Method of producing derivatives of aminoacridine-alfa,beta-(d)- and (l)-n-glycosides or hydrochlorid

专利摘要:
The invention relates to novel aminoacridine- alpha , beta -(D)- and -(L)-N-glycoside derivatives, the salts thereof and to a novel process for the preparation of such compounds and salts. The novel compounds have the formula I <IMAGE> I wherein R is hydrogen or a group of the formula II <IMAGE> II wherein n=0 or 1, p=1 or 2, A-p is an anion, preferably halogenide, R1 is hydrogen or a methyl group and R2 is hydrogen or a sugar residue, or R is dimethylamine, and the two substituents X and X1 are identical or different and stand for hydrogen, a group of the formula II, dimethylamine, halogen, a C1-4 alkyl group, a C1-4 alkoxy group, for a nitro-, cyano-, carbomethoxy-, carbamoyl-, phenyl- or a C1-4 alkylphenyl group, with the restriction that at least one of the substituents R, X and X1 represents a group of formula II with R2=sugar residue, and R3 is hydrogen or a C1-5 alkyl group.
公开号:SU1346045A3
申请号:SU823396152
申请日:1982-02-26
公开日:1987-10-15
发明作者:Ковач Антал；Липтак Андраш；Нанаши Пал；Яношши Лорант；Чернуш Иштван；Эрдей Янош；Касаб Иштван；Полиа Кальман；Несмельи Андраш
申请人:Биогал Дьедьсердьяр (Инопредприятие)；
IPC主号:

专利说明:

This invention relates to a process for the preparation of new aminoacidine derivatives, ch1, y- (B) or - (b) N-glycoeids.
and their hydrochloric salts of general formula I:
Uh
where or 1;
R-H or CH
with X, Xj-H, ZH, NH, NHR ,, Y, -NO, NHR,, Yj-CHj,, Br, NHR ,, where R, -, p, B-glucopyranosyl and 2,3, 4, 6 -tetraacetyl-S -, / 3 -B-gluco pyranosyl residue, with Y, X, Xg - NHR, or X, -NH ,,, and Xi -NHR ,,
where R, is the sugar residue as defined above, as well as p-D-galactopyranosyl, 2,3,4,6-tetraadethyl-o6-1 -D-galactopyranosyl, ot-L-ram-pyranosyl, s. -, - B-ribopyranosyl, fi-lactopyranosyl residues, or X, - -D-glucopyranosylaminogroup X -oi-L-ramnopyranosylaminogroup, pa,
having antitumor and antifungal activity.
The purpose of the invention is to obtain new aminoacidine glycoside derivatives with anti-fungal and antitumor activity and less toxicity.
Example 1. 3,6-Di- (| 6-B-glucopyranosylamino) acridine.
In a refluxed condenser and stirrer with a 3-liter round-bottomed flask, 66.0 g (0.33 mol of D-glucose monohydrate and 36.9 g (0.15 mol) of 3,6-diamino-acridine-hydrochloride in a mixture of 1350 ml of acetone and 150 ml of water. The suspension is heated to

45 C and then mixed with IO ml of concentrated hydrochloric acid. After stirring for about 5 minutes, the solution becomes clear, after another 2-3 minutes the product begins to precipitate. The reaction mixture is kept in an ice-water bath for 1 h, after which the precipitate is separated. The precipitate is dissolved in 250 ml of water and the solution is mixed with 2 liters of acetone. The flocculated precipitate is separated, washed first with 200 ml of ethyl acetate, for 4604545. 2
The 100 ml of ether and dried in vacuo. The reprecipitation is repeated 2 more times.
70.0 g (87.5%) of the product are obtained. 5 m.p. 190-95 ° C; Mo - 5.8 ° ((75,
ten
dimethylformamide); TLC: silica gel 60 F 254, eluent acetone and ammonium hydroxide 65:35; , 41.
, 01oNz (mol. Bev 533.27)
15

Calculated,%: C 56.26; H 5.86; N 7.88.
Found,%: C 55.42; H 5.69; N 8.0 b
PRI mme r 2. 3-Amino-6th-0-glucopyranosyl-amino-acridine.
The liquid phase separated according to example 1 from the precipitate, along with the unreacted starting compound and a small amount of diglucoside, also contains a monoglucoside. The solution is evaporated in vacuo. 3 g of the obtained 15 g of the residue after melting are introduced into a 300 g filled Silica Gel C column with a diameter of 7 cm and a height of 25 cm and eluted with a mixture of acetone and ammonium hydroxide prepared in a ratio of 65:35. 10 ml fractions are collected, their composition is monitored by thin layer chromatography. For this purpose, the same solvent mixture is prepared as for column chromatography. Monoglycoside containing fractions are combined and evaporated in vacuo. The residue is treated with 50 ml ethyl 5
acetate and then filtered.
Yield 1.25 g; m.p. 190 ° C; , 3 (, 55, dimethylformamide); TLC: silica gel 50 F 254, 0 solvent - acetone with ammonium hydroxide in the ratio of 65:35; , 79.
Calculated,%: C 61, 42; H 5.70; N 1 1.32.
C „H, OjNj (mol. Weight 371.19).
Found,%: C 60.95; H 5.60; N 15.05.
PRI me R 3. 3,6-Di - (- o;, - B-galactopyranosyl-amino) acridine.
In a 3 L round-bottom flask equipped with a reflux condenser and stirrer, 60.0 g (0.33 mol) of D-galactose and 36.9 g (0.15 mol) of 3,6-diaminoacridine hydrochloride are suspended in the mixture with stirring
5 1350 ml of ethanol and 150 ml of water. The suspension is heated to 70 ° C. with stirring and mixed with 7.5 ml of concentrated hydrochloric acid. Slowly turbid due to flocculent sediment
3 13460454
the solution is stirred for another 2 hours at YP-PR and me R 5. 3,6-Di- (2, 3, 4,
This temperature and then b-tetra-O-acetyl-β-B-galactopyranuate for 16 hours in refrigerator-amino-acridine.
