IL38023A - Isoindoline derivatives and process for their preparation - Google Patents

Description

ISOINDOLINE DERIVATIVES AND PROCESS FOR THEIR PREPARATION and and to a process for their In recent years the search for with c and activity shifted fields of cortisone congeners endowed with hormonal end morphine narcotics to other classes of While products with undeniable pharmacological activity have been the problem is far from completely because of these products are quite toxic and poorly causing as among other gastrointestinal they cause harmful secondary Certain isoindoline have been found to be characterized by a negligible toxicity and to be tolerated very since they cause no secondary The object of this have the following general wherein R is a member selected from the group consisting of hydrogen and lower alkyl of 1 to 4 carbon and is a member selected from the group consisting of lower alkyl of 1 to 4 carbon atoms and a group of general formula n is 1 or 2 and and are independently selected from the group of hydrogen and lower alkyl of 1 to 4 carbon The scope of the invention also comprises the salts of the compounds of general formula wherein is with physiologically genera with physiologically acceptable organic or inorganic Tho compounds general formula may be prepared by the following reacting as prepared by bromination commercially available with at a temperature of about with a compound of general formula wherein is or cyano group and is as defined as prepared by reduction with Fe and NH CI or by catalytic hydrogenation of the corresponding nitroderivative obtained in its turn by nitration of the compound of formula page with methods described in literature for analogous at a temperature of about 75 to about in polar such as methanol or the to form a compound of general formula wherein R and X are as defined which is subsequently r with suitable such for or the or with suitable such for of about 75 to about to give compounds of general formula is and if esterifying at a temperature of about 60 to about the compounds of general formula wherein is thus the according to the usual methods organic or reacting commercially available phthalide with a compound of general formula at a temperature of about about obtaining a compound of formula wherein X and are as defined which is subsequently with suitable such for K CO or the or with suitable such for at a temperature of about 75 about to give compounds of general formula wherein is and if esterifying at a temperature of about 60 to about the compounds of general formula wherein is thus le oho according to the usual methods of organic or reacting tiophthalide as prepared according to the method of Prey and 1 disclosure of which is hereby incorporated by with a compound of formula at a temperature of about to about preferably in sealed so obtaining a compound of formula which is subsequently to give compounds of general formula wherein is if are esterified as described in process or with a compound of formula at a temperature of about 50 to about in polar such for dimethyl and the so obtaining a compound of formula which is subsequently to give compounds of general formula wherein is if are esterified as described in process or reacting commercially available phthalic anhydride with a compound of formula at a temperature bout 60 to about so obtaining a compound of formula wherein X and R are as defined which is subsequently reduced with a suitable reducing such for Zn and and the at a temperature of about 60 to about to give a compound of formula which is sub sequently to give compounds of general formula wherein is if are esterified as described in process or reacting commercially available compounds of general formula wherein the groups are both both methyl or both ethyl with a compound of formula at a temperature of about 80 to about in the presence or absence of a so obtaining a compound of formula wherein X and R are as defined which is subsequently reduced to give a compound of formula which is then saponified to give compounds of general formula wherein is if are esterified as described in process Prom the above reaction sequences it appears evident that if compounds of general formula wherein is an ethyl are desired to be processes and may be the case when the compounds of general formula wherein X is the carbethoxy As hereabove esterification of the compounds of general formula wherein is hydrogen to if compounds of general formula wherein is different from is performed according methods of organic as is known to those skilled in the For the esters of the compound of general formula wherein is may be prepared by treatment of said compounds with SOClg at a temperature of about βθ to about in the presence or absence of and subsequently by reacting the acid chloride so at room temperature in apolar such for and the The compounds of general formula wherein is may alsc be if into their salts with physiologically ceptable the according to the usual methods of organic as is known to those skilled in the For the salts of the compounds of general formula wherein is with may be obtained by at room temperature co if into their salts with physiologically acceptable organic or inorganic according to the usual methods of organic as is known to those skilled in the The object of the present possess a good analge and as shown by the data reported in the table herebelow where hen lbutazone i A L Analgesic activity was assessed by means of phenylquinone test in mice according to Siegmund et 1 activity was assessed by means of carrageenin induced edema test in rats according to Winter et 544 and Table 2 shows the activity of in comparison with acid scribed in Eelgian Patent Table 2 In table 2 activity was determined employing both the as previously and granuloma pouch technique Stevenson 153 205 The potency ratios were estimated following the parallel line biological assay method Statistical Method in Biological Assay Griffin London The pharmacological data hereabove reported have been confirmed by clinical trials performed on The compounds of