JP5646606B2 - Method for producing anticancer agent - Google Patents
Method for producing anticancer agent Download PDFInfo
- Publication number
- JP5646606B2 JP5646606B2 JP2012510671A JP2012510671A JP5646606B2 JP 5646606 B2 JP5646606 B2 JP 5646606B2 JP 2012510671 A JP2012510671 A JP 2012510671A JP 2012510671 A JP2012510671 A JP 2012510671A JP 5646606 B2 JP5646606 B2 JP 5646606B2
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- Japan
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- formula
- phosphine
- compound represented
- group
- reaction
- Prior art date
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- 239000002246 antineoplastic agent Substances 0.000 title claims description 33
- 238000004519 manufacturing process Methods 0.000 title claims description 13
- -1 phosphine transition metal Chemical class 0.000 claims description 95
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 53
- 229910052717 sulfur Inorganic materials 0.000 claims description 53
- 238000006243 chemical reaction Methods 0.000 claims description 52
- 150000001875 compounds Chemical class 0.000 claims description 40
- 229910052723 transition metal Inorganic materials 0.000 claims description 36
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 34
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 23
- 229910000085 borane Inorganic materials 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 16
- BWJRMVLPCQPWGR-UHFFFAOYSA-N boron;phosphane Chemical compound [B].P BWJRMVLPCQPWGR-UHFFFAOYSA-N 0.000 claims description 12
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 10
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Natural products C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 10
- 238000005859 coupling reaction Methods 0.000 claims description 9
- 239000012948 isocyanate Substances 0.000 claims description 9
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 8
- 229910052802 copper Inorganic materials 0.000 claims description 8
- 239000010949 copper Substances 0.000 claims description 8
- 229910052737 gold Inorganic materials 0.000 claims description 8
- 239000010931 gold Substances 0.000 claims description 8
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims description 7
- 230000003287 optical effect Effects 0.000 claims description 6
- 238000000354 decomposition reaction Methods 0.000 claims description 4
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 claims description 4
- 150000003216 pyrazines Chemical class 0.000 claims description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 21
- 239000002585 base Substances 0.000 description 18
- 239000002904 solvent Substances 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 230000001093 anti-cancer Effects 0.000 description 14
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- 239000000243 solution Substances 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 11
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- 125000001424 substituent group Chemical group 0.000 description 10
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 125000000217 alkyl group Chemical group 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
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- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
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- 229910052751 metal Inorganic materials 0.000 description 7
- 239000002184 metal Substances 0.000 description 7
- 125000004437 phosphorous atom Chemical group 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- UBZMCXNAFPDBOK-UHFFFAOYSA-N (3-phosphanylpyrazin-2-yl)phosphane Chemical class PC1=NC=CN=C1P UBZMCXNAFPDBOK-UHFFFAOYSA-N 0.000 description 6
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
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- 150000001450 anions Chemical class 0.000 description 6
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- 229910052698 phosphorus Inorganic materials 0.000 description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- 125000003277 amino group Chemical group 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- FDWREHZXQUYJFJ-UHFFFAOYSA-M gold monochloride Chemical compound [Cl-].[Au+] FDWREHZXQUYJFJ-UHFFFAOYSA-M 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- DRZBLHZZDMCPGX-VXKWHMMOSA-N (r)-tert-butyl-[3-[tert-butyl(methyl)phosphanyl]quinoxalin-2-yl]-methylphosphane Chemical compound C1=CC=C2N=C([P@](C)C(C)(C)C)C([P@](C)C(C)(C)C)=NC2=C1 DRZBLHZZDMCPGX-VXKWHMMOSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
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- 231100000111 LD50 Toxicity 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 229940043377 alpha-cyclodextrin Drugs 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 125000001246 bromo group Chemical group Br* 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 3
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- 239000000839 emulsion Substances 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
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- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 3
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- SPSSDDOTEZKOOV-UHFFFAOYSA-N 2,3-dichloroquinoxaline Chemical compound C1=CC=C2N=C(Cl)C(Cl)=NC2=C1 SPSSDDOTEZKOOV-UHFFFAOYSA-N 0.000 description 2
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
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- A61P35/02—Antineoplastic agents specific for leukemia
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6509—Six-membered rings
- C07F9/650952—Six-membered rings having the nitrogen atoms in the positions 1 and 4
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Description
本発明は、ホスフィン遷移金属錯体を含有する抗がん剤に関する。 The present invention relates to an anticancer agent containing a phosphine transition metal complex.
本出願人は先に、以下の式(1’)で表されるホスフィン遷移金属錯体を含有する抗がん剤を提案した(特許文献1参照)。式中、R1、R2、R3、R4はアルキル基等である。またMは、金、銅又は銀である。この抗がん剤は、従来用いられてきた抗がん剤であるシスプラチン等の白金製剤やタキソール(登録商標)に比較して、高い抗がん活性を有するものである。The present applicant has previously proposed an anticancer agent containing a phosphine transition metal complex represented by the following formula (1 ′) (see Patent Document 1). In the formula, R 1 , R 2 , R 3 and R 4 are alkyl groups and the like. M is gold, copper or silver. This anticancer agent has a high anticancer activity as compared with platinum preparations such as cisplatin and Taxol (registered trademark), which are conventionally used anticancer agents.
前記のホスフィン遷移金属錯体は、不斉なリン原子を4個有するので、数多くの異性体が存在する。特許文献1には、これらの異性体の種類は特に制限されないと記載されており、リン原子上の立体が、例えば(S,S)(S,S)や、(R,R)(R,R)のように、単一のエナンチオマーから構成されていてもよく、また(R,R)(S,S)のように、配位子のラセミ体から構成されていてもよく、更に(R,S)(S,R)のように、お互いにメソ体から構成されていてもよく、(R,R)(S,R)のように、1つのエナンチオマーとそのメソ体から構成されていてもよいと記載されている。 Since the phosphine transition metal complex has four asymmetric phosphorus atoms, there are many isomers. Patent Document 1 describes that the types of these isomers are not particularly limited, and the stereo on the phosphorus atom is, for example, (S, S) (S, S) or (R, R) (R, R) may be composed of a single enantiomer, and may be composed of a racemic ligand, such as (R, R) (S, S). , S) (S, R) may be composed of meso form each other, and (R, R) (S, R) is composed of one enantiomer and its meso form. It is also described as good.
一般に、化合物の抗がん活性と抗がんスペクトルは、その化合物の化学構造に依存し、個人によっても、その効果に差があることが知られている。例えば、上述のタキソール(登録商標)は、高活性を有する抗がん剤として知られているところ、その有効率は30%程度である。そのため、化学構造が異なる種々の新規な抗がん剤の開発が望まれている。また、抗がん活性が高いだけでなく、毒性が低いことも抗がん剤に要求される特性である。 In general, it is known that the anticancer activity and anticancer spectrum of a compound depend on the chemical structure of the compound, and the effect varies depending on the individual. For example, Taxol (registered trademark) described above is known as a highly active anticancer agent, and its effectiveness is about 30%. Therefore, development of various new anticancer agents having different chemical structures is desired. In addition to high anticancer activity, low toxicity is a characteristic required for anticancer agents.
上述の現況に鑑み、本発明の課題は、本出願人が提案した前述の抗がん剤の改良にある。 In view of the above-mentioned present situation, an object of the present invention is to improve the aforementioned anticancer agent proposed by the present applicant.
本発明は、以下の工程IないしIVを有することを特徴とする以下の式(1)で表されるホスフィン遷移金属錯体を含有する抗がん剤の製造方法を提供するものである。This invention provides the manufacturing method of the anticancer agent containing the phosphine transition metal complex represented by the following formula | equation (1) characterized by having the following processes I thru | or IV.
以下の式(4)で表される水素−ホスフィンボラン化合物と、A hydrogen-phosphine borane compound represented by the following formula (4):
工程Iで得られた式(6')で表されるホスフィンボラン化合物を分解反応に付して、The phosphine borane compound represented by the formula (6 ′) obtained in step I is subjected to a decomposition reaction,
以下の式(4')で表される光学活性な水素−ホスフィンボラン化合物を得る。An optically active hydrogen-phosphine borane compound represented by the following formula (4 ′) is obtained.
工程IIで得られた式(4')で表される光学活性な水素−ホスフィンボラン化合物と、以下の式(7)で表される2,3−ジハロゲノピラジンとを反応させて、An optically active hydrogen-phosphine borane compound represented by the formula (4 ′) obtained in Step II is reacted with 2,3-dihalogenopyrazine represented by the following formula (7):
工程IIIで得られた式(3)で表される(S,S)−2,3−ビスホスフィノピラジン誘導体と、金、銅又は銀の塩とを反応させて前記の式(1)で表されるホスフィン遷移金属錯体を得る。In the above formula (1), the (S, S) -2,3-bisphosphinopyrazine derivative represented by the formula (3) obtained in Step III is reacted with a gold, copper or silver salt. The phosphine transition metal complex represented is obtained.
本発明によれば、高い抗がん活性を有しつつ、毒性の低い抗がん剤が提供される。 According to the present invention, an anticancer agent having low antitoxicity while having high anticancer activity is provided.
本発明の抗がん剤は、前記の式(1)で表されるホスフィン遷移金属錯体を含有している。このホスフィン遷移金属錯体は、中心金属イオンMに対して、2,3−ビスホスフィノピラジン誘導体からなる配位子が2個配位した構造を有している。2,3−ビスホスフィノピラジン誘導体においては、R1とR2が異なる基であることによって、2つのリン原子がキラル中心となる。その結果、この2,3−ビスホスフィノピラジン誘導体は、立体配置の異なる(R,R)体、(S,S)体及び(R,S)体の3種類の異性体が存在する。これら3種の異性体のうち、式(1)で表されるホスフィン遷移金属錯体に含まれている配位子は、(S,S)体の2,3−ビスホスフィノピラジン誘導体である。これに対して、先に背景技術の項で述べた特許文献1に具体的に記載されているホスフィン遷移金属錯体に含まれている配位子は、(R,R)体の2,3−ビスホスフィノピラジン誘導体である。本発明者らが鋭意検討した結果、配位子として(S,S)体の2,3−ビスホスフィノピラジン誘導体を用いたホスフィン遷移金属錯体を含む抗がん剤は、特許文献1に記載の抗がん剤よりも高い抗がん活性を有し、かつ毒性が低くなることが見出された。The anticancer agent of the present invention contains a phosphine transition metal complex represented by the above formula (1). This phosphine transition metal complex has a structure in which two ligands composed of a 2,3-bisphosphinopyrazine derivative are coordinated to the central metal ion M. In the 2,3-bisphosphinopyrazine derivative, two phosphorus atoms become chiral centers because R 1 and R 2 are different groups. As a result, this 2,3-bisphosphinopyrazine derivative has three types of isomers, (R, R), (S, S) and (R, S), which have different steric configurations. Of these three isomers, the ligand contained in the phosphine transition metal complex represented by the formula (1) is an (S, S) isomer of 2,3-bisphosphinopyrazine derivative. On the other hand, the ligand contained in the phosphine transition metal complex specifically described in Patent Document 1 described in the background section above is an (R, R) isomer of 2,3- Bisphosphinopyrazine derivative. As a result of intensive studies by the present inventors, an anticancer agent containing a phosphine transition metal complex using an (S, S) -form 2,3-bisphosphinopyrazine derivative as a ligand is described in Patent Document 1. It was found to have higher anticancer activity and lower toxicity than other anticancer agents.
