CH641454A5 - CYCLIC ACETALS, METHOD FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS. - Google Patents

Description

The object of the present invention are new compounds which show cytostatic, hypotensive and analgesic effects, and new agents which are effective for the treatment of cancer and hypertension as well as for pain relief. The object of the invention is also a process for the preparation of new compounds which are suitable as or for antitumor agents, as agents for reducing blood pressure and as analgesics.

The drawings show:

1 shows the nuclear magnetic resonance spectrum (NMR) of pure methylglyoxal,

2 shows the NMR spectrum of methylglyoxal dissolved in deuterium oxide,

3 shows the NMR spectrum of the product (in acetone D6) of the reaction between L-ascorbic acid and methylglyoxal,

Fig. 4 shows the NMR spectrum of the product of Example 3 and

5 shows the infrared spectrum of the product of Example 3.

The new compounds of the formula (1) according to the invention are prepared by mixing preferably approximately equal amounts of an aldehyde or ketone of the formula r.

Aryl or R1 means, and an endiol compound of the formula

5 HO - C ^

R ~

ho - c

V

wherein R3 and R4 are hydrogen, alkyl or aryl or together the group

15

r ~!

c

\

O

/

c -

r8

r r

25th

form in which Rs to R8 are hydrogen, alkyl or aryl or in which R5 and R6 together can form the group -C = 0 and R8 a group of the formula

30 r9o - c - h

'10 may be chlorine, in which R9 and R10 are hydrogen, alkyl or aryl 35, and allowing the components to react and inert, 2,3-nitrogen atmosphere at room temperature in an aqueous medium, e.g. for about an hour.

The new cyclic acetals are compounds of the formula (1)

40

i

0 - C

(1)

r "

45 d2 '/ \

r 0 - c v

c = o in R1 means:

r in which R1 one of the groups ho - c - oh,

1

X

is where X is hydrogen, alkyl, cycloalkyl, aryl, hydroxyaryl or arylalkyl and R2 is hydrogen, alkyl,

50

C = 0,

c

- H or

C.

- H

60

1

II

ff

X

c

- H

C.

- H

1

X

1

C.

= O

f

X

65

HO - C -

OH,

1

X

1

i

1

O

II

u

C - H

or

C.

- H

r

If

II

X

C - H

C.

- H

1

X

C.

= O

X

in which X is hydrogen, alkyl, cycloalkyl, aryl, hydroxyaryl or arylalkyl, R2 is hydrogen, alkyl, aryl or] and R3 and R4 are hydrogen, alkyl or aryl.

New cyclic acetals according to the invention are also those in which R3 and R4 together form the group

5

641454

r5

i c - \

0 /

c -

r8

r r

form in which R5 to R8 are hydrogen, alkyl or aryl.

The invention also includes compounds in which the above groups R5 and R6 together form the group = 0, and compounds in which R8 the group r9o -

c - h

1

Choir

10th

io

15

20th

where R "and R10 are hydrogen, alkyl or aryl.

The invention also includes the hydrated forms of the new compounds described above.

If the reaction components are purified methylglyoxal and L-ascorbic acid, the reaction can be recognized by the decrease in the reducing properties of L-ascorbic acid 25 compared to iodine down to about 5% of the original value. The purified reaction product can by

Evaporation in vacuo and subsequent column chromatography or azeotropic distillation can be obtained. The hydrated product is called AM for short.

It should be noted that purified methylglyoxal can be replaced with commercially available methylglyoxal with or without polymerization inhibitors and that this product can contain hydrated or oligomeric methylglyoxal.

Nuclear magnetic resonance spectra (NMR) were recorded for pure methylglyoxal (FIG. 1), for methylglyoxal dissolved in deuterium oxide (FIG. 2) and for AM monohydrate (FIG. 3). The IR spectrum of AM monohydrate was also recorded. The NMR spectrum showed two different methyl proton resonances, one of which was expected for a methyl ketone (at 5 2.2) and the second can be attributed to a hydrated methyl ketone (at 8 1.8). The comparison of FIGS. 2 and 3 shows that the absorption caused by the aldehyde proton of methylglyoxal has obviously been shifted into the acetal region (S 4.0-4.5). The integration shows a 1: 1 (or 4: 4) ratio of the total L-ascorbic acid to the total methylglyoxal-C-H protons.

