WO2011078121A1 - Anti-cancer agent - Google Patents
Anti-cancer agent Download PDFInfo
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- WO2011078121A1 WO2011078121A1 PCT/JP2010/072901 JP2010072901W WO2011078121A1 WO 2011078121 A1 WO2011078121 A1 WO 2011078121A1 JP 2010072901 W JP2010072901 W JP 2010072901W WO 2011078121 A1 WO2011078121 A1 WO 2011078121A1
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- transition metal
- cancer
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- 0 Cc(nc1P(*)I)c(*)nc1P(*)* Chemical compound Cc(nc1P(*)I)c(*)nc1P(*)* 0.000 description 1
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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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/34—Copper; Compounds thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/38—Silver; Compounds thereof
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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
Definitions
- the present invention relates to an anticancer agent containing a phosphine transition metal complex.
- 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).
- 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.
- Patent Document 1 describes that the types of these isomers are not particularly limited, and the stereo on the phosphorus atom is, for example, (R, R) (R, R) or (S, S) (S, It may be composed of a single enantiomer, such as (S), or may be composed of a racemate of a ligand, such as (R, R) (S, S), and (R). , 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.
- Taxol registered trademark
- anticancer activity and anticancer spectrum of a compound depend on the chemical structure of the compound, and the effect varies depending on the individual.
- Taxol registered trademark
- its effectiveness is about 30%. Therefore, development of various new anticancer agents having different chemical structures is desired.
- low toxicity is a characteristic required for anticancer agents.
- the subject of the present invention is to improve the above-mentioned anticancer agent proposed by the present applicant.
- the present invention provides an anticancer agent comprising at least one phosphine transition metal complex selected from the group of compounds represented by formulas (1a) to (1c). .
- the present invention also provides an anticancer agent comprising a phosphine transition metal complex represented by the formula (2).
- an anticancer agent having an anticancer activity equivalent to that of the prior art and having low toxicity is provided.
- the anticancer agent of the present invention contains at least one phosphine transition metal complex selected from the group of compounds represented by the above formulas (1a) to (1c).
- This phosphine transition metal complex has a structure in which two ligands made of a 2,3-bisphosphinopyrazine derivative are coordinated with a central metal ion M.
- R 1 and R 2 are different groups, so that two phosphorus atoms become chiral centers.
- this 2,3-bisphosphinopyrazine derivative has three types of isomers, (R, R), (S, S) and (R, S), which have different steric configurations.
- the compounds represented by the formulas (1a) to (1c) are isomers having different steric configurations.
- the phosphine transition metal complex represented by (1 ′) including the formulas (1a) to (1c) contains many isomers having different configurations.
- an anticancer equivalent to the anticancer agent described in Patent Document 1 is used. It has been found that an anticancer agent having activity and low toxicity can be obtained.
- the compounds represented by the above formulas (1a) to (1c) may be used alone or in combination of two or more.
- the compounds represented by the formulas (1a) to (1c) can be used in combination of two or more, rather than using them alone, to further reduce the toxicity. From this point, it turned out to be advantageous. In particular, it has been found that using all the compounds represented by formulas (1a) to (1c) in combination significantly reduces toxicity while maintaining high anticancer activity.
- the compounding ratio (molar ratio) of the two compounds is 25/75 to 75 / 25, particularly 40/60 to 60/40. Toxicity can be further reduced by using a combination of two compounds within this molar ratio.
- the mixing ratio (molar ratio) among these three components is not particularly critical.
- (1a) :( 1b) :( 1c) 10 to 40:20 to 80:10 to 40, particularly 20 to 30:40 to 60:20 to 30.
- Toxicity can be further reduced by using a combination of three compounds within this molar ratio.
- the current HPLC technique cannot separate the compounds represented by the formulas (1a) to (1c), but according to the production method described later, the product contains the compounds represented by the formulas (1a) to (1a) to (1a) to (1c). It is considered that the compound represented by the formula (1c) is contained in the above molar ratio.
- a phosphine transition metal complex represented by the above formula (2) may be contained instead of the compounds represented by the above formulas (1a) to (1c). .
- the compound represented by the formula (2) also has an anticancer activity equivalent to that of the anticancer agent described in Patent Document 1, like the compounds represented by the formulas (1a) to (1c). , Low toxicity.
