IL23275A - 9,10-dihydro-4h-benzo(4,5)-cyclohepta(1,2-b)thiophene derivatives and a process for their preparation - Google Patents

Description

•HIUJI fH3 TJinr m PATENT ATTORNEYS · □ ' D ] □ 3 ' D Ί 11) PATENTS AND DESIGNS ORDINANCE SPECIFICATION 9,10-Dihydro-4H-benzo ~4, 5/-cyclohepta l, 2-bJ thiophene derivatives ana a process for their preparation RDS>m^j?»s [5,4] iT3a-H4-T»T»n* -10,9 nn in tnasn 'jnni †ai»n [b-2tl] I (we) siiiiDoz A.G., a oc/iss company, of Basle, Switzerland do hereby declare the nature of this invention and in what manner the same is to be performed, to be particularly described and. ascertained in and by the following statement:- Case 194 The present invention relates to new heterocyclic compounds and a process for their production.

The present invention provides 9»10-dihydro-H-benzo[4,5]-cycloheptatl,2-b)thiophene derivatives of formula I, t Rl in which R^ signifies a lower alkyl radical, each of Rg and signifies a hydrogen atom or one of them signifies a hydrogen atom and the other a halogen atom of atomic number greater than 9 but smaller than 53, and their acid addition salts. The term "lower alkyl" as used herein signifies an alkyl radical of from 1 to carbon atoms inclusive, the methyl radical being the preferred one. The halogen atoms referred to herein are chlorine and bromine.

The present invention further provides a process for the production of compounds I and their acid addition salts, characterized in that water is split off from a compound of formula V, - - acid and, when an/addition salt is required, the resulting compound of formula I is reacted with an organic or inorganic acid.

The compounds of formula V may be obtained in such a way that a compound of formula IV, in which R^, R2 and have the above meaning, is reduced to give a compound of formula V. She compounds of formula IV may be obtained in such a way that a 9»10-dihydro~4H-benzo / ,57cyclo-hepta^l,2~b7thiophen 4-one of formula II, in which R2 and have the above signi icance, is reacted with a pyrrolidone-(2) derivative of formula III, H in which R^ has the above significance, in the presence of an alkali metal amide or an alkali metal hydride.

One method of producing the compounds of formula I is as follows: A pyrrolidone-(2) derivative of formula III, e.g. l-methyl~pyrrolidone-(2) , is added to a suspension of an alkali metal amide, e.g. lithium, sodium or potassium amide, compound of formula II dissolved in a suitable solvent, e.g. diethyl ether, is then added thereto. After stirring for from half to one hour at -35°C ammonium chloride and a suitable organic solvent, e.g. diethyl ether, are added to the reaction mixture, the ammonia is allowed to evaporate and the reaction mixture is subsequently stirred with ice water and a solvent suitable for extraction, e.g. dichloro-methane, diethyl ether or benzene. The resulting condensation product of formula IV is then isolated and purified in manner known per se. The reduction of the carbonyl compound is advantageously effected with lithium aluminium hydride or diborane in an inert organic solvent, e.g. tetrahydrofuran. The resulting complex is subsequently decomposed with saturated sodium sulphate solution, the inorganic compounds are filtered off and the reduction product of formula V is isolated from the filtrate in manner known per se. It may be purified by crystallization and, if required, converted into an acid addition salt. The required compound of formula I may then be obtained from the compound of formula V by the action of an agent for removing water. Examples of water removing agents which may be used are: mineral acids, strong organic acids, acetic anhydride, thionyl chloride, acetyl chloride, zinc chloride and phosphorus oxychloride. The resulting compound of formula I is isolated from the reaction mixture and purified by crystallization and/or by conversion into an acid addition salt.

Examples of preferred acids for acid addition salt formation are: hydrochloric, hydrobromic, phosphoric, sulphuric, methane-sulphonic, acetic, malonic, fumaric, maleic, tartaric, hexahydro-benzoic and ja-toluenesulphonic acid.