(+4 ° C), the liquid phase is separated and the iostoma-mother liquor, from which the extract is dissolved in 150 ml of water. Once the product is crystallized, the product is in contact with constant stirring at a tide. According to Example 4, the mixture is evaporated to 75 ml. are in 3 liters of ethanol containing 5% solution; solution is kept in the refrigerator, dy. Falling flocculent sediment. After aging for 8 hours, the precipitate is filtered off and dried. The transfer of small needle-like crystals, the deposition in the manner described, the repeat — they are filtered and dried, and twofold. 35.0 g (35.8%) of the product are obtained;
Yield 60.5 g (75.6%); m.p. 200 C; m.p. 195 ° C; And ,, -20.3 ° (, 48, and Wj, -25.4 (, 31, dimethylformamide); chloroform); TLC: silica gel, 60 F 254,
TLC: silica gel 60 F 254, eluent -15 eluent - dichloromethane and acetone with ootsetone and ammonium hydroxide in the ratio 7: 3; 56.
Session 7: 3; 33.Calculated,%: C 56.66; H 5.45;
Calculated,%: C: 56.26; H 5.86; N 4.83.
N7,88.С4, dM, (mol. Weight 869.51)
Found,%: C 55.49; H 5.69; 20 Found,%: C 56.08; H 5.29;
N 7.96. I, N 4.68.
 PRI me R 4. 3,6-Di- (2, 3, 4., P p and me R 6. 3,6-Di- (ob-b-frame 6-tetra-0-acetyl- ("; -B-galactopyra-pyranosyl-amino) -acridine,
nosyl-amino) acridine (additional 2.46 g (10 mol) 3,6-diamino-acetylation). 25 readin-hydrochloride and 4.0 g (2.2
60.0 g of L-ramno-monohydrate susra 3 3,6-di ((li, f.-D-galactopyranosyl-pendyrate) obtained in a mixture of 10 ml of water with 90 ml
amino) -acridine is suspended in ethanol mixture. The reaction mixture, intense 600 ml of pyridine and 600 ml of acetic acid, is stirred and heated to 70 ° C.
anhydride. The reaction mixture was stirred After adding 0.5 ml, the mixture was stirred at room temperature for 18 hours at room temperature of hydrochloric acid and then evaporated to a further 90 minutes at a specified temkum (12 Torr) to a volume of 150 ml. The sample, in which case the gloss volume is released, is poured into 600 g of ice-like flaky crystals. Mixture
Noah water. With besieging badly from-. stand 12 hours at room temperature powdered and then filter out. Semi - sediment drain the liquid phase. 3.6 g (71.8%) of the product are precipitated. Him
dissolved in 1 l of dichloromethane. Rast-dissolve in a solution of 0.5 ml of the concentrateant shake (ml), sucked hydrochloric acid in 120 ml
boil over sodium sulfate and then water and the solution is dropped to 240 ml
soar in a vacuum. The residue after you-ethanol. The precipitate being filtered off by evaporation is dissolved at boiling and dried,
reflux in 200 ml of this-T.pl. 185 C; "G.p + 145 ° (, 25,
nola. When cooled to room dimethylformamide); TLC: silica gel
temperature precipitates 8.0 0 254, eluent acetone and hydroxide
(8.2%) substances in the form of long ammonia needles in a ratio of 85:15; 21
shaped crystals. Sediment twiceCalculated,%: C 59.93; H 6.23;
recrystallized from ethanol .. N 8 39.
 G- ° - -. Lde °; | / С ° 6оП9; 2 b c;
chloroform); TLC: silica gel 60F254
e-luent - dichloromethane and acetone, in accordance with p and m e r 7. 3,6-Di- («i-D-ribopinochenia 7: 3;, 62. i-
  ranosyl amino) acridine.
2.46 g () of 3,6-diamino-acCalcined,%: C 56.65; H 5.45; 55 Readin-hydrochloride and 3.3 g (2.2 x
N 4.83.) D-ribose with stirring C4iH4iO, gN3 (mol. Weight 869.51); NII suspended in a mixture of 90 ml of acetone;%, C 55.92; H 5.36; Nna with 10 ml of water. To heated to 45 C
4.96. Suspensions add 0.5 ml of concentrated hydrochloric acid. After 2–3 minutes a clear solution forms, after another 4–5 minutes a precipitate begins to form. 25 minutes after the addition of the acid, the liquid phase is separated, the precipitate is dissolved in 20 ml of water and the solution is poured into 200 ml of acetone. Replanting is repeated 2 more times.
The product is filtered off and dried, ig also containing solid. Yield 2.5 g (52.8%); m.p. 180- part washed with acetone (twice
50 ml) is then dissolved in 170 ml of water and the solution is added dropwise to a mixture of 15 acetone and ethanol (1700 ml) prepared in a 1: 1 ratio. The orange-colored precipitate was filtered off, washed first with ethyl acetate and then with ether and dried in vacuo. Exit 18 g.
For further purification
1 ": DI, + 14 1 (c 1, 2-0, dimethylformamide); TLC: silica gel 60 F 254, eluent acetone and ammonium hydroxide in the ratio 75:25; 43
Calculated,%: C 58.32; H 5.75; N 8.88.
