CN101092417B - Folacin analogue, and salt of folacin analogue in use for medical treatment - Google Patents

Folacin analogue, and salt of folacin analogue in use for medical treatment Download PDF

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CN101092417B
CN101092417B CN2006100278440A CN200610027844A CN101092417B CN 101092417 B CN101092417 B CN 101092417B CN 2006100278440 A CN2006100278440 A CN 2006100278440A CN 200610027844 A CN200610027844 A CN 200610027844A CN 101092417 B CN101092417 B CN 101092417B
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salt
folacin
amino
medical treatment
compound
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CN101092417A (en
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毛振民
刘增路
朱高军
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SHANGHAI JINSE MEDICAL TECHNOLOGY DEVELOPMENT Co Ltd
Shanghai Jiaotong University
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SHANGHAI JINSE MEDICAL TECHNOLOGY DEVELOPMENT Co Ltd
Shanghai Jiaotong University
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Abstract

This invention discloses folic acid analogues as shown in general chemical formula (I), and their salts used in therapy. In general chemical formula (I), R is OH, Cl, NH2, OCH3 or OCH2CH3. This invention also discloses the application of the folic acid analogues and their salts in drugs for treating cancers. The folic acid analogues and their salts have strong inhibitive activity on the growth of multiple cancer cells.

Description

A kind of folacin and be used for the salt of folacin of medical treatment
Technical field:
The present invention relates to chemical field, relate in particular to medicine, particularly a kind of folacin and be used for the salt of folacin of medical treatment.
Background technology:
Reduced form folic acid (FH 4) be that biosynthesizing of purine class and deoxyuridylic acid (dUMP) change into essential one carbon unit transporter in thymidylic acid (dTMP) process.In these biochemical reactions, reduced form folic acid is oxidized, is regenerated as active reduced form folic acid through Tetrahydrofolate dehydrogenase (DHFR).
Methotrexate (MTX) and similar compound are known consumingly in conjunction with the medicine of DHFR, these medicines can suppress dihydrofolate reduction and become tetrahydrofolic acid (THFA), cause dTMP and/or purine class defective, and DNA is synthetic to interrupt, and then the generation cytotoxicity, cause necrocytosis.These medicines have been developed into cancer therapy drug, and have occupied very important position as clinical medicine at present.Pemetrexed (MTA) is the antifolic thing of many target spots of researching and developing recently, comprise DHFR thymidylate synthase (TS) by suppressing at least 3 kinds of enzymes synthetic relevant with folic acid metabolism, purine and pyrimidine, phosphoribosyl glycinamide formyl transferase (GARFT) has antitumous effect to multiple solid tumor.
Developed a plurality of cancer therapy drugs cooperatively by the E.C.Taylor of Princeton university professor research group and gift Lay (Eli Lily) company, it has the basic framework of pteridine ring Lometrexol (DDATHF).But its mechanism of action is different with the medicine of this class formation, Tetrahydrofolate dehydrogenase (DHFR) is not suppressed active, and mainly be to finish (medical chemistry magazine 28,9149 (1985)) by the mechanism that in the initial step of purine biosynthetic pathway, suppresses phosphoribosyl glycinamide formyl transferase (GARFT).
MTX is mainly anticancer by the folic acid antagonist effect, and stronger toxicity is arranged, and is little to the solid tumor effect, also exists the resistance of tumour cell to this medicine, therefore can not obtain satisfactory therapeutic effects.Therefore the mechanism of action that special expectation exploitation makes new advances demonstrates the cancer therapy drug of selective toxicity to cancer cells.
Summary of the invention:
The object of the present invention is to provide a kind of folacin and be used for the salt of folacin of medical treatment, described this folacin and the salt that is used for the folacin of medical treatment will solve the prior art cancer therapy drug strong toxicity,, technical problem that tumour cell to cancer therapy drug develop immunity to drugs limited to the solid tumor effect.
