Method of producing derivatives of neocarsinestatin

专利摘要:
Neocarzinostatin derivatives, having anticancer activity. have the formula (A) wherein (NCS) represents a divalent neocarzinostatin residue in which a hydrogen atom is removed from each of the primary amino groups of the alanine residue at the N-terminal of neocarzinostatin and of the primary amino group of the lysine residue at the 20th position from the N-terminal of neocarzinostatin and (SMA) represents a monovalent partially half-esterified styrene-maleic acid copolymer residue having a weight-average molecular weight of 800 to 2,500 and consisting of structural units of (a) the styrene residue (b) the half-esterified maleic acid residue wherein R is an alcohol residue wherein the hydroxyl group has been removed from an alkanol having 1 to 4 carbon atoms, ethylene glycol monoalkyl ether in which the alkyl group has 1 or 2 carbon atoms or glycerine dialkyl ether wherein the alkyl group has 1 or 2 carbon atoms; (c) the maleic acid residue and (d) a residue having the following formula in which a hydroxyl group of one carboxyl group of a maleic acid residue has been removed to provide the link bonding the monovalent partially half-esterified styrene-maleic acid copolymer residue to the neocarzinostatin residue
公开号:SU1428206A3
申请号:SU843783009
申请日:1984-08-07
公开日:1988-09-30
发明作者:Маеда Хироси；Канамару Риуносуке；Исида Накао；Еситаке Тосихико；Уеда Минору
申请人:Курарей Ко.,Лтд (Фирма)；Яманоути Фармасьютикал Ко.,Лтд (Фирма)；Каяку Антибиотикс Рисерч Ко.,Лтд (Фирма)；Хироси Маеда (Фирма)；
IPC主号:

专利说明:

