FI57410B - FREQUENCY REFRIGERATION OF NEW NEUTROLEPTIC ACTIVATED 6-FLUORINE SUBSTITUTES WITHOUT DESSAS SALTER - Google Patents

Description

RSF ^ I [B] (11) advertisement publication 574-10 J & jTA l J '' UTLAGGN I NGSSKMFT 3 '* 1 wc (45) “" - ·' · 41 ^ 4 -1 ': l "' ^ ^ (51) Kv.lk.3 / lnt.a.3 C 07 D 409/06 FINLAND —FINLAND (21) Pwenttlhukemu · - PK «ntara6kning 3618/73 (22) Hakumlipilvt - AiMOknlngadtg 23.11 · 73 (23) Alkupiivi — Glltlghuttdag 23.11.73

(41) Tullut | ulklMksl - Bllvlt offwitllg 09 · 06.7U

Patent · And register controlled / 4 «NthtivUuipano and month of publication——

Patent och regitterttyrelMn '' AmMom uttagd och utUkrHtM pubiictrad 30.0U.80 (32) (33) (31) Requested etuolkeui — Begird prlorltat 08.12.72

England-England (GB) 56910/72 (71) Kefalas A / S, Ottiliavej 7_9 »2500 Ktfbenhavn-Valby, Denmark-Damnark (DK) (72) J ^ rn Lasse Martin Buus, Bjaeverskov, Niels Lassen, Gentofte, Allan Johan Bigler, K ^ benhavn, Denmark-Danmark (DK) (7 **) Oy Kolster Ab (5U) Method for the preparation of new neuroleptically active 6-fluoro-substituted thiaxanthene compounds and their salts - Förfarande for framställning av nya neuroleptiskt aktiva 6-fluoro-substituerade tiaxantenföreningar och dessas salter

The present invention relates to a process for the preparation of novel neuroleptically active 6-fluoro-substituted thiaxanthene compounds and their salts which have relatively few harmful side effects. The formula for the new compounds is / x ö - Öv 'w

F

2,57410 wherein X is -Cl, -CF 2 or -SO 2 CH 2), R 1, and R 2 are hydrogen atoms or form a second bond between the carbon atoms, and Y is ^ NCH 2,> NCH 2 CH 2 OH,> CHCH 8 CH 2 OH or> NCH2CH2CAc or> CHCH2CH2CAc, wherein -Ac is an acyl group of an aliphatic carboxylic acid having 1 to 16 carbon atoms, and for the preparation of these acid addition salts.

The process according to the invention is characterized in that a) thiaxanthenol of the formula ό V -— / .OH, _, Γ \ / / \ s c-ch0-ch9-ch -H} (II) 0

V

wherein X and Y are as defined above, are dehydrated to give a compound of formula I wherein R 1 and R 2 form a second bond between carbon atoms, and the resulting compound is optionally catalytically reduced to give a compound of formula I wherein R 1 and R 2 are hydrogen atoms, or b) a compound of formula ύ SC = -CH-CH = CH2 (III)

P

wherein X is as defined above, is reacted with an amine of formula 5741 0 / ^ λ ΗΝ Υ ν_7 wherein Υ is as defined above to give a compound of formula I wherein and Rg form a second bond between carbon atoms, and the resulting compound is reduced if desired. to give a compound of formula I wherein R 1 and R 2 represent hydrogen atoms, or c) a compound of formula ύ S CHM (IV)

F

wherein X is as defined above and M is an alkali metal, is reacted with a reactive ester of a compound of formula V (where Y is as defined above and wherein the optionally present hydroxy group is protected, and the resulting compound of formula I is obtained). a compound in which R1 and R8 are hydrogen atoms is separated after removal of any protecting group present, or d) a compound of formula

S C —CH — CH0 - CH0 - N P

Wherein R 1 and have the same meaning as above are reacted with ethylene oxide to give a compound of formula I wherein Y is> NCH 2 CH 2 OH, or e) a compound of formula 0 CH - CH? - hai (VI) V _ / \ \ / \ R1 R2 μ

F

wherein X, R 1 and R 8 are as defined above and the shark is chlorine, bromine or iodine is reacted with an amine of formula

HN Y

W

wherein Y is as defined above, or f) a compound of formula

X

0 \ = ch-ch2-ch2-n (ch3) 2 (VII) 0

F

wherein X is as defined above, is reacted with an amine of formula

HN Y

W

5 57410 wherein Y is as defined above to give a compound of formula I wherein R 1 and R 9 forms a second bond between carbon atoms, and the resulting compound is hydrogenated if desired, and the resulting compound of formula I is separated as the free base or non-toxic acid addition salt, that any hydroxy group present is esterified with a reactive derivative of an aliphatic carboxylic acid having 1 to 17 carbon atoms, and When Rg denotes a second bond between the carbon atoms, the isomers are separated in a conventional manner, if desired.

In the past, several tricyclic drugs have been found to be useful in the treatment of severe mental disorders, particularly schizophrenia. The tertiary amino group may also form part of a heterocyclic ring system, and such a system, especially the piperazine ring, is present in several very potent neuroleptic drugs. Thiaxanthenes substituted at equivalent positions with similar groups and having an unsaturated bond have also been found to be useful in the treatment of mental illness. It is known that the above-mentioned monosubstituted phenothiazines or thiaxanthenes cause severe extrapyrimidial symptoms in many patients, in which case it becomes difficult or impossible to continue treatment.

It has now surprisingly been found that some thiaxanthene derivatives substituted at position 6 by fluorine atom 11a and having an piperazine or piperidine group in the alkyl or alkylidene side chain have the same level of neuroleptic properties as known neuroleptic drugs, but with extrapyretic effects well-known reliable standard tests are used. Furthermore, the duration of action of some substituted alkylidene compounds has been found to be much longer than that of compounds without a fluorine atom at position 6 when these compounds are administered to animals.

Pharmaceutically acceptable salts of the bases of formula I include those formed with non-toxic organic or inorganic acids, especially the dihydrochloride. Such salts can be readily prepared by known methods. Examples of such organic salts are those formed with the following acids: maleic, fumaric, benzoic, ascorbic, amber, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, wine, salicylic, lemon, gluconic, lactic, malic, mandelic, cinnamon, citracone, asparagine, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulphonic and theophylline acetic acids and 8-halogenophenyls, for example 8-bromothiophylline. Examples of inorganic salts are those formed with the following acids: hydrochloric, bromic, hydro, sulfuric, sulfamic, phosphoric and nitric acid. These salts are prepared by classical methods.