CjjHj OgN, (mol. Weight 473.24)
20
Found,%: C 57.90; 5.89; 8.56. PRI me R 8. 3,6-Di - ((3-lactopyranosyl-amino) -acridine. Dissolved in 120 ml of distilled
2.46 g (10 mol) of 3,6-diamine-water and the solution is poured into 1200 ml of Ridin and 7.92 g (2.210 mol) prepared in a 2: 1 ratio of lactose hydride at constant acetone with ethanol. The resultant stirring is suspended in a mixture of 80 ml 25 14.5 g of precipitate, which is washed in the manner described and dried. Replanting is repeated three more times.
300 g of silica gel 40 (70–230 mesh, 0.063 mm) are suspended in 600 ml of an acetone – ammonia – water mixture prepared at a ratio of 70:15:15 at 30. The suspension is introduced into a column of silica-ethanol with 20 ml of water. The reaction mixture heated to 70 ° C is mixed with 1 ml of concentrated hydrochloric acid and stirred at 70 ° C for 3 hours. Then, 3.96 g (1.1-10 mol) of lactose are added and the mixture is stirred for 4 hours at the indicated temperature. The mixture is then incubated for 10 hours at room temperature, the liquid phase is decanted and the solution is dissolved in 115 ml of water. The solution is added dropwise to 1150 ml of ethanol. The reprecipitation is repeated three more times. The product is filtered and dried.
Yield 6.1 g (70.8%); m.p. 210 C; otj -1 12, 7 ° (, 52; dimethylformamide); TLC: silica gel 60 F 254, eluent acetone and ammonium hydroxide in the ratio 1: 1; , 35.
Calculated,%: C, 51.81; H 5.99; N 4.90.
 (mol. weight 857.82)
Found,%: C 50.61; H 6.32; N 4.61.
PRI me R 9. 3- (| 3-.B-Glucopyranosyl-amino) -6- (oi-L-romino-pyranose yl-amino) -acridine.
14.76 g (0.06 mol) of 3,6-diamino-acridine hydrochloride ,. 12.00 g (0.06 mol) of B-glucose monohydrate and 10.92 g (0.06 mol) of L-rhamnose monohydrate are suspended in a mixture of 552 ml of acetone with 48 ml of water with stirring. The reaction mixture is heated to
45 ° C and mixed with 4.0 ml of concentrated hydrochloric acid. After 5-6 minutes, the solution becomes clear, and after another 4-5 minutes, the oily product begins to discharge. 45 minutes after the addition of the acid, the mixture is cooled to room temperature and then the phases are separated. Oily
gel precipitates in the column. 1.5 g of the crude product are introduced into 60 ml of this solvent mixture, the mixture is stirred vigorously overnight, and 1 g of the substance is dissolved. The solution is filtered and then introduced into the column. The column was eluted with the indicated solvent mixture.
The pure fractions are evaporated, a suspension containing the precipitate is obtained. The product is precipitated with acetone, filtered, washed and dried. The purity of the product is examined by high pressure liquid chromatography. T. 2 0-214 ° C; 6i j., - 7, I5 (, 42, water); TLC: silica gel 60 F 254, eluent acetone and ammonia in the ratio 75:25; ,five.
, 81 min (n-butanol: acetic acid: water 4: 1: 1).
Calculated,%: C 58.02; H 6.04; N8.12.
, 0, N ,, (mol. Weight 517.54) Found,%: C 58.30; H 6.09;
N 8.03.
Example 10. 3,6-Di- (pB-glucopyranosyl-amino) -10-K-methyl acridinium chloride.
20.8 g (o, 08 mol) of pulverized 3,6-diamino-I0-methyl acridinium chloride and 35.2 g (0.16 mol) of glucose monohydrate are suspended in a mixture of 695 ml of acetone with 105 ml of distilled water. The suspension is heated to 50 ° C. with stirring and then mixed with 5.6 ml of concentrated hydrochloric acid. The reaction mixture is stirred for another half an hour and then cooled to room temperature. The phases are decanted, separated from each other, and the solid is washed with acetone (twice 650 ml). After that, the product is dissolved in 250 ml of distilled water and the solution is dropped to 2500 ml of absolute ethanol with constant stirring. To the opalescent solution was added 12.5 ml of 10% sodium chloride solution. After a few minutes the precipitate begins to settle. After 2 hours, the precipitate is stripped off, suspended twice with 50 ml in anhydrous ethanol, filtered off and rinsed with 150 ml of ether.
The precipitate is dissolved in 260 ml of distilled water, the solution is added dropwise to 2700 ml of anhydrous ethanol, and a little of the salt solution is added to speed up the formation of a precipitate. The re-precipitation described is repeated twice.
24.2 g (51.35%) of product are obtained; tf 250 ° C-, (, 80, water); TLC: silica gel 60 F 254, eluent n-butanol, acetic acid and water in a ratio of 2: 1: 1; ,20.
Calculated,%: C, 53.49; H 5.87; N 7.20.
C „H„ 0
oNjCl (mol. weight 583.76)
Found,%: C 53,12; H 6.01; N 7.32.
EXAMPLE 11 3,6-Di- (pD-ga-gal-topi. N-i-amino) -1O-N-methyl acridinium chloride.
5.2 g of 3,6-diamino-10-methylacridine and 10.8 g of D-galactose in 200 ml of a mixture of ethanol and water prepared in a ratio of 88:12 are heated to boiling with stirring. To the mixture is added 1 ml of concentrated hydrochloric acid, then boiled for 1 h under reflux and then stirred for a day during
room temperature. Then 3.6 g of D-galactose are added again and the mixture is refluxed for 1 hour. The precipitate is then separated and washed with a small amount of ethanol. After that, the sediment does not contain D-galactose, but contains 5-10% unreacted
the original product. B: the rest of the sediment consists of mono- and digalactoside in a ratio of 1: 4. The precipitate is dissolved in 60 ml of water with gentle heating and the solution is added dropwise with 700 ml of ethanol with stirring. The mixture is mixed with 2 ml of 10% sodium chloride solution and then left to stand. The solid is filtered off, washed first with a small amount of alcohol, with ethyl acetate and then with ether, dried in a vacuum desiccator.