式(1)で表される化合物が、抗がん活性が高く、かつ毒性の低い理由については完全に明確になっていないが、抗がん剤の抗がん活性や抗がんスペクトルは、その抗がん剤の化学構造に大きく依存するためではないかと本発明者らは考えている。例えば、以下の(1a’)で表される化合物は、特許文献1に記載の化合物(1’)で表される化合物に包含されるものの、この化合物(1a’)は毒性が相対的に高いことが、本発明者らの検討の結果判明している(後述する比較例1参照)。 The reason why the compound represented by the formula (1) has high anticancer activity and low toxicity has not been fully clarified, but the anticancer activity and anticancer spectrum of anticancer agents are The present inventors consider that it is because it depends largely on the chemical structure of the anticancer agent. For example, although the compound represented by the following (1a ′) is included in the compound represented by the compound (1 ′) described in Patent Document 1, this compound (1a ′) has relatively high toxicity. This has been found as a result of the study by the present inventors (see Comparative Example 1 described later).
前記の式(1)において、R1及びR2は、直鎖状若しくは分岐鎖状のアルキル基、シクロアルキル基、置換基を有するシクロアルキル基、アダマンチル基、フェニル基又は置換基を有するフェニル基を表す。R1及びR2は、炭素数が1〜10である。また、R1及びR2は互いに異なる基である。更に、R1及びR2は、RS法に従う順位付けにおいて、R1はR2よりも優先順位が高い基である。In the above formula (1), R 1 and R 2 are a linear or branched alkyl group, a cycloalkyl group, a cycloalkyl group having a substituent, an adamantyl group, a phenyl group, or a phenyl group having a substituent. Represents. R 1 and R 2 have 1 to 10 carbon atoms. R 1 and R 2 are groups different from each other. Furthermore, R 1 and R 2, in ranking according to the RS method, R 1 is priority than R 2 is a high group.
R1及びR2に係るアルキル基としては、例えば、メチル基、エチル基、イソプロピル基、n−プロピル基、イソブチル基、n−ブチル基、sec−ブチル基、tert−ブチル基、イソヘプチル基、n−ヘプチル基、イソヘキシル基、n−ヘキシル基が挙げられる。R1及びR2に係るシクロアルキル基としては、シクロペンチル基、シクロヘキシル基が挙げられる。R1及びR2が置換基を有するシクロアルキル基又は置換基を有するフェニル基である場合、該置換基としては、アルキル基、ニトロ基、アミノ基、ヒドロキシル基、フルオロ基、クロロ基、ブロモ基、ヨード基等が挙げられる。特に、R1がtert−ブチル基又はアダマンチル基であり、R2がメチル基であることが、抗がん活性が高くなる点で好ましい。Examples of the alkyl group related to R 1 and R 2 include methyl group, ethyl group, isopropyl group, n-propyl group, isobutyl group, n-butyl group, sec-butyl group, tert-butyl group, isoheptyl group, n -A heptyl group, an isohexyl group, n-hexyl group is mentioned. Examples of the cycloalkyl group related to R 1 and R 2 include a cyclopentyl group and a cyclohexyl group. When R 1 and R 2 are a cycloalkyl group having a substituent or a phenyl group having a substituent, examples of the substituent include an alkyl group, a nitro group, an amino group, a hydroxyl group, a fluoro group, a chloro group, and a bromo group. And an iodo group. In particular, R 1 is preferably a tert-butyl group or an adamantyl group, and R 2 is a methyl group, from the viewpoint of increasing anticancer activity.
R3及びR4は、水素原子又は直鎖状若しくは分岐鎖状のアルキル基を表す。R3及びR4のアルキル基は炭素数が1〜6である。R3及びR4は、同一の基であっても異なる基であってもよい。またR3及びR4が互いに結合して飽和又は不飽和の環を形成する場合、飽和又は不飽和の環は、置換基を有していてもよい。R 3 and R 4 represent a hydrogen atom or a linear or branched alkyl group. Alkyl groups R 3 and R 4 are 1 to 6 carbon atoms. R 3 and R 4 may be the same group or different groups. When R 3 and R 4 are bonded to each other to form a saturated or unsaturated ring, the saturated or unsaturated ring may have a substituent.
R3及びR4に係るアルキル基としては、例えばエチル基、イソプロピル基、n−プロピル基、イソブチル基、n−ブチル基、sec−ブチル基、tert−ブチル基、イソヘプチル基、n−ヘプチル基、イソヘキシル基、n−ヘキシル基、シクロペンチル基、シクロヘキシル基等が挙げられる。Examples of the alkyl group related to R 3 and R 4 include ethyl group, isopropyl group, n-propyl group, isobutyl group, n-butyl group, sec-butyl group, tert-butyl group, isoheptyl group, n-heptyl group, Examples include isohexyl group, n-hexyl group, cyclopentyl group, cyclohexyl group and the like.
R3及びR4は、互いに結合して飽和又は不飽和の環を形成していてもよい。そのような場合、該環としては、飽和又は不飽和の五員環又は六員環が挙げられる。例えば、フェニル基、シクロヘキシル基、シクロペンチル基等が挙げられる。該環は、一価の置換基を有してもよく、その置換基としては、例えば、直鎖状又は分岐鎖状でありかつ炭素数が1〜5のアルキル基、ニトロ基、アミノ基、ヒドロキシル基、フルオロ基、クロロ基、ブロモ基、ヨード基が挙げられる。R 3 and R 4 may be bonded to each other to form a saturated or unsaturated ring. In such a case, the ring includes a saturated or unsaturated 5-membered ring or 6-membered ring. For example, a phenyl group, a cyclohexyl group, a cyclopentyl group, etc. are mentioned. The ring may have a monovalent substituent, and examples of the substituent include a linear or branched alkyl group having 1 to 5 carbon atoms, a nitro group, an amino group, Examples include a hydroxyl group, a fluoro group, a chloro group, a bromo group, and an iodo group.
特にR3及びR4は、これらが互いに結合してベンゼン環を形成していることが、抗がん活性が高くなる点で好ましい。その場合、金属Mに配位している配位子は、キノキサリン誘導体となり、本発明のホスフィン遷移金属錯体は以下の式(2)で表される。このキノキサリン誘導体におけるベンゼン環は、4個の水素原子のうちの少なくとも1個が、置換基R5によって置換されていてもよい。具体的には、R5として、同一の又は異なるアルキル基、ニトロ基、アミノ基、ヒドロキシル基、フルオロ基、クロロ基、ブロモ基、ヨード基等を用いることができる。In particular, R 3 and R 4 are preferably bonded to each other to form a benzene ring from the viewpoint of high anticancer activity. In that case, the ligand coordinated to the metal M is a quinoxaline derivative, and the phosphine transition metal complex of the present invention is represented by the following formula (2). In the benzene ring in the quinoxaline derivative, at least one of the four hydrogen atoms may be substituted with a substituent R 5 . Specifically, as R 5 , the same or different alkyl group, nitro group, amino group, hydroxyl group, fluoro group, chloro group, bromo group, iodo group and the like can be used.
Mは、金、銅及び銀の群から選ばれる遷移金属原子の一価のイオンを表す。特にMが金のイオンであることが、抗がん活性が高くなる点で好ましい。 M represents a monovalent ion of a transition metal atom selected from the group consisting of gold, copper and silver. In particular, M is preferably a gold ion from the viewpoint of high anticancer activity.
X-は、アニオンを表し、例えば、塩素イオン、臭素イオン、ヨウ素イオン、四フッ化ホウ素イオン、六フッ化リン酸イオン、過塩素酸イオン等が挙げられる。これらのうち、X-が、塩素イオン、臭素イオン、ヨウ素イオンであることが、抗がん活性が高くなる点で好ましい。X − represents an anion, and examples thereof include chlorine ion, bromine ion, iodine ion, boron tetrafluoride ion, hexafluorophosphate ion, and perchlorate ion. Among these, X − is preferably a chlorine ion, a bromine ion, or an iodine ion from the viewpoint of high anticancer activity.
次に、本発明の抗がん剤に含まれるホスフィン遷移金属錯体の好適な製造方法について説明する。このホスフィン遷移金属錯体は、以下の式(3)で表される(S,S)−2,3−ビスホスフィノピラジン誘導体と、金、銅又は銀の塩とを反応させることで得られる。式(3)で表される(S,S)−2,3−ビスホスフィノピラジン誘導体の製造方法については後述する。 Next, the suitable manufacturing method of the phosphine transition metal complex contained in the anticancer agent of this invention is demonstrated. This phosphine transition metal complex is obtained by reacting a (S, S) -2,3-bisphosphinopyrazine derivative represented by the following formula (3) with a gold, copper or silver salt. A method for producing the (S, S) -2,3-bisphosphinopyrazine derivative represented by the formula (3) will be described later.
式(3)で表される(S,S)−2,3−ビスホスフィノピラジン誘導体の好ましい化合物の具体例としては、(S,S)−2,3−ビス(tert−ブチルメチルホスフィノ)キノキサリン、(S,S)−2,3−ビス(アダマンチルメチルホスフィノ)キノキサリン、(S,S)−2,3−ビス(tert−ブチルメチルホスフィノ)ピラジン等が挙げられる。 Specific examples of preferred compounds of the (S, S) -2,3-bisphosphinopyrazine derivative represented by the formula (3) include (S, S) -2,3-bis (tert-butylmethylphosphino). ) Quinoxaline, (S, S) -2,3-bis (adamantylmethylphosphino) quinoxaline, (S, S) -2,3-bis (tert-butylmethylphosphino) pyrazine and the like.
式(3)で表される(S,S)−2,3−ビスホスフィノピラジン誘導体と反応する金、銅又は銀の塩は、例えば、これらの金属のハロゲン化物、硝酸塩、過塩素酸塩、四フッ化ホウ素酸塩、六フッ化リン酸塩等である。また、これらの金属の価数は、一価である。また、これらの金属の塩は、金属又はアニオンのいずれか一方又は両方が異なる2種以上の塩であってもよい。 Gold, copper or silver salts that react with the (S, S) -2,3-bisphosphinopyrazine derivative represented by the formula (3) include, for example, halides, nitrates, and perchlorates of these metals. , Tetrafluoroborates, hexafluorophosphates and the like. Moreover, the valence of these metals is monovalent. In addition, these metal salts may be two or more salts in which either one or both of the metal and the anion are different.