It can be concluded from these data that the enolic hydroxyl groups (in positions 2 and 3) of ascorbic acid reacted with the aldehyde carboxyl group of methylglyoxal to form a cyclic acetal as follows:

o c

h-c = 0 ho-c i

c = 0 + ho-c / ^ C-H

i ho-c-h f

o ch,

ch2oh o-c /

h c-c-c-h

"X0-C o

O

II

c o /

-c-h

+ H2 °

ho o-c • / h0c-c-c-h

3 '\

ho o-c

(a)

ho-c-h f

ch2oh o

II

-c o

(b)

c-h i

ho-c-h i

ch2oh

The ketonic carbonyl group (A) undergoes hydration (up to about 90%) to form the product of structure 45 (B). The invention is not limited to any particular reaction mechanism. The reaction can proceed via the reaction between methylglyoxal monohydrate and L-ascorbic acid or between methylglyoxal and L-ascorbic acid, the latter product then being hydrated.

The elementary analysis of this product (AM) gave the following values (%):

Analysis calculated for C9HÌ2O8: S5

Calc .: C 43.55, H 4.84, O 51.61 Found: C 43.91, H 5.93, O 51.16.

Similar NMR and IR analyzes were carried out with compounds which were obtained from other aldehydes or ketones which can be used according to the invention instead of methylglyoxal, and with compounds which were prepared from other endiols which can be used according to the invention instead of L-ascorbic acid. In all cases 65 the NMR and IR spectra were consistent with the cyclic acetal structure of the products.

It is surprising and unexpected that the inventive

moderate implementation takes place in aqueous solution. It is generally known and expected in this field of organic chemistry that acetalization and ketalization reactions require a non-aqueous medium. It is also surprising that the aldehydes and ketones described here react selectively on the 2,3-hydroxyl groups of L-ascorbic acid, since all known acetals of L-ascorbic acid are formed by the 5,6-hydroxyl groups.

The process according to the invention is explained using the following production examples.

example 1

100 g of L-ascorbic acid were dissolved in 400 ml of oxygen-free distilled water under a nitrogen atmosphere. 205 ml of methylglyoxal (40% aqueous solution, available from Aldrich Chemical Co., Inc., Milwaukee, Wisconsin) was added to the L-ascorbic acid solution and the mixture was allowed to stand at room temperature under a nitrogen atmosphere for about 1 hour. After flushing the rapid evaporator with nitrogen, the mixture was freed from water to constant weight at room temperature by evaporation and gave 130 g of a pale yellow sticky mass. This product was spotted on thin layer chromatography plates made of cellulose and placed in a chamber containing ethyl acetate: benzene (2: 3) as a solution

641454

6

contained medium. The methylglyoxal rose with the solvent front. The product had an Rf of about 0.3; the ascorbic acid did not chromatograph.

When titrated with iodine solution, the product showed the presence of 5% ascorbic acid or its corresponding equivalent of reducing substance.

Example 2

1.52 g (0.01 mol) of phenylglyoxal monohydrate were added to a solution of 1.76 g (0.01 mol) of L-ascorbic acid in 50 ml of water and stirred for 1 hour under a nitrogen atmosphere. The whole was then evaporated to dryness in vacuo. Alternatively, the product can also be freeze-dried. The product was then isolated as in Example 1. The NMR spectrum of the main product portion showed absorption at about 8 4.0-4.5, which is characteristic of the acetal-C-H. The IR spectrum showed two different carbonyls, one from a lactone and another from an aroylcarbonyl group. About 50% iodine consumption was determined during titration, which indicates a partial reaction of the free endiol groups.