The invention relates to a process for the preparation of neocarzinostatin derivatives, new biologically active compounds which can be used in medicine,
The purpose of the invention is to obtain new derivatives, neocarzinostatin, less toxic, possessing high antitumor activity with intra-arterial use, increased lipid solubility.
FIG. l-e shows the curves explaining the proposed method.
Example 1. A, Polymerization of a copolymer of styrene and maleic anhydride. 30 liters of cumene are loaded into a high-pressure apparatus with an internal volume of 150 liters, into which also a homogeneous solution containing 3.5 kg of maleic anhydride is supplied; a, 20 liters of cumene, 3.7 kg of styrene and 200 g of benzoyl peroxide, are fed continuously for 65 minutes, while the mixture is heated to 150 ° C. After loading, stirring is carried out for 60 minutes at 150 ° C, the reaction mixture is cooled to room temperature, then 30 l of n-hexane is added to it to the polymer was precipitated, the liquid phase was drained, thus obtaining azhdenny polymer. After grinding the polymer, it is washed with n-hexane and then dried. The yield of the obtained polymer was 7.3 kg. The number average molecular weight (MCH) of the polymer, measured by vapor pressure osmometry (RDP), was 1680. It is consistent with measurements by NMR spectroscopy, which also show that the polymer thus obtained is a copolymer of styrene and maleic anhydride in a 1: 1 molar ratio (Fig. 1).
B. Fractionation of a copolymer of styrene and maleic anhydride.
40 g of a copolymer of styrene and maleic anhydride (CMA) obtained in stage A are dissolved in 1.4 liters of acetone, 3.8 kg of glass beads (average particle size O, 1 mm) are added to the solution, the surface of which is pretreated using coupling agent silane. The acetone is then evaporated to precipitate the SMA on the surfaces of the glass beads.
Glass beads with precipitated NL and 1.4 L of a mixed solvent of acetone and n-hexane (the volume ratio is 8:92 at 25 s) are loaded into a column having an internal diameter of 80 mm and a length of 80 cm, while the temperature of the system is maintained at 25 ° C, and then three types of mixed acetone and n-hexane mixers are successively served (such mixed solvents at 25 ° C are 0.6 liters of a mixture in the ratio of 8:92; 3.0 liters of a mixture in the ratio of 22:78 and 3.0 liters of a mixture in the ratio of 34:66, the solvents are fed in this order), and the liquid flows out of the bottom knogo apertures column. The eluate obtained by using a mixed solvent of acetone and n-hexane with a volume ratio of 34:66 is concentrated and dried under reduced pressure, as a result of which a sample of 6.3 g is obtained. This sample,. Gel permeation chromatography (GPC) has a weight average molecular weight (MW) of 1350, and a mean molecular weight (Mch) of 1170 (Mv / Mch of 1.16). The & no. Of the NDP Mth method is 1170.
B. Partial semi-n-butyl sterilization of fractionated SMA.
6.0 g of CMA obtained in Step B. 1.95 g of n-butyl alcohol, 15 ml of dioxane and 0.06 g of lithium acetate are placed in a glass test tube, then the test tube is sealed and shaken for 24 hours. h at room temperature. Then this solution is kept at 90 ° C for 17 hours and cooled to room temperature. Next, the reaction liquid is drained. The reaction liquid that has been drained is diluted with twice the volume of dioxane and lyophilized, then the product obtained is dried under vacuum to obtain a material in the form of light yellowish flakes, which is triturated to obtain 7.8 g of powder. Infrared absorption spectrum obtained by the powder method.), KBr. He confirmed, through optical densities with a wavenumber of 1780 and 700, that the resulting powder was a partially semi-n-butyl esterified copolymer of styrene and ml maleic anhydride (BuSMA), in which the content of the remaining maleic rings was
31428206
nhydride is 30.5 mol.% (kos. 10 / m and m
lec maleic anhydride in one molecule is 1.7). According to GPC, MB is 1480, Mch is 1290, and Mv / Mch is 1.15.
G. Reaction of X with BuSMA. 0.20 g of neocarzinostatin (ICS) is dissolved in 5.0 ml of a 0.8 M aqueous solution of sodium bicarbonate with ice cooling in the dark. Powdered BuSMA in the amount of 1.02 g is added in portions to the solution. The reaction is then carried out for 97 hours while the pH of the solution is maintained at about 8.5 to obtain a degree of conversion of primary amino groups of X-ray to 97.5 mol%. The degree of conversion of such primary amino groups can be determined by the TNBS method, according to which a small amount of a sample taken from the reaction liquid is diluted and then this sample is reacted with trinitrobenzene (mono) sulfonic acid in order to obtain a nitrobenzene derivative, which is determined based on the amount of primary amino groups spectrophotometrically using an absorption spectrometer in the 420 nm range.
