CN1073572C - Dialkyl tin compound of mononuclear diacyl hydroxamic acids and its synthesis - Google Patents

Dialkyl tin compound of mononuclear diacyl hydroxamic acids and its synthesis Download PDF

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CN1073572C
CN1073572C CN99108251A CN99108251A CN1073572C CN 1073572 C CN1073572 C CN 1073572C CN 99108251 A CN99108251 A CN 99108251A CN 99108251 A CN99108251 A CN 99108251A CN 1073572 C CN1073572 C CN 1073572C
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tin compound
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hydroxamic acid
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杨频
王联红
王丽
丁健
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Shanxi University
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Abstract

HOHNOC-R-*** The present invention relates to a dialkyl tin compound of mononuclear diacyl hydroxamic acid class. The right formula shows the general structural formula. The dialkyl tin compound has a synthetic method of R'OOCRCOOR'+2NH2OH. HCl-<KOH>->KOHNOCRCONHOK-<H+>->HOHNOCRCONHOH, and R2'SnO+2HOHNOCRCONHOH->H2O+R2'Sn(OHNOCRCONHOH)2O. When the dosage of the compound is low (10<-8>mol/L), the compound has the advantages of wide application, low toxicity and strong anticancer activity.

Description

Dialkyl tin compound of mononuclear diacyl hydroxamic acids and synthetic
The present invention relates to organo-tin compound and synthetic method thereof that a class has antitumour activity.
Gielen etc. have synthesized the substituted benzoic acid dialkyl tin compound RR ' Sn (00CR ") of a series of monokaryons 2(see document Appl.Organomet.Chem., 1991,5,497-506.; 1993,7,119-125.; 1993,7,201-206.), generally have external anti-MCF one 7 (mammary cancer) and WiDr (colorectal carcinoma) activity better, but limited antitumour activity because of the toxicity of compound own is too big than cis-platinum (Cisplatin).
The objective of the invention is to develop a series of at low dosage (10 -8Mol/L) has wide spectrum the time, low toxicity, the organo-tin compound of potent antitumour activity.
Synthetic dialkyl tin compound of mononuclear diacyl hydroxamic acids R 2" Sn (OHNOCRCONHOH) 26 kinds, synthetic and preparation synthetic reaches tens of kinds.By ultimate analysis, infrared spectra and proton nmr spectra have confirmed that the general structure of such title complex is: Wherein, R "=Et, Bu, Ph etc.; R=(CH 2) n, n=O, l, 2,3,4 etc.And Deng.(part of compounds see attack 1) be synthetic route (synthetic route in the table 1 is as follows :) 1. [1] [2]
Table 1 is synthetic two acyl hydroxamic acid dialkyl tin compound synthetic routes ownership Annotate: the corresponding title of abbreviation part is as follows in the table:
OxHA:Oxalylhydroxamic acid, the oxalyl hydroxamic acid;
SuHA=Succinylhydroxamic acid, the succinyl hydroxamic acid;
AdHA=Adipylhydroxamic acid. hexanedioyl hydroxamic acid;
MaHA=Malonylhydroxamic acid, the malonyl-hydroxamic acid;
GlHA:Olutarylhydroxamic acid, the glutaryl hydroxamic acid;
P-PhHA=p-Phthaloylhydroxamic acid, the terephthaloyl hydroxamic acid.2. make each method (working method of each route is as follows in the synthetic route :) route [1]:
17.37 gram (0.25 mole) oxammonium hydrochlorides are dissolved in 90 ml methanol with circumfluence method, 20.20 gram (0.36 mole) potassium hydroxide are used with method to be dissolved in 60 ml methanol in addition.When treating that the two is cooled to 30-40 ℃, under the situation of shaking while cooling off, back solution is poured in the preceding solution, left standstill 5 minutes, guarantee that Repone K precipitates fully, elimination precipitates, and gets the methanol solution of azanol and potassium hydroxide.In this filtrate, add ester R_OOCRCOOR_0.075 mole, stirred 3 hours, placed 24 hours, get the KOHNOCRCONHOK precipitation, leach, be dissolved in less water, stir,, stirred 3 hours to PH=5 with the 2N acidifying with acetic acid, filter, get thick product, water recrystallization twice, vacuum-drying gets part hydroxamic acid HOHNOCRCONHOH.Route [2]:
The part hydroxamic acid HOHNOCRCONHOH of 8 mmoles is dissolved in (also available toluene: dehydrated alcohol is that 200 milliliters of mixed solutions of 3: 1 are made solvent) in 200 milliliters of dehydrated alcohols with circumfluence method, adds the dialkyl stannic oxide R of 4 mmoles then 2" SnO, refluxed 6 hours.After reaction finishes, boil off half solvent, remaining evaporates under evacuated, thick product, use the dehydrated alcohol recrystallization, suction filtration is collected, vacuum-drying gets two acyl hydroxamic acid dialkyl tin compound R of monokaryon 2" Sn[OHNOCRCONHOH] 2
The ultimate analysis and the physical property data of part HOHNOCRCONHOH and title complex see Table 2, and ir data sees Table 3, and the nucleus magnetic hydrogen spectrum data see Table 4.3. test used instrument: the digital fusing point instrument that Shanghai Physics Optics Instrument Factory is produced: 240C elemental analyser and Vario EL type elemental analyser; Tianjin, island IR-435 infrared spectrometer and Perkin-Elmer-983 type infrared spectrometer: 1H NMR BrukerDRX300MHZ and Bruker AM-500MHZ nmr determination, TMS is interior mark, is solvent with deuterium for DMSO and deuterochloroform; Molecule is put reduction method mensuration admittedly with doubting, and solvent is a naphthalene.
The ultimate analysis of table 2 part and title complex and physical property data
Compound Molecular weight Outward appearance mp/℃ Yield Ultimate analysis/% measured value (calculated value)
Mr ％ C H N
OxHA 120 White 63 decompose 56 19.18(20.00) 3.14(3.33) 22.68(23.33)
[(OxHA) 2SnBu 2] 471 White ＞300 70 29.97(30.57) 4.91(5.09) 11.68(11.89)
SuHA 148 White 147.0-147.2 47 32.13(32.43) 5.33(5.41) 18.83(19.08)
[(SuHA) 2SnBu 2] 527 White 217.1-218.8 70 36.23(36.43) 6.22(6.07) 10.23(10.63)
AdHA 176 White 167 decompose 50 40.59(40.91) 7.00(6.82) 15.77(15.61)
[(AdHA) 2SnBu 2] 583 White 282.4-283.9 75 40.03(40.96) 7.19(6.86) 9.43(9.61)
MaHA 134 White 149.4-149.6 89 26.55(26.87) 4.47(4.48) 20.74(20.90)
[(MaHA) 2SnBu 2] 499 White 157.8-158.5 89 33.49(33.67) 5.42(5.61) 1.38(11.22)
GIHA 162 White 149.8-151.3 88 37.19(37.04) 5.01(6.17) 7.01(17.28)
[(GIHA) 2SnBu 2] 555 White 162.0-162.6 89 38.68(38.92) 6.30(6.49) 9.91(10.09)
P-PhHA 196 White 202.0-203.3 48 43.33(42.86) 4.17(4.08) 14.06(14.29)
[(P-PhHA) 2SnBu 2] 623 White 236.1-237.7 78 45.97(46.22) 5.21(5.14) 8.66(8.99)
The ir data of table 3 part and title complex (v cm -1)
Compound V NH-OH V C=O’ V C=O’ V N-O V N-O’ V Sn-C V Sn-O
OxHA 3220-3000 1630 ---- 840 ---- ---- ----
[(OxHA) 2SnBu 2] 3300-3100 1630 1550 845 890 560 463
SuHA 3200-3040 1630 ---- 965 ---- ---- ----
[(SuHA) 2SnBu 2] 3260-3040 1635 1550 900 980
AdHA 3220-3050 1655 ---- 965 ---- ---- ----
[(AdHA) 2SnBu 2] 3200-3040 1630 1550 890 980 520 456
MaHA 3200-3050 1650 ---- 980 ---- ---- ----
[(MaHA) 2SnBu 2] 3180-2900 1610 1540 870 990 568 468
GIHA 3480-2800 1650 ---- 1000 ---- ---- ----
[(GIHA) 2SnBu 2] 3160-3030 1600 1540 980 1010 543 448
P-PhHA 3300-2800 1650 ---- 900 --- ---- ----
[(P-PhHA) 2SnBu 2] 3260-3040 1650 1550 860 900
4. structural characterization (1). (1) Infrared spectroscopy