7.4 g of product is obtained, which contains practically no unreacted starting compound, and monogalactoside contains 10-15%. The obtained after three-time reprecipitation of 4.9 g of the substance contains, as is shown by the NMR-c spectrum, still mono-galactoside.
After five times re-precipitation
five
0
five
0
five
(yield 4.1 g, 35%) the product does not contain monogalactoside.
T. 200-210 s; And j + 522.7 ° (, 90; water); TLC: silica gel 60 F 254, eluent butanol, acetic acid and water in a ratio of 2: 1: 1; ,14.
Calculated,%: C, 53.49; H 5.87; N 7.20.
C2bN, 0, oK, C1 (mol. Weight 583.76)
Found,%: C 53.05; H 5.69; N 7.29.
Example 12. 3,6-Di- (ob-b-raminopyranosyl-amino) -1O-K-methlacryidinium chloride.
3.62 g (1, 4 10 mol) of 3,6-diamino-1 O-N-methyl acridine are suspended in a mixture of 126 ml of acetone with 14 ml of water with stirring. The suspension is mixed with 0.7 ml of concentrated hydrochloric acid and then boiled for 2 hours. Then, 5.6 g (3.07) of L-rhamnose monohydrate is added. The reaction mixture was heated under reflux for 6 hours and then stirred overnight at room temperature. The precipitate is filtered off, washed on the filter with first 10 ml of ethyl acetate, then 10 ml of ether and then dissolved in 20 ml of water. 140 ml of acetone is added to the solution. The precipitate is separated and re-precipitated twice. The resulting precipitate is dissolved in 40 ml of solid and then acetone (ca. 60 ml) is added dropwise until the precipitate begins to form. Replanting is repeated three times. After
This product consists of pure DI-
rhamnoside. The amorphous solid is dissolved in 100 ml of water and the solution is lyophilized.
T. 250-254 ° C; 0) H. + 486.5 °; And ", -52.2; And 5 ,, -281.9 (water); those: silica gel 60 F 254, eluent n-butanol, acetic acid and water in the ratio 3: 1: 1; ,sixteen.
Calculated,%: C 56.70; H 6, N 7.65.
 (mol. weight 551.76)
Found,%: C 56.65; H 6.18; N 7.49.
Example 13. 3-Amino-6- (ramnopyranosyl-amino) -10-methyl acridine chloride.
The filtrates described in Example 12 of reprecipitation are combined and, with stirring, poured into 200 ml of acetone, and mono-monoside is precipitated. The material is filtered, dissolved in water and lyophilized.
T. 216-222 ° C; bi p -350.6 °; ,,,, - 701.0 °. (Water); TLC: silica gel 60 F 254, eluent n-butanol, acetic acid and water in a ratio of 3: 1: 1; 42
Calculated,%: C 59.19; H 5.95; N 10.35.
 (mol. weight 405.86)
Found,%: C 59.85; H 6., 03; N 10.41.
EXAMPLE 14 3-Amino-6- (p-lactosyl-amino) -1 O-N-methyl acridinium chloride.
.
A suspension of 2.60 g (0 mol) of 3,6-diamino-10-H-methyl acridine in 100 ml of a 7: 3 mixture of ethanol and water prepared is mixed with 0.2 ml of concentrated hydrochloric acid and then boiled until until the solution is clear. After adding 5.40 g (1.5) of lactose monohydrate, the reaction mixture is stirred for 1 hour at boiling point and then overnight at room temperature. The precipitate is filtered off and then dissolved in 30 ml of light heat.
g
0
five
ABOUT
Q
five
five
0 g
water. The solution is added dropwise with stirring to 300 ml of ethanol. Re-precipitation is repeated. Then the precipitate is washed with 20 ml of ethyl acetate, then 20 ml of ether and dried in air.
Obtain 2.03 g (34.8%) of a yellow powdery substance (G + 226, I (, 20, water); TLC: silica gel 60 F 254, eluent n-butanol, acetic acid and water in a ratio of 2: 1 : 1;, 32.
Calculated,%: C, 53.47; H 5.87; N 7.19.
,,, 0, about N, C1 (mol. Weight 584, 02)
Found,%: C 54.10; H 5.91; N 7.03.
Example 15. 3,6-Di - (- lactosyl-amino) -1O-N-methyl acridinium chloride.
2.60 g of 3,6-diamino-10-methyl-acridine (10 mol) is dissolved in 50 ml of water. 10.8 g (3 mol) lactose monohydrate and 0.2 ml of concentrated hydrochloric acid are added to the solution. The reaction mixture is stirred at 50 ° C for 24 hours. At the 12th hour, 4 g (1 51 1 10 mol) of lactose monohydrate and 0.2 ml of concentrated hydrochloric acid are added. After cooling, the mixture is mixed with 200 ml of ethanol. The separated oily product is separated and dissolved in 100 ml of water. The solution is added dropwise to 600 ml of ethanol. 200 ml of acetone are added, which speeds up the precipitation. The precipitate is washed with 20 ml of ethyl acetate, then with 20 ml of ether and in air. 3.38 g of a yellow powder are obtained, which is a 1: 1 mixture of mono- and di-lactoside.
