DK170171B1 - Glyceropentulose derivatives, processes for their preparation, and pharmaceutical agents containing them - Google Patents

Abstract

Sugar derivatives of the general formula I and II <IMAGE> in which R1 is a hydrogen atom or an alkyl group with 1 to 7 carbon atoms, R2 and R3 are a hydrogen atom or, if R1 is an alkyl group, are also an acyl group R4CO, R is a hydrogen atom or an acyl group R5CO, and R4 and R5 are an alkyl group with 1 to 7 carbon atoms, have an excellent antiproliferative/cytotoxic activity with very low toxicity. The compounds of the formula I and II can be prepared by treating alpha- or beta-1,4-linked di- or oligosaccharides which contain at their reducing end a glucose, fructose or mannose molecule with inorganic or organic bases, isolating in a manner known per se from the resulting reaction mixture the 3-deoxy-D-glyceropentulose (3-DGP) of the formula I in which R1, R2 and R3 are a hydrogen atom, and, if required, converting the 3-DGP in a manner known per se into its glycoside (I, R1 = alkyl, R2, R3 = H), diacylglycoside (I, R1 = alkyl, R2, R3 = R4CO), dianhydride (II, R = H) or diacyl dianhydride (II, R = R5CO).

Description

in DK 170171 B1

The present invention relates to novel glyceropentulose derivatives, to a process for their preparation and to medicaments containing these compounds as active substance.

5 By cytostat in ka is meant chemotherapeutic agents that have an inhibitory effect on cell growth. Since, in particular, fast-growing cells, such as those found in tumors and leukemias, are affected by this inhibitory effect, chemotherapy drugs are commonly understood to treat cancer (cancer, cardnostics). Despite extensive studies, it has not yet been possible to indicate a clear mechanism of action for cytostatics. The known and tested cytostatics can be divided into the following groups: alkylating compounds; cytostatic natural substances; antimetabolites; connections with different constitution and mode of action. A major disadvantage of cytostatics is their high toxicity, and in addition, many cytostatics themselves act as carcinogens and / or mutagens.

It is therefore the object of the present invention to provide cytostatically effective compounds of low toxicity.

Surprisingly, it has been found that certain novel sugar derivatives of the following general formulas I and II exhibit a high antiproliferative-cytostatic-antimicrobial effect at a very low general toxicity.

Thus, the present invention relates to novel glyceropentulose derivatives which are characterized in that -has the general formulas I and II

35 DK 170171 B1 2 C320R2 H, C -

1 I

ro «/: - ro-ck -i- lo“ ~ c ~ a E-C-3

5 I O.

Π - ^ - ΟΛλ * rv pr? - Λ— i2, i 2 I — 51 Γ'-ο- "2

In E-C-H

fc) O J (> U

lO In H-c-0R

R 2 represents a hydrogen atom or an alkyl group or acyl group having each 1 to 7 carbon atoms, R 2 and R 3 represent a hydrogen atom or an acyl group R 4 CO, R 1 represents a hydrogen atom or an acyl group R 5 CO, and R 4 and R 5 represent an alkyl group of 1 to 7 carbon atoms.

An alkyl group R 1, R 4 or R 5 may be branched, but is preferably straight chain; it preferably has 1 to 4 carbon atoms and is e.g. methyl, ethyl, propyl or n-butyl. An acyl group R 1 is preferably an acetyl group. R4 and R5 are especially methyl. The groups R2 and R3 may also be different, but are in principle the same. Compounds of formula I, wherein R 2 f R 2 and not simultaneously a hydrogen atom are also preferred.

Particularly preferred compounds of the general formula I are: Methyl 3-deoxy-D-glyceropentuloside (R 1 = CH 3, R 2, R 3 = H), n-butyl-3-deoxy-D-glyceropentuloside (R 1 * n-C 4 Hg, R 2 , R3 = 30 H), n-butyl-diacetyl-3-deoxy-D-glyceropentuloside (R 1 = n-C 4 H 9, R 2 * R 3 s COCH 3), triacetyl-3-deoxy-D-glyceropentulose (R 2, R 2, R 3 = COCH3) and optionally 3-deoxy-D-glyceropentulose (3-DGP; R 1, R 2, R 3 = H); particularly preferred compounds of the general formula II are Di- (3-deoxy-D-glyceropentulose) -dianhydride (R = H) and diacetyl-di-3- (deoxy-D-glyceropentulose).-dianhydride (R = COCH3) .