Example 3

According to Clauson-Kaas and Limborg (Act. Chem. Scand., 1: 2-methyl-2,5-dimethoxy-2,5-dihydrofuran (2,5-dimethoxy-2,5-dihydrosylvan) was 619, 1977). 10 g of this material was added to an aqueous solution of L-ascorbic acid (5 g / 25 ml water) under a nitrogen atmosphere. A pale yellow solution was obtained after 10 min. Water was removed overnight by vacuum evaporation at room temperature. No iodine consumption was found during titration, which indicates that the 2,3-hydroxyl groups of L-ascorbic acid have reacted. The crude product showed two spots (Rf 0.65 and 0.3) on silica gel thin layer chromatography plates using chloroform: methanol (9: 1) as solvent.

An NMR spectrum at 60 megahertz (Fig. 4) in acetone-d showed the presence of H-C = C-H (vinyl),

i!

JÒ-

H-Cc; (Acetal) and CHj-C-

I ^ O'- II

O

(Methylcarbonyl) protons in addition to signals for the C4, C5 and Ca protons of L-ascorbic acid. The IR spectrum (in Nujolmull, Fig. 5) indicated the presence of several hydroxyl groups and two distinguishable carbonyl groups.

Example 4

According to the method explained in Example 2, 5.6 g (0.1 mol) of acrolein was added to an aqueous solution (20 ml) of 20 g of L-ascorbic acid. Immediately after the disappearance of the oily acrolein, a colorless precipitate of the monoacetal separated. This was filtered off and identified in a conventional manner as 2,3-monoacetal of L-ascorbic acid and acrolein.

Example 5

The yellow product obtained in Example 1 was dissolved in a little ethyl acetate: benzene (2: 3) and applied to a chromatography column which contained DEAE cellulose (diethylaminoethyl cellulose) as the adsorbent. As the ethyl acetate: benzene (2: 3) solvent was passed through the column, a narrow band of the yellow product slowly moved down the column. The product was collected in a small volume of filtrate.

Example 6

The yellow product obtained according to Example 1 was dissolved in a little ethyl acetate and adsorbed onto «Celite» (diatomaceous earth) and dried. The dried «Celite» powder was washed 5 with chloroform to remove excess methylglyoxal. The product was then eluted from the "Celite" with ethyl acetate.

10 Example 7

13 g of the yellow product obtained according to Example 1 were dissolved in 200 ml of ethyl acetate and the solvent was evaporated at room temperature. Excess methylglyoxal was removed as an azeotropic mixture. Alternatively, chloroform or water can be used in place of ethyl acetate. The methylglyoxal in the ethyl acetate was precipitated as 2,4-dinitrophenyl hydrazone and was found in an amount of about 8%.

Further investigations of the product purified according to Examples 5 or 20 6 and the following evaporation showed:

(a) that the product is hygroscopic and tends to form an amorphous mass;

(b) that the product contains 5-8% ascorbic acid (based on iodine consumption), and

(c) that when reacted with excess 2,4-dinitrophenylhydrazine, the 2,4-dinitrophenylhydrazone of methylglyoxal is formed over a period of 4-5 days; results from the formation of 2,4-dinitrophenylhydrazone

30 a molar ratio of L-ascorbic acid: methylglyoxal in the product of 1: 1.

35 Example 8

The procedure of Examples 1 and 5 was repeated using freshly distilled methylglyoxal. The product obtained after the chromatographic purification was a colorless white powder which was less hygroscopic than the product of Example 5.

The following application examples serve to explain the pharmacological properties:

45 (I) 0.25 ml of a 2.5% aqueous solution of the product from Example 6 were administered intraperitoneally (i.p.) twice daily to Swiss albino mice (25 g each). No signs of toxicity were observed.

A single injection per day of 0.25 ml of a 5.0% aqueous solution of the product of Example 7 resulted in weight loss, diarrhea and finally death.

(II) 20 Swiss albino mice (25 g each) were injected with 4 x 106 Ehrlich carcinoma cells. A further 20 animals were similarly injected with 4 x IO6 Sarcoma-180 55 cells. The following day, half of the animals received two injections (i.p.) of 0.25 ml of a 2.5% aqueous solution of the product from Example 7. The injections were repeated daily. The animals were sacrificed on day 8 and the peritoneal cavity of each animal was washed with 20 ml of phy-60 siological saline (0.9%). The washing liquids were combined and centrifuged and the sediment volume measured. This sediment contained the malignant cells formed. Table I presents the results of summing the cell volumes obtained from the peritone 65 wells of 20 mice. Apart from slight bleeding in the peritoneal cavity of the treated animals, neither weight loss nor toxic symptoms were observed.

