NZ206317A

NZ206317A - Acridanone derivatives and pharmaceutical compositions

Info

Publication number: NZ206317A
Application number: NZ206317A
Authority: NZ
Inventors: U Brombacher; H Link; M Montavon
Original assignee: Hoffmann La Roche
Priority date: 1982-11-26
Filing date: 1983-11-18
Publication date: 1987-06-30
Also published as: PH19364A; NO160139C; ES8504184A1; CA1258854A; IE832770L; FI79847C; PT77730B; ES8505367A1; ATE34749T1; ZA838639B; EP0110298B1; JPS59108783A; AR240934A2; DOP1983004180A; NO160139B; IL70273A0; IE56311B1; AR240934A1; DK542383D0; FI79847B

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £06317 2063 Priority Date(s) .. .3«&7.li.-13.<k Complete Specification Filed: Class: oqid.zi 0^ .conoorj .x. ... .CiCxiPiu.nv.. Bjfcj&a i /M&S .J Publication Date: .... .. P.O. Journal, No: . nq3, NEW ZEALAND patents act, 1953 > r J8«0VB8t1 V, *l No.: Date: complete Specific ation acridanone derivatives 31/we. f- ho^mann-lailoche & co. aktiengesellschaft, ^QA Wt, — Vjf of 124-184>><fcoagaeheggfcra8eaT Basle, Switzerland, a Swiss companyt hereby declare the invention for which Ji / we pray that a patent may be granted to me/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - - 1 - (followed by la) 2063 1 _g,ATI 1171 /H. 5 The present invention is concerned with acridanone derivatives of the general formula 10 IS 30 35 wherein the dotted line signifies an 20 optional bond, R^" signifies hydrogen, 2 halogen or nitro, R signifies hydrogen or lower alkyl, one of the substituents 3 4 R and R signifies hydrogen or lower • a-lkyl and the other together with R sig-25 nlfles an additional bond, A signifies lower alkylene,. R"* signifies a 5-membered nitrogen-containing/ optionally lower alky1-substituted aromatic hetexocycle, amino or the group .<B)n—A1—R6 or-0 , R7 the symbol -iQ signifies a 5- or 6--membered, optionally lower alkyl-sub-stltuted saturated heterocycle which nrn/id ? m 2063f 7 - 2 - © can contain as a ring member an oxygen or sulphur atom or the group ^NH or B signifies the group ~C0-, -COO- or -SO,-, 1 * n signifies the number O or 1, A signifies g lower alkylene# R signifies hydrogen, amino, lower alkylamino or di(lower alkyl)amino and R7 signifies hydrogen or lower alkyl, and pharmaceutically acceptable acid addition salts thereof. 10 These novel substances possess valuable pharmacological properties and can be used in the control or prevention of illnesses. 15 Objects of the present invention are acridanone deri vatives of formula I above and their pharmaceutically acceptable salts per se and as pharmaceutically active substances , the manufacture of these compounds and salts; intermediates for their manufacture, medicaments containing 20 these compounds and salts and the manufacture of these medicaments.. Depending on the significance of the dotted line and 3 4 of the substituents R, R and R , the compounds of formula I 25 above can be present in various tautomeric forms \ the present invention includes all possible tautomeric forms. ^ The term "lower" as used in the present description signifies that the compounds or groups denoted in such a 30 manner contain up to 7, preferably up to 4, carbon atoms and can be straight-chain or branched-chain. The term "lower alkyl" denotes saturated hydrocarbon groups such as methyl, ^ ethyl, propyl, isopropyl, n-butyl, n-pentyl and the like. The term "lower alkylene" denotes divalent hydrocarbon 35 groups such as methylene, dimethylene, trimethylene, 1,2-—propylene,1,4—butylene,1,5-butylene and the like. The term "halogen" signifies fluorine, chlorine, bromine or iodine. - 3 - 2 063 f 7 o The term "5-membered, nitrogen-containing aromatic heterocycle" denotes heterocycles containing one or two hetero atoms, whereby, insofar as two hetero atoms are 5 present, one hetero atom can be different from nitrogen and can be, for example, an oxygen or sulphur atom. These heterocycles can be linked with group A via a carbon atom or, if desired, also via a nitrogen atom. The following are examples of heterocycles which come into consideration: 10 l-methyl-4-imidazolyl, 2-pyrrolyl, 2-thiozolyl, 4-oxazolyl, 1-pyrazolyl, 3-isoxazolyl. The term "5- or 6-membered saturated heterocycle which can contain as a ring member an oxygen or sulphur atom or w ]_5 the group ^NH or (B)n-A^-R®" denotes 5- or 6-membered saturated heterocycles which contain only one hetero atom, namely a nitrogen atom, such as 1-pyrrolidinyl and 1-piperi-dinyl, or which contain two hetero atoms, namely one nitrogen atom and, in addition, one oxygen, sulphur or nitrogen 20 atom such as 4-morpholinyl, 3-thiazolidinyl and 1-pipera-zinyl, whereby the latter can be substituted on the second nitrogen atom by the group - (B^-A^-R6. As the symbol—10) indicates, these heterocycles are linked with group A via a nitrogen atom. 25 The substituent r\ insofar as it is different from hydrogen, is preferably situated in the 1-position. However, 1 2 R preferably signifies hydrogen. R preferably signifies ' -j 3 4 ^ hydrogen. Preferably, one of the substituents R and R 30 signifies hydrogen and the other together with R signifies an additional bond. A preferably signifies dimethylene or tri- methylene. ^ R^ preferably signifies amino, 1-pyrrolidinyl, 1- 35 -piperidinyl, 1-morpholinyl, 1-piperazinyl or the group -NR^A1^61 or -N N-CB1) -A1-R61 in which A1 signifies \^J n lower alkylene, B signifies the group -CO-, n signifies 61 7 the number 0 or 1, R signifies hydrogen and R signifies hydrogen or lower alkyl. Especially preferred groups denoted o o - 4 - ^063 1 7 5 by are amino, dimethylamino, diethylamino, 1-pyrroli-dinyl, 1-piperidinyl, 4-methyl-l-piperazinyl and 4-acetyl--1-piperaziny1. Especially preferred compounds of formula I are: 10—[2-(4-Methyl-l-piperazinyl)ethyl-9-acridanone (2--thia zoly1)hydrazone, 10 10- [2-(4-methyl-l-piperazinyl)ethyl] -9r-acridanone (2- -thiazolidinylidene)hydrazone, 10-[2-(4-acetyl-l-piperazinyl)ethyl]-9-acridanone (2--thiazolidinylidene)hydrazone, 10-[2-(dimethylamino)ethyl]-9-acridanone (2-thiazoli-15 dinylidene)hydrazone, 10-[2-(diethylamino)ethyl]-9—acridanone (2-thiazolyl)-hydrazone, 10—[2.—(1-piperidinyl)ethyl] —9-acridanone (2-thiazolyl)-hydrazone, 20 10-(2-aminoethy1)-9-acridanone (2-thiazolyl)hydrazone, 10—[2—(dime thy lamino) ethyl] -9—acridanone (2-thiar zolyl)hydrazone, 10-[2—(4-acetyl-l-piperazinyl)ethyl]-9-acridanone (2-thiazolyl)hydrazone, 25 10-[3—(dime thy lamino) propyl] -9-acridanone (2-thia- zolyl)hydrazone, 10-[2-(diethylamino)ethyl]-9-acridanone (2—thiazolidinylidene )hydrazone, 10-[2—(1-pyrrolidinyl)ethyl]-9-acridanone (2-thiazoli-30 diny lidene) hydrazone and 10-[3-(dimethylamino)propyl]-9-acridanone (2-thiazolidinylidene) hydrazone. Examples of other compounds of formula I are: 35 10-[2—(4-Propyl—1-piperaziny1)ethyl]-9-acridanone (2--thiazolidinylidene)hydrazone, 2 063 1 7 10-[2-(dimethy lamino)propyl] -9-acridanone (2-thia-zolidinylidene)hydrazone, 10-[2-(1-piperidinyl)ethyl]-9-acridanone (2-thiazolidinylidene ) hydrazone , 10-[2- (2,6-dimethyl-l-piperidinyl)ethyl]-9-acridanone (2-thiazolidinylidene)hydrazone, 10-[2-(4-morpholinyl)ethyl]-9-acridanone (2-thiazoli-dinylidene)hydrazone, 10-[2-(4-ethoxycarbonyl-l-piperazinyl)ethyl]-9--acridanone (2-thiazolidinylidene)hydrazone, 10-[ 2-(4-pivaloyl-l-piperazinyl) ethyl]-9-acridanone (2-thiazoli diny lidene) hydrazone, 10- [2- [4- (methylsulphonyl)-1-piperaziny 1] ethyl]-9--acridanone (2-thiazolidinylidene)hydrazone, 10-[ (l-methyl-4-imidazolyl)methyl]-9-acridanone (2--thiazolidinylidene)hydrazone, 10-[2-[4-[2-(dimethylamino)acetyl]-1-piperaziny1]-ethyl]-9-acridanone (2-thiazolidinylidene)hydrazone, 1-chloro—10-[2-(diethylamino)ethyl]-9-acridanone (2--thiazolidinylidene)hydrazone, 10-(2-aminoethyl)-9-acridanone (2-thiazolidinylidene)-hydrazone, 10-[2-[ (methylsulphonyl) amino] ethyl]-9-acridanone (2--thiazolidinylidene)hydrazone, 10- [ 4- (diethylamino) butyl] -9-acridanone (2-thiazoli -dinylidene)hydrazone, 10-[5-(diethylamino)pentyl]-9-acridanone (2-thiazoli-dinylidene)hydrazone, 10-[2-(diethylamino)ethyl]-9-acridanone methyl-(2--thiazolin-2-yl)hydrazone, 10-[2-(diethylamino)ethyl-9-acridanone (3-raethyl-2--thiazolidinylidene)hydrazone, 10-[2-(diethylamino)ethyl]-9-acridanone methyl(2-thiazolyl)hydrazone, 10-[2-(4-morpholinyl)ethyl]-9-acridanone (2-thiazolyl)-hydrazone, ^063 | 7 - 6 - 10 10-[2-(4-ethoxycarbonyl-l-piperazinyl] ethyl-9-acri-danone (2-thiazolyl)hydrazone, 10- [ 2- (4-pivaloyl-l-piperazinyl) ethyl] -9-acridanone (2-thiazolyl)hydrazone/ 10-[2-[4-(methylsulphonyl)-1-piperazinyl] ethyl]-9--acridanone (2-thiazolyl)hydrazone, 10- [ 2- [ 4- [2- (diethylamino)ethyl] -1-piperazinyl] ethyl] • -9-acridanone (2-thiazolyl)hydrazone and 10- [2- (4-propyl-l-piperazinyl) ethyl]-9-acridanone (2--thiazolyl)hydrazone. The acridanone derivatives of formula X above and their pharmaceutically acceptable acid addition salts can be manu-15 factored in accordance with the invention by (a) cyclizing a compound of the general formula 20 25 IX, 30 35 V, - 7 2063l7 10 VI or VII 15 20 25 30 or .31 and wherein one of the substituents R* 41 R signifies hydrogen or lower alkyl and 42 the other signifies hydrogen, R signifies hydrogen or lower alkyl, R^"®" ■ signifies-a group R^ defined above, but which does not contain a primary or secondary basic amino group, X* signifies a leaving group 12 5 and R, R , R and R have the above significance. (b) reacting a compound of the general formula VIII 35 1 42 51 wherein A, R , R and R have the significance, with a compound of the general formula oJl.7 - 8 - X" .N IX 10 or 15 wherein X" signifies a leaving group and 2 the dotted line and R have the above significance, (c) reacting a compound of the general formula 20 X 25 wherein Y ® signifies an anion, X signifies a leaving group and A, R1 and R5 have the above significance, with a confound of the general formula 30 35 H2N-N XI wherein the dotted line, R, R2, R3 and R4 have the above significance, or 10 - 9 - 206317 (d) cleaving off the N-protecting group in a compound of the general formula XII 8 5 IS wherein R signifies a group R defined above which contains a primary or secondary basic amino group blocked by a N--protecting group and the dotted line, R, R1, R2, 20 nificance, and 12 3 4 R, R , R , R and R have the above sig- (e) if desired, converting a compound of formula I obtained into a pharmaceutically acceptable acid addition 25 salt. In accordance with process variant (a)/ the compounds of formula I can be manufactured by cyclizing a compound of formula II, III, IV, V, VI or VII according to methods which 30 are known per se and which are familiar to any person skilled in the art. The leaving group denoted by X' in formulae IV and VI is preferably a halogen atom, especially a bromine or chlorine atom. Depending on the starting material used, the ring closure reaction is carried out fairly readily and 35 can be accomplished or completed, if necessary, by standing for a long time and/or by applying heat. The starting materials for the ring closure reaction need not necessarily be used in isolated form; as a rule it has been found to be ® -10- 2 0 63 7 convenient to cyclize these starting materials directly or to leave these starting materials to cyclize without isolation from the reaction mixture in which they 5 have been prepared. Depending on the reaction conditions used, in some cases, an isolation is even not possible, since the cyclization is effected spontaneously. Suitable solvents for the process variant (a) are, 10 for example, ethers such as tetrahydrofuran, dioxan, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and the like, alcohols such as methanol, ethanol and the like, dimethylformamide, dimethyl sulphoxide, aceto-nitrile and the like. The reaction is conveniently carried 15 out at a temperature in the range of about room temperature to the boiling point of the reaction mixture. In accordance with process variant (b), the compounds of formula I can be manufactured by reacting a compound of 20 formula VTII with a compound of formula IX. The leaving group denoted by X" in formula IX is preferably a halogen atom (e.g. a chlorine or bromine atom) or the thiol group. The following organic solvents which are inert under the reaction conditions can be used: ethers such as tetrahydro-25 furan, dioxan, diethyl ether and the like, alcohols such as methanol, ethanol and the like, dimethylformamide, dimethyl sulphoxide, acetonitrile and the like. The reaction is conveniently carried out at a temperature in the range of about room temperature to the boiling point of the reaction 30 mixture. In accordance with process variant (c), the compounds of formula I can be manufactured by reacting a compound of formula X with a compound of formula XI. The leaving group 35 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 acetoxy group or a 2 063 f 7 11 methoxy group. The compounds of formula X are to some extent substances which are not especially stable. They are therefore conveniently prepared shortly before the reaction 5 with a compound of formula XI from a compound of the general formula significance, 20 as described below and, optionally without previous isolation, processed directly. The compound of formula XI is conveniently used in the form of an acid addition salt, for example in the form 25 of a hydrochloride or hydrobromide. The reaction can be carried out in the presence of an acid-binding agent, especially suitable acid-binding agents being sodium and potassium carbonates, bicarbonates and acetates. Suitable solvents for the process aspect (b) are, for example, lower 30 alcohols such as methanol and ethanol and other organic solvents which are inert under the reaction conditions such as dimethylformamide, acetonitrile and the like. The reaction is conveniently carried out at a temperature in the range of about room temperature to the boiling point of the 35 reaction mixture. 0 10 XIV 15 wherein A, R- and have the above In accordance with process variant (d), the compounds of formula I which contain a primary or secondary basic amino group in the group R^ can be manufactured by cleaving 12 206317 off the N-protecting group in a compound of formula XII. Suitable protecting groups for the purpose of the present invention are primarily acyl groups, preferably readily 5 cleavable alkoxycarbonyl groups or phenylalkoxycarbonyl groups optionally substituted on the phenyl ring, especially the t-butoxycarbonyl group, the benzyloxycarbonyl group etc, as well as readily cleavable phenylalkyl groups optionally substituted on the phenyl ring, such as the benzyl group. 10 The cleavage of the protecting group is carried out according to methods known per se, whereby, of course, the nature of- the protecting group to be removed must be taken into consideration when choosing the cleavage method to be used. Likewise, it will, of course, be appreciated that there can 15 be used only those methods which selectively remove the protecting group without affecting other structural elements present in the molecule. 20 groups can be cleaved off hydrolytically. Thus, for example, the benzyloxycarbonyl group and the t-butoxycarbonyl group can be 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 tri-25 fluoride or boron tribromide in an inert organic solvent such as dichloromethane• The t-butoxycarbony1 group can also be cleaved off by treatment with hydrogen chloride in an inert organic solvent such as dioxan, tetrahydrofuran or the like or by treatment with trifluoroacetic acid. In accordance with process variant (e), the acridanone derivatives of formula I above can be converted into pharmaceutically acceptable acid addition salts. The manufacture of such acid addition salts is carried out according to 35 generally usual methods. There come into consideration not only salts with pharmaceutically acceptable inorganic acids but also salts with pharmaceutically acceptable organic The groups mentioned above as examples of protecting 30 » 206377 acids? for example, hydrochlorides, hydrobromides, sulphates, citrates, acetatest succinates, methanesulphonates, p-toluenesulphonates and the like. 5 The compounds of formula X used as starting materials as well as the compounds of formulae II, III, IV, V, VI, VII, VIII and XII can be prepared from compounds of formula XIII in accordance with the following Formula Scheme in which the 10 dotted line and the substituents A, R^, R2, R^, R^"S R^2, 518 9 91 R , R , X and X1 have the above significance, R and R each signify lower alkyl or together signify lower alkylene, 52 5 R signifies a group R which contains a primary or secondary basic amino group and R^"0 signifies lower alkyl/ phenyl 15 or substituted phenyl. The compounds of formula XIII belong to a class of substance which is known per se. 20 30 35 V-/ i H XIII I I I lsQ» X1VS OR*' IVk Ulk IV » • - 2063f7 The compounds of formula XIV can be prepared from compounds