A dilactoside containing 10% solution of this mixture is added to a 10-fold amount of ethanol. Add 2-3 drops of an all-saturated solution of sodium chloride, which improves the filterability of the precipitate. Replanting is repeated five times. The obtained dilactoside is chromatographically homogeneous.
otlj, + 253.9 ° (, 92, water); TLC: silica gel 60 F 254, eluent isobutanol, acetic acid and water in a ratio of 2: 1: 1; ,12.
Calculated,%: C 50.27; H 6.0; N 4.62. ,
C,. ,, Cl (mol. Weight 907.92)
Found,%: C 50.46; H 6.8; N 4.56.
Example 16. 3,6-Di- (vol, p-B-ri-pyranosyl-amino) -10-methyl acridinium chloride.
2.60 g of 3,6-diamino-10-methyl acridine and 4.50 g of D-ribose in a mixture of 90 ml of acetone and 10 ml of water after adding 0.2 ml of concentrated hydrochloric acid are stirred for 1 hour at
4.0 g of the obtained crude product is dissolved in 40 ml of water. The solution is poured with constant stirring in 400 ml of acetone. The flocculent precipitate is filtered and washed with 50 ml of ethyl acetate and 50 ml of ether. The reprecipitation is repeated two more times.
Vcode 3.2 g (48%); m.p. 300 in 50 ml of water and with stirring, the solution is added dropwise to 200 ml of ethanol. After adding 600 ml of acetone, give
40 ° C. When the substance reacts, the solution is io (decomp.); -67.5 (s-0.86,
incompletely, the nature of the precipitate of cheme dimethylformamide); TLC: silica gel
The timeout is changed. Osa - 0 F 254, eluent - acetone: ammonia
the dock is combed (stuck together) at the bottom of the 80:20 count; , 35.
would. The solution is drained, the precipitate is washed Calculated,%: C 60,71; H 6.06;
a small amount of acetone and again 15 10.11.
decant. Then the precipitate is dissolved, (MM 415.44)
Found,%: C 60.50; H 6.12; N 10.21.
Example 18: 9- (2, 3, 4.6, settle a little, then the precipitate from -20-7® ° / ° ™ ° ° ™ is filtered, it is washed on a filter) -2-methyl acridine. In a small amount of ethyl acetate, (410 mol) of 9-amino-2-, then a small amount of ether and methyl acridine were added with 100 ml of benzene and 100 ml of nitromethane. Then, at 25 atmospheric pressure, half of the solvent is distilled off. To the mixture cooled to 60 ° C, 14.4 mg (4) HgBr, 1212 mg (4.8 x) Hg (CN) and 1947 mg (4.8
thirty
dried in vacuum. 3.9 g of product are obtained, which, as the thin-layer chromatogram shows, consist of approximately 30% unreacted starting material, as well as a mixture of mono- and diriboside (2: 1-3: 1). By reappointment seven times
k10 mol) acetobromglucose. The reaction mixture was stirred at 60 ° C for 36 hours.
1.4 g (13%) of pure diriboside are obtained. T. 186-200 ° C; Mj, +188.9 (, 24, water); TLC: silica gel 60 F 254, eluent methyl ethyl ketone, pyridine, water and acetic acid in a ratio of 70: 15: 15: 15; ,14. Calculated,%: C 55.04; H 5.77; N 8.02.
 (mol. weight 523.73) Found,%: C 55.21; H 5.81; N 7.91.
After cooling, filtration is carried out and the residue is washed with dichloromethane (4-20 ml). United filter you evaporate. The residue is dissolved in 200 ml of dichloromethane, washed first with 5% KI solution (2-30 ml), then with water (ml) and dried on sodium sulfate. The product obtained after centrifugation was purified on 120 g of silica gel G using dichloromethane-ethyl acetate 6: 4 mixture using column chromatography.
EXAMPLE 17 9-Amino-2-ethoxy-6- (y-B-glucopyranosyl-amino) -acridine.
In a 45 500 ml round-bottomed flask, equipped with a reflux condenser and a stirrer, in a mixture of 140 ml of acetone and 15 ml of water are suspended at
vigorous stirring 6.15 g. Receive 453 mg (21.0%) of amorphous D-glucose and 4.0 g of 6.9-diamino-2-ethok-50 vitreous; , -8.8 ° C acridine. The suspension is heated at (, 45, chloroform); TLC: silica stirring to 50 ° C and mixed with gel 60 F 254, dichloromethane: ethyl acetate — 1.6 ml of concentrated hydrochloric acid 6: 4; ,nineteen. lots. Substances dissolve within
a few minutes, then the product started: 55 Calculated,%: C 62.45; H 5.61; Says down slowly. After 1 h N 5.20. the precipitate is filtered from a cooled mixture
si and rinse 50 ml of ethyl acetate and Found,%: C 62,68; H 5.80; A small amount of ether. N5.11.
512
4.0 g of the obtained crude product is dissolved in 40 ml of water. The solution is poured with constant stirring in 400 ml of acetone. The flocculent precipitate is filtered and washed with 50 ml of ethyl acetate and 50 ml of ether. The reprecipitation is repeated two more times.
Vcode 3.2 g (48%); m.p. 300® ° / ° ™ ° ° ™ amino) -2-methyacridine. (410 mol) of 9-amino-2-methyl acridine, 100 ml of benzene and 100 ml of nitromethane are added. Then, at atmospheric pressure, half of the solvent is distilled off. To the mixture cooled to 60 ° C, 14.4 mg (4) HgBr, 1212 mg (4.8 x) Hg (CN) and 1947 mg (4.8
k10 mol) acetobromglucose. The reaction mixture was stirred at 60 ° C for 36 hours.
After 24 hours, 505 mg (2 x 10% ol) Hg (CN), i and 822 mg (2 "10 mol) of acetobromglucose are added.