As seen from Table 3: the infrared spectra of part HOHNOCRCONHOH is at 2800-3480cm -1Occur NH and OH stretching vibration absorption peak in the scope, still, in title complex, have only an end coordination, so NH and OH absorption peak do not disappear owing to part.V in the part C=OAt 1630-1655cm -1Near peak of appearance is in title complex, at 1630-1655cm -1And 1540-1550cm -1The place all has strong peak to occur, and proves part one end ketonic oxygen and tin coordination, and the other end is coordination not.Because of the hydroxyl absorption peak does not disappear, so can not prove conclusively the hydroxyl oxygen coordination.But, V in part N-OAt 840-1000cm -1Near, in title complex, situ V N-OThe peak still exists, and, a V has also appearred at high frequency treatment N-OPeak, and absorption intensity increases, this has got rid of the coordination of nitrogen-atoms in the NH-OH group on the one hand, and also having proved on the other hand is oxygen and tin coordination among the NH-OH.Because tin belongs to hard acid, this meets the hard and soft acid and base rule.In title complex IR spectrum, only observe V Sn-OAbsorption peak is not observed V really Sn-NAbsorption peak, this peak is greatly about 415cm -1The place.
Above IR parameter indicating, part are with Sauerstoffatom in the CO-NHOH group of an end and tin chelating coordinate, and generally speaking, hydroxamic acid is with CO-NHO-coordinate strong chelating agent.In title complex, only observe a V Sn-C, shown two alkyl R " and be in trans position.
The nucleus magnetic hydrogen spectrum data of table 4 part and title complex (δ ppm)
Compound (CH 2) nOr ring CH 3 CH 2 (CH 2) 2Sn -NHOH(-NHO-)
OxHA ---- ---- ---- ---- 11.66(2H)9.31(2H)
[(OxHA) 2SnBu 2] ---- 1.00(6H) 1.45(4H) 1.73(8H) ----
SuHA 2.34(4H) ---- ---- ---- 10.32(2H)9.30(2H)
[(SuHA) 2SnBu 2] 2.45(8H) 1.00(6H) 1.45(4H) 1.74(8H) ----
AdHA 1.61-2.09(8H) ---- ---- ---- 10.52(2H)8.87(2H)
[(AdHA) 2SnBu 2] 1.64-2.29(16H) 0.99(6H) 1.44(4H) 1.75(8H) 12.06(2H)10.52(2H)8.87(2H)
MaHA 2.75(2H) ---- ---- ---- (9.72 wrapping 4H greatly)
[(MaHA) 2SnBu 2] 2.28(4H) 0.95(6H) 1.25(4H) 1.41-1.69(8H) ----
GIHA 1.67(2H)1.92(4H) ---- ---- ---- 10.35(2H)8.69(2H)
[(GIHA) 2SnBu 2] 1.37-4.94(12H) 0.84(6H) 0.71(4H) 1.26(8H) 11.96(2H)10.36(2H)8.70(2H)
P-PhHA (7.98-8.18 ring 4H) ---- ---- ---- 11.01(2H)9.30(2H)
[(P-PhHA) 2SnBu 2] (8.06-8.16 ring 8H) 1.00(6H) 1.45(4H) 1.73(8H) 11.50(2H)9.33(2H)
(2): 1HNMR (nucleus magnetic hydrogen spectrum) analyzes
As seen from Table 4: the R group in all title complexs, i.e. (CH on the part 2) nOr obvious variation all taken place than free ligand in the absorption peak of proton of ring, and this is due to the inductive effect after part and the tin coordination.After the AdHA coordination, 12.06,10.52,8.87ppm locate to occur proton peak, belong to the NH of coordination one end respectively, not NH and the OH of the NH-OH of coordination one end show the deprotonation of hydroxyl among the NH-OH of part one end and the coordination of oxygen, got rid of the coordination of nitrogen-atoms in the NH-OH group, inferred consistent with the IR spectrographic.Absorption signal does not appear in proton on the nitrogen of the title complex coordination end of P-PhHA, may be relevant with the quick exchange of reactive hydrogen, reactive hydrogen in the part on the coordination end nitrogen-atoms is transferred on the Sauerstoffatom, exist with the HO-C=N-OH form, after the Sauerstoffatom dehydrogenation with the tin coordination, so in title complex, do not observe the NH proton peak of coordination end.OxHA after the coordinations such as SuHA, NH do not occur, and the proton peak of OH may be that replacement(metathesis)reaction has taken place for proton and deuterated reagent on the OH because of NH.Therefore, 1H NMR result has proved that also part is to infer with Sauerstoffatom in CO-NHOH (or HO-C=N-OH) group and tin chelating coordinate.In addition, " showing as multiplet, also showing R " is to be in the non-rectilinear antiposition to alkyl R.