This folacin of the present invention and the salt of folacin that is used for medical treatment are following general formulas
(I) Biao Shi compound,
Figure S06127844020060705D000021
General formula (I)
Wherein R=OH or NH 2, or OCH 3
When R=OH, that is: N-{4-[2-(2-amino-4-methoxyl group-5,6,7,8-tetrahydrochysene-9H-Mi Dingbing [4,5-b] [1,4] phenodiazine Zhuo-6-yl)]-ethyl-benzoyl }-L-L-glutamic acid.
Work as R=NH 2The time, that is: N-{4-[2 (2-amino-4-hydroxy-5,6,7,8-tetrahydrochysene-9H-Mi Dingbing [4,5-b] [1,4] phenodiazine Zhuo-6-yl)]-ethyl-benzoyl }-L-L-glutamic acid.
Work as R=OCH 3The time, that is: N-{4-[2-(2,4-diamino-5,6,7,8-tetrahydrochysene-9H-Mi Dingbing [4,5-b] [1,4] phenodiazine Zhuo-6-yl)]-ethyl-benzoyl }-L-L-glutamic acid.
Further, R can also be or Cl or OCH 2CH 3
Further, described salt is sodium salt or sylvite or other metal cation salts that is suitable for or ammonium salt or diethyl amine salt or ethylenediamine salt or other organic amine salts that is suitable for.
The present invention also provides above-mentioned folacin and has been used for the application of the salt of medical folacin at the medicine of preparation treatment cancer.
The present invention also provides a kind of intermediate for preparing above-mentioned folacin and be used for the salt of medical folacin, and described intermediate is the compound of the following general formula of tool (II) expression,
Figure S06127844020060705D000031
General formula (II)
Wherein R=OH or Cl or NH 2, or OCH 3, or OCH 2CH 3R ' is lower alkoxy or benzyloxy or glutamate.
Further, lower alkoxy is selected from methoxyl group or oxyethyl group.
Further, glutamate is selected from dimethyl ester or diethyl ester.
The present invention also provides a kind of intermediate for preparing above-mentioned folacin and be used for the salt of medical folacin, and described intermediate is the compound of general formula (III) expression,
Figure S06127844020060705D000041
Logical formula III
Wherein R=OH or Cl or NH 2, or OCH 3, or OCH 2CH 3R ' is lower alkoxy or benzyloxy or glutamate.
Further, lower alkoxy is selected from methoxyl group or oxyethyl group.
Further, glutamate is selected from dimethyl ester or diethyl ester.
The present invention building-up process can make earlier intermediate III (R '=OCH 3, OC 2H 5, etc.) react (route A) with glutamate again, also can introduce glutamate earlier, introduce azo structure again, ring (route B) is closed in reduction then.
With R=OCH 3Be example, but be not limited only to this functional group.
Synthetic route A: with divinyl and Nitromethane 99Min. react 5-vinyl-4,5-dihydro-oxazole, reduce again 3-hydroxyl-4-alkene-amylamine, the amine of gained and 2-amino-4,6-two chloro-pyrimidines react 2-amino-6-(3-hydroxyl-4-alkene-1-yl)-amino-4-chloro-pyrimidine, replaced by methoxyl group with chlorine after the sodium methylate effect, products therefrom and 4-Iodobenzoic acid methyl esters carry out Heck react 4-[5-(2-amino-4-methoxyl group-pyrimidine-6-amino)-3-oxo-amyl group]-methyl benzoate, reaction generates red-brown solid 4-{5-[2-amino-4-methoxyl group-5-(4-chlorobenzene azo-group)-6-pyrimidine then and to the chlorobenzene diazonium salt]-amino-3-oxo-amyl group }-methyl benzoate, this compound in acetic acid, reduce close encircle key intermediate 4-[2-(2-amino-4-methoxyl group-5,6,7,8-tetrahydrochysene-9H-Mi Dingbing [4,5-b] [1,4] phenodiazine Zhuo-6-yl)-ethyl]-methyl benzoate.This intermediate is through hydrolysis; then with glutamate react N-{4-[2-(2-amino-4-methoxyl group-5; 6; 7,8-tetrahydrochysene-9H-Mi Dingbing [4,5-b] [1; 4] phenodiazine Zhuo-6-yl)]-ethyl-benzoyl }-L-glutamate diethyl ester (7); compound (7) be hydrolyzed again N-{4-[2-(2-amino-4-methoxyl group-5,6,7; 8-tetrahydrochysene-9H-Mi Dingbing [4; 5-b] [1,4] phenodiazine Zhuo-6-yl)]-ethyl-benzoyl }-L-L-glutamic acid (8), compound (8) gets N-{4-[2-(2 with ammonia treatment; 4-diamino-5; 6,7,8-tetrahydrochysene-9H-Mi Dingbing [4; 5-b] [1; 4] phenodiazine Zhuo-6-yl)]-ethyl-benzoyl-L-L-glutamic acid, compound (7) with trimethylammonium iodate silicon handle N-{4-[2-(2-amino-4-hydroxy-5,6; 7; 8-tetrahydrochysene-9H-Mi Dingbing [4,5-b] [1,4] phenodiazine Zhuo-6-yl)]-ethyl-benzoyl }-L-L-glutamic acid (9).