In embodiment a) the dewatering is preferably carried out by heating with hydrogen chloride in an organic solvent such as alcohol or chloroform. However, other reagents suitable for removing water from tertiary alcohols such as phosphorus oxychloride, p-toluenesulfochloride, sulfuric acid, zinc chloride, potassium bisulfate and the like in inert organic solvents such as chloroform or methylene chloride can also be used. The reduction is most conveniently performed with hydrogen iodine or any modification of ibahan that produces hydrogen iodine in situ. If a hydrogen iodine sensitive group is present, the reduction may be performed in the presence of a reduction catalyst such as platinum oxide or palladium on carbon.

In embodiment b) the reduction of the tertiary hydroxyl compound is preferably carried out by dissolving the compound in, for example, acetic acid, adding a reducing agent, preferably hydrogen iodine, and refluxing until the reaction is complete. An iodine reducing agent such as phosphorus or hypophosphorous acid can be used, if desired, to convert the liberated iodine back to hydrogen iodine.

A process variant corresponding to embodiment c) is described in U.S. Patent No. 3,116,291, which also describes the preparation of compounds of formula III as starting materials.

In embodiment c) the alkali metal M is preferably lithium, sodium or potassium and the reactive ester of the compounds of formula V according to the invention may be a halide such as chloride or bromide or an aryl sulphonate such as p-tosylate or phenyl sulphonate in a suitable inert aromatic solvent such as benzene or toluene. The compound of formula IV is formed from the corresponding thiaxanthene when the reaction is carried out in the presence of one of the following compounds: butyllithium, phenyllithium, sodium amide, potassium amide, sodium hydride and the like.

A method alternative corresponding to embodiment f) is described in U.S. Patent No. 3,119,103.

When preparing esters of compounds of formula I having a hydroxyl group, i. when Y is? Acids which may be mentioned are acetic acid, propionic acid, butyric acid, valeric acid, enantylic acid, caproic acid and palmitic acid. Other acids can also be used.

When and R 1 form a second bond with each other between carbon atoms, the compounds of formula I are generally obtained as a mixture of geometric isomers. In most cases, the individual isomers have the desired degree of effect. Accordingly, it is preferred that the isomers be separated according to the invention by conventional methods such as fractional crystallization of base mixtures or as the corresponding acid addition salt.

The starting materials of formulas II, III, IV and VII, which are also novel compounds, are best prepared by methods normally used in the preparation of such compounds, and reference may also be made to U.S. Patent Nos. 2,951,982 and 3,282,930, as well as two previously to said patent publication, which describe in detail analogous methods for the preparation of starting materials.

Pharmacological experiments

The neuroleptic activity of the compounds according to the invention was studied in experiment (1) described in Pedersen, V. & Christensen, A.V., Methylphenidate antagonism in mice as a rapid screening test for neuroleptic drugs., Acta Pharmacol. and Toxicol. 1971, 29. suppl. 4, M. This test is based on the fact that a substance has neuroleptic activity if it acts against amphetamine and methylphenidate, which activate the central nervous system.

(1) Male NMRI mice weighing 18-25 g, 3x2 or 5x2 mice for each dose level were used as experimental animals. The test substance was administered by intraperitoneal injection. Thirty minutes after injection, 1 h, 2 h, 3 h, etc., 60 mg / kg methylphenidate was administered by subcutaneous injection. Different groups of mice were used for each time interval. After administration of methylphenidate, mice were placed in observation cages, 2 mice in each cage where they were allowed to stand for 1 h. The cages were placed on corrugated cardboard with the corrugated side facing up. Unless the mice were bitten on corrugated board, the test substance had an anti-methylphenidate activity. Unless one or more of the control pairs had also bitten the cardboard, the experiment was repeated in new mice. The maximum efficacy of several known neuroleptic agents was also determined.

In another experiment (2), the ketaleptic-inducing effect was investigated in Juluo, L., On the interaction between neuroleptics and antiparkinson drugs,

Modern problems of pharmacopsychiatry, vol. 5, pp. 50-5 ^.

(2) Male Wistar rats weighing 189-220 g were used as experimental animals, 5 rats for each dose level. At least .6 consecutive dose levels were selected from the following geometric series: 6U0, 320, 160, 80, Uo, 20, 10, 5, 2.5, 1.25, 0.63, 0.32, 0.16, 0.08, 0.0¾ and 0.02 mg / kg body weight.

Test substances were injected subcutaneously at 5 ml / kg body weight. The carrier was usually physiological saline.

The experimental animals were kept in the laboratory in groups of five rats for at least 16 h before the experiment. Animals were placed in front of a vertical metal wire mesh (50 x 1 * 9 cm) for 60, 120, 180, 2 ^ 0, 300 and 360 min after administration of test substance.

Animals were considered ketaleptic if they were immobile for 15 s 8 57410. The ketaleptic reaction was denoted + (plus). Untreated animals normally climbed upside down along the net. The absence of catalepsy was marked - (minus). The results are presented in fractions 0/5, 1/5, 2/5, 3/5, U / 5 and 5/5, where 0, 1, 2,3, bja5 means the number of cataleptic animals out of 5 animals studied.

Both of the above experiments were performed using several novel compounds of formula I and several related thiaxanthene derivatives. Known neuroleptic active drugs were used as reference compounds, thiotixene, clopentixol and flupentixol in the form of active, pure O (isomers), as well as other related compounds.

The results are shown in the following table.

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The table shows that the anti-catalepsy / anti-methylphenidate ratio ratio is considerably improved when the 6-position has a fluorine substituent instead of another substituent, especially in the case of piperazine-type compounds. Comparing compounds 1 and 8, the only difference being that the 6-position has a different halogen substituent, it is found that the anti-methylphenidate activity of compound 1 is about 100 times better and the cat / met ratio is about 1-fold better. The cat / met ratio of the known neuroleptic drugs clopentixol to flu-pentixol is 0.7-1.7%, which is of the same order of magnitude as other known neuroleptic drugs. The cataleptic activity of the neuroleptic drug chlorpromazine is U, 0 and the anti-methylphenidate activity is U, 0 and the ratio cat / met = 1.0.

