GB2124219A - Thienobenzothiepins - Google Patents

Abstract

4-(1-Methyl-4-piperidylidene)- 4,9-dihydrothieno(2,3-c)-2- benzothiepin of formula I <IMAGE> and its hydrogen (+) tartrate (a novel salt) are prepared by the reaction of thieno(2,3-c)-2-benzothiepin-4(9H)- one with 1-methyl-4- piperidylmagnesium chloride in tetrahydrofuran and subsequent acid- catalysed dehydration of the resulting 4- (1-methyl-4-piperidyl)-4,9- dihydrothieno(2,3-c)-2-benzothiepin- 4-ol after removal of the simultaneously formed 7-(1-methyl-4- piperidyl)thieno(2,3-c)-2-benzothiepin -4(9H)-one. Compound I and especially its hydrogen (+) tartrate possess high antihistamine, antiserotonin, antireserpine and anticataleptic activity and are expected to find use in the therapy of migraine.

Description

SPECIFICATION A process for the preparation of - (1 - methyl - 4 piperidylidene) - 4,9 - dihydrothieno (2, 3 - c) - 2 benzothiepin and its hydrogen (+)tartrate.

The invention relates to a process for the prepa ration of 4 - ( 1 - methyl - 4 - piperidylidene) - 4,9 dihydrothieno (2,3 - c) -2 - benzothiepin offormula I

and a novel salt thereof i.e. its hydrogen (+) tartrate.

The compound oftheformula I (pipethiadene) its hydrogen (+)tartrate are found to have a high degree of antihistamine, antiserotonin, antireserpine and anticataleptic activity and, due to their comparatively low toxicity, are expected to find use in the therapy of migraine.

This compound I waspharmacologicallytested by the inventors in the form of its hydrogen (+) tartrate; the salt was administered orally and intraperitoneally. The doses given are calculated for the base. Its effects in a number of pharmacological tests are similar to those oftricyclic antidepressants of the imipramine group: the compound acts antagonisticallytowards reserpine in mice (it antagonizes significantly the reserpine hypothermia in a does of 2mg/kg i.p.) and in rats (starting with a subcutaneous dose of 20mg/kg, it statisticallysignificantlysuppres- ses the ulcerogenic effect of reserpine), has a markedly pronounced anticataleptic effect in rats (its medium protective dose PD50 in the test of perphenazine catalepsy is 7.0mg/kg s.c.), and also antagonizes the oxotremorine tremor in mice (the threshold dose which significantly inhibits the tremor is 1 .Omg/kg i.p.).In addition to this, compound I has a pronounced central antiserotonin activity; this property is shown by influencing the behavioural manifestations induced bythe administration of 5 - hydroxy- tryptophan in rats, by influencing the quipazine hyperthermia in rabbits and, to a certain extent, by the interaction with tryptamine in rats.The intensity ofthe central antiserotonin effect of compound I on the behavioural syndrome after the administration of 5- hydroxytryptophan in rats is expressed by the medium protective doses (PD50 on subcutaneoous administration) against tremor (2.9mg/kg) and againstvertical motions oftheforepaw ("tapping"), (2.6mg/kg). The effect of compound I in this test is similarto that of cyproheptadine and substantially strongerthan the effect of amitriptyline.

The antihistamine and antiserotonin effects of compound I arethe most intensive among its peripheral effects. On oral administration to guineapigs, the antihistamine effect in the histamine aerosol test as expressed as the medium protective dose PD50 is 0.046mg/kg. In the tests of histamine detoxication 'and histamine bronchoconstriction, compound I compares in potency with the most potent antihistaminics known. The antiserotonin effect in the test of rat paw oedema after 5 - hydroxytryptamine is statistically significant after an oral dose of 0.3mg/kg.

Compound I has also mild peripheral anticholinergic effects: it acts mydriatically in mice and blocks the lethal action of acetylcholine in guinea-pigs.