7

641 454

Table I

Treated injected cells untreated

Honest carcinoma

1.27 *

0.14

Sarcoma-180

1.46

0.05

20th

• Sum of the volumes of cells obtained in mi

(III) Seven patients with various advanced forms of cancer were treated by oral administration of 250 mg of substance (AM) in orange juice four times a day or by intravenous (iv) administration of 1 mg AM / ml 0.9% saline with a total daily dose of 1 g treated. A full clinical examination was performed before administration. Pulse, temperature and blood pressure were monitored during the infusion period. In addition, the usual biochemical and hematological examinations and tests for liver function, urine composition, blood sugar, serum enzymes and blood proteins were carried out before, during and after the administration of the treatment agent as required. As far as possible, the tumor was measured by palpation, X-rays and photography.

25th

Patient A - female, age 40 years:

Histological diagnosis:

undifferentiated carcinoma of the right kidney with metastases.

Previous treatment: 30

Adriamycin, cyclophosphamide, vincristine, 5-fluorouracil, steroids, warfarin sodium. Three processes with partial remission only after the first and second process.

Status at the start of AM therapy:

Patient very sick, dyspnotic, coughing, pain in the 35th

Stomach and chest area; Abdominal tumor fixed (R) 12x8 cm; Virchow glands fixed 4 x 2 cm; ulcerating injuries on the top of the head, 1 x 1 and 1 x 2 cm; Secondary effects on the lungs as evidenced by an x-ray.

Dose: 40

1 gram (g) IV during 24 hours on day zero, 1 g IV during 24 hours on day 2; lg orally for 24 hours a day 4,5 and 8; 1 g IV during 24 hours on days 15-21 - continuously.

45

Results: Significant clinical improvement in breathing within 12 hours. Pain-free after 24 hours. Virchow glands after 48 hours free of deep structuring; No inflammation around the gland. Head injuries dry and crusted (healing), no inflammation of the environment. Blood pressure steadily falling from the beginning from 130/90 to 75/50 on day 3. Hemoglobin value fell from 12.5 g to 9.0 g during the first 24 hours. Signs of congestive heart failure with edema in the ankle and sacral region. Lungs dull in the base area. No dyspnea - slow improvement 55 on completion of IV therapy. Three units of blood administered. Abdominal distension and diarrhea. Day 15: IV

started again; no improvement for the first 24 hours, then slow improvement for the next 24 hours. Painless and free breathing. Abdominal distension 60 waning, diarrhea ended; i.v. continued. Virchow glands again free of deep tissue attached to the skin. Abdominal tumor 10x6 cm. X-ray according to Lund:

no change in tumor size, but sharper line. 65

Biochemistry and hematology:

abnormal findings in hydroxybutyrate dehydrogenase,

alkaline phosphatase; Serum albumin; Blood sugar.

Patient B - female, age 56 years:

Histological diagnosis:

5 Colon adenocarcinoma with metastases in the liver.

Previous treatment:

Surgical resection, colostomy. 5-fluorouracil, leva misol, cyproheptadine, warfarin sodium.

Status at the start of AM therapy:

Patient highly jaundiced; Nausea, vomiting. Liver 5 cm below the rib border hard and nodular. Ascites with bilateral pleural effusion; Liver function test abnormal. Dose:

15 oral 1 g in 24 hours

Results: Vomiting ended, no changes otherwise; acute congestive heart failure after 24 hours - death. No change in hemoglobin levels.

Biochemistry and hematology:

abnormal findings in bilirubin, aspartate transaminase, alanine transaminase, alkaline phosphatase, leukocyte count.