of formula XIII by alkylation with an agent which yields the group -A-R^ in the presence of a strong base 5 such as sodium hydride or the like. This reaction is carried out according to methods which are known per se and which are familiar to any person skilled in the art. Those compounds of formula X in which X signifies a 10 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 the halogenating agent and a halogenated hydrocarbon such as methylene chloride, 15 chloroform, 1,2-dichloroethane or the like, acetonitrile or excess halogenating agent is used as the solvent, there being obtained a compound of formula X in which X signifies chlorine. The reaction temperatures advantageously vary in a range of about room temperature to the boiling point 20 of the reaction mixture. Compounds of formula X in which X signifies a leaving group other than a halogen atom can be obtained from the corresponding halogen compounds. For example, the halogen 25 atom in such a compound can be replaced in a manner known per se by other leaving groups, for example, by lower alkoxy groups or lower alkanoyloxy groups. The compounds of formula X are quaternary ammonium 30 salts, of which some, as mentioned earlier, are not particularly stable; these are conveniently processed immediately after their preparation. The nature of the anion denoted by Y® depends on the manner in which the corresponding compound of formula X has been prepared. For 35 example, if a compound of formula X in which X signifies chlorine is prepared and oxalyl chloride is used as the halogenating agent, then there is obtained a compound of - 16 - 3 2063 | 7 formula X in which Y® signifies a chloride anion? if phosphorus oxychloride is used as the halogenating agent, then there is obtained a corresponding compound in which 5 Y ® signifies P02C12 ® . 5 Those compounds of formula II in which R does not contain a primary or secondary basic amino group, i.e. compounds of formula Ila, can be prepared by reacting a compound ^ 10 of formula X with a thiosemicarbazide of the general formula 15 35 p41 31 f ^.NHR 1 H2N—N—XVIII 31 41 wherein R and R have the above significance, whereby the reaction conditions described above for process 2o variant c) can be used, and reacting the resulting compound of formula XVII a with a compound of the general formula 25 X1— CH2— or XIX 2 wherein X1 and R have the above signifi-cance. 30 The leaving group denoted by X' is preferably a chlorine or bromine atom. Lower alcohols such as methanol and ethanol cure especially suitable solvents. The reaction is conveniently carried out at a temperature in the range of about room y temperature to the boiling point of the reaction mixture. The compounds of formula II in which R^ contains a primary or secondary basic amino group can be prepared by o 15 20 25 - 17 - *06J 17 alkylating a compound of formula XIII with an agent which Q yields the group -A-R (in analogy to the preparation of a compound of formula XIV), converting the resulting compound 5 of formula XIVS (in analogy to the preparation of the compounds of formula X) into a compound of formula XS, reacting the latter (in analogy to the preparation of the compounds of formula XVIIa) with a thiosemicarbazide of formula XVIII, cleaving off the N-protecting group in the O 10 resulting compound of formula XVIIS [using the reaction conditions described above for process variant (d)] and reacting the resulting compound of formula XVIlb with a compound of formula XIX (in analogy to the preparation of the compounds of formula Ila). The compounds of formula III can be obtained by 31 reacting a compound of formula XVIIa or XVIIb in which R in each case signifies hydrogen with a compound of the general formula ^NHR32 X'—- CH-—CH XX 2 ' \ 2 R . ' ' 2 wherein X' and R have the above signifi-32 cance and R signifies hydrogen or, where 41 R in the compound of formula XVIIa or XVIIb signifies hydrogen, also lower alkyl. 30 The amine is conveniently used in the form of an acid addition salt, the hydrochlorides or hydrobromides being preferred. Suitable solvents are, for example, lower alcohols such as methanol and ethanol, ethers such as tetra-hydrofuran, dioxan and ethylene glycol dimethyl ether, di-35 methylformamide, dimethyl sulphoxide, acetonitrile and the like. The reaction is preferably carried out at a temperature between about room temperature and the boiling point of the reaction mixture. ^ - 18 - ^ 20 25 *0 The compounds of formula IV can be obtained by reacting a compound of formula XVIIa or XVIIb in an inert organic solvent and at a temperature in the range of about 5 room temperature to the boiling point of the reaction mixture with a compound of the general formula Xr' ^ 10 X'—CH-—CH XXI • ■ . *2 2 wherein X' and R have the above sig-. nificance, ' 15 there being preferably used a dichloride or dibromide. Suitable solvents are, for example/ alcohols such as methanol* ethanol and the like, ethers such as tetrahydrofuran, dioxan and the like, dimethylformamide/ dimethyl sulphoxide and the like. The compounds of formula V can be prepared by reacting a compound of formula X with a hydrazine of the general formula H2N—NHR42 XXII 42 wherein R has the above significance, whereby the reaction conditions described above for process 30 variant (c) can be used, treating the resulting compound of formula VIII in a manner known per se with an agent which yields the group -COOR^0 (e.g. a dialkyl or diphenyl carbamate or an alkyl or phenyl chloroformate) and reacting the resulting compound of formula XVI with a thiol of the 35 general formula - 19 - W 71 £ 20 30 D 35 ij 33 ^,NHR ' HS—CH~—-CH XXIII 5 * 2 wherein R has the above significance and 33 42 R signifies hydrogen or, where R in the compound of formula XVI signifies hydrogen, also lower alkyl. This third step is preferably carried out at a temperature between about room temperature and the boiling point of the reaction mixture in an inert organic solvent, especially an ether such as diethyl ether, tetrahydrofuran and the like or 15 a lower alcohol such as methanol and ethanol. Alternatively, the compounds of formula XVI can be prepared by reacting a compound of formula X with a hydrazine of the general formula /r42 H,N—N XXIV > '• 10 ' ■ COOR 25 wherein R^2 and R^° have the above signifi cance. This reaction can be carried out in a manner known per se; for example, under the reaction conditions described above for process variant .(c).. The compounds of formula VI can be prepared by reacting a compound of formula VIII with an isothiocyanate of the general formula R2 ' ' ' " . . ' I . S® C =N—CH— CH2— X' XXV 206317 2 wherein X* and R have the above significance . This reaction can be carried out conveniently at a temperature of about room temperature to the boiling point of the reaction mixture and in an inert organic solvent, for example an ether such as diethyl ether, t-butyl methyl ether and tetrahydrofuran or dimethylformamide, acetonitrile or the like. The compounds of formula VXI can be prepared by reacting a compound of formula VIII with an isothiocyanate of the general formula R2 OR9 I ■ .y- . S~C=N—CH— CH XXVI ' NOR91 2 9 91 wherein R , R and R have the above significance, and subsequently hydrolyzing the acetal group in the resulting compound of 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 the boiling point of the reaction mixture. The hydrolysis of the acetal group can be carried out by means of an aqueous acid, optionally in the presence of a solubilizer such as tetrahydrofuran, dioxan, methanol, ethanol, dimethylformamide or the like. The acid can be, for example, sulphuric acid, hydrochloric acid, p-toluenesulphonic acid and the like. The temperature is not critical and can vary in a wide range. As mentioned above, it is not necessary (and in many cases also not possible) to isolate the compounds of formula II, III, IV, V, VI and VII; on the contrary it has been found to be convenient as a rule to cyclize these compounds 2063 1 - 21 - directly or to leave these compounds to cyclize without isolation from the reaction mixture in which they have been prepared. 