Comprehensive above-mentioned IR, 1Parameters such as H NMR and ultimate analysis can think that this compounds is a hexa-coordinate monokaryon distorted octahedron structure.The antitumour activity of (shown in general formula) compound
Through Beijing Medical University's natural drug and bionical medicine (the table 5A of National Key Laboratory, show 5B) and new medicament screen National Key Laboratory of Shanghai medicine institute of the Chinese Academy of Sciences (table 6, table 7) above-claimed cpd is carried out screening active ingredients, find that above-claimed cpd has potent activity.Table 5A-5B evaluation of result :-invalid+weak effect ++ produce effects +++potent
Table 5A different concns title complex is to the inhibiting rate % of growth of tumour cell
Compound The test sequence number KB° BGC-823°
0.1 μ M 1 μ M 10 μ M estimate 0.1 μ M 1 μ M 10 μ M estimate
[(MaHA) 2SnBu 2] 98203690 12.14 57.48 94.36 ++ -29.24 -3.22 96.96 +
[(GlHA) 2SnBu 2]
Annotate °: human nasopharyngeal carcinoma KB: adopt sulfanilamide (SN) rhodamine (SRB) protein staining method; People's cancer of the stomach BGC-823 (srb assay)
Table 5B different concns title complex is to the inhibiting rate % of growth of tumour cell
The test sequence number Bel-7402° HCT-8° HL-60°
0.1 μ M 1 μ M 10 μ M estimate 0.1 μ M 1 μ M 10 μ M estimate 0.1 μ M 1 μ M 10 μ M estimate
98203690 -18.89 -20.52 93.15 + 18.89 38.59 93.30 + -18.62 45.40 72.98 +
Annotate °: people's liver cancer Bel-7402 (srb assay); Human colon carcinoma HCT-8 (srb assay); Human leukemia HL-60: adopt tetrazolium (MTT) colorimetry; Screening method: tetrazolium (microculture tetrozolium, MTT) reduction method cell strain: P 388Mouse leukemia action time: 48h result evaluation: invalid: 10 -5Mol/L＜85%;
The weak effect: 10 -5Mol/L 〉=85% or 10 -6Mol/L＞50%;
Potent: 10 -6Mol/L 〉=85% or 10 -7Mol/L＞50%;
Table 6 different concns (mol/L) title complex is to the inhibiting rate % of growth of tumour cell
Compound Sample number into spectrum 10 -4 10 -5 10 -6 10 -7 10 -8Estimate
[(OxHA) 2SnBu 2] 1025 35.1 33.3 24.6 5.3 14.0 is invalid
[(SuHA) 2SnBu 2] 1027 90.2 54.1 39.3 36.1 36.1 is invalid
[(AdHA) 2SnBu 2] 1029 84.5 63.1 50.0 46.4 44.0 weak effects
(MaHA) 2SnBu 2] 1088 97.5 96.3 71.3 63.8 61.3 is potent
[(GlHA) 2SnBu 2] 1104 94.6 96.8 97.8 95.7 67.7 is potent
[(P-PhHA) 2SnBu 2] 1031 84.5 66.6 45.2 48.8 44.1 is invalid
Screening method: sulfanilamide (SN) rhodamine B (sulforhodamine B, SRB) protein staining method cell strain: A-549 human lung adenocarcinoma action time: 72h result evaluation: invalid: 10 -5Mol/L＜85%;