Synthetic route B: with N-(4-phenyl-iodide formyl)-glutamate diethyl ester and 2-amino-4-methoxyl group-6-(3-hydroxyl-4-alkene-1-penta amino)-pyrimidine (2) carry out Heck react N-{4-[5-(2-amino-4-methoxyl group-pyrimidine-6-yl)-amino-3-oxo-amyl group]-benzoyl-L-L-glutamic acid (10); compound (10) with to the chlorobenzene diazonium salt react N-{4-[5-(2-amino-4-methoxyl group-5-(4-chlorobenzene azo-group)-pyrimidine-6-yl)-amino-3-oxo-amyl group]-benzoyl-L-glutamate diethyl ester (11); then reduction close encircle compound (7), consistent with synthetic route A gained compound.
Though a large amount of unsymmetrical carbons is present in compound of the present invention and the intermediate thereof, unsymmetrical carbon has the absolute configuration of S (L) in the side chain of L-glutamic acid, and the absolute configuration of other asymmetric center can be the miscellany of S or R.In this case, there is diastereomer, and can separates by routine when needing and separate it with means of purification.
Figure S06127844020060705D000061
Figure S06127844020060705D000071
The present invention compares with prior art, and its technical progress is conspicuous.Folacin of the present invention or its salt can have powerful inhibition growth activity to a plurality of tumour cells.
Embodiment:
Method A:
Embodiment 1
Synthesizing of 4-chloro-2-amino-6-(3-hydroxyl-4-thiazolinyl-1-penta amino)-pyrimidine (1)
50mmol 4, and 6-two chloro-2-amino-pyrimidines and 5mmol～60mmol 3-hydroxyl-4-alkene-1-amylamine is dissolved in and adds 51mmol triethylamine, N in the 200ml ethanol 2Protection is backflow 4h down.Remove and desolvate, residual solids adds CH 2Cl 2Dissolution with solvents removes by filter insolubles, and filtrate concentrates, the residue silica gel column chromatography.Eluent MeOH/CH 2Cl 2=2/98.Get product 8.31g, yield 73%.
1H?NMR(CDCl 3)δ：1.65～1.85(2H，dm)，3.30-3.63(m，2H)，4.2(1H，dm)，4.97(2H，sb)，5.03(1H，d)，5.27(1H，d)，5.80(1H，s)，5.91(1H，m)。
Embodiment 2
Synthesizing of 2-amino-4-methoxyl group-6-(3-hydroxyl-4-thiazolinyl-1-penta amino)-pyrimidine (2)
In 100ml methyl alcohol, add 6.48g (120mmol) sodium methylate and 5g (22mmol) 4-chloro-2-amino-6-(3-hydroxyl-4-thiazolinyl-1-penta amino)-pyrimidine, N 2Protection is backflow 48h down, and most of solvent is removed in decompression, adds the saturated NH of 100ml 4The Cl aqueous solution is used CH 2Cl 2Extraction (100mlx3), the organic layer anhydrous Na 2SO 4Dry.Concentrate faint yellow solid 3.13g, productive rate 63.6%.
