CA1258854A - Acridanone derivatives - Google Patents

Abstract

Abstract The present invention is concerned with acridanone derivatives of the general formula I

wherein the dotted line signifies an optional bond, R1 signifies hydrogen, halogen or nitro, R2 signifies hydrogen or lower alkyl, one of the substituents R3 and R4 signifies hydrogen or lower alkyl and the other together with R sig-nifies an additional bond, A signifies lower alkylene, R5 signifies a 5-membered nitrogen-containing, optionally lower alkyl-substituted aromatic heterocycle, amino or the group

Description

258~S4 ~N 447~

The present invention is concerned with acridanone derivatives of the general formula R4 R I ~

lS l ~ I
A~R5 where:Ln the dotted line signi~ies an optional bond, Rl si.gnifies hydrogen, halogen or ni.tro, R2 signiies hydrogen or lower-alkyl., one of. the ~ubstituents R3 and R4 signlfies hydrogen or lower alk~l and the other together with R si.g-ni~ies an addi.tional bond, A si.gnifies lower alkylene, R5 signifie~ a 5-membered nitrogen-containing, optionally lower aIkyl substituted aroma~ic heterocycle, amlno or the group ~(B)n--Al--R6 -N ~ ox ~N~

the symbol -N~ signi~ies a 5- or 6-membered, optionally lower alkyl=sub~
~tituted saturated heterocycle whlch Hen/14.9.83

- 2 - ~5~5~

can ccntain as a ring member an oxygen or sulphur atoM or the group ~N~ or -N(B)n-Al-R6, B signifies the group CO , -COO- or -S02-, n signifies the number O or 1, Al signi~ies lower alkylene, R6 signifies hydrogen, amino, lower alkylamino or di(lower alkyl)amlno and R7 signi~ies hydrogen or lower alkyl, and pharmaceutically acceptable acid addition salts ~hereof.

These novel sub~tances possess ~-aluable pharmaco-logical properties and can be used in the contxol or pre-vention of illnessesO

Objects of the present invention are acridanone deri vatives o~ formula I above and their pharmaceutically acceptable salts per se and as pharmaceuticaLly active sub-stances, the manufacture of these compounds and salts, intermedia~es for their manufacture, medicaments containing these compounds and salts and the manufacture of these medicaments.

Depending on the significance o the dotted line and of the substituents R, R3 and R4, the compounds of formula I
above can be present in various tautomeric ~orm~; the present invention includes all possible tautomeric ~orms.

T~e term "lower" as used in the present description signifles that the compounds or groups denoted in such a mannex contain up to 7, preerably up to 4, carbon atoms and can ~e straight-chain or branched-chain. The term "lower aIkyl" denotes saturated hydrocarbon groups such as methyl, ethyl, propyl, isopropyl, n-butyl, n-pentyl and the like.
The term "lower alkylene" denotes divalent hydrocarbon groups such as methylene, dimethylene, trimethylene, 1,2--propylene, 1,4-butylen~, l,S-butylene and the like. ~he ~erm "halogenl' signi~ies ~luorine, chlorine, bromine or iodine~

3 ~2 ~885~

The term "5-membered, nitrogen-containing aromatic heterocycle" denotes heterocycles containinq one or two hetero atoms, whereby, insofar as two hetero atoms are present, one hetero atom can be diferent 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:
1-methyl-4-imidazolyl, 2-pyrrolyl, 2-thiozolyl, 4-oxazolyl, l-pyrazolyl, 3-isoxazolyl.

The term "5- or 6-membered saturated heterocycle which can contain as a ring member an oxygen or sulphur atom or the group =N~ or ~(B)n-Al-R6" denotes 5- or 6-memhered saturated heterocycles which contain only one hetero atom, namely a nitrogen atom, such as l--pyrrolidinyl and l-piperi-dlnyl, or which co~tain two hetero atoms, namely one nitro-gen atom and, in addition, one oxygen, sulphur or nitrogen 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)n-Al-R6. As the symbol -N~
indicates, these heterocycles are linked with group A via à
ni~rogen atom.
The substituent Rl, inso~ar as it is dif~erent ~rom hydrogen, is preferably situated ln the l-position. ~owever, Rl pre~erably signifies hydrogen. R2 preferably signifies hydrogen. Preferably, one of the substituents R3 and R4 signi~ies hydrogen and the other together with R signifies an additional bond. A preferably signifies dimethylene or tri-methylene~

R5 preferably signi~ies amino, l-pyrrolidinyl~ 1--piperidinyl, l-morpholinyl, l~piperazinyl or the group -NR -A -R 1 or ~N~_~N-(Bl)n-Al-R61 in which Al signi~ies lower alkylene, Bl signi~ies the group -CQ-, n signi~ies the number 0 or 1, R61 signi~ies hydrogen and R7 signi~ies hydrogen or lower alkyl. Especially preferred groups denoted ~ 4 ~ 125~5~

by R5 are amino, dimethylamino, cliethyl~nino, 1 pyrroli-dinyl, l-piperidinyl, 4-methyl-1-piperazinyl and 4-acetyl--l-piperazinyl.
Especially preferred compounds of formula I are:

lo-L2 (4 Methyl l-pipexazinyl)ethy~-9-acridanone (2--thiazolyl)hydrazone, 10~[2-(4-methyl-1-piperazinyl)ethyl]-9-acridanone (2--thi azolidinyli dene)hydraæone, 10-[2-(4-acetyl-1-piperazinyl)ethyl]-9-acridanone (2--thiazolidinylidene)hydrazone/
- 10-[2-(dimethylamino)ethyl]-9-a~ridanone (2-thiazoli~
dinylidene)hydrazonel 10 [2-(diethylamino)ethyl]-9-a ridanone (2-thia201yl)-hydrazone, 10 ~2~ piperidinyl)ethyl]-9-acridanone (2-thlazolyl)-h.ydxazo~e, 10-(2-aminoethyl)-9-acridano.ne (2-~hiazolyl)hydrazone, 10-~2-(dimethylamino)ethyl]-9-acridanone (2-thia zolyl)hydrazone, 10-[2-~4 acetyl-l-piperazinyl)ethyl~-9-acridanone (2-thiazolyl)hydrazone, 10-[3-(di~ethylamino)propyl~9-acridanone (2-thia-zolyl~hydrazone, 10 ~2 (diethylamino)ethyl]-9~acridanone (2-thiazoli-dinylidene)hydrazone, 10-[2~ pyrrolldinyl)ethyl] 9 acridanone ~2-thiazoli-dinylidene)hydra~one and 10-~3-(dimethyl~nino)propyl]-9-acridanone (2-~hiazoli-dinylidene)hydrazone.

Examples of other compounds of formula I are:
10 ~2-(4~Propyl-l-piperazinyl)ethyl]-9-acridanone ~2-~hiazolidinylidene)hydrazone, - 5 1~S !3~359L

10-[2-(dimethylamino) propy 1 ] - 9 -acri danone (2-thia-zolidinylidene)hydxazone, 10-[2~ piperidinyl)ethyl]-g-acridanone (2-thiazoli-dinylidene)hydrazone, 10-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-3~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-pi~aloyl-l~piperazlnyl)e~hyl]-9-acrldanone 2-thiazolidinylidene )hydrazone, 10-[2-[4-(methylsulphonyl)-1-piperazinyl]ethyl]-9--acrida~one (2-thlazolidinylidene)hydrazone, 10-[(l-methyl-4-imidazolyl)methyl]-9-acridanone ~2--thiazolidinylidene)hydrazone, 10-~Z-[4-[2-(dimethylamino)acetyl]-1-piperazinyl]-ethyl]-9-acridanone (2-thiazolidinylidene)hydrazone, 1-chloro-10-~2-(diethylamlno)ethyl]-9-acridanone (2--thiazolldinylidene)hydrazone, 10 (2-aminoethyl)-9-acridanone (2-thiazolidinylidene)-hydrazone, 10-~2-~(methylsulphonyl)amino]ethyl~-9-acridanone (2--thlazolidinylidene)hydxazone~
10-~4-~d~ethylamino)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-Z-yl)hydrazone, 10-~2-(diethylamino)ethyU-9-acrldanone (3-methyl-2--~hiazolidinylidene)hydrazone, 10-~2-(dieth~l~mino)ethyl]-9-acridanone ~ethyl(2-thiazolyl)hydrazone, 10-~2-(4~morpholinyl)ethyl]-9-acridanone (2-thiazolyl)-hydrazo~e, ~2S~385~

-10-[2-(4-ethoxycarbonyl-1-piperazinylje~hy.~-9-acri-danone (2-thiazolyl)hydrazone, 10-[2-(4-pivaloyl-1-piperazlnyl)ethyl]-9-acridanone (2-~hiazolyl)hydrazone, L0-[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-1-piperazinyl)ethyl]-9-acridanone (2--thiazolyl)hydrazone.