好ましい金の塩としては、例えば、塩化金(I)酸、塩化金(I)、あるいはテトラブチルアンモニウムクロリド・塩化金(I)等(「第5版 実験化学講座21」、編者 社団法人日本化学会、発行所 丸善、発行日 平成16年3月30日、p366〜380、Aust.J.Chemm.,1997,50,775-778頁参照)が挙げられる。好ましい銅の遷移金属塩としては、例えば、塩化銅(I)、臭化銅(I)、ヨウ化銅(I)等(「第5版 実験化学講座21」、編者 社団法人日本化学会、発行所 丸善、発行日 平成16年3月30日、p349〜361)が挙げられる。また、好ましい銀の遷移金属塩としては、例えば、塩化銀(I)、臭化銀(I)、ヨウ化銀(I)等(「第5版 実験化学講座21」、編者 社団法人日本化学会、発行所 丸善、発行日 平成16年3月30日、p361〜366)が挙げられる。なお、本発明のホスフィン遷移金属錯体の製造方法に係る遷移金属塩は、無水物であっても含水物であってもよい。 Preferred examples of the gold salt include gold chloride (I) acid, gold chloride (I), tetrabutylammonium chloride / gold chloride (I), etc. ("5th edition Experimental Chemistry Course 21", editor Nihon Kagaku) Society, issue place Maruzen, issue date March 30, 2004, p366-380, Aust. J. Chemm., 1997, 50, pages 775-778). Preferred transition metal salts of copper include, for example, copper chloride (I), copper bromide (I), copper iodide (I), etc. ("Fifth edition Experimental Chemistry Course 21", Editor, The Chemical Society of Japan, published) Tokoro Maruzen, issue date March 30, 2004, p349-361). Preferred silver transition metal salts include, for example, silver chloride (I), silver bromide (I), silver iodide (I), etc. ("5th edition Experimental Chemistry Course 21", Editor, The Chemical Society of Japan). Issue place Maruzen, issue date March 30, 2004, p361-366). The transition metal salt according to the method for producing a phosphine transition metal complex of the present invention may be an anhydride or a hydrate.
金、銅又は銀の塩に対する、式(3)で表される(S,S)−2,3−ビスホスフィノピラジン誘導体のモル比は、金属1モルに対して好ましくは1〜5倍モル、更に好ましくは1.8〜2.2倍モルとする。反応は、アセトン、アセトニトリル、メタノール、エタノール、テトラヒドロフラン、ジクロロメタン、クロロホルム等の溶媒中で行うことができる。反応温度は好ましくは−20〜60℃、更に好ましくは0〜25℃であり、反応時間は好ましくは0.5〜48時間、更に好ましくは1〜3時間である。この反応によって、式(1)で表されるホスフィン遷移金属錯体が得られる。反応終了後は、必要に応じて常法の精製を行うことができる。 The molar ratio of the (S, S) -2,3-bisphosphinopyrazine derivative represented by the formula (3) to the gold, copper or silver salt is preferably 1 to 5 times the mole of the metal. More preferably, it is 1.8 to 2.2 times mol. The reaction can be carried out in a solvent such as acetone, acetonitrile, methanol, ethanol, tetrahydrofuran, dichloromethane, chloroform and the like. The reaction temperature is preferably -20 to 60 ° C, more preferably 0 to 25 ° C, and the reaction time is preferably 0.5 to 48 hours, more preferably 1 to 3 hours. By this reaction, a phosphine transition metal complex represented by the formula (1) is obtained. After completion of the reaction, conventional purification can be performed as necessary.
このようにして得られた式(1)で表されるホスフィン遷移金属錯体におけるアニオンを、他の所望のアニオンに変換してもよい。例えば、先ず、上述の製造方法に従い、式(1)中のX-が、ハロゲン化物イオンであるホスフィン遷移金属錯体を合成し、次いで、このホスフィン遷移金属錯体と、所望のアニオンを有する無機酸、有機酸又はそれらのアルカリ金属塩とを、適切な溶媒中で反応させることにより、X-が、所望のアニオンであるホスフィン遷移金属錯体を得ることができる。このような方法の詳細は、例えば特開平10−147590号公報、特開平10−114782号公報及び特開昭61−10594号公報等に記載されている。The anion in the phosphine transition metal complex represented by the formula (1) thus obtained may be converted into another desired anion. For example, first, a phosphine transition metal complex in which X − in formula (1) is a halide ion is synthesized according to the production method described above, and then the phosphine transition metal complex and an inorganic acid having a desired anion, A phosphine transition metal complex in which X − is a desired anion can be obtained by reacting an organic acid or an alkali metal salt thereof in a suitable solvent. Details of such a method are described in, for example, JP-A-10-147590, JP-A-10-114782, and JP-A-61-15944.
このようにして得られたホスフィン遷移金属錯体は、抗がん剤として用いられる。本発明の抗がん剤が適用されるがんの種類は、特に限定されるものではなく、例えば、悪性黒色腫、悪性リンパ腫、消化器癌、肺癌、食道癌、胃癌、大腸癌、直腸癌、結腸癌、尿管腫瘍、胆嚢癌、胆管癌、胆道癌、乳癌、肝臓癌、膵臓癌、睾丸腫瘍、上顎癌、舌癌、口唇癌、口腔癌、咽頭癌、喉頭癌、卵巣癌、子宮癌、前立腺癌、甲状腺癌、脳腫瘍、カポジ肉腫、血管腫、白血病、真性多血症、神経芽腫、網膜芽腫、骨髄腫、膀胱腫、肉腫、骨肉腫、筋肉腫、皮膚癌、基底細胞癌、皮膚付属器癌、皮膚転移癌、皮膚黒色腫等が挙げられる。更に、悪性腫瘍ばかりでなく良性腫瘍にも適用され得る。また、本発明の抗がん剤は、がん転移を抑制するために使用されることができ、特に、術後のがん転移抑制剤としても有用である。 The phosphine transition metal complex thus obtained is used as an anticancer agent. The type of cancer to which the anticancer agent of the present invention is applied is not particularly limited. For example, malignant melanoma, malignant lymphoma, digestive organ cancer, lung cancer, esophageal cancer, stomach cancer, colon cancer, rectal cancer. , Colon cancer, ureteral tumor, gallbladder cancer, bile duct cancer, biliary tract cancer, breast cancer, liver cancer, pancreatic cancer, testicular cancer, maxillary cancer, tongue cancer, lip cancer, oral cancer, pharyngeal cancer, laryngeal cancer, ovarian cancer, uterus Cancer, prostate cancer, thyroid cancer, brain tumor, Kaposi's sarcoma, hemangioma, leukemia, polycythemia vera, neuroblastoma, retinoblastoma, myeloma, cystoma, sarcoma, osteosarcoma, myoma, skin cancer, basal cell Cancer, skin appendage cancer, skin metastatic cancer, cutaneous melanoma and the like can be mentioned. Furthermore, it can be applied not only to malignant tumors but also to benign tumors. In addition, the anticancer agent of the present invention can be used to suppress cancer metastasis, and is particularly useful as a postoperative cancer metastasis inhibitor.
本発明の抗がん剤は、溶解性を向上させるため、シクロデキストリン化合物と併用して用いることができる。前記シクロデキストリン化合物としては、例えばα―シクロデキストリン、β−シクロデキストリン、γ―シクロデキストリン、メチル−β−シクロデキストリン、ジメチル−β−シクロデキストリン、トリメチル−β−シクロデキストリン、2−ヒドロキシプロピル−β―シクロデキストリン、2−ヒドロキシプロピル−α−シクロデキストリン、ジヒドロキシプロピル−β−シクロデキストリン、ヒドロキシエチル−β−シクロデキストリン、カルボキシメチル−β−シクロデキストリン、モノアセチル−β―シクロデキストリン、2−ヒドロキシプロピル−γ−シクロデキストリン、グルコシル−β−シクロデキストリン、マルトシル−α−シクロデキストリン、マルトシル−β−シクロデキストリン、パーシャリーメチル−β−シクロデキストリン、α−シクロデキストリンスルフェート、β−シクロデキストリンスルフェート等が挙がられる。 The anticancer agent of the present invention can be used in combination with a cyclodextrin compound in order to improve solubility. Examples of the cyclodextrin compound include α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methyl-β-cyclodextrin, dimethyl-β-cyclodextrin, trimethyl-β-cyclodextrin, and 2-hydroxypropyl-β. -Cyclodextrin, 2-hydroxypropyl-α-cyclodextrin, dihydroxypropyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, carboxymethyl-β-cyclodextrin, monoacetyl-β-cyclodextrin, 2-hydroxypropyl -Γ-cyclodextrin, glucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, partial methyl-β-cyclodextri , Α-cyclodextrin sulfate, β-cyclodextrin sulfate and the like.
本発明の抗がん剤の使用においては、種々の形態でヒト又は動物に、本発明の抗がん剤を投与することができる。投与形態としては、経口投与でもよいし、静脈内、筋肉内、皮下又は皮内等への注射、直腸内投与、経粘膜投与等の非経口投与でもよい。経口投与に適する製剤形態としては、例えば錠剤、丸剤、顆粒剤、散剤、カプセル剤、液剤、懸濁剤、乳剤、シロップ剤などを挙げることができる。非経口投与に適する医薬組成物としては、例えば、注射剤、点滴剤、点鼻剤、噴霧剤、吸入剤、坐剤、あるいは、軟膏、クリーム、粉状塗布剤、液状塗布剤、貼付剤等の経皮吸収剤等が挙げられる。更に、本発明の抗がん剤の製剤形態として、埋め込み用ペレットや公知の技術を用いた持続性製剤が挙げられる。 In the use of the anticancer agent of the present invention, the anticancer agent of the present invention can be administered to humans or animals in various forms. The administration form may be oral administration, or parenteral administration such as intravenous, intramuscular, subcutaneous or intradermal injection, rectal administration, transmucosal administration and the like. Examples of the dosage form suitable for oral administration include tablets, pills, granules, powders, capsules, solutions, suspensions, emulsions, syrups and the like. Examples of pharmaceutical compositions suitable for parenteral administration include injections, drops, nasal drops, sprays, inhalants, suppositories, ointments, creams, powdered coatings, liquid coatings, patches, etc. And the like. Furthermore, examples of the dosage form of the anticancer agent of the present invention include an embedding pellet and a sustained-release preparation using a known technique.
上述したうち、好ましい投与形態や製剤形態等は、患者の年齢、性別、体質、症状、処置時期等に応じて、医師によって適宜選択される。 Among the above-mentioned, a preferable dosage form, formulation form, etc. are suitably selected by a doctor according to the patient's age, sex, constitution, symptoms, treatment timing, and the like.
