NO160139B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE ACRIDANON DERIVATIVES. - Google Patents

Description

The present invention relates to the production of acridanone derivatives with the general formula

where the dotted line means a facultative bond,

R<1> is hydrogen or halogen, one of the substituents R

and R<4> is hydrogen or C1 - C4 alkyl and the other together with R is an additional bond, A is C1 - C4 alkylene, R5 is an optionally C1 - C4 alkyl, N-substituted imidazole ring attached to A above a C atom/an amino group or the group

the symbol

is a pyrrolidine ring, an optionally med

C - C4~alkyl substituted piperidino ring, a morpholino or a piperazino ring where the piperazino ring can optionally be substituted in the 4-position with a group

t-a(Bll) ^ et -A 0 1 -R el6l, is B e1r , A gr1 uper peCn , -C- OC-, .-a-Cl0ky0- lenel, lR is 6e-r S0h_y-d, ron geenr or di (C 1 -C 4 -alkyl)amino and R 7 is hydrogen or

C1 - C4 alkyl,

as well as pharmaceutically acceptable acid addition salts thereof.

These new substances have valuable pharmacological properties and can be used to fight or prevent diseases.

According to the meaning of the dotted line and the substituents R, R and R 4 , the compounds with the above-mentioned formula I can exist in different tautomeric forms; the present invention includes all possible tautomeric forms.

The term "lower" as used in the present description means that the compounds or residues thus designated have up to 4

carbon atoms and can be straight chain or branched. The term "C 1 -alkyl" denotes saturated hydrocarbon radicals such as methyl, ethyl, propyl, isopropyl, n-butyl, n-butyl, and the like. The term "C 1 - alkylene" means divalent hydrocarbon residues such as methylene, dimethyl, trimethylene, 1,2-propylene, 1,4-butylene, 1,5-butylene and the like. The term "halogen" means fluorine, chlorine, bromine or iodine.

The substituent R"*" is, if it is different from hydrogen, preferably in the 1-position. However, the preferred meaning of R is hydrogen. Preferably, one of the substitu-

either R 3 and R 4 are hydrogen and the other together with R a further bond. A preferably means dimethylene or trimethylene.

R^ preferably means amino, 1-pyrrolidinyl, 1-piperidinyl, 1-morpholinyl, 1-piperazinyl or the group -NR 7 -A 1 -R 61 or -N N-(B^") -A^-R^"* ", where A"*" means lower alkylene, B"*" the group n £- -| <_ >-CO-, n the number 0 or 1, R hydrogen and R hydrogen or lower alkyl. The particularly preferred meaning possibilities of R^ are amino, dimethylamino, diethylamino, 1-pyrrolidinyl, 1-piperidinyl, 4-methyl-1-piperazinyl and 4-acetyl-1-piperazinyl.

The acridanone derivatives with. the above-defined formula I and their pharmaceutically acceptable acid addition salts can, according to the invention, be prepared by

a) cyclizes a compound of the general formula

where one of the substituents R<31> and R<41> means hydrogen

or lower alkyl and the other means hydrogen, R<42 >means hydrogen or lower alkyl, R<51> means a residue R 5 as defined above, which however does not contain any primary or secondary, basic amino group, and R and R 5 have the above stated meaning,

or

b) reacts a compound with the general formula

where yO means an anion and X is a leaving group, preferably a halogen atom, and A, R and R have the above meanings, with a compound of the general formula

3 4

where the dotted line, R, ,R and R have the above meaning,

or

c) cleaves the N-protecting group in a compound of the general formula

8 5

where R means a residue R as defined above,

containing a primary or secondary basic amino group blocked by an N-protecting group,

and the dotted line, R, R"*", R and R% have the above meaning,

and

if desired, an obtained compound of formula I is transferred into a pharmaceutically acceptable acid addition salt.

According to process variant a), the compounds of formula I can be prepared by cyclizing a compound of formula II, or VII according to methods known in and of themselves and common to every person skilled in the art. The cyclization reaction takes place since whichever starting material is used, rather easily and. can also be carried out or completed by a longer delay and/or application of heat. The starting materials used for the ring closure reaction do not necessarily have to be used in an isolated state; as a rule, it proves appropriate to cyclize these starting materials directly or allow them to cyclize without isolation from the reaction mixture in which they have been prepared. Given the reaction conditions used, in some cases isolation is not possible at all because the cyclization occurs spontaneously.

Solvents which are suitable for the present method aspects are e.g. ether such as tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, etc., alcohols such as methanol, ethanol, etc., dimethylformamide, dimethyl sulfoxide, acetonitrile, etc. The reaction temperature is suitably in a range between approximately room temperature and the boiling point of the reaction mixture.

According to method variant b), the compounds of formula I can be prepared by reacting a compound of formula X with a compound of formula XI. The leaving group denoted by X in the compound of formula X is preferably a halogen atom, a lower alkanoyloxy group or a lower alkoxy group, especially a chlorine atom, an acetyloxy group or a methoxy group. The compounds of formula X are partly substances that are not particularly stable. They are therefore suitably prepared shortly before the reaction with a compound of formula XI from a compound of the general formula

1 51

where A, R and R have the above meaning,

which is produced as described below and further processed directly, possibly without prior isolation.

The compound of formula XI is suitably used in the form of an acid addition salt, e.g. in the form of a hydrochloride or hydrobromide. The reaction can be carried out in the presence of an acid-binding agent, as acid-binding agents in particular sodium and potassium carbonates, bicarbonates and acetates are relevant. As a solvent for the present process aspect, e.g. lower alcohols such as methanol and ethanol, and other organic solvents inert under the reaction conditions such as dimethylformamide, acetonitrile, etc. The reaction temperature is suitably in a range between approximately room temperature and the boiling temperature of the reaction mixture.

According to process variant c), compounds of formula I can be prepared which have a primary or secondary basic amino group in the residue R 1 , while in a compound of formula XII the N-protecting group is cleaved off. As a protecting group suitable for the purpose of the present invention primarily acyl groups, preferably easily cleavable alkoxycarbonyl or optionally substituted on the phenyl ring, t-butoxycarbonyl groups, benzyloxycarbonyl groups, etc., in addition also easily cleavable, on the phenyl ring optionally substituted -substituted phenylalkyl groups such as the benzyl group. The removal of the protecting group takes place according to methods known per se, as naturally when choosing the method to be used, consideration must be given to the nature of the protecting group to be removed. Likewise, it must be taken into account that only such methods can be used which remove the protective group selectively without other structural elements present in the molecule being implicated.

The above-mentioned residues, which are given as examples for the relevant protecting groups, can be cleaved off hydrolytically. Thus, e.g. the benzyloxycarbonyl group and the t-butoxycarbonyl group are cleaved off under selective acidic conditions, for example by treatment with a mixture of hydrogen bromide and glacial acetic acid or by treatment with boron trifluoride or boron tribromide in an inert organic solvent such as dichloromethane. The t-butoxycarbonyl group can also be cleaved by treatment with hydrogen chloride in an inert organic solvent such as dioxane, tetrahydrofuran etc., or by treatment with trifluoroacetic acid.

The acridanone derivatives with it initially

defined formula I, can be transferred in pharmaceutical

tically acceptable acid addition salts. The production of such acid addition salts takes place here according to usual methods. Both salts with pharmaceutically acceptable inorganic acids and salts with pharmaceutically acceptable organic acids can be used, e.g. hydrochlorides, hydrobromides, sulfates, citrates, acetates, succinates, methanesulfonates, p-toluenesulfonates, etc.

The compounds of formula X used as starting materials

as well as the compounds of formula II, VII,

and XII, can be prepared from the compounds of formula XIII according to the following formula scheme; the dotted line and the substituents A, R1, R31, R41, R42, R51, R8,

9 91

X and S<1> have the above meaning, R and R mean C. -

52 5 alkyl or together C-1 - C4 alkylene, R means a residue R containing a primary or secondary basic amino group, and R ^ means lower alkyl, phenyl or substituted phenyl. The compounds of formula XIII belong to a class of substances known per se.

The compounds of formula XIV can be prepared from the compounds of formula XIII by alkylating a compound of formula XIII in the presence of a strong base such as sodium hydride or the like with an agent which supplies the residue -A-R^. This reaction takes place according to methods known in and of themselves and to each person skilled in the art.

The compounds of formula X where X means a halogen atom can be prepared by treating a compound of formula XIV in an inert organic solvent with a halogenating agent. In a preferred embodiment, oxalyl chloride or phosphorus oxychloride is used as halogenating agent and halogenated hydrocarbons as solvent, such as ethylene chloride, chloroform, 1,2-dichloroethane etc., acetonitrile or excess halogenating agent, obtaining a compound of formula X where X is chlorine. The reaction temperature preferably varies in a range between approximately room temperature and the boiling temperature of the reaction mixture.

Compounds of formula X where X is a leaving group different from halogen can be obtained from corresponding halogen compounds. One can e.g. replace the halogen atom in such a compound in a manner known per se with other leaving groups, e.g. with lower lacoxy groups or lower alkanoyloxy groups.

The compounds of formula X are quaternary ammonium salts, some of which, as already mentioned, are not particularly stable; these are further processed appropriately immediately after production. The nature of the anion denoted by Y^ depends on the method of preparation of the corresponding compound of formula X. One prepares, e.g. a compound of formula X where X is chlorine, and using oxalyl chloride as a halogenating agent, a compound of formula X is obtained where Y ® is a chloride anion; if phosphorus oxychloride is used as a halogenating agent, a corresponding compound is obtained where Y <®> means PC^CI^ The compounds of formula II where the radical R^ does not contain any primary or secondary, basic amino group, i.e. compounds of formula IIa, can be prepared by that one reacts a compound of formula X with a thiosemicarbacid of the general formula

31 41

where R and R have the above meaning,

in that one can use the reaction conditions specified in method variant ) as mentioned above, and react the obtained compound with the general Formula XVIIa with a compound with the general formula

where X<1> has the above meaning.

The leaving group denoted by X<1> is preferably a chlorine or bromine atom. Lower alcohols such as methanol and ethanol are particularly suitable as solvents. The reaction temperature is suitably in a range between approximately room temperature and the boiling temperature of the reaction mixture.

The compound of formula II, where R^ contains a primary or secondary basic amino group, can be prepared by alkylating a compound of formula XIII (analogous to the preparation of a compound of formula XIV) with an agent which supplies the residue -A-R g, transfers the obtained compound of formula XIVS (analogous to the preparation of the compound of formula X) in a compound of formula XS, reacts this (analogous to the preparation of the compound of formula XVIIa) with a thiosemicarbacid of formula XVIII, in the obtained compound of the general formula XVIIS (using the above method variant

<c>) specified reaction conditions) cleaves N-protection

group and reacts the obtained compound of formula XVIIb (analogous to the preparation of the compound of formula Ila) with a compound of formula XIX. The compounds of formula VII can be prepared by reacting a compound of formula VIII with an isothiocyanate of the general formula

9 91

where R and R have the above meaning,

and then hydrolyzes the acetal group in the obtained compound of the general formula XV. The first step is conveniently carried out in an inert organic solvent, e.g. in an ether such as diethyl ether, t-butyl methyl ether and tetrahydrofuran, or in dimethylformamide, acetonitrile or the like, at temperatures between about room temperature and boiling temperature. The hydrolysis of the acetal group can be carried out with the help of an aqueous acid, as one can optionally work in the presence of a solvent such as tetrahydrofuran, dioxane, methanol, ethanol, dimethylformamide etc. As acids are e.g. sulfuric acid, hydrochloric acid, p-toluenesulfonic acid etc. relevant. The temperature is not critical and can vary over a larger area.

As mentioned above, it is not necessary (and in some cases not even possible) to isolate the compounds of formula II, '.and VII; rather, it has usually shown

it is appropriate to cyclize these compounds directly or allow them to cyclize without isolation from the reaction mixture in which they have been prepared.

The compounds of formula XII used as starting materials can be prepared from the compounds of formula XS analogously to the preparation of the compounds of formula I from the compounds of formula X according to method variants a) and b) described above and the methods described for the preparation of the corresponding starting materials.

The acridanone derivatives of the above formula I and their pharmaceutically acceptable acid addition salts have valuable pharmacological properties; they have particularly valuable schistosomicidal effects and can be used to combat and prevent schistosomiasis.

The schistosomicidal effect of the substances produced according to the invention can be demonstrated by animal experiments as follows: Albino mice weighing 15-18 g are infected subcutaneously with 60+ cercariae of a Liberian strain of Schistosoma mansoni. 46 days after the infection, the animals are treated once orally with the substances to be evaluated. 5 - 10 animals are used per substance and dosage. As a control, 10 untreated animals serve. The dissection takes place after 19 days, after which pairs of worms and individual worms are taken out from the mesenteric veins, main artery and liver and counted. The vermicidal effect is shown in a reduced number of live parasites compared to the number in the control animals.

For assessment, the percentage reduction of the parasites in the treated animals is calculated in comparison to the untreated control animals. VD^-q is determined according to the probit method. VD5Q is a vermicidal dose that causes a 50% reduction in the number of worms.

The following table shows the results obtained with some representative substances produced according to the invention. For each compound, VD^-q is given in mg/kg p.o. and for some of these compounds l°5q is stated in mg/kg for single oral administration.

As mentioned at the outset, the products produced according to the invention can be used in the fight against the prevention of diseases. They are particularly suitable for fighting and preventing schistosomiasis. The dosage can vary within wide limits and must of course be adapted in each case to the individual circumstances. In cases of schistosomiasis, a single dose of approx. 1-50 mg/kg body weight may be suitable, as this dose can also be administered spread over an entire day.

The following examples shall explain the present invention in more detail. All temperatures are given in degrees Celsius.

EXAMPLE 1

a) A mixture of 8.5 g of 9-acridanone, 180 ml of dimethylformamide and 3.3 g of sodium hydride is stirred for 0.5 hours, mixed in portions with 10.3 g of 2-/1-(4-methyl)-piperazinyl/ ethyl chloride-dihydrochloride, stir for 3 days at 80°C, evaporate, mix the residue with water and extract with methylene chloride. The extract is washed with water, dried over sodium sulfate and evaporated, after which the residue is recrystallized first from ether and then from ethyl esters. 10-[2-(4-methyl-1-piperazinyl)ethyl]-9-acridanone is obtained, m.p. 156-157°C.

A solution of 2.2 g of 10-[2-(4-methyl-1-piperazinyl)ethyl]-9-acridanone in 100 ml of dichloromethane at -5°C is mixed in portions with 1.17 ml of oxalyl chloride, stirring again in 0 .5 hours at room temperature and evaporates. The residue (9-chloro-10-(2-(4-methyl-1-piperazinyl)ethyl7acridinium chloride) is mixed with 100 ml of methanol, 1.346 g of 2-hydrazino-2-thiazoline hydrobromide and 1.67 g of sodium acetate, heated under return to the boiling point, cool after 10 minutes and evaporate. The residue is mixed with saturated soda solution, extracted with methylene chloride, the extract is washed with water, dried over sodium sulfate and concentrated. After addition of ethyl alcohol, the crystallized product is filtered off and washed successively with ethyl alcohol and petroleum ether 10-[2-(4-methyl-1-piperazinyl)ethyl]-9-acridanone-(2-thiazolidinylidene)hydrazone is obtained, mp 204-205°C.

Analogously, one achieves:

b) From 9-acridanone and 3-(dimethylamino)propyl chloride the 10-/3-dimethylamino)propyl/-9-acridanone with m.p. 89°C"And hence 10-(3-(dimethylamino)propyl/-9-acridanone-(2-thiazolidinylidene)hydrazone, m.p. 191-192°C; c) from 9-acridanone and 2-(diethylamino) ethyl chloride hydrochloride 10-/2-(diethylamine)ethyl/-9-acridanone with mp 109-111°C and hence 10-/2-(diethylamino)ethyl/-9-acridanone-(2-thiazolidinylidene)hydrazone , mp 153-155°C; d) from 9-acridanone and 2-(1-pyrrolidinyl)ethyl chloride-hydrochloride the 10-/2-(1-pyrrolidinyl)ethyl/-9-acridanone with mp 14 3-145° C and hence 10-/2-(1-pyrrolidinyl)ethyl/-9-acridanone-(2-thiazolidinylidene)hydrazone, m.p. 220°C (decomposition); e) from 9-acridanone and 2-(1-piperidinyl) ethyl chloride-hydrochloride 10-[2-(1-piperidinyl)ethyl]-9-acridanone with m.p.

165°C and hence the 10-/2-(1-piperidinyl)ethyl7~9-acridanone-(2-thiazolidinylidene)hydrazone, m.p. 207°C;

f) from 9-acridanone and 2-(4-morpholinyl)ethyl chloride hydrochloride 10-/2-(4-morpholinyl)ethyl/-9-acridanone with m.p. 196°C

and hence the 10-[2-(4-morpholinyl)-ethyl]-9-acridanone-(2-thiazolidinylidene)hydrazone, m.p. 236°C.

EXAMPLE 2

a) A mixture of 4.5 g of 9-acridanone, 1.1 g of sodium hydride and 100 ml of dimethylformamide is stirred for 0.5 hours, mixed

then with 5.2 g of 2-(4-acetyl-1-piperazinyl)-ethyl chloride hydrochloride, stir for 15 hours at 70°C and evaporate. The residue is mixed with water, extracted with methylene chloride, the extract is washed with water, dried over sodium sulphate and evaporated. Crystallization from ethanol gives 10-[2-(4-acetyl-1-piperazinyl)ethyl]-9-acridanone,

m.p. 241-243°C.

A suspension of 3.5 g (10 mmol) of 10-[2-(4-acetyl-1-piperazinyl)ethyl]-9-acridanone in 100 ml of acetonitrile is mixed with 1.7 ml (20 mmol) of oxalyl chloride, filtered off after 0.5 hours and wash the filtered off material (9-chloro-10-[2-(4-acetyl-1-piperazinyl)ethyl/acridinium chloride). first with acetonitrile and then with ether. A mixture of the substance obtained with 2 g (10 mmol) 2-hydrazino-2-thiazoline hydrobromide, 2.5 g (30 mmol) sodium acetate and 100 ml methanol is heated under reflux to boiling, evaporated after 15 minutes, mixing the residue with water, making it alkaline with soda solution and extracting with methylene chloride. The extract is washed with water, dried and evaporated, after which the residue is crystallized from methanol. After the recrystallization from n-butanol, 10-[2-(4-acetyl-1-piperazinyl)ethyl]-9-acridanone-(2-thiazolidinylidene)-hydrazone is obtained,

m.p. 256°.

Analogously, one achieves:

b) From 9-acridanone and 2-(4-ethoxycarbonyl-1-piperazinyl)ethyl chloride hydrochloride 10-(2-(4-ethoxycarbonyl-1-piperazinyl)ethyl)-9-acridanone, m.p. 147°, and hence the 10-[2-(4-ethoxycarbonyl-1-piperazinyl)ethyl]-9-acridanone-(2-thiazolidinylidene) hydrazone, m.p. 231° (decomposition); c) from 9-acridanone and 2-(4-pivaloyl-1-piperazinyl)-ethyl chloride hydrochloride 10-(2-(4-pivaloyl-1-piperazinyl)ethyl)-9-acridanone, m.p. 184°C, and hence the 10-[2-(4-pivaloyl-1-piperazinyl)ethyl]-9-acridanone-(2-thiazolidinylidene)hydrazone, m.p. 208°C; d) from 9-acridanone and 2-(4-(methylsulfonyl)-1-piperazinyl-7-ethyl chloride hydrochloride) the 10-(2-/4-(methylsulfonyl)-1-piperazinyl)ethyl-9-acridanone, m.p. 244-246°C, and hence the 10- /2- /4-(methylsulfonyl)-1-piperazinyl/ethyl/-9-acridanone-(2-thiazolidinylidene)-hydrazone, m.p. 223-235°C (decomposition).

EXAMPLE 3

a) A mixture of 3.9 g of acridanone, 1.0 g of sodium hydride and 80 ml of dimethylformamide is stirred for 0.5 hours, then mixed with 2.9 g of 1-chloro-2-dimethylaminoethane hydrochloride, stirred for 18 hours at 6 0°C, evaporate and extract the residue with methylene chloride. The extract is washed with water, dried over sodium sulphate and evaporated. Crystallization from isopropyl ether gives 10-(2-(dimethylamino)ethyl7~9-acridanone, m.p. 145-146°C.

A solution of 3 g of 10-(dimethylamino)-ethyl7~9-acridanone in 100 ml of dichloromethane and 1.93 ml of oxalyl chloride is stirred for 0.5 hours. After evaporation, the residue is stirred with 2.25 g of 2-hydrazino-2-thiazoline hydrobromide and 3 g of sodium acetate in 100 ml of methanol, after which it is heated to boiling for 10 minutes under reflux and evaporated again. The residue is mixed with water, made alkaline with soda solution and extracted with methylene chloride. The extract is washed with water, dried over sodium sulphate and evaporated. After crystallization from acetonitrile, 10-[2-(dimethylamino)-ethyl]-9-acridanone-(2-thiazolidinylidene)hydrazone is obtained, m.p. 192-194°C.

Analogously, one achieves:

b) From 9-acridanone and 2-(dimethylamino)propyl chloride hydrochloride 10-/2-(dimethylamino)propyl/-9-acridanone, m.p.114°C, and hence 10-/2-(dimethylamino)-propyl/- 9-acridanone-(2-thia-zolidinylidene) hydrazone, m.p. 152°C; c) from 9-acridanone and 2-(2,6-dimethyl-1-piperidinyl)-ethyl chloride hydrochloride 10-(2-(2,6-dimethyl-1-piperidinyl)ethyl)-9-acridanone, m.p. 146°C, and hence 10-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-9-acridanone-(2-thiazolidinylidene)hydrazone m.p. 161°C; d) from 9-acridanone and (1-methyl-4-imidazolyl)methyl chloride-hydrochloride 10-(1-methyl-4-imidazolyl)-methyl/-9-acridanone, m.p. 205-207°C. and hence the 10-[(1-methyl-4-imidazolyl)methyl]-9-acridanone-(2-thiazolidinylidene)hydrazone, m.p. 206-208°C; e) from 9-acridanone and 2-/4-/2-(dimethylamino)acetyl/-l-piperazinyl/ethyl chloride hydrochloride 10/2-/4-/2-(dimethylamino)acetyl/-l-piperazinyl7ethyl/- 9-acridanone, m.p. 146-147°C and hence 10-/2-/4-/2-(dimethylamino)acetyl/-1-piperazinyl/ethyl/-9-acridanone-(2-thiazolidinylidene)hydrazone, m.p. 129-131°C; f) from 1-chloro-9-acridanone and 2-(diethylamino)ethyl chloride hydrochloride 10-(2-(diethylamino)ethyl)-1-chloro-9-acridanone, m.p. 121°C and hence the 10-[2-(diethylamino)ethyl]-1-chloro-9-acridanone-(2-thiazolidinylidene)hydrazone, m.p. 181-183°C; g) from 9-acridanone and 2-(4-propyl-1-piperazinyl)ethyl chloride dihydrochloride 10/2-(4-propyl-1-piperazinyl)-ethyl/-9-acridanone and from it 10-/2- (4-n-propyl-1-piperazinyl)ethyl/-9-acrylacridanone-(2-thiazolidinylidene)hydrazone, m.p. 205-205°C (decomposition).

EXAMPLE 4

A solution of 4.94 g (16.8 mmol) of 10-(diethylamino)ethyl/-9-acridanone in 300 ml of dichloromethane is stirred with 2.85 ml (33.6 mmol) of oxalyl chloride for 1 hour. The resulting salt (9-chloro-10-/2-(diethylamino)ethyl/-acridinium chloride) is filtered off and mixed with 100 ml of methanol, 2.82 g (16.8 mmol) of 2-(3-methyl)thiazolidinylidene- hydrazine hydrochloride and 4.1 g

(50 mmol) sodium acetate. It is heated for 10 minutes under reflux to the boiling point, evaporated, the residue is mixed with water, made alkaline with soda solution and extracted with dichloromethane. The extract is washed with water, dried and evaporated. Crystallization from ethanol gives 10-[2-(diethylamino)ethyl]-9-acridanone-(3-methyl-2-thiazolidinylidene)hydrazone,

m.p. 123-125°C.

EXAMPLE 5

a) A solution of 11.5 g of 10-/2-(diethylamino)ethyl7~9-acridanone is mixed in 250 ml of dichloromethane at -5°C and within

0.5 hours with 6.7 ml of oxalyl chloride, stirring for 1 hour at room temperature, filtering off the yellow crystals (9-chloro-10-/2-(diethylamino)ethyl/acridinium chloride) which have formed and washing these first with methylene chloride and then with petroleum ether. The material obtained is taken up in 200 ml of methanol, mixed with 3.6 g of thiosemicarbacid, stirred for approx. 18 hours at room temperature, filter off the precipitated salt and wash it first with ethanol and then with ether. One obtains 10-[2-(diethylamino)ethyl]-9-acridanone-thiosemicarbazone dihydrochloride (crystallized with 1 mol of methanol), m.p. 124°C (decomposition), mixing this with 1N sodium hydroxide solution and extracting with dichloromethane. The solution is washed with water, dried and evaporated, after which the product is crystallized from acetonitrile. One obtains 10-[2-(diethylamino)ethyl]-9-acridanone-thiosemi-

carbazone, m.p. 154-156°C.

A solution of 6.1 g of 10-[2-(diethylamino)ethyl]-9-acridanone-thiosemicarbazone in 100 ml of dimethylformamide is stirred for approx. 18 hours with 4.3 ml of chloroacetaldehyde (50% solution in water). The mixture is then evaporated, the residue is taken up in 50 ml of ethanol, adjusted with ethanolic hydrochloric acid until acidic to Congo red and the crystals are filtered off. It is first washed with ethanol, then with ether and then with petroleum ether and 10-(2-(diethylamino)ethyl)-(9-acridanone-(2-thiazolyl)hydrazone dihydrochloride is obtained, m.p. 214-216°C (decomposition).

Analogously, one achieves:

b) From 10-/2-(1-piperidinyl)ethyl/-9-acridanone and thiosemicarbazide 10-/2-(1-piperidinyl)ethyl/-9-acridanone-thiosemi-carbazone, m.p. 187°C (decomposition) and hence 10-(2-(1-piperidinyl)ethyl7-9-acridanone-(2-thiazolyl)hydrazone-1,5 HCl, m.p. 190°C (decomposition); c) from 10-/2-(4-morpholinyl)ethyl/-9-acridanone and thiosemicarbacid 10-/2-(4-morpholinyl)ethyl7-9-acridanone-thiosemi-carbazone, m.p. 240°C (decomposition) and hence the 10-(2-(4-morpholinyl)ethyl7~9-acridanone-(2-thiazolyl)hydrazone dihydrochloride, m.p. 225°C (decomposition); d) from 10-/2-(4-acetyl-1-piperazinyl)ethyl7-9-acridanone and thiosemicarbacid 10-/2-(4-acetyl-1-piperazinyl)-ethyl7-9-acridanone-thiosemicarbazone, m.p. 225°C (decomposition) and hence the 10-(2-(4-acetyl-1-piperazinyl)ethyl7~9-acridanone-(2-thiazolyl)hydrazone dihydrochloride, m.p. 180° (cleavage); e) from 10-(2-(4-pivaloyl-1-piperazinyl)ethyl7-9-acridanone and thiosemicarbazide 10-(2-(4-pivaloyl-1-piperazinyl)-ethyl7-9-acridanone-thiosemicarbazone, m.p. 179° (decomposition) and hence the 10-(2-(4-pivaloyl-1-piperazinyl)ethyl7~9-acridanone-(2-thiazolyl)hydrazone dihydrochloride, m.p. 210° (cleavage); f) from 10-/3-(dimethylamino)propyl/-9-acridanone and thiosemicarbazide 10-/3-(dimethylamino)propyl/-9-acridanone-thiosemi-carbazone, m.p. 202-204°C, and hence the 10-[3-(dimethylamino)propyl]-9-acridanone-(2-thiazolyl)hydrazone dihydrochloride, m.p. 195°C (Decomposition).

EXAMPLE 6

a) A mixture of 3 g (9.33 mmol) 10-(4-methyl-1-piperazinyl)ethyl7~9-acridanone, 100 ml dichloromethane is stirred

and 1.6 ml (18.66 mmol) oxalyl chloride for 0.5 h, evaporate to half volume and precipitate the salt (9-chloro-10-(2-(4-methyl-1-piperazinyl)ethyl/acridinium chloride) by adding of 100 ml of heat test. It is filtered off, washed with petroleum ether and dried. The red-brown powder is heated together with 1.4 2 g (9.33 mmol) of 2-thiazolyl-hydrazine hydrochloride, 2.3 g (28 mmol) of sodium acetate and 100 ml of methanol for 5 minutes under reflux to the boiling point, evaporated, mixes the residue with 50 ml of water, makes alkaline with soda solution and extracts with dichloromethane. The extract is washed with 10% sodium chloride solution, dried and evaporated. The residue is taken up in 100 ml of methanol, acidified with ethanolic hydrochloric acid, the precipitated product is filtered off and washed first with a little cold ethanol and then with petroleum ether. One obtains 10-[2-(4-methyl-1-piperazinyl)ethyl]-9-acridanone-(2-thiazolyl)hydrazone 2.5 HCl, m.p. 230°C (decomposition).

Analogously, one achieves:

b) From 10-/2-(dimethylamino)ethyl/-9-acridanone and 2-thiazolylhydrazine hydrochloride the 10-/2-(dimethylamino)ethyl7~9-acridanone-(2-thiazolyl)hydrazone dihydrochloride, m.p. > 200°C (decomposition); c) from 10-/2-(4-ethoxycarbonyl-1-piperazinyl)ethyl7-9-acridanone bg 2-thiazolyl-hydrazine-hydrochloridy 10-/2-(4-ethoxy-carbonyl-1-piperazinyl)ethyl7-9- The acridanone-(2-thiazolyl)hydrazone dihydrochloride, m.p. 185° C (decomposition); d) from 10-/2-/4-(methylsulfonyl)-1-piperazinyl)ethyl7~9-acridanone and 2-thiazolyl-hydrazine hydrochloride 10-/2-/4-(methylsulfonyl)-1-piperazinyl/ethyl/ -9-acridanone-(2-thiazolyl) hydrazone dihydrochloride, m.p. 200°C; e) from 10-/2-(4-propyl-1-piperazinyl)ethyl/-9-acridanone and 2-thiazolyl-hydrazine hydrochloride 10-/2-(4-propyl-1-piperazinyl)ethyl/-9- acridanone-(2-thiazolyl)hydrazone.2.5 HCl, m.p. 220°C (decomposition).

EXAMPLE 7

a) A mixture of 9.75 g (50 mmol) 9-acridanone is stirred,

200 ml of dimethylformamide and 4.8 g (200 mmol) of sodium hydride

for 0.5 hours, mixing portionwise with 17.8 g (50 mmol) of 2-/4-/2-(diethylamino)ethyl/-1-iperazinyl-7-ethyl chloride-trihydrochloride, stirring for 18 hours at 70°C, heating in 8 hours under reflux to the boiling point and evaporate. The residue is mixed with 100 ml of water, extracted with dichloromethane, the extract is washed with water, dried and evaporated. The product is crystallized twice from petroleum ether and 10-/2-/4-/2-(diethylamino)ethyl7-1-piperazinyl/ethyl-9-acridanone is obtained,

m.p. 106-108°C.

A suspension of 4.06 g (10 mmol) of this product is mixed in 100 ml of dry acetonitrile with stirring in portions with 1.7 ml (20 mmol) of oxalyl chloride, evaporated after 0.5 hours, the remainder mixed with acetonitrile, filtered off, washed the obtained material first with ether and then with petroleum ether and drying it. The brown powder (9-chloro-10-/2-/4-/2-(diethylamino)ethyl7-1-piperazinyl7ethyl7acridinium chloride) is taken up in 100 ml of methanol, mixed with 1.52 g (10 mmol) of 2-thiazolylhydrazine -hydrochloride and 2.46 g (30 mmol) sodium acetate and heat for 10 minutes under reflux to the boiling point. After evaporation, the residue is mixed with 100 ml of water, made alkaline with 2N caustic soda phenolphthalein, the precipitated product is taken up in 100 ml of dichloromethane, the solution is washed neutrally with water, dried and evaporated. The residue is dissolved in 100 ml of methanol, after which it is acidified with ethereal hydrochloric acid, the precipitated salt is filtered off and washed first with methanol, then with ether and petroleum ether. 10-/2-/4-/2- (diethylamino)ethyl/-1-piperazinyl/ethyl/-9-acridanone-(2-thiazolyl)hydrazone is obtained. 3.5 HCl, m.p. 235°C (decomposition).

Analogously, one achieves:

b) From 10-/2-/4-/2-(diethylamino)ethyl/-1-piperazinyl7-ethyl7-9-acridanone and 2-hydrazino-2-thiazoline hydrobromide 10-/2-/I-/2- (diethylamino)ethyl/-1-piperazinyl7-ethyl7-9-acridanone-(2-thiazolidinylidene)hydrazone, m.p. 144-146°C (decomposition).

EXAMPLE 8

a) A mixture of 4.94 g (16.8 mmol) 10-(diethylamino)ethyl7~9-acridanone, 300 ml dichloromethane and 2.85 ml

(33.6 mmol) oxalyl chloride for 20 minutes, filter the crystals obtained (9-chloro-10-[2-(diethylamino)ethyl7-acridinium chloride) and wash them with ether. This material is taken up in 100 ml methanol, mixed with 2.8 g (16.8 mmol) N-methyl-N-(2-thiazolyl)hydrazine hydrochloride and 4.1 g (50 mmol) sodium acetate, heated for 15 minutes under reflux to the boiling point and evaporate. The residue is made alkaline with soda solution, after which it is extracted with dichloromethane,

wash the extract with water, dry and evaporate. Crystallization of the residue from isopropyl ether gives 10-(2-(diethylamino)ethyl7~9-acridanone-methyl(2-thiazolyl)hydrazone, m.p. 103-104°C.

Analogously, one achieves:

b) From 10-/2-(diethylamino)ethyl7~9-acridanone and N-methyl-N-(2-thiazolin-2-yl)hydrazone 10-/2-(diethylamino)ethyl7-9-acridanone-methyl(2 -thiazolin-2-yl)hydrazone, m.p. 109-110°C.

EXAMPLE 9

A suspension of 58.6 g (0.3 mol) 9-acridanone in 200 ml of dimethylformamide is mixed in portions with a total of 60 g (0.33 mol) of ethylene carbamic acid benzyl ester, which is heated to the boiling point at reflux. After 53 hours it is cooled, the crystalline product is filtered off and washed first with dimethylformamide, then with acetone and then with ether. The mother liquor is mixed with water, after which the precipitated product is filtered off and washed as indicated above. The combined material is crystallized from ethanol and /2-(9-oxo-10(9H)-acridinyl)ethyl/carbamic acid benzyl ester is obtained, m.p. 224-226°C.

9.31 g (25 mmol) of this product are suspended in 100 ml of dichloromethane. Mix with 4.5 ml (50 mmol) oxalyl chloride, stir for 1 hour and evaporate the solution. The residue is taken up in 400 ml of acetonitrile, mixed with 5.55 g (28 mmol) of 2-hydrazino-2-thiazoline hydrobromide and heated for 24 hours at reflux to the boiling point. The still warm mixture is filtered, the material obtained is washed first with acetonitrile and then with ether, it is mixed with methylene chloride and water and the base is released by adding soda solution. The free base is purified by chromatography on silica gel eluting with dichloromethane and transferred with ethanolic hydrochloric acid to the hydrochloride. By adding ether to the resulting solution, crystalline /2-/9-(2-thiazolidinylidenehydrazono)-10-acridanyl/-ethyl/carbamic acid benzyl ester dihydrochloride is obtained, m.p. 167.7-170.8°C (decomposition).

A suspension of 3.5 g (6.4 mmol) of the above product

in 300 ml of glacial acetic acid is stirred with 10 ml of hydrobromide-containing glacial acetic acid (approx. 30%) for 3 days, after which the product is filtered off and washed with glacial acetic acid and ether. It is then absorbed in water, the base is released with soda and this is absorbed in methylene chloride. The methylene chloride solution is dried over sodium sulfate and evaporated. The residue is dissolved in ethanol containing hydrogen chloride and the salt is crystallized by adding ether. 10-(2-aminoethyl)-9-acridanone-(2-thiazolidinylidene)hydrazone dihydrochloride is obtained, m.p. 226-231°C.

EXAMPLE 10

2.25 g (6 mmol) of /2-(9-oxo-10(9H)-acridinyl)ethyl/carbamic acid benzyl ester are suspended in 20 ml of methylene chloride and mixed with 1.05 ml (12 mmol) of oxalyl chloride. After 1 hour, the solution is evaporated, after which the residue is taken up in 200 ml of acetonitrile, mixed with 1.09 g (7.2 mmol) of 2-thiazolylhydrazine hydrochloride and heated for 1.5 hours at reflux to the boiling point. It is allowed to cool, the crystals are filtered off and these are washed with acetonitrile and ether. /2-/9-(2-thiazolylhydrazono)-9-acridanyl/ethyl/carbamic acid benzyl ester hydrochloride is obtained, m.p. 207-209°C (decomposition).

A suspension of 7.6 g (15 mmol) of this product in 450 ml of glacial acetic acid is mixed with 20 ml of hydrobromide-containing glacial acetic acid

(approx. 30%) and stirred for 2 days. The product is sucked off and washed with glacial acetic acid and ether. The salt mixture is transferred to the hydrochloride by means of a hydrochloric acid ion exchanger. The aqueous solution is freeze-dried and the crystalline residue is repeatedly recrystallized from methanol/ether. 10-(2-aminoethyl)-9-acridanone-2-thiazolyl-hydrazone dihydrochloride is obtained, m.p. 204-214°C (decomposition).

EXAMPLE 11

A suspension of 11.2 g (30 mmol) /2-(9-oxo-10(9H)-acridinyl)ethyl/carbamic acid benzyl ester in 100 ml of glacial acetic acid is mixed with 20 ml of hydrobromide-containing glacial acetic acid (approx. 30%) and stirred in 1 hour. The product is filtered off and washed with glacial acetic acid and ether. 10-(2-aminoethyl)-9-acridanone hydrobromide is obtained,

m.p. > 250°C. The free base is precipitated from an aqueous solution with sodium bicarbonate solution, filtered off and washed

kes with water and acetone. The hydrochloride obtained and analyzed melts above 250°C.

6.11 g (27 mmol) of the above-mentioned free base is suspended in 100 ml of pyridine, after which it is mixed with 2.33 ml (30 mmol) of methane sulfochloride. During heating, a clear solution occurs,

which is added to 700 ml of water after 3 hours. Little by little, crystals form. Concentrate to 300 ml, add 500 ml of water and concentrate again in vacuum to 300 ml. The product is filtered off, washed with water and recrystallized from ethanol. This gives N-(2-(9-oxo-10-acridanyl)-

ethyl/methanesulfonamide, m.p. 226-227°C.

950 mg (3 mmol) of this substance is suspended in 10 ml of methylene chloride, after which it is mixed with 0.8 ml (9 mmol) of oxalyl chloride. After 1 hour, evaporate. The residue is taken up in 100 ml of acetonitrile and mixed with 713 mg (3.6 mmol) of 2-hydrazino-2-thiazoline hydrobromide. After 20 minutes at reflux, the product is filtered off, washed with ether and dissolved in 150 ml of methylene chloride/methanol (97:3). It is made alkaline with sodium bicarbonate solution, extracted with methylene chloride, dried over sodium sulfate and evaporated. After crystallization from methylene chloride/methanol/petroleum ether, N-(2-(9-(2-thiazolin-2-yl)hydrazono7-10-acridanyl/ethyl7methanesulfonamide) is obtained, m.p. 206-207°C (decomposition).

EXAMPLE 12

a) A suspension of 1.44 g (60 mmol) of sodium hydride in 100 ml of dimethylformamide is mixed inertly for 10 minutes with 9.75 g

(50 mmol) 9-acridanone and kept at 50°C for 2 hours. At 120°C, 9.5 g (53 mmol) of 4,4-diethoxybutyl chloride are added. After 16 hours it is cooled, the mixture is poured onto water, extracted with dichloromethane, the extract is dried over sodium sulphate and evaporated. The residue is extracted with hexane and crystallized twice from hexane. 10-(4,4-diethoxy-butyl)-9-acridanone is obtained, m.p. 73-74.5°C.

8.5 g (25 mmol) of this product is dissolved in 20 ml of diethylamine, then mixed with 15 ml of formic acid, heated for 2 0

hours at 100°C, cool, add water and dilute hydrochloric acid and wash the aqueous solution with ether. The aqueous solution is mixed with caustic soda and extracted with methylene chloride. The extract is dried over sodium sulfate and evaporated. The residue is crystallized from hexane. 10-[4-(diethylamino)butyl7-9-acridanone is obtained, m.p. 66.5-68.7°C. The hydrochloride has a melting point of 126.8-128.3°C.

To a solution of 3.0 g (9.3 mmol) of the above

free base in 200 ml of dichloromethane is added dropwise at 0°C

for 3 minutes 2.4 ml (27.9 mmol) oxalyl chloride. Stir for 1 hour at room temperature, evaporate, take up the residue (9-chloro-10-/4-(diethylamino)butyl/-acridinium chloride) in 300 ml of acetonitrile, mix with 1.57 g (10.2 mmol) 2 -hydrazino-2-thiazoline hydrochloride, heat for 0.5 hours at reflux to the boiling point, stir for a further 1.5 hours at room temperature and cool to 0°C. The product is filtered off, washed with acetonitrile and ether and taken up in water. The solution is made alkaline with soda, extracted with methylene chloride, the methylene chloride solution is dried over sodium sulphate and evaporated. By crystallization from dichloromethane/ether/petroleum ether, 10-(4-(diethylamino)butyl7-9-acridanone-(2-thiazolidinylidene)hydrazone is obtained, m.p. 105.6-107.2°C.

Analogously, one achieves:

b) From 9-acridanone and 5,5-diethoxypentyl chloride The 10-(5,5-diethoxypentyl)-9-acridanone, m.p. 82-83°C, of which the 10-/5-(diethylamino)pentyl7~9-acridanone, m.p. 59-61.2°C and hence the 10-/5-(diethylamino)pentyl7~9-acridanone-(2-thiazolidinylidene) hydrazone, m.p. 128-5-130.1°C.

Claims (2)

1. Analogous process for the preparation<g> of therapeutically active acridanone derivatives of the general formula where the dotted line means an optional bond, R<1> is hydrogen or halogen, one of the substituents R 3 and R<4> is hydrogen or C^-C^ alkyl and the other together with R is an additional bond, A is C^-C^ alkylene, • R 5 is an optionally with C^-C^ alkyl, N-substituted imidazole ring which is bound to A through a C atom, an amino group or the group the symbol is a pyrrolidine ring, an optionally C₁-C₁ alkyl substituted piperidino ring,. a morpholino or a piperazino ring where the piperazino ring may optionally be substituted in the 4-position with a group -(B) -A'-R6. B is the group -CO-, -C00- or -SO,-, n is the number 0 or 1, A is.C,-C. alkylene, R is hydrogen, or di(C2-C4-alkyl)amino and R is hydrogen or C1~C6 alkyl, as well as pharmaceutically acceptable acid addition salts thereof, characterized in that one a) cyclizes a compound with the general formula or 31 41 where one of the substituents R and R means hydrogen 42 or lower alkyl and the other means hydrogen, R means hydrogen or lower alkyl, R5"1" means a residue R 5 as defined above, which however does not contain any primary or secondary , basic amino group, and R and R <5> have the meaning indicated above or b) reacts with a compound of the general formula where Y means an anion and X is a leaving group, preferably a halogen atom, and A, R<1> and R<51> have the above meanings in with a compound of the general formula 3 4 where the dotted line, R, R and R have the above meaning, or c) cleaves the N-protecting group in a compound with the general formula 8 5 where R means a residue R as defined above, which contains a primary or secondary basic amino group blocked by an N-protecting group, and the dotted line, R, R 1, R 3 and R 4 have the above meaning , and if desired, an obtained compound of formula I is transferred into a pharmaceutically acceptable acid addition salt. 2. Process as stated in claim 1 for the production of 10-[2-(4-methyl-1-piperazinyl)ethyl]-9-acridanone-(2-thiazolyl) hydrazone, characterized in that corresponding output connections are used.