The acrida~one derivatives of formula I above and their pharmaceutically acceptable acid addition salts ~an be manu-factuxed in accordance with ~he invention by (a) cyclizing a compound of the general form~la 2' 1~ R~--A~5 ~ R

II, III, R41 R~ R41 R~

N ~S--)-- N~

~ R
N N
R5 ~ ~51 IV, V, 8S~

R42 H R2 ¦ ~N ~
R~3~ ~O/~_a A ~ R
10 ~ R51 Vl or VII

wherein one o~ the substituents R31 and R41 signifies hydrogen or lower alkyl and the other signifies hydrogen, R42 signi-fies hydrogen or lower alkyl, R51 signifies a group RS defined above, but which does not contain a primary or secondary basic amino group, X' signi~ies a leaving group and R, Rl, R2 and R5 have ~he above signi~i-cance, or (b) reacting a compound of the general formula I

1 N~NH
R ~ VIII

~R51 wherein A, Rl, R~2 and R51 have the above slgnificance, with a compound o~ the general formula 1~51~354 8 ~-X" ~ / ~ IX
S

wherein X" signifies a leaving group and the dotted line and R2 have the above significance, or tc) reacting a compound o the general ormula X

~ ~ X

~ R51 wherein Y ~ signi~ies an a~lion, X sig-nif~es a leaving group and A, Rl and R5 have the above ig~i~icance, with a compound of the general.formula ~ ~ XI

wherein the dotted line, R, R2, R3 and R4 have khe above signi~icance, or ~258~35~
_ 9 _ (d) cleaving off the N-protecting group in a compound o~ the general ~ormula Rl ~ ~ R2 XII

~ R
wherein R8 signifies a group R5 defined above which contains a pximary or second ary basic amino group bloc~ed by a N--protectiny group and the dotted line, R, Rl, R2, R3 and R4 have the above sig-nificance, and (e) if desired, converting a compound of formula I ob-tained into a pharmaceu~-ically acceptable acid addition salt~

In accordance wi~h proc~ss variant (a), the compounds o~ formula I can be manufactured by cyclizing a compound of formula II, III, IV, V, VI or VII according to methods whlch 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 pre~erably a halogen atom, especially a bromine or chlorine atom. ~epending on the starting ma~exial used, the rlng closure reaction is carried out fair~y readily and can be accomplished or completed, if necessary, by standing ~or a long time and/or by applying heat. The starting ma~erlals for the ring closure reaction need not necessarily be used in isolated form; as a rule it has been found to be ~ "
~L258850~

convenient to cyclize these starting materials directly or to leave these starting materials to cyclize without isolation from the reaction mlxture in which they have been pr~pared. 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, 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 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 ~ormula I can be manufactured by reacting a compound of formula VIII with a compound of ormula IX. The leaving group denoted by X" in formula IX is preferably a halogen atom (e.g. ~ chlorine or bromine atom) or the ~hiol group.
The following organic solvents which are inert under the reaction conditions can be used: ethers such as tetrahydro-furan, dioxan, dle~hyl ether and ~he like, alcohols such asmethanol, ethanal and the like, dlmethylformamide, dimethyl sulphoxlde, acetonitrile and the ~ike. The reaction is conveniently carried out at a temperature in the range of about room temperature to the boiltng point o~ the reaction mixture.

In accordance with procPss variant (c)~ the compounds of formula I can be manufactured by reacting a compound of formula X with a compound of fo~mula XI. The leaving group denoted by X in the compound of formula X is pre~erably a halogen atom, a lower alkanoyloxy group or a lower alkoxy group, especially a chlorine atom, an acetoxy group or a 2S~ 4 methoxy group. The compounds of formula X are to some extent substa~ces which are not especially stable. They are therefore conveniently prepared shortly be~ore the reaction with a compound of formula XI from a compound of the general formula ~ XIV

A ~ 5l wherei.n A, Rl and R51 have the above significance, as described below and, optionally without previous iso-latlon, processed directly.

The compound of ~ormula XI is conve~iently used in the ~orm of an acid addition salt, for example in the form o~ a h~drochloride or hydrobromlde. The reaction can be carried out 1n the presence o~ 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, lowar alcohols such as methanol and ethanol and othex organic solvents which are inert under the reac~lon conditions such a-~ dimethylformamlde, acetonltrile and the like. The re-action ls conveniently carried out at a temperature in the range o~ abou~ room temperature to ~he boiling point of the reac~ion mixture.

In accordance with process variant ~d), the compounds o~ formula I which contain a primary or secondary basic amino group in the group R can be manufactured by cleaving . , - 12 - ~ ~588S~

off the N-protecting group in a compound of formula XII.
Suitable protecting groups ~or the purpose of the present invention are primarily acyl groups, preferably readily cleavable alkoxycarbonyl groups or phenylalkoxycarbonyl groups optionally substituted on the phenyl ring, especially the t-~utoxycarbonyl group, the benzyloxycarbonyl group etc, as well as readily cleavable phenylalkyl sroups optionally substituted on the phenyl ring, such as the benzyl group.
The cleavage of the protecting group is carried out accord-ing to methods known per se, whereby, of course, the nature of the protecting group to be removed must be t~ken into con-sideration when choosing the cleavage method to be used.
Likewise, it will, of course, be appreciated that there can be used only those methods which selectively remove the pro-tecting group without affecting other structural elements present in the molecule.

The groups mentioned above as examples of protecting groups can be cleaved of~ hydrolytically. Thus, for example, the be~zyloxycarbonyl group and the t-butoxycarbonyl group can be clea~ed of~ under selective acidic conditions, for example by treatment with a mixture of hydrogen bromide and glacial acetic acid or by treatment with boron tri-fluoride or boron tribromide in an inert organic solventsuch as dichloromethane. The t-buto~ycarbonyl 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 ~ormula I above can be converted into pharma-ceutically acceptable acid addition salts. The manufacture of such acid addition salts is carried out according to generally usual methods. There come into consideration not only salts with pharmaceutically acceptable inorganic acids but also salts with pharmaceutically acceptable organic ~25~3854 acids; for example, hydrochlorides, hydrobromides, sul-phatec, citrates, acetates, succinates, methanesulphonates, p-toluenesulphonates and the like.
s The compounds of ~ormula 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 o for~ula XIII
in accordance with the following Formula Scheme in which the dotted line and the substituents A, Rl, R2, R31, R41, R 2, R51, R8, X and X' have the above significance, R9 and R91 each signify lower alkyl or together signify lower alkylene, R52 signifies a group R5 which contains a primary or second-ary basic amino group and R10 signiies lower alkyl, phenyl or ~ubstituted phenylO The compounds of formula XIII beLong to a class of substance which is known per se.

5~85~L

~ ~o o ~
~ Y~ A ;--\ ~ Z
`-Y _ Z~ Z ~

_ e~ ~
~y , 1~
~_</ ~ </
S Y ' y _ ~y ~
/Z

x _ ~ ~ Y Y-- \ ~ / Z ~ ~e x ~ ~S ~_ X

~( ~3 ~ / --~ Z ~ 2-'t ~ ~ ~ ~
T t ~h ~ ~

~C y :C Z

~ ~Y
0~2 ~ ~ _ ~ 0~<~2 _ <1~
_~ " ~ _ - 15 - 125~85at The compounds o formula XIV can be prepared from compounds of formula XIII by al]cylation with an agent which yields the group -A-RSl in the presence of a strong base 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 halogen atom can be prepared by treating a compound of form-ula 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, chloroform, 1,2-dichloroethane or the like, acetonitrile or excess haloganating agent is used as the solvent, there being obtained a compound o formula X in which X signifies chlorine. The reaction temperatures advantageously ~ary in a range of about room temperature to the boiling point of the reaction mixture.