5 The compounds of formula XII used as starting materials can be prepared from compounds of formula XS in analogy to the manufacture of the compounds of formula I from compounds of formula X in accordance with process variants, (a) , (b) and ^ 10 (c) described above and the methods described for the preparation of the corresponding starting materials. The starting materials of formulae II, III, TV, V, VI, VII and XII are novel and also form objects of the present 15 invention. The acridanone derivatives of formula I above and their pharmaceutically acceptable acid addition salts possess valuable pharmacological properties? in particular, 20 they display valuable schistosomicidal activities and can accordingly be used in the control or prevention of schistosomiasis. The schistosomicidal activity of the acridanone 25 derivatives of formula I and their pharmaceutically acceptable acid addition salts can be demonstrated in an animal test as follows: Albino mice weighing 15-18 g are infected subcutaneous-30 ly (sic) with 60+5 cercaria of a Liberia strain of Schistosoma mansoni. 46 days after the infection the animals are treated once perorally with the substance to be tested. 5-10 animals are used per substance and dosage. 10 untreated animals serve as controls. The autopsy is carried 35 out after 19 days, whereupon worm pairs and individual worms in the mesenteric veins, portal vein and liver are dissected out and counted. The vermicidal activity shows itself in a reduced number of living parasites in comparison to the o 20 25 ff i' j * - - 22 - number in the control animals. 206317 For the evaluation the percentage reduction in the parasites in treated animals in comparison to untreated control animals is calculated. The VD^0 is determined according to the Probit method. The VD5Q is that vermisidal dosage which brings about a 50 percent reduction in the number of worms. 10 The following Table contains the results obtained with representative products provided by the invention. In the Table there are given for each of the compounds listed therein the VD^q in mg/kg p.p. and/ for some of these 15 compounds, the LD^q in mg/kg in the case of single oral administration to mice. 30 35 - 23 - Table 206317 Compound of formula I ^50 in mg/kq p.o LD5g in mg/kg p.o. 10-[2-Diethy lamino) ethyl ]-9--acridanone (2-thiazolidinylidene)-hydrazone 9 .5 312-625 10-[3-(Dimethylamino)propyl]-9--acridanone (2-thiazolidinylidene)-hydrazone 4.7 125-250 10-[2-(4-Methy1-1-piperazinyl)ethyl]--9-acridanone (2-thiazolidinylidene)-hydrazone 4.0 156-312 10-[2-(Dimethylamino)ethyl]-9-acrida-none (2-thiazolidinylidene)hydrazone 6.4 250-500 10-[2-(1-Pyrrolidinyl)ethyl]-9-acridanone (2-thiazolidinylidene)hydrazone 6.2 156-312 10-[2-(4-Acetyl-l-piperaziny1)ethyl]--9-acridanone (2-thiazolidinylidene)-hydrazone 3.4 1250-2500 10-[2-(Diethylamino)ethyl]-9-acrida-none (2-thiazolyl)hydrazone/2 HC1 3. 3 >5000 10-[3-(Dimethylamino)propyl]-9-acrida-none (2-thiazolyl)hydrazone/2 HC1 3.5 312-625 10-[2-(1-Piperidinyl)ethyl]-9-acrida-none (2-thiazolyl)hydrazone/2:3 HC1 9.0 312-625 10-[2-(4-acetyl-l-piperazinyl)ethyl]--9-(acridanone (2-thiazolyl)hydrazone/ 2 HCL 2.6 312-625 10-(2-Aminoethyl)-9-acridanone (2--thiazolyl)hydrazone/2 HC1 2.6 156-312 10-[2-(Dimethylamino)ethyl]-9-acrida-none (2-thiazolyl)hydrazone/2 HCl 4.9 312-625 10-[2-(4-Methyl-l-piperazinyl)ethyl]--9-acridanone (2-thiazolyl)hydrazone/ 2:5 HCl 2.4 625-1250 2063 1 7 The acridanone derivatives of formula I and their pharmaceutically acceptable acid addition salts can be used as medicaments, for example, in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example, in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions* For the manufacture of pharmaceutical preparations, the acridanone derivatives of formula I and their pharmaceutically acceptable acid addition salts can be processed with pharmaceutically inert inorganic or organic carriers. Examples of carriers which can be used for tablets, coated tablets, dragees and hard gelatine capsules are lactose, maize starch or derivatives thereof, talc, stearic acid or its salts and the like. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active substance no carriers are, however, generally required in the case of soft gelatine capsules. Suitable carriers for the manufacture of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose and the like. In addition, the pharmaceutical preparations can contain preserving agents, solubilizers, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, colouring agents, flavouring agents, salts for varying the osmotic pressure, buffers, coating agents or antioxidants. They can also contain still other therapeutically valuable substances. As mentioned earlier medicaments containing an acridanone derivative of formula I or a pharmaceutically acceptable acid addition salt thereof are likewise an object of the present invention as is a process for the manufacture of such medicaments, which process comprises bringing one o o 2 0631 >-"£5 ^ a m r 1 - 25 - or more compounds of formula I or pharmaceutically acceptable acid addition salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical 5 administration form. As mentioned earlier, the acridanone derivatives of formula I and their pharmaceutically acceptable acid addition salts can be used in the control or prevention of illnesses. 10 They are especially suitable for the control or prevention of schistosomiasis. The dosage can vary within wide limits and is, of course, fitted to the individual requirements in each particular case. In general, a single dosage of about 1 to about 50 mg/kg body weight should be appropriate for 15 the treatment of schistosomiasis, whereby this dosage can also be administered in sub-divided dosages several times during one day. 20 25 30 35 CO 6 5 o The following Examples illustrate the present invention in more detail, but are not intended to limit its extent. In the Examples all temperatures are given in 5 degrees Centigrade. Example 1 (a) A mixture of 8.5 g of 9-acridanone, 180 ml of dimethyl— O 10 formamide and 3.3 g of sodium hydride is stirred for 0.5 hour, treated portionwise with 10.3 g of 2-[l-(4-methyl)-piperazinyl]ethyl chloride dihydrochloride, stirred at 80° for 3 days and evaporated. The residue is treated with water and extracted with methylene chloride. The extract is 15 washed with water, dried over sodium sulphate and evaporated, whereupon the residue is recrystallized firstly from ether and then from ethyl acetate. There is obtained 10-[2-(4--methyl-l-piperazinyl)ethyl]-9-acridanone of melting point 156-157°. 20 A solution of 2.2 g of 10-[2-(4-methyl-l-piperazinyl) -ethyl]-9-acridanone in 100 ml of dichloromethane is treated portionwise at -5° with 1.17 ml of oxalyl chloride, stirred at room temperature for a further 0.5 hour and evaporated. 25 The residue (9-chloro-10-[2-(4-methyl-l-piperazinyl)ethyl]-acridinium chloride) is treated with 100 ml of methanol, 1.346 g of 2-hydrazino-2-thiazoline hydrobromide and 1.67 g of sodium acetate, heated to boiling under reflux, cooled after 10 minutes and evaporated. The residue is treated 30 with saturated sodium carbonate solution and extracted with methylene chloride. The extract is washed with water, dried over sodium sulphate and concentrated. After the addition of ethyl acetate, the crystallized-out product is filtered off and washed successively with ethyl acetate and 35 petroleum ether. There is obtained 10-[2-(4-methyl-l-pip-erazinyl)ethyl] -9-acridanone (2-thiazolidinylidene)hydrazone of melting point 204-205°. W - 27 - ^ © 6 3 1 y * -ii In an analogous manner there Is obtained: (b) . From 9-acridanone and 3-(dimethylamino)propyl chloride 5 the 10-[3-dimethylamino)propyl]-9-acridanone of melting point 89° and therefrom the 10-[3-(dimethylam±no)propyl]-9--acridanone (2-thiazolidinylidene)hydrazone of melting point 191-192°; 0 10 (°) from 9-acridanone and 2-(diethylamino)ethyl chloride hydrochloride the 10-[2-(diethylamino)ethyl]-9-acridanone of melting point 109-111° and therefrom the 10-[2-(diethyl-amino) ethyl] -9-acridanone (2-thiazolidinylidene)hydrazone of melting point 153-155°; 0 15 (d) from 9-acridanone and 2-(1-pyrrolidinyl)ethyl chloride hydrochloride the 10-[2-(1-pyrrolidinyl)ethyl]-9-acridanone of melting point 143-145° and therefrom the 10^-[2-(1-pyrrolidinyl) ethyl]-9-acridanone (2-thiazolidinylidene)hydrazone 20 of melting point 220° (decomposition); (e) from 9-acridanone and 2-(1-piperidinyl)ethyl chloride hydrochloride the 10-[2-(1-piperidinyl)ethyl]-9-acridanone of melting point 165° and therefrom the.10-[2-(1-piperidinyl)-25 ethyl]-9-acridanone (2-thiazolidinylidene)hydrazone of melting point 207°; (f) from 9-acridanone and 2-(4-morpholinyl)ethyl chloride hydrochloride the 10-[2-(4-morpholinyl)ethyl]-9-acridanone 30 of melting point 196° and therefrom the 10-[2-(4-morpholinyl)-ethyl]-9-acridanone (2-thiazolidinylidene)hydrazone of melting point 236°. 