IE45583B1 - 5-(indol-3-ylmethylene)-1,3-dimethyl-2-methylimino-4-imidazolidinone - Google Patents

Abstract

5-(3-Indolylmethylene)-1,3-dimethyl-2-methylimino-4-imidazolidinone s which are optionally substituted in position 6 by lower alkyl and have antidepressant activity are prepared by methylation of 5-(3-indolylmethylene)-1,3-dimethyl-2-imino-4-imidazolidinones which are optionally substituted in position 6 by lower alkyl.

Description

This invention relates to the novel cyclic compound 5 - (indol - 3 - ylmethylene) - 1,3 - dimethyl - 2 - methylitnino ~ 4 - imidazolidinone, to a process for the manufacture thereof, and to pharmaceutical compositions containing the novel compound.

. This novel compound can exist in isomeric forms, e.g. the E-isomer of the formula and the Z-isomer-of the formula The compound of the formula E-l, i.e. (E) - 5 (indol - 3 - ylmethylene) - 1,3 - dimethyl - 2 methylimino - 4 - imidazolidinone, exists in small quantities in, and can be isolated by extraction from, a sponge belonging to the order Dictyoceratida, which can be collected on the Australian seacoasts.

- (Indol - 3 - ylmethylene) - 1,3 - dimethyl 2 - methylimino - 4 - imidazolidinone can be prepared in accordance with the invention by a process wherein a) indole - 3 - aldehyde is condensed with 1,3 dimethyl - 2 - methylimino-4-imidazolidinone (II), or b) 5 - (indole - 3 - ylmethylene) - 1,3 15 dimethyl - 2 - imino - 4 - imidazolidinone is reacted with a methylating agent.

The imidazolidinone starting material utilized in embodiment (a) of this process has the formula S 5·8 3 - 4 The E- and Z-isomers of the imidazolidinone starting materials utilized in embodiment (b) of this process have the formulae respectively.

The condensation of an indole-3-aldehyde derivative with Compound IX, in accordance with embodiemnt 10 (a) of the present process, can be carried out in a manner known per se, e,g. by heating equimolar quantit ies of the starting materials in the presence of a condensation agent, at a temperature up to the reflux temperature of the reaction mixture, preferably at a temperature of from 50° to 150°C. Examples of condensation agents which can be utilized in the above reaction are aliphatic carboxylic acids and the alkali - 5 metal salts of these acids, e.g. acetic acid containing anhydrous sodium acetate, secondary or tertiary amines, e.g. piperidine, and mixtures thereof.

The methylation in accordance with embodiment (b) of the present process can be carried out in a manner known per se, for example by heating 5 - {indol - 3 ylmethylene) - 1,3 - dimethyl - 2 - imino - 4 imidazolidinone with a methylating agent, such as methyl iodide, dimethyl sulfate or methylated derivatives of dimethyl sulphoxide, in an inert solvent, such as diethyl ether or ethanol, at a temperature up to the reflux temperature of the reaction mixture. - (indol - 3 - ylmethylene) - 1,3 - dimethyl 2 - imino - 4 - imidazolidinone can be prepared by condensing indole-3-aldehyde with 1,3 - dimethyl - 2 imino - 4 - imidazolidinone (suitably in the form of an acid salt), in a manner analogous to that described above for the condensation of indole-3-aldehyde with compound (II).

- (Indol - 3 - ylmethylene) - 1,3 - dimethyl 2 - methylimino - 4 - imidazolidinone has antidepressant activity. This can be demonstrated in warmblooded animals using standard procedures.

