DE2240211A1 - FLUORUBSTITUTED 3- (METHYLAMINO) - AND 3- (DIMETHYLAMINO) -TETRAHYDROCARBAZOLES - Google Patents

Description

Dr. F. Zumslein jun.

pg.entanwölt

8 Munich 2, Bräuhauistroß 4 / HI

Case DN-5O21F
12/10 / ka

STERLING DRUG INC., New York, USA

Fluorine-substituted 3- (methylamino) - and 3- (dimethylamino) -tetra-

hydroearbazole.

The present invention relates to fluorine-substituted 3- (methylamino) - and 3- (Dimethylamine) -tetrahydrocarbazole ,,

British Patent 1,225,664 describes 3- (subst _e amino)-1,2,3,4-tetrahydrocarbazoles with psychotropic activity demonstrated by their ability to prevent reserpine-related ptosis in mice associated with antidepressant efficacy.

In the context of the present invention it has now been found that a selected group of 3- (subst. Amino) -1 _? 2 _? 3 _s 4 "tetrahydrocarbazoles, which are not directly mentioned in British patent specification 1,225,664, do not have the ability to prevent reserpine-related ptosis in mice," which

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well-known screening test for antidepressants represents; how however will be explained in more detail below, these compounds have a dopaminergic blocking activity in rats, which indicates their potential use as antipsychotic agents.

The above selected group of compounds according to the present invention are 3- (NRCH ₅ ) -Q _n -I, 2,3,4-tetrahydrocarbazoles having the structural formula

NRCH3

wherein R is hydrogen or a methyl group and Q _{n is} 6-fluorine, 8-fluoro, 6,7-difluoro or 6,8-difluoro.

D-amphetamine in rats produces a syndrome of effects that are referred to as stereotyped behavior: _r licking, gnawing, biting and continuous head movement. This syndrome is linked to the release of dopamine in the central nervous system by amphetamine. Aporaorphine produces a syndrome similar to that produced by amphetamine. The most noticeable features after treatment with apomorphine are chewing and licking. This syndrome includes direct stimulation of dopamine receptors in the central nervous system by apomorphine. Antipsychotic drugs, of which chlorpromazine, [2-chloro-10- (3 ~ dimethylaminopropyl) phenothiazine], is the prototype, prevent both syndromes by blocking dopamine receptors in the central nervous system. Chlorpromazine does not prevent reserpine-induced ptosia in mice. The compounds according to the invention have similar characteristics (or a similar profile) to those mentioned above for chlorpromazine and are effective as antipsychotic agents.

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The following is a description of how to determine the dopaminergic blocking effectiveness of the compounds according to the invention given tests used:

Prevention of being caused by apomorphine or d-amphetamine Rats caused stereotypical behavior

The test preparations and chlorpromazine HCl were each prepared in a 1 fo-strength tragacanth gum (GiD) suspension and administered parenterally (PO). Apomorphine HCl and d-amphetamine sulfate are dissolved in distilled water and injected subcutaneously (SC). The volume administered was 1 ml / kg body weight. All dosages are given in mg / kg of free base. It was not known to the observers what agents the rats received.

Ten male Sprague-Dawley rats were subjected to each treatment process without further selection and treated with the examined agent, chlorpromazine or GT 180 minutes before administration of either 1.7 mg / kg apomorphine or 3 ₉ 7 mg / kg d-amphetamine, . The animals were observed for 1 minute each 20, 25 and 30 minutes after the apomorphine treatment and 90, 100 and 110 minutes after the amphetamine treatment. A rat was considered to be attacked by apomorphine if it showed chewing or licking in all three observation periods and as attacked by amphetamine if it showed licking, gnawing, biting or continuous head movements during any of the three observation periods. The dose (ED ™) was determined for each agent tested that prevented the amphetamine and apomorphine induced stereotypical behavior.