35 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 hour, then treated with 5.2 g of 2-(4-acetyl-l-piperazinyl)-ethyl chloride hydrochloride, stirred at 70° for 15 hours n ■O 25 - 28 - 2 063 t 7 and evaporated. The residue is treated with water and extracted with methylene chloride. The extract is washed with water, dried over sodium sulphate and evaporated. By crystal-5 lization from ethanol there is obtained 10-[2-(4-acetyl-l--piperazinyl)ethyl]-9-acridanone of melting point 241-243°. A suspension of 3.5 g (10 mmol) of 10- [2- (4-acetyl-.l--piperazinyl)ethyl]-9-acridanone in 100 ml of acetonitrile 10 is treated with 1.7 ml (20 mmol) of oxalyl chloride, suction filtered after 0.5 hour and the suction filter material (9-chloro-10-[2-(4-acetyl-l-piperazinyl)ethyl]acridinium chloride) is washed successively with acetonitrile and ether. A mixture of the substance obtained is heated to 15 boiling under reflux with 2 g (10 mmol) of 2-hydrazino-2--thiazoline hydrobromide, 2.5 g (30 mmol) of sodium acetate and 100 ml of methanol and evaporated after 15 minutes. The residue is treated with water, made alkaline with sodium carbonate solution and extracted with methylene chloride.. 20 The extract is washed with water, dried and evaporated, whereupon the residue is crystallized from methanol. After recrystallization from n-butanol, there is obtained 10-[2-(4--acetyl-l-piperazinyl)ethyl]-9-acridanone (2-thiazolidinyl-idene)hydrazone of melting point 256°. In an analogous manner there is obtained: (b) Prom 9-acridanone and 2-(4-ethoxycarbonyl-1-piperazinyl) ethyl chloride hydrochloride the 10-[2-(4-ethoxy- 30 carbony1-1-piperaziny1)ethyl]-9-acridanone of melting point 147° and therefrom the 10-[2-(4-ethoxycarbonyl-1-piperazinyl) ethyl]-9-acridanone (2-thiazolidinylidene)hydrazone of melting point 231° (decomposition); 35 (c) from 9-acridanone and 2-(4-pivaloyl-l-piperazinyl)-ethyl chloride hydrochloride the 10-[2-(4-pivaloyl-l-pip-erazinyDethyl] -9-acridanone of melting point 184° and therefrom the 10-[2-(4-pivaloyl-l-piperazinyl)ethyl]-9-acridanone 206317 (2-thiazolidinylidene)hydrazone of melting point 208°; (d) from 9-acridanone and 2-(4-(methylsulphonyl)-1-pip-erazinyl]ethyl chloride hydrochloride the 10-[2-[4-(methylsulphonyl) -1-piperazinyl] ethyl] -9-acridanone of melting point 244-246° and therefrom the 10-[2-[4-(methylsulphonyl)-1--piperazinyl]ethyl]-9-acridanone (2-thiazolidinylidene)-hydrazone of melting point 223-235° (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 treated with 2.9 g of l-chloro-2-dimethylamino-ethane hydrochloride, stirred at 60° for 18 hours and evaporated. The residue is extracted with methylene chloride. The extract is washed with water, dried over sodium sulphate and evaporated. By crystallization from isopropyl ether there is obtained 10-[2-(dimethylamino)ethyl]-9-acridanone of melting point 145-146°. A solution of 3 g of 10-^2-(dimethylamino)ethylj-9--acridanone in 100 ml of dichloromethane and 1.93 ml of oxalyl chloride is stirred for 0.5 hour. After evaporation, the residue is stirred with 2.25 g of 2-hydrazino-2-thia-zoline hydrobromide and 3 g of sodium acetate in 100 ml of methanol, whereupon the mixture is heated to boiling under reflux for 10 minutes and evaporated. The residue is treated with water, made alkaline with sodium carbonate solution and extracted with methylene chloride. The extract is washed with water, dried over sodium sulphate and evaporated. After crystallixation from acetonitrile, there is obtained 10-[2-(dimethylamino)ethyl]-9-acridanone (2-thiazolidinyl-idene)hydrazone of melting point 192-194°. - 30 - 206317 In an analogous manner there Is obtained: (b) From 9-acridanone and 2-(dimethylamino)propyl chloride hydrochloride the 10- [2-dimethy lamino) propyl]-9-acridanone of melting point 114° and therefrom the 10-[2-(dimethylamino) propyl]-9-acridanone (2-thiazolidinylidene)hydrazone of melting point 152°; (c) from 9-acridanone and 2-(2,6-dimethyl-1-piperidinyl)-ethyl chloride hydrochloride the 10-[2-(2,6-dimethyl-l--piperidinyl) ethyl]-9-acridanone of melting point 146° and therefrom the 10-[2-(2,6-dimethyl-l-piperidinyl)ethyl]-9--acridanone (2-thiazolidinylidene)hydrazone of melting point 161° y (d) from 9-acridanone and (l-methyl-4-imidazolyl)methyl chloride hydrochloride the 10- [ (l-methyl-4-imidazolyl) — methyl]-9-acridanone of melting point 205-207° and therefrom the 10-[ (l-methyl-4-imidazolyl)methyl] -9-acridanone (2—thiazolidinylidene)hydrazone of melting point 206-208°; (e) from 9-acridanone and 2-[4-[2-(dimethylamino) acetyl] - • -1-piperazinyl]ethyl chloride hydrochloride the 10-[2-[4- [2-- (dimethylamino) acetyl]-1-piperazinyl) ethyl]-9-acridanone of melting point 146-147° and therefrom the 10-[2-[4-[2--(dimethylamino) acetyl] -l-piperazinyl]ethyl-9-acridanone (2—thiazolidinylidene)hydrazone of melting point 129-131°; (f) from l-chloro-9-acridanone and 2-(diethylamino)ethyl chloride hydrochloride the 10-[2-(diethylamino) ethyl]-1--chloro-9-acridanone of melting point 121° and therefrom the 10- [2- (diethylamino) ethyl] -l-chloro-9-acridanone (2-thia-zoli dinylidene) hydra zone of melting point 181-183°; (g) from 9-acridanone and 2-(4-propyl-l-piperazinyl)ethyl chloride dihydrochloride the 10-[2-(4-propyl-l-piperazinyl)-ethyl]-9-acridanone and therefrom the 10- [2- (4-propyl-l--piperazinyl)ethyl]-9-acridanone (2-thiazolidinylidene)- o ^0631 hydrazone of melting point 205-207° (decomposition). Example 4 5 A solution of 4.94 g (16.8 mmol) of 10-[2-(diethyl-amino) ethyl]-9-acridanone in 300 ml of dichloromethane is stirred for 1 hour with 2.85 ml (33.6 mmol) of oxalyl chloride. The resulting salt (9-chloro-lO-[2-(diethylamino) -0 10 ethyl]acridinium chloride) is filtered off and treated with 100 ml of methanol, 2.82 g (16.8 mmol) of 2-(3-methyl)-thiazolidinylidenehydrazine hydrochloride and 4.1 g (50 mmol) of sodium acetate. The mixture is heated to boiling under reflux for 10 minutes and evaporated. The residue is treated 15 with water, made alkaline with sodium carbonate solution and extracted with dichloromethane. The extract is washed with water, dried and evaporated. By crystallization from ethanol there is obtained 10-[2-(diethylamino)ethyl]-9--acridanone (3-methyl-2-thiazolidinylidene)hydrazone of melt-20 ing point 123-125°. Example 5 25 (a) A solution of 11.5 g of 10-[2-(diethylamino)ethyl]-9--acridanone in 250 ml of dichloromethane is treated at -5° and within 0.5 hour with 6.7 ml of oxalyl chloride, stirred at room temperature for 1 hour, the yellow crystals (9--chloro-10- [2- (diethylamino) ethyl] acridinium chloride) which 30 have formed are filtered off and washed successively with methylene chloride and petroleum ether. The material obtained is taken up in 200 ml of methanol, treated with 3.6 g of thiosemicarbazide and stirred at room temperature for about 18 hours. The precipitated salt is filtered off and 35 washed successively with ethanol and ether. There is obtained 10-[2-(diethylamino) ethyl]-9-acridanone thiosemi-carbazone dihydrochloride (crystallizing with 1 mol of methanol) of melting point 124° (decomposition). This material i 206317 - 32 - O O is treated with IN sodium hydroxide solution and extracted with dichloromethane. The solution is washed with water, dried and evaporated, whereupon the product is crystallized 5 from acetonitrile. There is obtained 10-[2-(diethylamino)-ethyl]-9-acridanone thiosemicarbazone of melting point 154--156°. A solution of 6.1 g of 10-[2-(diethylamino)ethyl]-9-10 -acridanone thiosemicarbazone in 100 ml of dimethylformamide is stirred for about 18 hours with 4.3 ml of chloroacetalde-hyde (50 percent solution in water). The mixture is subsequently evaporated, the residue is taken up in 50 ml of ethanol, made acid to Congo red with ethanolic hydrochloric 15 acid and the crystals formed are filtered off. The crystals are washed successively with ethanol, ether and petroleum ether and there is obtained 10- [2-(diethylamino)ethyl] -9--acridanone (2-thiazolyl)hydrazone dihydrochloride of melting point 214-216° (decomposition). 