- the compounds represented by the above formulas (1a) to (1c) and the compound represented by the above formula (2) may be used in combination.
- the compounding ratio (molar ratio) between the total amount of the compounds represented by the formulas (1a) to (1c) and the compound represented by the formula (2) is effective even if the ratio is arbitrary. Therefore, the mixing ratio of the former / the latter may be arbitrary, and the ratio of 20/80 to 70/30 is particularly preferable because the synergistic effect becomes high.
- the compounds represented by the formulas (1a) to (1c) only one of them may be used, or any two may be used in combination. Furthermore, you may use combining all 3 types, Formula (1a), Formula (1b), and Formula (1c).
- R 1 and R 2 are each 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 is shown.
- R 1 and R 2 have 1 to 10 carbon atoms.
- R 1 and R 2 are groups different from each other.
- R 1 and R 2 in ranking according to the RS method, R 1 is priority than R 2 is a high group.
- 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 -Heptyl group, isohexyl group, n-hexyl group.
- Examples of the cycloalkyl group related to R 1 and R 2 include a cyclopentyl group and a cyclohexyl group.
- R 1 and R 2 are a cycloalkyl group having a substituent or a phenyl group having a substituent
- substituents 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.
- R 1 is a tert-butyl group or an adamantyl group and R 2 is a methyl group from the viewpoint of increasing anticancer activity.
- R 3 and R 4 represent a hydrogen atom or a linear or branched alkyl group.
- the alkyl group of R 3 and R 4 has 1 to 6 carbon atoms.
- R 3 and R 4 may be the same group or different groups.
- the saturated or unsaturated ring may have a substituent.
- alkyl group related to R 3 and R 4 examples 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.
- examples of the ring include a saturated or unsaturated 5-membered ring or 6-membered ring.
- 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.
- R 3 and R 4 are preferably bonded to each other to form a benzene ring from the viewpoint of high anticancer activity.
- the ligand coordinated to the metal M is a quinoxaline derivative.
- the benzene ring in the quinoxaline derivative at least one of the four hydrogen atoms may be substituted with the above-described substituent.
- M represents a monovalent transition metal atom selected from the group consisting of gold, copper and silver.
- M is a gold atom from the viewpoint of high anticancer activity.
- X ⁇ represents an anion, and examples thereof include chlorine ion, bromine ion, iodine ion, boron tetrafluoride ion, hexafluorophosphate ion, and perchlorate ion.
- X ⁇ is preferably a chlorine ion, a bromine ion, or an iodine ion from the viewpoint of high anticancer activity.
- This phosphine transition metal complex can be obtained by reacting a 2,3-bisphosphinopyrazine derivative represented by the formula (3) with a salt of gold, copper or silver.
- the 2,3-bisphosphinopyrazine derivative represented by the formula (3) includes, for example, as shown in the reaction formula (9), 2,3-dichloropyrazine (6) and phosphine-borane (7). Reaction is carried out to obtain bis (phosphine-borane) pyrazine (8), and then the resulting bis (phosphine-borane) pyrazine (8) is subjected to a deboraneation reaction.
- reaction formula (9) the reaction between 2,3-dichloropyrazine (6) and phosphine-borane (7) is carried out, for example, in the presence of a base such as n-butyllithium in an inert solvent such as tetrahydrofuran.
- the reaction is carried out at ⁇ 78 to 30 ° C. for 1 to 24 hours.
- 2,3-dichloropyrazine (6) and phosphine-borane (7) are produced by known methods.
- 2,3-dichloropyrazine (6) is commercially available.
- the phosphine-borane (7) can be obtained by using the method described in, for example, JP-A No. 2003-300908, JP-A No. 2001-253889, J. Org. Chem. 2000, vol. 65, P4185-4188, etc. Manufactured.
- the deboraneation reaction of bis (phosphine-borane) pyrazine (8) is carried out by adding N, N, N ′, N ′,-tetramethylethylenediamine (TMEDA) to a reaction system containing bis (phosphine-borane) pyrazine (8). And the like, and a reaction is carried out at 0 to 100 ° C. for 10 minutes to 3 hours.
- TEDA trimethylethylenediamine
- this 2,3-bisphosphinopyrazine derivative represented by the formula (3), two phosphorus atoms become chiral centers because R 1 and R 2 are different groups.