It was found that the compounds according to the invention in the above test for the effectiveness in preventing the stereotypical behavior induced by amphetamine, in a dosage range (ED ₅₀ ) of 1.4 to 8 mg / kg (free base) of body weight and that induced by apomorphine stereotypical behavior in a dose range (ED ™) of 5 to 16 mg / kg (free base) body weight are effective. Chlorpromasin showed up to prevent it

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" ⁴ " 22A0211

of the stereotypes induced by d-araphetamine and apomorphine Behavior in a dose range (ED, -q) of 8.6 mg / kg (free Base) or 22.5 mg / kg (free base). The following table shows the results of the above tests:

ED ₁ T ₀ [mg / kg (base)] to prevent compound (formula I) from stereotypical behavior

Rats

6,8-difluoro II 6,8-difluoro CH ₃ 6-fluoro CH ₃ 6,7-difluoro CH, 8-plus Chlorpromazine

induced by induced by d-amphetamine Apomorphine 1.4 5 4th - 4th 16 4th - 8th 16 8.6 22.5

It can be seen from the table above that the compounds according to the invention prevent the stereotypical behavior of rats induced by amphetamine and apomorphine at doses (ED ^ q) which are lower than the doses required for chlorpromazine. A preferred compound according to the present invention is 3- (dimethylamino) -6,8-difluoro-1,2,3,4-tetrahydrocarbazole, because of the required dosages (ED _ro ) to prevent the doses caused by d -Amphetarain and apomorphine-induced stereotypical behavior in rats.

The compounds according to the invention having the structural formula I v / are prepared by various processes described below, where R and Q _{n have} the meanings given above.

According einom first ancestors V according to the invention are _e rbin-

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Mouths through. Reaction of a Q '^ - phenylhydrazine (il), in which Q' _{n is} 2-Fluor, 4T-I ¹ IuOr, 3,4-difluoro and 2,4-difluoro, with a 4- (NRGH,) - gyelohexanone (III ) prepared in the presence of a suitable acid. The reaction proceeds via the intermediate product 4- (NRCH ₅ ) -cyclohexanone-Q ^f -phenylhydrazone (17), which is cyclized in the presence of excess acid to the end product or which can optionally be isolated if milder reaction conditions are used, ie if an amount is used which is equivalent to the amount of the Q '-phenylhydrazine or is preferably less than this amount and the reaction is carried out at room temperature. Suitable acids that can be used are inorganic acids, for example hydrochloric acid and hydrobromic acid, mineral acids, for example sulfuric acid and phosphoric acid, organic acids, for example acetic acid and methanesulfonic acid and Lewis acids, for example boron trifluoride and zinc chloride. If isolation of the hydrazone intermediate (IY) is not desired, an excess of the appropriate acid is used in the reaction, preferably one mole excess per mole of the Q'-phenylhydrazine. The reaction is expediently carried out by heating the reaction components in acetic acid or in an alcoholic solution of the acid, for example ethanolic hydrochloric acid, preferably at reflux temperature. The time required to complete the reaction depends on the conditions used. A reaction time of about one to about 4 hours has generally been found to be satisfactory. The hydrazines (II) and cyclohexanones (III) used as intermediates are known compounds.

In a second process, the compounds according to the invention are prepared by reacting an amine of the formula IDTRCH ₃ (V) with a 3-YQ _n ~ 1,2,3,4-tetrahydrocarbazole (Vl), in which X represents any suitable replaceable group, v / ie it is known to the person skilled in the art, such as a halide, - preferably chloride, bromide or iodide od et an organic sulfonyl oxy group, daiges te 31t by the I'OrrnoL Ζ-ΠΟ ^, - Ο, where 2 via oL'j- .an Lacher rest iut, v / ie a nie-CIi ¹ Lf ₁ -AL ¹ CyI, cycloalkyl, phenyl or phenyl-lower-alkyl radical ,. wob ·! L 'Phenyl ^ ti ^ ebericmf / iLls subet.Ltiii.ert may be, e.g. by

one or more lower alkyl groups, such as the methyl group, halogen or nitro groups, in each case lower alkyl having 1 to 6 carbon atoms. A particularly preferred I group is the p-toluenesulfonyloxy group. The reaction is advantageously carried out, if appropriate, in a suitable solvent at elevated temperatures, which are preferably in the range from about 60 ^° C. to about 200 ^° C., for about 1 hour to about 24 hours. The pressure of the system can vary over a wide range from normal atmospheric pressure to about 42.2 kg / cm (600 psi). In general, the reaction components are introduced into a pressure reaction vessel and heated under the autogenous pressure. A preferred method according to this second process is 3- (Z-SO ₂ O) -Q _n -I, 2,3,4-tetrahydrocarbazole (YI A) with the amine (V) in a pressure ^{reaction vessel at a temperature of 90 0} C to 150 ⁰ C heated for about 20 hours.