Compounds of formula X in which X signifies a leaving group other than a halogen atom can be obtained rom the corresponding halogen compounds. For example, the halogen 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 group~.

The compounds of ~ormula X are ~uaternary ammonium 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 example, if a compou~d o~ formula X i~ which X signiies chLorine is prepared and oxalyl chloride is used as the halogenating agent, then there is obtained a compound of - 16 - 1~58~5~

formula X in which Y signifies a chloride anion~ if phosphorus oxychloride is used as the halogenating agent, then thexe is obtained a coxresponding compound in which Y ~ signifies P02C12 ~3 .

Those compounds of formula II in which RS does not contain a primary or secondary basic amino groupt i.e. com-pounds of ~ormula IIa, can be prepared by reacting a compound of formula X with a thiosemicarbazide of the general formula l41 NHR31 H2N - N- C~ XVIII
S

wherein R31 and R4l have the above sig-nificance, whereby the reaction conditions described above for process variant c) can be used, and reacting the resulting compound of formula XVIIa with a compound of the general ~ormula ,~0 X'~ CH2- C ~IX

wherein X' and R2 have the above signi~i-cance.
The leaving group denoted by X' i~ preferably a ahLorine or bromine atom. Lower alcohols such as methanoL and ethanol are especially,suitable solvents. The reaction is convenient-ly carried out at a temperature in the range of about room temperature to the boilin~ point of the reaction mixture. 5 The compounds o~ formula II in which R5 contains a primary or secondary basic amino group can be prepared by ~25~354 alkylating a compound of ~ormula XIII with an agent which yields the group -A-R8 (in analogy to the preparation o~ a compound of formula XIV), converting the resulting compound of formula XIVS (in analogy to the preparation o~ the com-pounds of formula X) into a compound of formula XS, re-acting the l~tter (in analogy to the preparation o~ the compounds of formula XVIIa) with a thiosemicarbazide o formula XVIII, cleaving off the N-protecting group in the resulting compound of formula XVIIS [using the reaction conditions described above for process variant (d)] and reacting the resulting compound of formula XVIIb with a compound of formula XIX (in analogy to the preparation of the compounds of formula IIa). 5 The compounds of formula III can be obtained by reacting a compound of formula XVIIa or XVIIb in which R31 in each case signifies hydrogen ~ith a compound of the general formula 0 ~ NHR32 X CH2 CH ~ 2 Y.X

wherein X' and R2 have the above signifi-cance and R3~ signifies hydrogen or, where R41 in the compound of formula XVIIa or XVIIb signi~ies hydrogen, also lower alkyl~
The amine is conveniently used in the form of an acid addition salt, the hydrochlorides or hydrobromides being pre~erred. Suitable solven~s are, for example, lower alcohols such as methanol and ethanol, ethers such as tetra-hydrofuran, dioxan and e~hylene glycol dimethyl ether, di-methylformamide, dimethyl sulphoxide, acetonitrile and thelike. The reaction is preferably carr~ed out at a temper-ature between about room temperature and the boiling point o~ ~he reaction mixture.

~ 18 - ~2~8~54 The compounds of ormula IV can be obtained by re-acting a compound of formula XVIIa or XVIIb in an inert organic solvent and a~ a temperature in the range o~ about room temperature to the boiling point of the reaction mixture with a compound of the general formula X'- C~2- CH XXI

wherein X' and R2 have the above sig-nificance, thexe being preferably used a dichloride or dibromide.
Suitable solvents are, for exampl~, alcohols such as methanol, ethanol and the like, ethers such as tetrahydrofuran, dioxan and the like, dimethylormamide, dimethyl sulphoxide and the like. 0 The compounds of formula V can be prepared by reactlng a compound o~ formula X with a hydrazine of the general formula H~N- ~HR42 XXII

wherein R42 has the a~ove significance, whereby the reaction conditions descrlbed above or process ~ariant (c) can be used, treating the resulting compound o~
formula VIII in a manner known per se with an agent whlch yield~ the group -COOR10 (e.g. a dialkyl or diphenyl carbamate or an alkyl or phenyl chloroformate) and reacting the resulting compound o~ formula XVI with a thiol of the general ormula 19- ~IL2588S~

wherein R2 has the above significance and R33 signifies hydrogen or, where R42 in the compound of formula XVI signifies 10hydrogen, also lower alkvl.
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 a l~wer alcohol such as methanol and et~anol.
Alternatively, the compounds of formula XVI can be prepared by reacting a compound of formula X wlth a hydrazine of the general formula H2N -N~ XXIV

25wherein R42 and R10 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 comp~unds o ormula VI can be prepared by reacting a compound of formula VIII with an isothiocyanate of the general formula ~2 S= C -N -CH CH2 X' XXV

- 20 - ~25~85~

wherein X' and R2 have the above signifi-cance.
This reaction can ~e carried out conveniently at a temper-S ature of a~out room temperature to the ~oiling point of the reaction mixture and in an inert organic solvent, for example an ether such. as diethyl ether, t-~utyl methyl ether and tetrahydrofuran or dimethylformamide, acetonitrile or the like.
The compounds of formula VII can ~e prepared by reacting a compound of formula VIII with an iso~hiocyanate of the general formula S = C = N - CH- CX XXVI
OR~l wherein R2, R9 and R91 have the a~ove sisniicance, and subsequently hydrolyzing ~he acetal group in the result-ing compound of formula XV. The first. step is convenlently carried out in an inert organic solvent. (e.g. in an ether 2S such as diethyl ether, t-butyl methyl ether and tetrahydro-furan or in dimethylformamide, acetonitrile or the li~e) at temperatures between about room temperature and the boilins poin~ of the reaction mi~ture. The hydrolysls of the acetal group can be carried ou~ by means o~ an aqueous acid, optionally ln the presence of a solu~ilizer such as tetra-hydrofuran, dioxan, methanol, ethanol, dimethylformamide or the like. The acid can be, for example, sulphuric acid, hydrochloric acid, p-toluenesulphonic acld and the like.
The temperature is not critical and can vary ln 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 lt has been ~ound to be convenien~ as a rule to cyclize these compounds 5~85~

direGtly or to leave these ccmpounds to cycli2e without isolation from the reaction mixture in which they have been prepared.
;

The compounds of ~ormula XII used as starting materials can be prepared from compounds of formula XS in analogy to the manufacture of the compounds of ormula I ~rom compounds o~ formula X in accordance with process variants (a), (b) and (c) described above and the methods described for the preparation of the corresponding starting materials.

The starting materiaLs of formulae II, III, IV, V, VI, VII and XII are novel and also form object~ of the present invention.

The acridanone derivatives of formula I above and their pharmaceutically accepta~le acid addition salts possess valua~le pharmacological properties; in particular, they display valuable schistosomicidal activities and can accordingly be used in the control or prevention o~ schisto-somiasis.

The schistosomicidal activity of t~e acridanone derivatives o~ formula I and theix pharmaceutically accept-able acid addition sal~s can be demonstrated in an animal test as follows:

Albino mlce weighing 15~18 g are infected subcutaneous-ly (sic) with 60 ~ 5 cercaria of a Liberia strain of Schisto-soma mansoni. 46 days a~ter the ln~ection the animals are treated once perorally wlth the substance to be tested.
5-10 animals are used per substance and dosage. 10 un-treated animals serve 3S controls. The autopsy is carried 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 itsel~ in a reduced number o~ living parasites in comparison to the - 22 - ~ ~588 number in the control animals.

For the evaluation the percentage reduction in the parasites in treated animals in comparison to untreated control animals is calculated. The VD50 is determined according to the Probit method. The VD50 is that vermicidal dosage which brings about a 50 percent reduction in the number of worms~
The following Table contains the results o~tained with representative products provided by the invention. In the Table there are given or each of the compounds listed therein the V~50 in mg/kg p.o. and, for some of these compounds, the LD50 in mg~kg in the case of single oral administration to mice.

- 23 - ~L2S~854 Table ~ _ . _ _ --Compound of formula I VD50 in 50 in mq/kq ~.o. mq/kq p.o.
____ ___ 10-[2-Diethylamino)ethyl]-9--acridanone (2-thiazolidinylidene)-hydrazone 9.5 312~625 lO-[3-(Dimethylamino)pxopyl]-9 -acridanone (2-thiazolidinylidene)~
hydrazone 4.7 125-250 10-[2-(4-Methyl-l-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-acrida-none (2-thiazolidinylidene)hydrazone 6.2 156-312 lO-~2-(4-Acetyl-l-piperazinyl)ethyl~--9-acridanone (2-thiazolidinylidene)-hydrazone 3.4 1250-2500 10-~2-(Diethylamino)ethyl]-9-acrida-nona (2-thiazolyl)hydrazone/2 HCl 3.3 >5000 10-[3-(Dimethylamino)propyl]-9-acrida-none (2-thiazolyl)hydrazone/2 HCl 3.5 312-625 10-[2 (l-PiperidinyL)ethyl]-9-ac:rida-none t2-~hiazolyl)hydrazone/2:3 HCl 9.0 312-625 10-~2-(4-acetyl-1-piperazinyl)ethyl]--9-(acridanone (2-thiazolyl)hydrazone~ , 2 HCL 2.6 3l2-625 lO-(2-Aminoethyl)-9-acridanone (2--thiazolyl)hydrazone./2 HCl 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-plperazinyl)ethyl]--9-acridano~e (2-thiazolyl)hydrazone/
2:5 HCl 2.4 625-1250 ~ . . . ~ . ~

- 24 - 1~5~54 The acridanone derivatives of formula I and their pharmaceutically acceptable acid addition salts can be used as medicaments, for exampLe, in the form o~ pharmaceutical preparations. The pharmaceutical preparations can be admini-stered oraLly, for example, in the form o 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 pharma-ceutically acceptable acid addition salts can he processed with pharmaceutically inert inorganic or organic carriers.
Examples of carriers which can be used for tablets, coated tablets, dragées and hard gelatine capsules are lactose, maize starch or derivatives ~hereo~, talc,s~earic acid or its salts and the like. Suita~le carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solld and liquid polyols and the like; depending on the nature of the active substance no carriers are, however, generally required in the case of so~t gelatine capsules.
Suitable carriers for the manu~acture of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose and the like.
In addition, the pharmaceutlcal preparations can contaln preserving agents, solubiLizers, stabilizing agents.
wetting agents, emulsi~ying agents, sweetening agents, colouring agents, f~avouring agents, salts ~ar varying the osmotic pressure, buffers, coating agents or antioxidants.
They can also contain still other therapeutically valuable subs~ances.

As msntioned earlier medicaments containing an acri-danone derivative of formula I or a pharmaceuticallyacceptable 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 - 25 - ~25~85~

or more compounds of ~ormula I or pharmaceutically acceptable acid addition salts thereo~ and, if desired, one or more other therapeutically valuable substances into a galenical S 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 o~ illnesses.
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 appropria~e for the treatment of schistosomiasis, whereby this dosage can aLso be admi.nistered in sub-divided dosages several times during one clay.

~25~354 The following Examples illustxate the present in-vention in more detail, but are not intended to limit its extent. In the Exzmples all temperatures are given in degrees Centigrade.

Example 1 (a) A mixture of 8.5 g of 9-acr1danone, 180 ml of dimethyl-formamide and 3~3 g of sodium hydride is stirred for 0.5 hour, treated portionwise with 10.3 g of 2~ (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 washed with water, dried over sodium sulphate and evaporated, whereupon the residue ls recrystallized firstly from ether and then from ethyl acetate. There is obtained 10-~2-(4--methyl-l-piperazinyljethyl]-9-acridanone of melting point 15~-157.
A solutlon of 2.2 ~ of 10-~2-(4-methyl-1-piperazinyl)-ethyl]-9~acridanone in 100 ml of dichloromethane is treated portionwise a~ -5 with 1.17 ml of oxalyl chloride, stirred at room temperature for a further 0~5 hour and evap~rated.
The residue (9-chloro-10-~2-(4-methyl-1-plperazinyl)ethyl]-acrldinium chLoride) is treated wi.th 100 ml of methanol, 1.346 g o~ 2-hydrazino-2-thiazoline hydrobromide and 1.67 g of sodium acetate, heated ~o ~oiling under re1ux, cooled after 10 minutes and evaporated. The residue is treated with saturated sodium carbonate solution and extracted with methylene chloride. The extract is washed with water, dried over sodium sulphate and concentratedO After the addition of ethyl acetate, the crystallized-out product is filtered off and washed successively wlth ethyl acetate and petroleum ether. There is obtaired 10-~2-(4-methyl-1-pip-erazinyl)ethyl]-9-acridanone (2-thiazolidinylidene)hydra-zone of melting point 204-205.

-- 27 ~ ~5~5~

In an analogous manner there is obtained:

(b) From 9-acridanone and 3-(dimethylamino)propyl chloride the 10-[3-dimethylamino)propyl]-9-acridanone o~ melting point 89 and there.from the 10-[3-(dimethylamino)propyl]-9--acridanone (2-thiazolidinylidene)hydrazone of melting point 191-192;

~c) from 9-acridanone and 2 (diethylamino)ethyl chloride hydrochloride the 10-[2-(diethylamino)ethyl]~9-acridanone of melting paint 109-111 and ~herefrom the 10-[2-(diethyl-amino)ethyl]-3-acridanone (2-thiazolidinylidene)hydrazone of melting point 153-155;

(d) ~rom 9-acridanone and 2-(1-pyrrolidinyl)ethyl chloride hydrochloride the10-[2-(l-pyrrolidinyl)ethyl]-9-acridanone of melting point 143-145 and therefrom the 10-[2-(l-pyrroli-dinyl)ethyl] 9-acridanone (2-thiazolidinylidene)hydrazone Of m~l.tin~ 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.lO-~2-(l-piperidinyl)-ethyl]-9-acridanone (2-thiazolidinylidene)hydxazone o melting point 207;

(f) from 9-acridanone and 2-(4-morpholinyl)ethyl chloride hydrochloride the lO-~2-(4-morpholinyl)ethyl]-9-acridanone of melting point 196 and there~rom the 10-~2-(4~moxpholinyl)-ethyl]-9-acridanone (2-thiazolidinylidene)hydrazone of melting poin~ 236~

: Ex~ le 2 (a) A mix~ure o~ 4.5 g of 9-acridanone, 1.1 g o~ sodium hydride and lO0 ml o~ dim2thyl~0rmamide is stirred ~or O.S
hour, then treated wlth 5.2 g o~ 2-(4-ace~yl-1-piperazinyl)-ethyl chloride hydroch:loride, stirred at 70 ~or 15 houxs - 28 _ ~25~4 and evaporated. The residue is treated with water and ex-tracted with methylene chloride. The extract is washed with water, dried over sodium sulphate and evaporated. By crystal-lization from ethanol there is o~tained 10-~2-~-acetyl-1~
-piperazinyl)ethyl] 9-acridanone of melting point 241-243.

A suspension o~ 3.5 g (10 mmol) of 10-[2-(4-acetyl-1--piperazinyl)ethyl]-9-acridanone in 100 ml of acetonitrile is treated with 1.7 ml (20 mmol) of oxalyl chloride, suction filtered after 0.5 hour and ~he suction filter material (9-chloro-10-[2-(4-acetyl-1-piperazinyl)ethyl~acridinium chloride) is washed successively with acetonitrile and ether. A mixture of the substance obtained is heated to boiling under reflux with 2 g (10 mmol) of Z-hydrazino-2--thiazoline hydrobromide, 2.5 g (30 mmol) of sodium acetate and 100 ml of methanol and evaporated a~ter 15 minutes. The re~idue is treated with water, made alkaline with sodium car~onate solution and extracted with methylene chloride.
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 7 ( 4--acetyl-l-piperazinyl)ethyl]-9-acridanone (2-thiazolidinyl-idene)hydrazone of melting polnt 256.
In an analogous manner there is obtained:

(b) From 9-acridanone and 2-(4-ethoxycarbonyl-1-pipera-zinyl)ethyl chloride hydrochloride the 10-~2-(4-ethoxy-carbo~yl-l-piperazinyl)ethyl]-9-acridanone of melting point 147 and therefrom the 10-~2-~4-ethoxycarbonyl-1-pip-erazinyl)ethyll-9-acridanone (~-thiazolidinylidene)hydrazone of melting point 231 (decomposition)i 3s (c) from g-acrldanone and 2-(4-pivaloyl-1-piperazinyl)-ethyl chloride hydrochloride the 10-~2-(4-pivaloyl-1-pip-~xazinyl)ethyl]-9-acridanone of melting point 18~ and there-~rom the 10-~2~ pivaloyl-1-piperazinyl)ethyl]-9-acridanone - 29 _ ~5~8S4 (2-thiazolidinylidene)hydrazone of melting point 208~

(d) from 9-acrida~one and 2- E4~ (methylsulphonyl)-l-pip erazinyl]ethyl chloride hydrochloride the 10-[2-~4-(methyl-sulphonyl)-l~piperazinyl]ethyl]-9--acridanone of melting point 244-246 and ~herefrom the 10-~2-[4-(methylsulphonyl)-1--piperazinyl]ethyl]-9-acridanone (2-thiazolidinylidene)-hydrazone of melting point 223-235 (decomposition).

(a) A mixture of 3.9 ~ of acridanone,-l.0 g o s~dium hydride and 80 ml of dimethylformamide is stixred for 0.5 hours, then treated with 2~9 g of 1-chloro-2-dimethylamino-ethane hydrochloride, stirred at 60 for 18 hours and e~ap-orated. The residue is extracted with methylene chloride.
The extract is washed with water, dried over sodium sulphate and evaporated. By crystallization fxom isopropyl ether there is obtained 10-[2-(dimethylamino)ethyl]-9-acridanone of melting point 145-146.

A solution o 3 g of 10-~2-(dimethylamino)ethyl~-9--acridanone in 100 ml of dichloromethane and 1.93 ml o~
oxalyl chloride is stirred for 0.5 hour. Ater evaporation, the residue is stirred with 2.25 ~ of 2-hydrazino-2 ~hia-zoline hydrobromide and 3 g o sodium acetate in 100 ml of methanol, whereupon the mlxture is hea~ed ~o boiling under reflux for 10 mlnut~s and evaporated. The residue is treated with water, made alkaline with sodium carbonate solution and extracted wlth methylene chloride. The extract is washed with water, dried over ~odium 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.

~L~S885a~

In an analogous manner there is obtained:

(b) From 9-acridanone and 2-(dimethylamino)propyl chloride hydrochloride the 10-[2-dimethylamlno)propyl]-9-acridanone of melting point 114 and therefrom the 10~ (dimethyl-amino)propyl]-9-acridanone (2-thiazolidinylidene)hydrazone of melting point 152;

(c) from 9-acridanone and 2-(2,6-dlmethyl-1-piperidinyl)-ethyl chloride hydrochloride the 10-[2-(2,6-dimethyl-1--piperidinyl)ethyl~-9-acridanone of melting point 146 and therefrom the 10-[2~(2,6-dimethyl-1-piperidinyl)ethyl]-9--acridanone (2-thia~olidinylidene)hydrazone of melting point 161;

(d) from 9-acridanone and (1-methyl-4-imidazolyl)methyl chloride hydrochloride the 10 ~(1 methyl-4-imidazolyl)-methyl]-9-acridanone of melting point 205-207 and there-from ~he 10-[(1-methyl-4-imidazolyl)methylJ-9-acridanone (2-thiazolidinylidene)hydrazone of melting point 205-208;

(e) from 9-acridanone and 2-[4-[2-(dimethylamino)acetyl]--l-piperazi~yl]ethyl chloride hydrochloride the 10-~2-[4-[2--(dlmethylamino)acetyl]-l-pipera~inyl~ethyl]-9-acridanone of melting point 146-147 and therefrom the 10-~2-~4-[2--(di~e~hylamino)acetyl]-L-piperazinyl]ethy~-9-acridanone (2-thia2011dinylidene)hydrazone of me~ting point 129-131;

(f) from l-chloro-9-acridanone and 2-(diethylamino)ethyl chloride hydrochloride the 10-[2-(diethylamino)ethyl] 1--chloro-9-acridanon~ of melting point 121 and therefrom ~he 10-[2-(diethylamino)ethyl]-1-chloro-9-acridanone (2-thia-zolidinylidene)hydrazone of melting point 181-183;
(g) from 9-acridanone and 2-(4-propyl-1-piperazinyl)ethyl chloride dihydrochloride the 10-[2-(4-propyl-1-pipQrazinyl)-ethyl]-9-acridanone and therefrom the 10 ~2-~4-propyl-1--pip~razlnyl)ethyl]-g-acridanone (2-thiazolidinylidene)-. ~ . .

- 31 - ~5885~

hydrazone of melting point 205 207 (decomposition).

Example 4 s A solution o~ 4.94 g (16.8 mmol) of 10-[2-(diethyl-amino)ethyl]-9-acridanone in 300 ml of dichloromethane is ~tirred for 1 hour with 2.85 ml (33.6 mmol) of oxalyl chlor-ide. The resulting salt (9-chloro-10-[2~(diethylamino)-ethyl]acridinium chloride) is filtered off and treated with100 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 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-ing poin~ 123-125.

(a) A solution of 11.5 g of 10-~2-tdiethylamino)ethyl~-9--acrldanone 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 ye~low crystals ~9--chloro-10-~2-(diethylamino)ethyl]acridinium chloride) which have ~ormed are filtered off and washed successively with ~ethylene chloride and petroleum ether. The material ob-tained is taken up in 200 ml of methanol, treated with 31~
g of thiosemicarbazide and stirred at room temperature for about 18 hours. The precipitated salt is filtered off and washed successively with ethanol and ether. There is ob-tained 10-[2-(diethylamino)ethyl]-9-acridanone thiosemi-carbazone dihydrochloride (crystallizing with 1 mol of meth-anol) o~ meltlng poln~ 124 (decomposition). This material - 32 1~S~85~

is treated with 1~ sodium hydroxide solution and extracted with dichloromethane. The solution is washed with water, dried and evaporated, whereupon the product is crystallized from acetonitrile. There is obtained 10-[2-tdie~hylamino~-ethyl]-9-acridanone thiosemicarba:zone of melting point 154--156.

A solution of 6.1 g of 10-[2~(diethylamlno)ethyl]-9-10 -acridanone thiosemicarbazone in 100 ml of dim~thylformamide is stirred for about 18 hours with 4.3 ml o~ chloroacetalde-hyde (S0 percent solution in water). The mixture is sub-sequently 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 offO The crystals are washed successively with ethanol, ether and petroleum ether and there is obtained 10-[2-(diethylamin~)ethyl]-9--acridanone (2-thiazolyl)hydrazone dihydrochloride of melt-ing point 214-216 (decomposition).
In an analogous manner there is obtained:

(b) From 10-[2-(1-piperidinyl)ethyl]-9-acridanone and thiosemicarbazide the 10 [2~ piperidinyl)ethyl]-9~acrida-25 none thiosemicarbazone of melting point 187 (decompositio~)and therefrom the 10-[2-(1-piper.iclinyl)ethyl]-9-acridanone (2-thiazolyl)hydrazone 1.5 ~Cl of melting point 190 (decomposition);

30 (c) ~rom 10-[2-~4-morpholi~yl)ethyl]-9-acridanone and thiosemicarbazide the 10-~2-(4-morpholinyl)ethyl]-9-acr.ida-none thiosemicarbazone o~ melting point 240 (decomposition) and therefrom the 10-[2-(4-morpholinyl)ethyl]-9-acridanone (2-thaizolyl)hydrazone dihydrochloride o~ melting point 3S 225 (decomposition);

1~5885~

(d) from 10-[2-(4-acetyl-1-pipexazinyl)ethyl~-9-acridanone and thiosemicarbazide the 10-[2-(4-acetyl-1-piperazinyl)-ethyl]-9-acridanone thiosemicarbazone of melting point 225 ~ (decomposition) and there~rom the 10-~2-(4-acetyl l-pipera-2inyl)ethyl]-9-acridanone (2-thiazolyl)hydrazone dihydro-chloride o melting point 180 (decomposition);

(e) from 10-[2-(4-pivaloyl-1-piperazinyl)ethyl]-9-acrlda-none and thiosemicarbazide the 10-[2-(4-pivaloyl l-pipera-zinyl)ethyl]-9-acridanone thiosemicarbazone of melting point 179 (decomposition) and therefrom the 10-~2-(4 pivaloyl-l--piperazinyl)ethyl]-9-acridanone (2-thiazolyl)hydrazone di-hydrochloride of melting point 210 (decomposition);
(f) from 10-[3-(d~methylamino)propyl~-9-acridanone and thiosemicar~azide the 10-~3-(dimathylamino)propyl] 9-acrida-none thiosemicarbazone of melting point 202-204 and there-from the 10~3-(dimethylamino)propyl]-9-acridanone (2-thia-zolyl)hydrazone dihydrochloride of meltint poin~ 1~5(deco~position)~

~.

(a) A mixture of 3 g (9.33 mmol) of 10-~2-(4-methyl-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--10-~2-(4-methyl-1-piperazinyl)ethyl]acridinium chloride) is precipitated by the additlon of 100 ml of ethyl acetate.
The salt is filtered of~, 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-thiozolyl-hydrazine hydrochloride, 2.3 g (28 mmol) of ~odium acetate and 100 ml of me~hanol and then evaporated.
The residue is treated with 50 ml of water, made alkaline with sodium carbonate solution and extracted with dichloro-methane. The extract is washed with 10 percent sodium chlo-ride solution9 dried and evaporated. The residue is taken "~ i ~L~S~

up in 100 ml of methanol, acidified with ethanolic hydro-chloric acid, the precipitated product is filterPd off and washed successively with a small amount of cold ethanol and petroleum ether. There is obtained 10-[2-(4-methyl-1--pipera2inyl)ethyl]-9-acridanone (2-thiazolvl)hydrazone. 2.5 HCl of mel~ing point 230 (decomposition).

In an analogous manner there is obtained:
(b) From 10-~2-(dimethylamino)e~hyl]-9-acridanone and 2--thiazolyl-hydrazine hydrochloride the 10-~2-(dimethylamlno)-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--[2-(4-ethoxycarbonyl-1-piperazinyl)ethyl]-9-acridanone (2-thiazolyl)hydrazone dihydrochloride of melting point 185 (decomposition);

(d) from 10-~2-[4-(methylsulphonyl)-1-piperazinyl]ethyl]---9-acridanone and 2-thiazolyl-hydrazine hydrochloride ~he 10-[2- [4~(methylsulphonyl)-1-piperazinyl]ethyll-9-acrida-none (2-thiazolyl)hydrazone dihydrochlor1de of melting potnt 200;

(e) fram 10-[2-(4-propyl-1-piperazinyl)ethyl]-9-acridanone and ~-thiazolyl-hydrazine hydrochloride the 10-~2-(4-propyl--l-piperazinyl)ethyl]-9-acridanone (2-thiazolyl)hydrazone.
2.5 ~Cl of melting point 220 (decomposition).

Example 7 (a) A mixture of 9.75 g (50 mmol) o 9-acridanone, 200 ml of dimethyl~ormamide and 4.8 g (200 mmol) of sodium hydride $s Rtirred ~or 0.5 hour, treated portionwise wlth 17.8 g (50 mmol) o~ 2-(dicthylamino)ethyl]-1-piperazinyl]-e~hyl chloride trihydrochloride, stirred at 70 for 18 hours, ~5~35'~

then heateid to boiling under reXlux ~or 8 hours and evap-orated. The residue is treat~d with lO0 ml~of water and extracted with dichloromethan~i~ The extract is washed wl~h wat~r, dried and evaporated. The product is crystallized twice from petroleum ether and there is obtained 10-~2-~4--[2-(diethylamino)ethyl]-l-piperazinyl]ethyl]-~acrida-none of melting point 106-108.

'O A suspension of 4.06 g (lO mmol) of this substance ln 100 ml o~ dry acetonitrile is treated portionwise while stirri~g with 1.7 ml (20 mmol) of oxalyl chloride and evap-orated a~ter O.5.hour. The residue is treated.with aceto-nitrile and filtered of under suction. ~he mate~i 1 ob-tained is washed successively with ether and petroleum ether and then dried. The brown powder (9-chloro-10-~2-~4O[2 di-ethylamino)ethyl]-l-pipexazinyl]ethyl]acridinium chloride) is taken up ln 100 ml of methanol, treated with 1.52 g (lO
mmol) of 2-thiazolyl-hydrazine hydrochloride and 2.46 g (30 mmol) of sodium acetate and heated to boili~g under re1ux for 10 minutes. After evaporation~ the residue ls treated with 100 ml o~ water, made alkaline to phenolphtbalein with 2N sodium hydroxide solution t the precipitated product is taken up in lO0 ml of dichloromethane, the solution is washed neutral with water, dried and evaporated. The residue i5 dis~olved in 100 ml o~ metbanol and acidiied with etber-eal hydrochloric acid. The pxecipitated salt is fiLtered of~ and washed successlvely with methanol, ether and petrol-eum ether. There i5 obtained 10-~2-~4-~2-(disthylamino)-ethyl]-l-piperazinyl]ethyl]-g-acridanone (2-thiazolyl)hydra-zone.3.5 HCl of melting p~in~ 235 (decomposition).

In an analogous manner there is obtained:

(b) From 10-~2-~4-~2-(diethylamino)ethyl~ pi~erazinyl]-ethyl]-9-acridanone and 2-hydrazino-2-thiazoline hydrobromide the 10-~2-~4-~2-(diethylamino)Qthyl~-l piperazinyl]ethyl]-~:~ 3 .~
, ,i;!

- 36 ~ ~58~54 -9 acridanone (2-lhia201idinylidene)hydrazone of melting point 144-146 (decomposition).

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 minutes, the crystals (9-chloro-10-[2-(diethylamino)ethyl]-~acridinium chloride) obtained are filtered off and washed with ether. This material is taken up in 100 ml o~ 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, heated to bolling under reflux for 15 minutes and evaporated~
The resldue is made alkaline with sodium carbonate solution, extracted wi ~ dichloromethane, the extract is washed with water, dried and evaporated. By crystallization of the residue ~rom isopropyl ether there is obtained l~-[2-(diethyl-amino)ethyl]-9-acridanone methyl(2 thiazolyl)hydrazone of melting point 103-104.

In an analogous manner there is obtained:

(b) ~rom 10-~2-(diethylamino)ethyl]-9-acridanone and N--methyl-N-(2-thiazolin-2-yl)hydrazone the 10-~2-~diethyl-amino)ethyl]-9-acridar.one mathyl(2-thiazolin-2-yl)hydrazone of melting point 109-110.

Example 9 A suspension of 58A6 g (0.3 mol) of 9-acridanone in 200 ml o~ dimethylformam~de, heated ~o boiling under reflux, is treated portionwise with a total o~ 60 g (0.33 mol) of benzyl ethylenecarbamate. A~ter 53 hours, the mixture i5 left to cool, the crystalline product is ~iltered off and washed successively with dimethylformamide, acetone and ether.

, . ,.. , . ~

~L~51;3~5~L

The mother liquor is treated with water, whereupon the precipitated product is filtered o~f and washed as above.
The combined matexial is crystallized from ethanol and there is obtained benzyl [2-(9-oxo-10(9H)-acridinyl)e~hyl]carbamate of melting point 224 226~.