20 In an analogous manner there is obtained: (b) Prom 10-[2-(1-piperidinyl)ethyl]-9-acridanone and thiosemicarbazide the 10-[2-(1-piperidinyl)ethyl]-9-acrida-25 none thiosemicarbazone of melting point 187° (decomposition) and therefrom the 10-[2-(1-piperidinyl)ethyl]-9-acridanbne (2-thiazolyl)hydrazone 1.5 HCl of melting point 190° (decomposition); 30 (c) from 10-[2-(4-morpholinyl)ethyl]-9-acridanone and thiosemicarbazide the 10-[2-(4-morpholinyl)ethyl]-9-acrida-none thiosemicarbazone of melting point 240° (decomposition) and therefrom the 10-[2-(4-morpholinyl)ethyl]-9-acridanone (2-thaizolyl)hydrazone dihydrochloride of melting point 35 225° (decomposition)? o ' ' 2u(iin~ - 33 - (d) from 10-[2-(4-acetyl-l-piperazinyl)ethyl]-9-acridanone and thiosemicarbazide the 10-[2-(4-acetyl-l-piperazinyl)-ethyl]-9-acridanone thiosemicarbazone of melting point 225° 5 (decomposition) and therefrom the 10-[2-(4-acetyl-l-pipera-zinyl) ethyl] -9-acridanone (2-thiazolyl)hydrazone dihydro-' chloride of melting point 180° (decomposition); (e) from 10-[2-(4-pivaloyl-l-piperazinyl)ethyl]--9-acrida-. ^ 10 none and thiosemicarbazide the 10-[2-(4-pivaloyl-l-piperazinyl) ethyl] -9-acridanone thiosemicarbazone of melting point 179° (decomposition) and therefrom the 10-[2-(4-pivaloyl-l--piperazinyl)ethyl]-9-acridanone (2-thiazolyl)hydrazone dihydrochloride of melting point 210° (decomposition);. 0 15 (f) from 10-[3-(dimethylamino)propyl)-9-acridanone and thiosemicarbazide the 10-[3-(dimethylamino)propyl]-9-acrida-none thiosemicarbazone of melting point 202-204° and therefrom the 10-[3-(dimethylamino)propyl]-9-acridanone (2-thia- 20 zolyl)hydrazone dihydrochloride of meltint point 195° (decomposition). Example 6 25 (a) A mixture of 3 g (9.33 mmol) of 10-[2-(4-methy1-1- -piperazinyl)ethyl]-9-acridanone, 100 ml of dichloromethane and 1.6 ml (18.66 mmol) of oxalyl chloride is stirred for 0.5 hour, concentrated to half volume and the salt (9-chloro- ' 'A \i> -10-[2-(4-methyl-l-piperazinyl)ethyl]acridinium chloride) is 30 precipitated by the addition of 100 ml of ethyl acetate. The salt is filtered off, washed with petroleum ether and dried. The red-brown powder is heated to boiling under reflux for 5 minutes together with 1.42 g (9.33 mmol) of 2-thiazolyl-hydrazine hydrochloride, 2.3 g (28 mmol) of 35 sodium acetate and 100 ml of methanol and then evaporated. The residue is treated with 50 ml of water, made alkaline with sodium carbonate solution and extracted with dichloro- O methane. The extract is washed with 10 percent sodium chlb- ^4 o ^ ride solution, dried and evaporated.- The residue is taken I 0 0 15 - 34 - 2 063 J 7 10 up in 100 ml of methanol, acidified with ethanolic hydrochloric acid, the precipitated product is filtered off and washed successively with a small amount of cold ethanol and petroleum ether. There is obtained 10-[2-(4-methy1-1--piperazinyl)ethyl]-9-acridanone (2-thiazolyl)hydrazone. 2.5 HCl of melting point 230° (decomposition). In an analogous manner there is obtained: (b) From 10-[2-(dimethylamino)ethyl]-9-acridanone and 2--thiazolyl-hydrazine hydrochloride the 10-[2-(dimethylamino)-ethyl]-9-acridanone (2-thiazolyl)hydrazone dihydrochloride of melting point >200® (decomposition); (c) from 10-[2-(4-ethoxycarbonyl-1-piperazinyl)ethyl]-9--acridanone and 2-thiazolyl-hydrazine hydrochloride the 10--12- (4-ethoxycarbonyl-1-piperazinyl)ethyl]-9-acridanone (2-thiazolyl)hydrazone dihydrochloride of melting point 185° 20 (decomposition); (d) from 10-[2-[4-(methylsulphonyl)-1-piperazinyl]ethyl]--9-acridanone and 2-thiazolyl-hydrazine hydrochloride the 10- [2- ([4- (methylsulphonyl) -1-piperazinyl]ethyl.] -9-acrida-25 none (2-thiazblyl)hydrazone dihydrochloride of melting point 200°; (e) from 10—[2-(4-propyl-l-piperazinyl)ethyl]-9-acridanone and 2-thiazolyl-hydrazine hydrochloride the 10-[2-(4-propyl-30 -1-piperazinyl)ethyl]-9-acridanone (2-thiazolyl)hydrazone. 2.5 HCl of melting point 220° (decomposition). Example 7 35 (a) A mixture of 9.75 g (50 mmol) of 9-acridanone, 200 ml of dimethylformamide and 4.8 g (200 mmol) of sodium hydride is stirred for 0.5 hour, treated portionwise with 17.8 g (50 mmol) of 2-[4-[2-(diethylamino)ethyl]-1-piperazinyl]-ethyl chloride trihydrochloride, stirred at 70° for 18 hours. o - 35 - 17 then heated to boiling under reflux for 8 hours and evaporated. The residue is treated with 100 ml, of water and extracted with dichloromethane. The extract is washed with 5 water, dried and evaporated. The product is crystallized twice from petroleum ether and there is obtained 10-[2-[4--[2-(diethylamino)ethyl]-1-piperazinyl]ethyls9-acrida-none of melting point 106-108°. 10 a suspension of 4.06 g (10 mmol) of this substance in 100 ml of dry acetonitrile is treated portionwise while stirring with 1.7 ml (20 mmol) of oxalyl chloride and evaporated after 0.5 hour. The residue is treated, with acetonitrile and filtered off under suction. The material ob-15 tained is washed successively with ether and petroleum ether and then dried. The brown powder (9-chloro-10-[2-[4-[2-di-ethylamino)ethyl] -1-piperazinyl]ethyl]acridinium chloride) is taken up in 100 ml of methanol, treated with 1.52 g (10 mmol) of 2-thiazolyl-hydrazine hydrochloride and 2.46 g 20 (30 mmol) of sodium acetate and heated to boiling under reflux for 10 minutes. After evaporation, the residue is treated with 100 ml of water, made alkaline to phenolphthalein with 2N sodium hydroxide solution, the precipitated product is taken up in 100 ml of dichloromethane, the solution is 25 washed neutral with water, dried and evaporated. The residue is dissolved in 100 ml of methanol and acidified with ethereal hydrochloric acid. The precipitated salt is filtered off and washed successively with methanol, ether and petroleum ether. There is obtained 10-[2-[4-[2-(diethylamino)-30 ethyl]-1-piperazinyl]ethyl]-9-acridanone (2-thiazolyl)hydrazone.3.5 HCl of melting point 235° (decomposition). In an analogous manner there is obtained: 35 (b) Prom 10-[2-[4-[2-(diethylamino)ethyl]-1-piperazinyl]-ethyl]-9-acridanone and 2-hydrazino-2-thiazoline hydrobromide the 10-[2-[4-[2-(diethylamino)ethyl]-1-piperazinyl]ethyl]- 1 S - 36 _ -9-acridanone (2-thiazolidinylidene)hydrazone of melting point 144-146° (decomposition). 5 Example 8 (a) A mixture of 4.94 g (16.8 mmol) of 10-[2-(diethyl-amino) ethyl] -9-acridanone, 300 ml of dichloromethane and 2.85 ml (33.6 mmol) of oxalyl chloride is stirred for 20 W io minutes, the crystals (9-chloro-l0-[2-(diethylamino) ethyl] --acridinium chloride) obtained are filtered off and washed with ether. This material is taken up in 100 ml of methanol, treated with 2.8 g (16.8 mmol) of N-methyl-N-(2-thiazolyl)-hydrazine hydrochloride and 4.1 g (50 mmol) of sodium acetate, 15 heated to boiling under reflux for 15 minutes and evaporated. The residue is made alkaline with sodium carbonate solution, extracted with dichloromethane, the extract is washed with water, dried and evaporated. By crystallization of the residue from isopropyl ether there is obtained 10-[2-(diethy1- 20 amino)ethyl]-9-acridanone methyl (2-thiazolyl)hydrazone of melting point 103-104°. In an analogous manner there is obtained: 25 (b) from 10-[2-(diethylamino)ethyl]-9-acridanone and N--methyl-N-(2-thiazolin-2-yl)hydrazone the 10- [2-(diethyl-amino) ethyl] -9—acridanone methyl(2-thiazolin-2-yl)hydrazone ^ of melting point 109-110°. 30 Example 9 A suspension of 58.6 g (0.3 mol) of 9-acridanone in 200 ml of dimethylformamide, heated to boiling under reflux, is treated portionwise with a total of 60 g (0.33 mol) of 35 benzyl ethylenecarbamate. After 53 hours, the mixture is left to cool, the crystalline product is filtered off and washed successively with dimethylformamide, acetone and ether, €063 J 7 - 37 - The mother liquor is treated with water, whereupon the precipitated product is filtered off and washed as above. The combined material is crystallized from ethanol and there 5 is obtained benzyl [2-(9-oxo-10(9H)-acridinyl)ethyl]carbamate of melting point 224-226°. 9.31 g (25 mmol) of this substance are suspended in 100 ml of dichloromethane. The suspension is treated with 10 4.5 ml (50 mmol) of oxalyl chloride, stirred for 1 hour and the solution is evaporated. The residue is taken up in 400 ml of acetonitrile/ treated with 5.55 g (28 mmol) of 2--hydrazino-2-thiazoline hydrobroxnide and heated to boiling under reflux for 24 hours. The still warm mixture is fil-15 tered, the material obtained is washed successively with acetonitrile and ether, treated with methylene chloride and water and the base is liberated by the addition of sodium carbonate solution. The free base is purified by chromatography on silica gel while eluting with dichloromethane and 20 it is converted into the hydrochloride with ethanolic hydrochloric acid. By the addition of ether to the solution obtained there is obtained crystalline benzyl [2-[9-(2-thia-zolidinylidenehydrazono) -10-acridanyl] ethyl] carbamate dihydrochloride of melting point 167.7-170.8° (decomposition). 