DK 170171 B1 3

The compound of the invention of formula I wherein R 1, R 2 and R 3 are a hydrogen atom (3-deoxy-D-glyceropentulose; 3-DGP) is formed by the alkaline treatment of α- or β-1,4-linked di- or oligosaccharides, which contain at their reducing end a glucose, fructose or mannose molecule (maltose, maltulose, epilactose, lactose, lactulose, cellobiose, oligo-maltoside). The compound is obtained by treating these di- and oligosaccharides with alkali, such as preferably e.g. with hydroxides, carbonates or sulfites of alkali or alkaline earth metals, or with organic bases, preferably e.g.

pyridine or triethylamine, in a yield of ca. 0.5 to 5% relative to saccharide used. 3-Deoxy-D-glyceropentulose (3-DGP), a novel sugar, is like 3-deoxy-ketose isomer with 2-deoxy-ribose, which plays a significant role in the inheritance mass.

From a mixture of reaction products, 3-DGP can be recovered in enriched form or purely in various ways known per se, e.g. by liquid-liquid extraction with ethanol, acetone 20 or acetonitrile (these give 2-phase mixtures with concentrated sugar solutions in which the upper phase is strongly enriched with 3-DGP), but also preferably by liquid-solid chromatography. To this end, as stationary phases, strongly acidic cation exchangers of cross-linked polystyrene as alkali or alkaline earth tea, preferably in Na, K or Ca form, as well as strongly basic anion exchangers of cross-linked polystyrene as salts, preferably in Cl SO4 or HSOo form particularly suitable. When using e.g. water as the eluent, the unreacted sugars and their isomerization products appear 30 'first in the eluate, then well separated 3-DGP.

From the appropriate fractions, highly purified 3-DGP can be obtained as colorless, non-crystallizing syrup. Since the substance is prone to the formation of dimeric anhydrides under anhydrous or water-poor conditions, it is convenient to prepare it and store it as a ca. 50% aqueous solution. However, the aqueous solution is also relatively unstable and decomposes slowly during tanning, plating and formation of various furan bodies. Raising the temperature and lowering the pH accelerates this degradation. Therefore, for storage, it is appropriate to maintain the temperature of 5 <4 ° C and pH values between 5 and 6. In such solutions, there is evidently a mixture of α- and β-furanoses and open-chain keto sugars.

3-DGP is biologically active in this form. Instead of the free 10 3-DGP, more stable derivatives are used, namely the triacyl compounds, the corresponding glycosides or their diacyl compounds (compounds of formula I wherein R 1 represents an acyl or alkyl group and R 2 and R 3 represent a hydrogen atom or an acyl group R 4 CO), usually non-crystallizing, oily compounds, or the dianhydride of formula II (R = H) or the diacyl ester thereof of formula II (R = acyl), whereby these are usually compounds which are readily crystallizes.

The glycosides are extremely readily formed from the solutions of 3-DGP in the corresponding alcohols in the presence of very small amounts of acid or ion exchange in H + form as a catalyst already after a short time at room temperature. Equally, hydrolysis of the glycosides occurs in aqueous solution, so that under physiological conditions an equivalence of free 3-DGP can be expected.

The dianhydride of formula II (R = H) can easily be formed by treating moderately acidic 3-DGP solutions with water-sucking agents, such as e.g. anhydrous sodium sulfate or calcium sulfate, or by evaporation of aqueous or organic solutions of 3-DGP and standing the anhydrous product. The dianhydride (of formula II) can be readily cleaved in aqueous solution to monomers, similar to the glycosides. *

The acyl compounds of formulas I and II, wherein R 1, R 2 and R 3 are respectively an acyl group, can be prepared from the compounds of formula I wherein R 1 is hydrogen or an alkyl group (glycosides) or from the dianhydride of formula II, wherein R is a hydrogen atom, in a manner known per se, e.g. by reaction with acetic anhydride in pyridine.