As compared with the known antimigraine agent pizotifen Dixon et al., Arzneim.-Forsch. 27, 1968, 1977), compound I has a distinct advantage in its lower antidepressant activity. Oral administration, compound I inhibits the exploratory activity of mice in the observation test according to Boissier and Simon three times less intensively than pizotifen (D50 of compound I is 23mg/kg and D50 of pizotifen is 7mg/kg). In the test of spontaneous locomotor activity in mice with the use of the photo-cell method by Dews, the inhibitory activity of compound I is even seven times lowerthan the effect of pizotifen (D50 of compound I is 24.2mg/kg, D50 Of pizotifen is 3.4mg/ kg).In a less specific test ofthiopental sleep potentation in mice, the threshold dose of compound I corresponds to 10% of its oral LD50whereasthe threshold dose of pizotifen is only 2.5% of its oral LD50 (the oral toxicities ofthetwo compounds in mice are similar).Compound I has a distinct tendency to behavioural stimulation in rats: in observing its effect on the total activity ofthe animals with the use of the Animex instrument, the oral doses of 10 and 30mg/kg of compound I have a mild stimulatory effect (the animal activity increase to a value of 125 to 131 % of the control group), while oral doses of to 30mg/kg of pizotifen elicit a statistically significant suppression ofthetotal activity of the animals (to a value of 57 to 64% as compared with the control group).

The oral toxicity of compound I in rats is suprisingly low: after administration of a doseoflg/kg p.o. not a single animal out of a ten-membertest group died within 7 days. only mild depression was observed in the in the interval of 30 minutes after the administration. In mice the oral LD50is 129mg/kg. A single administration of compound I in doses of 50 and 100mg/kg p.o. to dogs does not induce any behavioural changes,toxic manifestations or anima death.

The compound offormula I was described in the litrature (Rajsner M., Metys J. and Protiva M., Collect.

Czech. Chem. Commun. 32,2854, 1967; Czechoslov.

patent No. 115241 ).ltwas prepared by the reaction of thieno (2,3 - c) - 2 - benzothiepin - 4 (9H) - one with 1 methyl -4- piperidylmagnesium chloride in tetrahy drofu ran and subsequent acid-catalyzed dehydration oftheformed 4- (1 - methyl -4- piperidyl) -4,9 dihydrothieno (2,3 - c) - 2 - benzothiepin - 4 - ol of formula II.

(1I)

At that time it was overlooked that compound II, which resulted from the Grignard reaction allegedly in a yield of 74%, was not homogeneous but considerably contaminated with another compound which remained unchanged during the subsequent acid-catalyzed dehydration (heating with diluted sulphuric acid) and so contaminated the final pro duct, i.e., compound I. The dehydration yield of 95% as reported in the mentioned paper related to an evaporation residue, i.e., to the crude compound I, which contained undefined amounts of the above impurity in the obtained product can also account for the low melting points as reported for compound II (125from benzene - petroleum ether and even 119 to 120from acetone).Those low-melting products were considered to be solvates; in fact, however, they were mixtures of compound II with the above mentioned impurity.

The reaction ofthieno (2,3 - c) - 2 benzothiepin - 4 (9H) - one with 1 - methyl - 4 - piperidylmagnesium chloride in tetrahydrofuran has recently been sub jected to a more detailed study, and the crude product obtained was separated by a combination of crystal lization and chromatographic methods. With the use of thin-layer chromatography on silica gel, the material obtained was shown to be rather in homogeneous and to contain, in addition to the amino alcohol II, also substantial amount of a less polar component. The pure amino alcohol II can be obtained from that crude product by extraction with ethanol; the desired compound II remains undis solved while the less polar substance passes into the solution.The latter substance can be isolated from the mother liquor by column chromatography on silica gel and purified by crystallization. It is most surprising that both the pure amino alcohol II and the pure less polar component melt exactly atthe same temperature of 212 to 21 30C. Their mixture, however, melts with a deep depression, and these are the melting points ofthe "solvates" as reported in the above-mentioned previous paper.