1H?NMR(CDCl 3)δ：1.61-1.80(2H，dm)，3.21-3.62(2H，dm)，3.80(3H，S)，4.19(1H，d)，4.73(2H，S，NH 2)，4.88(1H，S，NH)，5.09(1H，d)，5.25(1H，d)，5.14(1H，s)，5.88(1H，m)。
Embodiment 3
4-[5-(2-amino-4-methoxyl group-pyrimidine-6-amino)-3-oxo-amyl group]-methyl benzoate (3)
560mg (2.5mmol) 2-amino-4-methoxyl group-6-(3-hydroxyl-4-thiazolinyl-1-penta amino)-pyrimidine, 720.5mg (2.75mmol) 4-iodo-benzoic acid methyl esters, 577.5mg (6.87mmol) NaHCO 3, 28mg (0.125mmol) Pd (AcO) 2, 885.5mg (2.75mmol) Bu 4The 4A molecular sieve that NBr and 0.5g pulverize is dissolved in the 20ml dry DMF N 2Protection is stirring at room 72h down, filters, and filtrate decompression is removed and desolvated, and gets the red-brown solid, silica gel column chromatography gradient elution 1.CH 2Cl 2, 2.CH 2Cl 2/ MeOH (98:2) gets slightly light brown solid 0.77g, yield 86%, mp110-113 ℃, R f=0.489 (CH 2Cl 2/ MeOH=20:1).
1H?NMR(CDCl 3)δ：2.66(2H，t)，2.74(2H，t)，2.93(2H，t)，3.46(2H，m)，3.77(3H，s)，3.88(3H，s)，4.67(2H，s，NH 2)，4.95(1H，s，NH)，5.09(1H，s)，7.21(2H，d)，7.92(2H，d)。
Embodiment 4
4-{5-[2-amino-4-methoxyl group-5-(4-chlorobenzene azo-group)-6-pyrimidine]-amino-3-oxo-amyl group }-methyl benzoate (4)
1.4g the 4-chloroaniline is dissolved in the 22.5ml 3N hydrochloric acid, is cooled to 0 ℃, adds 0.75g NaNO 2The aqueous solution (15ml), make diazonium salt.10mmol (3.58g) 4-[5-(2-amino-4-methoxyl group-pyrimidine-6-amino)-3-oxo-amyl group]-methyl benzoate (compound 3) is dissolved in 45ml Glacial acetic acid and 45ml H 2In the miscellany of O, add 18g CH 3CO 2Na3H 2O is cooled to 0 ℃, drips the diazonium salt solution that had before made then, adds afterreaction miscellany stirred overnight at room temperature, has yellow solid to separate out.The suction filtration solid is used massive laundering, dry faint yellow solid 3.39g, yield 68%, mp63～65 ℃.
1H?NMR(CDCl 3)δ：2.71～2.78(4H，m)，2.95(2H，t)，3.84(2H，q)，3.89(3H，s)，4.02(3H，s)，5.10(2H，b)，7.19(2H，d)，7.39(2H，d)，7.67(2H，d)，7.89(2H，d)，10.79(1H，b)。
Embodiment 5
4-[2-(2-amino-4-methoxyl group-5,6,7,8-tetrahydrochysene-9H-Mi Dingbing [4,5-b] [1,4] phenodiazine Zhuo-6-yl)-ethyl]-methyl benzoate (5)
1.31g (2.7mmol) 4-{5-[2-amino-4-methoxyl group-5-(4-chlorobenzene azo-group)-6-pyrimidine]-amino-3-oxo-amyl group }-methyl benzoate (compound 4) is dissolved among the 200ml AcOH, adds 81mmol (5.26g) zn powder, N 2Protection is backflow 2h down, and cooling is filtered, and filtrate decompression is removed and desolvated silica gel column chromatography, eluent CH 2Cl 2/ MeOH gets faint yellow solid product 0.573g, yield 59.4%, R f=0.52 (CH 2Cl 2/ MeOH=15:1).
