IE42363B1 - New cyclic imides, processes for their preparation and medicaments containing these imides - Google Patents

Abstract

The novel compounds correspond to the formula: in which R represents the methyl, ethyl or n-propyl radical. They are prepared starting from beta -phthalimidoglutaric acid or one of its functional derivatives by reaction with an amine H2N-R or a salt thereof, or from a 4-aminopiperidine-2,6-dione substituted on N<1> by R or one of its salts by reaction with phthalic anhydride, phthaloyl chloride or an activated derivative of phthalimide. The compounds, in particular those in which R represents the n-propyl radical, are able to suppress the growth of tumours and have a very low toxicity.

Description

l'lie present Invention relates to new cyclic imides which themselves have valuable properties as pharmaceuticals and which may be used as intermediates foi' the manufacture of pharmaceuticals. Further, the present invention relates to processes for the manufacture of these compounds, The compounds according to the invention have the wherein R indicates the methyl-, ethyl- or n-propylΙθ radicals. A preferred compound is that in which ft is n-propyl.

Tho compounds according to the invention are able to inhibit or reverse the growth of tiimours, as can he shown using the following test method: If female Sprague-Dawley rats on tlieir 50tli, 53rd and 57th day of life with a mean weight of l60 grams are given 2 rag of 7,12-dimethyl-benzanthracene in a leeithineemnlsion intraveneously, there occur, in the region of the milkridge, tumours, the number of which may he counted and 20 the size of which may he measured. Treatment of animals, in which mammary tumours were induced in the mannei' described above, with compounds of the formula I results in a decrease in the number and size of the tumours in comparison with untreated control animals.

The following tabic shows the favourable influence on numbers and size of tumours in relation to the time of treatment when an amount of 0.25$ of each of the compounds of formula I is given to the animals in their food. All figures contained in the table ai’e average values from groups of 20 animals.

Table 1 number of tumours/animal area of tumours (mm^)/animal time of treatment in weeks Compound of formula (1) [untreated control tt o II £ IA tt ci o II tt C'- w ΙΛ o if II tt untreated control in tt Q II tt in w 0 II tt Τ'* tt in o I al u tt 0 4.1 4.2 4. 2 4.1 802.6 810.6 801.2 821.9 2 5.7 3.4 3.7 3.8 1336.6 453.9 577.1 359.6 4 6.3 2.5 2.7 2.1 1544.7 364.6 344.8 140.7 6 7.1 2.3 2.4 1.3 1778.3 370.6 375.2 162.4 The LDj-θ, that is the dosage in mg/kg body weight on which treatment 50 $ of the animals treated die, was evaluated on fully grown mice and rats of both sexes. The following results were obtained: LD 50 (mgzkg body ueiglit ) R Mice Application Rat Application oral intraperi- toneal oral intraperi- toneal cn3 460 410 5100 350C2n5 246 185 660 172 n-C3ll7 2000 860 2130 350 As can be seen from the above figures the compounds of the general formula (I), particularly the n-propyl-derivative, exhibit a very remarkable activity in inhibiting the growth of the dimethyl-benzanthracene-induced tumours of rats and have only a slight toxicity.

Compounds of the general formula (I) in which R represents the radical -CU2 - N R iii which R’ and K are the same or different and represent optionally substituted lower alkyl or aralkyl radicals or R’ and R together with the nitrogen atom represent an optionally substituted 5 or 6-membered heterocyclic radical optionally additionally containing other hetero atoms, are known from the German Offenlegungsschrift No. 1,545,706. For example, the 1-(morpholinomethyl)-4-phthalimido-piperidine-dione-2,6-( known as CG 603) is known and its activity of the dimethyl-benzanthracene induced tumours of rats is described in Europ. J, Cancer, 8., 157 - 158 (1972). In an amount of 1-37% in food this 2o compound is able to decrease the (average) number of tumours from 2.2 to 1.3, a decrease of 40%· By contrast, the 1-npropyl-4~phthalimido-piperidine-dione-2,6 administered in an - 4 42363 amount of only 0.25% in food leads to decrease in the average numbers of tumours per animal of from 4.1 to 1.3.

The compounds according to this invention give a reduction of more than 70% in the average number of tumours per animal therefore, at a dosage which is less than 20% of the dosage at which the known compound provides a reduction of only 40% in the same parameter. Moreover the new compounds of the general formula (I) show a favourable effect on the endocrinic system and can be used to influence favourable auto-immunediseases.

The new and valuable compounds of the general formula (l) may be prepared by converting β-phthalimido-glutaricacid or a reactive derivative thereof, with an amine of the general formula h2n-r (II) wherein R has the same meaning as indicated above to a mono-or diamide and cycli.zing it. A preferred reactive derivative of g-phthalimido~giutaric acid is the anhydride thereof, but halogenides and esters with aliphatic alcohols 1 to 3 carbon atoms or aromatic alcohols or phenols may be used also.

