IL25595A - New derivatives of cyclic imide compounds and process for the manufacture of these compounds - Google Patents

Description

Hess Patent Attorney Patents Designs Ordinance Speci ication derivatives of cyclic compounds and process for the manufacture of these compounds i Griinenthal a German of Stolberg do declare the nature of this invention and in what manner the same is to be to be particularly described and ascertained in and by the following v The present invention relates to new derivatives of cyclic compounds and to a for of these The new according to the invention have the general Also included in the of the invention are cally acceptable salts of the compounds of the general mula I with inorganic or organic In I the of the symbols radical froja a acid or the residue of an represents hydrogen or and together vith the nitrogen represent a five raembered heterocyclic radical which taay be condensed with condensed cycle aliphatic or heterocyclic ring which ring bear a halogen a or radical and in which the nitrogen bearing the radicals and member of a or a and have same or a different meaning indicate of the group consisting of hydrogen and lower and n represent o different namely 1 or whereby the of and n is 1 or X represents a single bond or the wherein indicates a lover alkyl and the same or a meaning and benzyl hydroxy alkyl indicate lover hale substituted lover alkyl or radicals or represent together with the nitrogen atom bearing these radicals a or saturated heterocyclic radical which may contain as a further an a sulfur or a nitrogen such nitrogen be substituted by alkyl or carbalkoxy radicals and such heterocyclic radicals may be substituted by alkyl or phenyl In Formula the group preferably represents an heterocyclic or aromatic dicarboxylic acid or an imide of a dicarboxylic the first carboxylic group of which is bound to an aromatic or heterocyclic ring system consisting of one or more rings and the second carboxylic group of which is bound to an aliphatic radical standing in neighbour position to the first carboxyl these dicarboxylic acid attached to the cyclic imide radical with the nitrogen Such acid imides may be those of succinic phthalic or h lie dihydrophthalic ac as ve l as of substituted or ted derivatives of the dicarboxyl c aeids mentioned Further imides which may be used may be taken from the examples following be substituted by or halogen ease and represent heterocyclic radicals they may indicate If and together with the nitrogen atom form a heterocyclic radical those radicals may be members of the group consisting of the the the the thiomorpholino group or a piperazino group substituted in position 4 as for instance the the the the The compounds of the general I contain at least one asymmetrically substituted carbon atom and therefore they exist in isomeric Within the scope of present invention are the racemic forms of the compounds of formula I or the mixtures of as well as the pure isome the optically active forms of the of I the manufacture of these different forms of the compounds o formula The new derivatives of cyclic imides according to the vention show a of extraordinarily valuable actions which may be applied in Especially the new compounds have marked actions as could be demonstrated using the following test If female rats between 50 65 days old with a mean weight of 160 grams are given a single dose of 20 in 1 ml sesame oil through a stomach there in the region of the milk ridge tumors the number of which may be counted and the size of which may be Treatment of animals in which mammary tumors were induced in the manner described before with compounds of the formula I results in decrease of the number and size of the tumors in comparison to the untreated 2 control The size of the tumor was calculated in mm as the product of the largest and smallest diameters of the tumor ascertainable Starting with an average 2 size of mm in 10 animals the tumor size in untreated animals increases in four weeks to a size of 769 mm and the number of tumors is increased from to value from 10 These and further values observed in groups of untreated animals are included in the wing table at the first six If the animals were given a feed containing compounds of formula I for a period of weeks in the quantities stipulated on the following table results were in dance with those in the table figures contained in the table are average values from groups of 10 The substances to be tested were used in form of their Compound Amount in Food Starting tumor Tumor area Tumor Area number 4 weeks