The intermediate product 3- (Z-SOpO) -Q _n -1,2,3,4-tetrahydrocarbazole (VI A) is made from the corresponding 3- (OH) -Q -1,2,3,4-tetrahydrocarbazole (VII) by reaction with a sulfonyl chloride of the formula Z-SOpCl with the use of customary process measures, for example in the presence of an acid acceptor such as pyridine. The intermediate product 3- (OH) -Q _n -I, 2,3,4-tetrahydrocarbazole (VII) is made from the corresponding Bonzoyloxyester with the formula 3- (O-COC ₆ H ₅ JQ _n -I, 2,3,4 -Tetrahydrocarbazole (VIII) obtained by conventional methods such as alkaline hydrolysis. The benzoyloxy ester intermediate (VIII) is obtained by reacting a suitable O ^ -phenylhydrazine (II) with 4-benzoyloxycyclohexanone, a known compound, using the above The intermediate 3-1-Q _n -I, 2,3,4-tetrahydrocarbazole (VI), where Y is a halide, is prepared from the corresponding 3- (OH) -Q -j, 2,3 4-Tetrahydrocarbazole (VII) using conventional methods, for example by replacing the 3-hydroxyl group with halogen using a suitable halogenating agent, for example in the case of the chloride of thionyl chloride.

3 0 ') »OB / 1 348

In a third process, the compounds according to the invention are prepared by reducing a formamide with the formula 3- [N (CHO) R] -0 ^ -1,2,3,4-tetrahydrocarbazole (IX). The reduction is carried out in a suitable solvent, i.e. tetrahydrofuran or diethyl ether, using a suitable reducing agent, for example a hydride reducing agent such as lithium aluminum hydride (LiAlH.), Borane (BEU.) - or lithium tri- (2 methoxyethoxy) aluminum hydride [LiAlH (OGH ₂ CH ₂ OCH _x ) "]. The implementation will

generally at temperatures τοη about 20 C "to about 60 ⁰ C., wherein the reaction time between about one and 20 hours. The reduction is conveniently carried out by treatment of the formamide (IX) in tetrahydrofuran with the appropriate hydride" at reflux temperature for from about 1 carried out up to 4 hours.

The intermediate 3- [M (CHO) R] -Q _n -I, 2,3,4-tetrahydrocarbazole

(IX) is prepared by reacting a Q ' _n -phenylhydrazine (II) with a 4- [N (CHO) R] -cyclohexanone (X) according to the first method described above. The 4- [N (CHO) R] cyclohexanone

(X) is obtained by oxidation of a K- (4-formyloxy-cyclohexyl) -NR-formamide (XI) Prepared in acetone with chromic acid-sulfuric acid in water (Jones reagent). The formamide (Xl) is made by reacting a 4- (HHR) -cyclohexanol (XII) with formic acid in a suitable Solvent such as toluene prepared. The cyclohexanols (XII) are known compounds.

The following reaction scheme illustrates the three synthetic methods.

3098-087 13E

- O -

Procedure (1)

HIiNH ₂

.NRC H-

II

111

Procedure (2)

Formula I.

Procedure (3)

N (CHO) R

IX

Since the erfindunp ^ emäßen Verbindun tric PColilü-nirtoffatom besjtzin, dcrci in the 3-Stcllun ^ tion 1,2,3,4-T'-i.jsie in the form of optical inomercM isoraerc forms (J ^ uintiomei-n)) other like picture xmd i / pjerelbiild \ or). rfindim; -indj d.-O di:> - i. (; rr Inoiumu, di <■■ nachfoDy, it. will be drawn]] now their d, ll-ji rr. '<

3 U 9 Ö 0 ti / *. en of the formula I is an asymmetrical carbon atom liy (iroo «irba: 3ol -] {ini?; c! 3, ]: ömvm before !; iranmn, ie

2 i \ tvi: uQ-

iioilclrtflßstukturen auoin ü um. Hence .f η Hen unto 3.the (rl,;, torjnchcn and the levorotn-

.-Oh the d- and 1-l ^ oror «ul, r- unn η (raceinjuoho Iiii

BATH ORIGINAL

22402

dor compounds of the formula I. The racemic mixture of each specific compound falling under the formula I, then obtained directly by the synthesis methods described above, is burned using conventional separation methods into the d-isomer and 1-isomer, Uo convert the racemic mixture into a mixture of 2 diastereomeric acid addition salts by reacting a suitable optically active acid, for example d-tartaric acid, according to conventional methods mlb. 1-malic acid, 1-mandoleic acid, d-camphor-IO-sulfonic acid, dibenzoyl-1-tartaric acid and the like converted and the 2 diastereomeric salts in the mixture, which no longer behave like image and mirror image • and therefore different physical properties are separated by conventional physical methods such as crystallization. The two separate diastereomeric salts thus obtained can then be converted into the corresponding d-isomer and 1-isomer by customary processes, for example by treatment with bases.