The resulting reaction mixture is transferred to a dialysis tube (Union Carbide Co., Ltd., USA), which cuts off molecular weights of 8000, while dialysis is carried out for three days against an aqueous 5 μm solution of ammonium bicarbonate while cooling with ice in the dark, at the same time, the outer layer of fluid is sometimes replaced.
A portion of the partially purified solution was diluted with 10 mM ammonium bicarbonate aqueous solution to provide a pH of 7.9. The clear PC curves were obtained using a 1-3000 SU column produced by Toyo. Soda Wo, Dep. The peaks (Fig. 2a, b) with a retention time of 16 minutes at 254 and 280 nm have maxima approximately equal to each other and are associated with the derivatives of formula (I), while the absorption at retention time is 19 minutes in the range of 254 nm, it is associated only with the hydrolyzed and disintegrated ring product BuSMA.
D. Purification NCC-derivatives of formula (I).
five
Half of the dialyzed reaction liquid is poured into a column having an internal diameter of 50 mm, a length of 60 cm (K 50/60, Pharmacia Fann Keminelz AB, Uppsala, Sweden) and filled with the Sephadex G-75 substrate, and the zlation is performed with volumetric rate of 6.0 ml / 0 / min in the dark with 5 mM aqueous ammonium bicarbonate solution. The eluate is continuously measured at a range of 254 nm (Fig. 3). The eluate fraction is from 60 to 100 minutes after the sample is introduced and then subjected to lyophilization. This procedure is repeated under the same conditions. The resulting purified NCC derivatives, (I) have a total weight of 186 mg .:
When conducting electrophoresis using a polyacryl amide gel containing sodium dodecyl sulfate, the obtained ICS derivative gives one spot. As shown in FIG. 4a, GPC was obtained at pH 7.9 using a column of 1-3000 SU produced by Toyo Soda Co., Ltd., and the mobile phase — 10 mM aqueous ammonium bicarbonate solution, has a sharp peak.
Elementary analysis, wt.%: N 11,43; C, 51.99; H 6.32.
The average molecular weight of the NCL-derivative in terms of nitrogen content was 13,300. The average molecular weight was calculated according to the following formula:
0
five
0
five
Md Mts-NN / Noi,
40
MN NN where Md is the average molecular weight of the NCN-derived, the molecular weight of the IRS is 10,700;
the nitrogen content in accordance with the elementary analysis of the X, 14,24 weight,%; Nd is the nitrogen content (weight,%) according to the elemental analysis of the NCL derivative. The average molecular weight of the NCN derivative having formula (I) is. 10700 + 1480 X 2 13660 in terms of the weight-average molecules of p-weight of E-CMA (1480), obtained with the help of GPC. Since this average molecular weight, in terms of nitrogen content, is consistent with this value, it can be thought that the resulting NCS-derived two residues of the partially semi-paired styrene-maleic acid copolymer residues are linked to one IR residue, as shown in the formula ( I). The average molecular weight (MCH) of the partially semi-paired residue of a copolymer of styrene and maleic acid contained in the NCC-derived compound is determined from the average molecular weight of the NCC-drive drives, "determined by the following formula:
Mr
where is Mr
(Moi.- Mm) / 2,
the average molecular weight of the partially semi-superheated residue of a copolymer of styrene and maleic acid in the HKS-derivative; Mfti - average molecular weight
AUC-derivative; MN -. molecular weight X
(10700).
According to this formula, Mr is equal to 1300. This value is not very different from the average weight molecular weight of the starting material E-CMA, which is equal to 1480 and obtained using P1X.
The compound has no melting points, оС1 - 34.3.
- W and UV spectra confirm the structure of the NCN derivative of formula (I), which is the subject of the invention (Fig. 5a and 6a).
Example 2. Fractionated CMA with MB 1480 and Mch 1230 (Mv / Mch 1.20) are obtained using a procedure similar to Example 1, except that the mixed solvent of acetone and n-hexane with respect to 3862 is used as the third mixed liquid acetone and n-hexane by fractionation of the CMA obtained in Example 1A. 4.0 g of fractionated CMA is subjected to esterification under the same conditions as in Example 1B, except that 0.80 g of ethanol, 12 ml of dioxane and 40 mg of lithium acetate are used. As a result, 4.9 g of a partially semi-ethyl esterified copolymer of styrene and maleic anhydride (abbreviated as EtCMA), the anhydride ring content of which is 24.0 mol.% (average 1., 6 rings of anhydride per
molecule). MB 1580 and Mch 1340 (Mv / Mch 1.18) -.