1H?NMR(CDCl 3)δ：1.6～2.1(4H，m)，2.6～3.2(4H，m)，3.50(1H，m)，3.58(1H，b)，3.9(6H，s)，4.66(2H，b)，5.28(1H，b)，7.25(2H，d)，7.96(2H，d)。
Embodiment 6
4-[2-(2-amino-4-methoxyl group-5,6,7,8-tetrahydrochysene-9H-Mi Dingbing [4,5-b] [1,4] phenodiazine Zhuo-6-yl)-ethyl]-phenylformic acid (6)
1.6mmol (0.57g) compound (5) adds 30ml MeOH, 10ml0.5N NaOH, N 2Protection is backflow 4h down, and most of solvent is removed in decompression, remains about 5ml, dropping AcOH to pH=5～6. have faint yellow solid to separate out, and suction filtration, washing, vacuum-drying gets product 0.438g, yield 80%.
1H?NMR(DMSO-d 6)δ：1.4～1.9(4H，m)，2.49～2.99(4H，m)，3.29(1H，m)，3.75(3H，s)，5.75(2H，b)，5.88(1H，b)，7.29(2H，d)，7.82(2H，d)。
Embodiment 7
N-{4-[2-(2-amino-4-methoxyl group-5,6,7,8-tetrahydrochysene-9H-Mi Dingbing [4,5-b] [1,4] phenodiazine Zhuo-6-yl)-ethyl]-benzoyl }-L-glutamate diethyl ester (7)
1mmol (0.343g) compound (6), and 5.4mmol (0.6ml, 0.548g) N-methylmorpholine, 1.7mmol (0.3g) 2-chloro-4,6-dimethoxy-l, 3, the 5-triazine is dissolved in 30ml DMF, N 2Protection is stirring at room 3h down, and (0.3ml, 0.274g) N-methylmorpholine and 1.75mmol (420mg) L-diethyl glutamate hydrochloride, reaction mixture stir and spend the night to add 2.7mmol again.Removal of solvent under reduced pressure, silica gel column chromatography (CH 2Cl 2/ MeOH=50:1) wash-out, product 0.26g, yield 49%, R f=0.44 (CH 2Cl 2/ MeOH=15:1).
1H?NMR(CDCl 3)δ：1.22(3H，t)，1.3(3H，t)，1.67～2.43(6H，m)，2.48(2H，m)，2.75～3.2(4H，m)，3.50(1H，m)，4.0(3H，s)，4.10(2H，q)，4.23(2H，q)，4.82(1H，m)，5.18(2H，b)，5.26(1H，b)，6.05(1H，b)，7.04(1H，t)，7.25(2H，d)，7.74(2H，d)。
HRMS：m/z(MH+)calcd?for?C 26H 37N 6O 6529.2775，found?529.2792。 13C?NMR：14.03，27.20，30.43，32.25，35.56，37.79，41.97，52.27，54.14，56.45，60.69，61.61，104.43，127.33，128.43，131.49，145.68，153.84，154.80，162.14，166.14，166.94，171.99，173.12。
Embodiment 8
N-{4-[2-(2-amino-4-methoxyl group-5,6,7,8-tetrahydrochysene-9H-Mi Dingbing [4,5-b] [1,4] phenodiazine Zhuo-6-yl)-ethyl]-benzoyl }-L-L-glutamic acid (8)
0.6mmol (315mg) N-{4-[2-(2-amino-4-methoxyl group-5,6,7; 8-tetrahydrochysene-9H-Mi Dingbing [4,5-b] [1,4] phenodiazine Zhuo-6-yl)-ethyl]-benzoyl }-L-glutamate diethyl ester (7) is dissolved in the 10ml methyl alcohol; add the 3.6ml1N NaOH aqueous solution, N 2Stirring at room 2h under the protection, most of solvent is removed in decompression, drips AcOH and transfers pH=5～6 to separate out solid, suction filtration washing, the dry product that gets.