Comparing compounds 1 and 6 to Cf-flupentixol, it is found that although the peak of the anti-methylphenidate activity is of the same order of magnitude, the duration of the peak effect is much longer, compound 6 had a significant effect even after 2 h. The most surprising effect was with compound 13, which had a peak duration of action of 2-3 d.

The compounds of formula I and their non-toxic acid addition salts can be administered to humans and animals such as dogs, cats, horses, sheep both orally and parenterally, for example in the form of tablets, capsules, powder, syrup or conventional sterile injectable solutions. The compounds of formula I have proved to be very promising in human medicine.

11 5741 0

The following examples illustrate the method of this invention.

Example 1 2-Trifluoromethyl-6-fluoro-9- [3- (4- (2-hydroxyethyl) -piperazin-1-yl) -propylidene] -thiaxanthene, its isomers, their dihydrochlorides and their dihydro derivative.

The starting material, 2-trifluoromethyl-6-fluoro-9- (3-4-methylaminopropylidene) -thiaxanthene, was prepared as follows: 104 g of 3-fluorothiophenol and 50 g of sodium stanate were dissolved in 500 ml of $ 99 ethanol, followed by the addition of I65 g. -trifluoromethyl-2-chloro-benzonitrile and the mixture was refluxed for 4 hours. Then -65 g of potassium hydroxide and 30 ml of water were added and refluxing was continued for 4 hours.

The reaction mixture was dissolved in 4 liters of water and the solution was acidified with concentrated hydrochloric acid, filtered and the collected precipitate was washed and dried in a desiccator. Yield: 250 g of 2- (3'-fluorophenylthio) -5-trifluoromethylbenzoic acid.

25c g of 2- (3-fluorophenylthio) -5-trifluoromethylbenzoic acid was dissolved in 1500 ml of concentrated hydrochloric acid and the mixture was heated to about 65 ° C. After cooling, the reaction mixture was poured onto ice crumb. The precipitate was collected by filtration and recrystallized from a mixture of acetone and concentrated aqueous ammonia and washed. The precipitate was dissolved in chloroform, and the chloroform solution was dried over anhydrous potassium carbonate. Evaporation of chloroform gave 101 g of 2-trifluoromethyl-6-fluorothiazxanthone. Sp. 195.5 to 196.5 ° C.

100 g of 2-trifluoromethyl-6-fluorothiazxanthone was added to a mixture of 500 ml of 2N dimethylaminopropylmagnesium chloride in tetrahydrofuran, and the mixture was refluxed for 30 minutes. The reaction mixture was poured into crushed ice containing ammonium chloride. The resulting mixture was extracted with ether, the ether solution was washed and dried over anhydrous potassium carbonate. The ether was evaporated and the residue was recrystallized from petroleum ether. Yield: 10 g of 2-trifluoromethyl-6-fluoro-9- (3-4-methylaminopropyl) -thiaxanthen-9-ol, m.p. 132.5 to 134 ° C.

50 g of 2-trifluoromethyl-6-fluoro-9- (3-dimethylaminopropyl) -thiaxan-ten-9-ol was dissolved in 150 ml of glacial acetic acid, and 150 ml of concentrated hydrochloric acid was added to the solution. The liquid was evaporated off in 150 ml. The residue was poured into ice water and made alkaline with concentrated sodium hydroxide solution. The mixture was extracted with ether, the ether phase dried over anhydrous potassium carbonate and the ether evaporated. The residue was dissolved in acetone and 2-trifluoro-12,541,400 ethyl-6-fluoro-9- (3-dimethylaminopropylidene) -thiaxanthene was precipitated with dry hydrogen chloride. Yield 42 g.

cr-isomer m.p. was 248-250 ° C and the t-'isomer 216-218 ° C.

A mixture of 47 g of 2-trifluoromethyl-6-fluoro-9- (3-dimethylaminopropylidene) -thiaxanthene, 105 g of N- (2-hydroxyethyl) -piperazine and 1C ml of 2-propanol was heated to 140-150 ° C. at 24 hours. After cooling, the mixture was poured into a mixture of isopropyl ether and methylene chloride (1: 1), the organic layer was washed with water, dried over anhydrous potassium carbonate and 2-trifluoromethyl-6-fluoro-9- [3- (4- (2-hydroxyethyl) piperazin-1-yl) -propylidene β-thiaxanthene was precipitated as the dihydrochloride using dry hydrogen chloride. The product consisted of a mixture of geometric isomers. Yield 30 g. Sp. 236-259 ° C. Recrystallization of 15 g of this mixture twice from 200 ml of 99 Io ethanol gave 5 to 5 g of the most active α-form as white crystals, m.p. was 240-242 ° C.

3C g of 2-trifluoromethyl-6-fluoro-9- [3- (4- (2-hydroxyethyl) piperazin-1-yl) propylidene] -thiaxanthene dihydrochloride was dissolved in methanol and catalytically reduced with hydrogen at 110 atmospheres and 100 ° C for 2 hours. using palladium on carbon (6 g, 10 ° β>) as catalyst. The catalyst was filtered off and 2-trifluoromethyl-6-fluoro-9- [3- (4- (2-hydroxyethyl) piperazin-1-yl) propyl] thiaxanthene crystallized when the methanol was evaporated and cooled. Yield 26 g. Sp. 225-228 ° C.

Example 2 2-Trifluoromethyl-6-fluoro-9- [3- (4- (2-hydroxyethyl) piperazin-1-yl] propyl] thiananthene, its dihydrochloride and 2-trifluoromethyl-6-fluoro-9- (3- (piperazin-1-yl) 1-yl) propyl) thiaxanthene and its dioxalate.

A mixture of 40 g of 2-trifluoromethyl-6-fluoro-9- (3-dimethylaminopropylidene) -thiaxanthene, 80 g of piperazine and 10 ml of 99 l of ethanol was refluxed for 24 hours. The mixture was dissolved in isopropyl ether, cooled and filtered, and the filtrate was extracted with water. The ether phase was dried over anhydrous potassium carbonate and evaporated. The residue was stirred in a mixture of 40 ml of hydrogen chloride solution, 80 ml of glacial acetic acid, 10 ml of water and 8 g of red phosphorus and refluxed for 18 hours. The reaction mixture was filtered, the filtrate was dissolved in water, started with concentrated sodium hydroxide and extracted with ether. The ether phase was washed with water, dried over anhydrous potassium carbonate, the ether was evaporated, the residue was dissolved in 200 ml of 99 ° ethanol, of which 2-trifluoromethyl-6-fluoro-9- (3- (piperazin-1-yl) -propyl) -thiaxanthene dioxalate (m.p. 181-183 ° C when recrystallized from 13,571 O 0 of ethanol) could be crystallized by cooling the solution to 10 ° C and adding 10 ml of ethylene oxide. The reaction mixture was allowed to stand for 4 hours and evaporated.