The new 1,2,3,4-tetrahydrocarbazole end products of the present Invention are the compounds of the formula I and their acid addition salts. The compounds of the formula I in the free base form are converted into the acid addition salt by reacting the base with an acid converted. On the other hand, the free bases can be recovered from these acid addition salts in the usual way, i.e. by treating the salts with strong aqueous bases such as alkali metal hydroxides, alkali metal carbonates and alkali metal ! carbonates. The bases regenerated in this way can then be reacted with the same or a different acid in order to obtain the same or a different acid addition salt. So the new bases and all their acid addition salts can easily can be converted into each other.

So it can be seen that the formula I not only the structural Configuration of the bases of the formula I represents, but also repi'üsenlaLiv for the essence of the structure that is common to all compounds common to formula I is whether they are in the form of the free biscuits or in the form of the acid addition salts of the bases.

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BATH ORIGINAL

gen. It has been found that due to this common Structural unit the bases and their acid addition salts have a pharmfikodynamische effectiveness, which here in more detail is described. Serve them sugenic pharmacodynamic activity can be used in a nutritious form for pharmaceutical purposes by the fact that the. · free bases themselves or those with The salts formed in pharmaceutically acceptable acids are consumed, i.e. salts whose anions in the animal organism are in effective dosages of Salije do not harm oo that valuable Properties that are inherent in them because of the structural unit represented by the free bases, not through weaving effects impaired v / earths attributable to the anions.

When utilizing the pharmacodynamic activity of the invention Salts are, of course, preferred pharmaceutically acceptable salts. Although some special types of salt by their Insolubility in water, higher toxicity or the low crystalline Character as such for pharmaceutical use are unsuitable or not very suitable, those in water cannot soluble or toxic salts by decomposition of the salts with aqueous base, as explained above, into the corresponding pharmaceutically acceptable bases or, alternatively, they can be converted into a desired pharmaceutically acceptable one Acid addition salt by double tfimjet tongue reactions that the Anion concern, for example converted by ion exchange operations v / ground.

In addition, the salts, apart from their possible uses Handles for pharmaceutical purposes, as derivatives for characterization or useful for identification of the free base or for isolation and purification processes. As with all acid addition salts such salt derivatives can be used for characterization or for purification, if necessary for the regeneration of the pharmaceutical Compatible free bases can be verv / ends by reaction of the salts with aqueous base or alternatively they can be converted into a pharmaceutically acceptable acid addition salt can be converted by, for example, ion exchange operations.

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From the foregoing it can be seen that all acid addition salts of the new bases according to the present invention are useful and valuable compounds are, regardless of their solubility, Toxicity, physical form, etc, so they fall into the range of the present invention.

The essence of the compounds according to the invention therefore lies in the bases and cationic forms of the new 3- (HI1CH-) - Q 1,2,3,4-tetrahydrocarbazoles and turn to any special ones acidic parts or acidic anions, which occur in the salt form of these compounds. Rather, the acid parts are ■ or anions, which can occur in the form of the salts, themselves neither new nor critical and can therefore be any acid anion or any acidic substance that causes salt to form with Bases is suitable. Indeed, in aqueous solutions, they have both the form of the bass and the form of the water-soluble acid addition salts of the compounds according to the invention a protonated Cation or ammonium ion.