number er 4 weeks 769 311 1 595 1 216 992 1 1 61 dione dipne c olinomet dione dro dione ple dione dione Moreover new compounds of the general formula I show a favourable effect on survival of transplanted living particles of tissue transplanted from one organism to This effect was tested in rats in which skin grafts were transplanted to animals of the same The animals were inspected whether or the grafts were rejected after In untreated animals 9 days after the transplantation only 8 of the grafts were free of the animals had been fed for a period of five days before transplantation with a feed containing of 56 of the grafts remained free of necroses on the 9th day after These immunosuppressive properties may be also an explanation for the fact that by the compounds of the general formula I leprous diseases as well as damages caused by and autoimmune diseases may be influenced Administration of compounds of the general formula I influences on the endocrine system Moreover many of the compounds of formula I could be shown to have a marked sedative Compounds of the general formula I in which m represents the number 0 and n represents the number 1 or especially 2 are able to influence the blood pressure markedly and for a long For example the intraduodenal administration of of to cats narcosis resulted in levering of blood presspre by and for more than 2 The of sola I be by a of the general the same meaning as a of t sane a salt of of general formula in presence Preferably is of of there used such which able to the conditions of the or 1 It is to the reaction in of or there are solvents such as or mixtures of water and organic The is at at c or is possible to at room There ma be II is also possible to use an excess of 1 or of the three The compounds of the formula I be by adding to the reaction a in which the products of the reac ion are insoluble or at least poorly In being poorly soluble in a mixture of water eloohol it is to add h precipitation of the Fur rffiore products may be isolated by cooling the react ion whereupon the products crystallise especially when the reaction was concentre ted or the solvent or diluent may be by di the residue thus then be from proper solvents or mixtures if desired it is possible to the compounds of the general I into with far as the compounds of the III had not been used in form of the compounds of the formula I may be reac ting pared by a compound of the general CO a and above and z represents ester if hydroxy group or a halogen with a of the general reaction be im of an organic solvent and possibly vlth of the during the 25595 2 the compounds general I can by a of the general II with a compound of the 9 wherein and Z have the same meaning as above This reaction is made preferably in presence of an organic solvent and possibly with azeotropic removing of the compound formed during the reaction The compounds of the general formula I obtained in the manner described before if be transformed into salts by reacting with inorganic or organic With respect to the therapeutic application of the compounds this transformation into is not In the manufacture of the compounds of formula I in optically active forms it is possible to proceed as described using optically active starting or to re compounds of formula I in racemic form and to split these into the optically active forms in a manner known per se The starting materials of the general formulae and are obtained in manners known per se The following examples serve as a further explanation of the invention without limiting it All temperature data are In performing the examples maximum yields were not intended to be 10 10 Example 1 dione 52 g of suspended with 5OO ml of ethanol and ml of a solution of formaldehyde formaldehyde in are added dropwise followed by ml of The reaction mixture is refluxed for After the filtrate is diluted with absolute After dione as obtained white 169 after recrystallization from Example 2 dione 12 g of suspended with 150 ml of ethanol and 25 ml of a solution of formaldehyde are The reaction mixture is refluxed til a clear solution is After chilling the as obtained in white 167 after recrystallisation from g of dissolved in of ethanol and 2 g of morpholine are The reaction mixture is refluxed for 5 After chilling the obtained in white 169 after recrystallization from Example 3 dione 12 g of are suspended with ml of ethanol and ml of a solution of formaldehyde are added followed by ml of The reaction mixture is refluxed for 1 The solvent is distilled off under reduced The residue is dissolved in absolute