- this 2,3-bisphosphinopyrazine derivative has three types of isomers, (R, R), (S, S) and (R, S), which have different steric configurations.
- the (R, S) isomer is a meso isomer, and an equimolar mixture of (R, R) isomer and (S, S) isomer is a racemate.
- a 2,3-bisphosphinopyrazine derivative by using an (R, S) isomer, that is, a meso isomer, a phosphine transition metal composed of three compounds represented by the formulas (1a) to (1c) A complex is obtained.
- the phosphine transition metal complex which consists of a compound represented by Formula (2) is obtained by using the racemic body of a (R, R) body and a (S, S) body.
- (R, S) 2,3-bisphosphinopyrazine derivative can be obtained by the following method. That is, in the above reaction formula (9), a racemate of R and S forms is used as phosphine-borane (7).
- the resulting 2,3-bisphosphinopyrazine derivative is a mixture of a meso form (ie, (R, S) form) and a racemic form (ie, (R, R) form and (S, S) form). Become. By separating this mixture by chromatography, a meso form (that is, (R, S) form) and a racemic form (that is, (R, R) form and (S, S) form) are separated, and (R, S) The body can be isolated. Racemic, that is, (R, R) and (S, S) isomers are not separated.
- the (R, R) isomer of 2,3-bisphosphinopyrazine derivative can be obtained, for example, according to the method described in Example 1 of Japanese Patent Application Laid-Open No. 2007-56007 related to the previous application of the present applicant.
- Gold, copper or silver salts that react with the 2,3-bisphosphinopyrazine derivative represented by the formula (3) include, for example, halides, nitrates, perchlorates, and tetrafluoroboric acids of these metals. Salts, hexafluorophosphate 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.
- Preferred gold transition metal salts include, for example, gold chloride (I) acid, gold chloride (I), tetrabutylammonium chloride / gold chloride (I), etc. ("5th edition, Experimental Chemistry Course 21", editors) The Chemical Society of Japan, publisher Maruzen, issue date March 30, 2004, p. 366-380, see 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. (“5th edition, Experimental Chemistry Course 21", edited by The Chemical Society of Japan, published by the Chemical Society of Japan) 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, pages 361-366).
- 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.
- the molar ratio of the 2,3-bisphosphinopyrazine derivative represented by the formula (3) to the gold, copper or silver salt is preferably 1 to 5 times mol, more preferably 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.
- the reaction time is preferably 0.5 to 48 hours, more preferably 1 to 3 hours.
- the anions in the phosphine transition metal complexes represented by the formulas (1a) to (1c) or (2) thus obtained may be converted into other desired anions.
- a phosphine transition metal complex in which X ⁇ in formula (1a) to formula (1c) or formula (2) is a halide ion is synthesized according to the above production method, and then this phosphine transition metal complex is synthesized.
- an inorganic acid, organic acid or alkali metal salt thereof having a desired anion in an appropriate solvent a phosphine transition metal complex in which X ⁇ is a desired anion can be obtained. Details of such a method are described in, for example, JP-A-10-147590, JP-A-10-114782, and JP-A-61-15944.
- 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.
- 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.
- the anticancer agent of the present invention can be used to suppress cancer metastasis, and is particularly useful as a postoperative cancer
- the anticancer agent of the present invention can be used in combination with a cyclodextrin compound in order to improve solubility.
- a cyclodextrin compound examples include ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, methyl- ⁇ -cyclodextrin, dimethyl- ⁇ -cyclodextrin, trimethyl- ⁇ -cyclodextrin, and 2-hydroxypropyl- ⁇ .
- -Cyclodextrin 2-hydroxypropyl- ⁇ -cyclodextrin, dihydroxypropyl- ⁇ -cyclodextrin, hydroxyethyl- ⁇ -cyclodextrin, carboxymethyl- ⁇ -cyclodextrin, monoacetyl- ⁇ -cyclodextrin, 2-hydroxypropyl - ⁇ -cyclodextrin, glucosyl- ⁇ -cyclodextrin, maltosyl- ⁇ -cyclodextrin, maltosyl- ⁇ -cyclodextrin, partial methyl- ⁇ -cyclodextri , ⁇ -cyclodextrin sulfate, ⁇ -cyclodextrin sulfate and the like.