After cooling, filtration is performed and the residue is washed with dichloromethane (4-20 ml). The combined filtrates are evaporated. The residue is dissolved in 200 ml of dichloromethane, washed first with 5% KI solution (2-30 ml), then with water (ml) and dried on sodium sulfate. The product obtained after purification was purified on 120 g of silica gel G using dichloromethane-ethyl acetate 6: 4 mixture using column chromatography.
13 1346045, 14
PRI me R 19. 9- (o-B-Glyukopira-kagel 60 F 254, eluent n-butanol:
nosyl-amine-o) -acridine and 9- (y-B-gluco-methanol: water 4: 2: 1; 72.
, pyranoyl-amine). Calculated,%: C 64.85; H 5.99;
660 mg of 9- (2,3,4,6-tetra-0-ace-N 7.56.
Tyl-ag, b-B-glucopyranosyl-amino) -ac-C U O N
Ridine is dissolved in 66 ml of Absolutely Found,%: C 64.68; H 5.83;
go methanol. 7.62 N is added to the solution.
5 mg sodium methoxide. The solution remains, PRI me R 21. 2-Bromo-9- (2, 3,
poured overnight and then neutralized with 6-tetra-O-acetyl-c-P-glucopyraco-ion exchange resin — amberlithomyl-amino) -acridine and 2-bromo-9- (2,3,
IR 120 (). Filtered solution of 4,6-tetra-0-acetyl-B-B-glucopyran is evaporated to a volume of 10 mp. Add-zyl-amino) -acridine,
After 5 ml of ethyl acetate and 30 ml of prospectus to 546 mg (1-10 mol) of 2-bromo-9-ether, the product precipitated, washing with amino-acridine was added 70 ml of benzoyl ether, 10 ml of ethyl acetate and then followed by 70 ml of nitromethane. Then with at simple ether (2-10 ml), half the pressure is distilled off under atmospheric pressure.
. 164 mg (36.6%) of a yellow solvent are obtained. The residue is cooled to
a powdery substance that is 60 ° C and mixed with 7.2 mg (2-10g mol) turned out to be oi-aHOMepoM. M.p. 154-156 C ;, HgBr, 606 mg (2.4-10 mol) Eg (CN
Wp + 12.9 ° (0.75; dimethylformamide); and 987 mg (2.4-10 mol) of acetobromgluTSH: silica gel 60 F 254, eluent-goses. The reaction mixture is stirred n-butanol: methanol: water 4: 2: 1; , 64. at 60 ° C for 36 hours. After the 24th
Calculated,%: C 64.04; H 5.66; 253 mg (10 mol) added per hour
N 7.86.25 Hg (CN) and 411 mg (10 mol) of acetobromC, i, Hjo05N2 glucose.
Found,%: C 64.30; H 5.50; After cooling, the mixture is filtered
N 7,75. and the residue washed with dichloromethane
From stock solution re-precipitated (4-15 ml). The combined filtrates are crystallized after several evaporation. Evaporation residue
days spontaneously /% - anomer (24 mg, dissolved in 150 ml of dichloromethane,
5.3%). M.p. 140-144 ° C; f, p -67,6 ° solution washed with 5% solution
(, 36; dimethylformamide); TLC: sily-KI, (2-20 ml), then with water (2k
kagel 60 F 254, eluent n-butanol: 20 ml), dried over sodium sulfate
methanol input 4: 2: 2; , 70. and evaporated.
Calculated,%: C 64.04; H 5.66; The product is purified by chromatography on
N 7,86. Column, first on 120 g of silica gel
C ,, H gO Nj mixture of dichloromethane - ethyl acetate in%, C: 63.91; H 5.70; In the ratio of 6: 4, then on 45 g of silicate7, 83. l 6 with a mixture of dichloromethane - acetone in
Example 20. 9- (o.;, 3-B-Glukopi-ratio 8: 2.
ranosyl-amino) -2-methyacridine. 31 mg (2.6%) of the anomer are obtained.
400 mg of 9- (2,3,4,6-tetra-0-ace- (vitreous solid);
Tyl-b /, | 3-B-glucopyranosyl-amino) -2-Wu + 28, l ° (, chloroform); TLC:
methyl acridine is dissolved in 40 ml of ab-silica gel 60 F 254, and eluent is dichloro-absolute methanol. Add methane to the solution - acetone 8: 2, 64.
4 mg sodium methoxide are added. SolutionCalculated,%: C 53.73; H 4.51;
left overnight and then neutralizing-N 4.64; Br 13.23.
are ion exchange resin-amberlitom, H O N, Br
IR 120 (). After filtering up-Found,%: C 53.90: H 4.60;
Saw up to 8 ml. Adding 4 N 4.59; Br 13.00. ethyl acetate and 40 ml of ether
The product is precipitated, filtered. Also receive 161 mg (15.0%).
and clean by rubbing first with 10 ml of anomer (glassy solid ethyl acetate and then 240 ml of simple), -6.8 ° (, 47, chlorof P-form); TLC: as anodomer,, 52.
This gives 212 mg (77.1%) of the product. Calculated,%: C 53.73; H 4.51;
in the form of a yellow powder. + 21.4N 4.64; Br 13.24.
(, 75, dimethylformamide); TLC: CIL-C, H27 O,
Found,%: C 53.73; H 4.47; N 4.70; Вг 13,36.
PRI me R 22. 9 (2,3,4,6-Tetra-0-acetyl-c, | 5-B-glucopyranosyl-amino) - acridine.