Adding the is 11 11 Example dione 12 g of suspended 300 ml of ethanol and ml of a solution of formaldehyde are added followed ml of a solution of dimethylamine in containing 33 of dimethyl After one hour the solvent is distilled off under reduced The residue is dissolved in absolute Adding diisopropylether t is 5 Example dione 12 g of suspended with 100 ml of 5 g of in ml of ethanol are mixed with ml of a solution of formaldehyde in containing 35 of thus obtaining a solution of The before mentioned solution of is added dropwise to the reaction After heating for 10 tes the solvent is distilled off under reduced The residue is dissolved in Adding petrolether is Example dione 5 g of suspended with ml of After heating 5 ml of a solution of aldehyde in containing 35 of formaldehyde added followed by 3 g of dissolved in ml of After few minutes the l dione 209 210 C after recrystallization 12 12 Example 7 3 g of Example 8 dione 60 g of 5 are suspended ml of After heating ml of a solution of aldehyde in water are added followed by 20 ml of dissolved in 30 ml of The reaction mixture is refluxed for one After chilling the dione is 216 Example 9 dione g of are suspended with ml of ml of a solution of formaldehyde in water are added followed by 2 g of dissolved in ml of After standing for 12 hours 100 ml of ethanol are The dione precipitates in white 1 Example 0 dione 5 g of suspended ml of ethanol and A mixture of ml of a solution of formaldehyde in containing 35 of and 4 g of 3 in ml of ethanol are added The reaction mixture is refluxed for 10 After chilling the pitates in white 152 13 13 Example 1 Following the procedure of the dione Q 5 126 128 C tained from 5 g of a mixture of of a solution of formaldehyde in water and 3 g of Example dione 3 g of suspended with a mixture of 7 5 ml of ethanol and 2 5 of a solution of formaldehyde in 35 of The suspension is added to 1 5 g of under The reaction mixture becomes clear and after a few minutes the precipitates white 139 Example 13 dione 10 3 g of pended with ml of absolute ethanol and stirring 3 g of a solution of formaldehyde in taining 35 of formaldehyde are added followed by 3 5 g of The reaction mixture is refluxed for From the if necessary after filtration clear tion 7 2 g of the dione precipitate by 176 177 The before mentioned starting material 5 was obtained by the following 1 g of and g anhydride are suspended with 300 ml of absolute pyridine and refluxed for The solvent is distilled off under reduced The residue is dissolved with 0 ml of acetic anhydride and refluxed for 10 After chilling the 191 is 14 g of phth t inic nhydride g of Under stirring the reaction mixture is heated After the fey g of dissolved in of g of are The reaction ted for one From after clear solution the 1 rrol 139 is obtained by of the theoretical g of with of absolute l are added dr reaction is for Most e solvent of the necessary after clear solution is distilled off under re By chilling the is obtained as white crystals s 121 Yield of the theoretical g of suspended ml of absolute and s are added reaction mixture is refluxed tor 20 Most vent of the after solution distilled off reduced By chilling the Example 1 Following the procedure of example the dione is 62 Yield 16 49 of the theoretical yield Example 18 dione 80 g of suspended with 400 ml of ethanol and 160 ml of a solution of aldehyde in containing of are added dropwise followed by 64 ml of The reaction mixture is refluxed for one The if necessary after filtration clear solution is diluted with absolute ethanol until the ning of By chilling the dione obtained white 190 1 from Example 19 dione 258 g of 30 g of formaldehyde are suspended with 1 000 ml of dioxane and rapid stirring 87 12 g of morpholine are added Prom the if necessary after filtration clear tion the dione is obtained in white 190 191 The product is identical with that of example Yield 222 62 of the theoretical yield Example 20 dione g of are dissolved in of ethylene and 150 ml of a solution of formaldehyde in containing of are added followed by 60 ml of The reaction mixture is refluxed for some By chilling 48 g 203 after zation from 16 16 Example 21 dione are suspended with 0 ml of and heated at 10 ml of a solution of formaldehyde in containing of hyde are added followed g of The solvent of if necessary after filtration clear solution is distilled off under reduced The residue is dissolved in Adding ether the dione 1 is Example 22 Following the procedure of example 21 the dione 136 C is obtained from Example 23 dione g of refluxed with 500 ml of Under rapid stirring 125 g of