5

The present invention also relates to a process for preparing the subject compounds of general formulas I or II, wherein R 1, R 2, R 3, R 4, R 5 and R have the above meanings, which process is peculiar in treating a or / 5-1,4-linked di- or oligosaccharides, which at their reducing end contain a glucose, fructose or mannose molecule, with inorganic or organic bases, from which the resulting reaction mixture isolates 3-deoxy-D -glyceropentulose 15 (3-DGP) of formula I wherein R 2 and R 2 represent a hydrogen atom and, if desired, in a manner known per se, 3-DGP transfers to pure triacyl compound (formula I, = acyl, R 2 R R 3 = R CO), its glycoside (of formula I, R 2 = alkyl), diacyl glycoside (of formula I, R 2 = alkyl, R 2, R 3 = R 4 CO), dianhydride (of formula II, R = h) or diacyl dianhydride -. (of formula II, R = RcCO).

D

The process is preferably carried out in aqueous medium. The reaction temperature is preferably between room temperature and 25 ° C.

To study their antiproliferative-cytostatic-antimicrobial properties, the compounds of formulas I and II are tested by means of a human ovarian cell arcinoma cell culture (HOC-7), using as a test system the so-called "human tumor cloning assay" "(HTCA), a system in which the clonal growth of malignant single cells is selectively recorded in semisolid media (cf. S. Hamburger, Science 197 (1977), 461), thereby showing the compounds a surprisingly high antiproliferative-cytostatic-antimicrobial effect. equipment.

DK 170171 B1 6

In toxicity study (mouse, oral), it was found that the compounds of formulas I and II exhibited no apparent acute toxicity.

Because of their remarkable antiproliferative-cyto-static-antimicrobial action and the favorable toxicity * study results, the compounds of the present invention exhibit an exceptionally broad pharmacological index (coefficient of effective dose of ED and toxicity LD50). In addition, a bactericidal effect was established.

The present invention further relates to a medicament characterized in that it contains one or more of the compounds of general formulas I and / or II and conventional pharmaceutical carriers and / or diluents. In addition to the usual pharmaceutical confectioners (carriers) and / or diluents, these drugs, in addition to the compounds of formulas I and / or II, may optionally contain additional active ingredients to support the therapy if, together with the compounds of the invention, they do not exhibit any undesirable side effects. . Suitable, appropriate dosage forms, dosage and use methods for e.g. oral administration, topical administration, administration by infusion, administration by injection, etc., substantially correspond to the known conditions for recognized antiproliferative / cytotoxic agents, however, due to the better therapeutic width (significantly poorer toxicity). of the compounds of the invention, higher dosages and / or a more frequent administration are discussed.

The compounds may be administered once or several times daily. Thus, the most appropriate amount and frequency of administration is directed mainly to the area of disease and the severity of the disease and to the general condition of the patient. * In the following Tables 1 to 3, Rp values for the compounds of the invention, the DC running agents used and HPLC systems for examination thereof are given.

DK 170171 B1

Table i 7

Thin Layer Chromatography (DC) Run 5 "Hdler - Rp Values 3-DGP in r 1 0.49 3-DGP 2 0.29 3-DGP 4 MT *

Methyl DGP 4 0.42 and 0.55 * 10 Ethyl DGP 4.

1 H 0.67 i-Propyl DGP 4 0.90 n-Butyl DGP 4 1.0+, running distance 76 mm n-Butyl-DGP diacetate 3 0.73 and 0.64 ++ 15 Di-DGP -dianhydride 2 0.35

Di-DGP dianhydride 4 0.25+ DGP-4-nitrophenylosazone 0.21

Di-DGP dianhydride diacetate 4 0.64 3-DGP triacetate 4 0.74 20 ._____ + Rr value for n-butyl DGP = 1.0; running distance 3 x 10 cm ++ Running distance 2 x 10 cm +++ see table 2 25

The following DC running agents and HPLC systems were used: 1 35

Table 2 DK 170171 B1 8 DC running gear

5 No. (DC finished sheet silica gel 60 F254 10x20 cm MERCK

(Best, No. 5729) _____ 1 Methyl ethyl ketone / glacial acetic acid / methanol 10 60 20 20 2 Methyl ethyl ketone / water 92.5 7.5 15 _ 3 Methyl ethyl ketone / toluene 20 80 20 4 Methyl ethyl ketone / toluene 50 50 25 5 Benzene / tetrahydrofuran / glacial vinegar 75 20 5

Trace reagent: 200 mg of 1,3-naphthalenediol in 50 ml of methanol 30 + 50 ml of sulfuric acid 20%; 10 minutes 100 ° C

-3-DGP and its derivatives appear as blue-green spots.

