DEG0014632MA - - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

Day of _{registration:;} June 11, 1954 Advertised on February 16, 1956

GERMAN PATENT OFFICE

PATENT APPLICATION

CLASS 12ο GROUP 25

G 14632 IVb / 12 ο

Dr. Willy Stoll and Dr. Franz Litvan, Basel (Switzerland)

have been named as inventors

J. R. Geigy A.-G., Basel (Switzerland)

Representative: Dr. F. Zumstein, patent attorney, Munich 2

A process for the preparation of 2,2'-carboxy and 2, 2'-Carbalkoxymethylen-bis-l, 3-indandiones

The priority of the registration in Switzerland of June 12, 1953 has been claimed

It is known that the 3, 3'-methylene-bis-4-oxycoumarin after oral administration already in very low doses a strong blood clotting retardation based on the lowering of the prothrombin level Has an effect. The 2, 2'-methylene-bisi, 3-indanedione, on the other hand, is according to studies by K. F. Jansen and K. A. Jensen, Hoppe-Seylers Zeitschrift für Physiologische Chemie, Vol. 277, 1942, P. 66, practically ineffective.

It has now been found that the 2, 2'-carbalkoxymethylene bisi, not previously known 10 3-indandione of the general formula

CO

CO "

CH-CH-CH

COOR

509 658/65

G 14632 IVb / 12 ο

in which R denotes an alkyl radical, exert a very strong blood coagulation-retarding effect. in the With regard to a safe therapy and prophylaxis for z. B. ' thrombotic disease symptoms it is also important that the prothrombin level after discontinuation of the new compounds the blood level returns to normal within a short period of time. This therapeutically favorable property possesses in the series of

ίο oxycoumarin derivatives also 3,3'-carbethoxymethylene-bis-4-oxycoumarin, of which, however, used significantly higher doses than of 3,3'-methylene-bis-4-oxycoumarin to achieve the same effect Need to become. It is all the more surprising that by introducing a alkoxy group into the practically ineffective 2, 2: -Methylene-bis-i, 3-indandione Compounds are obtained which act in similarly low doses as the highly effective 3,3'-methylene-bis-4-oxycoumarin.

The new compounds can by reacting 2 moles of i, 3-indanedione with 1 mole of one Alkyl glyoxylate or one of its functional derivatives with respect to the aldehyde group, e.g. B. with the oxime, an alcoholate or the bisulfite addition compound.

The reactions are preferably carried out in inert solvents or diluents. When choosing the reaction conditions, it should be borne in mind that the 1,3-indanedione is easy with itself self, d. H. a keto group of one molecule with the reactive methylene group of a second Molecule, condensed.

The optionally formed 2, 2'-carboxymethylene bis-i, 3-indandione (bis-i, 3-indanedionyl-2-acetic acid) can be obtained using the usual gentle esterification methods be converted into the corresponding alkyl esters. For example, you can use the Acid with the desired alcohol in the presence of a dehydrating agent, e.g. B. Chlorinated water

substance, implement. You can also use the acid in the form of an alkali salt or the silver salt with a Alkyl halide, dialkyl sulfate, alkyl toluenesulfonate or an alkali salt of an alkylsulfuric acid or react with diazomethane. The 2,2'-carboxymethylene-bis-i, 3-indanedione is obtained by condensation of 2 moles of i, 3-indanedione with 1 mole of glyoxylic acid manufactured. .

In the following example, the production of the new compounds is explained in more detail. The parts therein mean parts by weight g and parts by volume cm ³ .

example

14.6 parts of 1,3-indanedione are suspended in 100 parts by volume of benzene and a solution of .5.1 parts of ethyl glyoxylate in 50 parts by volume of benzene is added. The mixture obtained is heated under reflux with the aid of a water separator until the elimination of water, which occurs after a short time, comes to a standstill. The residue obtained after the benzene has been distilled off is repeatedly recrystallized from ethanol. This gives the 2, 2'-Carbäthoxymethylen-bis-i, 3-indandione in the form of yellowish crystals, mp = 181 to 183 ^0th

In a corresponding manner, for example, the 2,2'-carbopropoxymethylene-bis-i, 3-indanedione (F. = 155 ⁰ ) and the 2, 2'-carboisopropoxymethylene-bisi, 3-indanedione (F. = 175 to 176 ⁰ ) getting produced.