1H?NMR(DMSO-d 6)δ：1.05～2.11(6H，m)，2.35(2H，t)，2.71(2H，t)，3.21～3.51(3H，m)，3.92(3H，s)，4.41(1H，m)，7.71(1H，s)，7.29(1H，d)，7.33(2H，d)，7.44(1H，b)，7.82(2H，d)，8.52(2H，d)。
HRMS：m/z(MH+)calcd?for?C 22H 29N 6O 6473.2149，found?473.2112。
13CNMR：26.391，30.930，31.641，32.673，35.496，52.461，55.511，57.823，114.522，128.27，128.923，132.102，145.877，153.250，154.623，165.102，167.492，173.964，174.652。
Embodiment 9
N-{4-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydrochysene-9H-Mi Dingbing [4,5-b] [1,4] phenodiazine Zhuo-6-yl)-ethyl]-benzoyl }-L-L-glutamic acid (9)
0.37mmol (196mg) N-{4-[2-(2-amino-4-methoxyl group-5,6,7,8-tetrahydrochysene-9H-Mi Dingbing [4,5-b] [1,4] phenodiazine Zhuo-6-yl)-ethyl]-benzoyl }-L-glutamate diethyl ester (7) is dissolved in the anhydrous CHCl of 20ml 3, add 2.97mmol (CH 3) 3SiI (594mg, 0.424ml), N 2Protect following 40～50 ℃ of reacting by heating 20h, removal of solvent under reduced pressure, with ether wash faint yellow solid; the gained solid adds less water (2ml); add NaOH (1N, 2～3ml), stirring at room; the elimination insolubles; filtrate drips AcOH and transfers pH to 5～6, has solid to separate out, suction filtration; washing, vacuum-drying.
1H?NMR?δ：1.6～2.11(6H，m)，2.33(2H，t)，2.43(1H，m)，2.67(2H，t)，3.24(1H，m)，3.39(1H，m)，4.40(1H，m)，7.0(1H，b)，7.21(2H，d)，7.79(2H，d)，8.51(2H，d)，8.65(1H，b)，8.96(1H，s)，9.24(1H，s)，10.65(1H，s)。 13C?NMR?δ：：26.28，28.19，30.76，32.22，35.01，36.41，48.39，52.27，65.76，128.07，128.67，132.13，145.36，156.64，167.12，169.23，172.77，173.73，174.32，175.65。
Method B:
Embodiment 10
N-{4-[5-(2-amino-4-methoxyl group-pyrimidine-6-yl)-amino-3-oxo-amyl group]-benzoyl }-L-glutamate diethyl ester (10)
10mmol (4.31g) N-(4-phenyl-iodide formyl)-glutamate diethyl ester, 2.75mmol (2.32g) NaHCO 3, (2g4A molecular sieve and 9mmol (2.02g) 2-amino-4-methoxyl group-6-(3-hydroxyl-4-thiazolinyl-1-penta amino)-pyrimidine (2) is dissolved among the 80ml DMF N to 0.5mmol for 112m children palladium, 11mmol (3.54g) Tetrabutyl amonium bromide 2Protection is stirred 72h down, filters, and filtrate decompression is removed and desolvated residue silica gel column chromatography (CH 2Cl 2/ MeOH=15:1) blush jelly 3.211g, productive rate 67%.
1H?NMR(CDCl 3)δ：1.23(3H，t，J＝7Hz)，1.32(3H，t，J＝7Hz)，2.15～2.55(4H，m)，2.73(2H，t，J＝7H Z)，2.81(2H，t，J＝7H Z)，2.96(2H，t，J＝7H Z)，3.54(2H，m)，3.90(3H，s)，4.12(2H，m)，4.24(2H，m)，4.78(1H，m)，4.85(2H，s)，5.07(1H，s)，5.15(1H，t)，7.23(2H，d，J＝8H Z)，7.24(1H，d)， 7.72(2H，d，J＝8Hz)。
Ultimate analysis (C 26H 35N 5O 7) calculated value C:58.97%, H:6.16%, N:13.22%; Measured value C:58.71%, H:6.53%, N:13.17%.