«9 35 DK 170171 B1

Table 3 9 HPLC systems 5 System 1 System 2 Column SHOOEX S 801 Vertex-Hypersie APS 3 μηι 8 x 500 mm 4.0 x 250 mm

Eluent Calcium azide in H 2 O Acetonitrile phosphate buffer 0.02% pH 5.1 0.01 mol / l pH 7.0 80 + 20 Liquid rate ml / minute 0.9 1.2

Detector RI RI

15 Ti 1 before volume of volume μ 20 20 20

Temperature ° C 60 Room temperature 20 Retention times approx. minutes: 3-DGP 26.80 (Fig. 4) 3.29 (Fig. 5)

Dianhydride (II, R = H) 25.54 --- 25

The following examples further illustrate the invention. The drawing shows: fig. 1 shows an IR spectrum of the compound of Example 6; FIG. 2 is an HNMR spectrum of the compound of Example 6; FIG. 3 The IR spectrum of the compound of Example 2; FIG. 4 shows an HPLC elution diagram in system 1 for 3-DPG; FIG. 5 an HPLC diagram in system 2 for 3-DPG; and FIG. 6 is an HPLC diagram in system 1 for the dianhydride V.

35

Example 1 DK 170171 B1 10

Preparation of 3-DGP from lactose S 52.63 g of 1actose monohydrate, corresponding to 50.0 g of anhydrous lactose, was dissolved in 25 g of water at 100 ° C, c 0.65 g of anhydrous sodium sulfite was added and the mixture was kept at 100 ° C for 20 min. and then quickly cooled to room temperature, seeded at ca. 1 mg of lactose monohydrate, and after approx. For 10 hours, the crystals of unreacted lactose were aspirated from the mother liquor during post-washing with slightly ice-cold water.

The filtrate contained 9.5 g of saccharide in 36.4 g of solution. It was desalted under mixed-bed ion exchanger and the obtained neutral solution was evaporated to 20 g in vacuo.

The product was applied to a glass column (26 mm internal diameter, with jacket heating to 60 ° C, 100 cm in length, filled with approximately 500 ml of cation exchanger "LEWATIT MDS" 1368 (strong 20 acid polystyrene matrix manufactured by Bayer AG , Leverkusen, in sodium form) and eluted with water. After a drug-free course of 175 ml, a 110 ml fraction was collected which contained the major amount of lactose and accompanying saccharides.

An additional 150 ml fraction contained the entire 3-DGP with 25 small amounts of accompanying saccharides.

The 3-DGP fractions from a total of 10 reactions were combined, evaporated in vacuo to ca. 20 g and chromatographed over the same system again. The 3-DGP fraction now contained only trace amounts of accompanying sugars. The fraction was evaporated in vacuo to 10 g.

Water content according to Karl Fischer: 49.2¾ ♦

HPLC analysis (system 1) yielded: 48.9% 3-DGP

35 0.8% galactose 1.1% other sugars Specific rotation: -22.1 ° (c = 3.0 in water) DK 170171 B1 11

This product was used for the cell culture experiments described in Example 8.

Structure Determination; 5

The novel substance reduces Fehling's solution, but not bromine in a slightly acidic environment. So it is a ketosis. It gives reaction according to Keller-Ki1iani (H. Kiliani, Ar. 234, (1986), 273) and according to Dische (Z. Dische, Microch. 8, 10 (1930), 4-32) to deoxy sugar. Specific rotation [α] 20 ° = -22.1 ° (c = 3.0 in water). It consumes 1 mole of periodate per day. mole, i.e. thus it has only 1 diol group. The crystal 1 in serous nitrophenylosazone appears, as expected, with melting point (25 ° C) and by elemental analysis as identical to the product described for 15 3-deoxy-xylose (S. Mukherjee and A.R. Todd,

Soc. 94 (1947), 969-973). Rp value in solvent 5: 0.21. Since the methyl glycoside (I, R 1 s CH 3, R 2, R 3 = H), the n-butyl (1) glycoside (I, R 1 = nC 2 g, R 2, R 3 = H) and the dianhydride (II, R = H) consuming no periodate, a hydroxy group in the glycosidic group is adjacent, the n-butyl glycoside (I, R

n-C4Hg, R2, R3 = H) can be reacted with acetic anhydride in pyridine to a diacetyl compound (I, R4 = n-C4Hg, R2, R3 = COCH3) which can be distilled in high vacuum. Boiling point: 90 ° C

(0.002 Torr = 0.26 Pa). Saponification with NaOH gave a molecular weight of 272.5 (calculated for C13H2206: 274,319). The IR spectrum (f in g.