The weak effect: 10 -5Mol/L 〉=85% or 10 -6Mol/L＞50%;
Potent: 10 -6Mol/L 〉=85% or 10 -7Mol/L＞50%;
Table 7 different concns (mol/L) title complex is to the inhibiting rate % of growth of tumour cell
Compound Sample number into spectrum 10 -4 10 -5 10 -6 10 -7 10 -8Estimate
[(OxHA) 2SnBu 2] 1025 89.6 80.2 000 is invalid
[(SuHA) 2SnBu 2] 1027 96.1 93.5 92.2 92.2 90.9 is potent
[(AdHA) 2SnBu 2] 1029 94.8 93.5 92.2 92.2 89.6 is potent
[(MaHA) 2SnBu 2] 1088 91.7 91.7 92.7 92.7 87.5 is potent
[(GlHA) 2SnBu 2] 1104 91.2 93.4 67.0 2.2 0.0 weak effects
[(P-PhHA) 2SnBu 2] 1031 97.4 96.1 94.8 93.5 87.2 is potent
Screening method: sulfanilamide (SN) rhodamine B (sulforhodamine B, SRB) protein staining method, tetrazolium (microculturetetrozolium, MTT) reduction method cell strain: HO-8910 human ovarian cancer, SPC-A4 people's lung cancer, HCT-116 human colon carcinoma action time: 72h result evaluation: invalid: 10 -5Mol/L＜85%;
The weak effect: 10 -5Mol/L 〉=85% or 10 -6Mol/L＞50%;
Potent: 10 -6Mol/L 〉=85% or 10 -7Mol/L＞50%;
Table 8 different concns (mol/L) cis-platinum is to the inhibiting rate % of growth of tumour cell
Cell strain 10 -4 10 -5 10 -6 10 -7 10 -8Estimate
The invalid HCT-116 of the invalid SPC-A4 of HO-8910 84.4 56.3 0.4 4.7 0.0 48.7 8.0 0.4 0.0 0.0 78.8 0.0 0.0 0.0 0.0 is invalid
From the test result of table 5-table 8 as can be known, serial organotin platform thing tool wide spectrum of the present invention, low toxicity and potent antitumour activity: (1) wide spectrum: this series compound is to human nasopharyngeal carcinoma KB, people's cancer of the stomach BGC-823, people's liver cancer Bel-7402, human colon carcinoma HCT-8, human leukemia HL-60, P 388Mouse leukemia and A-549 human lung adenocarcinoma tumour cell etc. all have stronger restraint.(2) low toxicity: with the Wish-human amniotic cell is example, uses srb assay, and action time, 72h found that this series compound is 10 to Normocellular toxic concentration -6Mol/L is than its inhibition concentration 10 to tumour cell -8Mol/L differs from two orders of magnitude.(3) potent: this series compound is to P 388The inhibiting rate of mouse leukemia and A-549 human lung adenocarcinoma tumour cell is potent property.And be widely used in clinical cis-platinum at present to the HO-8910 human ovarian cancer, and SPC-A4 people's lung cancer, the inhibiting rate of HCT-116 human colon carcinoma is invalid (seeing Table 8).