By analogy with Example 1G, 0.2 g of IRS is dissolved in 5.0 ml of 0.8 and sodium bicarbonate aqueous solution, 1.2 g
EtCMA is added in portions to the resulting solution. During this reaction, the pH of the solution is maintained at about 8.5. After 27 hours from the start of the addition, the degree of transformation of the primary amino groups was 97.5 mol%. Immediately after this, the reaction liquid is subjected to dialysis, and 38 MP dialysate is subjected to gel
filtering. Then the filtrate is lyophilized, resulting in 148 mg of purified NCC derivative of formula (I).
During electrophoresis, the obtained NCM derivative gives one spot. GPC is shown in FIG. 4b. Elementary analysis, weight. %: N 10.74; C 52.90; H 6.18. The average molecular weight in terms of this data is
14200, and the average molecular weight of the partially semi-ethyl-esterified residue of a copolymer of styrene and maleic acid is 1750. The UV and IR spectra are reduced (Fig. 56 and
6b). These data confirm the structure of the NCS-derivative, which is the subject of the invention, which is described. formula (I).
Example 3. CMA, obtained in
Example 1A is fractionated using the method described in Example 1B, except that the volume fraction of acetone in the second and third mixed liquids of acetone and n-hexane is 23 and 37%, respectively, resulting in 9.1 g. fractionated SMA with MB 1480, Mch 1250 (Mch 123iO when determined by
ODP), and Mv / Mch 1.18. 4.0 g of the obtained fractionated CMA interacts as in Example 1B using 1.60 g of ethylene glycol monoalkyl ether as the alcohol
and 0.04 g lithium acetate. The result is 4.9 g of a partially semi-2-ethoxyethyl-esterified copolymer of styrene and maleic anhydride (abbreviated as Al-Cell-CMA),
the content of anhydride rings in which is 25.4 mol. % (average of 1.6 rings of anhydride per lu). MB 1,700 and Mch 1440 (Mv / Mch 1.19).
By analogy with Example 1, Et-Cell-CMA is added and dissolved in portions with a total amount of 1.3 g in 5.0 ml of a 0.8 M aqueous solution of sodium bicarbonate in which 0.2 g of X-ray has been previously dissolved. . Maintaining the pH of the solution at about 8.5, the reaction is carried out. After 98 h after the start of the Al-Cell-CMA addition, the degree of transformation of the amino groups was 97.6 mol%. The reaction mixture thus obtained is subjected to dialysis, gel filtration and lyophilization. As a result, 189 mg of purified NCC derivative (I) is obtained.
During electrophoresis of the obtained NCS derivative, one spot is observed. GPC is shown in FIG. 4c. Elemental analysis data, weight. %; N 10.72, C 53.49; H 6.38. The average molecular weight, in terms of these data, is 14,200, and the average molecular weight of the partially semi-2-ethoxyethyl-esterified residue of styrene-maleic acid copolymer 1750. The UV and IR spectra are shown (Fig. 5c). 6c). These data confirm the structure of the NCL-procursus of formula (I), which is the subject of the invention (Fig. 4d, 5d, 6d).
Example 4. Fractionated SMASMv 1480 and Mch 1230 (Mv / Mch 1,2) were prepared according to the procedure of Example 1, except that mixed liquid was used as the third mixed liquid of acetone and n-hexane in fractional chemical CM obtained in Example 1 a solution of acetone and n-hexane in the ratio of 38:62.
6.0 g of fractionated CMA is produced by a fraction of half-certifying using 1.60 g of n-butyl alcohol, 16 ml of dioxane and 0.06 g of lithium acetate. The result is 6.3 BuSMA, the content of anhydride rings in which is 44.4 mol.% (On average, 2.8 rings of anhydride per molecule). The MV is 1,660, and the 1Sh is 1390 (Mv / Mch 1.18). The BuSMA thus obtained interacts for hours, as in Example 1G, as a result of which the degree of conversion of the primary amine to an IR of 99.3 mol% is obtained. The product is subjected to dialysis, gel filtration and lyophilization. The result is 182 mg of purified ICS-derived
five
Q 5
about
0
five
0
five
0
five
Formula (I). Elementary analysis data, weight. %: N 10.67; C, 52.06; H 6.22. The average molecular weight is 14,300, and the average molecular weight of the partially semi-n-butyl-etherified residue of the styrene-maleic acid copolymer is 1800,
g ,, 7.0 „„ about
jc "lj o - J l, 8,
Example 5. Fractionated CM is subjected to partial semi-methyl esterification with methanol, resulting in a partially semi-methyl esterified copolymer of styrene and maleic anhydride (abbreviated ShEM MeM), the content of anhydride rings in which is 25.0 mol% (on average this content is 1.7 anhydrous rings per molecule), fv 1510 and mch 1280 (mV / mch 1.18). The MeCM thus obtained interacts with IR, then purification is carried out by analogy with Example 2 and the corresponding NCC derivative of formula (I) is isolated. Receive the following yes1-. s elementary analysis, weight. %: N 10.87; C, 52.81; H 6.11. The average molecular weight is 14,000, and the average molecular weight of the partially semi-methyl-etherified styrene-male copolymer residue and maleic acid is 1650