While the elemental analysis ofthe less polar component showed a composition which was quite similartothat of the amino alcohol li, the mass spectrum proved its exact composition C17H16NOS2, which corresponds to a compound containing two hydrogen atoms less than the amino alcohol 11. The ultraviolet spectrum of the new compound indicated a high degree of conjugation, which corresponds to a structure of a diaryl ketone. The infrared spectrum confirmed the diaryl ketone structure by a band at 1611cm-1. Both the infrared and 1H NMR spectra proved the abscene ofthe hydroxyl group.The difference in the 1H NMR spectra ofcompound II and ofthe less polar substance was especially significant in the region of signals of aromatic protons. While the spectrum of compound II indicates the presence of six aromatic protons, out of which the signals of five are merged to an unresolved multipletand onlythe signal ofthe proton in the position 5 of the skeleton is clearly separated, the H NMR spectrum of the less polar compound evidences the presence of onlyfive aromatic protons, the signals of which are all clearly differentiated and can be localized into the individual positions ofthe skeleton, the proton in the position 7 being absent.Further evidence of the structural difference between compound land andthe less polar 5 component is given by the mass spectra in the region corresponding to the fragments. While the main fragment of compound II has an m/z of 98, which corresponds to the ammonium ion with a preserved 1 - methylpiperidine structure, the main fragment of the less polar impurity has an m/z of 70; this correspondsto afragmentofmethylpiperidinewith only 4 carbon atoms. The first case istypical for a methylpiperidyl radical attached to an aliphatic carbon, the second case corresponds to the be haviourofa methylpiperidyl group bound to an aromatic carbon atom.All these spectral findings indicateforthe less polarcompoundthestructureof7 - (1 - methyl - 4 - piperidyl)thieno(2, 3 -c)- - 2 benzothiepin - 4(9H) - one offormula Ill

The formation of compound lil can be explained by a 1,6 - addition ofthe Grignard reagentto a system of three double bonds in the molecule ofthe starting ketone (including also the double bond ofthe keto group C = 0) orto a dipole formed by the forced enolization of the starting ketone underthe reaction conditions used (cf. Gaertner R., Chem. Revs. 45,493, 1949).Such an addition and subsequent hydrolysis had to befollowed byeliminationoftwo hydrogen atoms, i.e., by oxidation, probable under the action of the air oxygen. This wasthe case of a rather rarely observed reaction sequence which had previously been studied in reactions of sterically strongly hindered aromatic ketones, for example of 2,3,5,6 tetramethyl and 2,3,5,6 - tetramethyl - 2 methoxybenzophenone, with Grignard reagents (Fuson R. C. et al., J. Amer. Chem. Soc. 65,60, 1943; 71,2543, 1949; J. Org. Chem. 13,496, 1948).

An objectofthe present invention isto provide an improved processforthe preparation ofcompound I.

According to the present invention a process for the preparation of 4 - (1 - methyl -4- piperidylidene) 4,9 - dihydrothieno (2,3 - c) - 2 - benzothiepin of formula I

comprises the reaction of thieno (2,3 - c) - 2 - benzothiepin -4 (9H) - one with 1 - methyl -4piperidylmagnesium chloride in tetrahydrofuran and subsequentacid-catalyzed dehydration of the resulting 4 - (1 - methyl - 4 - piperidyi) - 4,9 - dihydrothieno (2,3 - c) - 2 - benzothiepin -4-ol of formula II

wherein said crude alcohol offormula II is made free ofthe simultaneously formed 7 - (1 - methyl - 4 piperidyl)thieno(2, 3 - c) - 2 - benzothiepin -4 (9H) - one offormula Ill

by extraction with ethanol, the pure alcohol of formula II is separated as the insoluble materia and subjected to said dehydration, and the obtained crude base offormula I is made free of the last residue of said ketone of formula lil by crystallization from ethanol, whereupon the pure base offormula I may be recovered.

Preferablythe process is continued by converting 4 - (1 - methyl - 4 - piperidylidene) - 4,9 - dihydrothieno (2,3 - c) - 2 - benzothiepin to its hydrogen (+) tartrate by neutralisation thereof with (+) tartaric acid in aqueous ethanol to provide a novel salt.

The process of this invention allows removal of the compound lli from the amino alcohol It, which is then used in an almost pure stateforthe dehydration, and also elimination of even the last residues of com pound Ill from the desired final product. These important additional operations make use of a better solubilityofcompound III in ethanol. The crude product of the first reaction step, i.e., of the Grignard reaction, is suspended in ethanol,thesuspension is heated to boiling point and after cooling the almost pure amino alcohol II is filtered by suction.This substance is obtained in a yield of approx. 50%; the mother liquorsthat contain rather considerable amountsofcompound Ill do notalloweconomic recoveryfurther amounts of the desired amino alcohol intermediate 11. The last residues of com pound III are eliminated from the final product I by crystallization from ethanol; this impurity remains in the mother solution. Finally, an integral part of the preferred process of the present invention is the preparation of a new hydrogen (+) tartrate of compound I by its neutralization with (+) tartaric acid in aqueous ethanol.The hydrogen (+) tartare readily crystallizes, is moderately soluble in water and much more suitableforthe preparation of final dosage forms than other acid addition salts (succinate, fumarate and hydrogen maleate), which were pre viously described (cf. Rajsner Metal., I. c.). The process forthe preparation of compound Ill in pure state is not described herein below, because it is not included in the present invention.