the present invention are preferably administered but they can also be administered by parentheral or topical The pharmaceutical compositions containing the compounds of this vention can be therefore either Examples of the substances which can serve as pharmacological carriers or diluents for the pharmaceutical compositions of the compounds of the invention are magnesium as well as other compatible substances used in pharmaceutical formulations The following examples but do not the scope of the present Example 1 A mixture of ethyl and 5 2 in EtOH 9 is heated with a reflux condenser for added char and filtered during The filtrate is concentrated to about one third and then poured in ethyl ether The precipitate is tered and washed again with ethyl ether 100 to obtain HBr In the same and by reacting with the proper amino the following compounds are 1 Example 2 dissolved in EtOH is added to dissolved in water The mixture of the reagents is heated with a reflux condenser under mixing for 8 hours thus obtaining a complete Ethyl alcohol is evaporated under the solved residue filtered and the filtrate is acidified with HC1 60 The precipitate thus formed is washed with water with HC1 and again with water to after crystallizat ion from EtOH doline yield In the same and by employing the compounds prepared according to Example the following compounds are Example 3 A mixture of and acid in EtOH is heated with a reflux condenser for 6 evaporated to little volume under vacuum and then poured in ethyl ether 400 The separated solid is crystallized from EtOH ethyl ether to obtain HBr yield This product dissolved in EtOH 9 is added to dissolved in water The mixture of the reagents is refluxed for 12 hours to obtain a complete Ethyl alcohol is evaporated under the undissolved residue filtered and the trate is acidified with HC1 The precipitate thus formed is washed with water with HC1 and again with water to after crystallization from EtOH 7 yield In the same and by reacting with the proper amino the following compounds are 1 arboxy me hylj C Example 4 Phthalide and ethyl are heated to for 4 hours in a sealed then treated with water acidified with HC1 and extracted with ethyl acetate The organic layer is washed with water dried and evaporated to dryness in r The oily residue is crystallized from ligroin to obtain yield In the same and by reacting phthalide with the proper amino esters the following compounds are thy l 1 iso indol ine Example Tiophthalide and ethyl are heated to for hours in a sealed then treated with water acidified with HC1 and extracted with ethyl acetate The ganic layer is washed with dried and evaporated to ness in The residue is crystallized from ligroin to obtain 1 isoindoline yield In the same and by reacting tiophthalide with the proper amino the following compounds are Example 6 To a solution of phthalic aldehyde suspended in dimethylforraamide 200 heated to ethyl 86 dissolved in dimethylformamide is added in the course of an The mixture is stirred again for 2 hours at the solvent is evaporated under The oily residue is dissolved in ethyl acetate 80 washed with HCl and with water 30 The organic layer is evaporated to dryness and the residue is cristallized ligroin to obtain 5 25 yield In the same and by reacting phthalic aldehyde with the proper amino the following compounds are Example 7 A mixture of phthalic anhydride 1 and ethyl 1 in acid 70 is heated with a reflux condenser for 4 then cooled at about and diluted with water 50 An oily thus solidifies after is then cooled at filtered and washed with water 40 to after crystallization from EtOH 30 yield 1 In the same and by reacting phthalic anhydride with the proper amino the following compounds are 1 Example 8 A mixture of phthalic acid and ethyl e is heated in an oil bath at for and a then to aftor crystallization from EtOK yield In the same and by reacting phthalic acid with the proper amino the following compounds are iinide C Example 9 Ethyl ester of phthalic acid and ethyl suspended in anhydrous heated with a reflux condenser for 4 The mixture is evaporated to under the residue is redissolved in ethyl acetate then washed with HC1 with water dried and evaporated to dryness under to after crystallization from EtOH 9 yield In the same and by reacting ethyl ester of phthalic acid with the proper amino the following compounds are imi de Example 10 To a solution of suspended in acetic acid Zn in powder added under The mixture is with a reflux condenser for 4 and the residue is then washed with warm acetic acid The filtrate is evaporated to dryness under the residue is redissolved in water and neutralized with sodium bonate to give pH The thus is filtered to after crystallization from yield In the same and starting phthalimides prepared according to Examples 8 and following compounds are 1 carbethoxyme ndol ine thy l indol Example A mixture of 1 indoline and in EtOH and water is heated with a reflux condenser for 8 hours to obtain a complete Ethyl is evaporated under the aqueous solution is acidified with HC1 and thus is washed with water to after crystallization from EtOH yield In the same and starting from the derivatives prepared according to Examples and the following compounds are carboxymethyl indol Example A mixture of and in EtOH 99t9 is heated with a reflux condenser for 6 hours and evaporated to obtain o yield In the same and by reacting with the proper the following compounds are HBr HBr HBr HBr Example To HBr dissolved in EtOH dissolved in water 20 is The mixture is heated a reflux condenser for 10 hours and The residue is washed with water to after crystallization EtOH 99 yield In the same and starting from the derivatives prepared according to Example 12 the following compounds are Example 14 A mixture of phthalide and is heated to for 4 hours in a sealed treated with water 100 acidified with HCl and extracted with ethyl acetate 200 The organic layer is washed with water 80 dried and evaporated to dryness under The residue is crystallized from EtOH 99 9 to obtain 57 yield In the same and by reacting phthalide with the proper