PRI me R 6. (1 unrationed SMA is subjected to partial esterification using 1,3-diethoke-2-propanol, as a result of which partially semi-1- (ethoxymethl) -2-to-toxyethyl-esterified copolymer is obtained styrene and maleic anhydride, the content of anhydride rings in which is 25.3 mol% (in the middle anhydride rings per molecule) j MB 1960, Mch 1650 (Yv / Mch 1.19) .The copolymer thus obtained interacts with the IRS. Then, the resulting product was purified in Example 3 in order to select the corresponding derivative of the NCM of formula (I). elemental analysis, wt.%: N 10.2; C 53.58; H 6.5 K The average molecular weight is 14,900, and a similar indicator dl is partially semi--1- (ethoxymethyl) -2-ethoxyethyl-ateri- the residual styrene-maleic acid copolymer residue - 2100. J
Example 7. NCC-prokavodnoy formula (I) receive in accordance with the described procedure using
BusMA (MB 1620, Mv / Mch t, 10), which was obtained previously under conditions similar to those in Example 1A-1BJ, except that dicoumenyl peroxide was used as a polymerization catalyst instead of benzoyl peroxide.
After 0.67 g of X-ray is dissolved in 20 ml of i; Under cooling with ice and without access to light, 0.8 M aqueous sodium bicarbonate solution is added to the resulting solution in portions of just 8.00 g of BuSMA with stirring, then the reaction is carried out for 50 hours while the pH of the reaction is maintained at more than 8 ,, 3. The degree of conversion of the primary amino groups of the IRS is 97.8 mol.% (The total concentration of IRS and the CUMA is 30%).
The resulting reaction mixture is diluted with water to a volume of 90 ml, and then poured into a column having an internal diameter of 50 mm and a length of 90 cm, filled with the Sephadex G-75 substrate (Pharmacia Fain Chemicals AB, Uppsala, Sweden). Elution was carried out at a volumetric rate of 4.0 ml / min in the dark at 5 ° C using 5 mM ammonium bicarbonate aqueous solution as a carrier solvent. By analogy with example 1, simultaneously with obtaining an absorption spectrum of the eluate in the range with a wavelength of 254 nm, the eluate fraction is collected from 1 2/3 hours to 6 2/3 hours after sample administration. The volume of this fraction is 1050 ml. It is concentrated to a volume of 60 ml using a 6M 14539 membrane ultrafilter (Sartorius BMHG, West Germany: molecular weight 10,000 is cut off) (Fig. 7).
One half of the concentrated liquid fraction, namely 30 ml, nano- t per column with a diameter of 50 and a length of 6 x) cm, is filled with Biogel P-60 substrate (Bio-Red Laboratories, USA), elution is carried out with. flow rate of 1.2 ml / min in the dark using 5 mM ammonium bicarbonate aqueous solution. The eluate fraction is collected from 12 3/4 to 16 1/12 h after sample introduction, and the concentration is carried out using membrane ultrafiltration, then lyophilized. The yield of the purified product, an NCL derivative of formula (I), is 266.5 mg.
j
u 15 0
5 0 o
j
five
As a result of the elementary analysis, the following data were obtained for the derivative, wt.%: N 11.31; C 52.97; H 6.40. The average molecular weight was 13.470, and the average molecular weight of the partially semi-butyl esterified copolymer of styrene and maleic acid was 1.385 W –34.3.
Biological tests of neocarzinostatin derivatives have been carried out.
Biological activity was measured for each of the NCC derivatives obtained in Example 1. Portions in twenty ml of the NCC derivative, having various concentrations, are placed on a paper disk 8 mm in diameter, which is placed on an agar plate with culture medium ( Mühler-Hinton), onto which Sarcina lutea PCI 1001 strain was previously grafted. After some time required for diffusion (5 hours) at 4 ° C, the cultivation was resumed at 37 ° C for 12 ° h. In this case, the concentration of the diluted the solution needed to get and an inhibition diameter of 13 mm. Such an effective concentration of IRS is denoted by 1, and certain concentrations of NCS derivatives are given in the form of relative values in terms of the value of IRS 1. The relative values obtained are used as indicators of biological activity.
With regard to acute toxicity with respect to mice, the diluted solution is administered once intravenously by injecting the solution into the tail of the male ICE (one group — 6 mice) at the age of 5-6 weeks, then the above-mentioned mice are observed for 14 days to determine the value.
