CH616671A5 - Process for the preparation of novel cyclic imides - Google Patents

Description

The present invention relates to processes for the preparation of new cyclic imides with valuable therapeutic properties. The new compounds can serve both as drugs and as intermediates for the manufacture of drugs.

The compounds obtainable according to the invention correspond to the general formula

15

(ii) 20

25th

fid ili

30th

where R has the meaning given above,

or a salt of a compound of the general formula III with phthalic anhydride, phthalyl chloride or an activated derivative of the phthalimide to give a compound of the general formula I.

2. The method according to claim 1, characterized in that R represents the n-propyl radical.

3. The method according to claim 1, characterized in that one carries out the implementation according to paragraph a) with heating.

35

40

45

where R represents the methyl, ethyl or n-propyl radical.

The invention preferably relates to the preparation of the compound of the general formula I in which R represents the n-propyl radical. The compounds obtainable according to the invention are able to suppress the growth of tumors, as can be shown, for example, by the following experimental setup:

If female Sprague-Dawley rats weighing an average of 160 g are given a dose of 2 mg of dimethylbenzanthracene in a lecithin emulsion intravenously on their 50th, 53rd and 57th day of life, tumors develop predominantly in the area of the milk bar whose number you can count and whose size can be determined by measurement. If animals which were induced in the manner described breast tumors with a compound of the general formula I are treated, the number and size of the tumors decrease in comparison to the untreated control animals.

The table below shows the advantageous effect of the compounds of the formula I on the number and size of the tumors as a function of time at a dosage of 0.25% in the feed. Average values of 20 animals per group are listed.

Duration in number of tumors per animal Size of the tumors in mm2 per animal

Weeks untreated «/ -irr n xj n f-i u untreated« in t> n u t> p u

Substance control R ~ CHs R ~ C2H = R = (n) CsH7 control R = CHs R = C2Hs R = CsH?

0

4.1

4.2

4.1

4.1

802.6

810.6

801.2

821.9

2nd

5.7

3.4

3.7

3.8

1336.6

453.9

577.1

359.6

4th

6.3

2.5

2.7

2.1

1544.7

364.6

334.8

140.7

6

7.1

2.3

2.4

1.3

1778.3

370.6

375.2

162.4

An examination of the acute toxicity after a single oral 651 or intraperitoneal application to adult mice and rats of both sexes showed the following LD50 values (i.e. the dose in mg / kg body weight at which 50% of the test animals used die):

LDso mg / kg body weight R mouse oral mouse i. p. Rat oral rat i. p.

ch3

460

410

5100

350

c2h5

246

185

660

172

nC3h7

2000

860

2130

350

It can be seen from this that the compounds of the general formula I, in particular the one in which R represents the n-propyl radical, have a considerable inhibition of the dimethylbenzanthracene-induced tumor of the rat with a comparatively low toxicity.

Compounds in which R represents the rest of a Mannich base are described in DOS 1 545 706, e.g. the l- (morpholinomethyl) -4-phthalimido-piperidinedione - 2,6 (CG 603), about which also in Europ. J. Cancer. Vol. 8, 157-158 (1972). For this compound, a reduction in the tumor centers from 2.2 to 1.3, ie a reduction in the tumor centers by 40%, is given at a dosage of 1.37% in the feed. In contrast, e.g. the l- (n) -propyl - 4-phthalimido-piperidinedione-2,6- obtainable according to the invention at a dosage of 0.25%, that is less than 20% of the amount used by the compound described above, the tumor centers of 4, 1 to 1.3, that's a 70% reduction.

The compounds obtainable according to the invention are further able to exert advantageous effects in the event of endocrine disorders and are also suitable for the treatment of autoimmune diseases.

The compounds of general formula I are prepared by ß-phthalimidoglutaric acid or one of its reactive functional derivatives with an amine of the general formula

H2N — R (II)

in which R has the abovementioned meaning, or converts a salt thereof to a mono- or diamide and then cyclizes it, preferably without prior separation or isolation. The functional derivative of ß-phthalimidoglutaric acid is, in particular, its anhydride. However, their halides and their esters with lower aliphatic or aromatic alcohols or phenols can also be used.