本発明の抗がん剤が、錠剤、丸剤、散剤、粉剤、顆粒剤等の固形製剤の場合、これらの固形製剤は、式(1)で表されるホスフィン遷移金属錯体を、常法に従って適当な添加剤、例えば乳糖、ショ糖、D−マンニトール、トウモロコシデンプン、合成若しくは天然ガム、結晶セルロース等の賦形剤、デンプン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、アラビアゴム、ゼラチン、ポリビニルピロリドン等の結合剤、カルボキシメチルセルロースカルシウム、カルボキシメチルセルロースナトリウム、デンプン、コーンスターチ、アルギン酸ナトリウム等の崩壊剤、タルク、ステアリン酸マグネシウム、ステアリン酸ナトリウム等の滑沢剤、炭酸カルシウム、炭酸ナトリウム、リン酸カルシウム、リン酸ナトリウム等の充填剤又は希釈剤等と適宜混合して製造される。錠剤等は、必要に応じて、ヒドロキシプロピルメチルセルロース、白糖、ポリエチレングリコール、酸化チタン等のコーティング剤を用いて、糖衣、ゼラチン、腸溶被覆、フイルムコーティング等が施されても良い。 When the anticancer agent of the present invention is a solid preparation such as a tablet, pill, powder, powder, granule or the like, these solid preparations contain a phosphine transition metal complex represented by the formula (1) according to a conventional method. Suitable additives such as lactose, sucrose, D-mannitol, corn starch, synthetic or natural gums, excipients such as crystalline cellulose, starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, gum arabic, gelatin, polyvinylpyrrolidone, etc. Binders, disintegrants such as calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, starch, corn starch, sodium alginate, lubricants such as talc, magnesium stearate, sodium stearate, calcium carbonate, sodium carbonate, calcium phosphate, sodium phosphate They are prepared by mixing as appropriate with fillers or diluents such as the like. Tablets and the like may be subjected to sugar coating, gelatin, enteric coating, film coating, and the like, if necessary, using a coating agent such as hydroxypropylmethylcellulose, sucrose, polyethylene glycol, and titanium oxide.
本発明の抗がん剤が、注射剤、点眼剤、点鼻剤、吸入剤、噴霧剤、ローション剤、シロップ剤、液剤、懸濁剤、乳剤等の液状製剤である場合、これらの液状製剤は、式(1)で表されるホスフィン遷移金属錯体を、精製水、リン酸緩衝液等の適当な緩衝液、生理的食塩水、リンゲル溶液、ロック溶液等の生理的塩類溶液、カカオバター、ゴマ油、オリーブ油等の植物油、鉱油、高級アルコール、高級脂肪酸、エタノール等の有機溶媒等に溶解して、必要に応じてコレステロール等の乳化剤、アラビアゴム等の懸濁剤、分散助剤、浸潤剤、ポリオキシエチレン硬化ヒマシ油系、ポリエチレングリコール系等の界面活性剤、リン酸ナトリウム等の溶解補助剤、糖、糖アルコール、アルブミン等の安定化剤、パラベン等の保存剤、塩化ナトリウム、ブドウ糖、グリセリン等の等張化剤、緩衝剤、無痛化剤、吸着防止剤、保湿剤、酸化防止剤、着色剤、甘味料、フレーバー、芳香物質等を適宜添加することにより、滅菌された水溶液、非水溶液、懸濁液、リポソーム又はエマルジョン等として調製される。この際、注射剤は、生理学的なpHを有することが好ましく、6〜8の範囲内のpHを有することが特に好ましい。 When the anticancer agent of the present invention is a liquid preparation such as injection, eye drop, nasal drop, inhalant, spray, lotion, syrup, liquid, suspension, emulsion, etc., these liquid preparations Is a phosphine transition metal complex represented by the formula (1), purified water, a suitable buffer solution such as phosphate buffer, physiological saline solution such as physiological saline, Ringer's solution, lock solution, cocoa butter, It is dissolved in vegetable oils such as sesame oil and olive oil, mineral oil, higher alcohols, higher fatty acids, ethanol and other organic solvents, and emulsifiers such as cholesterol, suspending agents such as gum arabic, dispersion aids, wetting agents, Polyoxyethylene hydrogenated castor oil-based, polyethylene glycol-based surfactants, solubilizers such as sodium phosphate, stabilizers such as sugar, sugar alcohol and albumin, preservatives such as parabens, sodium chloride, Sterilized by appropriate addition of isotonic agents such as dough sugar and glycerin, buffers, soothing agents, adsorption inhibitors, moisturizers, antioxidants, colorants, sweeteners, flavors, fragrances, etc. It is prepared as an aqueous solution, non-aqueous solution, suspension, liposome or emulsion. In this case, the injection preferably has a physiological pH, and particularly preferably has a pH within the range of 6-8.
本発明の抗がん剤が、ローション剤、クリーム剤、軟膏等の半固形製剤の場合、これらの半固形製剤は、前記式(1)で表されるホスフィン遷移金属錯体を脂肪、脂肪油、ラノリン、ワセリン、パラフィン、蝋、硬膏剤、樹脂、プラスチック、グリコール類、高級アルコール、グリセリン、水、乳化剤、懸濁化剤等と適宜混和することにより製造される。 When the anticancer agent of the present invention is a semi-solid preparation such as a lotion, cream or ointment, these semi-solid preparations contain a phosphine transition metal complex represented by the above formula (1) as a fat, fatty oil, It is produced by mixing with lanolin, petrolatum, paraffin, wax, plaster, resin, plastic, glycols, higher alcohol, glycerin, water, emulsifier, suspending agent and the like as appropriate.
本発明の抗がん剤中の式(1)で表されるホスフィン遷移金属錯体の含有量は、投与形態、重篤度や目的とする投与量などによって様々であるが、一般的には、抗がん剤の全質量に対する式(1)で表されるホスフィン遷移金属錯体の割合が、好ましくは0.001〜80質量%、更に好ましくは0.1〜50質量%である。 The content of the phosphine transition metal complex represented by the formula (1) in the anticancer agent of the present invention varies depending on the dosage form, severity, target dose, etc., but in general, The ratio of the phosphine transition metal complex represented by the formula (1) with respect to the total mass of the anticancer agent is preferably 0.001 to 80 mass%, more preferably 0.1 to 50 mass%.
本発明の抗がん剤の投与量は、例えば患者の年齢、性別、体重、症状及び投与経路などの条件に応じて適宜医師により決定されるものであるが、一般的には、成人一日あたりの有効成分の量として1μg/kgから1,000mg/kg程度の範囲であり、好ましくは10μg/kgから10mg/kg程度の範囲である。この投与量の範囲内において、抗がん剤を一日一回で投与することができ、あるいは数回(例えば、2〜4回程度)に分けて投与することができる。 The dose of the anticancer agent of the present invention is appropriately determined by a doctor according to conditions such as the age, sex, weight, symptom, and administration route of the patient. The amount of the active ingredient per unit is in the range of about 1 μg / kg to 1,000 mg / kg, preferably in the range of about 10 μg / kg to 10 mg / kg. Within this dosage range, the anticancer agent can be administered once a day, or can be administered in several divided portions (for example, about 2 to 4 times).
本発明の抗がん剤の使用においては、既知の化学療法、外科的治療法、放射線療法、温熱療法や免疫療法などと組み合わせることもできる。 In the use of the anticancer agent of the present invention, it can be combined with known chemotherapy, surgical treatment, radiation therapy, hyperthermia, immunotherapy and the like.
最後に、先に述べた式(3)で表される(S,S)−2,3−ビスホスフィノピラジン誘導体の好適な製造方法について説明する。式(3)で表される化合物は、以下の工程I、II及びIIIを経ることによって好適に製造される。 Finally, a preferred method for producing the (S, S) -2,3-bisphosphinopyrazine derivative represented by the above-described formula (3) will be described. The compound represented by the formula (3) is preferably produced through the following steps I, II and III.
〔工程I〕
以下の式(4)で表される水素−ホスフィンボラン化合物と、[Process I]
A hydrogen-phosphine borane compound represented by the following formula (4):
以下の式(5)で表される光学活性イソシアネート化合物とをカップリング反応に付して、 An optically active isocyanate compound represented by the following formula (5) is subjected to a coupling reaction,
以下の式(6)で表されるホスフィンボラン化合物を得た後、 After obtaining a phosphine borane compound represented by the following formula (6),
得られた式(6)で表されるホスフィンボラン化合物を光学分割により精製して、以下の式(6’)で表される光学活性なホスフィンボラン化合物を得る。 The obtained phosphine borane compound represented by the formula (6) is purified by optical resolution to obtain an optically active phosphine borane compound represented by the following formula (6 ').
〔工程II〕
工程Iで得られた式(6’)で表されるホスフィンボラン化合物を分解反応に付して、
以下の式(4’)で表される光学活性な水素−ホスフィンボラン化合物を得る。[Process II]
The phosphine borane compound represented by the formula (6 ′) obtained in step I is subjected to a decomposition reaction,
An optically active hydrogen-phosphine borane compound represented by the following formula (4 ′) is obtained.
〔工程III〕
工程IIで得られた式(4’)で表される光学活性な水素−ホスフィンボラン化合物と、以下の式(7)で表される2,3−ジハロゲノピラジンとを反応させて、[Step III]
An optically active hydrogen-phosphine borane compound represented by the formula (4 ′) obtained in Step II is reacted with 2,3-dihalogenopyrazine represented by the following formula (7):
以下の式(8)で表される光学活性なビス(ホスフィン−ボラン)ピラジン化合物を得た後、 After obtaining an optically active bis (phosphine-borane) pyrazine compound represented by the following formula (8),
前記の式(8)で表されるビス(ホスフィン−ボラン)ピラジン化合物の脱ボラン化反応を行って、前記の式(3)で表される(S,S)−2,3−ビスホスフィノピラジン誘導体を得る。 A deboraneation reaction of the bis (phosphine-borane) pyrazine compound represented by the above formula (8) is performed, and (S, S) -2,3-bisphosphino represented by the above formula (3) is performed. A pyrazine derivative is obtained.
以上の工程I〜工程IIIについて、以下にそれらの詳細を説明する。 The details of Step I to Step III will be described below.
(1)工程Iについて
工程Iにおいては、反応容器中で、式(4)で表される水素−ホスフィンボラン化合物と式(5)で表される光学活性イソシアネート化合物を混合し、カップリング反応を進行させる。その際、反応系に塩基を加えて反応を促進させることが好ましい。このカップリング反応により、式(6)で表されるホスフィンボラン化合物が生成する。式(4)で表される水素−ホスフィンボラン化合物としては、S体とR体との混合物(例えばラセミ体)を用いることができる。式(4)で表される水素−ホスフィンボラン化合物としてS体とR体との混合物を用いると、カップリング反応により生成する式(6)で表されるホスフィンボラン化合物は、Sp体とRp体との混合物となる(Sp体は不斉リン原子の立体配置がSである化合物を意味し、Rp体は不斉リン原子の立体配置がRである化合物を意味する)。(1) About Step I In Step I, a hydrogen-phosphine borane compound represented by Formula (4) and an optically active isocyanate compound represented by Formula (5) are mixed in a reaction vessel to carry out a coupling reaction. Make it progress. In that case, it is preferable to promote the reaction by adding a base to the reaction system. By this coupling reaction, a phosphine borane compound represented by the formula (6) is generated. As the hydrogen-phosphine borane compound represented by the formula (4), a mixture of an S form and an R form (for example, a racemate) can be used. When a mixture of an S form and an R form is used as the hydrogen-phosphine borane compound represented by the formula (4), the phosphine borane compound represented by the formula (6) produced by the coupling reaction is an Sp form and an Rp form. (The Sp form means a compound in which the configuration of the asymmetric phosphorus atom is S, and the Rp form means the compound in which the configuration of the asymmetric phosphorus atom is R).