Embodiment 11
N-{4-[5-(2-amino-4-methoxyl group-5-(4-chlorobenzene azo-group)-pyrimidine-6-yl)-amino-3-oxo-amyl group]-benzoyl }-L-glutamate diethyl ester (11)
4mmol (510mg) p-Chlorobenzoic acid amide is dissolved in the 8ml3N hydrochloric acid, is cooled to 0 ℃ and adds 4mmol (276mg) NaNO 2Diazonium salt, the diazonium salt of gained is added drop-wise to 3.75mmol (1.98g) N-{4-[5-(2-amino-4-methoxyl group-pyrimidine-6-yl)-amino-3-oxo-amyl group at 0 ℃]-benzoyl-Glacial acetic acid of L-glutamate diethyl ester (10) adds water (20ml+18ml) and 7.2gCH 3CO 2Na3H 2In the mixed solvent of O, then with the reaction mixture stirred overnight at room temperature, suction filtration, the gained solid product washes with water, then vacuum-drying.Get (11) 2.21g, yield 88%. 1H?NMR(CDCl 3)δ：1.24(3H，t，J＝7H Z)，1.32(3H，t，J＝7H Z)，2.15～2.45(4H，m)，2.79(4H，m)，2.96(2H，t，J＝7.2H Z)，3.95(2H，m)，4.10(3H，m)，4.12(2H，m)，4.24(2H，m)，4.77(1H，m)，5.11(2H，s)，6.96(1H，d)，7.18(2H，d，J＝7.4H Z)，7.44(2H，d，J＝8H Z)，7.64(2H，d，J＝8H Z)，7.79(2H，d，J＝7.4H Z)。Ultimate analysis (C 32H 38N 7O 7Cl0.25H 2O) calculated value C:57.14%, H:5.77%, N:14.58%; Measured value C:56.94%, H:5.74%, N:14.33%.
Embodiment 12
N-{4-[2-(2-amino-4-methoxyl group-5,6,7,8-tetrahydrochysene-9H-Mi Dingbing [4,5-b] [1,4] phenodiazine Zhuo-6-yl)-ethyl]-benzoyl }-preparation method two of L-glutamate diethyl ester (7)
1.5mmol (1.0g) compound (11), 30mmol (1.96g) Zn powder joins acetate (5ml), in the mixed solvent of water (20ml) and methyl alcohol (20ml), and N 2Protection is backflow 6h down.Suction filtration, filtrate decompression is removed and is desolvated, and residue gets (7) 0.43g, 54% with silica gel column chromatography.
1H NMR shows consistent with preceding a kind of method products therefrom.
Embodiment 13
N-{4-[2-(2,4-diamino-5,6,7,8-tetrahydrochysene-9H-Mi Dingbing [4,5-b] [1,4] phenodiazine Zhuo-6-yl)-ethyl]-benzoyl }-L-L-glutamic acid (12)
4mmol N-{4-[2-(2-amino-4-methoxyl group-5,6,7,8-tetrahydrochysene-9H-Mi Dingbing [4,5-b] [1,4] phenodiazine Zhuo-6-yl)-ethyl]-benzoyl }-L-L-glutamic acid, add the 5ml strong aqua, stirring at room 30h, most of ammonia is removed in decompression, and HPLC separates.
Embodiment 14
N-{4-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydrochysene-9H-Mi Dingbing [4,5-b] [1,4] phenodiazine Zhuo-6-yl)-ethyl]-benzoyl }-L-disodium glutamate salt (13)
Compound 9 (23.0mg, 50.2 μ mol) joins in the flask, adds distilled water (1.5ml) again, 1N NaOH solution (0.1ml), and stirring reaction is 0.5 hour under the room temperature, boils off solvent under the decompression, and water-ethyl alcohol recrystallization obtains solid (14.2mg, 56%).