Embodiment 1 title complex [(MaHA) 2SnBu 2], structure as previously mentioned, R=CH wherein 2, R "=Bu; (1): synthetic route [1] [2] (2): preparation method's route [1]: (synthetic ligands MaHA)
17.37 gram (0.25 mole) oxammonium hydrochlorides are dissolved in 90 ml methanol with circumfluence method, 20.20 gram (0.36 mole) potassium hydroxide are used with method to be dissolved in 60 ml methanol in addition.When treating that the two is cooled to 30～40 ℃.Under the situation of shaking while cooling off, back solution is poured in the preceding solution, left standstill 5 minutes, guarantee that Repone K precipitates fully, elimination precipitates, and gets the methanol solution of azanol and potassium hydroxide.In this filtrate, add diethyl malonate 12.014 grams (0.075 mole, 11.39 milliliters), stirred 3 hours, placed 24 hours.Get malonyl-hydroxamic acid sylvite white precipitate, leach, be dissolved in less water, stir, to PH=5, stirred 3 hours, filter, get thick product with the 2N acidifying with acetic acid, water recrystallization twice, vacuum-drying gets white powder part malonyl-hydroxamic acid.Route [2]: (synthetic compound [(MaHA) 2SnBu 2])
The malonyl-hydroxamic acid of 1.0728 grams (8 mmole) is dissolved in (also available toluene: dehydrated alcohol is that 200 milliliters of mixed solutions of 3: 1 are made solvent) in 200 milliliters of dehydrated alcohols with circumfluence method, adds the Dibutyltin oxide Bu of 0.996 gram (4 mmole) then 2SnO refluxed 6 hours. after reaction finishes, boil off half solvent, remaining evaporates under evacuated, thick product, with dehydrated alcohol/toluene mixture liquid recrystallization, suction filtration is collected, vacuum-drying, white powder [(MaHA) 2SnBu 2].(3): purposes
This compound is to human nasopharyngeal carcinoma KB, people's cancer of the stomach BGC-823, and people's liver cancer Bel-7402, human colon carcinoma HCT-8, human leukemia HL-60 has stronger restraint, to P 388The inhibiting rate of mouse leukemia and A-549 human lung adenocarcinoma tumour cell is potent property.

Claims (2)

1. dialkyl tin compound of mononuclear diacyl hydroxamic acids is characterized in that its general structure is:
Figure C9910825100021
R in the formula "=Bu;
R=(CH in the formula 2) n, n=0,1,2,3,4 reaches
Figure C9910825100022
2. as the synthetic method of tin compound as described in the claim l, it is characterized in that step is as follows: (1):
17.37 gram (0.25 mole) oxammonium hydrochlorides are dissolved in 90 ml methanol with circumfluence method, 20.20 gram (0.36 mole) potassium hydroxide are used with method to be dissolved in 60 ml methanol in addition.When treating that the two is cooled to 30～40 ℃, under the situation of shaking while cooling off, back solution is poured in the preceding solution, left standstill 5 minutes, guarantee that Repone K precipitates fully, elimination precipitates, and gets the methanol solution of azanol and potassium hydroxide.In this filtrate, add ester R_OOCRCOOR_0.075 mole, stirred 3 hours, placed 24 hours, get the KOHNOCRCONHOK precipitation, leach, be dissolved in less water, stir,, stirred 3 hours to PH=5 with the 2N acidifying with acetic acid, filter, get thick product, water recrystallization twice, vacuum-drying gets part hydroxamic acid HOHNOCRCONHOH:(2)
Be dissolved in 200 milliliter dehydrated alcohols with circumfluence method the part hydroxamic acid HOHNOCRCONHOH of 8 mmoles or be dissolved in toluene: dehydrated alcohol is in 200 milliliters of mixed solutions of 3: 1, adds the dialkyl stannic oxide R of 4 mmoles then 2" SnO.Refluxed 6 hours. after reaction finishes, boil off half solvent, remaining evaporates under evacuated, thick product, use the dehydrated alcohol recrystallization, suction filtration is collected, vacuum-drying gets two acyl hydroxamic acid dialkyl tin compound R of monokaryon 2" Sn[OHNOCRCONHOH] 2
CN99108251A 1999-06-02 1999-06-02 Dialkyl tin compound of mononuclear diacyl hydroxamic acids and its synthesis Expired - Fee Related CN1073572C (en)

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US5155248A (en) * 1990-12-11 1992-10-13 Rhein Chemie Rheinau Gmbh Polyurethane catalysts

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US5155248A (en) * 1990-12-11 1992-10-13 Rhein Chemie Rheinau Gmbh Polyurethane catalysts

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