カップリング反応時には、適宜溶媒が使用される。この溶媒としては、反応基質を分解しない溶媒が使用され、具体例としては、トルエン、ヘキサン、テトラヒドロフラン(THF)、ジエチルエーテル、ジオキサン、アセトン、酢酸エチル、クロロベンゼン、ジメチルホルムアミド(DMF)、アセトニトリル、メタノール、エタノール、水等が挙げられる。好ましくはトルエン又はTHFである。 A solvent is appropriately used during the coupling reaction. As this solvent, a solvent that does not decompose the reaction substrate is used. Specific examples include toluene, hexane, tetrahydrofuran (THF), diethyl ether, dioxane, acetone, ethyl acetate, chlorobenzene, dimethylformamide (DMF), acetonitrile, methanol. , Ethanol, water and the like. Preferably it is toluene or THF.
反応時の溶媒の添加量は、反応時における反応混合物の流動性及び溶媒の反応に与える効果を考慮して、適宜に設定することができる。 The amount of the solvent added during the reaction can be appropriately set in consideration of the fluidity of the reaction mixture during the reaction and the effect of the solvent on the reaction.
反応時の原料の仕込み量は、式(5)で表される光学活性イソシアネート化合物を基準として、式(4)で表される水素−ホスフィンボラン化合物が好ましくは0.4〜1.5当量である。 The amount of raw material charged during the reaction is preferably 0.4 to 1.5 equivalents of hydrogen-phosphine borane compound represented by formula (4) based on the optically active isocyanate compound represented by formula (5). is there.
反応時に塩基を加えると反応が促進する。塩基としては、例えばピリジン、トリエチルアミン、トリブチルアミン、1,8−ジアザビシクロ[5.4.0]ウンデセン−7(DBU)、1,5−ジアザビシクロ[4.3.0]ノネン−5(DBN)、4−(N,N−ジメチルアミノ)ピリジン(DMAP)等の有機塩基、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム等の無機塩基、n−ブチルリチウム、sec−ブチルリチウム、tert−ブチルリチウム、リチウムジイソプロピルアミド、イソプロピルマグネシウムクロリド、メチルマグネシウムブロミド等の有機金属が挙げられる。好ましい塩基はn−ブチルリチウムである。 Addition of a base during the reaction promotes the reaction. Examples of the base include pyridine, triethylamine, tributylamine, 1,8-diazabicyclo [5.4.0] undecene-7 (DBU), 1,5-diazabicyclo [4.3.0] nonene-5 (DBN), Organic bases such as 4- (N, N-dimethylamino) pyridine (DMAP), inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, n-butyllithium, sec-butyllithium, tert-butyl And organic metals such as lithium, lithium diisopropylamide, isopropylmagnesium chloride, and methylmagnesium bromide. A preferred base is n-butyllithium.
塩基の仕込量は、必要とされる反応の促進の度合いに応じて適宜に設定することができる。例えば式(5)で表される光学活性イソシアネート化合物に対し、塩基を通常0.1mol%〜150mol%用い、好ましくは1mol%〜10mol%用いる。原料及び塩基を仕込む順序は本製造方法において特に臨界的ではなく、作業性等に応じて任意に決定できる。 The amount of base charged can be appropriately set according to the required degree of reaction promotion. For example, with respect to the optically active isocyanate compound represented by the formula (5), the base is usually used in an amount of 0.1 mol% to 150 mol%, preferably 1 mol% to 10 mol%. The order in which the raw materials and the base are charged is not particularly critical in this production method, and can be arbitrarily determined according to workability and the like.
反応温度は、通常−80〜50℃であり、特に0〜30℃とすることが、反応が促進されかつ副反応及びラセミ化が抑制される点から好ましい。反応時間は、通常1分〜24時間であり、特に30分〜4時間であれば反応が完結するのに十分であるので好ましい。 The reaction temperature is usually −80 to 50 ° C., and in particular, 0 to 30 ° C. is preferable from the viewpoint of promoting the reaction and suppressing side reactions and racemization. The reaction time is usually 1 minute to 24 hours, and particularly 30 minutes to 4 hours is preferable because it is sufficient for the reaction to be completed.
カップリング反応に用いられる式(4)で表される水素−ホスフィンボラン化合物としては、市販品を使用することができる。そのような市販品は例えば日本化学工業(株)から入手可能である。式(5)で表される光学活性イソシアネート化合物も、市販品を使用することができ、例えば東京化成工業(株)から入手可能である。 A commercially available product can be used as the hydrogen-phosphine borane compound represented by the formula (4) used in the coupling reaction. Such commercial products are available from, for example, Nippon Chemical Industry Co., Ltd. A commercially available product can also be used as the optically active isocyanate compound represented by the formula (5), and for example, it can be obtained from Tokyo Chemical Industry Co., Ltd.
式(5)で表される光学活性イソシアネート化合物において、R6は、不斉炭化水素基又は置換不斉炭化水素基を示す。不斉炭化水素基としては、例えば(S)−1−フェニルエチル基、(R)−1−フェニルエチル基、(S)−1−(p−トルイル)エチル基、(R)−1−(p−トルイル)エチル基、(S)−1−(1−ナフチル)エチル基、(R)−1−(1−ナフチル)エチル基、(S)−1−シクロヘキシルエチル基、(R)−1−シクロヘキシルエチル基、(S)−2−(4−メチルフェニル)−1−フェニルエチル基、(R)−2−(4−メチルフェニル)−1−フェニルエチル基等が挙げられる。これらの中でも、工業的に安価に利用できる(S)−1−フェニルエチル基、(R)−1−フェニルエチル基が好ましい。In the optically active isocyanate compound represented by the formula (5), R 6 represents an asymmetric hydrocarbon group or a substituted asymmetric hydrocarbon group. Examples of the asymmetric hydrocarbon group include (S) -1-phenylethyl group, (R) -1-phenylethyl group, (S) -1- (p-toluyl) ethyl group, (R) -1- ( p-toluyl) ethyl group, (S) -1- (1-naphthyl) ethyl group, (R) -1- (1-naphthyl) ethyl group, (S) -1-cyclohexylethyl group, (R) -1 -Cyclohexylethyl group, (S) -2- (4-methylphenyl) -1-phenylethyl group, (R) -2- (4-methylphenyl) -1-phenylethyl group and the like. Among these, (S) -1-phenylethyl group and (R) -1-phenylethyl group which can be used industrially at low cost are preferable.
R6で表される置換不斉炭化水素基としては、前記の不斉炭化水素基の少なくとも1個の水素原子が炭化水素基、アルコキシ基、ハロゲン原子、アミノ基、ニトロ基、保護基を有するアミノ基等の置換基で置換された炭化水素基、又は上記不斉炭化水素基の少なくとも1個の炭素原子が酸素、窒素、硫黄、リン等のヘテロ原子で置換した基等が挙げられる。As the substituted asymmetric hydrocarbon group represented by R 6 , at least one hydrogen atom of the asymmetric hydrocarbon group has a hydrocarbon group, an alkoxy group, a halogen atom, an amino group, a nitro group, or a protecting group. Examples include a hydrocarbon group substituted with a substituent such as an amino group, or a group in which at least one carbon atom of the asymmetric hydrocarbon group is substituted with a heteroatom such as oxygen, nitrogen, sulfur, or phosphorus.
カップリング反応後に、副生塩を除去し、光学分割によって式(6)で表されるホスフィンボラン化合物の対掌体(Sp体とRp体)のうち、Rp体、すなわち式(6’)で表されるホスフィンボラン化合物を単離する。式(6’)で表されるホスフィンボラン化合物は、リン原子上又はリン原子を不斉面の一点とする不斉部分、及び光学活性カルバモイル基を有することを特徴とする、不斉点を2点有するジアステレオマーである。光学分割には、分液洗浄、晶析、蒸留、昇華、カラムクロマトグラフィー等を用いることができる。工業的な観点から好ましい光学分割の方法は晶析である。 After the coupling reaction, by-product salts are removed, and among the enantiomers (Sp isomer and Rp isomer) of the phosphine borane compound represented by formula (6) by optical resolution, Rp isomer, that is, formula (6 ′) The represented phosphine borane compound is isolated. The phosphine borane compound represented by the formula (6 ′) has an asymmetric part having an asymmetric part on the phosphorus atom or the phosphorus atom as one point of an asymmetric surface, and an optically active carbamoyl group. It is a diastereomer having dots. For optical resolution, liquid separation washing, crystallization, distillation, sublimation, column chromatography, and the like can be used. From the industrial viewpoint, the preferred optical resolution method is crystallization.
式(6)で表されるホスフィンボラン化合物の対掌体から、式(6’)で表されるホスフィンボラン化合物を首尾よく単離するためには、R6で表される基を適切に選択すればよい。例えば式(6’)においてR1がtert−ブチル基であり、R2がメチル基である場合には、R6で表される基として(S)−不斉炭化水素基又は(S)−置換不斉炭化水素基を用いると、晶析によって式(6’)で表されるホスフィンボラン化合物(つまりSp体)が優先的に沈殿する一方で、Rp体は溶液中にとどまったままとなるので、両者を首尾よく分離することができる。In order to successfully isolate the phosphine borane compound represented by the formula (6 ′) from the enantiomer of the phosphine borane compound represented by the formula (6), the group represented by R 6 is appropriately selected. do it. For example, in the formula (6 ′), when R 1 is a tert-butyl group and R 2 is a methyl group, the group represented by R 6 is (S) -asymmetric hydrocarbon group or (S) — When a substituted asymmetric hydrocarbon group is used, the phosphine borane compound represented by the formula (6 ′) (that is, the Sp isomer) is preferentially precipitated by crystallization, while the Rp isomer remains in the solution. So both can be separated successfully.
(2)工程IIについて
工程Iで得られた式(6’)で表されるホスフィンボラン化合物と塩基とを反応容器中で混合し、該ホスフィンボラン化合物を分解する。分解反応促進のためにアルコールを添加することが好ましい。反応後、副生物を除去し、式(4’)で表される光学活性な水素−ホスフィンボラン化合物を得る。(2) Step II The phosphine borane compound represented by the formula (6 ′) obtained in Step I and a base are mixed in a reaction vessel to decompose the phosphine borane compound. It is preferable to add alcohol to promote the decomposition reaction. After the reaction, by-products are removed to obtain an optically active hydrogen-phosphine borane compound represented by the formula (4 ′).
反応時には適宜溶媒が使用される。この溶媒としては、反応基質を分解しない溶媒が使用され、具体例としては、トルエン、ヘキサン、テトラヒドロフラン(THF)、ジエチルエーテル、ジオキサン、アセトン、酢酸エチル、クロロベンゼン、ジメチルホルムアミド(DMF)、アセトニトリル、メタノール、エタノール、水等が挙げられる。特にDMF又はアセトニトリルを用いることが好ましい。 A solvent is appropriately used during the reaction. As this solvent, a solvent that does not decompose the reaction substrate is used. Specific examples include toluene, hexane, tetrahydrofuran (THF), diethyl ether, dioxane, acetone, ethyl acetate, chlorobenzene, dimethylformamide (DMF), acetonitrile, methanol. , Ethanol, water and the like. It is particularly preferable to use DMF or acetonitrile.