amino Example A mixture of tiophthalide and is to for 4 hours in a sealed redissolved in water acidified with HCl and extracted with ethyl acetate The organic layer is washed with water dried and evaporated to dryness under The residue is crystallized from EtOH obtain indoline yield In the same and by reacting tiophthalide with the proper amino the following compounds are 1 Example To a solution of phthalic aldehyde suspended in dimethylformamide heated to tonitrile dissolved in dimethylformamide OO is added in the course of an The mixture is stirred again for 4 hours at the solvent is evaporated under The oi residue is dissolved in ethyl acetate washed with HCl 8 ml then with water The organic layer is dried and evaporated to dryness under The residue crystallized from EtOH obtain yield 1 In the same and by reacting phthalic aldehyde with the proper amino the following compounds are ne Example 1 7 A mixture of phthalic anhydride 12 and in glacial acetic acid 0 is heated with a reflux condenser for 4 hours thus taining a complete The mixture is then and the solid separated is washed with water and dried to obtain 1 yield In the same and by reacting phthalic anhydride with the proper amino the following compounds are Example A mixture of phthalic acid 32 and is heated in an oil bath to for an hour and a then redissolved with water and the thus is filtered to obtain yield 21 In the same and by reacting phthalic acid with the proper amino the following compounds are hthalimide Example 19 A of ethyl ester of phthalic acid and o suspended in anhydrous dimethylforrnamide 100 is heated with a reflux condenser for 4 evaporated to dryness under the residue is then redissolved with ethyl acetate washed with HCl then with water subsequently dried and evaporated to dryness under The residue is crystallized from EtOH to obtain 3 yield 75 21 In the same and by reacting ethyl ester of phthalic acid with the proper amino the following compounds are Example 20 To a suspension of 76 in glacial acetic acid 50 heated to Zn in powder is added The mixture is then heated with a reflux condenser for 14 The inorganic layer is the filtrate is and the solid thus is treated with then with and filtered The residue is crystallized from EtOH 9 obtain 1 yield In the same and starting from the derivatives prepared according to Example 1 and the following compounds are A suspension of indoline in H SO and water is heated with a reflux condenser 16 then poured into cold water 100 The solid separated is then treated with NaOH The insoluble residue is the filtrate is acidified with HC1 30 the solid is filtered and crystallized from EtOH to obtain 39 yield 85 21 In same and starting from the derivatives prepared according to Example 14 15 and the following compounds are Example 22 A solution of and concentrated sulfuric acid in anhydrous methyl alcohol 18Ο is heated with a reflux condenser for 6 then cooled and and the precipitate is washed with 100 to after crystallization from methyl yield 6 In the same and by reacting methyl alcohol with the proper isoindoline the following compounds are Example A solution of 20 O S0C1 1 20 is heated with a reflux condenser for 3 the then distilled then anhydrous with petroleum a solid is which by crystallization from a mixture of benzene and petroleum ether gives the acid chloride of 15 yield This acid chloride 12 is now dissolved in anhydrous dioxane and this solution is added under effective to a solution 12 in anhydrous dioxane to produce a slightly exothermic The mixture is agitated 3 hours at room The precipitate thus formed is then and the filtrate is evaporated under vacuum to make oily This residue is dissolved in the chloroform solution is washed with 2 100 dried on anhydrous sodium sulfate and evaporated to dryness under The residue is then extracted with hot and subsequently cooled to obtain ethanol ester of indoline yield In the same and by reacting with the acid chlorides of the proper the following compounds are obtained ester ester of methylj ester of ester of methyl Example 24 1 is added to moles suspended in water The solution is then lyophilized to obtain salt of o In the same and by reacting with the proper the following compounds are salt of salt of salt of methylj salt of insufficientOCRQuality

Claims (1)

1. WHAT WE Isoindoline derivatives of the general formula a from the group consisting of and lower alkyl of 1 to carbon and member from group consisting of lower to 4 and a group of general formula wherein n 1 or 2 are from the group of hydro and lower alkyl of 1 to 4 and physiologically acceptable basic addition salts of the compounds ine A process for the preparation of isoindoline derivatives according to any one of the preceding the process reacting with a compound of general formula wherein X is wherein R and X are as which is subsequently suitable bases or with to e compounds of general formula wherein and if the of general formula where in is thus with reacting phthalide with a compound of formula compound of formula reacting phthalic anhydride with a compound formula so obtaining a compound of formula wherein X and are as defined which is reduced with a suitable reducing to give a compound of formula which is subsequently saponif compounds of general wherein is if are esterified as described in process or reacting compounds of general formula wherein the grou are both both or both ethyl with a compound of formula obtaining a compound of formula wherein X and R are as defined which is subsequently reduced to give a compound of formula which is then saponi ed to give compounds of general formula wherein is if are esterified as described in process if reacting the compounds of general formula wherein appropriate base a physiologically salt or reac the compounds of general formula wherein is the group with an appropriate acid to give a physiologically A process according to claim substantially as described A compound of general formula prepared by a process according to claim or A pharmaceutical composition comprising a compound of general insufficientOCRQuality