 胸管リンパ液を 24 時間持続的に採取した。 経口投与後、 0〜1 時間、 1 〜2時間、 2〜3時間、 3〜5時間、 5〜7時間、 7〜9時間、 9〜24時間に採取した リンパ液をリンパ液サンプルとした。 サンプル中 5'- DFUR濃度は HPLC により測 定した。 その結果を表 1に示した。
試験例 2 : in vivoラットリンパ液中薬物濃度測定試験 (A製剤、 B製剤投与) 胸管リンパに力ニューレを施したラッ 卜 (n=3)に無麻酔下、 それぞれ A製剤及 び B製剤を経口投与した後、 試験例 1と同様の方法でリンパ液サンプルを採取し た。 サンプル中薬物濃度はサンプルをエステラーゼ処理し、 サンプル中に一部含 まれる未変化体の 2,, 3'-ジデカノィル- 5'- DFUR (総薬物濃度の 10〜57%) を全て 5'-DFURに変換後、 その 5'-DFUR濃度を HPLCにより測定した。 結果を表 1に示す。 表 1 リンパ液中薬物濃度 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
表 1に示されるように、 対照薬投与群のリンパ液中の 5'- DFUR濃度は持続せず に速やかに消失し、 9時間目以降では検出限界以下であった。 これに対して A製 剤及び B製剤投与群のリンパ液中薬物濃度は高濃度であり、 しかも長時間持続し ていることが判明した。 試験例 3 : in vivoラット血漿中薬物濃度測定試験 (対照薬投与) 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)
頸動脈力ニューレを施したラッ トに無麻酔下、 対照薬を経口投与した後、 0. 33 時間、 0. 67 時間、 1時間、 1. 5 時間、 3時間、 5時間、 7時間、 9時間、 24 時 間目と経時的に血液を採取し、 除蛋白後の血漿をサンプルとした。 サンプル中 5'-DFUR濃度は、 HPLCにより測定した。 その結果を表 2に示した。
試験例 4 : in vivoラット血漿中薬物濃度測定試験 (A製剤、 B製剤投与) 頸動脈力ニューレを施したラット (n=3)に無麻酔下、 A製剤及び B製剤をそれ ぞれ経口投与した後、 試験例 3と同様の方法で血漿サンプルを得た。 サンプル中 5' - DFUR濃度は、 HPLCにより測定した。 その結果を表 2に示した。 表 2 血漿中薬物濃度 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
表 2の結果から明らかなように、 対照薬では血漿中の 5'-DFUR濃度は持続せず に速やかに消失し、 7時間目以降では検出限界以下であった。 一方、 A製剤及び B製剤投与群の血漿中薬物濃度時間推移については、 最高血漿中濃度こそ低レ、も のの、 対照薬と比較して明らかな血漿中薬物濃度の持続が観察された。 表 1及び 表 2の薬物濃度 時間経過の曲線下面積 (AU :,) と薬物の滞留性の指標である薬 物平均滞留時間 (MRT,:.: ) を表 3にまとめた。
表 3 薬物投与後の AU C。: (nmole - hr/ml) , MR T∞ (hr) 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)
リンパでの AUC∞については、 対照薬に比較し A製剤で約 7倍、 B製剤で約 3. 6 倍と明らかに大きく、 リンパへの移行が増大したことが示された。 更に MRT∞に ついても明らかに長くなりリンパでの薬物濃度が持続することも示された。一方、 血漿中での AUC∞については、 対照薬と比較して A製剤で約 74%、 B製剤で約 63% と、 リンパへの移行が増大したにもかかわらず顕著な低下がないことが確認でき た。 また、 MRT∞については A製剤、 B製剤とも対照薬に比べて長くなり血漿中 薬物濃度の持続が観察された。 試験例 5 :腸管内での 5- FUの遊離 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 は腸管への毒性が強く、 悪心、 嘔吐、 下痢、 食欲不振などの副作用が 生じるが、 これは腸管内で酵素により生成する 5- FU が原因しているものと考え られる。 本発明の医薬について、 腸管内での 5-FUの遊離を調べた。 2', 3'-ジブチ リル- 5'-DFUR (本発明医薬) と 5'- DFUR (対照) をラッ 卜に経口投与し、 血漿中 での 5'-DFURの AU と小腸管膜中での 5-FUの AUC∞を測定したところ、 本発明 の医薬ではコントロールと比較して血漿中の 5'-DFURの AU 。力; 1. 3倍に上昇し たにもかかわらず、 小腸管膜中での 5-FUの AU は 60%に抑えられていた。 この
ように、 本発明の医薬は 5' - DFUR よりも腸管膜中で酵素により変換される 5- FU の量が少ないため、 腸管での副作用を低減できる。 産業上の利用分野 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
本発明の医薬は、 経口投与後に、 プロドラッグのままリンパに移行することが でき、 従来の 5'- DFURに比べて、 より高濃度で長時間にわたってリンパ内に滞留 するという特徴がある。 従って、 本発明の医薬は、 悪性リンパ腫などのリンパ系 の癌の治療、 リンパ系への癌転移予防及びリンパを介した他の組織への癌転移予 防、 又はリンパ系に転移した癌の治療を目的とした化学療法に適している。
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
請 求 の 範 囲 下記の式 ( I ) : Scope of Claim Formula (I) below:
[式中、 R 1は C 3〜C 13の直鎖又は分岐鎖のアルキル基を示す] で表される 5- フルォロウリジン誘導体若しくは生理学的に許容されるその塩又はそれらの水和 物若しくはそれらの溶媒和物を有効成分として含む医薬。 [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 . 抗癌剤として用いる請求の範囲第 1項に記載の医薬。 2. The medicament according to claim 1, which is used as an anticancer agent.