1) and the mass and NMR spectrum (f in g. 2) confirms the structure indicated.

Elemental analysis (C 13 H 22 O 6) found: 56.61% C, 7.93% H, 35.6% 0 calculated: 57.0% C, 8.09% H, 35.0% 0 HPLC see Table 3 DC see table 1 35 DK 170171 B1 12

Example 2

Preparation of Di- (3-deoxy-D-glyceropentulose) dianhydride (II, R = H) · 5 g of the product obtained in Example 1, which contained 2,445 g of 3-DGP, was extensively evaporated in water jet vacuum at ca. ς 50 ° C bath temperature and the remaining syrup was taken up in 10 ml of methyl ethyl ketone and evaporated again, and the same process was repeated several times. Finally, the dry residue was heated for another hour in vacuo at 100 ° C. After several weeks of standing in vacuo, spontaneous crystallization occurred to a dense crystal porridge. Recrystallization from 1-butanol and methanol yielded 0.8 g of colorless crystals having a melting point of 148-149 ° C.

Specific rotation [α] 20β = -12.0 ° (c = 2.3 in water)

Elemental analysis: found: 51.35% C, 6.83% H, 41.26% 0 20 calculated: 51.72% C, 6.94% H, 41.34% 0 (for C 10 H 16 ° 6) IR spectrum is shown in FIG. Third

The substance does not reduce Fehling's solution and does not consume 25 periodate in neutral solution.

The diacetyl compound (II, R = acetyl) obtainable with acetic anhydride / pyridine is also a good crystallizing agent.

30 DC's Table 1.

Example 3

C

35 DGP yield from lactose with different reaction participants

Each 52.63 g of lactose monohydrate corresponding to 50 g of anhydrous lactose was dissolved in 25 g of water at 100 ° C, as in Example 1, and 25 ml of the solution of the reaction participants was added (concentration is given in Table 4) and the temperature was maintained at 100 ° C for 20 min. After rapid cooling, the DGP content of the reaction mixture was calculated as% of the anhydrous lactose used by HPLC system 1. The results are shown in the following Table 4.

Table 4

10 Reaction participant Concentration g / 100 ml% formed DGP

N32SO3 0.96

Na 2 CO 3 4 0.17

NaOH 1.5 2.01 Triethylamine 0.25 ml + 0.25 ml H 2 O 0.34

Pyridine 0.25 ml 0.13

Example 4 DGP yield from different di- and oligosaccharides In this example, the same procedure as in Example 3. In place of lactose, 50 g (dry mass) of different di- and d. oligosaccharides. As Reactor 25, each 25 ml of a sodium hydroxide solution was added 1.5 g / 100 ml each.

The results are shown in the following Table 5.

30 35

Table 5 DK 170171 B1 14

Applied saccharide_% formed DGP_? Lactulose 2.07

Maltose 1.54 c

Epilactose 1.34 01igomaltoside + 1.51

Cellobiose 1.75 10 + Glucose-free, from starch acid by precipitation with methanol Μη approx. 2300

Example 5 15

Preparation of n-butyl-3-deoxy-D-glyceropentuloside

To 5 g of the product obtained in Example 1 containing 2.445 g of DGP was added 5 ml of n-butanol and the reaction mixture 20 was evaporated in vacuum rotation evaporator to ca. starting volume. The process was repeated 3 more times to remove all water and the volume was supplemented with n-butanol to 25 ml and stirred at room temperature for 10 min. after the addition of 0.5 g of finely powdered, strong acidic cation exchanger in H + form 25 ("DU0LITE Microionex H"). After filtration and addition of 50 μΐ pyridine, all solvent was distilled off in vacuo.

There remained 3.40 g of a light yellow oily liquid which was easily soluble in water, alcohols and lower ketones. Thin-layer chromatography see Table 1.