Data on biological analysis using strain lutea and acute toxicity are given in table. 1. From the obtained results it can be seen that NCC-derivatives obtained under the conditions of the proposed method have a biological activity comparable to the biological activity of X, but the acute toxicity of the first one is much lower. FIG. 8 shows the inactivation curve obtained; by using a change in residual biological activity against lutea NCC-derivative.
When incubating the NCS-pro-acid formula (I) against lutea at a concentration of 100 mg / ml in fresh human blood at 37 ° C, it was found that the time of the loss of half the activity in whole blood is 32 min and 8 min for the NCS-derivatives, obtained in the examples. The same indicator for IRS, which is JQ ry used as a control compound, was 2-3 minutes. Consequently, NCC derivatives obtained under the conditions of the proposed method are much more stable-j5 in terms of their biological activity in whole blood or serum compared to the original NCC.
20
In addition, the antitumor activity against Ehrlich carcinoma (solid type) is determined using the NCN derivative of Example 1. The results are shown in Table 25. 2. NCC-derivative, obtained by the proposed method, possesses molecular-tumor activity, equal to the sensitivity of the NCC,
thirty
Table. one
Control NCC
T, 33
Note. 1. Use strain Sarcina lutea PCI-1001.
2. The concentration at which the zone of inhibition has a diameter of 13 mm on an agar plate is indicated in the relative value, in which case the corresponding concentration of NCC is taken as a standard.
Table 2
Tumor; Ehrlich carcinoma (hard fHn).
Graft cell count: 5 x X 10 / msh (subcutaneous).
Mice: ddY, age - five weeks
Drug use: intraperitoneal method once a day (5 times in all): 1,2, 4, 5 and 6 days after tumor transplantation. Evaluation of the effect of the drug: tumor inhibition rate (%) is equal to / CT / xlOQ / C, where C is the average tumor size (mm) in the control group, T is the average tumor size (mm) in the treated group.
An estimate of the rate of tumor inhibition was obtained at the end of the second week after tumor transplantation; The proportion of Survivors younger is counted 4 weeks after tumor transplantation.
Neocarzinostatin derivatives of general formula (I) have high lipid solubility (in lipidol), while neocarzinostatin and its known derivatives are dissolved only in water.
Thus, the neocarzinostatin derivatives obtained by the proposed method are less toxic than neocarzinostatin, which is comparable to the bnological activity, retain their biological activity 4 times longer than neocarizinostatin, while they are soluble in water.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining neocarzinostatin derivatives of general formula (I)
Busma - X - By CM,
50
de IKS is a bivalent neocarzinostatin residue in which one hydrogen atom is removed from each primary amino group in the alanine residue in the N-terminus of neocarzinostatin and in the lysine residue in the 20th position from the N-terminus of neocarinostatin;
BuSMA is a monovalent partially esterified butanol copolymer residue of styrene and maleic acid.
having an average molecular weight of Mn of 1480-1660 and a ratio of MB to the number average molecular weight of Mch 1.10-1.18 MB and consisting of the following structural units: styrene residue
-012 - С-partly esterified with butanol maleic acid residue
- sn
-sn
COOCt g COOH
maleic acid residue
-sn -sn
1 I
COO COO
residue of formula
-SN- I - I
C COOH
I
where the hydroxyl group of one carboxyl group of the maleic acid residue is removed and this carboxyl is combined with neocarinostatin, characterized in that the neocarzinostatin is reacted in aqueous medium with powdered partially esterified butanone with styrene maleic anhydride copolymer consisting of structural blocks of styrene residue
50
HE -
- SI
maleanol acid residue partially esterified with butanol
- SI
I
SI
COOCiJIg COOH
and the residue of maleic anhydride
- sn - sn-5
taken in a mass ratio of 1: 5 to 12 with a total concentration of neocarzinostatin and partially esterified with butanol copolymer, styrene and maleic acid 19–30%, then the recovery mass is dialyzed, the residue is filtered through Sephadex G-75 or biogel P-60 The product is eluted with 5 mM ammonium bicarbonate aqueous solution in the dark at a speed of 4-6 ml / min.
U9ij XufiuvfCKau fdSue {Ouley per million)
"Cs
I
/ (/ 2 Г «1Ь 1Ь W 22 2Ц 2В 2В W Г2 / 4 16 18 20 22 24 Time (/ depmt / SoHuff (MUff) Time of striking) niani (min.}
ABOUT
50100150
Retention time (min) Fi. H
Thebes. 2
 ude01ki6ani. (min)
„JuLJi. / 1Ж;
ii it 16 IB20 rz2 H ° ZHU Time ydepmuOoHUR mini d Fick.
Wiemi uder Kidani (fiuH.)
Jfy IS 18 20 22 lit 26 28
   - - J HT
П J6 18 20 22 g 2S 28
Time d'ertiban / 1 (nin)
9
hao. 2SOO 2000 then poo SOD dsh gsh
BoflHOioe number (
then that s soo Vahanoboe number (fH-ij