ESI-MS：m/z228.1(Neg)
Embodiment 15
N-{4-[2-(2-amino-4-methoxyl group-5,6,7,8-tetrahydrochysene-9H-Mi Dingbing [4,5-b] [1,4] phenodiazine Zhuo-6-yl)-ethyl]-benzoyl }-L-L-glutamic acid two diethyl amine salt (14)
Compound 8 (33.0mg, 70 μ mol) joins in the flask, adds distilled water (2ml) again, diethyl amine salt (11mg, 140 μ l), and stirring reaction is 0.5 hour under the room temperature, boils off solvent under the decompression, and water-recrystallizing methanol obtains solid (23.8mg, 55%).
ESI-MS：m/z?235.2(Neg)。
Embodiment 16
Compound 8, tetrazolium (microculturetetrozolium has been selected in 9 anti-tumor biological test for use, MTT) reduction method, to human leukemia cell line (CCRF-CEM), the inhibition activity of human lung carcinoma cell line (A549) and three kinds of cell strains of mouse leukemia cell strain (L1210) is tested respectively.
The anti-tumor biological of compound 8,9
Compound CCRF-CEM， EC 50(nM/ml) L1210， EC 50(nM/ml) A549， EC 50(nM/ml)
8 275.57 ∞ 148.23
9 24.24 16.75 87.56
From the inhibiting rate relation of drug level and growth of tumour cell and the EC that calculates according to regular Bliss method 50, can infer as drawing a conclusion:
1. 8 couples of CCRF-CEM of compound and A549 tumour cell show restraining effect.
2. compound 9 couples of CCRF-CEM, L1210 and A549 tumour cell all have restraining effect.
Compound 8,9 shows that different tumour cells is had the activity of inhibition, and the prospect that is applied to clinical treatment is arranged.

Claims (6)

  1. A folacin and be used for the medical treatment salt, it is characterized in that: described folacin is the represented compound of following general formula (I),
    General formula (I)
    In general formula (I), R=OH or OCH 3, or OCH 2CH 3
  2. 2. folacin as claimed in claim 1 and be used for the medical treatment salt, it is characterized in that: described salt is metal cation salt or organic amine salt.
  3. 3. folacin as claimed in claim 1 and be used for the medical treatment salt, it is characterized in that: described salt is sodium salt or sylvite.
  4. 4. folacin as claimed in claim 1 and be used for the medical treatment salt, it is characterized in that: described salt is ammonium salt or diethyl amine salt or ethylenediamine salt.
  5. 5. folacin as claimed in claim 1 and be used for of the application of the salt of medical treatment at the medicine of preparation treatment cancer.
  6. 6. intermediate of salt for preparing folacin as claimed in claim 1 and be used for medical treatment, it is characterized in that: described intermediate is the compound of following general formula (III) expression,
    Figure FSB00000385029000021
    Wherein R=OH or OCH 3, or OCH 2CH 3R " be CH 3, or CH 2CH 3
CN2006100278440A 2006-06-19 2006-06-19 Folacin analogue, and salt of folacin analogue in use for medical treatment Expired - Fee Related CN101092417B (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0431953A2 (en) * 1989-12-08 1991-06-12 Takeda Chemical Industries, Ltd. Pyrrolopyrimidine derivatives, their production and use
EP1180369A1 (en) * 1999-05-24 2002-02-20 Sankyo Company, Limited MEDICINAL COMPOSITIONS CONTAINING ANTI-Fas ANTIBODY
CN1778802A (en) * 2004-11-25 2006-05-31 重庆医药工业研究院有限责任公司 Crystal form of Peimeiqusai disodium and its preparation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0431953A2 (en) * 1989-12-08 1991-06-12 Takeda Chemical Industries, Ltd. Pyrrolopyrimidine derivatives, their production and use
EP1180369A1 (en) * 1999-05-24 2002-02-20 Sankyo Company, Limited MEDICINAL COMPOSITIONS CONTAINING ANTI-Fas ANTIBODY
CN1778802A (en) * 2004-11-25 2006-05-31 重庆医药工业研究院有限责任公司 Crystal form of Peimeiqusai disodium and its preparation

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