Thus, the acid addition salts discussed above and claimed here are prepared from any organic acid, inorganic acid (including organic acids with an inorganic group) or organometallic acid. Examples of these are organic mono- and polycarboxylic acids, as they are "for example in Beilstein's Organische Chemie, A. are found XXI, XXII and XZV au - edition, volumes III, IV, IX, X, XIV, XVII, XIX; organic mono- and polysulfonic acids and -sulfinic, as described for example in Beüstein B _a nd VI, XI, XVI, and XXII, organic phosphonic acids and phosphinic acids, such as can be found, for example, in Beilstein Volume XI and XVl; organic acids of arsenic and antimony, as can be found, for example, in Beilstein Volume XVI; organic heterocyclic carboxylic, sulfonic and sulfinic acids, such as are never found, for example, in Beilstein · Volumes XVIII, XXIII and XXV; acidic ion exchange resins; and inorganic acids of any acid scavenger element or combinations of elements as described in Mellor, Comprehensive Treatise on Inorganic and Theoretical Chemistry, Longman's

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Green and Co., New York, N.Y. Volumes I-XVI can be found. "Additionally fall under the numerous acids used to prepare the acid addition salts of the compounds of the invention Other salt-forming compounds which have acidic chemical properties, but which generally do not, can be used as acids in the same sense as carboxylic acids or sulfonic acids. This also includes acidic phenolic ones Compounds such as can be found, for example, in Beilstein Volume VI, acidic compounds with "activated" or acidic Hydrogen atoms, for example picrolonic acid or barbituric acid derivatives with an acidic proton, as described, for example, in Cox et al, Medicinal Chemistry, Vol. IV, John Wiley and Sons, Inc., New York, N.Y. (1959) can be found. The salt-forming compounds also include so-called Lewis acids, which lack an electron pair in the outer electron shell and those with basic ones Compounds that have a lone pair of electrons react to form salts, for example boron trifluoride.

Examples of acids for forming the acid addition salts include formic acid, acetic acid, trifluoroacetic acid, isobutyric acid, α-mercaptopropionic acid, malic acid, fumaric acid, oxalic acid, succinic acid, succinamic acid, glutamic acid, tartaric acid, citric acid, Emboxylic acid, lactic acid, glycolic acid, gluconic acid, sugar acid, ascorbic acid, penicillin, benzoic acid, 4-methoxybenzoic acid, Phthalic acid, salicylic acid, acetylsalicyclic acid, anthranilic acid, 1-naphthalenecarboxylic acid, cinnamic acid, cyclohexanecarboxylic acid, Mandelic acid, tropic acid, crotonic acid, acetylenedicarboxylic acid, sorbic acid, pyric acid, cholic acid, pyrene carboxylic acid, 2-pyridine carboxylic acid, 3-indole acetic acid, quinic acid, amidosulfuric acid, Methanesulphonic acid, ethanesulphonic acid, isethionic acid, benzenesulphonic acid, p-toluenesulfonic acid, benzenesulfinic acid, butylarsonic acid, Diethylphosphinic acid, p-aminophenylarsinic acid, phenylantimonic acid (phenylstibnic acid), phenylphosphinous acid, methanephosphonic acid, phenylphosphinic acid, acid resins, hydrofluoric acid, hydrochloric acid off acid, hydrobromic acid, iodine / aqueous acid, perchloric acid, Nitric acid, sulfuric acid, phosphoric acid, hydrogen cyanide acid, phosphotungstic acid, molybdic acid, phosphomolybic

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denic acid, ■ pyrophosphoric acid, arsenic acid,

Picric acid, picrolonic acid, barbituric acid, boron trifluoride and the like. '

The acid addition salts are either by dissolving the free base in an aqueous solution containing the appropriate acid, and isolation of the salt obtained by evaporating the solution or by reacting the free base and the acid in an organic Solvent, whereby the salt precipitates directly or can be obtained by concentrating the solution.

The compounds of the invention having the formula I can be used for therapeutic purposes by dissolving in the form of a salt of the Compounds in water (or an equivalent amount of a non-toxic acid if the free base is used) or in one physiologically acceptable aqueous medium, such as a saline solution and stored in ampoules for intramuscular injection. Alternatively, they can be in unit dosage forms can be incorporated, in the form of tablets or capsules for oral administration, either alone or in combination with suitable adjuvants such as calcium carbonate, starch, lactose, Talc, magnesium stearate, acacia and the like. Furthermore can the compounds for oral administration in aqueous alcohol, Glycol or in oil solutions or in oil-water emulsions in. made in the same way as common medicinal substances be formulated.

The concrete. Determination of the numerical biological values that Valid for a particular compound is easily done through standard testing procedures carried out by technicians who have experience in pharmacological tests without the need for an extensive one Experimentation would be necessary.

