US2842596A - Indandione derivatives - Google Patents

Description

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INDANDIBNE DERIVATIVES Louis Freedman, Mount Vernon, and Seymour L. Shapiro, Hastings on Hudson, N. Y., and Karl Geiger, Passaic, N. L,- assignors to U. S. Vitamin Corporation, a corporation of New York No Drawing. Application December 8, 1955 Serial No. 551,751

3 Claims. Cl. 260-592) This invention relates to indandione derivatives.

These derivatives are useful in medicine as anticoagulants and will, therefore, be described in connection with such use.

It is well known that vitamin K is essential for the coagulation of blood and in fact was designated K as an abbreviation of the German word Koagulationsvitamin.

In seeking to find a material of opposite reaction in "blood or an anti-K factor, we have conceived of making a material that is similar in general molecular pattern to that of vitamin K but different in essential, although minor, features. Our theory was that such a material might fit into the chain of reactions by which vitamin K contributes to the mechanism of blood coagulation but, because of what may be described as a non-meshing variation, would interfere with the final reactionleading to coagulation.

Since vitamin K is a derivative of naphthoquinone, a

two ringcompound, we have made and tested a series of compounds containing acyl groups jointed to a two ringed nucleus having 2 keto groups. Our two rings are those of indane as distinguished from the naphthalene nucleus of vitamin K.

In testing the general concept of providing in this manner an anticoagulant or anti-K factor, we have tried in guinea pigs the anticoagulant efiect of various indane derivatives as compared to the anticoagulant effect of a material now being sold for this purpose, namely, phenylindandione (sometimes abbreviated herein to PID). We have found that many groups substituted within the framework of our general theory do not contribute an anticoagulant factor. Thus the introduction of the group at the 2-position in the indandione molecule gives a product without discernible anticoagulant activity as compared with PID. The same effect was noted when the group introduced was either i i -COH2CCI-I3 or a structurally related phenyl ketone of the formula Further work, however, has demonstrated that we do obtain anticoagulant properties when the group introduced into the indandione is an acyl group containing a relatively large number of carbon atoms. With the substitution of acyl groups with 8-18 carbon atoms, for example, we have made anticoagulants that show approximately 6-14 times the anticoagulant activity of that obtained with the PID used as the standard for comparison.

Stats atent Ofiice Patented July 8, 1958 Briefly stated, the invention comprises the new compounds and the process of making them described herein. More particularly, the invention comprises indandione derivatives containing an acyl group introduced at the 2- position and metal salts thereof, the number of carbon atoms in the acyl groups being within the range 8-18.

In testing our new products the sodium salt was administered to guinea pigs in subcutaneous doses of 5 mg. per kg. of animal weight. Administrations were at O, 6 and 24 hours, respectively, with the prothrombin time determined at 30 hours.

In determining this prothrombin time, the animal plasma was used with standard technique and the results converted to percentage prothrombin. For this conversion, normal guinea pig plasma prothrombin) is serially diluted with saline. The prothrombin time: are determined for the various dilutions and plotted on a curve; 50% plasma for example, represents 50% prothrombin. The prothrombin times of the treated animals are referred to the standard curve and the percent pro thrombin is thus established under the conditions of the test. This value is substracted from 100% prothrombin to show percent loss of prothrombin. The greater the percent loss of prothrombin, the more effective is the anticoagulant.

The effectiveness of the compounds is then expressed in terms of their activity as compared to phenylindandione (PlD), a commercially available, clinically recommended anticoagulant as follows:

Comparative activity to PID:

Percent reduction in prothrombin with test compoundX 10( Percent reduction in prothrombin with PID Activity, Percent, as Compared to PID taken as 100 Total No. of Carbon Atoms In Acyl Group (RCO) Our new compounds whiie showing better anticoagulan activity than PID are also less toxic and better'tolerated The LD for PID has been found to be 245 mg. per kg. while the 12 carbon chain compound is 775 mg. per kg and the 16 carbon chain compound is over 1000 mg. pe; kg.

Our compounds may be made by the following genera method. 0

Anortho-phthalate, such as dimethyl-o-phthalate, i1 condensed with a ketone containing one more carbon aton than the number to be present in the acyl group intro duced. This ketone must be one that contains a methy group joined directly on one side of aketone (.CO.] group, with a longer alkyl chain to supply the necessary carbons on the other side of the ketone group. The con densation is effected to advantage in solution in an an hydrous organic solvent for the selected phthalate ant ketone. The reaction is ordinarily made in contact witl sodium methylate or other sodium lower alcoholate. Tht resulting acyl derivative is isolated in the form of the sodium salt of the enol compound which may be represented by the formula in which R is an alkyl group of such length that the acyl group'RCO contains from 818 carbon atoms.

The reaction mixture is stirred and refiuxed and the product is separated from the solvent and by-products in any convenient manner, as, for example, as illustrated in the specific examples given later herein.

The proportions of the various reactants are suitably equimolecular.

When it is desired to use the indandione derivative in the ketone (non-enolized) form, then the metal salts made as described herein are acidified at the end, as illustrated in Examples V below.

The invention will be further illustrated by detailed description in connection with the following specific examples of our new compounds and the process of making and using them.

Example I.2-0ctan0yl-indandione sodium salt To a suspension of 0.1 mole (5.4 g.) of sodium methylate in 100 moles of benzene were added 0.1 m. (20 g) of dimethylphthalate and 0.1 m. (14.4 g.) of methyl heptyl ketone. The reaction mixture was stirred and refluxed for 24 hours. The excess benzene and any unreacted ketone were removed by distillation. The residue of product which remains was washed with 1.2 1. of water and the insoluble sodium salt of the product filtered off and recrystallized from water. The product so obtained still contained bound water which was removed by azeotropic distillation with benzene. When all the water had been thus removed, the pure product was filtered ofiF. M. P. 266267 C. Yield, 3 g. of yellow crystals. Analysis calculated for C H O Na: C, 69.40%; H, 6.51%. Found C, 69.71%;1-1, 6.96%.