反応時の溶媒の添加量は、反応時における反応混合物の流動性及び溶媒の反応に与える効果を考慮して、適宜に設定することができる。 The amount of the solvent added during the reaction can be appropriately set in consideration of the fluidity of the reaction mixture during the reaction and the effect of the solvent on the reaction.
前記の塩基としては、例えばピリジン、トリエチルアミン、トリブチルアミン、1,8−ジアザビシクロ[5.4.0]ウンデセン−7(DBU)、1,5−ジアザビシクロ[4.3.0]ノネン−5(DBN)、4−(N,N−ジメチルアミノ)ピリジン(DMAP)等の有機塩基、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム等の無機塩基が挙げられる。均一系又は液−液の二相系で反応させるために、塩基は溶液として供給されることが好ましい。例えば塩基として水酸カリウムを用いる場合には、例えば1〜70質量%の水溶液又はメタノール溶液とすることが好ましい。 Examples of the base include pyridine, triethylamine, tributylamine, 1,8-diazabicyclo [5.4.0] undecene-7 (DBU), 1,5-diazabicyclo [4.3.0] nonene-5 (DBN). ), 4- (N, N-dimethylamino) pyridine (DMAP) and the like, and inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate. In order to react in a homogeneous system or a liquid-liquid two-phase system, the base is preferably supplied as a solution. For example, when potassium hydroxide is used as the base, it is preferable to use, for example, a 1 to 70% by mass aqueous solution or a methanol solution.
塩基の仕込量は、必要とされる反応の促進の度合いに応じて適宜に設定することができる。例えば式(6’)で表されるホスフィンボラン化合物に対し、塩基を通常0.01当量〜10当量添加することができ、特に0.1当量〜5当量添加することが好ましい。式(6’)で表されるホスフィンボラン化合物及び塩基を仕込む順序は本製造方法において特に臨界的ではなく、作業性等に応じて任意に決定できる。 The amount of base charged can be appropriately set according to the required degree of reaction promotion. For example, with respect to the phosphine borane compound represented by the formula (6 '), a base can be usually added in an amount of 0.01 equivalent to 10 equivalents, particularly preferably 0.1 equivalent to 5 equivalents. The order in which the phosphine borane compound represented by formula (6 ') and the base are charged is not particularly critical in this production method, and can be arbitrarily determined according to workability and the like.
反応を促進する目的で、上述のとおりアルコールを加えることが好ましい。このアルコールとしては、例えばメタノールやエタノールを用いることができ、特にメタノールを用いることが好ましい。 For the purpose of promoting the reaction, it is preferable to add alcohol as described above. For example, methanol or ethanol can be used as the alcohol, and methanol is particularly preferable.
反応温度は、通常−80〜50℃であり、特に0〜30℃とすることが、反応が促進されかつ副反応及びラセミ化が抑制される点から好ましい。反応時間は、通常1分〜24時間であり、特に3時間〜20時間であれば反応が完結するのに十分であるので好ましい。 The reaction temperature is usually −80 to 50 ° C., and in particular, 0 to 30 ° C. is preferable from the viewpoint of promoting the reaction and suppressing side reactions and racemization. The reaction time is usually 1 minute to 24 hours, and 3 hours to 20 hours is particularly preferable because it is sufficient for the reaction to be completed.
反応後、得られた生成物は、副生塩の除去のみといった簡単な精製作業の後に工程IIIに供することができる。あるいは、分液洗浄、晶析、蒸留、昇華、カラムクロマトグラフィーといった精製作業によって、式(4’)で表される光学活性な水素−ホスフィンボラン化合物のみを単離した後に、これを工程IIIに供することもできる。 After the reaction, the obtained product can be subjected to Step III after a simple purification operation such as only removal of by-product salts. Alternatively, after isolating only the optically active hydrogen-phosphine borane compound represented by the formula (4 ′) by a purification operation such as liquid separation washing, crystallization, distillation, sublimation, and column chromatography, Can also be provided.
(3)工程IIIについて
本工程において用いられる式(7)で表される化合物において、Xで表されるハロゲン原子としては、フッ素、塩素、臭素、ヨウ素が挙げられる。(3) Step III In the compound represented by the formula (7) used in this step, examples of the halogen atom represented by X include fluorine, chlorine, bromine and iodine.
式(7)で表される2,3−ジハロゲノピラジン誘導体としては、例えば市販品を使用することができる。そのような市販品としては、例えば東京化成工業(株)から入手可能な化合物である2,3−ジクロロキノキサリンが挙げられる。 As the 2,3-dihalogenopyrazine derivative represented by the formula (7), for example, a commercially available product can be used. Examples of such commercially available products include 2,3-dichloroquinoxaline, which is a compound available from Tokyo Chemical Industry Co., Ltd.
工程IIIにおいて、工程IIで得られた式(4’)で表される光学活性な水素−ホスフィンボラン化合物と、式(7)で表される2,3−ジハロゲノピラジン誘導体との反応は、例えば塩基の存在下、不活性溶媒中、−78〜30℃で、1〜24時間行われる。この反応により、式(8)で表されるビス(ホスフィン−ボラン)ピラジン化合物が得られる。 In Step III, the reaction between the optically active hydrogen-phosphine borane compound represented by Formula (4 ′) obtained in Step II and the 2,3-dihalogenopyrazine derivative represented by Formula (7) For example, it is carried out in the presence of a base in an inert solvent at −78 to 30 ° C. for 1 to 24 hours. By this reaction, a bis (phosphine-borane) pyrazine compound represented by the formula (8) is obtained.
反応時の原料の仕込み量は、式(7)で表される2,3−ジハロゲノピラジン誘導体を基準として、式(4’)で表される光学活性な水素−ホスフィンボラン化合物が好ましくは2〜10当量であり、更に好ましくは2〜3当量である。 The amount of raw material charged during the reaction is preferably an optically active hydrogen-phosphine borane compound represented by the formula (4 ′) based on the 2,3-dihalogenopyrazine derivative represented by the formula (7). -10 equivalents, more preferably 2-3 equivalents.
本工程において用いられる前記の不活性溶媒としては、例えばテトラヒドロフラン、N,N−ジメチルホルムアミド、ジエチルエーテル、ジブチルエーテル、ジオキサン、ヘキサン、トルエン等が挙げられる。特にテトラヒドロフランを用いることが好ましい。反応時の不活性溶媒の添加量は、反応時における反応混合物の流動性及び溶媒の反応に与える効果を考慮して、適宜に設定することができる。 Examples of the inert solvent used in this step include tetrahydrofuran, N, N-dimethylformamide, diethyl ether, dibutyl ether, dioxane, hexane, toluene and the like. In particular, it is preferable to use tetrahydrofuran. The addition amount of the inert solvent during the reaction can be appropriately set in consideration of the fluidity of the reaction mixture during the reaction and the effect of the solvent on the reaction.
本工程において用いられる前記の塩基としては、例えばn−ブチルリチウム、メチルマグネシウムブロミド、t−ブトキシカリウム、水酸化カリウム、水酸化ナトリム等が挙げられる。特にn−ブチルリチウムを用いることが好ましい。塩基の仕込量は、必要とされる反応の促進の度合いに応じて適宜に設定することができる。例えば式(7)で表される2,3−ジハロゲノピラジン誘導体に対し、塩基を通常2〜10当量添加することができ、2〜3当量添加することが好ましい。本工程において各化合物を仕込む順序は臨界的でなく、作業性等に応じて任意に決定できる。 Examples of the base used in this step include n-butyl lithium, methyl magnesium bromide, t-butoxy potassium, potassium hydroxide, sodium hydroxide and the like. It is particularly preferable to use n-butyllithium. The amount of base charged can be appropriately set according to the required degree of reaction promotion. For example, 2 to 10 equivalents of a base can be usually added to the 2,3-dihalogenopyrazine derivative represented by the formula (7), and it is preferable to add 2 to 3 equivalents. The order in which the respective compounds are charged in this step is not critical, and can be arbitrarily determined according to workability and the like.
式(8)で表されるビス(ホスフィン−ボラン)ピラジン化合物の脱ボラン化反応は、例えば、前記反応によって得られた該ビス(ホスフィン−ボラン)ピラジン化合物を含有する反応系に、脱ボラン化剤を添加し、0〜100℃で、10分〜3時間行われる。この脱ボラン化反応によって、目的物である式(3)で表される光学活性な(S,S)−2,3−ビスホスフィノピラジン誘導体が得られる。 In the deboranation reaction of the bis (phosphine-borane) pyrazine compound represented by the formula (8), for example, the reaction system containing the bis (phosphine-borane) pyrazine compound obtained by the above reaction is deboranated. The agent is added and the reaction is performed at 0 to 100 ° C. for 10 minutes to 3 hours. By this deboraneation reaction, an optically active (S, S) -2,3-bisphosphinopyrazine derivative represented by the formula (3), which is the target product, is obtained.
前記の脱ボラン化剤としては、例えばN,N,N’,N’,−テトラメチルエチレンジアミン(TMEDA)、トリエチレンジアミン(DABCO)、トリエチルアミン等が挙げられる。特にTMEDAを用いることが好ましい。脱ボラン化剤の仕込量は、式(8)で表されるビス(ホスフィン−ボラン)ピラジン化合物を得る際に用いた前記式(7)で表される2,3−ジハロゲノピラジン誘導体に対し、通常2〜20当量であり、好ましくは2〜10当量である。 Examples of the deboronating agent include N, N, N ′, N ′,-tetramethylethylenediamine (TMEDA), triethylenediamine (DABCO), and triethylamine. It is particularly preferable to use TMEDA. The amount of the deboronating agent charged relative to the 2,3-dihalogenopyrazine derivative represented by the formula (7) used in obtaining the bis (phosphine-borane) pyrazine compound represented by the formula (8) is as follows. , Usually 2 to 20 equivalents, preferably 2 to 10 equivalents.
脱ボラン化反応により生成した式(3)で表される光学活性な(S,S)−2,3−ビスホスフィノピラジン誘導体は、必要に応じて分液洗浄、晶析、蒸留、昇華、カラムクロマトグラフィーといった精製作業に付してもよい。 The optically active (S, S) -2,3-bisphosphinopyrazine derivative represented by the formula (3) generated by the deboraneation reaction is separated and washed as necessary, crystallization, distillation, sublimation, It may be subjected to purification work such as column chromatography.
以下に実施例を挙げて本発明を具体的に説明するが、かかる実施例はあくまで例示であって、本発明の適用範囲はこれに限定されない。 Hereinafter, the present invention will be specifically described with reference to examples. However, such examples are merely examples, and the scope of application of the present invention is not limited thereto.
すべての合成操作は、よく乾燥させたガラス容器を使って行った。反応は窒素雰囲気下で行った。原料試薬及び溶媒は、一般の試薬を使用した。ラセミのtert−ブチルメチルホスフィンボランは、日本化学工業(株)製のものを使用した。 All synthesis operations were performed using well-dried glass containers. The reaction was performed under a nitrogen atmosphere. General reagents were used as the raw material reagent and the solvent. A racemic tert-butylmethylphosphine borane manufactured by Nippon Chemical Industry Co., Ltd. was used.