The dihydrochloride of 2-trifluoromethyl-6-fluoro-9- [3- (N- (2-hydroxyethyl) piperazin-1-yl) propyl] thiaxanthene was precipitated with dry hydrogen chloride in acetone. Yield 36 g. Sp. 225-228 ° C.

Example 3 2-Trifluoromethyl-6-fluoro-9- (3- (4- (2-hydroxyethyl) piperazin-1-yl) propyl] thiaxanthene and its dihydrochloride

A mixture of 10 g of 2-trifluoromethyl-6-fluoro-9- [3- (k- (2-hydroxyethyl) piperazin-1-yl) propylidene-7-thiaxanthene dioxalate (m.p. 214-216 ° C), 9 g of hydrogen iodide 57% aqueous solution, 18 ml glacial acetic acid, 1 ml water and 1 g red phosphorus were refluxed for 18 hours. The reaction mixture was filtered, the filtrate dissolved in water, basified with concentrated sodium hydroxide solution and extracted with ether. The ether phase was washed with water, dried over anhydrous potassium carbonate and The residue gave 2-trifluoromethyl-6-fluoro-9-4- (2-hydroxyethyl) piperazin-1-yl) -propyl] -thiaxanthene dihydrochloride as white crystals when precipitated with dry hydrogen chloride in acetone, yield 5 g · mp 225-228 ° C.

Example 4 2-Trifluoromethyl-6-fluoro-9- [3- (4- (2-hydroxyethyl) piperazin-1-yl) propyl] thiaxanthene and its dihydrochloride 4 g of LiAlH 2 was dissolved in 100 ml of ether and 13 g of 3 g of AlCl 3 under a nitrogen atmosphere. A solution of 10.9 g of AlCl 3 and 24 g of 2-trifluoromethyl-6-fluoro-9-thiaxanthone in tetrahydrofuran was then added dropwise. After standing for 30 minutes, ISO ml of water was added dropwise, followed by 100 ml of 6N sulfuric acid. The ether phase was separated, washed with water, dried over anhydrous potassium carbonate and evaporated. Recrystallization of the residue from ether-petroleum ether (1: 1) gave 17 g of 2-trifluoromethyl-6-fluorothiazxanthene as white crystals, m.p. 60-62 ° C.

15 g of 2-trifluoromethyl-6-fluorothiazxanthene were dissolved in 100 ml of ether, cooled to 0 ° C, 40 ml of a 15 * 96 solution of butyllithium in hexane under a nitrogen atmosphere were added dropwise, and the mixture was allowed to stand for 30 minutes. A solution of this lithium salt was added dropwise to a solution of 39 g of 3-bromo-1-chloropropane in 100 ml of ether, and the mixture thus obtained was allowed to stand for a further 30 minutes and then refluxed for about 57410 minutes. Water was added dropwise to the reaction mixture, the ether phase was separated, washed with water and dried. The ether was evaporated and the residue was distilled under reduced pressure (0.01 mm Hg). There was thus obtained 16 g of 2-trifluoromethyl-6-fluoro-9- (3-chloropropane) -thiaxanthene as a yellow oil.

A mixture of 16 g of 2-trifluoromethyl-6-fluoro-9- (3-chloropropane) -thiaxanthene and 48 g of N- (2-hydroxyethyl) -piperazine in 300 ml of toluene was refluxed for 16 hours. The reaction mixture was evaporated, the residue was dissolved in water and isopropyl ether was added. The isopropyl ether phase was separated, washed with water, dried and evaporated. The residue was dissolved in acetone, and 2-trifluoromethyl-6-fluoro-9- [3- (4- (2-hydroxyethyl) piperazin-1-yl) -propyl] -thiaxanthene dihydrochloride was mixed with dry hydrogen chloride. Yield 6 g. Sp. 225-228 * 0.

Example 5 2-Trifluoromethyl-6-fluoro-9- [5- (4- (2-hydroxyethyl) piperazin-1-yl) propyl] thiaxanthene and its dihydrochloride 144 g of N- (2-methoxyethyl) piperazine and 157 g of g of 3-bromo-1-chloropropane was dissolved in 500 ml of ethanol and the solution was refluxed for 2 hours. The ethanol was evaporated, the residue was dissolved in water, the aqueous solution was made basic with sodium hydroxide solution, the solution was extracted with ether, the ether solution was separated, washed with water, dried and evaporated. There was thus obtained 110 g of 4- (2-methoxyethyl) -1- (3-chloropropyl) -piperazine as a yellow oil.

15 g of 2-trifluoromethyl-6-fluorothiazxanthene were dissolved in 100 ml of ether, mixed with the oily product obtained in the previous step, the resulting solution was cooled to 0 ° C, 40 ml of a 15% butyllithium solution of butyllithium in a nitrogen atmosphere were added dropwise, allowed to stand For 30 minutes and then refluxed for 30 minutes. Water was added dropwise, the organic phase was separated, washed with water, dried over anhydrous potassium carbonate and evaporated. The oily residue contained mainly 2-trifluoromethyl-6-fluoro-9- [3- (4- (2-methoxythietyl) piperazin-1-yl) propyl] thiaxanthene. Yield 22 g.

22 g of 2-trifluoromethyl-6-fluoro-9- [3 - (* [1- (2-methoxyethyl) -piperazin-1-yl] propyl] thiaxanthene and 150 ml of concentrated hydrobromic acid were mixed and distilled at 120 ° C. After an additional 50 mL of concentrated hydrobromic acid was added and distilled, and after 2 hours the reaction mixture was cooled, basified with concentrated sodium hydroxide solution, extracted with ether, the ether phase separated, washed with water and dried over anhydrous potassium carbonate. Fluoro-9- [3- (1 * -fc (2-hydroxyethyl) -piperazin-1-yl] propyl] -thiaxanthene dihydrochloride as white crystals, mp 225-228 ° C.