dissolved in 100 ml of are added The solvent of the if necessary after filtration clear solution is distilled off under reduced The residue is dissolved in Adding the dione 152 is Example 24 Following the procedure of example the 162 is obtained from 150 g of 110 g of 17 Example 25 Following the procedure of example the 151 dione is obtained from ample 26 g of 7 g of aldehyde are suspended with 200 ml of absolute dioxane and 7 g of piperidine are added From necessary after clear solution the dione is obtained by after recrystallization from under dec Example 27 of suspended with 500 ml of absolute Under heating a solution of 100 g of in 100 ml of absolute dioxane is added By chilling the dione 1 162 C after recrystallization from Example 28 Following the procedure of example 21 the 124 is obtained from dione and Example 29 Following the procedure of example 21 the ione 160 is obtained from 18 j g of suspended with ml of Under is heated to for the of the clear solution is off under reduced The residue is dissolved in Adding ether the is Yield of the theoretical Follow ing e procedure of the is obtained us ing instead of t pi per id Following the procedure of example the is obtained using instead of Following the procedure of 18 the is obtained one instead are with 2000 ml of and h ated to tinder rapid stirring of s solution of 19 clear solution is distilled off under reduced adding at the same The precipitates 201 Yield 100 of the theoretical Example 35 298 g of dione g of paraformaldehyde are suspended with 1 000 ml of dioxane and Under rapid stirring g of piperidine are added Stirring and heating is continued until a clear solution is By chilling the as yellow 207 Yield 356 90 of the Example Following the procedure of example 35 the as o is obtained 190 C by using 7 g of pyrrolidine instead of 85 2 g of The before mentioned starting material by the following 6 g of and g of glutamic acid are suspended with 100 ml of dry pyridine and refluxed for 6 The solvent of the sary after clear solution is distilled off under reduced The residue is refluxed with 100 ml of acetic anhydride for 10 By if necessary after distilling off a part of the the y 20 20 is yellow Yield 93 of the 1 g of the before mentioned compound are mixed with 5 g of urea and heated to for 15 The dione s obtained yellow 266 after zation from Yield 70 of the theoretical one Example 37 0 g of 5 dione e are refluxed with 300 ml of Under stirring 80 g of are added By chilling the dione 5 tates yellow 192 Yield 75 of the theoretical Example 38 Following the procedure of example 37 the 5 yellow 161 by using 80 g instead of Yield 80 of the Example 39 0 g of 5 aree suspended with 5 0 ml of absolute dioxane and heated to Under stirring 80 g of dissolved in 200 ml of absolute are added The 5 dione tetrahydro precipitates the necessary after clear solution on Yellow 21 21 The before starting 1 e t r r o pht ha 1 r was obtained y the following 75 g of acid and 95 g of h anhydride are al of y and solvent of the if necessary after clear solution Is distilled off under Xhe residue is ref uxed al of acetic anhydride for 10 is as 90 g of the before mentioned are refluxed with al of Under rapid stirring dry gas is bubbled into the reaction mixture until a filtered portion of the reaction does not precipitate bubbling in solvent is poured o f and the residue is dissolved in Adding hydrochloric taining hy the 100 g of the before compound are with a oi of acetic anhydride 50 al for 1 e ione precipitates 5 g of refluxed ml of rapid stirring of a of in containing of are added fey 6 of 100 g of are suspended with of to rapid stirring 100 ral dry are A part of the of necessary after clear is distilled off tinder reduced Adding ether the precipitate s yield of the The before b was obt the following 190 g of 1 and g of c acid are r with 2000 ml of y pyridine obtaining clear is off reduced The sidue is 2000 ml of for a short By if necessary after distilling off a of the the Λ de precipitates w ite yield the theoretical g of the mentioned c are mixed with S of Under the is to G for After 11 the clopropy et dr its is in crystals a yield of the 22a 386 g of a formaldehyde suspended with 1000 of g of no refluy ing is continued until clear solution is By chilling the precipitates white Yield 40 of the The before mentioned starting material was obtained by the following procedure 276 g of succinic de and 147 g of glutamic acid are refluxed with 2 000 ml of for 6 An unreacted part of glutamic acid is filtered off and the solvent is distilled off under reduced The residue is refluxed