NMRスペクトル測定は、JEOL製(1H;300MHz、13C;75.4MHz、31P;121.4MHz)NMR装置で行った。内部標準としてテトラメチルシラン(1H)を使用した。比旋光度測定は、堀場製作所製比旋光度計SEPA−300で行った。NMR spectrum measurement was performed with a JEOL ( 1 H; 300 MHz, 13 C; 75.4 MHz, 31 P; 121.4 MHz) NMR apparatus. Tetramethylsilane ( 1 H) was used as an internal standard. The specific rotation was measured with a specific rotation polarimeter SEPA-300 manufactured by Horiba.
〔実施例1〕
<工程I> (S P )−tert−ブチル(メチル)[N−((S)−1−フェニルエチル)カルバモイル]ホスフィン−ボランの製造
3L四つ口フラスコに、機械撹拌シール、温度計、等圧滴下ろうと及び排気部を備えた。そこへ、ラセミ−tert−ブチルメチルホスフィンボラン141.8g(1202mmol)及びTHF600ccを入れ、ラセミ−tert−ブチルメチルホスフィンボランを溶解させ、10℃以下に保持しながら1.59mol/Lのn−ブチルリチウム−ヘキサン溶液75cc(119mmol)を滴下した。続いて、同温度にて(S)−(−)−α−メチルベンジルイソシアネート176.8g(1201mmol)を滴下した。その後室温に戻し、一晩撹拌熟成した。5重量%塩酸90g加えて反応を停止した後、ヘキサン240cc及び水240ccを加えて2層に分画した。水層を除去し、有機層を2.5重量%重曹水240g、続いて水240ccで洗い、濃縮して、粗生物(白色フレーク状固体)として、一般式(3)で表されるホスフィンボラン化合物を得た(348.3g)。粗生物を酢酸エチル240cc+ヘキサン1800ccで晶析し、ろ過、乾燥して無色粉末を得た。NMR分析により、得られた無色粉末は表題化合物と同定された。NMR分析結果を以下に示す。また、得られた無色粉末は、収量118.6g(447mmol)、収率37%(イソシアネートから)、ジアステレオマー過剰率>97%deであった。ジアステレオマー過剰率は、1H−NMRのSP及びRPの特定部プロトンの面積比から決定した。[Example 1]
<Step I> (S P) -tert- butyl (methyl) [N - ((S)-1-phenylethyl) carbamoyl] phosphine - the production 3L four-necked flask borane, mechanical stirring seal, a thermometer, etc. A pressure dropping funnel and an exhaust part were provided. Thereto, 141.8 g (1202 mmol) of racemic-tert-butylmethylphosphine borane and 600 cc of THF were added, and the racemic-tert-butylmethylphosphine borane was dissolved, and 1.59 mol / L n-butyl was maintained at 10 ° C. or lower. 75 cc (119 mmol) of a lithium-hexane solution was added dropwise. Subsequently, 176.8 g (1201 mmol) of (S)-(−)-α-methylbenzyl isocyanate was added dropwise at the same temperature. Thereafter, the temperature was returned to room temperature and aged with stirring overnight. The reaction was stopped by adding 90 g of 5% by weight hydrochloric acid, and then 240 cc of hexane and 240 cc of water were added to separate into two layers. The aqueous layer was removed, and the organic layer was washed with 240 g of 2.5% by weight aqueous sodium bicarbonate followed by 240 cc of water and concentrated to give a crude product (white flaky solid) as a phosphine borane represented by the general formula (3). Compound was obtained (348.3 g). The crude product was crystallized with 240 cc of ethyl acetate and 1800 cc of hexane, filtered and dried to obtain a colorless powder. The colorless powder obtained was identified as the title compound by NMR analysis. The NMR analysis results are shown below. The obtained colorless powder had a yield of 118.6 g (447 mmol), a yield of 37% (from isocyanate), and a diastereomeric excess> 97% de. The diastereomeric excess was determined from the area ratio of specific part protons of SP and RP of 1 H-NMR.
(NMR分析結果)
1H−NMR(CDCl3);
(SP)−体(目的物);−0.5−1(3H,m),1.14(9H,d,14.7Hz),1.45(3H,d,10.5Hz),1.53(3H,d,6.9Hz),5.15(1H,pent,6.9Hz),7.2−7.4(6H,m).
(RP)−体;−0.5−1(3H,m),1.25(9H,d,14.7Hz),1.42(3H,d,10.5Hz),1.53(3H,d,6.9Hz),5.15(1H,pent,6.9Hz),7.2−7.4(6H,m).(NMR analysis result)
1 H-NMR (CDCl 3 );
(S P ) -body (object); -0.5-1 (3H, m), 1.14 (9H, d, 14.7 Hz), 1.45 (3H, d, 10.5 Hz), 1 .53 (3H, d, 6.9 Hz), 5.15 (1 H, pent, 6.9 Hz), 7.2-7.4 (6H, m).
(R P ) -body; -0.5-1 (3H, m), 1.25 (9H, d, 14.7 Hz), 1.42 (3H, d, 10.5 Hz), 1.53 (3H , D, 6.9 Hz), 5.15 (1H, pent, 6.9 Hz), 7.2-7.4 (6H, m).
<工程II> 光学活性水素−ホスフィンボラン化合物〔(R)−tert−ブチルメチルホスフィン−ボラン〕の製造
200cc四つ口フラスコに、機械撹拌シール、温度計及び排気部を備え、そこへ、工程Iで得られた(SP)−tert−ブチル(メチル)[N−((S)−1−フェニルエチル)カルバモイル]ホスフィン−ボラン10.03g(37.8mmol)及びDMF100ccを入れ、ホスフィン−ボランを溶解させた後、氷水浴にて10℃以下とした。ここに50重量%水酸化カリウム水溶液21.26g(189mmol)とメタノール25ccを添加した。次に、氷水浴をはずして18時間撹拌熟成した。次いで、500cc三角フラスコに冷水100ccと石油エーテル100ccを入れ、ここに反応液を分散させることで反応を停止した。水層と有機層とを分離し、水層を石油エーテル100ccで再抽出し、先に分離した有機層と合わせた後、水50ccで2回洗い、無水硫酸ナトリウムにて乾燥した。シリカゲルカラムクロマトグラフィー(ワコーゲルC200)にて精製し、無色粉末を得た。NMR分析により、得られた無色粉末は表題化合物と同定された。NMR分析結果を以下に示す。また、得られた無色粉末は、収量3.01g(25.5mmol)、収率67%であった。<Step II> Production of optically active hydrogen-phosphine borane compound [(R) -tert-butylmethylphosphine-borane] A 200 cc four-necked flask is equipped with a mechanical stirring seal, a thermometer, and an exhaust part, and step I (S P ) -tert-butyl (methyl) [N-((S) -1-phenylethyl) carbamoyl] phosphine-borane obtained in 1) and 100 cc of DMF were added, and phosphine-borane was added. After dissolution, the temperature was adjusted to 10 ° C. or lower in an ice water bath. Thereto were added 21.26 g (189 mmol) of a 50 wt% aqueous potassium hydroxide solution and 25 cc of methanol. Next, the ice-water bath was removed and the mixture was aged with stirring for 18 hours. Next, 100 cc of cold water and 100 cc of petroleum ether were placed in a 500 cc Erlenmeyer flask, and the reaction was stopped by dispersing the reaction solution therein. The aqueous layer and the organic layer were separated, the aqueous layer was re-extracted with 100 cc of petroleum ether, combined with the previously separated organic layer, washed twice with 50 cc of water, and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (Wakogel C200) gave a colorless powder. The colorless powder obtained was identified as the title compound by NMR analysis. The NMR analysis results are shown below. The obtained colorless powder had a yield of 3.01 g (25.5 mmol) and a yield of 67%.
(NMR分析結果)
1H−NMR(CDCl3);
−0.5−1(3H,m),1.22(9H,d,14.7Hz),1.32(3H,dd,10.5Hz,6.0Hz),4.4(1H,dm,355Hz).(NMR analysis result)
1 H-NMR (CDCl 3 );
-0.5-1 (3H, m), 1.22 (9H, d, 14.7Hz), 1.32 (3H, dd, 10.5Hz, 6.0Hz), 4.4 (1H, dm, 355 Hz).
<工程III> (S,S)−2,3−ビス(tert−ブチルメチルホスフィノ)キノキサリンの製造
工程IIで得られた(R)−tert−ブチルメチルホスフィン−ボラン3.01g(25.5mmol)をフラスコ中で脱水THF25ccに溶解し、−78℃に冷却した。ここに1.65mol/Lのn−ブチルリチウム−ヘキサン溶液15.5cc(25.6mmol)を滴下して加え、同温度で15分撹拌熟成した。続いて2,3−ジクロロキノキサリン1,703mg(8.56mmol)をよく撹拌しながら一度に加えた。添加後、1時間かけて室温に戻し、3時間撹拌した。続いてテトラメチルエチレンジアミン10.07g(87mmol)を添加し、室温(25℃)で2時間撹拌熟成した。1M塩酸を加えて反応停止し、ヘキサンを加えて有機成分を抽出した。有機層を1M塩酸、続いて飽和食塩水で分液洗浄し、無水硫酸ナトリウム上で乾燥した。溶媒を減圧留去し、残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル=30/1)で精製し、表題化合物を橙色粉末として得た。更に熱メタノールから再結晶精製して橙色立方晶の結晶を得た。収量は2,149mg(6.427mmol)、収率は75%であった。得られた表題化合物の分析結果を以下に示す。<Step III> 3.01 g (25.5 mmol) of (R) -tert-butylmethylphosphine-borane obtained in Production Step II of (S, S) -2,3-bis (tert-butylmethylphosphino) quinoxaline ) Was dissolved in 25 cc of dehydrated THF in a flask and cooled to -78 ° C. To this was added dropwise 15.5 cc (25.6 mmol) of a 1.65 mol / L n-butyllithium-hexane solution, and the mixture was aged and stirred at the same temperature for 15 minutes. Subsequently, 1,703 mg (8.56 mmol) of 2,3-dichloroquinoxaline was added all at once with good stirring. After the addition, the mixture was returned to room temperature over 1 hour and stirred for 3 hours. Subsequently, 10.07 g (87 mmol) of tetramethylethylenediamine was added, followed by stirring and aging at room temperature (25 ° C.) for 2 hours. The reaction was stopped by adding 1M hydrochloric acid, and hexane was added to extract organic components. The organic layer was washed with 1M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 30/1) to obtain the title compound as an orange powder. Further, the crystals were recrystallized and purified from hot methanol to obtain orange cubic crystals. The yield was 2,149 mg (6.427 mmol), and the yield was 75%. The analysis results of the obtained title compound are shown below.
(分析結果)
1H−NMR(CDCl3);
1.02(18H,t,6.0Hz),1.4(6H,t,3.2Hz),7.68−7.75(2H,m),8.07−8.14(2H,m).
13C−NMR(CDCl3);
4.8(d),27.6(t),31.9(t),129.6(d),141.6,165.1(d),165.2(d).
31P−NMR(CDCl3);
−16.6.