3 . R 1が C 5〜C i iの直鎖アルキル基である請求の範囲第 1項又は第 2項に記 載の医薬。 3. The medicament according to claim 1, wherein R 1 is a C 5 -C ii linear alkyl group.
4 . R 1が C 7〜C 9の直鎖アルキル基である請求の範囲第 1項又は第 2項に記載 の医薬。 4. The medicament according to claim 1, wherein R 1 is a C 7 to C 9 linear alkyl group.
5 . 油性製剤又は乳剤の形態の請求の範囲第 1項ないし第 4項に記載の医薬。 5. The medicament according to claims 1 to 4 in the form of an oily preparation or an emulsion.
6 . 生理学的に許容される油類、 水、 及び界面活性剤を含む乳剤の形態の請求の 範囲第 5項に記載の医薬。 6. The medicament according to claim 5, which is in the form of an emulsion containing physiologically acceptable oils, water, and a surfactant.
7 . リンパを介した癌転移の予防剤である請求の範囲第 1項ないし第 6項に記載 の医薬。 7. The medicament according to any one of claims 1 to 6, which is an agent for preventing cancer metastasis via lymph.
[式中、 R 2は C 4〜C 13の直鎖又は分岐鎖のアルキル基を示す] で表される 5 - フルォロゥリジン誘導体若しくはその塩、 又はそれらの水和物若しくはそれらの 溶媒和物。 [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 . 請求の範囲第 1項ないし第 7項に記載の医薬の製造のための請求の範囲第 1 項に記載の式 (I ) で表される 5-フルォロウリジン誘導体若しくは生理学的に 許容されるその塩又はそれらの水和物若しくはそれらの溶媒和物の使用。 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. 癌の治療方法であって、 請求の範囲第 1項に記載の式 (I ) で表される 5 - フルォロゥリジン誘導体及び生理学的に許容されるその塩並びにそれらの水和物 及びそれらの溶媒和物からなる群から選ばれる物質の治療有効量を患者に投与す る工程を含む方法。 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. リンパを介した癌転移の予防方法であって、 請求の範囲第 1項に記載の式 ( I ) で表される 5-フルォロウリジン誘導体及び生理学的に許容されるその塩 並びにそれらの水和物及びそれらの溶媒和物からなる群から選ばれる物質の予防 有効量を癌患者に投与する工程を含む方法。
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.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP9269169A JPH1192386A (en) | 1997-09-17 | 1997-09-17 | Carcinostatic containing 5-fluorouridine derivative as active component |
PCT/JP1999/000705 WO2000049030A1 (en) | 1997-09-17 | 1999-02-18 | 5-fluorouridine derivatives and anticancer agents containing the same as the active ingredient |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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JP9269169A JPH1192386A (en) | 1997-09-17 | 1997-09-17 | Carcinostatic containing 5-fluorouridine derivative as active component |
PCT/JP1999/000705 WO2000049030A1 (en) | 1997-09-17 | 1999-02-18 | 5-fluorouridine derivatives and anticancer agents containing the same as the active ingredient |
Publications (1)
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WO2000049030A1 true WO2000049030A1 (en) | 2000-08-24 |
Family
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PCT/JP1999/000705 WO2000049030A1 (en) | 1997-09-17 | 1999-02-18 | 5-fluorouridine derivatives and anticancer agents containing the same as the active ingredient |
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JP (1) | JPH1192386A (en) |
WO (1) | WO2000049030A1 (en) |
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RU2770081C2 (en) * | 2016-06-28 | 2022-04-14 | Селликс Био Прайвет Лимитед | Compositions and methods for treating cancer |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS59144798A (en) * | 1979-06-15 | 1984-08-18 | エフ・ホフマン・ラ・ロシユ・ウント・コンパニ−・アクチエンゲゼルシヤフト | 5-fluorouracil derivative |
JPH0692987A (en) * | 1992-09-17 | 1994-04-05 | Tanabe Seiyaku Co Ltd | Uridine derivative and its production |
-
1997
- 1997-09-17 JP JP9269169A patent/JPH1192386A/en active Pending
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1999
- 1999-02-18 WO PCT/JP1999/000705 patent/WO2000049030A1/en active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS59144798A (en) * | 1979-06-15 | 1984-08-18 | エフ・ホフマン・ラ・ロシユ・ウント・コンパニ−・アクチエンゲゼルシヤフト | 5-fluorouracil derivative |
JPH0692987A (en) * | 1992-09-17 | 1994-04-05 | Tanabe Seiyaku Co Ltd | Uridine derivative and its production |
Non-Patent Citations (1)
Title |
---|
LADISLAV NOVOTNY ET AL: "The Effect of Structural Modifications of 5-Fluorouracil Derivatives on their Transport and Biodegradation by Isolated rat Jejunum", CANCER CHEMOTHER. AND PHARMACOL., vol. 24, 1989, pages 238 - 242, XP002929203 * |
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