with 6 000 ml of acetic a hydride for a short By chilling the acid anhydride precipitates 283 yield 300 of the retical 38 g of the before mentioned compound are mixed with 3 g of Under stirring the mixture is heated to for ter recrystallisation from the dione obtained white 279 281 Yield 40 of the theoretical Example 5 g of re ded with of Under heating 8 g of dissolved in 20 ml of are added By chilling the as 226 228 C precipitates white Example 44 Following the procedure of example 43 212 is obtained by using 10 g instead of 24 Example 45 Following the procedure of example the 160 165 is obtained by using 10 g of instead of The before mentioned starting material is obtained according to the described for the other starting from naphthaline anhydride and glutamic Example 46 dione 5 g of 192 are dissolved in of Under heating 10 g of in 20 ml of are added After one hour the solvent is distilled off under reduced The residue is dissolved in Adding petrolether the precipitates in white 124 Yield 80 of the cal Example 47 Following the procedure of example 46 the in white crystal by using instead of 80 after recrystallization from Yield of the theoretical Example 48 5 g of 219 221 are dissolved in ml of Under heating 10 g of dissolved in 20 ml of are added After one hour the solvent is distilled off under reduced The residue is dissolved in Adding ether the in white 174 25 procedure of the piper id obtained by using thy of th 168 5 g of dissolved ml of and 10 dissolved 20 ml of solvent is distilled off The residue is dissolved Adding the d precipitates in white 167 g of are in of absolute heated up to reflux 100 of dissolved in 200 of absolute added with Upon cooling addition of there are obtained from vhich may be clear upon in the form of The process is out to Example are g of 100 ml of in the form 165 process is carried out according to obtained from 5 26 in the of white 153 yield The introduced in Examples 53 as starting was as g of and are dissolved in 200 ml of absolute and heated for twenty minutes at After dilut ion ith 600 ml of water whereby acid diethylester is 62 62 g of the above compound are with ml of trated hydrochloric for hours at After cooling are obta ined the ic 11 g of the above stated compound are heated in a of ml of acetic anhydride and g of for five hours at reflux After cooling are the acid yield 80 10 g of the above stated compound are dissolved in 100 ml of absolute vivid later under heating at 80 a dry flow of sssaonia is induced unt il such time as a filtered solut ion wi th gas no longer forms The dissolved in After addition of concentrated hydrochloric acid are ed the acid 221 ield S of the compound are heated a Mixture of ml of of thlonylchlorlde for hours yield g of suspended in 100 vit g h and heated for 90 minutes at reflux may be clear upon is dried with so sulfate and concentrated in deposit is dissolved in absolute Upon of end ther are obtained the yield Analogous to Example is by use of piper id yield g are with S 35 and g and b heate over a water mixture la cooled in By addition of ere the yield of are suspended with ml of absolute d at stirring are added 10 of dissolved in 10 ml of The clear solution is diluted h ml of ether and added until opalescence is obta eooling the etrahy dr ido r are obtained s the form of light yellow g of s ido py id ine ione d issolved in 0 ml of absolute heate at and a solution of of pyrrolidine in 10 al of d ioxane is added The clear solution is diluted with ml of absolute nnd the is opalescence is obta 3y cooling the W is obtained which identical the product obta ined accord ing to Example Analogous to Example obtained by use of the 150 in the form of light yellow Analogous to is obtained use of holine the of 1 p r r dissolved in 100 of absolute g of ine the solution is heated thirty minutes at reflux concentrated in residue in and diluted with After addition of is 1 thy r 1 one use in are obtained in the following Q of sold anhydride i g acid nd of absolute pyridine stirring for hours till reflux tempera re is the solution is filtered hot of vent removed in cooling the ne salt of the acid the form of ght yellow pyridine salt is sucked off out with et her and the dried salt is heated at 130 until no more pyridine distils The residue is heated with ml of hydride for 10 till Upon add of ether the anhydride is obtained in the form of y cr g of the stated are mixed with g of urea heated for at After cooling and t i from water are obtained the lor a of yellow 10 g of above compound sus ended in 100 ml of absolute and heated at refloat of solution of