- 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.
- 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.
- 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.
- preferred administration forms, preparation forms, and the like are appropriately selected by a doctor according to the age, sex, constitution, symptoms, treatment timing, etc. of the patient.
- 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 are represented by formula (1a) to formula (1c) or formula (2).
- the phosphine transition metal complex is converted into a suitable additive according to a conventional method, for example, lactose, sucrose, D-mannitol, corn starch, synthetic or natural gum, excipient such as crystalline cellulose, starch, hydroxypropylcellulose, hydroxypropylmethylcellulose , Binders such as gum arabic, gelatin, polyvinyl pyrrolidone, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, starch, corn starch, disintegrating agents such as sodium alginate, lubricants such as talc, magnesium stearate, sodium stearate, calcium carbonate, Sodium carbonate, phosphorus Calcium, is prepared by mixing as appropriate with such fillers or diluents sodium phosphate. Tablets and the like may
- 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 formula (1a) to formula (1c) or formula (2), purified water, a suitable buffer solution such as phosphate buffer, physiological saline, Ringer's solution, lock solution
- a suitable buffer solution such as phosphate buffer, physiological saline, Ringer's solution
- lock solution such as cocoa butter, cocoa butter, sesame oil, olive oil and other vegetable oils, mineral oil, higher alcohols, higher fatty acids, ethanol and other organic solvents, etc.
- the injection preferably has a physiological pH, and particularly preferably has a pH within the range of 6-8.
- 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 general formula (1) as a fat or fatty oil.
- a phosphine transition metal complex represented by the general formula (1) as a fat or fatty oil.
- the content of the phosphine transition metal complex represented by the formula (1a) to the formula (1c) or the formula (2) in the anticancer agent of the present invention depends on the dosage form, the severity, the intended dose, etc.
- the ratio of the total amount of the phosphine transition metal complex represented by the formula (1a) to the formula (1c) or the formula (2) to the total mass of the anticancer agent is preferably 0. 0.001 to 80% by mass, more preferably 0.1 to 50% by mass.
- 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 ⁇ g / kg to 1,000 mg / kg, preferably in the range of about 10 ⁇ g / kg to 10 mg / kg.
- the anticancer agent can be administered once a day, or can be administered in several divided doses (for example, about 2 to 4 times).
- the anticancer agent of the present invention can be combined with known chemotherapy, surgical treatment, radiation therapy, hyperthermia, immunotherapy and the like.
- Example 1 (1) ⁇ Synthesis of racemic meso-mixed-2,3-bis (tert-butylmethylphosphino) quinoxaline> To a 1 L four-necked flask that had been sufficiently removed of water and replaced with nitrogen gas, 84.2 g (750 mmol) of potassium tert-butoxide and 375 ml of dehydrated THF were added. This was cooled to 0 ° C. in an ice bath, and 177.0 g (900 mmol) of a 60% THF solution of racemic tert-butylmethylphosphine borane was added dropwise and stirred for 30 minutes.
- Example 2 (1) Racemic of ⁇ (R, R) -2,3-bis (tert-butylmethylphosphino) quinoxaline and (S, S) -2,3-bis (tert-butylmethylphosphino) quinoxaline Synthesis> In (1) of Example 1, (R, R) -2,3-bis (tert-butylmethylphosphino) quinoxaline and (S, S) -2,3 were separated by a step of separating the meso form and the racemic form. A racemate with -bis (tert-butylmethylphosphino) quinoxaline was obtained.
- the in vitro antitumor activity test was done about the phosphine transition metal complex obtained by the Example and the comparative example. Specifically, using KB (oral squamous cell carcinoma) and A375 (malignant melanoma) as cancer cells, 10% inactivated neonatal calf serum, L-glutamine, sodium pyruvate, 1 ⁇ 10 5 U / L The cells were cultured at 37 ° C. in an incubator in a medium supplemented with penicillin and 100 mg / L streptomycin (RPMI-1640 or DEME). 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.
- KB oral squamous cell carcinoma
- A375 malignant melanoma
- the anticancer agent containing the phosphine transition metal complex of the present invention has low antitoxicity while having anticancer activity equivalent to the conventional one.