The molecular structure of the compounds according to the invention was increased to the basis of their synthesis process, by studying their infrared and nuclear magnetic resonance spectra and was determined by the correspondence between the calculated and found -

Values for the elemental analysis of representative examples confirmed. - *.

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example 1

3- (Dimethylainino) -6,8-difluoro-1,2,3,4-tetrahydrocarbazole

Procedure 1

A mixture of 19.4 g of 4- (dimethylamine) cyclohexanone hydrochloride and 18.1 g of 2,4-difluorophenylhydrazine hydrochloride in 250 ml of absolute ethyl alcohol was refluxed for 4 hours, cooled to room temperature and filtered. The filtrate was evaporated to dryness and the crude hydrochloride salt was dissolved in 500 ml of water, the solution made alkaline and the resulting white plague filtered to give 11.2 g of 3- (dimethylamino) -6,8-difluoro-1,2, 3,4-tetrahydrocarbazole, mp. 180-183 ⁰ C (ethylene dichloride).

The free base was converted into aas hydrochloride salt of pp. 268-270 ⁰ C ¹ .

The free base was slurried in isopropyl alcohol and an equivalent amount of methanesulfonic acid was added. The solution was concentrated, cooled and filtered under reduced pressure to give the methanesulfonate salt of Pp. 187-189 ⁰ C.

12.5 g (0.05 mol) of the free base and 13.8 g (0.05 mol) of dibenzoyl-1-tartaric acid hydrate were dissolved in 300 ml of methyl alcohol and 100 ml of water were added. An aliquot of this solution was scratched until crystals formed and the main solution was inoculated with these crystals and refrigerated overnight. The crystals obtained were filtered off, the filtrate was cooled for 4 days and the additional crystals obtained were filtered. Two crystal shots are combined, slurried in 100 ml of water, mixed with 5 ml of 35% sodium hydroxide and stirred for 15 minutes. The resulting pesticide was filtered and removed from benzene-hexane to give 2.4 g of crude 1,3- (dimethylamino) -6,8-difluoro-1,2,3,4-tetrahydrocarbazole hydrochloride, mp 278-279 ⁰ C recrystallized; [a] £ ⁵ -69.8 °

30 9 8 08/1348

(2 io in HPO). A sample of the hydrochloride salt was converted into the free 1,3- (dimethylamino) -6,8-difluoro-1,2,3,4-tetrahydrocarbazole base Tom ITp. 142.5-143.5 ⁰ converted.

Each a process similar to the one described above, but replacing the dibenzoyl-1-tartaric acid hydrate with the corresponding d-isomer, gave d-3- (dimethylamine) -6,8-difluoro-1,2,3,4- tetrahydrocarliazole of Pp ,, 143-144 ⁰ C; [a] ^ ⁴ = + 86.3 ° (2 io in MeOH).

Method 2 (steps a Ms d)

a) 3-BCnZOyIoXy-S, 8- difluor-1,2,3,4-tetrahydrocarbazole

A solution of 50.5 g of 2,4-difluorophenyl hydrazine and 76 g of 4-benzoyloxycyclohexanone in 400 ml of absolute ethyl alcohol containing one equivalent of hydrogen chloride was heated under reflux for 4 hours. A pest precipitated on cooling and was obtained through mitration. 48.5 g of 3-benzoyloxy-6,8-difluoro-1,2,3,4-tetrahydrocarbazole was obtained from Pp. 184-186 ⁰ C (isopropyl alcohol).

b) 3-hydroxy-6,8-difluoro-1,2.34 4-tetrahydrocarbazole

A solution of 14.8 g of 3-benzoyloxy-6,8-difluoro-1,2,3,4-tetrahydrocarbazole in 100 ml of ethyl alcohol containing 3.3 g of potassium hydroxide and 10 ml of water was heated and refluxed for 3 hours then poured into Viasser. The resulting oil crystallized on standing and the crystals were collected by filtration. C. This gave 7.9 g of 3-hydroxy-6,8-difluoro-1,2,3,4-tetrahydrocarbazole from Pp. 140-142 ⁰

c) 3- (p-Toluenesulfonyloxy) -6, 8-difluoro-1,2,3,4-tetrahydrocarbazole

A mixture of 7.9 g of 3-hydroxy-6,8-difluoro-1,2,3,4-tetrahydrocarbazole and 7.45 g of p-toluenesulfonyl chloride was in 25 ml of pyr'idine excited / poor. The crystalline 3- (p-toluenesulfonyloxy) -6,8-difluoro-1,2,3,4-tetrahydrocarbazole, that said goodbye, vmrde through. Filtration recovered, washed with isopropyl alcohol and without further Cleaning used.