Example Fifty ml I ml ofdrytetrahydrofuran are added to 249 of magnesium, and approx. 25% of a solution of 1349 of 4 - chloro - 1 - methylpiperidine (Adlerova et al., Cesk.

farm. 12, 122, 1963) in 300ml of dry tetrahydrofuran (dried overthe molecular sieve Potasit4A) is let in and the mixture is warmed in an oil bath preheated to a temperature of 50to 55 C. Iodine (0.59) and 1 ml of 1, 2 - dibromoethane are added and the mixture is allowed to stand for approx. 10 to 30 minutes until the reaction starts. When the mixture begins to reflux vigorously the oil bath is removed and the remaining portion of the 4 - chloro - 1 - methylpiperidine solution is dropped in at such a rate that the reaction mixture continues to reflux intensely. When the reaction begins to run full rate, stirring is started. After approx.

40 - 50 minutes, by which time most ofthe solution has dropped in, the reaction mixture is warmed moderately. The refluxing is continued under stirring for another 1.5 hour. The mixture is then cooled with ice-cold water to 1 00C and treated, within one hour, under constant stirring and ice-water cooling, with a solution of 1 55g ofthieno (2,3 - c) - 2 - benzothiepin - 4 - (9H) - one (Protiva M., Rajsner M. et al., Collect.

Czech. Chem. Column. 29,2161, 1964; 3Z 2854, 1967; 39,1366, 1974) in 325 ml of dry tetrahydrofuran. The reaction mixture is maintained at a temperature of 10 to 15"C. When the solution was dropped incomplete- ly, the cooling is discontinued and the mixture is stirred for approx. 30 minutes until it warms spon taneouslyto room temperature.The resulting dark solution is treated, under vigorous stirring with a solution of 2259 of (+)tartaric acid in 2 litres of water at such a rate that the temperature ofthe mixture does not exceed 20 C (intensive external cooling is at first necessary). After that, 500m I oftoluene is added and the mixture is stirred vigorously for 10 minutes.

The toluene layer containing neutral substances is then separated, the aqueous portion is washed with 200ml of toluene, 1600ml of chloroform are added and the mixture is made alkaline, under intensive stirring and cooling, with 300ml of concentrated aqueous ammonia. The chloroform layer is sepa rated,the aqueous portion is extracted with 200ml of chloroform, and the combined chloroform solutions are washed with 300ml of water and allowed to stand for 12 hours over 30g of anhydrous potassium carbonate and 10g of active carbon. The solids are then filtered off and washed with 50ml of chloroform.

The chloroform is distilled off under moderately reduced pressure (10to 20kPa),the residue is diluted with 200ml of ethanol, and the mixture is shortly 0 refluxed and cooled to 5 C. The precipitated crystal line 4 - (1 - methyl -4-piperidyl) -4,9 - dihydrothieno (2,3-c) -2 - benzothiepin -4-ol (II) is filtered with suction, washed successively with 1 OOml of ethanol and 100ml of petroleum ether, and dried at room Stempernturn under reduced pressure. The yield is 1139 (51 % ) and the product melts at 209 - 211 C. The obtained material is almost pure and quite suitable forfurthertreatment. Crystallization of a sample from ethanol affords a completely pure substance having a Om.p. of 212-213 C.

A solution of 2409 of sulphuric acid in 1 170ml of water is treated at 40 to 50 C with 166g of the foregoing amino alcohol II and the mixture is refluxed for 15 minutes with stirring. After cooling, the mixture is diluted with 200ml of water,400ml of chloroform are added, and the stirred mixture is made alkaline with 2209 of concentrated aqueous ammonia, added dropwise. The temperature ofthe mixture is maintained at 20 to 30"C. The chloroform layer is separated and the aqueous portion is extracted with 2 x 100ml of chloroform. The combined chloroform solutions are washed with 1 some of water, dried over 20g of potassium carbonate, and after standing overnight the drying agent is filtered off.The filtrate is evaporated under moderately reduced pressure (10 to 2OkPa), the crystalline residue is treated with 900ml of ethanol and dissolved under stirring by heating to the boiling temperature. The solution is decolorized while hot by filtration with 1 0g of charcoal and the filtrate is allowedto crystallize at 5"C. After 12 hours of standing, the crystallized base of 4- (1 - methyl -4- piperidylidene) -4,9 - dihydrothieno - (2,3 - c) - 2 benzothiepin (I) is collected by suction and washed successively with 50ml of ethanol and 100ml of petroleum ether. On drying at room temperature, a yield of 1249 ofthe product is obtained.Evaporation ofthe mother liquor to a volume of 200ml and standing at 5 C affords a second batch of 149 ofthe product of a satisfactory purity; the overall yield is then 1389 (88%), m.p. 160 - 161 C. The entire amount of the material is suitable for the subsequent conver siontothesalt. Furthercrystallization of a sample yieldsthe completely pure base I melting at 162 164"C.