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Abstract
Description
(1)<ラセミメソ混合-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>
水分を充分に除去し窒素ガスで置換した1L四ツ口フラスコに、カリウム-tert-ブトキシド84.2g(750mmol)、脱水THF375mlを加えた。これを氷浴で0℃に冷却し、ラセミ-tert-ブチルメチルホスフィンボランのTHF60%溶液177.0g(900mmol)を滴下して30分撹拌した。水分を充分に除去し窒素ガスで置換した別の3L四ツ口フラスコに、2,3-ジクロロキノキサリン59.7g(300mmol)、脱水THF300mlと脱水DMF75mlの混合溶液を加え-10℃にした。ここに、最初に合成したホスフィンボラン溶液を滴下して1時間攪拌した。続いてテトラメチルエチレンジアミン139.4g(1200mmol)を加えて室温に戻し3時間攪拌した。10%塩酸600gを滴下してクエンチして分液し、続いて5%塩酸150g、更に2.5%重曹水300gで洗浄した。更に、ヘキサン200mlを加えて純水150mlで洗浄した。得られた有機層を乾固させた後、40℃でメタノール300mlを加え1時間攪拌し、発生した固体をろ過することで、橙色固体の2,3-ビス(tert-ブチルメチルホスフィノ)キノキサリン69.9gを得た(収率69.7%)。同定データは次のとおりである。
・31P-NMR(CDCl3);ラセミ体:-18.1、メソ体:-15.4
・HPLC(カラム Cosmosil 5C18-MS-II 4.6×250mm、移動層 メタノール、流速0.5ml/min、温度30℃、UV 254nm、溶離時間ラセミ体15分、メソ体17分)ラセミ体:メソ体のモル比=52:48 [Example 1]
(1) <Synthesis of racemic meso-mixed-2,3-bis (tert-butylmethylphosphino) quinoxaline>
To a 1 L four-necked flask that had been sufficiently removed of water and replaced with nitrogen gas, 84.2 g (750 mmol) of potassium tert-butoxide and 375 ml of dehydrated THF were added. This was cooled to 0 ° C. in an ice bath, and 177.0 g (900 mmol) of a 60% THF solution of racemic tert-butylmethylphosphine borane was added dropwise and stirred for 30 minutes. To another 3 L four-necked flask after sufficiently removing water and replacing with nitrogen gas, 59.7 g (300 mmol) of 2,3-dichloroquinoxaline, 300 ml of dehydrated THF and 75 ml of dehydrated DMF were added to reach −10 ° C. The synthesize | combined phosphine borane solution was dripped here and it stirred for 1 hour. Subsequently, 139.4 g (1200 mmol) of tetramethylethylenediamine was added and the mixture was returned to room temperature and stirred for 3 hours. 600 g of 10% hydrochloric acid was added dropwise for quenching and liquid separation, followed by washing with 150 g of 5% hydrochloric acid and 300 g of 2.5% aqueous sodium bicarbonate. Furthermore, 200 ml of hexane was added and washed with 150 ml of pure water. After the obtained organic layer was dried, 300 ml of methanol was added at 40 ° C. and stirred for 1 hour, and the generated solid was filtered to obtain an orange solid 2,3-bis (tert-butylmethylphosphino) quinoxaline. 69.9 g was obtained (yield 69.7%). The identification data is as follows.
31 P-NMR (CDCl 3 ); racemate: −18.1, meso form: −15.4
HPLC (column Cosmosil 5C18-MS-II 4.6 × 250 mm, moving bed methanol, flow rate 0.5 ml / min, temperature 30 ° C., UV 254 nm, elution time racemate 15 minutes, meso form 17 minutes) racemate: meso Body molar ratio = 52: 48
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(R,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、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6.60g(収率89.2%)を得た。この化合物は、式(1a)、式(1b)及び式(1c)で表される化合物の混合物から構成されていた。
・31P-NMR(CDCl3);8.5-9.6(m)、11.6-12.6(m) (2) <Synthesis of bis (2,3-bis (tert-butylmethylphosphino) quinoxaline) gold (I) chloride>
To a 500 ml two-necked flask purged with nitrogen gas, 5.50 g (16.4 mmol) of (R, S) -2,3-bis (tert-butylmethylphosphino) quinoxaline obtained by the above method was added to 220 ml of general THF. Dissolved in. 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 6.60 g of bis (2,3-bis (tert-butylmethylphosphino) quinoxaline) gold (I) chloride. (Yield 89.2%) was obtained. This compound was comprised from the mixture of the compound represented by Formula (1a), Formula (1b), and Formula (1c).