t
2800 goooo isoo rzoo soo SBO
3200 uoa - ,, ,,
BoffHoSoe number (
i
| i
I gi
w
mo 2800 mo rsoo izm soo t
3200 2WOSojimioe wcnofcfi- l
Thebes. five
zftQ 280 t Length are long (nm)
s
five
t ztfO 2BO t t too
Wavelength (HMJ
200 280 320 ZVO ifOO
Wave Length (Hff)
"
 10 i
Sl
I o 1o
0.7
lfl, ff
1.5
I.
gv
I o /
l y
S. M 2 itQ 280320 360 00
ut.6
Wavelength- (np
S
g
12 Ify G6 f8 20 22 2ft 26
BpCMff invertyboni (MUff)
X-derivative (Lr.7)
15 fil, 8
Editor M.Petrova
1 (5 60 7590
Wren inactidation {fiUH)
Compiled by V. Volkov
Tehred A. Kravchuk Proofreader S. Cherni
f m
 2BQHH

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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US3085994A|1959-10-30|1963-04-16|Sinclair Research Inc|Chain terminated copolymer of styrene and maleic anhydride of low solution viscosity|

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US3121043A|1960-05-11|1964-02-11|Scient Associates Inc|Sustained release pharmaceutical preparation and methods for making same|

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US3245933A|1960-05-19|1966-04-12|Sinclair Research Inc|Styrene-maleic anhydride copolymers cross-linked with aliphatic polyhydroxy compounds|

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JPS6017206B2|1977-03-24|1985-05-01|Hiroshi Maeda|

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JPH0123480B2|1983-01-31|1989-05-02|Kurare Kk|JP2556865B2|1986-09-19|1996-11-27|山之内製薬株式会社|Composition for non-injection administration of neocarzinostatin derivative|

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CA1327161C|1987-09-01|1994-02-22|Mitsugu Kobayashi|Lyophilized pharmaceutical composition of neocarzinostatin derivative|

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JPH01156925A|1987-09-01|1989-06-20|Yamanouchi Pharmaceut Co Ltd|Freeze-dried drug composition of neocartinostatin derivative|

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WO2001083548A1|2000-04-28|2001-11-08|Effector Cell Institute|Novel derivative of cell chemotactic factor|

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EP1386927B1|2002-08-02|2005-03-30|Institut Curie|Shiga toxin B-subunit as a vector for tumor diagnosis and drug delivery to GB3 expressing tumors|

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EP3072910A4|2013-11-19|2018-02-21|Hiroshi Maeda|Derivative of styrene-maleic acid copolymer|

法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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JP58145418A|JPH0133119B2|1983-08-08|1983-08-08|

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