Patient C - female, age 46 years:

Histological diagnosis:

Intraduct breast cancer; Stage IV; Bone metastases. Previous treatment:

Combined cyclic chemotherapy with cyclophosphamide, 5-fluorouracil, adriamycin and methotrexate. Deep X-rays of secondary effects on the backbone; Hyperthermia through radio frequency treatment (RF).

Status at the start of AM therapy:

Metastases to the liver and bones, severe pain; Relief from morphine.

Dose:

1 g IV during 24 hours on day zero and day 2.

Results: Pain-free 6 hours after the start of the infusion; Pain recurs 12 hours after the end of the infusion on day zero. Repeated infusion produced a pain-free period 24 hours after the infusion. No toxic effects. No effects on hemoglobin.

Biochemistry and hematology:

abnormal blood sedation findings.

Patient D - female, age 43 years:

Histological diagnosis:

advanced undifferentiated carcinoma of the breast with

Multiple metastases.

Previous treatment:

Deep x-ray therapy. Cyclic chemotherapy. Warfarin sodium; RF hyperthermia.

Status at the start of AM therapy:

Secondary effects on the bones, lungs and liver. Back pain and breathlessness. Ulcerating lesions of the chest wall 5 x 6 cm and 2x2 cm.

Dose:

1 g IV in 6 hours on day zero and day 7.

Results: relief of pain and dyspnea; no pain relievers required from day zero; no effect on visible tumor; extraordinary tiredness; Blood pressure fell on day zero from 130/80

641454

100/60; Rose again on day 1 to 130/80; falling again on day 7 from 130/90 to 100/70.

Biochemistry and hematology:

abnormal levels of hydroxybutyrate dehydrogenase and lactic acid dehydrogenase.

Patient E - female, age 40 years:

Histological diagnosis:

recurrent melanoma; metastatic.

Previous treatment:

B.C.G.-Levamisol, D.T.I.C .; surgical excision with

Block dissection; RF hyperthermia.

Status at the start of AM therapy:

large, partially necrotic lesions 14 x 10 cm on the

Groin (L) with sinus secretion of 100+ ml daily;

Pain.

Dose:

1 g for 6 hours on day zero.

1 g for 6 hours on day 5.

1 g for 6 hours on day 9.

Results: Painless at the end of the first infusion; Outflow at the sinus stopped at the end of the infusion on day zero; no change in tumor size, but slow decrease in skin inflammation; Recurrence of pain on days 7 and 8. Vomiting after infusion on day 5. Extreme fatigue on days 6 to 9. Blood pressure stable.

Biochemistry and hematology:

Abnormal findings in blood creatinine, aspartate transaminase, alanine transaminase, hydroxybutyrate dehydrogenase, lactate dehydrogenase and alkaline phosphatase.

Patient F - female, age 53 years:

Histological diagnosis:

Adenocarcinoma of the breast with brain metastases; recurrent. Previous treatment:

surgical resection of brain metastases; Cobalt radiation therapy; cyclic combined chemotherapy.

Status at the start of AM therapy:

Malaise with headache and sudden vomiting due to increased intercranial pressure; Papilloedema, multiple spinal metastases; Pain.

Dose:

1 g IV continued for 24 hours on day zero, 1,2,3,4,5,6,7.

Results: Vomiting stopped on day 2, pain reduction, but pain when rotating in the lumbar region. Decreasing papilloedema; Headache disappeared on day 5. No side effects; Patient clear and confident on day 7. Blood pressure constant.

Biochemistry and hematology:

abnormal findings of alkaline phosphatase and serum albumin.

Patient G - male, age 73 years:

Histological diagnosis:

Flaky cell carcinoma of the lungs; inoperable; chronic bronchitis and emphysema.

Previous treatment:

RF hyperthermia.

Status at the start of AM therapy:

Karnofsky O deteriorating; severe dyspnea; Chest pain reduced by pain reliever.

Dose:

1 g IV in 24 hours

Results: Apart from the decrease in chest pain during 24 hours, no effect; The patient's condition worsened and he died on day 3. Hemoglobin levels stable.

Biochemistry and hematology:

abnormal findings in leukocytes; Lowering blood, blood urea, serum sodium, serum chloride, serum calcium, aspartate transaminase, alanine transaminase, alkaline phosphatase.