31 P-NMR (CDCl 3 ); 8.5-9.6 (m), 11.6-12.6 (m)
(1)<(R,R)-2,3-ビス(tert-ブチルメチルホスフィノ)キノキサリンと(S,S)-2,3-ビス(tert-ブチルメチルホスフィノ)キノキサリンとのラセミ体の合成>
実施例1の(1)において、メソ体とラセミ体との分離工程によって、(R,R)-2,3-ビス(tert-ブチルメチルホスフィノ)キノキサリンと(S,S)-2,3-ビス(tert-ブチルメチルホスフィノ)キノキサリンとのラセミ体を得た。 [Example 2]
(1) Racemic of <(R, R) -2,3-bis (tert-butylmethylphosphino) quinoxaline and (S, S) -2,3-bis (tert-butylmethylphosphino) quinoxaline Synthesis>
In (1) of Example 1, (R, R) -2,3-bis (tert-butylmethylphosphino) quinoxaline and (S, S) -2,3 were separated by a step of separating the meso form and the racemic form. A racemate with -bis (tert-butylmethylphosphino) quinoxaline was obtained.
(R,R)-2,3-ビス(tert-ブチルメチルホスフィノ)キノキサリンと(S,S)-2,3-ビス(tert-ブチルメチルホスフィノ)キノキサリンとのラセミ体を用いる以外は、実施例1の(2)の工程と同様にして、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(2)で表される化合物から構成されていた。
・31P-NMR(CDCl3);10.2 (2) <Synthesis of bis (2,3-bis (tert-butylmethylphosphino) quinoxaline) gold (I) chloride>
Except for using a racemate of (R, R) -2,3-bis (tert-butylmethylphosphino) quinoxaline and (S, S) -2,3-bis (tert-butylmethylphosphino) quinoxaline, Bis (2,3-bis (tert-butylmethylphosphino) quinoxaline) gold (I) chloride was obtained in the same manner as in the step (2) of Example 1. This compound was comprised from the compound represented by Formula (2).
31 P-NMR (CDCl 3 ); 10.2
(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 according to the description of Example 1 in Japanese Patent Application Laid-Open No. 2007-56007 related to the applicant's previous application.
(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(2)の工程と同様にして、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’)で表される化合物から構成されていた。
・31P-NMR(CDCl3);13.6
・[α]D=+195.3(c=0.5、メタノール、25℃) (2) <Synthesis of bis (2,3-bis (tert-butylmethylphosphino) quinoxaline) gold (I) chloride>
Except for the use of (R, R) -2,3-bis (tert-butylmethylphosphino) quinoxaline, bis (2,3-bis (tert-butyl) was obtained in the same manner as in step (2) of Example 1. Methylphosphino) quinoxaline) gold (I) chloride was obtained. This compound was composed of a compound represented by the formula (1a ′).
31 P-NMR (CDCl 3 ); 13.6
[Α] D = +195.3 (c = 0.5, methanol, 25 ° C.)
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、マウスに経口投与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経口投与した。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。この結果を以下の表1に示す。 [Evaluation]
Toxicity tests were conducted when the phosphine transition metal complexes obtained in Examples and Comparative Examples were orally administered to 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 fasted overnight prior to administration recorded corn oil as a solvent, and the phosphine transition metal complexes obtained in Examples and Comparative Examples had enough deaths to determine LD 50 A single oral dose was set up to be included. 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. The results are shown in Table 1 below.
Claims (3)
- 式(1a)~式(1c)で表される化合物の群から選択される少なくとも1種のホスフィン遷移金属錯体及び式(2)で表されるホスフィン遷移金属錯体を含有することを特徴とする抗がん剤。
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US11773120B2 (en) | 2017-07-11 | 2023-10-03 | Nippon Chemical Industrial Co., Ltd. | Method for producing optically active 2, 3-bisphosphinopyrazine derivative and method for producing optically active phosphine transition metal complex |
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