5741 0

Example 6 2-Trifluoromethyl-6-fluoro-9- [3- (U-methyl-1-piperazinyl) propyl] thiaxanthene and its dihydrochloride.

17 g of 2-trifluoromethyl-6-fluorothiazxanthene were dissolved in 250 ml of dry ether, and the solution was cooled to 0 ° C, and then 00 ml of a 20% solution of butyllithium in hexane was added dropwise. The reaction mixture was allowed to stand for 30 minutes at 0 ° C, and then 12 g of 1-methyl-1- (3-chloropropyl) piperazine was added dropwise, and the reaction mixture was allowed to stand for 15 minutes. The reaction mixture was then poured into water and the organic phase was separated, washed with water, extracted with dilute acetic acid, the acetic acid solution basified with sodium hydroxide solution, extracted with ether, the ether phase separated, washed with water, dried over anhydrous potassium carbonate and evaporated. -trifluoromethyl-6-fluoro-9- [3- (U-methyl-1-piperazinyl) propyl] -thiaxanthene dihydrochloride was mixed as white crystals using dry hydrogen chloride, mp 270-272 ° C. Yield 8.7 g.

Example 7 2-Chloro-6-fluoro-9 - [* 3- (H- (2-hydroxyethyl) -1-piperazinyl) -propyl] -thiaxanthene and its dihydrochloride 2-Chloro-6-fluorothiazxanthone (m.p. 215-218 ° C) was prepared as described in Example 1.

From a mixture of 15 g of 2-chloro-6-fluorothiazxanthone and 3-dimethylaminopropylmagnesium chloride in tetrahydrofuran, 15 g of 2-chloro-6-fluoro-9- (3-dimethylaminopropyl) -thiaxanthen-9-ol were obtained in a known manner. (mp.

15 ^ -156 ° G).

From this carbinol, water is cleaved in a known manner when treated with a mixture of glacial acetic acid and concentrated hydrochloric acid (1: 1) and evaporated to half volume. The residue was basified with sodium hydroxide solution, extracted with ether, the ether phase washed with water, dried and evaporated. 2-Chloro-6-fluoro-9- (3-dimethylaminopropylidene) -thiaxanthene was isolated as the hydrochloride, m.p. was 192-19 ° C.

A mixture of 60 g of 2-chloro-6-fluoro-9- (3-dimethylaminopropylidene) -thiaxanthene, 180 g of piperazine and 10 g of 2-propanol was heated at 14 DEG C. for 18 hours. the mixture was dissolved in ether, the ether phase extracted with water, dried over anhydrous potassium carbonate and evaporated, the residue weighing 55 g containing mainly 2-chloro-6-fluoro-9- [3- (1-piperazinyl) -propylidene] -thiaxanthene.

50 g of the residue was mixed with a solution of 5 ° g of an aqueous solution of hydrogen iodide 57, ICO g of glacial acetic acid and 8 g of red phosphorus, and refluxed for 18 hours. The reaction mixture was filtered, basified with sodium hydroxide solution and extracted with ether. The ether phase was washed with water, dried over anhydrous potassium carbonate, dissolved in $ 99 in ethanol and treated with 10 u / o excess ethylene oxide at 10 ° C for 2 l / 2 hours. The mixture was then evaporated, the residue was dissolved in acetone and dry hydrogen chloride was added to precipitate 45 g of 2-chloro-6-fluoro-9- [3- (4- (2-hydroxyethyl) -1-piperazinyl) propyl] thiaxanthene dihydrochloride as white crystals. mp.

011 252-235 ° C.

Example 8 2-Trifluoromethyl-6-fluoro-9- [3- (4- (2-hydroxy-ethyl) -piperazin-1-yl) -propyl] -thiaxanthene-palmitic acid ester.

21.6 g of 2-trifluoromethyl-6-fluoro-9- [3- (1 + - (2-hydroxyethyl) piperazin-1-yl) propyl} thiaxanthene were dissolved in 200 ml of acetone, 25 g of palmitic acid chloride were added. and the mixture was refluxed for 1 hour. There was thus obtained 20 g of an oily ester.

IE absorption: 1170 cm -1, 1129 cm -1 x 902 cm -1, 858 cm -1, 832 cm -1 m UV spectrum: Max 280 nm; = * 550

In a similar manner, 2-trifluoromethyl-6-fluoro-9- [3- (U- (2-hydroxyethyl) piperazin-1-yl) propyl] -thiaxanthenecaproic acid ester was prepared.

IR absorption 1171 cm -1, 1130 cm -1, 1091 cm -1 901 cm -1 m, 855 cm -1 m, 821 cm -1 m UV spectrum: Max 282 nm; = 1765

Example 9 2-Dimethylsulfamoyl-6-fluoro-9- [3- (4-methyl-piperazinyl) -propyl] -thiaxanthene and its dihydrochloride.

The intermediate, 2-dimethylsulfamoyl-6-fluoro-9- [3- (4-methylpiperazin-1-yl] propylidene] -thiaxanthene, was prepared as follows: 17 5741 0

A mixture of 69 g of 3-dimethylsulfamoyl-6-bromobenzoic acid, 31 g of 3-fluorophenol, 24 g of sodium carbonate, 350 ml of dimethylformamide and 1 g of Adam's copper catalyst was refluxed with stirring for 1 hour. The mixture was poured into 2 liters of ice water, filtered, the filtrate was washed with ether and acidified with concentrated hydrochloric acid. The precipitate was collected by filtration and dissolved in 2.5 liters of chloroform, and the solution was dried over anhydrous magnesium sulfate, filtered and evaporated to a volume of about 300 ml. 500 ml of ether were added and the mixture was cooled. 6 g of 2- (3-fluorophenylmercapto) -5-dimethylsulfamoylbenzoic acid crystallized out as white crystals, m.p. was 220-223 ° C. This material was mixed with 500 ml of concentrated sulfuric acid and the mixture was heated at 60-65 ° C until complete dissolution and then the mixture was poured onto ice crumb. The precipitate was filtered off and washed with water. Recrystallization from 500 ml of pyridine gave 41.5 g of 2-dimethylsulfamoyl-6-fluorothiazxanthone as a pale yellow solid, m.p. was 213-216 ° C.