To 971 mg (5-10 mol) of 9-amino-acridine, 100 ml of benzene and 100 ml of nitromethane are added. Then, at atmospheric pressure, half of the solvent is evaporated. The residue is cooled to and mixed with 18 mg (5 10 mol) of HgBr, 1516 mg (6 10 mol) of Hg (CN) and 2467 mg (6-10 mol) of acetobromoglucose. The reaction mixture is stirred at 60 ° C for 36 hours. After the 24th hour, 632 mg (2.5-10 mol) of HgCCN) 10 mol) of acetobromide, 56 mg (77.6%) are added; m. 170 ° C; Ir + 41.9 ° (41, dimethylformamide); TLC: DC-Alurolle, silica gel 60 F 254 g, article 5562, Merck, eluent n-butanol, methanol and water in the ratio 4: 2: 1; , 79.
Calculated,%: C, 52.43; H 4.40; N 6.44; Вг 18,36.
ten
C ,, H ,, 0, N, Br
N
Found,%: C 52.81; H 4.31; 6.29; Вг 18,11.
PRI me R 24. 9-Amino-2,7-di- (B-D-glucopyranosyl-amino) -acridine-15 hydrochloride.
50 mg of 2,7,9-triamino-acridine and 200 mg of D-glucose monohydrate are boiled in a mixture of solvents (30 ml) prepared from acetone and water at 1028 mg (2.5 glucose.
After cooling, filtering is performed at a ratio of 9: 1, under constant stirring, and the residue is washed with dichlorification for 10 minutes. Then with Dometan (420 ml). The combined filtrates are evaporated. The residue is dissolved in 200 ml of dichloromethane, the solution is washed first with a 5% KI solution, (ml), then water (ml) and, after drying on sodium sulfate, evaporated. The product is purified on 150 g of silica gel with a mixture of dichloromethane and ethyl acetate in the ratio of 6: 4 by column chromatography.
660 mg (25.2%) of solid foam are obtained; Er + 16.6 ° (; 79, chloroform); TLC: silica gel 60 F 254, eluent dichloromethane: ethyl acetate 6: 4, 22.
C, 61.83; H
Calculated
N 5.34.
Found%:
5.35.
5.38;
C, 61.70; H 5.44; N
700 mg of 2,9-diamino-7-nitro-acridine and 700 mg of D-glucose monohydrate
Etc. and measure 23. 2-Bromo-9-01-D-glucopyranosyl-amino) -acridine.
100 mg of 2-bromo-9- (2,3,4,6-tetra-0- 45) are boiled in 30 ml of a mixture of acetone and water acetch1- / -B-glucopyranosyl-amino) -ac- (9: 1) with mixing for
10 min. After adding 3 drops of 2N. hydrochloric acid mixture is boiled
Ridine is dissolved in 20 ml of absolute methanol. The solution is mixed with 2 mg of sodium methoxide. The mixture is left overnight, then neutralized by ion exchange. 50 The residue is dissolved in 15 ml of boiling resin - amberlite 1 P 120 (H-form), water and the product is precipitated again while being filtered and evaporated to approximately 3 ml. 3 ml of ethyl acetate and 18 ml of ether are added, a precipitate is formed. The latter is filtered and thoroughly triturated with 5 ml of ethyl acetate, then with ml of ether. The product is a yellow powder.
another 10 minutes and then the precipitate is separated.
care 100 ml of acetone. The crude product contains a little more glucose and the original substance, and therefore it is re-precipitated two more times.
152 mg of chromatographically homogeneous amorphous red-brown final product are obtained; m.p. Above 220 C (decomp.); AND -229.3 ° (, 10; dime Exit 56 mg (77.6%); m decomp. 170 ° C; Ir + 41.9 ° (41, dimethylformamide) ; TLC: DC-Alurolle, silica gel 60 F 254, article 5562, Merck, eluent n-butanol, methanol and water in the ratio 4: 2: 1;, 79.
Calculated,%: C, 52.43; H 4.40; N 6.44; Вг 18,36.
C ,, H ,, 0, N, Br
N
Found,%: C 52.81; H 4.31; 6.29; Вг 18,11.
PRI me R 24. 9-Amino-2,7-di- (B-D-glucopyranosyl-amino) -acridine hydrochloride.
50 mg of 2,7,9-triamino-acridine and 200 mg of D-glucose monohydrate are boiled in a mixture of solvents (30 ml) prepared from acetone and water and 3 drops of 2N are added. hydrochloric acid and boil for 10 minutes. The precipitated product is separated by decanting, then 25 is dissolved in 2 ml of water and again precipitated with acetone. Replanting is repeated 2 more times.
45 mg of a yellowish brown amorphous substance are obtained; tpl 210 C (decomp.); Ип -59,3 ° (, 35, water); TLC: silica gel 60 F 254, solvent acetone and 25% solution of Shz in the ratio 7: 3,. 08.
. Calculated,%: C 51.33; H 5.58; N 9.58.
thirty
35
,, 0, (MM 585.01)
N
0
Found,%: C, 51.88; H 5.62; 9.45.
EXAMPLE 25 9-AMHHo-2 - ((i, | 3-D-glucopyranosyl-amino) -7-nitroacridine hydrochloride.
700 mg of 2,9-diamino-7-nitro-acridine and 700 mg of D-glucose monohydrate
The residue is dissolved in 15 ml of boiling water and the product is precipitated again at
another 10 minutes and then the precipitate is separated.
The residue is dissolved in 15 ml of boiling water and the product is precipitated again at
care 100 ml of acetone. The crude product contains a little more glucose and the original substance, and therefore it is re-precipitated two more times.
152 mg of chromatographically homogeneous amorphous red-brown final product are obtained; m.p. higher than 220 ° C; (decomp.); And -229.3 ° (, 10; dime17
tilformamide); TLC: silica acetone and 25% solution of shenium 7: 3; 52

Calculated,%: C 50.39 H 4.57, N 12.37.