If one starts from β-phthalimidoglutaric anhydride and an amine of formula II for the preparation of compounds of general formula I, it is expedient to heat the reaction mixture to complete the reaction or to carry out the reaction in the presence of an agent which promotes the ring closure reaction. Such means are. e.g. Acetic anhydride, thionyl chloride, acetyl chloride and similar acidic water-releasing agents. In particular, however, the water formed in the reaction can also be distilled off or removed by azeotropic distillation.

According to the invention, the process described above can be applied not only to the amine of the formula II, but also to a salt which, under the reaction conditions, gives an amine of the formula II. Such salts are, for example, carbonates etc. of the amine of the formula II.

The compounds of general formula I are also prepared by using a compound of general formula

• 616671

0

n where R has the meaning given above,

or a salt of a compound of the general formula III is reacted with phthalic anhydride, phthalyl chloride or an activated derivative of the phthalimide. The reaction is expediently carried out in inert solvents, if appropriate with cooling and with the addition of acid-binding substances, such as triethylamine, trimethylamine, diisopropylethylamine, sodium carbonate or potassium carbonate. Ether and hydrocarbons are preferred as solvents. Instead of phthalic anhydride, an activated derivative of phthalimide, e.g. use the N-carbethoxyphthalimide. In this case, the reaction can be carried out, advantageously with the addition of sodium bicarbonate, in aqueous solution at room temperature.

The compounds of the general formula I obtained by one of the processes described above can be used for the production of medicaments in appropriately dosed medicament and, if appropriate, sustained release forms for enteral or parenteral administration. If desired, they can also be combined with other active ingredients. To produce suitable pharmaceutical forms, the active ingredients are processed with inorganic or organic pharmacologically indifferent auxiliaries. As auxiliary substances e.g. used:

For tablets and dragées: milk sugar, starch, talc, stearic acid, magnesium stearate, etc.

For syrups, drops and the like: cane sugar, invert sugar, glucose solution and the like. a.

For injectables: water, mono- or polyhydric alcohols, vegetable oils and the like.

For suppositories: natural or hardened oils and waxes etc. a. m.

In addition, the preparations can contain suitable preservatives, stabilizers, wetting agents, solubilizers, sweeteners and colorants, as well as flavorings.

The dosage of a compound of general formula I in pharmaceutical preparations with an anti-tumor effect is 1 to 200 mg / kg, preferably 20 to 60 mg / kg. The application takes place 1 to 5 times a day.

The following examples serve to further explain the invention. The temperature information is uncorrected throughout. Maximum yields were not sought when the examples were carried out.

example 1

350 g of β-phthalimido-glutaric anhydride are slurried in 2000 ml of absolute dioxane, and 188 ml of triethylamine are added. 112 ml of n-propylamine, dissolved in 200 ml of dioxane, are then added dropwise in such a way that the reaction temperature does not exceed 35 °. The mixture is left to react for an hour and activated carbon is added.

After filtration, the solvent is distilled off in vacuo. The oily residue is dissolved in 1000 ml of water and 300 ml of 18% hydrochloric acid are added. When standing under cooling, the β-phathalimido-glutaric acid - mono-N- [n] -propylamide crystallizes in the form of white crystals. Melting point 189-191 ° C after recrystallization from water. The yield is 343 g, which is 79% of theory.

3rd

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

616671

4th

150 g of the above compound are mixed with a mixture of 1000 ml of acetic anhydride and 120 ml of thionyl chloride and heated to reflux for 2 hours. The solvent is removed by distillation in vacuo. The residue is abs from 800 ml. Recrystallized ethanol. This gives the l-n-propyl-4-phthalimido-piperidine-dione-2,6- melting point 137-139 ° C. in a yield of 123 g, which is 87% of theory.

The compounds listed below are obtained in an analogous manner when the corresponding amine is used:

1-Methyl-4-phthalimido-piperidinedione-2,6, melting point 119-121 ° after recrystallization from water.

l-ethyl-4-phthalimido-piperidinedione-2,6, melting point 165-167 ° C after recrystallization from ethanol.

Example 2

178 g of l-methyl-4-aminopiperidinedione-2,6-hydrochloride and 148 g of phthalic anhydride are suspended in 2000 ml of toluene. After adding 121 g of triethylamine, the mixture is heated to reflux for several hours. The reaction solution is separated from the precipitated triethylamine hydrochloride and concentrated to dryness in vacuo. The solid residue is recrystallized from water. This gives l-methyl-4-phthalimido-piperidinedione-2,6 with a melting point of 119-121 °.