25 A suspension of 3.5 g (6.4 mmol) of the above substance in 300 ml of glacial acetic acid is stirred for 3 days with 10 ml of hydrogen bromide-containing glacial acetic acid (about 30 percent), whereupon the product is filtered 30 off and washed with glacial acetic acid and ether. It is subsequently taken up in water, the base is liberated with sodium carbonate and taken up in methylene chloride. The methylene chloride solution is dried over sodium sulphate and evaporated. The residue is dissolved in ethanolic hy-35 drogen chloride and the salt is crystallized by the addition of ether. There is obtained 10-(2-aminoethyl)-9-acridanone (2-thiazolidinylidene)hydrazone dihydrochloride of melting point 226-231°. o 38 - 2063 1 7 Example IQ 2.25 g (6 mmol) of benzyl [2-(9-oxo-10(9H)-acridinyl)-5 ethyl]carbamate are suspended in 20 ml of methylene chloride and treated with 1.05 ml (12 mmol) of oxalyl chloride. After 1 hour, the solution is evaporated, whereupon the residue is taken up in 200 ml of acetonitrile, treated with 1.09 g (7.2 mmol) of 2-thiazolyl-hydrazine hydrochloride and heated to ^2) 10 boiling under reflux for 1.5 hours. The mixture is left to cool, the crystals are filtered off under suction and washed with acetonitrile and ether. There is obtained benzyl [2--[9-(2-thiazolylhydrazono)-9-acridanyl]ethyl]carbamate hydrochloride of melting point 207-209° (decomposition). O 15 A suspension of 7.6 g (15 mmol) of this substance in 450 ml of glacial acetic acid is treated with 20 ml of hydrogen bromide-containing glacial acetic acid (about 30 percent) and stirred for 2 days. The product is filtered off 20 under suction and washed with glacial acetic acid and ether. The salt mixture is converted into the hydrochloride with a hydrochloric acidic ion exchanger. The aqueous solution is freeze-dried and the crystalline residue is recrystallized repeatedly from methanol/ether. There is obtained 10-(2-25 -aminoethyl)-9-acridanone 2-thiazolylhydrazone dihydrochloride of melting point 204-214° (decomposition). ^ Example 11 O 30 A suspension of 11.2 g (30 mmol) of benzyl [2-(9-oxo- -10(9H)-acridinyl)ethyl]carbamate in 100 ml of glacial acetic acid is treated with 20 ml of hydrogen bromide-con-^ taining glacial acetic acid (about 30 percent) and stirred for 1 hour. The product is filtered off and washed with 35 glacial acetic acid and ether. There is obtained 10-(2- -aminoethyl)-9-acridanone hydrobromide of melting point >250°. The free base is precipitated from an aqueous solution with - 39 - 206317 sodium bicarbonate solution, filtered off and washed with water and acetone. The hydrochloride obtained therefrom and analyzed melts above 250°. 6.11 g (27 mmol) of the above free base are suspended in 100 ml of pyridine, whereupon the suspension is treated with 2.33 ml (30 mmol) of methanesulphochloride. While warming there is obtained a clear solution, to which 700 ml of water are added after 3 hours. Crystals form gradually. The mixture is concentrated to 300 ml, 500 ml of water are added thereto and the mixture obtained is concentrated in vacuo to 300 ml. The product is filtered off, washed with water and recrystallized from ethanol. There is obtained N- [2-(9-oxo-10-acridanyl)ethyl]methanesulphonamide of melting point 226-227°. 950 mg (3 mmol) of this substance are suspended in 10 ml of methylene chloride, whereupon the suspension is treated with 0.8 ml (9 mmol) of oxalyl chloride. After 1 hour,-the mixture is evaporated. The residue is taken up in lOO ml of acetonitrile and treated with 713 mg (3.6 mmol) of 2-hydrazino-2-thiazoline hydrobromide. After 20 minutes under reflux, the product is filtered off, washed with ether and dissolved in 150 ml of methylene chloride/methanol (97:3). The solution is made alkaline with sodium bicarbonate solution, extracted with methylene chloride, dried over sodium sulphate and evaporated. After crystallization from methylene chloride/methanol/petroleum ether, there is obtained N-[2-[9-(2-thiazolin-2-yl)hydrazono]-10-acridanyl]-ethyl]methanesulphonamide of melting point 206-207° (decomposition) . Example 12 (a) A suspension of 1.44 g (60 mmol) of sodium hydride in 100 ml of dimethylformamide is treated within 10 minutes with 9.75 g (50 mmol) of 9-acridanone and held at 50° for 2 hours. 2 063 1 7 At 120° there are then added 9.5 g (53 mmol) of 4,4-diethoxy-butyl chloride. After 16 hours, the mixture is cooled, poured into water and extracted with dichloromethane. The extract is dried over sodium sulphate and evaporated. The residue is extracted with hexane and crystallized twice from hexane. There is obtained 10-(4,4-diethoxybutyl)-9-acrida-none of melting point 73-74.5°. 8.5 g (25 mmol) of this substance are dissolved in 20 ml of diethylamine, whereupon the solution is treated with 15 ml of formic acid, heated to 100° for 20 hours, cooled, water and dilute hydrochloric acid are added and the aqueous solution is washed with ether. The aqueous solution is treated with sodium hydroxide solution and extracted with methylene chloride. The extract is dried over sodium sulphate and evaporated. The residue is crystallized from hexane. There is obtained 10-[4-(diethylamino)butyl]-9--acridanone of melting point 66.5-68.7°. The hydrochloride has a melting point of 126.8-128.3°. 2.4 ml (27.9 mmol) of oxalyl chloride are added drop-wise at 0° within 3 minutes to a solution of 3.0 g (9.3 mmol) of the above free base in 200 ml of dichloromethane. The mixture is stirred at room temperature for 1 hour and evaporated. The residue (9-chloro-10-[4-(diethylamino)butyl]-acridinium chloride) is taken up in 300 ml of acetonitrile, treated with 1.57 g (10.2 mmol) of 2-hydrazino-2-thiazoline hydrochloride, heated to boiling under reflux for 0.5 hour, stirred at room temperature for a further 1.5 hours and cooled to 0°. The product is filtered off, washed with acetonitrile and ether and taken up in water. The solution is made alkaline with sodium carbonate and extracted with methylene chloride. The methylene chloride solution is dried over sodium sulphate and evaporated. By crystallization from dichloromethane/ether/petroleum ether there is obtained - 41 - 2 06317 10-[4-(diethylamino)butyl]-9-acridanone (2-thiazolidinylidene) hydrazone of melting point 105.6-107.2? 5 * In an analogous manner there is obtained: (b) From 9-acridanone and 5,5-diethoxypentyl chloride the 10-(5,5-diethoxypentyl)-9-acridanone of melting point 82--83°, therefrom the 10[5-(diethylamino)pentyl]-9-acrida-10 none of melting point 59-61.2° and therefrom the 10-[5-(diethylamino) pentyl] -9-acridanone (2-thiazolidinylidene)-hydrazone of melting point 128.5-130.1°. Example A 15 Manufacture of tablets of the following composition: mg/tablet 20 Active substance 100 Lactose 100 Maize starch 85 Povidone 10 Talc . 3 . 25 Magnesium stearate 2 Tablet weight 300 mg The active substance is mixed with the lactose and the maize starch, moistened with an aqueous solution of Povidone 30 and granulated. The granulate is dried at 40° and sieved. The sieved granulate is mixed with the talc and the magnesium stearate and the mixture is pressed to tablets. The following compounds of formula I can be processed 35 as the active substance as described above: </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 2063 f 7 - 42 - O ■ 10-[2-(4-Methyl-l-piperazinyl)ethy1-9-acridanone (2--thiazolyl)hydrazone, 10-[2-(4-methyl-l-piperazinyl)ethyl]-9-acridanone (2-5 -thiazolidinylidene)hydrazone, 10-[2-(4-acetyl-l-piperazinyl)ethyl]-9-acridanone (2--thiazolidinylidene)hydrazone, 10-[2-(dimethylamino)ethyl]-9-acridanone (2-thiazolidinylidene )hydrazone 10 10-[2-(diethylamino)ethyl]-9-acridanone (2-thiazolyl)- hydrazone, 10-[2-(l-piperadinyl)ethyl]-9-acridanone (2-thiazolyl)-hydrazone, 10-(2-aminoethyl)-9-acridanone (2-thiazolyl)hydrazone, 15 10-[2-(dimethylamino)ethyl]-9-acridanone (2-thiazolyl)- hydrazone, 10-[2-(4-acetyl-l-piperazinyl)ethyl]-9-acridanone (2--thiazolyl)hydrazone, 10-[3-(dimethylamino)propyl]-9-acridanone (2-thiazolyl) 20 hydrazone, 10-[2-(diethylamino)ethyl]-9-acridanone (2-thiazolidinylidene )hydrazone, 10-[2-(1-pyrrolidinyl)ethyl]-9-acridanone (2—thiazolidinylidene) hydrazone and 25 10-[3-(dimethylamino)propyl]-9-acridanone (2-thiazoli dinylidene) hydrazone . 