The clinical studies described above show that AM is useful for the treatment of various forms of cancer. Continuous intravenous administration inhibits tumor activity and leads to a general regression of the disease. In addition, the compounds according to the invention can be used to reduce excess blood pressure and to combat pain.

It is known that the rapid growth of cancer cells leads to an accumulation of toxic products in the tissues around the tumor and throughout the body; These toxic products can be thought to cause the general pain that many cancer types experience. The observed general pain reduction in the patients in the clinical tests of the inventive agents can be caused by the interruption of the formation of these toxic metabolic products.

The mode of action of the compounds according to the invention with regard to cytostatic, hypotensive and pain-reducing effects has not yet been clarified; The empirical observation that the cells stop proliferating when exposed to these compounds already justifies the use of these substances for the treatment of such serious, previously untreatable and often fatal diseases such as cancer. After clarifying the mode of action of these agents and determining their safety, the agents can also be used to treat high blood pressure and to combat pain.

8th

s io

15

20th

25th

30th

35

40

45

50

55

B

2 sheets of drawings

Claims (4)

641454 1 6 - c - r \ O / 7th - c - r r8 represent in which R5, R6, R7 and R8 are each hydrogen atoms or alkyl or aryl groups, or wherein R5 and R6 together can represent = 0, or / and R8 is a group of the formula r9o - c - h ch2-or10 can represent, in which R9 and R10 each represent hydrogen atoms or alkyl or aryl groups, and X is the hydrogen atom, an alkyl, cycloalkyl, aryl, hydroxyaryl or arylalkyl group. 1 x I. c II c t x h h or d ch tl ch è = 0 « x represents, R2 is the hydrogen atom or an alkyl or aryl group or has the meaning given for R1, R3 and R4 are each hydrogen atoms, alkyl or aryl groups or together a group of the formula R 1 10 ch "-or r in R1 one of the groups ho - c - oh, ■ x C = 0, (1) 2 / r in R1 is a group of the formula ho - C - oh, x C = O, x c - h II c - h I. x or c - h II c - h i - 0 I. x 55, in which X is the hydrogen atom or an alkyl, cycloalkyl, aryl, hydroxyaryl or arylalkyl group and R2 is the hydrogen atom or an alkyl or aryl group or has the meaning given for R1, and (b) Endiol compounds of the formula r " I. C. 60 r \ -R " O ho - c / 7 - c - r i8 ho - c V 2. Compound according to claim 1, characterized in that R3 and R4 together are a group of the formula in which R9 and R10 each represent hydrogen atoms or alkyl or aryl groups. 4. A compound according to any one of claims 1-3, 15 characterized in that R 'is the hydrogen atom and R2 is the group C = 0 20 ch., is. 5. A compound according to any one of claims 1-3, 25 characterized in that R2 is a group of the formula I. ho - c - oh i x 30th is. 6. A process for the preparation of therapeutically usable compounds of the formula (1) according to claim 1, characterized by mixing (a) aldehyde or 35 ketone of the formula r ' C = O 45 2 / \ R O - C r9o \ I. c - h 2nd PATENT CLAIMS 1. Compounds of formula (1) 3rd 641 454 in which R3 and R4 are each hydrogen atoms or alkyl or aryl groups or together are a group of the formula R ~ - C R O r R characterized in that L-ascorbic acid is used as the endiol compound. 11. Medicament, characterized in that it contains at least one compound of formula (1) according to claim 1. 12. Medicament according to claim 11, characterized in that it is a cytostatic or / and analgesic or / and antihypertensive agent. 13. Medicament according to claim 11 or 12, characterized in that it contains the compound of formula (1) dissolved in 10 to 10,000% by weight, based on the weight of the compound, water or physiological saline. form in which R5, R6, R7 and R8 are each hydrogen atoms or alkyl or aryl groups, where R5 and R6 together can represent the group = 0 and Rs a group of the formula 15 r9o - C -ch "- H • or 10th in which R9 and R10 are each hydrogen atoms or alkyl or aryl groups, and allowing the compounds to react at room temperature under an inert atmosphere in an aqueous medium. 