The superior therapeutic efficacy of the compounds of the invention is evident from the following described comparative experiments.

In a series of experiments with rabbits the mean dose was determined on the active substance, which was necessary to maintain a therapeutically effective prothrombin (corresponding to a coagulation value of 15 to 25 ° / ₀ of the normal value) in the blood. The results are given in the table below:

No.

Active substance

Quantity Ver
search
rows animals 17th . 8th IO 2 8th 4th 28 6th 15th 5

Medium
daily

Maintenance dose
in mg per kg

Full of

Onset of action
after .. . .Days

Complete

Normalization after. ... days

3 4th

5.

2,2'-carbethoxymethylene-bisi, 3-indandione

2-diphenylacetyl-i, 3-indanedione
3,3'-methylene-bis-4-oxycoumarin

3,3'-carbethoxymethylene-bis-4-oxycoumarin

2-phenyl-i, 3-indandione

6.76
0.91
3, i4

32.22
35.40

4 to 5
4 - 5

1-2
4 - 5

2
5
5

ι to 2
3-4

Explanations

Substance No. 1 (according to the example of this Registration) shows a good, quick-acting effect even in low doses, which is just as quick subsides again. This easy controllability of the desired effect is for clinical use very valuable.

Substance No. 2 is very effective, but its use in human medicine is not without risk, because the active substance is not excreted quickly, but stored in the body. she is therefore also used as a rodenticide.

Substance No. 3 is highly effective, but like No. 2 has the disadvantage that its effect is very slow unfolds and just as slowly goes back.

658/65

G 14632 IVb / 12 ο

This can lead to undesirable incidents in clinical use.

Substance no. 4 also shows a rapid onset of action like substance no. 1, but it has Disadvantage that it must be administered in 4 to 5 times higher doses. The same is true for

Substance No. 5, which also shows an effect that is difficult to control.

Substance no. 1 according to the invention is therefore the compound no. 2 used for comparison to 5, in that it is either effective in smaller doses or has the advantage of rapid onset of action having.

Claims (1)

PATENT CLAIM: Process for the preparation of 2,2'-carboxy- or 2,2'-carbalkoxymethylene-bis-1,3-indanedione the general formula COOR in which R denotes an alkyl radical, characterized in that 2 moles of 1, 3-indanedione are mixed with ι mole of glyoxylic acid, 1 mole of an alkyl glyoxylate or one of its functional derivatives with respect to the aldehyde group in itself in a known manner by heating, preferably in the presence of an inert solvent or diluent condensed and optionally • the 2, 2'-carboxymethylene-bis-1,3-indanedione formed converted into its alkyl esters. Referred publications: Houben-Weyl, Methods of Organic Chemistry, Vol. II, 1925, 3rd edition, pp. 835ff., 880, 885 and 895 to 896; BuI. Soc. Sc. Cluj, Vol. 1, 1923, pp. 628 to 630 (reported in Chemical Abstracts 1925, p. 494, paragraph 2); Bull. Soc. Chim. France, Vol. 37, 1925, p. 1069 to 1078; BuI. Chim., Soc. Chim. Romania [2], vol. 1, 1939, Pp. 7 to 17 (reported in Chemical Abstracts 1943, column 4070/2 to 4); Conf. on Blood Clotting and Allied Problems, Trans., Vol. 3, 1950, pp. 11 to 28 (reported in Chemical Abstracts 1951, column 35o8e to h); Proc. Soc. Exptl. Brol. Med., Vol. 80, 1952, Pp. 139 to 143 (reported in Chemical Abstracts 1952, Column 8759 e to g); '' Drug Cosmet. Ind., Vol. 73, 1953, pp. 472 to 473 and to 569 (reported in the Chemisches Zentralblatt, 1954, p. 7925); Development and Chemistry of Medicines, Vol. I, 1952, p. 356; Arch. Pharm., Vol. 287, 1954, pp. 323-326.