For example, the antagonism of tetrabenazineinduced ptosis is demonstrated in male mice weighing 18-25 g. Groups of 10 mice each are administered tetrabenazine methane-sulphonate at a dose of 100 mg/kg, one hour after oral administration of the compounds to be tested. One hour after tetrabenazine administration, each mouse is observed for the presence or absence of ptosis. An EDgQ value for the antagonism of tetrabenazine-induced ptosis is then determined. (E)-5(Indol-3-ylmethylene) - 1,3 - dimethyl - 2 - methylimino - 4 - imidazolidinone was fou:d to have an EDgQ of 5 mg/kg. - 6 5 - (Indol - 3 - ylmethylene) - 1,3 - dimethyl 2 - methylimino - 4 - imidazolidinone has antidepressant properties qualitatively similar to those of compounds such as imipramine, harmaline and pargyline, which are known for their therapeutic uses and properties. In contradistinction to these known compounds, 5 (indol - 3 - ylmethylene) - 1,3 - dimethyl - 2 methylimino - 4 - imidazolidinone has no anticholinergic or cardiovascular side effects. Furthermore, the known compounds are more toxic than 5-(indol-3-ylmethylene) 1,3 - dimethyl - 2 - methylimino - 4 - imidazolidinone, as can be seen from the following acute toxicity data, expressed in LD5Q mg/kg in mice: Compounds (E)-5-(indol-3ylmethylene)-1,3-dim.ethyl2-methylimino- 4-imidazolidinone imipramine pargyline harmalineLDSop.O. 900 430 720 . 380LD50i,p. 670 125 390 120 - (Indol - 3 - ylmethylene) - 1,3 - dimethyl 2 - methylimino - 4 - imidazolidinone is useful for the treatment of depression. It can be used in medicine in the form of pharmaceutical preparations which contain it in association with a compatible pharmaceutical carrier or diluent and/or an excipient, namely an organic or inorganic inert carrier material suitable for enteral, e.g. oral, or parenteral administration. Examples of such carrier materials are wafer, gelatin, lactose, starch, talc, magnesium stearate, gums, - 7 vegetable oils and petroleum jelly. The pharmaceutical preparations can be made up in a solid form, e.g. as tablets, capsules, dragees or suppositories, or in a liquid form, e.g. as solutions, emulsions or suspensions. The pharmaceutical preparations may be sterilised and/or may contain compatible adjuvants such as preservatives, stabilising agents, flavouring agents, colouring agents, emulsifying agents, salts for varying the osmotic pressure or buffering agents.

Convenient pharmaceutical dosage forms contain 1 to 100 mg of 5-(indol~3-ylmethylene) - 1,3 - dimethyl 2 - methylimino - 4 - imidazolidinone. Convenient oral dosages are in the range 0.1 mg/kg per day to 10 mg/kg per day. Convenient parenteral dosages are in the range 0.01 mg/kg per day to 0.5 mg/kg per day. However, the ranges mentioned can be extended upwards or downwards depending upon individual requirements.

The following Examples are given for the purpose of illustrating the invention.

Example 1. g of 1,3 - dimethyl - 2 - methylimino - 4 imidazolidinone and 5 g indole - 3 - aldehyde are refluxed in piperidine for 3 hours. The reaction mixture is poured into 250 ml of water, stirred for 30 minutes, filtered, washed with water and dried. There are obtained 8,45 g of (E)-5-(indol - 3 - ylmethylene) 1,3 - dimethyl-2-methylimino-4-imidazolidinone.

The product recrystallizes from methanol in the form of yellow needles, m.p, 226,5-228°C. ΧΗ n.m.r. (CD3COOD) d 9,01 (IH, S), 7,78 (lH, m), 7,58 (IH, m), 7,30 (2H, m), 6,87 (IH, S) , 3,33 (3H, S), 3,22 (3H, S), 3,13 (3H, S).

The following data are obtained by low resolution mass spectrometry: .5 8 3 - 8 M+ 268 (619%), 253 (21,6%), 170 (23,7%), 169 (33,0%), 155 (base peak), 128 (25,3%), 101 (19,1%).

. Example 2. a) The preparation of the starting material 255 mg. of 1,3 - dimethyl - 2 - imino-4-imidazolidinone hydriodide and 145 mg of indole-3-aldehyde are refluxed in 5 ml piperidine for 4 hours. After cooling, the reaction mixture is poured into 50 ml water. After stirring for 30 minutes the formed precipitate is filtered, washed with water and dried.

There are obtained 205 mg of (E)-5-(indol-3-ylmethylene) - 1,3 - dimethyl - 2 - imino - 4 - imidazolidinone.

The product recrystallizes from methanol as fine, yellow neddles, m.p. 231,8-233,1°C. b) The process 500 mg of (E) - 5 - (indol - 3 - ylmethylene 1,3 - dimethyl - 2 - imino - 4 - imidazolidinone are refluxed in methanol for 24 hours with 425 mg of methyl iodine. The product is chromatographed on silica gel and alumina. There are obtained 107 mg of (E) - 5 (indol - 3 - ylmethylene) - 1,3 - dimethyl-2-methylimino-4-imidazolidinone.

Example 3.