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d) A mixture of the above 3- (p-toluenesulfonyloxy) -6,8-difluoro-1,2,3,4-tetrahydrocarbazole and 65 ml of dimethylamine was heated in an autoclave to a temperature in the range from 120-140 ° for 20 hours warmed up. The excess amine was removed by distillation, the residue basified with sodium hydroxide and the mixture extracted with ether. The ethereal extracts were dried and the ether was evaporated to give 3 g of 3- (dimethylamino) -6,8-difluoro-1 ^^^ from Pp. 180-183 ⁰ C (ethylene dichloride).

Procedure 3 (steps a to d)

a) IT- (4-formyloxycyclohexyl) -F-methylformamide

A mixture of 133 g of 4- (methylamino) cyclohexanol, 460 ml Formic acid and 800 ml of toluene were heated under reflux and stirring for 16 hours, whereupon a Dean-Stark-V / water separator in the device was brought in and refluxed further until no heavier layer was deposited (das total volume removed was 390 ml). The toluene was evaporated in vacuo leaving an oil which by distillation under reduced pressure 150 g of N- (4-formyloxycyclohexyl) -N-methylformamide of bp 138-143 ° C / 0.3 mm.

b) H-methyl-N- (4-oxocyclohexyl) formamide

A solution of 150 g of N- (4-formyloxycyclohexyl) -M-methyIformamide in 900 ml of acetone and 140 ml of water is added dropwise at 20-25 ° C. with a solution of 82 g of chromium trioxide in 400 ml of water and 78 ml of concentrated sulfuric acid . After the addition was completed, the mixture was stirred at room temperature for 20 hours. The acetone was then evaporated under reduced pressure and the residue obtained was extracted with warm chloroform. The chloroform extract v / urde dried over magnesium sulfate and finally under reduced pressure to a ()] concentrated by distillation under the reduced pressure 7UE κ N-Hethyl-N- (4-oxocyclohexyl) formamide, bp. 115-118 ⁰ C / 0.2 mm er /: al ·.

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BAO ORIQfNAL

c) 3- (IT-Hethylformaido) -6,8-difluoro-1,2,3,4-t-ethrahydrocarbazole

A mixture of 15.5 g of N-methyl-M - ^ - oxocyclohexyl) formamide and 19.3 g of 2,4-difluorophenyl hydrazine sulfate in 250 ml of isopropyl alcohol, which contained 2.7 ml of concentrated sulfuric acid, was under nitrogen and under Stir under reflux for 3 hours. The mixture was cooled, made basic with a saturated solution of sodium bicarbonate, concentrated to dryness, added with water and extracted with chloroform. The dried Ghloroformextrakt was evaporated to dryness to obtain 17 g of 3- (N-methylformamido) ~ 6,8-difluoro-1,2,3,4-tetrahydrocarbazole, mp. 209-211 ⁰ C (isopropyl alcohol) received.

d) To a cooled solution of 9 g of lithium aluminum hydride

in 100 ml of tetrahydrofuran was a solution of 24 g of 3-H-methylformamido) -6,8-difluoro-1,2,3,4-tetrahydrocarbazole and 300 ml of tetrahydrofuran added dropwise with stirring. The mixture was refluxed for 4 hours and then for 16 hours left to stand at room temperature. The excess lithium aluminum hydride was followed by the addition of 36 ml of water decomposed by 120 ml of methylene dichloride, the resulting mixture was filtered and the filtrate was concentrated to dryness. Man received 16 g of 3- (dimethylamine) ~ 6,8-difluoro-1,2,3,4-tetrahydrocarbazole bp 183 ° C (isopropyl acetate).

Example 2,.

3- (methylamino) -6,8-difluoro-1,2,3,4-tetrahydrocarbazole

A solution of 3.5 g of 4- (methylamino) cyclohexanone, 5.1 g of 2,4-difluorophenylhydrazine hydrochloride and 4. g of methanesulfonic acid in 50 ml of absolute ethyl alcohol was refluxed for 4 hours, cooled and filtered. The solids obtained were washed with isopropanol and treated with a 10% potassium hydroxide solution in chloroform. The chloroform extract was evaporated to dryness to obtain 3- (methylamino) -6, S-difluoro-1,2, 3,4-tetrahydrocarbazol from Pp. 135-138 received ⁰ C, which in the hydrochloride salt, mp.> 280 ⁰ C was converted.