Base I (94g) is dissolved in 650ml of boiling ethanol.

After dissolution, heating is discontinued and a hot solution of 479 of (+) tartaric acid in 85 ml of water is added slowly. The solution formed is then cooled to 1 00C under stirring to induce crystallization. After 12 hours of cooling, the crystals are collected by suction and washed with 2 x 50ml of ethanol. The wet product is dissolved bywarming to the boiling temperature in a mixtureof 1250ml of ethanol and 1000my of water, the solution is filtered while hot and the filtrate is allowedfor4 hours under stirring and cooling in an ice bath to crystallize. The product is then washed with 2 x 30ml ethanol and dried in air at room temperature. The mother liquor is evaporated under reduced pressure (3 to 5kPa) to approx. one half ofthe initial volume and cooled to 5 Cto give a second batch ofthe product. The total yield is 1259 (90% ) of the hydrogen (+)tartrate ofthe base l; the salt melts (with decomposition) at 228 - 231"C.

Claims (9)

1. Aprocessforthe preparation of 4-(1 -methyl-4- piperidylidene)-4, 9-dihydrothieno (2, 3-c)-2-ben- zothiepin offormula I

by the reaction ofthieno (2, 3-c)-2-benzothiepin- 4(9H)-onewith l-methyl-4-piperidylmagnesium chloride in tetrahydrofuran and subsequent acid catalyzed dehydration ofthe resulting 4(1-methyl-4- II piperidyl)-4, 9-dihydrothieno (2, 3-c)-2-benzothieoin- 4-01 of formula II (11)

wherein said crude alcohol offormula II is made free ofthe simultaneously formed 7-(1-methyl-4- piperidyl)thieno(2, 3-c)-2-benzothiepin-4(9H).one of formula Ill

by extraction with ethanol, the pure alcohol of formula II is separated as the insoluble material and subjected to said dehydration, and the obtained crude base offormula I is made free ofthe last residue of said ketoneofformula Ill by crystallization from ethanol, whereupon the pure base offormula I may be recovered.

2. A process for preparing 4-(1-methyl-4-piper- idylidene)-4, 9-dihydrothieno (2, 3-c)-2-benzothiepin according to the Example hereinbefore.

3. 4-(1 -methyl-4-piperidylidene)-4, 9-dihyd- rothieno (2, 3-c)-2-benzothiepin whenever prepared by a process according to claim 1 orclaim2.

4. A process for converting 4-(1 -methyl-4-piperidylidene)-4, 9-dihydrothieno (2, 3-c)-2-benzothiepin to its hydrogen (+) tartrate comprising neutralisation thereofwith(+)tartaricacid inaqueousethanol.

5. Aprocessfor preparing the hydrogen (+) tartrate of 4-(1 -methyl-4-piperidylidene)-4, 9-dihyd- rothieno (2, 3-c)-2-benzothiepin according to the Example hereinbefore.

6. 4-(1 -methyl-4-piperidylidene)-4, 9-dihyd- rothieno (2, 3-c)-2-benzothiepin. hydrogen (+)tartrate.

7. A pharmaceutical composition comprising a therapeutically effective amount of 4-( 1 -methyl-4- piperidylidene)-4, 9-dihydrothieno (2, 3-c)-2-ben- zothiepin or a saltthereofwith a pharmaceutically acceptable acid, and a pharmaceutically acceptable excipient or carrier.

8. A pharmaceutical composition according to claim 7 wherein the acid is (+) tartaric acid.

9. 4-(1 -methyl-4-piperidylidene)-4, 9-dihyd- rothieno (2, 3-c)-2-benzothiepin or a pharmaceutically acceptable saltthereoffor use in thetherapy of migraine.