In cases where compounds of general formula (i) are prepared form β-phthalimido-glutaric-acid anhydride and an amine of formula (II), it is best to heat the reaction mixture in order to complete the reaction or to carry out the reaction in the presence of an agent which promotes the ring-closing reaction. The water formed during the reaction can also be distilled off or removed by azeotropic distillation. In cases where a mono- or diamide, substituted by the radical R is used as the starting material, the ring closing reaction can be effected by heating and/or by the presence of acidic condensation agents. It is preferred to use heating in the presence of condensation agents which promote ring closure - 5 4 2363 for example acetic anhydride, thionyl chloride, acetyl chloride and similar acidic agents which split off water. Λ preferred method for the preparation of the compounds according to the invention is provided by the manufacture and isolation of a monoamide of β-phtlui) imido-glutaric acid and the following cyclization. In this ease it is advisable to prevent the formation of diamides by adding an equivalent amount of a tertiary amine, as for example triethylamine.

It docs not matter so far as to the outcome of the process according to the invention is concerned whether the amine of formula (ll) is used as such or whether a compound which gives an amine of formula (II) under the reaction conditions is used. Examples of such compounds are salts, as for example eai'bonates of the amine of formula (ll), or ureas, thioureas or carboxylic acid amides derived from an amine of the particular type.

Alternatively the compounds of the general formula (I) can be obtained by reacting a compound of the general formula wherein R has the same meaning as indicated previously, or a salt thereof with phthalic acid anhydride or with phthalic acid chloride. The reaction is preferably carried out in an inert solvent, optionally under cooling and with the addition of acid-binding compounds, as for example triethylamine, trimethylamine, diisopropylaminc, sodium 2 3 6 3 or potassium carbonate. Preferred solvents for tho reaction are ethers and hydrocarbons. Instead of the phthalic acid anhydride, reactive derivatives thereof can be used, as for example N-earbethoxyphthalimide. In this case the reaction is carried out in water at room temperature, with addition of sodium hydrogen carbonate.

The compounds of the general formula (1), obtained according to any of the abovementioned procedures, can be used in the manufacture of pharmaceuticals in different dosage forms. If desired, retarded release forms may be made and enteral or parenteral application is possible. Compounds of the general formula (i) can be combined with other active compounds. In the production of tablets, pills, dragees and similar application forms, generally used inorganic or organic adjuvants are added. Such adjuvants may be for example: For tablets and dragees: lactose, starch, talc, octodeeanoic acid, magnesium stearate; For syrups, drops and the like: sugar, invert sugar and glucose solutions; For drugs of parenteral application: water, mono- or polyhydrie alcohols and vegetable fats; For suppositories: natural or hydrogenated oils and waxes.

Moreover suitable preservatives, vetting-, dissolvingand sweetening agents as well as colouring and aromatizing materials may be added.

The dosages of a compound of the general formula (I) which may be used to give pharmaceutical compositions with tumour-inhibiting activity ranges from 1 to 200 mg/kg, preferably from 20 to 60 mg/kg. Tlie application is from 1 2 3 6 3 to 5 times per day. , The following examples serve further to illustrate the invention. All melting point data are uncorreeted. In performing the examples it was not the intention to obtain maximum yields.

Example 1 350 g of β-phthalimido-glutarie acid anhydride are suspended in 2000 ml of absolute dioxane. 118 ml of triethylamine are added. 112 ml of n-propylamine, dissolved in 200 ml of dioxane are added at such a rate that tho reaction temperature remains below 35°G. The reaction mixture is allowed to stand for one hour. Charcoal is added, the solution is filtered and the solvent is distilled off under reduced pressure. The oily residue is dissolved in 1000 ml of water and 500 ml of 18?£ hydrochloric acid are added. On standing with cooling, β-plitlialimido-glutarie acid-N-(n)-propyl-monoamide precipitates in white crystals. The melting point is 1S9 - 191°C after recrystallization from water. The yield is 123 g5 2o i.e. 87# of the theoretical. Cyclization of this material gives the desired l-(n)-propyl-4-phtliali)nido-piperidindione2,6 product.

On following the procedure described above using t-hc appropriate aminos the following compounds are obtained: l-methyl-4-phthalimido-piperidindiot)e-2,6, melting point 119-121° after recrystallization from water. l-ethyl-k-plithalimido-pipcridindione-2,6, melting point 165-167° after recrystallization from ethanol.

Example 2 17S g of hydrochloride of l-methyi-4-ainino-piperidindione 2,6 (obtained as described below) and 148 g of phthalic acid anhydride are suspended in 2000 ml of toluene. 121 g of triethylamine are added and the reaction mixture is refluxed in a water separator for some hours. The precipitated triethylamine hydrochloride is filtered off and the solvent is distilled off under reduced pressure.

The residue is recrystallized from water. 1-methyl—410 phthalimido-piperidindione-2,6- is obtained, with melting point 119 - 121°.

On following the procedure described above 1-ethyl4-phthalimido-piperidindione-2,6 and l-n-propyl-4phthalimido-piperidindione-2,6 are obtained. The compounds are identical with these obtained according to example 1.

Example 5 17.8 g of hydrochloride of l-methyl-4-aminopiperidindione-2,15 (obtained as described below) are dissolved in 100 ml of water. 28.6 g of sodium carbonate ,θ decahydrate are added, and then over a period of 15 minutes g of N-carbethoxyphthalimide are added in portions.

After 30 minutes the reaction mixture is filtered if necessary. The clear solution is acidified with diluted hydrochloric acid until a pH-value of 6 is reached. The !5 precipitate is filtered off, dried and reerystallised from water. The resulting l-mcthyl-4-phthalimido-piperidindione2,6 is identical with the compound of Example 1.

On following the above described procedure 1-ethyland l-(n)-propyl-4-phthalimido-piperidindione-2,6 are obtained. ‘Λ 3 6 3 The l-a]ltyl-4-amino-piperidindiones-2,6 used as starting material in Examples 2 and 3, are obtained as follows: g of sodium hydroxide are dissolved in 2100 ml of water. 176.8 g of β-amino-glutarie acid are added.

Tlie clear solution is cooled to 0°C, Under vigorous stirring 372 g of carbobenzoxycliloride and 450 ml of 10% aqueous sodium hydroxide solution are added simultaneously, and the reaction mixture stirred for 10 hours. The alkaline solution is then extracted with ether several times, and the aqueous solution carefully acidified with diluted hydrochloric acid. The precipitate formed is filtered off, dried at 100°C under reduced pressui-e and recrystallized from ethyl acetate /petroleum ether. The N-earbobenzoxyβ-amino-glutarie acid thus obtained lias a melting point of 103°C. The yield is 70% of the theoretical. 100 g of the N-carbobenzoxy-^-amino-glutaric acid are reacted with 1000 ml of acetic acid anhydride for 3 hours.

The solvent is distilled off under reduced pressure, and the residue dissolved in acetic acid ethylate. This solution is cleared with charcoal, filtered and then a part of the solvent distilled off. On adding petroleum ether to the remaining solution, p-(N-carbobenzoxy)-glutaric acid anhydride precipitates. The melting point is 87 - 89°G.

The yield is 69 g. 75-3 % of the theoretical. 147 g of the p-(N-earbobenzoxy)-(jiu-fcari£ acid anhydride are dissolved in 900 mi of absolute dioxane. Dry gaseous methylamine is introduced until no more precipitate is obtained. The precipitate is filtered off and dissolved in a small amount of water. On acidifying with 18% of hydro10 chloric acid the Diethylamide of f3-(N-carbobenzoxy)-amino~ glutaric acid is obtained. The melting point of this material is 174 - 176°C after reerystallization from water and the yield is ll't g, 70 fp of the theoretical. 180 g of this product are heated under reflux in a mixture of 1800 ml of acetic anhydride and ISO ml of thionylehloride for 2 hours. The solvent is distilled off under reduced pressure, and the residue recrystallized from ethyl acetate- . -i/pet170!®11™ ether. The melting point of the l-iiietliyl-4-(N-carbobenzoxy)-amino-piperidi.ndione2,6 obtained is 130 - 131°C, and the yield is 150 g, 89 i> of the theoretical. g of this compound are dissolved in 13θ0 ml of acetic acid. 10 g of 5 % Pd-catalyst on charcoal are added, and the reaction mixture then hydrogenated at room temperature and normal pressure. When no more hydrogen is absorbed, the catalyst is filtered off and a solution of hydrogen chloride in ether is added. The solvent is distilled off under reduced pressure until crystallization sets in. On cooling 1-methyl—4-amino-piperidindione-2,6 is obtained. The melting point of this material is 213 215°C and the yield 45 g, 74.5 7° of the theoretical.

Claims (8)

1. CLAIMS :I. Cyclic Jniid.es of the general formula N-R (J.) wherein R indicates the methyl-, ethyl- or n-propylradical.

2. l-nietliyl-4-phtbalimido-piperidine-tii one-2,6.

3. 1-ethyl—'i-phthalimido-pipcridine-dione-2,6.

4. 1-n-propyl—4-phtlial inlido-pi peridini'-dione-2,6.

5. A process for the manufacture of compounds as claimed in claim 1 which comprises: (a) reacting β-phtlialimido-glutaric aeid or a functional derivative thereof with an amine of the general formula ii 2 n· - R (II) wherein R is as defined in claim 3, or with a compound that yields an amino of general formula (II.) under the. reaction conditions, optional ly wi tii heating; or (h) cyclizing a mononinide or diamide derived from an amino of tho general formula (II) and β-phtlinlimido-glutaric acid; (e) reacting a compound of the general formula r < H 2 N-( N-R (111) wherein R is as defined in claim 1 or a sail, thereof 4 2 3 6 3 with phthalic acid anhydride,phthalic acid chloride or Nearbocthoxyphthalimide, optionally with the addition of acidbinding compounds.

6. A process as claimed in claim 5(b), wherein said 5 cyclization is carried out by heating and/or in the presence of acidic condensation agents.

7. A process as claimed in claim 5(c), wherein said reaction is carried out by heating the reactants.

8. A process as claimed in claim 5, substantially as jO herein described with particular reference to the Examples.