30

Example 6

Preparation of n-butyl-1,4-diacetyl-3-deoxy-D-glyceropentuloside id 3.40 g of the n-butyl glycoside prepared in Example 4 was dissolved in 100 ml of pyridine and then 10 ml was added. of acidic anhydride and the mixture was allowed to stand for 24 hours at room temperature. The reaction mixture was then poured into a liter of ice water with stirring, and the precipitated colorless oil was washed several times with water and dried in vacuo over 5 P2 ° 5 *.

Yield: 3.67 g.

The product could be distilled in high vacuum of 0.002 mm Hg at approx. 80 ° C.

10

Specific rotation [α] 20g * -37.7 ° (c = 0.5; chloroform) Density 20/4: 1.86

Elemental analysis: C H 0 15 for C 13 H 22 O 6 calculated: 56.61 7.93 35.6 found: 57.0 8.09 35.0 IR spectrum see fig. First

HNMR spectrum see FIG. 2nd

20 Thin Layer Chromatography see Table 1.

Example 7

Preparation of 3-DGP Tri Acetate (R 1: acyl] 25 3.16 g of di-DGP diacetate was dissolved in 10 ml of 0, 1 HCl in glacial acetic acid and 0.5 ml of acetic anhydride was added and the mixture was kept at 40 ml. The mixture was evaporated in vacuo, leaving a yellow oil, 5.15 g, dissolved in 5 ml of toluene and placed on a column of 200 ml of silica gel 60 MERCK (230 ° C). - 400 mesh) and eluted first with 200 ml of toluene, then with 200 ml of toluene-ethyl acetate 80 + 20 and with 200 ml of toluene-ethyl acetate 60 + 40. In the 310-360 ml fraction, the main substance was evaporated. vacuo.

Colorless oil. Yield: 3.62 g.

Example 8 DK 170171 B1 16

Rp value see Table 1.

5 Biological study.

in

The 3-D6P and DGP-DA of Example 2 prepared in Example 1 were examined for their antiproliferative-cytostatic-antimicrobial properties by means of a human ovarian carcinoma cell culture (HOC-7), has called forth the so-called "human tumor cloning assay" (HTCA), a system in which the clonal growth of malignant single cells is selectively detected in semi-solid media (cf. S. Hamburger, Science 197 (1977), 461).

15

Method

An aqueous solution of 3-DGP and DGP-DA, respectively, was investigated in the following dilution series.

20

Test Condition Dilute Dilute% pg / ml Concentration in Drain in tube tube_Petrical Bowls_Petrical Bowls_ 25 C 1: 5 1:10 0.5 5000 D 1:10 1:20 0.25 2500 E 1:50 1: 100 0, 05 500 F 1: 100 1: 200 0.025 250 F1 1: 125 1: 250 0.02 200 30 F2 1: 165 1: 330 0.015 152 F3 1: 250 1: 500 0.01 100 G 1: 500 1: 1000 0.005 50 H 1: 1000 1: 2000 0.0025 25 I 1: 5000 1: 10000 0.0005 5 35 J 1: 10000 1: 20000 0.00025 2.5, which included both a negative control addition (in the form of HgCl2) and a solvent addition (Aqua bidest).

DK 170171 B1 17

The cultures were incubated at 37 ° C, 5% CO 2 # 100% humidity for 21 days, after which the culture systems were worked up, counting the growing colonies (Clones) under microscope.

5 As a result of the tested solution, a colon survival <50% of control was defined.

Result

Solvent control: VII: Colon survival 92% 10 = no inhibition of colony growth

Negative control: VI: Colon survival 0%

Linearity check: r = 0.968 Test substance concentration: D6P

C-F: Colon survival 0% = effect 15 F1: 0.08% = effect F2: 10% = effect F3: 44% = intermediate effect G-J: 65 - 84% = no effect 1 2 3 4 5 6 7 8 9 10 11 35

Test substance concentration: DGP-DA

2 C: Colon survival 30% = effect 3 D: 50% = intermediate effect 4 E: 57% = intermediate effect 5 F-J: 61-89% = no effect 6 7

The result shows a sharp dividing line between sensitivity and 8 resistance in the ovarian carcinoma line examined, where a high antiproliferative-cytostatic-antimicrobial effect could be detected in the sensitive area.