To a solution of allyl magnesium bromide in 500 ral of ether prepared from 60 g of allyl bromide was added, with stirring and cooling, 41 g of 2-dimethylsulfamoyl-6-fluorothiazantonone. The mixture was refluxed with stirring for 1 hour and then poured into ice water. The mixture was acidified with dilute hydrochloric acid and extracted with ether. From the ether phase 39 g of 2-dimethylsulfamoyl-6-fluoro-9- (2-propylidene) -thiaxanthen-9-ol were obtained as a white solid, m.p. was 150-154 ° C.

39 g of 2-dimethylsulfamoyl-6-fluoro-9- (2-propylidene) -thiaxanthen-9-ol were dissolved in 1 g of benzene, and 11 ml of acetic anhydride and 0.5 ml of acetyl chloride were added to the solution. The reaction was started in a few minutes and caused the temperature to rise to about 65 ° C. The mixture was heated on a steam bath for 5 minutes, poured onto ice, extracted with ether, the ether phase separated, washed with cold dilute sodium hydroxide solution, dried over aqueous sodium hydroxide solution, dried and evaporated to give 35 g of 2-dimethylsulfamoyl-6-fluoro-9- (propen-3-ylidene-1) -thiaxanthene as a yellow oil.

35 g of a yellow oil was mixed with 5C of N-methylpiperazine and the mixture was heated in a water bath for 18 hours. The mixture was poured into water and extracted with ether. The ether phase was extracted with dilute aqueous acetic acid, the aqueous phase was separated, made alkaline with sodium hydroxide solution and extracted with ether. The ether phase was separated, dried over anhydrous potassium carbonate, filtered and evaporated. There was thus obtained 1 * 0 g of 2-dimethylsulfamoyl-6-fluoro-9- [3 '(1 + -methylpiperazin-1-yl) -propylidene] -thiaxanthene as a yellow oil. It is a mixture of two geometric isomers.

20 g of this mixture was dissolved in 150 ml of diethyl ether, cooled and allowed to stand. The white crystalline precipitate was filtered off with suction and dried. There was thus obtained 7 g of the cy form, m.p. recrystallization from ethanol was 165-167 ° C. The corresponding hydrochloride had a melting point of 2i + 5-250 ° C. when recrystallized from ethanol. The Oi form, which was most active in pharmacological experiments, was separated by crystallization, and the remaining mother liquor gave the β-form as the hydrochloride, m.p. 270-275 ° C.

15 g of the isomer mixture was dissolved in 250 ml of ethanol and palladium on carbon (3 g, 10%) was added, and the mixture was hydrogenated at 100 ° C at 120 atmospheres for 2 hours. The reaction mixture was cooled and filtered, and ethereal dry hydrogen chloride solution was added until the pH was U. On standing, 10 g of 2-dimethylsulfamoyl-6-fluoro-9- [3- (U-methylpiperazin-1-yl) propyl] thiaxanthene dihydrochloride separated as white crystals, . was 265-270 ° C.

Example 10 2-Trifluoromethyl-6-fluoro-9- [3- (1 + - (2-hydroxyethyl) -piperazin-1-yl) -propyl] -thiaxanthene acetic acid ester and its dihydrochloride 5 g of 2-trifluoromethyl-6-fluoro-9- Β- (U- (2-Hydroxyethyl) -piperazin-1-yl) propyl-7-thiaxanthene was dissolved in 100 ml of acetone and then 5 ml of acetyl chloride was added. The mixture was heated on a steam bath for 30 minutes. After cooling, the mixture was poured into water, basified with sodium hydroxide solution and extracted with ether. The ether phase was washed with water, dried over anhydrous potassium carbonate and evaporated. There was thus obtained 1, 5.5 g of 2-trifluoromethyl-6-fluoro-9- [3- (U- (2-hydroxyethyl) -piperazin-1-yl) propyl] thiaxanthene ethyl acetate as a yellow oil. The dihydrochloride was prepared in the normal manner and its m.p. was 208-211 ° C.

Example 11 2-Dimethylsulfamoyl-6-fluoro-9- [3- (1- (2-hydroxyethyl) -1-piperidyl) propylidene] thiaxanthene and its oxalate.

Following the procedure described in Example 9 using 1 + - (2-hydroxyethyl) piperidine in place of N-methylpiperazine, 2-dimethylsulfamoyl-6-fluoro-9- [3- (U- (2-hydroxyethyl) -1- piperidyl) propylidene-thiaxanthene as a yellow oil containing a mixture of isomers. The second isomer was separated as the oxalate from ethanol by crystallization and its m.p. was 171-173 ° C. The second isomer was also separated from the mother liquor as an oxalate, m.p. was 11 + 9-1 52 ° C after recrystallization from ethanol.

19 5741 0

Example 12 2-Trifluoromethyl-6-fluoro-9- [3- (U- (2-hydroxyethyl) -1-piperidyl) -propylidene / thiaxanthene, its isomers, oxalate and hydrochlorides 150 g of 2-trifluoromethyl-6-fluoro-9 - (propen-2-ylidene-1) thiaxanthene and 300 g of 4- (2-hydroxyethyl) piperidine were heated at 90 ° C for 17 hours. The mixture was poured into 2 l of water and extracted with 2 l of ether, the ether phase was separated off, washed 3 times with 500 ml of water each time, dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo. The oxalate was recrystallized from acetone. The yield was 118 g of 2-trifluoromethyl-6-fluoro-9- [3- (N- (2-hydroxyethyl) -1-piperidyl) propylidene / thiaxanthene oxalate as a mixture of isomers, m.p. LU2-II + I + C.

The pharmacologically active isomer was separated by boiling the mixture of oxalate thi isomers with acetone. The acetone was evaporated in vacuo to give a mixture containing about 80% of the active isomer. The residue was precipitated with dilute sodium hydroxide solution and extracted with 200 ml of ether. The ether phase was washed 3 times with 50 ml of water each time, dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo. The residue was dissolved in acetone and precipitated with anhydrous hydrogen chloride dissolved in ether. The hydrochloride of the active o (-isomer) was obtained as a white crystalline solid, mp 166-168 ° C.

The β-isomer, which was pharmacologically inactive, was separated as the oxalate; recrystallized 1+ times from a mixture of 2-propanol and methanol (1: 1), m.p. 150-153 ° C.