The l-ethyl-4-phthalimido-piperidinedione-2,6 and the l-n-propyl-4-phthalimido-pipe-ridindione-2,6 are obtained in an analogous manner. The products obtained are identical to the compounds obtained according to Example 1.

Example 3

17.8 g of l-methyl-4-amino-piperidinedione-2,6-hydrachloride and 28.6 g of sodium carbonate decahydrate are dissolved in 100 ml of water. 22 g of N-carbethoxyphthalimide are added in portions over the course of 15 minutes. The mixture is left to react for 30 minutes with stirring, and any undissolved portion is filtered off. Dilute hydrochloric acid is added to the filtrate to a pH of 6. The precipitate is separated off, dried and recrystallized from water. This gives l-methyl-4-phthalimido-piperidinedione-2,6, identical to the product obtained according to Example 1.

The l-ethyl-4-phthalimido-piperidinedione-2,6 and the l- (n) -propyl-4-phthalimido-pi-peridinedione-2,6 are obtained in an analogous manner.

The 1-alkyl-4-aminopiperidine-2,6-diones used as starting material in Examples 2 and 3 are obtained in the following way:

96 g of sodium hydroxide are dissolved in 2.11 water and 176.8 g of β-aminoglutaric acid are added. The clear solution is cooled to 0 ° C. With vigorous stirring, 372 g of carbobenzoxychloride and 450 ml of 5 10% aqueous sodium hydroxide solution are simultaneously added dropwise. Stirring is continued for 10 hours. The alkaline solution is extracted several times with ether and then carefully acidified with dilute hydrochloric acid. The precipitate is filtered off, dried in vacuo at 100 ° C. and then recrystallized from ethyl acetate / petroleum ether. N-Carbobenzoxy-ß-aminoglutaric acid with a melting point of 163 ° is thus obtained in a yield of 70% of theory.

100 g of the above compound are refluxed with 1000 ml of acetic anhydride for 3 hours. The solvent is removed by distillation in vacuo and the residue is dissolved in ethyl acetate. After clarification with activated carbon, the solvent is partially removed in vacuo. The addition of petroleum ether crystallizes the ß- (N-carbobenzoxy) glutamic anhydride from melting point 87, 20 89 ° C. The yield is 69 g, which is 75.3% of theory.

147 g of the above compound are dissolved in 900 ml of absolute dioxane. Dry methylamine gas is introduced until complete precipitation. The precipitate 25 is filtered off and then dissolved in a little water. Acidification with 18% hydrochloric acid gives the methyl amide of ß- (N-carbobenzoxy) aminoglutaric acid with a melting point of 174-176 ° C. after recrystallization from water. The yield is 114 g, which is 70% of theory. 30 180 g of the above compound are refluxed in a mixture of 1800 ml of acetic anhydride and 180 ml of thionyl chloride for 2 hours. After distilling off the solvent in vacuo, the residue is recrystallized from ethyl acetate / petroleum ether. This gives 35 l-methyl-4- (N-carbobenzoxy) amino-piperidinedione-2,6 with a melting point of 130-131 ° C. in a yield of 150 g, which is 89% of theory.

94 g of the above compound are dissolved in 1.3 l of glacial acetic acid and 10 g of 3% palladium-carbon catalyst 40 are added. The mixture is hydrogenated with stirring at room temperature and normal pressure. After the hydrogen uptake has ended, the catalyst is filtered off and the filtrate is mixed with a solution of hydrogen chloride in ether. The solvent is distilled off in vacuo. The residue 45 is dissolved in methanol and ether is added until crystallization begins. The hydrochloride of l-methyl-4-amino-piperidinedione-2,6 with a melting point of 213-215 ° C. is thus obtained. The yield is 45 g, which is 74.5% of theory.

Claims (2)

616671 2nd PATENT CLAIMS 1. Process for the preparation of new cyclic imides of the general formula 4. The method according to claim 1, characterized in that one carries out the reaction according to paragraph b) with the addition of acid-binding substances, preferably with heating. R (I) 10th in which R represents the methyl, ethyl or n-propyl radical, characterized in that a) β-phthalimido-glutaric acid or one of its reactive functional derivatives with an amine of the general formula: H2H — R in which R has the abovementioned meaning, or converts a salt thereof into a mono- or diamide and then cyclizes the latter, or b) a compound of the general formula: