DE571449C - Process for the preparation of acridine droplets - Google Patents

Description

Process for the preparation of acridine derivatives The patent 553 072 protects processes for the preparation of 2-alkoxy-6-halogen-9-aminoacridines which have a basic substituted at their amino group. These compounds are characterized by a particularly beneficial effect against blood parasites.

In further processing of this area it was found that one to compounds of the same therapeutic effect if one takes in place of the 2-alkoxy-6-halogen-9-aminoacridines which are basically substituted on their amino group other 9-aminoacridines which are basically substituted at their amino group and which are in the 6-position contain a halogen atom or an alkyl group and those in the 2-position by a Halogen atom, an alkyl or alkoxy group may be substituted.

The new substitution products with a basic residue on the amino group des 9-aminoacridine can be obtained by the same methods as those described in patent 553 o72 are specified. So you can, for example, bases or their salts, which at least Contain 2 basic nitrogen atoms, one of which can be primary or secondary must react with such acridin substitution products that are in the 9-position carry an exchangeable substituent, a halogen atom or in the 6-position contain an alkyl group and those in the 2-position by a halogen atom, a Alky l or an alkoxy group can be substituted. Interchangeable substituents in the 9-position are, for example, ether- and ester-like groups, such as. B. halogen, Aryloxy, alkoxy, mercapto and substituted mercapto groups.

Such bases can also be used to insert the basic radical vertuenden, in which z. B. one of the amino groups by an easily cleavable one Remainder, e.g. B. an acyl radical, is closed, whereby the acidic radical is subsequently splits off in a known manner. To introduce the basic substituted amine in the 9-position can also be done in such a way that the basic radical is divided into several Work stages builds up, for example so, d-ate z. B. an amino alcohol or an amino-substituted halogen compound to an acridine substitution product of marked type and that the resulting in this way, at. acridine compounds carrying a halogenated or hydroxylated radical of the 9-amino group - If necessary after esterification of the hydroxyl group, z. B. by means of a hydrohalic acid - With primary or secondary amines to the corresponding, on the amino group a basic radical carrying substitution products of 9-aminoacridine.

Instead of acridines, the 9-position has an exchangeable substituent and contain a halogen atom or an alkyl group in the 6-position and those in the 2-position can be substituted by a halogen atom, an alkyl or alkoxy group, you can also use such acridine compounds as starting materials, except the exchangeable substituent in the 6-position is an in a halogen atom or an alkyl group which can be converted by known methods and the - position at the same time instead of halogen, alkyl or alkoxy can carry a substituent which can be converted into these groups or into hydrogen. Such substituents are primarily halogen atoms, hydroxyl, nitro and amino groups.

In those obtained after introduction of the basic radical in the 9-position Compounds are those optionally in -, - position, in hydrogen, Alky 1, halogen or alkoxy groups convertible and optionally in the 6-position standing, convertible into halogen or alkyl substituents according to the customary therefor Methods converted into a substituent of the type mentioned in each case.

Finally, one can also proceed in such a way that one for the acridine synthesis usable intermediates by the customary methods for building up the their amino group is basically substituted 9-aminoacridines, which are in the 6-position Contain halogen atom or an alkyl group and the -, - position by a halogen atom, an alkyl or alkoxy group may be substituted. To this end are z. B. the basic substituted diphenylamine-6-carboxylic acids on the acid amide group, those in the 3-position are a halogen atom or an alkyl group or one of these groups Contain convertible substituents and the q.`-position a halogen atom, a Alkvl- or alkoxy group or one which can be converted into these groups or into hydrogen Can carry substituents, shown according to the usual methods and the Subjected to ring closure to the acridine derivative in a manner known per se, whereby one if necessary, the in -, - position of the acridine formed substituents converts into hydrogen, halogen, alkyl or alkoxy groups and those in the 6-position standing substituents converted into halogen or alkyl.

The basic radical substituting the amino group can be one or more Contain nitrogen atoms and are replaced by other substituents, e.g. B. Hydroxyl groups, be substituted, it can contain ether- or thioether-like bonds and itself composed of aliphatic, isocyclic and heterocyclic components. Example 24.8 g of 6,9-dichloroacridine are mixed with 125 g of phenol in a boiling water bath melted together and to melt 1; g a-diethy lamino-d-aminopentane was added dropwise. After two hours of heating at 90 to 100 °, the reaction mixture is poured into 100 cc Entered 2-n-NaOH and the precipitated base was taken up in ether. By undressing the ethereal solution with 100% acetic acid and decomposition of the acetic acid solution the base is purified with potassium carbonate and ether and finally by steam distillation freed from the last remnants of the excess aliphatic diamine. One falls from the well-dried ethereal solution with ethereal hydrochloric acid the dihydrochloride of the 6-chloro-9- (a-diethylamino-c5-pentylamino) acridine obtained, this by recrystallization from a little alcohol in yellow crystals from the point of decomposition 234 to 236 ° is obtained.

In the same way, a-diethylamino, i-aminobutane (KP, 75 °) the dihydrochloride of 6-chloro-g- (a-diethylamino-ybutylamino) acridine from Decomposition point about 2q.0 °.

The previously unknown 6, 9-dichloroacridine (pale yellow crystals from benzene with a temperature of 167 to 168 °) is converted from 3-chloro-diphenylamine-6-carboxylic acid (from Alcohol prisms from F. 2ao to 2oi °) by closing and chlorination of the resulting Get acridons.

In an analogous manner, one obtains from: a) 2-methyl-6,9-dichloroacridine the 2-methyl - 6 - chloro - 9 - (a- diethylamino - ö - pentylamino) acridine, its Egg-yellow dihydrochloride from alcohol -f- ether crystallizes the decomposition point 245 to aq. 6 °.

To prepare the 2-methyl-6, 9-dichloroacrid, ins is 2, 4, dichlorobenzoic acid with q.-toluidine to q .'-methyl-3-chloro-diphenylamine-6-carboxylic acid (from alcohol F. 232 to 233 °) condensed, closed to form a ring and chlorinated. The 2-methyl-6,9-dichloroacTidine forms, recrystallized from benzene, pale yellow needles from F. 146 to 1q.7 °. b) 2,6-dichloro-g- (a-diethylamino-d-pentylamino) acridine is obtained from 2, 6, 9-tichloroacridine. Recrystallization from methyl alcohol and ether turns a yellow light into water and obtained Congo-neutral soluble hydrochloride.

2,4-Dichlorobenzoic acid is used to prepare 2,6-g-Trdchlo @ racridine with d.-chloroaniline to 3, 4 .'-dichloro-diphenyiamine-6-carboxylic acid (from alcohol decomposition point 236 to 237 °) condensed, closed to form a ring and chlorinated. The 2,6,9-trichloroacridine forms, recrystallized from benzene, pale yellow crystals with a temperature of 2o2 to 2o3 °.

c) From a-methoxy-6-methyl-g-chlora @ cridine, 2-methoxy-6-methyl-g (a-diiithylatnino-8-pentylamino) acridine is obtained, Its yellow dihydrochloride from methyl alcohol ether recrystallizes the decomposition point Shows 24.2 °.

4-Methyl-2-chlorobenzoic acid is used to prepare 2-methoxy-6-methyl-9-cliloracridine with α-anisidine to form 4'-methoxy-3-methvldiphenylatin-6-carboxylic acid (from benzene F. i82 °) condensed, closed to form a ring and chlorinated. The 2-methoxy-6-methyl-chloroacridine forms, recrystallized from gasoline, pale yellow needles from 159 to 160 °.

(1 ) 6-Methyl-9- (a-dietliylamino-a-pentylamino) -acridine is obtained from 6-methyl-g-chloracriidine, the yellow dihydrochloride of which, recrystallized from methyl alcohol + ether, has a decomposition point of 220 to 222 °.