7. A compound according to claim 6, characterized in that the endiol compound is one of the formula JZ ho ho C. II c_ Rf 0 .X \ 7 r is used in which R3, R6, R7 and R8 are each hydrogen atoms or alkyl or aryl groups, where Rs and R6 together can represent the group = 0. 8. A compound according to claim 6, characterized in that the endiol compound is one of the formula O II C. ho - c II ho - c. r9o O "c - h i - h ch" or10 is used in which R9 and R10 are each hydrogen atoms or alkyl or aryl groups. 9. The method according to any one of claims 6-8, characterized in that methylglyoxal is used as the aldehyde. 10. The method according to any one of claims 6-9, 25th 30th For many years, people have been looking for an effective treatment for all forms of cancer. Despite the great interest and numerous important discoveries, the major breakthrough in cancer treatment or treatment has so far not been achieved. According to the bioelectronic theory of protein interactions originating from A. Szent-Györgyi (see Szent-Györgyi, "Electronic Biology and Cancer", M. Dekker, New York, 1976), methylglyoxal can be used to control or prevent cell division because of its properties as stronger Electron acceptor play an important role. Due to its aldehydic carbonyl group, this compound interacts with proteins by attacking the primary amino groups of the proteins. Regardless of whether this theory actually applies, such regulation of cell division by methylglyoxal may be applicable for the development of effective chemotherapeutic agents. However, methylglyoxal and the compounds related thereto are extremely unstable in vivo because of the action of a glyoxalase enzyme system which converts these compounds into D-lactic acid in the presence of reduced glutathione. Accordingly, because of the effect of glyoxalase, any in vivo test for the effects of methylglyoxal on cell division would give negative results. According to Szent-Györgyi, bioelectronic theory can explain cancer as a disruption of the electronic configuration of proteins in cancer cells (see Szent-Györgyi, "The Living State and Cancer", in press); He starts from the assumption that methylglyoxal and related compounds restore the correct protein configuration and cause the cancer cells to return from the abnormal growth state to the normal "resting state". The use of an agent derived from methylglyoxal for the treatment of various forms of cancer has been described by Freireich et al. (see “Cancer Chemotherapy Reports”, 55 Volume 16, pages 183-186, 1962). These authors report clinical studies with methylglyoxal-bis (guanylhydrazone) in patients with acute myelocytic leukemia and observe a complete remission rate of 69% in thirteen patients, leaving no doubt as to the antitumor activity of this compound in 60; In particular, the authors indicate that all the therapy methods common at the time could only achieve a 13% complete remission. U.S. Patent No. 2,893,912 also shows that 65 shows that certain cyclic glyoxal compounds, e.g. Cyclo-hexylglyoxal, benzylglyoxal, etc., have antiviral activity. Considering evidence that some forms of cancer with the appearance of chromo45 viral 50 641454 3. A compound according to claim 2, characterized in that R5 and R6 together represent = 0 and R8 s is a group of the formula 3rd R \ / ° "C c R " form in which R5, R6, R7 and R8 are each hydrogen atoms or alkyl or aryl groups. 4th Something related to cancer cells, it can be speculated that these compounds may be useful for the prevention, treatment and healing of viral diseases, including some forms of cancer. U.S. Patent 2,927,054 describes the condensation of certain sugars, e.g. Glucose, mannose, fructose, etc., with an aldehyde or ketone to form cyclic sugar acetals. The mechanism appears to be based on the elimination of water by combining the oxygen of the carboxyl group of the aldehyde or ketone with hydrogen from each of the two hydroxyl groups of the sugar. This condensation reaction takes place when the mixture is heated to the boiling point of the aldehyde in the presence of an acidic acetylation catalyst, conditions prevailing which favor the open-chain form of the sugar. The two adjacent carbon atoms of the cyclic acetal ring are adjacent carbons of the aliphatic chain of the sugar molecule. Some cyclic acetal rings of this type can be formed on the same sugar molecule to form polymeric cyclic acetals.