A mixture of 5.10 g of indole-3-carboxaldehyde, .64 g of dimethylcreatinine and 60 ml of piperidine was heated, at reflux for 3 hours, cooled to room temperature and poured into 350 ml of water. The precipitate was collected by filtration and dried to give 8.2 g of a yellow Solid, m.p. 241-241.5°, which consisted of a 9:1 by weight mixture of E- and Zisomers. By heating a solution of the crude product in 2 1 of methanol and loo ml of piperidine at reflux 48583 - 9 for 2 hrs and removal of the solvents, a 1:1 by weight mixture of E- and Z-isomers was obtained.

A one-gram sample of the above mixture (1:1 ratio of isomers) was digested with 20 ml of hot acetone and the soluble portion (565 mg) was applied directly to a column of 15 g of silica gel prepared in ethyl acetate. Elution was carried out with acetone collecting 20 ml fractions. Fractions 6, 7 and 8 were combined (144 mg) and crystallized from acetonitrile to yield 126 mg of (Z) - 5 - (indol - 3 - ylmethylene) - 1,3 - dimethyl 2 - methylimino - 4 - imidazolidinone as a pale yellow solid, m.p. 241-242°. The analytical sample was recrystallized from acetonitrile, m.p. 241-242°. Mass spectrum m/e 268; UV (95% ethanol): 229 nm (ε 22,400), 271 nm (9200); 365 nm (22,450)? NMR (100 mHz, DMSO-dg): $ 7.67 (s, IH, H-2), 6.75 (s, 0.94 H, CH = C-CO, major*), 6.48 (s, 0.06 H, CH = CCO, minor*).

Corresponding data for the E-isomer, which was isolated by crystallization of a 9:1 mixture of isomers from methanol/methylene chloride: UV (95% ethanol): 232 nm (ε 20,600), 276 nm (6950) 394 nm (22,600)? NMR (100 mHz, DMSO-dg): δ 8.72 broad, IH, H-2); 6.47 (s, 0.67 H, CH = C-CO, major*), 6.30 (s, 0.33 H, CH - C-CO, minor ).

( Attributed to the isomers of the C = Ν-CHg).

Example A.

Tablets of the following composition are manufactured in conventional manner: (E)-5-(indol-3-ylmethylene)-1,3dimethyl-2-methylimino-4- imidazolidinone 50 mg Lactose 95 mg Maize starch 100 mg - 10 Talc Magnesium stearate 4,5 mg 0,5 mg Total weight 250,0 mg

Claims (13)

1. 5 - (Indol - 3 - ylmethylene) - 1,3 dimethyl - 2 - methylimino - 4 - imidazolidinone.

2. (E) 5 - (Indol - 3 - ylmethylene) - 1,3 dimethyl - 2 - methylimino - 4 - imidazolidinone.

3. (Z) - 5 - (Indol - 3 - ylmethylene) - 1,3 dimethyl - 2 - methylimino - 4 - imidazolidinone.

4. A process for the preparation of 5 - (indol 3 - ylmethylene) - 1,3 - dimethyl - 2 - methylimino 4 - imidazolidinone, which comprises a) condensing indole-3-aldehyde with 1,3 dimethyl - 2 - methylimino - 4 imidazolidinone, or b) reacting 5 - (indol - 3 - ylmethylene) 1,3 - dimethyl - 2 - imino - 4 - imidazolidinone with a methylating agent.

5. A process as claimed in claim 4 wherein the condensation is carried out at a temperature from 50° to 150°C.

6. A process as claimed in claim 4 or 5 wherein the condensation agent is an aliphatic carboxylic acid, an alkali metal salt thereof, a secondary or tertiary amine, or a mixture of two or more of these materials.

7. A process as claimed in claim 4 wherein the methylating agent is methyl iodide, dimethyl sulphate or a methylated derivative of dimethyl sulphoxide.

8. A process as claimed in claim 4 or 7 wherein the methylation is carried out by heating in an inert solvent.

9. A process as claimed in claim 4, substanti45383 - 12 ally as described in Example 1 or 2 hereinbefore.

10. A process as claimed in claim 4, substantially as described in Example 3 hereinbefore.

11. The compound of claim 1 whenever prepared 5 by a process as claimed in any of claims 4 to 10.

12. A pharmaceutical composition having antidepressant properties, containing 5 - (indol - 3 ylmethylene) - 1,3 - dimethyl - 2 - methylimino - 4 imidazolidinone as active ingredient together with a 10 pharmaceutically acceptable carrier or diluent.

13. A process for the manufacture of a pharmaceutical composition having anti-depressant properties, which comprises mixing 5 - (indol - 3 ylmethylene) - 1,3 - dimethyl - 2 - methylimino - 4 15 imidazolidinone with an inert, therapeutically compatible solid or liquid carrier and/or an excipient.