30 35 4' <1 2063 - 43 - WHAT^/WE CLAIM iSi £LAiMS: 1. Acridanone derivatives of the general formula 10 O o IS wherein the dotted line signifies an optional bond, R* signifies hydrogen, halogen or 2 nitro, R signifies hydrogen or lower alkyl, 3 4 one of the substituents R and R signifies 20 hydrogen or lower alkyl and the other together with R signifies an additional bond, A signifies lower alkylene, R^ signifies a 5--merabered, nitrogen-containing, optionally lower alkyl-substituted aromatic hetero-25 cycle, amino or the group (B)n~ aI—r6 -h\ . °r -O - 30 R7 the symbol -1^signifies a 5- or 6-membered, optionally lower alkyl-substituted saturated . heterocycle which can contain as a ring 35 member an oxygen or sulphur atom or the group I5NH or SN(B)n-A^-R6, B signifies the group -CO-, -COO- or -SO2-, n signifies the number 2063 | 7 - 44 - ES^44JZA/*1 10 0 or 1, A* signifies lower alkylene, R*' • signifies hydrogen, amino, lower alkyl- 7 amino or di(lower alkyl)amino and R signifies hydrogen or lower alkyl, and pharmaceutically acceptable acid addition salts thereof. 2. Compounds in accordance with claim 1, wherein the substituent R1, is situated in the 1-position. 3. Compounds in accordance with claim 1 or 2, wherein R^" signifies hydrogen. j4. Compounds in accordance with any one of claims 1 to 15 3, wherein R2 signifies hydrogen. 5. Compounds in accordance with any one of claims 1 to 3 4 4, wherein one of the substituents R and R signifies hydrogen and the other together with R signifies an additional 2o bond. 6. Compounds in accordance with any one of claims 1 to 5, wherein A signifies dimethylene or trimethylene. 25 7. Compounds in accordance with any one of claims 1 to 6, wherein R5 signifies amino, 1-pyrrolidinyl, 1-piperidinyl, 7 3. 63. 1-morpholinyl, 1-piperazinyl or the group -NR -A -R or -N* ^-(B1)^1^61 in which A^" signifies lower alkylene, S l 30 signifies the group -CO-, n signifies the number 0 or 1, R 7 signifies hydrogen and R signifies hydrogen or lower alkyl. 5 8. Compounds in accordance with claim 7, wherein R signifies amino, dimethylamino, diethylamino, 1-pyrrolidinyl, 35 1-piperidinyl, 4-methyl-l-piperazinyl or 4-acetyl-l-pipera-zinyl. o u *<0 - 45 - 1 7 9. 10- [ 2- (4- (Methyl-l-piperazinyl) ethyl] -9-acridanone (2-thiazolyl)hydrazone. 5 10. 10- [2- (4-Methyl-l-piperazinyl) ethyl]-9-acridanone (2-thiazolidinylidene) hydrazone. ^ 10 11. 10- [2- (4-Acetyl-l-piperazinyl) ethyl] -9-acridanone (2-thiazolidinylidene) hydrazone. 12. 10-[2-(Dimethylamino)ethyl]-9-acridanone (2-thiazolidinylidene )hydrazone. 13. 10- [2-(Diethylamino)ethyl] -9-acridanone (2-thia-15 zolyl)hydrazone. 14. 10- [2- (1-Piperidinyl) ethyl] -9-acridanone (2-thiazolyl) hydrazone . 20 15 . 10- (2-Aminoethyl) -9-acridanone (2-thiazolyl) hydrazone, 16. 10-[2-(Dimethylamino) ethyl]—9-acridanone (2-thia-zolyl)hydrazone. 25 17. 10-[2-(4-Acetyl-1-piperazinyl) ethyl] -9-acridanone (2-thiazolyl)hydrazone. 18. 10- [3- (Dimethylamino) propyl] -9-acridanone (2-thia-zolyl)hydrazone. 30 19. 10-[2-(Diethylamino)ethyl]-9-acridanone (2-thiazolidinylidene )hydrazone. 20. 10- [ 2- (1-Pyrrolidinyl) ethyl] -9-acridanone (2-thiazoli-35 dinylidene)hydrazone. 21. 10- [3- (Dimethylamino)propyl] -9-acridanone (2-thiazolidinylidene )hydrazone. o 2 063 1 7 - 46 - 22. A compound selected from: 10- [2- (4<-Propyl-l-pip§razinyl) ethyl] -9-acridanone 5 (2-thiazolidinylidene)hydrazone, 10- [2-(dimethylamino)propyl]—9-acridanone (2-thiazoli diny lidene )hydrazone, 10- [2-(1-piperidinyl)ethyl]-9-acridanone (2-thiazoli-dinylidene)hydrazone, 10 10-[ 2-(2,6-dimethyl-1-piperidinyl)ethyl]-9-acridanone (2-thiazolidinylidene)hydrazone, 10-[2-(4-morpholinyl)ethyl]-9-acridanone (2—thiazoli-dinylidene)hydrazone, 10- [ 2-(4-ethoxycarbonyl-1-piperazinyl)ethyl]-9-acri-15 danone (2-thiazolidinylidene)hydrazone, 10-[ 2-(4-pivaloyl-l-piperazinyl) ethyl]-9-acridanone (2-thiazolidinylidene)hydrazone, 10-[2-[4-(methylsulphonyl)-1-piperazinyl]ethyl] -9--acridanone (2-thiazolidinylidene)hydrazone, 20 10-[ (l-methyl-4-imidazolyl) methyl]-9-acridanone (2- -thiazolidinylidene)hydrazone, 10-C2-[4-[2-(dimethylamino)acetyl]-1-piperazinyl]ethyl] -9-acridanone (2—thiazolidinylidene)hydrazone, l-chloro-10-[2-(diethylamino)ethyl] -9-acridanone (2-25 -thiazolidinylidene)hydrazone, 10-(2-aminoethyl)-9-acridanone (2-thiazolidinylidene)-hydrazone, 10- [ 2- [ (methylsulphonyl) amino] ethyl] -9-acridanone (2— -thiazolidinylidene)hydrazone, 30 10-[4-(diethylamino)butyl]-9-acridanone (2-thiazoli- dinylidene)hydrazone, 10-[5-(diethylamino)pentyl]-9-acridanone (2-thiazolidinylidene) hydrazone , 10-[2-(diethylamino)ethyl]-9-acridanone methyl(2-thia-35 zolin-2-yl)hydrazone and 10-[2-(diethylamino)ethyl-9-acridanone (3-methyl-2--thiazolidinylidene)hydrazone. 206317 - 47 - 23. A compound selected from: 10-[2-(Diethylamino)ethyl]-9-acridanone methyl-(2-5 -thiazolyl)hydrazone, 10-[2-(4-morpholinyl)ethyl]-9-acridanone (2-thiazolyl) -hydrazone, 10-[2-(4-ethoxycarbonyl-1-piperazinyl)ethyl-9-acridanone (2-thiazolyl)hydrazone, 10 10-[2-(4-pivaloyl-l-piperazinyl)ethyl]-9-acridanone '(2-thiazolyl) hydrazone, 10-[2-[4-(methylsulphonyl)-1-piperazinyl]ethyl]-9--acridanone (2-thiazolyl)hydrazone, 10-[2-[4-[2-(diethylamino)ethyl]-1-piperazinyl]ethyl] -15 -9-acridanone (2-thiazolyl)hydrazone and • 10-[2-(4-propyl-l-piperazinyl)ethyl]-9-acridanone (2--thiazolyl)hydrazone. 24. Compotinds in accordance with any one of claims 1 to 20 23 for use as pharmaceutically active substances. 25. Compounds in accordance with any one of claims 1 to 23 for use as schistosomicidal substances. 25 26. A process for the manufacture of the compounds in accordance with any one of claims 1 to 23, which process comprises (a) cyclizing a compound of the general formula ,41 H .31 , N HN I // \ r2 - 48 - 2063 I 7 10 ,41 ,31 IV, V, o 15 20 25 30 35 or VI or 31 VII wherein one of the substituents R and 41 R signifies hydrogen or lower alkyl and 42 the other signifies hydrogen, R signifies hydrogen or lower alkyl, R53" signifies a group R5 defined in claim 1, but which does not contain a primary or secondary basic amino group, X' signifies a leaving 12 5 group and R , R and R have the significance given in claim 1, (b) reacting a compound of the general formula 206317 - 49 - <&£r-**7T7TT~~ ^R51 10 wherein A and R have the significance given 42 51 in claim 1 and R and R have the significance given earlier in this claim/ 15 with a compound of the general formula VIII 20 X" IX 25 or 30 wherein X" signifies a leaving group and the 2 dotted line and R have the significance given in claim 1, (c) reacting a compound of the general formula 35 - 50 - 206 31 BS-tpttTTII wherein yO signifies an anion, X nifies a leaving group, A and R^" srg-have the significance given in 'claim 1 and R^ has the significance given earlier in this claim, with a compound of the general formula h2n-n xi or 2 3 4 wherein the dotted line, R, R , R and R have the significance given in claim 1, (d) cleaving off the N-protecting group in a compound of the general formula xii 8 5 wherein R signifies a group R defined in claim 1 which contains a primary or secondary basic amino group blocked by a N-protecting group and the dotted line, o - 51 - 206317 12 3 4 R, R , R . , R and R have the significance given in claim 1, and 5 (e) if desired, converting a compound of formula I obtained into a pharmaceutically acceptable acid addition salt. with any one of claims 1 to 23. 28. A schistosomicidal medicament containing a compound in accordance with any one of claims 1 to 23. 15 29. Compounds of formulae II, III, IV, V, VI, VII and XII defined in claim 26. 30. A process for the manufacture of an acridanone 20 derivative as defined in claim 1, substantially as hereinbefore described with particular reference to any one of the foregoing Examples 1 to 12. 31. Acridanone derivatives as defined in claim 1 whenever 25 prepared according to a process claimed in claim 26 or claim 30 or by an obvious chemical equivalent thereof. 32. A medicament containing an acridanone derivative as defined in claim 1, substantially as hereinbefore described 3q with particular reference to the foregoing Example A. 10 27. A medicament containing a compound in accordance DATED THIS J Set- DAY OF 19^7 A. J. PARK & SON PER ' £ • '(U? AGENTS FOR THE APPLICANTS </div>