11

With the derivatives of 3-DGP described in Example 1 (methylglycoside, n-butyl glycoside, diacyl-n-butyl glycoside), a similar antiproliferative cytostat can also be obtained under similar anti-microbial action under similar test conditions.

DK 170171 B1

Example 9 18

Preservation according to DAB 9, VIII, NI

The compounds of the invention exhibit a bactericidal effect, as can be seen from the following test results:

Composition: di-deoxy-glyceropentulose dianhydride 0.3%, 1% and 3%.

10

The study was conducted with the following germs:

Escherichia coli ATCC 8739 Pseudomonas aeruginosa ATCC 9027 15 Staphylococcus aureus ATCC 6538 Candida albicans ATCC 10231 Aspergillus niger ATCC 16404 20 25 2

V

35 2 5 DK 170171 B1 19 to lo is (c in to in o o o o o o o o

rHIHi-H t-4 H ri ri H

ISLAND

σ xxx xxx xx L (0 0) 73 O 04 LO 00 lO O CM ΙΛ

UJ + J ΟΗΟβΙΗ O CO O O) (O O O O r-l LO

1n CQh-O * * * * - * · ~ i U ikC d) H r-l r-l Tt LO r-t LO CM Tt ττ co io oo to lo tom o o o o o o o o

Η Η Η H HH Η H

Φ XXX XXX XX

L · U

O) to O O) O r-l LO O CO o o o o o o o o

1 C LU 4-> 73 CO to 00 CM to CO 00 LO

(Q νμ *** »

^ (U 00 COrHli) ^ H CO rH CO

CO ID to CM LO to enter t - t o o o o o o o O r-l r-l r-l r-l t - I pH rH r-l at ^ x o x x o x o x x oooxx

jq i. d X

co a> co o · »io o o 10 r-

tU 1— LU -P 73 O CO r-i O CM CJt 05 CO CM

CO 4- »·.«. » * »*» ·.

^ (J H r-l r-l CO T t * 7 CO LO T t

I to LO LO LO to LO LO LO LO LO LO LO LO LO LO LO

£ - tn in ooooo ooooo o o o o o

<D c ^ H l-l i-i i-4 i-4 1 * 4 i-4 i-4 i-4 i-I 1-4 ι * 4 ι-4 τ4 H

tj at at 25 r- C tf) 73 xxxxx xxxxx xxxxx e 3> - c \ at> η μ oho to two to c * · looocnot LU 73 σ σ Μ Μ ^ M to t- Ο) CM CM 00 ΙΟ CO C * ri rt m at si at »^ ^ ^ --------

^> tf) .Ω r-l r-l CO CO CO O ri 1 CO CM O H CO CO CM

• co de de

O - r-l CO

. Λ C O

30 o V 1 in tn at in c · in c · in ce · s σ σ 3 co σ 3 co tf) OOt O 3 at O 30) 0 • r- 3 I_ -1- C_ £ - S- · < - U t_ C -i t_ CL 3 OO 0) 3130) 0) 3330) IB β β r- οι β β i “Ol B 10 i“ D) O) · γ- (0 CD -i · γ * CO * r * -r- (0 -r-

L. r- · · C i— · · C P „· · C

oc O ΟΌΓ · O 73 -C · O Ό £ · ^ 4J 0 3 CL 73 · O 3 a 73 · O 3 CL 73 · in ni o c a atffica at to c o.

0) · in - »-> m tn · tn +> to tn · in -w co cn I- UJ O. (O O <UJ CL W O <LU IL (O o <

Example 10 DK 170171 B1 20

Preservation according to DAB 9, VIII NI.