The inactive isomer can be converted to the partially active isomer by boiling in a solution containing a strongly basic substance such as sodium ethylate and separating the active isomer as above.

The base of the active O1 isomer was separated in a conventional manner, m.p. 128-129 ° C.

The starting material, 2-trifluoromethyl-6-fluoro-9- (propen-2-ylidene-1) thiaxanthene, was prepared as follows: 100 g of 2-trifluoromethyl-6-fluorothiazxanthone was added to a Grignard solution prepared from 80 g of allyl bromide and 95 g of g of magnesium turnings dissolved in 500 ml of ether. The mixture was refluxed for 15 min, and after cooling, the reaction mixture was poured into ammonium chloride solution. The ether phase was separated and extracted 3 times with 200 ml of water each time and evaporated to dryness in vacuo. The residue was dissolved in 300 ml of benzene, and a mixture of 35 ml of acetic anhydride, 2 ml of acetyl chloride and a drop of concentrated sulfuric acid was added. The mixture was heated on a steam bath at about 65 ° C until dehydration began and then for another 15 min. The mixture was poured onto crushed ice, acidified with sodium hydroxide solution and extracted with 500 ml of ether. The ether phase was washed 3 times with 100 ml of water each time, dried over anhydrous magnesium sulfate and evaporated to dryness in vacuo. The residue, which was a yellow oil, comprised 105 g of slightly impure 2-trifluoromethyl-6-fluoro-9- (2-propenylidene) thiaxanthene.

Example 13 2-Trifluoromethyl-6-fluoro-9H- [3- (b- (2-hydroxyethyl) -1-piperidyl) -propyl] thiaxanthene, its oxalate and hydrochloride 25 g of 2- (trifluoromethyl-6-fluoro) -3- (2-hydroxyethyl) -1-piperidyl) propylidene / thiaxeneene oxalate as a mixture of isomers, m.p. IU2-14U ° C, dissolved in methanol and catalytically reduced with hydrogen at 110 atm. and at 100 ° C using 5 g of 10- to 10% palladium on charcoal as a catalyst. The catalyst was filtered off and the methanol was evaporated and cooled to give 20 g of 2-trifluoromethyl-6-fluoro-9- [3- (N- (2-hydroxyethyl) -1-piperidyl] propyl] thiaxanthene oxalate, mp 1882-181 ° C.

The corresponding hydrochloride was obtained from ethanolic hydrogen chloride solution, m.p. ll8-120 ° C.

Example lU

2-Chloro-6-fluoro-9- [3- (1- (2-hydroxyethyl) piperidin-1-yl) propylidene] -thiaxanthene, its isomers and their hydrochlorides.

60 g of 2-chloro-6-fluoro-9- (3-dimethylaminopropylidene) thiaxanthene and 159 g of b- (2-hydroxyethyl) piperidine and 20 g of 2-propanol were mixed together and the mixture was heated at 11 + 0 ° C for 2b hours. The mixture was cooled and dissolved in ether. The ether phase was extracted with water, dried over anhydrous potassium carbonate and evaporated to dryness. The residue was essentially the 2-chloro-6-fluoro-9- [3- (U- (2-hydroxyethyl) piperidin-1-yl) propylidene / thiaxanthene / J isomer, yield 50 g.

25 g of this product were recrystallized twice from 250 ml of 99- $ ethanol to give 7 g of the isomer, m.p. II + 3-1 ^ 6 ° C. The mother liquor was obtained by precipitation with hydrogen chloride dissolved in ethanol and recrystallization from ethanol several times with the hydrochloride of the o (-isomer), mp 220-222 ° C.

Example 15 Palmitic acid ester of the α-isomer of 2-trifluoromethyl-6-fluoro-9- [3- (N- (2-hydroxyethyl) -1-piperidyl) -propylidene] thiazanthene

Example 8 was repeated using the C <-isomer of 2-trifluoromethyl-6-fluoro-9- (3- (U- (2-hydroxyethyl) -1-piperidyl) propylidene) thiaxanthene 2-trifluoromethyl-6-fluoro-9- ( 3- (1- (2-hydroxyethyl) piperazin-1-yl) propyl) -thiaxantoen to give 2-trifluoromethyl-6-fluoro-9- (3- (1- (2-hydroxyethyl) -1-piperidyl) propylidene) palmitic acid ester of the o (-isomer) of thiaxanthene as a waxy mass.

Analysis: ^ 0Η55 ^ Ν ° 25

Calculated%: C 69.60 ·, N 2.03 Found%: C 68.73; N 1.77.

21 5741 0

Example 16 2-Trifluoromethyl-6-fluoro-9β- (1- (methyl-piperazinyl) propylidene] -thiaxanthene and its dihydrochloride 20 g of 2-trifluoromethyl-6-fluoro-9- (3- (U-methylpiperazinyl) propyl) -thiaxanthene 9-Ol was added to 10 ml of 37 ~ / S hydrochloric acid, and the mixture was stirred for 1+ hours at room temperature. The mixture was then poured into a mixture of 200 ml of water and 500 ml of diethyl ether and basified to pH 10 with 25% aqueous ammonia solution. The ether phase was washed 3 times with 100 ml of water each time, dried over anhydrous magnesium sulphate, treated with activated carbon, filtered and filtered. dry in a heating bath. The residue was dissolved in 100 ml of acetone and precipitated with anhydrous hydrogen chloride dissolved in diethyl ether. Allow to stand overnight at 9 ° C whereupon the separated oil crystallized. The crystals were filtered off with suction and washed with 100 ml of acetone to give 1U, 5 g of 2-trifluoromethyl-6-fluoro-9- [3- (N-methylpiperazinyl) -propylidene / thiaxanthene dihydrochloride, m.p. 2k2-2k5 ° C.