Example ll.2-decanoyl-indandione sodium salt This compound was made as in Example I, except that the ketone used was 0.1 m. (17.2 g.) of methyl nonyl ketone. There was thus obtained 4 g. of yellow crystals of M. P. 172-175 C. Analysis calculated for C H O Na: C, 70.77%; H, 7.19%. Found C, 70.74%; H, 7.11%.

Example IIl.2-laur0yl-indandione sodium salt To a suspension of 0.1 m. (5.4 g.) of sodium methylate in 100 mls. of benzene were added 0.1 m. (20 g.) of dimethylphthalate and 0.1 m. (20.0) of methyl undecyl ketone. The reaction mixture was stirred and refluxed for 24 hours The excess benzene and unreacted ketone were then removed by distillation. The distillation residue was diluted with 1.5 l. of water, 200 mls. of ethyl ether added, and the solution acidified with hydrochloric acid shaken. The ethereal phase on treatment with 2% sodium hydroxide solution, yielded a crystalline mass of the comparatively water insoluble salt of the product. The product was recrystallized from boiling water and then dried by azeotropic distillation with benzene. The yellow crystalline product was filtered from the benzene and dried, there being obtained 6.5 g. of product of M. P. 156-158 C. Analysis calculated for C21H27O3N1Z C, 71.95%; H, 7.77%. Found C, 71.47%; H, 7.89%.

Example I V.2-palmitoyl-indandione sodium salt This compound was made as in Example III, except that the ketone used was 0.1 m. (25.6 g.) of methyl pentadecyl ketone. There was obtained 10.2 g. of yellow crystals of M. P. 191-192 C. Analysis calculated for C H O Na: C, 73.85%; H, 8.68%. Found C, 73.85%; H, 8.95%.

Example V.2-stearoyl-indandione This product has a sufliciently high melting point to give a solid at ambient temperatures. Accordingly our processing in this instance afiords an example of isolation of the free indandione without making the sodium salt.

To a suspension of 0.1 m. (5.4 g.) of sodium methylate in 100 mls. of benzene were added 0.1 m. (20 g.) of dimethylphthalate and 0.1 m. (28.2 g.) of methyl heptadecyl ketone. The reaction mixture was stirred and refluxed for 24 hours. The excess benzene and unreacted ketone were then removed by distillation. The distillation residue was diluted with water, acidified, and then extracted with 200 mls. of ether.

The ether phase, containing the product, was dried with sodium sulfate and the ether then separated from the drying agent and evaporated. The residue of the product was recrystallized from methanol and dried by azeotropic distillation with benzene. There is obtained 9.5 g. of dark tan crystals of M. P. 5961 C. Analysis calculated for C H O C, 78.59%; H, 9.77%. Found C, 78.68%; H, 9.80%.

Example VI.2-non0yl-indandione sodium salt The procedure of Example I is followed, except that methyl octyl ketone is substituted on an equimolecular basis for the ketone used in Example I.

The effectiveness of these compounds has been tested and is referred to in the table earlier herein.

Example VIIJ-Tableted compositions For oral administration as an anticoagulant, the in dandione derivatives made as described, as in Examples I VI ,are mixed with non-toxic spacing agents disposed between the particles of indandione derivatives. Examples of such spacing agents serving also as extenders and as binders in the finished tablets are gum acacia, starch, dextrine, carboxymethylcellulose sodium salt, corn syrup solids, and lactose, either alone or mixed, and suitably in total proportion in excess of the active anticoagulant.

Thus a typical formulation for a tablet of the compound made in Example III follows:

12.5 g. 2-lanroyl-indandione sodium salt 5.0 g. gum acacia 10.0 g. potato starch 66.5 g. lactose These materials are granulated with 50% isopropanol and dried in the usual way.

Then 3 g. talc and 3 g. magnesium stearate are thoroughly admixed, dried and the whole tableted as 200 mg. tablets containing 25 mg. of active ingredient.

It will be understood that it is intended to cover all changes and modifications of the examples of the invention herein chosen for the purpose of illustration which do not constitute departures from the spirit and scope of the invention.

What is claimed is:

1. An anticoagulant for blood comprising an indandione derivative selected from the group consisting of 2-palmitoyl-1,3-indandione and the sodium salt thereof.

2. An anticoagulant for blood consisting essentially of 2-palmitoyl-1,3-indandione.

3. An anticoagulant for blood consisting essentially of the sodium salt of 2-palmitoyl-1,3-indandione.

References Cited in thefile of this patent UNITED STATES PATENTS Ford et al. Feb. 16, 1943 Thomas Mar. 16, 1954 OTHER REFERENCES UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 2,842,596 July 8, 1958 Louis Freedman et a1.

It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 2, line 53, for "Whiie" read while column 3, line 53,

for "(20.0)" read vI-e (20.0 g.)

Signed and sealed this 23rd day of September 1958.

SEAL) ttest:

ROBERT C. WATSON KARL H. .AXLINTE Attesting Oflicer Commissioner of Patents!

Claims (1)

1. AN ANTICOAGULANT FOR BLOOD COMPRISING AN INDANDIONE DERIVATIVE SELECTED FROM THE GROUP CONSISTING OF 2-PALMITOYL-1,3-INDANDIONE AND THE SODIUM SALT THEREOF.