比旋光度;+53.5°([α]D 22(c=1,CHCl3);なお、(R,R)体は比旋光度−54.3°であることが既知である)
融点;102−103℃(result of analysis)
1 H-NMR (CDCl 3 );
1.02 (18 H, t, 6.0 Hz), 1.4 (6 H, t, 3.2 Hz), 7.68-7.75 (2 H, m), 8.07-8.14 (2 H, m ).
13 C-NMR (CDCl 3 );
4.8 (d), 27.6 (t), 31.9 (t), 129.6 (d), 141.6, 165.1 (d), 165.2 (d).
31 P-NMR (CDCl 3 );
-16.6.
Specific rotation: + 53.5 ° ([α] D 22 (c = 1, CHCl 3 ); the (R, R) isomer is known to have a specific rotation of −54.3 °)
Melting point: 102-103 ° C
<工程IV> (R,R,R,R)−ビス(2,3−ビス(tert−ブチルメチルホスフィノ)キノキサリン)金(I)クロリドの合成
窒素ガスで置換した500ml二口フラスコに、前記の方法で得られた(S,S)−2,3−ビス(tert−ブチルメチルホスフィノ)キノキサリン5.50g(16.4mmol)を一般品THF220mlに溶かした。ここにテトラブチルアンモニウム金ジクロリド4.19g(8.2mmol)を加え、室温で5時間撹拌した。生成した褐色沈殿をろ別し、次いでジクロロメタン42mlに溶かして水50mlで洗浄し、更に硫酸ナトリウムで乾燥した。これをろ過したのち溶液を乾固させた。この固体をジクロロメタン50mlに溶解し、ジエチルエーテル270mlを加え、0℃にしたところ固体が析出し、(R,R,R,R)−ビス(2,3−ビス(tert−ブチルメチルホスフィノ)キノキサリン)金(I)クロリド7.26g(収率98%)を得た。<Step IV> Synthesis of (R, R, R, R) -bis (2,3-bis (tert-butylmethylphosphino) quinoxaline) gold (I) chloride Into a 500 ml two-necked flask substituted with nitrogen gas, (S, S) -2,3-bis (tert-butylmethylphosphino) quinoxaline 5.50 g (16.4 mmol) obtained by the above method was dissolved in 220 ml of general THF. Tetrabutylammonium gold dichloride (4.19 g, 8.2 mmol) was added thereto, and the mixture was stirred at room temperature for 5 hours. The resulting brown precipitate was filtered off, then dissolved in 42 ml of dichloromethane, washed with 50 ml of water, and further dried over sodium sulfate. After filtering this, the solution was dried. This solid was dissolved in 50 ml of dichloromethane, 270 ml of diethyl ether was added, and the mixture was heated to 0 ° C., whereupon the solid was precipitated and (R, R, R, R) -bis (2,3-bis (tert-butylmethylphosphino) Quinoxaline) 7.26 g (98% yield) gold (I) chloride was obtained.
(分析結果)
・31P−NMR(CDCl3);13.6
・HPLC(カラム スミキラル OA−8000 4.6×250mm、移動層 ヘキサン:エタノール:メタノール:トリフルオロ酢酸=930:40:30:1、流速1.0ml/min、温度35℃、UV 254nm、溶離時間;49.5分(result of analysis)
31 P-NMR (CDCl 3 ); 13.6
-HPLC (column Sumichiral OA-8000 4.6 x 250 mm, moving bed hexane: ethanol: methanol: trifluoroacetic acid = 930: 40: 30: 1, flow rate 1.0 ml / min, temperature 35 ° C., UV 254 nm, elution time ; 49.5 minutes
〔比較例1〕
(1)<(R,R)−2,3−ビス(tert−ブチルメチルホスフィノ)キノキサリンの合成>
本出願人の先の出願に係る特開2007−56007号公報における実施例1の記載に従い、(R,R)−2,3−ビス(tert−ブチルメチルホスフィノ)キノキサリンを得た。[Comparative Example 1]
(1) <Synthesis of (R, R) -2,3-bis (tert-butylmethylphosphino) quinoxaline>
(R, R) -2,3-bis (tert-butylmethylphosphino) quinoxaline was obtained in accordance with the description of Example 1 in Japanese Patent Application Laid-Open No. 2007-56007 related to the applicant's previous application.
(2)<(S,S,S,S)−ビス(2,3−ビス(tert−ブチルメチルホスフィノ)キノキサリン)金(I)クロリドの合成>
(R,R)−2,3−ビス(tert−ブチルメチルホスフィノ)キノキサリンを用いる以外は、実施例1の工程IVと同様にして、(S,S,S,S)−ビス(2,3−ビス(tert−ブチルメチルホスフィノ)キノキサリン)金(I)クロリドを得た。この化合物は、式(1a’)で表される化合物に包含されるものである。
・31P−NMR(CDCl3);13.6
・[α]D=+195.3(c=0.5、メタノール、25℃)(2) <Synthesis of (S, S, S, S) -bis (2,3-bis (tert-butylmethylphosphino) quinoxaline) gold (I) chloride>
(S, S, S, S) -bis (2, similar to step IV in Example 1 except that (R, R) -2,3-bis (tert-butylmethylphosphino) quinoxaline is used. 3-Bis (tert-butylmethylphosphino) quinoxaline) gold (I) chloride was obtained. This compound is included in the compound represented by the formula (1a ′).
31 P-NMR (CDCl 3 ); 13.6
[Α] D = +195.3 (c = 0.5, methanol, 25 ° C.)
〔評価〕
実施例及び比較例で得られたホスフィン遷移金属錯体について、in vitro抗腫瘍活性試験及びマウスに経口投与したときの毒性試験を以下の方法で行った。それらの結果を以下の表1に示す。[Evaluation]
The phosphine transition metal complexes obtained in Examples and Comparative Examples were subjected to in vitro antitumor activity tests and toxicity tests when orally administered to mice by the following methods. The results are shown in Table 1 below.
〔in vitro抗腫瘍活性試験〕
また、実施例及び比較例で得られたホスフィン遷移金属錯体について、in vitroの抗腫瘍活性試験を行った。具体的には、癌細胞としてBGC−823(ヒト胃腺癌)を使用し、10%非働化新生仔ウシ血清、L−グルタミン、ピルビン酸ナトリウム、1×105U/Lペニシリン、100mg/Lストレプトマイシンを補足した培地(RPMI−1640又はDEME)中でインキュベータ中、37℃で培養した。細胞は1ウェルあたり2×105となるように加えた。次にジメチルスルホキシドに溶解したホスフィン遷移金属錯体溶液を加え48時間培養した。48時間培養した後、1ウェルあたり5mg/mlの(3,[4,5−dimethylthiazol−2−yl]−2,5−diphenyltetrazolium bromide、MTT)溶液を20μl加え、3〜4時間培養器で培養した。更に1ウェルあたり溶解液を100μl加え生成したホルマザン結晶を完全に可溶化させた。そして、492nmにおける吸光度を測定してIC50を算出した。[In vitro antitumor activity test]
Moreover, the in vitro antitumor activity test was done about the phosphine transition metal complex obtained by the Example and the comparative example. Specifically, BGC-823 (human gastric adenocarcinoma) was used as a cancer cell, 10% inactivated neonatal calf serum, L-glutamine, sodium pyruvate, 1 × 10 5 U / L penicillin, 100 mg / L streptomycin In a medium supplemented with (RPMI-1640 or DEME) at 37 ° C. in an incubator. Cells were added at 2 × 10 5 per well. Next, a phosphine transition metal complex solution dissolved in dimethyl sulfoxide was added and incubated for 48 hours. After culturing for 48 hours, 20 μl of a 5 mg / ml (3, [4,5-dimethylthiazol-2-yl] -2,5-diphenyltetrazole bromide, MTT) solution was added per well and cultured in an incubator for 3-4 hours. did. Further, 100 μl of the lysate per well was added to completely solubilize the produced formazan crystals. Then, the absorbance at 492 nm was measured to calculate IC 50 .
〔毒性試験〕
実施例及び比較例で得られたホスフィン遷移金属錯体を、マウスに静脈注射したときの毒性試験を行った。具体的には、KMマウスの雄雌を約1週間検疫・馴化飼育した後、選ばれたラット雄雌各10匹計20匹を一群とした。投与前一晩絶食させた体重を記録したラットに、溶媒としてコーンオイルを用い、実施例及び比較例で得られたホスフィン遷移金属錯体を、LD50を決定するために十分な死亡例が出る群が含まれるように設定して単回静脈注射した。投与後、10、30分、1、2、4時間及び以後毎日、14日目まで観察しラットの生存率から50%致死量(LD50)を求めた。[Toxicity test]
Toxicity tests were conducted when the phosphine transition metal complexes obtained in Examples and Comparative Examples were intravenously injected into mice. Specifically, after male and female KM mice were quarantined and acclimatized for about 1 week, 10 rats and 10 female rats were selected to make a group. Groups in which the body weight that was fasted overnight before administration was recorded in corn oil as a solvent, and the phosphine transition metal complexes obtained in Examples and Comparative Examples had enough deaths to determine LD 50 Was set up to include a single intravenous injection. After administration, it was observed for 10, 30 minutes, 1, 2, 4 hours and every day thereafter until the 14th day, and the 50% lethal dose (LD 50 ) was determined from the survival rate of the rats.
表1に示す結果から、本発明のホスフィン遷移金属錯体を含む抗がん剤は、従来よりも抗がん活性が高く、かつ毒性の低いものであることが判る。 From the results shown in Table 1, it can be seen that the anticancer agent containing the phosphine transition metal complex of the present invention has higher anticancer activity and lower toxicity than before.
Claims (1)
以下の式(4)で表される水素−ホスフィンボラン化合物と、
工程Iで得られた式(6')で表されるホスフィンボラン化合物を分解反応に付して、
以下の式(4')で表される光学活性な水素−ホスフィンボラン化合物を得る。
工程IIで得られた式(4')で表される光学活性な水素−ホスフィンボラン化合物と、以下の式(7)で表される2,3−ジハロゲノピラジンとを反応させて、
工程IIIで得られた式(3)で表される(S,S)−2,3−ビスホスフィノピラジン誘導体と、金、銅又は銀の塩とを反応させて前記の式(1)で表されるホスフィン遷移金属錯体を得る。 The manufacturing method of the anticancer agent containing the phosphine transition metal complex represented by the following formula | equation (1) characterized by having the following processes I thru | or IV.
A hydrogen-phosphine borane compound represented by the following formula (4):
The phosphine borane compound represented by the formula (6 ′) obtained in step I is subjected to a decomposition reaction,
An optically active hydrogen-phosphine borane compound represented by the following formula (4 ′) is obtained.
An optically active hydrogen-phosphine borane compound represented by the formula (4 ′) obtained in Step II is reacted with 2,3-dihalogenopyrazine represented by the following formula (7):
In the above formula (1), the (S, S) -2,3-bisphosphinopyrazine derivative represented by the formula (3) obtained in Step III is reacted with a gold, copper or silver salt. The phosphine transition metal complex represented is obtained.
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Free format text: JAPANESE INTERMEDIATE CODE: R250 |
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R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
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