C, q N, (MM 452 „85)
Found,%: C 50.50; H 4.55; N 12.20.
Pharmacological studies.
Antitumor properties of aminoacridine-N-glucosides.
For experiments in vitro, the cell-derived fibrosarcoma-A cell line extracted from the smaller one was used (Ph. Me, SI-, undifferentiated polymorphic, highly malignant: tumor).
The compounds under investigation were dissolved in the nutrient medium PM 1 1640: (0% of calf short, 0.63 mg / ml glutamine, 0.1 mg / ml gentamicin and 5 2-mercaptoethanol). Solutions containing I mg / ml of the active substance were filtered to a sterile state. Dilution series from 50.00 to 0.024 mg / ml were prepared from these strain solutions.
Experiments were performed under sterile tissue culture conditions in vessels that have 96 indentations; in the first row of the latter, solutions with a concentration of 0.05 mg / ml were injected. In each, 781 1.563 6.25
0, 781 1,563 6.25


0, 1950.3901.563
0, 195 0.390 1.563
45
18 to 10 deepening made 3-10 cells
(viable cell count) .. On the 3rd day, i.e. by the end of the period of an exponential increase in the number of cells, the cells were counted in a Bürkher chamber (in the control vessels by this time the number of cells had increased about ten times).
A growth brake counted for such dilutions in which, after 3 days, less than 80% of the cells contained in the control vessels survived.
In each dilution series, it was possible to observe the toxic concentration (not a single living cell), then the concentration at which growth inhibition appeared (less than 80% of the control - inhibition), and at the strongest dilutions - a neutral concentration at which it was impossible To establish any difference with the controls. These concentrations are different for each of the studied compounds, but all compounds show a good tumor inhibitory effect.
The results of the experiment are given in table. I.
The introduction of one or more sugar residues has a beneficial effect on the toxicity of the compounds.
The results of toxicity measurements carried out on CFLPs (females) are presented in Table. 2
Table 1
nineteen
3- (p-D-Glucopyranosyl-amino) -6- ("i-L-ramnopiran3-
amino) -6- ("i -L-ramnopyranosyl-amino) -10-methyl acridine-NS
3,6-Di- ((jt-L-ramnopyranosyl-amino) -1O-N-methyl acridine chloride
3,6-Di- (oi-L-galactopyranosyl-amino) -1O-N-methyl-acridine chloride
3,6-di- (y-lactosyl-amino) -10-methyl acridine chloride
3,6-diamino-acridine
3,6-diaminoacridine-diglucoside
3,6-Diamino-10-methylacridine
3,6-Diamino-10-methylacridine diglycoside
Compiled by Yu. Belousov Editor L. Veselovska Tekhred L. Serdyukova Proofreader N, King
.l. “.“, “.,.“. “m -“. “.“. “.”. “.-“. “.“. “. "" - m -. "-" - "-. - -." ----. - "----------- ---- -" - - "-" Order 4935/57 Circulation 347Subscription
VNIIPI USSR State Committee
for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5
Production and printing company, Uzhgorod, st. Project, 4
134604520
Continuation of table 1
12.5025.00
3.12525.00
0,3901,563
12.5025.00 blits2
84
65
280
87
60
14
210
37

权利要求:
Claims (1)
[1]
The test compounds were dissolved in a nutrient medium PM 1 1640 (10% calf serum, 0.63 mg / ml glutamine, 0.1 mg / ml gentamicin and 5 * 1 Osmol 2-mercaptoethanol). Solutions containing 1 mg / ml of active substance were filtered to a sterile state. A dilution series of 50.00 to 0.024 mg / ml was prepared from these strain solutions.
The experiments were carried out under conditions of sterile tissue culture in vessels that have 96 recesses; solutions with a concentration of 0.05 mg / ml were introduced into the first row of the latter. 3 · 10 ³ cells (a viable number of cells) were added to each well. On the 3rd day, i.e. by the end of the period of an exponential increase in the number of ° cells, the cells were counted in a Burker chamber (in the control vessels, by this moment the number of cells had increased approximately ten times).
.jQ Dilutions were considered as inhibitory growths, in which after 3 days less than 80% of the cells contained in the control vessels survived. In each dilution series can be ₁₅ to observe the toxic concentration (no living cells), and then the concentration at which a growth inhibition (at least 80% of the control - braking), and most sil2Q GOVERNMENTAL dilutions - neutral concentration at which it was impossible to establish any differences with control. These concentrations are different for each of the compounds studied, but all compounds show a good tumor inhibitory effect. The results of the experiment are given in table. I.

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GB1008625A|1963-12-09|1965-11-03|Farmaceutyczna Spoldzielnia Pr|Ascorbic acid derivative|

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PL106752B1|1976-02-25|1980-01-31|Politechnika Gdanska|HOW TO RECEIVE NEW 1-NITRO-9-ALKYL-ALKYL-ALKYL-ACID AND OR THEIR SALT|

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US4322424A|1980-01-24|1982-03-30|Bristol-Myers Company|Crystalline glucoconate salt of m-AMSA and compositions containing same|HU188856B|1983-03-23|1986-05-28|Biogal Gyogyszergyar,Hu|Compositions for the regulation of plant growth and development comprising 3,6-diamino-acridine-n-glycoside-derivative as active substance|

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HU203896B|1988-10-26|1991-10-28|Biogal Gyogyszergyar|Process for producing glycosides of aromatic amines|

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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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HU81474A|HU186383B|1981-02-27|1981-02-27|Process for producing new citostatic amni-acridie-alpha, beta-bracket-d-bracket closed, or aracket-l-bracket closed-n-glycoside derivatives and salts|

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