By cooling the pht is obtained is the form of yellow crystals 171 3 g of are in 20 of absolute and of solution of f are g of are in and for 10 minutes a boiling r Upon distilling the off the residue is the tion of to ined is the The ione being used as the above stated starting in the following ic are heated in 260 ml of absolute for f hours till filtration of any undissolved the e is tely possible by of distillation residue is heated with ml of for 10 minutes at reflux temperature and purified with After of is g of the above stated compound are 3 g of ures for 20 minutes at Upon dissolving the cooled in methanol is 199 to Exsraple btained by use of the ionorphol laaoae thy 197 Analogous to obtained are by of the 208 insufficientOCRQuality

Claims (1)

1. 32 A process for the of new derivatives of cyclic compounds of general wherein indicates radical derived from a acid or the hydrogen or and together with the atoai represent a five cal which he condensed with further or heterocyclic ring whieh ring may bear a halogen atom or or radical and in which the nitroge a bearing the radicals and member of a or a an have the o different meaning and indicate members of the group consisting of hydrogen and lower alkyl and or erent 1 or whereby the of and n is 1 or Ί a bond or the wherein indicates a lower alkyl ftg and have the same or a different meaning and indicate hydroxy alkyl halo substituted lower alkyl or aryl 33 or represent the nitrogen bearing tbese a or saturated heterocyclic radical which say cont as further an a sulfur or a nitrogen atom may be such ted by or radicals and heterocyclic radicals be substituted by a or phenyl radicals pharmaceutically acceptable salts of the compounds of the formula I with or organic acids comprising a of the wherein to a and n have same as above with a compound of the wherein have the same meaning indicated above a salt of a compound of the general formula presence of or in of such compounds which are able to form under the conditions of the reacting a compound of the general formula CK wherein to end n the as above and Z an group or atom compound of the general III or with a salt of of general formula III or reacting e of the formula II compound of the general formula wherein and Z the meaning as or k process in Clelm 1 wherein the ound of formula I is further reacted with an organic or inorganic seid so to convert it into a of general formula ft CH n 35 to n Y the ns indicated in compounds of the general formula CH C if to have meaning as above and represents of the numbers 1 or s of the general wherein to and Y have the same meaning as indicated above and p represents one of the numbers A or Cyclic imide compounds of the general formula wherein to m and n have the meaning as an alkylene indicated above and B group which completes the group to a or radical Cyclic imide compounds of the general formula wherein to m and n have the same meaning as indicated above Cyclic imide compounds of the general formula wherein to and n have the same meaning as indicated above and alkyl represents a lower radical 31 Cyclic imide compounds of the general formula wherein and Y have the same meaning as indicated above and represents the pyrrolidino or the piperidino Cyclic imide compounds of the general formula wherein to and n have the same meaning as cated Cyclic imide compounds of the general formula wherein to m and n have the same meaning as indicated above and alkyl represents a alkyl radical 52 8 Cyclic imide compounds the general formula wherein n and Y have the same meaning as indicated above Cyclic imide compounds of the general formula wherein to m and n have the same meaning as indicated above Cyclic imide compounds of the general formula wherein to m and n have the same meaning as in dicated above and alkyl represents a lower alkyl radical 33 9 33 Cyclic imide of the general formula wherein n and Y have the same meaning as indicated above Cyclic imide compounds of the general formula wherein Y and Rg have the same meaning as indicated Cyclic imide compounds of the general formula wherein Y and have the same meaning as indicated above Cyclic imide compounds of the general formula Y wherein Y and have the same meaning as indicated iaide formula wherein fig have the as iaide of the general X have the indicated iaide compounds the general wherein and Rg have meaning indicated A process o of new derivatives compounds of I as defined in Claim as d with reference to the derivatives of of the formula 1 as defined la whenever prepared the process ing to of Claim 2 or insufficientOCRQuality