4-Methyl-2-chlorobenzoic acid is used to prepare 6-methyl-g-chloracr: idin condensed with aniline to form 3-methyl-diphenylamine-6-carboxylic acid (from benzene, temperature 176 °), closed to a ring and chlorinated. The 6-1VIethvl-g-chloroacridine forms, from ether recrystallized, almost colorless little crystals from F. i2o to i21 °.

e) 2,6-Dimethyl-9- (a-diethylamina-dpentylamino) -acridine is obtained from 2,6-dimethyl-g-chloroacridine, its yellow dihydrochloride from methyl alcohol -f- ether recrystallizes the decomposition point Zig to 22I ° has.

4-Methyl-2-chlorobenzoic acid is used to prepare 2, 6 = dimethyl-9-chloroacridine with 4-toluidine to give 3, 4'-dimethyl-diphenylamine-6-carboxylic acid (from benzene, mp 178 °) condensed, closed to form a ring and chlorinated. The 2, 6-D@imethyl-g-chloracrid.in forms, recrystallized from gasoline, pale yellow needles of 120 ° F.

f) 6-methyl-2, g-dichloroacridine gives 6-methyl-2-chloro-g- (a-diethylaminob-pentylamino) -acridine, the yellow dihydrochloride of which, recrystallized from methyl alcohol + ether, has a decomposition point of 218 ° to 220 ° . For the preparation of 6-methyl-2; 9-dichloroecridine is q.-methyl-2-chlorobenzoic acid with.-Chloroaniline to give 4: '- chloro-3-methyldiphenylamine-6-carboxylic acid (from benzene F. 203') condensed, ring-closed and chlorinated. The 6-methyl-2, 9-dichloroacridiri crystallizes from chlorobenzene in greenish yellow crystals and gradually decomposes over 200 ° with a dark color.

g) From 2-ethyl-6, 9-dichloroacridine, 2-ethyl-6rchlo: r-9- (a-diethylamino-pentylamino) -acridine is obtained, its yellow dihydrochloride recrystallized from alcohol and ether, the decomposition point i4o ° has.

To prepare 2-ethyl-6, g-dichloroacridine, 2, d.-dichlorobenzoic acid is used with 4-Äthvlanilin to 4 .'-ethyl-3 = chlorodiphenyl-6-carbornic acid (from alcohol F. 18I °) condensed, closed to form a ring and chlorinated. The 2-ethyl-6,9-dichloroacridine crystallized from Benzcl in pale yellow needles of mp 10 °.

Claims (2)

PATENT CLAIM: i. Modification of that protected by patent 5 @ 3 072 Process for the preparation of acridine derivatives, characterized in that - Instead of 2-alkoxy-6-lialogenacrdinen - here a reactive one in the 9-position Substituent of other acridine compounds which are in the 6-Stelliing a halogen atom or contain an alkyl group or a substituent which can be converted into this group and those in the 2-position are a halogen atom, an alkyl or alkoxy group or a can carry substituents which can be converted into these groups or into hydrogen, according to the usual methods for a substituted by a basic radical primary or secondary amino group is exchanged and that approximately in the 6-position standing substituents which can be converted into halogen or an alkyl group into one of these Groups and approximately in the 2-position, in hydrogen, halogen, an alkyl or alkoxy group convertible substituents into one of these groups in per se known Way or that one suitable for the acridine synthesis, accordingly substituted intermediates by the methods customary for this purpose in those at their Amino group converted by a basic radical substituted g-aminoacridine, which contain halogen in the 6-position and halogen or an alkyl group in the 2-position may be substituted or contain an alkyl group in the 6-position and in 2-digit Jung substituted by halogen, an alkyl or alkoxy group could be. 2. Embodiment of the method according to claim i, characterized in that that one has amides of diphenylamine-6-carboxylic acids which are substituted on their acid amide group, those in the 3-position are a halogen atom or an alkyl group or one of these groups contain unsuccessful substituents, and in the .'-position a halogen atom, an alkyl or alkoxy group or one which can be converted into these groups or into hydrogen Can carry substituents, subject to acridine synthesis in a conventional manner and that one stands approximately in the 6-position of the acridine formed, in halogen or an alkyl group convertible substituents in one of these groups and approximately in the 2-position standing substituents which can be converted into hydrogen, halogen, an alkyl or alkoxy group converted into one of these groups according to the usual methods.