9.31 g (25 mmol) o~ this substance are suspended in lO0 ml of dichloromethane. The suspension is treated with

4.5 ml (50 mmol) of oxalyl chloride, stixred for 1 hour and the solution is evaporated. The residue is taken up in 400 ml of acetonitrile, treated with 5055 g (28 mmol) of 2--hydrazino-2-thiazoline hydrobromide and heated to boiling under reflux for 24 hours~ The stiLl warm mixture is fil-tered, the material obtained is washed successively withacetonitrile 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 chroma-tography on silica gel while eluting with dichloromethane and it is converted into the hydrochloride with ethanolic hydro-chlorlc acid~ By the addition of ether to the solution ob-tained there is obtained crystalline benzyl ~2-~9-(2-thia-zolidinylidenehydrazono)-10-acridanyl]ethyl~carbamate di-hydrochloride of melting point 167.7-170.8 (decomposition)~
A suspension of 3.5 g (6.4 mmol) of the above sub-stance in 300 ml of glacial acetic acid is stirred ~or 3 days with 10 ml o hydrogen bromide-containing glacial acetic acid (about 30 percent), whereupon the product is ~iltered o~f and washed with glacial acetic acid and ether~ It is subsequently taken up in water, the base is liberated with odium carbonate and taken up in methylene chloride. The methylene chloride solution is dried over sodium sul~hate and evaporated. The residue is dissolved in ethanolic hy-drogen chloride and the salt is crystalli2ed by the additiono ether. There is obtained lO-(2-aminoethyl)-9-acridanone ~2-thiazolidinylidene)hydraæone dihydrochloride o~ meltin~
polnt 226-231.

, .

~s~

2.25 g (6 mmol) of benzyl [2-(9-oxo-10(9H)-acridinyl)-ethyl]carbamate are suspended in 20 ml of methylene chloride and treated with l.OS ml (12 mmol) of oxalyl chloride. After 1 hour, the solution is evaporated, whereupon the residue is taken up in 200 mi of acetonitrile, treated with 1~09 ~ (7.2 mmol) of 2-thiazolyl hydrazine hydrochloride and heated to boiling under reflux for 1.5 hours. The mlxture is left to cool, the crystals are ~iltered 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).
A suspension of 7.6 g (lS mmol) of this substance in 450 ml o glacial acetic acid is tréated with 20 ml o~
hydrogen bromide-contain~ng glacial acetic acid (about 30 percent) and stirred ~or 2 days. The product is filtered off under suction and washed with glacial acetic acid and ether.
The salt mixture is converted into the hydrochlor~de 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--aminoethyl)-9-acridanone 2-thiazolylhydrazone dihydrochlo-ride of melting point 204 214 (decomposition).

Example 11 A suspension o~ 11.2 g (30 mmol) of benzyl ~2-(9-oxo--lO(9~I)-acridinyl)ethyl]car~amate ~n 100 ml of glacial acetic acid is treated with 20 ml of hydrogen bromlde-con-taining glacial acetic acid (about 30 percent) and stirred for 1 hour. The product is filtered off a~d washed with 3S glacial acetic acid and ether: There is obtained 10-(2-aminoethyl)-9-acrldanone hydrobromide of melting point >250, The free base is precipitated from an aqueous solution with - 39 - ~S885~

sodium bicarbonate solution, filtered of~ and washed with water and acetone. The hydrochlorlde obtained thererom 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) o methanesulphochloride. While warming there is obtained a clear solution, to which 700 ml ofwater are added af~er 3 hours~ Crystals form gradually.
The mixture is concentrated to 300 ml, 500 ml of water are added thereto and the mixture obtained i5 concentrated iR vacuo to 300 ml. The product is ~iltered off, washed wi~h water and recrystallized from ethanol. The~e is-obtained ~-[2-(9-oxo-10-acridanyl)ethyl]methanesulphonamide of melting point 226-227.

9S0 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 100 ml of acetonitrile and treated with 713 mg (306 mmol) of 2-hydrazino-2-thiazoline hydrobromide. After 20 minutes under reflux, the product is filtered off, washed with ether and dissolved Ln 150 ml o~ methyle~e chloride/methanol (97:3). The solutlon is made alkaline with ~odium bicar-bonate solution, ex~racted with methylene chloxide~ dried over sodium sulphate and e~aporated. 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 (de-composition).

Example 12 (a~ A suspension of 1.44 g (60 mmol) o~ sodium hydride in 100 ml o~ dlmethylformamide is treated within 10 minutes with 9.7S g (50 mmol) o~ 9-acridanone and held a~ 50 for 2 hours.

~s~s'~

At 120 there are then added 9.5 g (53 mmol) o~ 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 ~rom hexane. There is obtained lO-(4,4-diethoxybutyl~-9-acrida-none of m~lting 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 ~he 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 sul~
phate 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 1~8.3.

2.4 ml (27.9 mmol) o~ oxalyl chloride are added drop-wise at 0 within 3 minutes to a 501ution 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 evapo-rated. The residue (9-chloro-10-~4-(diethylamlno)b~tyl]-acridinium chloride) is taken up in 300 ml o~ acetonitrile, treated with 1.57 g (10.2 mmol) o~ 2-hydrazino-2-thiazoline hydrochloride, heated to boiling under reflux for 0.5 hour, stirred at room temperature ~or 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 thera is obtained ~L~S~3854 ~1 -10-[4-(diethylamino)butyl]-9-acridanone (2-thiazolidinylidene) hydrazone of melting point 105.6-107.2.

In an analogous manner there is obtained:

(b) From 9-acridanone and 5,5-diethoxypentyl chloride the 10-(5,5-diethoxypent~ 9-acridanone of melting point 82--83, therefrom the 10[5-(diethylamino)pentyl]-9-acrida-none of melting point 59-61.2 and therefrom the 10-[5-(di-ethylamino)pentyl]-9-acridanone (2-thiazolidinylidene)-hydrazone of melting point 128.5-130.1.

Manufacture of tablets of the followi~g composition:

mg~tablet 20 Active substance lC0 Lactose 100 Maize starch 85 Povidone 10 Talc 3 25 Magnesium stearate 2 Tablet wei~ht 300 mg The active substance is mixed with the lactose and the maize starch, moistened with an aqueous solutlon of Povidone and granulated. The granulate is dried at 40 and sieved.
The sieved granulate is mixed w~th the talc and the mag-nesium stearate and the mixture is pressed to tablets.

The following compounds of formula I can be processed as the active substance as described above:

5~385 10-~2-(4-Methyl-l-piperazinyl)e~hyl]~-acridanone (Z--thiazolyl)hydrazone, 10-[2-(4-methyl-1-piperazinyl)ethyl]-9-acridanone (2-S -thiazolidinylidene)hydrazone, 10-[2-(4-acetyl-1-piperazinyl)ethyl]-9-acridanone (2 -thiazolidinylidene)hydrazone, 10-[2-(dimethylamino)ethyl]-9-acridanone (2-thiazoli-dinylidene)hydrazone, 10-~2-(diethylamino)ethyl]-3-acridanone (2-thiazolyl)~
hydrazone, 10-[2~ piperadinyl)ethyl]-9-acridanone (2~thiazolyl)-hydrazone, 10-(2-aminoethyl~-9-acridanone (2 thiazolyl)hydrazone, 10-[2-(dimathylamino)ethyl]-9-acridanone (2-~hiazolyl)-hydrazone, 10-t2-(4-acetyl-1-piperazinyl)ethyl]-9-acrid~none (2 -thiazolyl)hydrazone, 10~[3-(dimethylamino)propyl]-9-acridanone (2-thiazolyl)-hydrazone, 10-[2-(diethylamino)ethyl]-9-acridanone (2-th~azoli-dinylidene)hydrazone, 10-[2-(1-pyrrolidinyl)ethyl]-9-acridanone (2-thiazoli-dinylidene)hydrazone and lOo~3-(dimethylamino)propyl]-9-acridanone ~2-thiazoll-dinylidene)hydrazone.

