IE42935B1 - Isoindole derivatives - Google Patents

Description

The present invention is concerned with isoindole derivatives..

The isoindole derivatives provided by the present invention have the following general formula CQQR' (X) wherein Y represents the group A represents an alkylene group containing 2-10 carbon atoms, A' and A each represent an alkylene group containing 1-9 carbon atoms subject to the proviso hereinafter relating to A, R* represents an alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl or aralkyl group, R^, Rg and R^ each independently represent a hydrogen or halogen atom or an alkyl, alkoxy or trifluoromethyl group, R'g and R'g each independently represent an alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, aryl or aralkyl group or R'g and R'g together represent the group —(CH2^n~/ wherein n stands for an integer from 2-7, or R'g and R'g together with the nitrogen atom to which they are attached represent a 5-membered or 6-membered heterocyclic ring containing an oxygen atom or a further nitrogen atom which is substituted with an alkyl group, R'''g represents a hydrogen atom or an alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, aryl or aralkyl group, Rg represents a hydrogen atom or an alkyl group (Rg iand Ά together containing at most 9 carbon atoms) and R-q represents an alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, aryl or aralkyl group (said alkyl groups containing a maximum of 5 carbon atoms).

In other words, the isoindole derivatives provided by this invention have the following general formulae COOR* (Ib) and (Ic) wherein R’, K^, R2, Rg, Rd, -R‘g, R” *5' R’g, Rg, Rj_]_r A, A* and A have the significance given earlier.

The isoindole derivatives provided by this invention are useful as starting materials for the manufacture of therapeutically valuable isoindole derivatives which form the subject matter of Patent Specification No. 42932.

As used in this specification, the term alkyl, alone or in combination such as in alkoxy, relates to straight^chain or branched-chain saturated hydrocarbon groups containing up to 6 carbon atoms such as the methyl, ethyl, propyl, isopropyl and butyl groups. The term “alkylene relates to - a 42935 straight-chain and branched-chain alkylene groups such as the ethylene, methylethylene, trimethylene and tetramethylene groups. The term cycloalkyl, alone or in combination, comprises Cg-Cg cycloalkyl groups (i.e. the cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups). The 5-membered or 6-membered heterocyclic ring is derived from a saturated heterocycle which contains two nitrogen atoms or one nitrogen atom and one oxygen atom, such as the morpholino, N-methyl-piperazino and piperazino groups. The term halogen means fluorine, chlorine, bromine and iodine. The term aryl relates to mononuclear or polynuclear aromatic groups in which one or more hydrogen atoms may be replaced by alkyl, alkoxy or halogen such as phenyl, halophenyl or methoxyphenyl.

In a preferred embodiment of the present invention, R^, R2, Rg and R4 each represent a hydrogen or halogen atom or a trifluoromethyl group. In a more preferred embodiment, R4 represents a hydrogen atom and R^ represents a chlorine or fluorine atom or a trifluoromethyl group. Again in a more preferred embodiment, Rg and Rg each represent a hydrogen, chlorine or fluorine atom.

As will be evident from the foregoing, there are especially preferred isoindole derivatives of formula I in which R4 represents a hydrogen atom, R^ represents a chlorine or fluorine atom or a trifluoromethyl group and Rg and Rg each represent a hydrogen, chlorine or fluorine atom.

More especially preferred isoindole derivatives of formula I are: -chloro-2-[(diethylc&rbamoyl) methyl3-3-phenylisoindoie-l-carboxylic acid ethyl ester, 2-[3-(N-ethyiacetamido)propyl]-5-chloro-3-phenyli=oindole-l-carbcxyiic acid ethyl ester and -chloro-2-(4-oxopsntyl)-3-phenylisoindole-l-carboxylic acid ethyl ester.

The isoindole derivatives of formula la hereinbefore can be prepared, for example, by reacting a compound of the general formula COOS' ί (IX) , wherein S', R^, K3 have the significance given earlier, in a manner known per se with an ω-haloalkanecarboxylic acid amide of the formula Hslogsn ϋϊ f-A-C-N .Ri (III) wherein A', B'. ana R', have the 3 5 Significance given earlier.

The reaction is carried out in an inert organic solvent (e.g. dimethylformamide, dimethyl sulphoxide, diethyleneglycol - a 4293S dimethyl ether, or hexamethylphosphoric acid triamide at a temperature between about 0°C and 100°C, preferably between 50°C and 80°C. The reaction is carried out after the prior conversion of a compound of formula II into a corresponding 2-alkali metal derivative which is prepared according to known methods using agents customary for this purpose (e.g. sodium hydride or sodium ethylate). The preferred 2-alkali metal derivative is the 2-sodio derivative.