Alternatively, this compound (p. 136-138 ⁰ C) was made by heating

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224Ü2I I.

8 g of 3- (p-toluenesulfonyloxy) -6,8-difluoro-1,2,3,4-tetrahydrocarbazole and 30 g of 40 ^f / £ sodium methylamine in 120 ml of 2-Äthoxyäthano 1, followed by that in Example 1 , Method 2 d) described working method.

Example 3

3- (Mmethylamino) -6-fluoro-1, 2,3,4-tetrahydrocarba.zol

If the procedure given in Example 2 was used, 8.7 g of 4- (dimethylamine) cyclohexanone and 10 g of 4-fluorobbenylhydrazine hydrochloride in ethyl alcohol and 50 ml of 5-n-ethanolic hydrogen chloride, 3- (dimethylamine) ~ 6 were obtained fluoro-1,2,3,4-tetrahydrocarbazole, which when moving in ether with ethereal hydrogen chloride, 10.9 g of the corresponding hydrochloride salt, mp. 264-268 ⁰ C yielded.

Example 4

3- (Dimethylainino) -8-f lnor-1,2,3,4-tetrahydrocarbazole

Following the procedure given in Example 2, using 7.8 g of 4- (dimethylamino) cyclohexanone and 9 g of 2-fluorophenylhydrazine hydrochloride in 50 ml of ethyl alcohol and 10 ml of 5-n-ethanolic hydrogen chloride 3- (dimethylamino) - 8-fluoro-1,2,3,4-tetrahydrocarbazole, which when moving in ether with ethereal hydrogen chloride 6.5 g of the corresponding liydrochloridsalzes of mp. 298-302 ⁰ C yielded.

A portion of the free base was slurried in isopropyl alcohol and an equivalent amount of methylene sulfonic acid was added. The solution was concentrated, cooled and filtered under reduced pressure to give the corresponding Methylensulfonatsalz of mp. 174-176 ⁰ C obtained.

Example 5

3 ~ (Dimethylamino) -6 _< 7-difluoro-1,2,3,4-tetrahydrocarbazole

309808/1348

2240η

After, dei? The procedure given in Example 2 was obtained using 11.6 g of 4- (dimethylamine) cyclohexanone hydrochloride and 10.7 g of 3,4-difluorophenylhydra, zin hydrochloride and 150 ml of absolute ethyl alcohol, 12.8 g of 3 -4) imethylamino) -6,7-di ~ fluoro-1,2,3,4-tetrahydrocarbazole from Pp. 160-164 ⁰ C. This was treated in isopropyl alcohol with ethanolic hydrogen chloride "to yield the corresponding hydrochloride salt, mp. 257-260 ⁰ C received.

309808/1348

Claims (4)

Patent claims 1. 3- (NRCH ₅ ) -Q _n -1,2,3,4-tetrahydrocarbazole has the general formula I. NRCHo where R is hydrogen or a methyl group and Q is 6-fluoro, 8-fluoro, 6,7-difluoro or 6,8-difluoro or an acid addition salt of that. 2. 3- (Dimethylamino) -6 _f 8-difluoro-1,2,3,4-tetrahydrocarbazole or one of its acid addition salts. 3. Process for the preparation of the compounds according to claim 1, characterized in that a) a compound of the general formula II NHNH. wherein Q ' _{n is} 2-fluoro, 4-fluoro, 3,4-difluoro or 2,4-difluoro, with a compound of the general formula NRCH ^ III implements, b) a compound of the formula 309808/1348 VI wherein Y is a halogen atom or the group Z-SOg-O "and
Z is an organic radical with an amine of the formula HHRCH, or
c) a compound of the general formula N (GHO) R IX reduced, where in each case R denotes hydrogen or the methyl group and Q _n denotes 6-eluor, 8-fluoro, 6,7-difluoro or 6,8-difluoro and optionally converting a basic compound obtained into an acid addition salt convicted. 4. Pharmaceutical composition, characterized by the content a compound according to claim 1 or 2 and a pharmaceutical carrier. 309803/1348