Claims (28)

CLAIMS:

1. Process for the manufacture of acridanone derivatives of the general formula I

wherein the dotted line signifies an optional bond, R1 signifies hydrogen, halogen or nitro, R2 signifies hydrogen or lower alkyl, one of the substituents R3 and R4 signifies hydrogen or lower alkyl and the other together with R signifies an additional bond, A sig-nifies lower alkylene, R5 signifies a 5--membered, nitrogen-containing, optionally lower alkyl-substituted aromatic hetero-cycle, amino or the group the symbol ? signifies a 5- or 6-membered, optionally lower alkyl substituted saturated heterocycle which can contain as a ring member an oxygen or sulphur atom or the group ?NH or ?N(B)n-A1-R6, B signifies the group -CO-, -COO- or -SO2-, n signifies the number 0 or 1, A1 signifies lower alkylene, R6 signifies hydrogen, amino, lower alkyl-amino or di(lower alkyl) amino and R7 sig-nifies hydrogen or lower alkyl, and pharmaceutically acceptable acid addition salts thereof, which process comprises (a) cyclizing a compound of the general formula II, III, IV, V, VI or VII

wherein one of the substituents R31 and R41 signifies hydrogen or lower alkyl and the other signifies hydrogen, R42 signifies hydrogen or lower alkyl, R51 signifies a group R5 defined above, but which does not contain a primary or secondary basic amino group, X' signifies a leaving group and R1, R2 and R5 have the signifi-cance given earlier in this claim, or (b) reacting a compound of the general formula VIII

wherein A, R1, R42 and R51 have the significance given earlier in this claim, with a compound of the general formula IX

wherein X" signifies a leaving group and the dotted line and R2 have the significance given earlier in this claim, or (c) reacting a compound of the general formula X

wherein Y ? signifies an anion, X sig-nifies a leaving group, A and R1 have the significance given above and R51 has the significance given earlier in this claim, with a compound of the general formula XI

wherein the dotted line, R, R2, R3 and R4 have the significance given earlier in this claim, or (d) cleaving off the N-protecting group in a compound of the general formula XII

wherein R8 signifies a group R5 defined above which contains a primary or secondary basic amino group blocked by an N-protecting group and the dotted line, R, R1, R2, R3 and R4 have the significance given earlier in this claim, and (e) if desired, converting a compound of formula I ob-tained into a pharmaceutically acceptable acid addition salt.

2. A compound of formula I as defined in claim 1 whenever prepared according to a process claimed in claim 1 or by an obvious chemical equivalent thereof.

3. Acridanone derivatives of the general formula I

wherein the dotted line signifies an optional bond, R1 signifies hydrogen, halogen or nitro, R2 signifies hydrogen or lower alkyl, one of the substituents R3 and R4 signifies hydrogen or lower alkyl and the other together with R signifies an additional bond, A sig-nifies lower alkylene, R5 signifies a 5-membered, nitrogen-containing, optionally lower alkyl-substituted aromatic hetero-cycle, amino or the group or ?

the symbol ? signifies a 5- or 6-membered, optionally lower alkyl-substituted saturated heterocycle which can contain as a ring member an oxygen or sulphur atom or the group =NH or =N(B)n-A1-R6, B signifies the group -CO-, -COO- or -SO2-, n signifies the number 0 or 1, A1 signifies lower alkylene, R6 signifies hydrogen, amino, lower alkyl-amino or di(lower alkyl)amino and R7 sig-nifies hydrogen or lower alkyl, and pharmaceutically acceptable acid addition salts thereof.

4. Compounds in accordance with claim 3, wherein the substituent R1 is situated in the 1-position.

5. Compounds in accordance with claim 3, wherein R1 signifies hydrogen.

6. Compounds in accordance with claim 5, wherein R2 signifies hydrogen.

7. Compounds in accordance with claim 6, wherein one of the substituents R3 and R4 signifies hydrogen and the other together with R signifies an additional bond.

8. Compounds in accordance with claim 7, wherein A signifies dimethylene or trimethylene.

9. Compounds in accordance with claim 8, wherein R5 signifies amino, 1-pyrrolidinyl, 1-piperidinyl, 1-morpholinyl, 1-piperazinyl or the group -NR7-A1-R61 or in which A1 signifies lower alkylene, B1 signifies the group -CO-, n signifies the number 0 or 1, R61 signifies hydrogen and R7 signifies hydrogen or lower alkyl.

10. Compounds in accordance with claim 9, wherein R5 signifies amino, dimethylamino, diethylamino, 1-pyrrolidinyl, 1-piperidinyl, 4-methyI-1-piperazinyl or 4-acetyl-1-pipera-zinyl.

11. 10-[2-(4-(Methyl-1-piperazinyl)ethyl]-9-acridanone (2-thiazolyl)hydrazone.

12. 10-[2-(4-Methyl-1-piperazinyl)ethyl]-9-acridanone (2-thiazolidinylidene)hydrazone.

13. 10-[2-(4-Acetyl-1-piperazinyl)ethyl]-9-acridanone (2-thiazolidinylidene)hydrazone.

14. 10-[2-(Dimethylamino)ethyl]-9-acridanone (2-thia-zolidinylidene)hydrazone.

15. 10-[2-(Diethylamino)ethyl]-9-acridanone (2-thia-zolyl)hydrazone.

16. 10-[2-(1-Piperidinyl)ethyl]-9-acridanone (2-thia-zolyl)hydrazone.

17. 10-(2-Aminoethyl)-9-acridanone (2-thiazolyl)hydrazone.

18. 10-[2-(Dimethylamino)ethyl]-9-acridanone (2-thia-zolyl)hydrazone.

19. 10-[2-(4-Acetyl-1-piperazinyl)ethyl]-9-acridanone (2-thiazolyl)hydrazone.

20. 10-[3-(Dimethylamino)propyl]-9-acridanone (2-thia-zolyl)hydrazone.

21. 10-[2-(Diethylamino)ethyl]-9-acridanone (2-thiazoli-dinylidene)hydrazone.

22. 10-[2-(1-Pyrrolidinyl)ethyl]-9-acridanone (2-thiazoli-dinylidene)hydrazone.

23. 10-[3-(Dimethylamino)propyl]-9-acridanone (2-thiazoli-dinylidene)hydrazone.

24. A compound selected from:

10-[2-(4-Propyl-1-piperazinyl)ethyl]-9-acridanone (2-thiazolidinylidene)hydrazone, 10-[2-(dimethylamino)propyl]-9-acridanone (2-thia-zolidinylidene)hydrazone, 10-[2-(1-piperidinyl)ethyl]-9-acridanone (2-thiazoli-dinylidene)hydrazone, 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)athyl]-9-acri-danone (2-thiazolidinylidene)hyarazone, 10-[2-(4-pivaloyl-1-piperazinyl)ethyl]-9-acridanone (2-thiazolidinylidene)hydrazone, 10-[2-[4-(methylsulphonyl)-1-piperazinyl]ethyl]-9--acridanone (2-thiazolidinylidene)hydrazone, 10-[(1-methyl-4-imidazolyl)methyl]-9-acridanone (2--thiazolidinylidene)hydrazone, 10-[2-[4-[2-(dimethylamino)acetyl]-1-piperazinyl]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-thia-zolin-2-yl)hydrazone and 10-[2-(diethylamino)ethyl-9-acridanone (3-methyl-2--thiazolidinylidene)hydrazone.

25. A compound selected from:

10-[2-(Diethylamino)ethyl]-9-acridanone methyl-(2--thiazolyl)hydrazone, 10-[2-(4-morpholinyl)ethyl]-9-acridanone (2-thiazolyl)-hydrazone, 10-[2-(4-ethoxycarbonyl-1-piperazinyl)ethyl-9-acrida-none (2-thiazolyl)hydrazone, 10-[2-(4-pivaloyl-1-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-1-piperazinyl)ethyl]-9-acridanone (2--thiazolyl)hydrazone.

26. Process for the preparation of pharmaceutical com-positions containing as active component a compound of formula I in claim 1, characterized in that the active compound is mixed with a pharmaceutically compatible carrier material.

27. A medicament containing a compound of formula 1 as defined in claim 1, together with a pharmaceutically acceptable carrier or excipient.

28. A schistosomicidal medicament composition comprising an effective amount of a compound of formula 1 as defined in claim 1, together with a pharmaceutically acceptable carrier or excipient.