The compounds of formula II hereinbefore are claimed per 10 se in Patent Specification No. 42934. and can be prepared as described therein.

The isoindole derivatives of formula Ib hereinbefore can be prepared, for example, by reacting a compound of formula II in a manner known per se with a compound of the general formula /®R13 Halogen- Α-θζ (IV)1 0R1A Rg 14 , wherein A and Rg have the significance given earlier and R^g and R^^ each represent an alkyl group or together represent the —CHg—CHg— or —CHg-CHg—CHg— group, to give a compound of the general formula •ii Cj) , wherein A, R’, R1? R2, Rj, R4, Rg, R^and R^a have the significance given earlier, v/hich is then hydrolysed in a manner known par se to give .an isoindole derivative of formula lb. The first step (i.e. the reaction) is carried out in an inert organic solvent (e.g. dimethylformamide, dimethyl sulphoxide, or hexamethylphosphoric acid triamide) at a temperature between 0°C and 100°C, preferably between 50°C and 80°C, the compound of formula II having been previously converted into a corresponding 2-alkali metal derivative, preferably the 2-sodio derivative, using an agent customary for this purpose (e.g. sodium hydride or sodium ethylate). The second step (i.e. the hydrolysis of the compound of formula V) is carried out according to methods known per se; for example, by treatment with ethanolic hydrochloric acid, or ethanolic p-toluenesulphonic acid at a temperature between 0°C and 100°C, expediently at about room temperature.

The isoindole derivatives of formula lc hereinbefore can be prepared by acylating a compound of the general formula - 8 42935 , wherein A, R', R^, Rg, Rg and R^ have the significance given earlier, Rg represents a hydrogen atom or an alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, aryl or aralkyl group and Rg represents a hydrogen atom, at the nitrogen atom in a manner known per se using a suitable acylating agent (e.g. an acid chloride or acid anhydride).

The compounds of formula VI are claimed per se in Patent Specification No. 42932, 29SS The following Examples illustrate the manner in whioh the isoindole derivatives provided by this invention can be prepared ' Example 1 A solution of 15.0 g (0.05 idol) of 5-chloro-3-phenylisoindole-l-carboxylic acid ethyl ester in 250 ml of hexamethylphosphoric acid triamide is treated under nitrogen at 5 °C with 0.055 mol of sodium hydride (2.5 g of a 55% dispersion in mineral oil) and then stirred at the same temperature for 15 minutes. At 5°-10°C a solution of 15 g (0.1 mol) of H,N-diethylchloroacetamide in 40 ml of ethanol is added thereto and the mixture stirred for 30 minutes at room temperature and subsequently heated for 4 hours at 80°C. The mixture is cooled and poured into 2.5 litres of ice-water. After the addition of 150 g of sodium chloride, the separated product is filtered off under suction, washed with water and then dissolved in methylene chloride. The aqueous layer is separated, the organic phase dried over sodium sulphate, filtered and evaporated to dryness. The residue is triturated with 100 ml of ether, unreaeted starting material crystallising out. The latter is filtered-off under vacuum and washed with ether.

The ethereal filtrate is evaporated to dryness. The oily residue is cooled and triturated with ether, crystals being obtained. Recrystallisation from ethanol yields 5-chloro-2-[(diethylcarbamoyl)methyl]-3-phenylisoindole-l-carboxylic acid ethyl ester; melting point 118°-12O°C.

Example 2 2.1 g (5 mmol) of 2-[3-(ethylamino)propyl]-5-chloro-310 4393S -phenylisoindole-l-carboxylic acid ethyl ester hydrochloride is treated with 10 ml of 1-N sodium hydroxide and the liberated base extracted with ether. After evaporation of the extracts, the oily residue is dissolved in a mixture of 10 ml of benzene and 2 ml of acetic anhydride and the solution boiled at reflux for 2 hours. There are then added 5 ml of ethanol, the mixture is boiled for a further 15 minutes and concentrated td dryness under reduced pressure. The oily residue is dissolved in methylene chloride and the obtained solution washed with a % sodium bicatbonate solution and then with water. The solution is dried over sodium sulphate, evaporated and the resulting oil chromatographed on 100 g of silica gel with ethyl acetate as the eluant. The uniform fractions yield 2-[3-(N-ethylacetamido)propyl]-5-chloro-3-phenylisoindole-l-carboxylic aoid ethyl ester; melting point 1O2°-1O4°C. Recrystallisation from ether does not increase the melting point.