The starting material, 2-trifluoromethyl-6-fluoro-9- [3- (n-methylpiperazinyl) -propyl] -thiaxanthen-9-ol was prepared as follows: To 15 g of magnesium step dissolved in anhydrous tetrahydrofuran was added 1 ml of bromoethane, followed by 30 ml of over 53 g of 1- (3-chloropropyl) -N-methylpiperazine under reflux. The mixture was stirred for 2 hours, after which 60 g of 2-trifluoromethyl-6-fluorothiazanthone were added over 15 minutes. The reaction mixture was stirred for 30 min and then poured into 500 ml of crushed ice. 500 ml of toluene and then glacial acetic acid (about 75 ml) were added until the pH was 3. The aqueous phase was removed and the organic phase was washed with 500 ml of water. The combined aqueous phases were washed with 100 ml of toluene and then basified with 80 ml of 25% aqueous ammonia solution to a pH of about 10. The mixture was extracted with 500 ml of methylene chloride, the methylene chloride phase was separated, dried over anhydrous magnesium sulphate, filtered over Heating bath. The residue was treated with 300 mL of hexane and allowed to stand overnight. The crystals were filtered off with suction and dried to give U0.2 g of some impure 2-trifluoromethyl-6-fluoro-9- [3- (4-methylpiperazinyl) propyl] thiaxanthen-9-ol, m.p. 151-153 ° C. Upon recrystallization from 99% ethanol, the melting point rose to 155-157 ° C.

Claims (1)

A process for the preparation of new neuroleptically active 6-fluoro-substituted thiaxanthene compounds of the formula / X e / \ SC - CH - CH_ - CEL - NY (I) VV MF wherein X is -Cl, -CF 4 or - SOgNfCHg), R1 and R2 are hydrogen atoms or form a second bond between carbon atoms, and Y is> Ν0Η ^ 9> NCHgCHgOH,> CHCH2CH2OH or> NCH2CH2Oc or SCHCHgCHgQAc, wherein -Ac is an aliphatic acrylic acid having 1 to 16 carbon atoms, for the preparation of these acid addition salts, characterized in that a) thiaxanthenol of the formula .X 0 / \ / H / \ ^ C-CH2-CH2-CH2-S Ϊ (II) P w F wherein X and Y have the same meaning as above, dehydrated to give a compound of formula I wherein R 1 and R 2 form a second bond between carbon atoms, and the resulting compound is optionally catalytically reduced to give a compound of formula I wherein R 1 and R 2 are hydrogen atoms, or b) a compound of formula X 5741 O 23 0 / \ SC = CH-CH = CHO (III) 0 F ✓ wherein X is as defined above is reacted with an amine of formula H1 / wherein Y is as defined above to give a compound of formula I wherein R and R 2 forms a second bond between carbon atoms, and the resulting compound is reduced, if desired, to give a compound of formula I wherein R 1 and R 2 represent hydrogen atoms, or c) a compound of formula O'S CHM (IV) O / F wherein X is as defined above and M is an alkali metal, is reacted with a reactive ester of a compound of formula V hoch2ch2ch2n q, (V) 2.1 5741 0 wherein Y is as defined above and the optionally present hydroxy group is protected, and a compound of formula I is obtained wherein R1 and are hydrogen atoms, are separated after removal of any protecting group present, or d) a compound of formula X ό / \ / \ νΛ \ w wherein X, Rj and Rg are as defined above is reacted with ethylene. with an oxide to give a compound of formula I wherein Y is> HC 2 CH 2 OH, or e) a compound of formula X 0 - CH - CH 0 - CH 2 - hal (VI) t / \ 2 2 '/ F wherein X, R 1 and R 8 are as defined above, and the shark is chlorine, bromine or iodine, is reacted with an amine of the formula / \ HN Y \ __ y wherein Y is the same as above, or f) a compound of the formula 254141 0 0 _ ^ = ch-ch2-ch2-n (ch3) 2 (VII) o / F wherein X is as defined above is reacted with an amine of formula / \ HN YW where Y is as defined above, to give a compound of formula I wherein R. | and R 9 forms a second bond between carbon atoms, and the resulting compound is hydrogenated if desired, and the resulting compound of formula I is separated as the free base or non-toxic acid addition salt, that any hydroxy group present is esterified with a reactive derivative of an aliphatic carboxylic acid having 1 to 17 carbon atoms, and when denoting a second bond between the carbon atoms, the isomers are, if desired, separated in a conventional manner. 26 5741 0 For the preparation of neuroleptic active 6-fluoro-substituted thiaxanthenes with the formula / C - CH-CH -CH_-N \ (I) F color X is -Cl, -CF ^ or -SOgNiCH ^ g, R 1 and R 2 are a hydrogen atom or an image or a single bond with a column, and Y is> NCH 2,> NCH 2 CH 2 OH,> CHCH 2 CH 2 OH or> NCH 2 Cl 2 QAc or> CHCH 2 HgQAc, color -Ac is an l-16 color atomic acid in the case of aliphatic carboxylic acid, and in addition to the cyanide addition salt, in turn, a) in the form of thiaxanthenol in the form X 0 Π / 0H / "Λ Ö: -ch2-ch2-ch2-n y (ii) / F color X och Y har ovan angiven bethelse, dehydratiseras förhavlande av en förening with formula I, color R ^ and R2 bildar en ytterligare bindning mellan kolatcmerna, och cm sä volunka, den ehällna föreningen reducer catalytictt for the form of I, color R1 and R2 or b) in the case of formula 27 5741 0 X Ö J \ s C = CH-CH = CH2 (III) 0 F color X har angan angiven betydelse, o msättes med en Amin med formuleln HN ^ \ värv Y har ovan angiven betydelse, för erhällande av en förening med Formeln I, colony R och R2 bildar en ytterligare bindning Mellon colatomerna, och om sa volunskas, den erhallna föreningen reduceras f en förening , color R ^ och Rg betecknar väteatcmer, eller c) en förening med formula S S CHM (IV) F color X har angan betivenelydydse och M är en alkalimetall, omsättes med en reactiv Ester av en förening med formuleln V / \ H0CHoCHoCHoN Y ( V) Y_ / 2β 5741 0 color Υ has an angular characterization and eventual action of the hydroxyl group in the form of a formulation, and the action of the formulation of formula I, color R1 and R2 have an effect, separate after the event of the action of the action ) in the formulation of formula X / 1 / \ / \ / color X, R1 and in the form of an angular derivative, having the same ethylene oxide as the formulation in formula I, color Y is> NCH2CH2OH, or e) in the formulation of formulation X 0 SC - CH-CH_ -CH0-hal (VI) \ / '' 22 0 "F color X, and R2 is oval angiven betydelse, och hai är chloro, Brom eller iod, omsättes med en Amin med formuleln / - \ HN Y w color Y har ovan angiven betydelse, eller f) en förening med formeln