5 Analogously to Example 9, the bactericidal effect of DGP

investigated. *

Preparation: DGP aqueous syrup 0.3%, 1% and 3%,

Charge: 91621 10

The study was conducted with the following germs:

Escherichia col in ATCC 8739 Pseudomonas aeruginosa ATCC 9027 Staphylococcus aureus ATCC 6538 15 Candida albicans ATCC 10231 Aspergillus niger ATCC 16404 20 25 1 35 DK 170171 B1 21

Table 7 KBE / ml at

examination- KBE KBE KBE

Test body beginning after after 5 niches__Wife, partition1 day__3 days 10 days E. coli l, lxl06 6.7xl05 3f9xl05 l, 7xl06

Pseud, aerug. 2.2x105 l, 9x105 8.4x103 0

Staph, aureus 0.3% Ι, δχΙΟ5 2.8x105 Ι, δχΙΟ5 0

Cand.

albicans 9.1x105 4.8x105 4.9x106 3.3x106 Asp. niger 1.9x10 * 5.5x103 1.3x10 * 2.4x10 * E.coli 1.2X106 5.9x105 5.4x105 <102

Pseud, aerug. 2.2x105 7.2x10 * 0 0

Staph, aereus 1% 1.7x105 l, 3x105 3x10 * 0

Cand.

albicans 1.3x106 4.3x106 9x106 3.9x106 Asp. niger 1.7x10 * 6x103 1.3x10 * 1.0x10 * E.Coli 1.2x106 4.4X105 2.8x103 0

Pseud.

aeruginosa 2.2x105 15 0 0

Staph, aureus 3% 1.4χ105 4.5x10 * 0 0 20 Cand.

albicans Ι, ΙχΙΟ5 3.8x106 1.1x10 '4.0x106

Asp. niger 1.1x10 * 4x103 4.5x10 * 3.6x10 * 25 1 35

Claims (10)

1. Glyceropentulose derivatives, characterized in that they have the general formulas I and II C3 03. S, 'C j2Uit2. 21 V * —1 R ° f o 10 b-c-h I 0 _ h-c-or. cs c., IJI 2 in HC- -CS 'CH 2 p ^ -O ^ SCH ^ 15 (1} o I ^ HC-OR in C22 wherein R 1 represents a hydrogen atom or an alkyl group or 20 acyl group with each 1 to 7 carbon atoms , R 2 and R 3 represent a hydrogen atom or an acyl group R 4 CO, R represents a hydrogen atom or an acyl group R 5 CO, and R 4 and R 5 represent an alkyl group having 1 to 7 carbon atoms. Compounds of formulas I and II according to claim 1, characterized in that R 1 is a hydrogen atom or an acyl or alkyl group having 1 to 4 carbon atoms each. Compounds of formulas I and II according to claims 1 or 2, 30, characterized in that R 4 or R 5 is an alkyl group having 1 to 4 carbon atoms. 4. 3-Deoxy-D-glyceropentulose (Formula I, R 1, R 2, R 3 = H). Λ 5. Methyl 3-deoxy-D-glyceropentuloside (Formula I, R 1 = CH 3, R 2 R R 3 = H). N-Butyl-3-deoxy-D-glyceropentuloside (Formula I, R 1 = n-C 4 H 9, R 2, R 3 = H). 7. n-BJtyl-diacetyl-3-deoxy-D-glyceropentuloside (formula i, r 1 = n-C 4 H 9, R 2, R 3 = COCH 3) · 8. Di - (3-deoxy-D-glyceropentulose) dianhydride (Formula II, R = H). 9. Diacetyl-di- (3-deoxy-D-glyceropentulose) dianhydride (Formula II, R m COCH 3). 10. Triacetyl-3-deoxy-D-glyceropentulose (Formula I, R 10 R3 «= COCH3). A process for preparing the compounds of formulas I and II according to claim 1, wherein r1 # R2, R3, R4, R5 and R have the meanings given in claim 1, characterized in that a- or / 3-1 is treated, 4-linked di- or oligosaccharides containing at their reducing end a glucose, fructose or mannose molecule, with inorganic or organic bases, from the resulting reaction mixture isolates 3-deoxy-D-glyceropentulose (3-DGP) of formula I wherein R 1, R 2 and R 3 are a hydrogen atom and, if desired, in a manner known per se, 3-DGP transfers to a triacyl compound (formula I, R 1 = acyl, R 2, R 3 = R 4 CO), its glycoside ( Formula I, R = = alkyl), its diacylglycoside (Formula I, R ± = alkyl, R₂, R3 = R4CO), its dianhydride (Formula II, R = H) or its diacyl dianhydride (Formula II, R = R RCO) . 1 30 Pharmaceutical agent, characterized in that it contains one or more of the compounds of the general formulas I and / or II according to any one of claims 1-10 and the usual pharmaceutical carriers and / or diluents.