Example 3 A solution of 24.0 g (0.08 mol) of 5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester in 480 ml of dimethyl20 formamide is treated under argon at -1O°C with 0.16 mol of sodium hydride (7.2 g of a 55% dispersion in mineral oil) and then stirred for a further 30 minutes in an ice-bath. There are added at 0°C 26.5 g (0.16 mol) of 2-(3-chloropropyl)-2-methyl-l,3-dioxolane in one batch, the mixture is then stirred for 1 hour at 2O°-25°C and subsequently heated for 2 hours at 140°C. The mixture is cooled and poured into 4 litres of ice-water. After the addition of 200 g of sodium chloride, the separated product is filtered off under suction, washed ν/ith water and then dissolved in methylene chloride. The aqueous layer is separated, the organic phase dried over sodium sulphate, filtered and concentrated to dryness. The residue is triturated with 300 ml of ethanol, unreacted starting material crystallising out. The latter is filtered off under vacuum and washed with ether. The filtrate is concentrated to dryness and the resulting oily residue purified by chromatography on 300 g of silica gel with chloroform as the eluant. There is obtained 5-chloro-2-[4-(1,3-dioxolan-2-yl)pentyl]-3-phenylisoindole-l-carboxylic acid ethyl ester; melting point 100°-l01°C.

A suspension of 8 g of 5-chloro-2-[4-(1,3-dioxolan-2-yl)pentyl]-3-phenylisoindole-l-carboxylic acid ethyl ester in a mixture of 40 ml of dioxane and 10 ml of water is treated with 2 ml of concentrated hydrochloric acid and then boiled at reflux' for 3 hours. The solution obtained is concentrated to dryness under reduced pressure and the residue partitioned between water and methylene chloride. The organic phase is washed with a 2-N sodium carbonate solution and then with a saturated aqueous sodium chloride solution. After drying over sodium sulphate, the solvent is removed, there being obtained 5-chloro-2-(4-oxopentyl)-3-phenylisoindole-l-carboxylic acid ethyl ester of melting point 93°-94°C. Crystallisation from ether/ hexane yields colourless crystals; melting point 94°-95°C.

Claims (7)

1. CLAIMS: Isoindole derivatives of the general formula COOR’ 20
2. 2. ) 20 2) wherein A' represents an alkylene group containing 1-9 carbon atoms, R' represents an alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl or aralkyl group, R^, Rg, Rg and R^ each independently represent a hydrogen or halogen atom or an alkyl, alkoxy or trifluoromethyl group and R'g and R'g each independently represent an alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, aryl or aralkyl group or R'g and R' g together represent the group —(CHg) n —, wherein n stands for an integer of 2-7, or R'g and R' g together with the nitrogen atom to which they are attached represent a 5-membered or 6-membered heterocyclic ring containing an oxygen atom or a further nitrogen atom which is substituted with an alkyl group. Isoindole derivatives of the general formula 13 335 wherein Rg represents a hydrogen atom or an alkyl group and A represents an alkylene group containing 1-9 carhon atoms (A and Rg together containing at most 9 carbon atoms), R* represents an alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl or aralkyl group and R^, Rj, Rj and R 4 each independently represent a hydrogen or halogen atom or an alkyl, alkoxy or trifluoromethyl group.
3. 3. ) Isoindole derivatives of the general formula wherein A represents an alkylene group containing 2-10 carbon atoms, R ! represents an alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl or aralkyl group, R^, Rg, Rg and R^ each independently represent a hydrogen or halogen atom or an alkyl, alkoxy or trifluoromethyi group, R' 5 5 represents a hydrogen atom or an alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, aryl or aralkyl group and R^ represents an alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, aryl or aralkyl group (said 10 alkyl groups containing a maximum of 5 carbon atoms).
4. 4. ) Isoindole derivatives according to claim 1, daim 2 or claim 3, wherein R^, Rg, Rg and each represent a hydrogen or halogen atom or a trifluoromethyi group. 15
5. 5. ) Isoindole derivatives according to claim 5, wherein R^ represents a hydrogen atom, R^ represents a chlorine or fluorine atom or a trifluoromethyi group and Rg and Rg each represent a hydrogen, chlorine or fluorine atom.
6. 6. ) Isoindole derivatives according to any one of claims 1 20 to 5 inclusive, wherein represents a hydrogen atom, R^ represents a chlorine or fluorine atom or a trifluoromethyi group and Rg and Rg each represent a hydrogen, chlorine or fluorine atom.
7. 7. ) 5-Chloro-2-[(diethylcarbamoyl)methyl]-3-phenylisoindole25 -1-carboxylic acid ethyl ester.