The compounds of formula I have valuable pharmacodynamic properties which could not be foreseen from their constitution; they In tests on animals they exhibit, inter alia, an inhibition of the vegetative and motor symptoms produced by reserpine or tetrabenazine, a potentiation of the noradrenalin effect and certain sedative and anticholinergic effects. The antidepressive effect is specific, whilst the neuroleptic properties are of secondary importance. These properties are especially pronounced in the case of 4-[l-methyl-pyrrolidinylidene-(3) }-9»10-dihydro-4H-benzo[4, 5]cyclohepta[1,2-b]- thiophene. The toxicity of the compounds of formula I is relatively low and they are therefore indicated for use in the treatment of neurotic and psychotic disorders, especially depressive conditions; another possible use is in the treatment of psychosomatic disorders. They are preferably administered in the form of their physiologically acceptable, water-soluble salts.

The compounds of formula I are indicated for use as pharmaceuticals on their own or in the form of appropriate medicinal preparations for administration, e.g. orally, enterally or parenterally. In order to produce appropriate medicinal preparations the compounds are worked up with organic or inorganic adjuvants which are inert and physiologically acceptable. Examples of such adjuvants are as follows tablets and dragees : lactose, starch, talc and stearic acid; injectable solutions : water, alcohols, glycerin and vegetable oils. The preparations may furthermore contain suitable preserving, stabilizin and wetting agents, solubilizers, sweetening and colouring substances and flavourings.

The present invention thus further provides pharmaceutical compositions containing, in addition to a physiologically acceptable carrier, a compound of formula I and/or an acid addition salt thereof.

The 9»10-dihydro- H-benzo[ ,5]cyclohepta[1,2-b]thiophen-4-one - 19*19 They may be produced by the following process: 2-thenyl-diethyl-phosphonate is condensed in a suitable anhydrous organic solvent and in the presence of an alkaline condensation agent with an o-phthal-aldehydic acid, which may be substituted in the 4- or 5-position by a chlorine or bromine atom, the resulting 2-[2-(2-thienyl)-vinyl)-benzoic acid, or its chlorine or bromine derivative, is reduced to the corresponding 2-[ - (2-thienyl)-ethyl]-benzoic acid and this is subjected to an intramolecular ring closure, whereby 9»10-dihydro-4H-benzo[4,5]cyclohepta[l,2-b]thiophen-4-one or its derivative substituted in the 7- or 6-position by a chlorine or bromine atom is obtained. Sodium amalgam in aqueous alcohol may, for example, be used as reducing agent and polyphosphoric acid as condensation agent for the ring closure.

In the following non-limitative Examples all temperatures are indicated in degrees Centigrade and are uncorrected.

E ample_l_: a) 4-hydroxy-4-[l-methyl-2-oxopyrrolidyl- (3) 3 -9, 10- dihydro-4H-benzo[4,53 oyolohepta[1, 2-b] thiophene.

Approximately 0.03 g of ferric nitrate are added to 100 cc of liquid ammonia, subsequently 0.49 S of lithium are added portionwise and the resulting dark blue mixture is stirred at -35° for half an hour. 4«5β g of l-Qethyl-pyrrolidone*(2) are then added to the gray resulting Lithium amide suspension. After stirring the mixture at -35° for half an hour a solution of 5·0 g of 9, 10-dihydro-4H-benzo[4, 53 cyclohepta[1, 2-b3 thiophen-4-one in 15 cc of absolute ether is added drop ise and stirring is effected for a further two hours. 4.2 g of ammonium chloride and 50 cc of ether are then added portionwise to the reaction mixture. After evaporating the ammonia, whereby the temperature rises to +10°, the reaction mixture is stirred with 300 cc of ice water and 100 cc of dichloromethane. The organic layer is separated, dried over sodium sulphate and evaporated. The residue is recrystallized from isopropanol. Melting point 73-86°. (mixture of diastereoisomers) . in b) -hydrox -4-[1-methy1-pyrrolidfr1- (3) 3 -9.10-dihydro- 4H-benzo [4. cyolohe ta[1, 2-b3 thiophene .

A solution of 5.2 g of 4-hydroxy-4-[l-methyl- in 2-oxo-pyrrolid l-(3) ]-9,10-dihydro-4H-benzo[4,53cyclo-hepta[l,2-b3 thiophene in 15 cc of absolute tetrahydro-furan is added dropwise whilst stirring at 5-10° to a suspension of 0.95 g of lithium aluminium hydride in 15 cc of absolute tetrahydrofuran. The mixture is subse uentl heated to the boil at reflux for a further hour, cooling and is effected /5 cc of saturated sodium sulphate solution are added dropwise whilst cooling. The resulting precipitate is filtered and extraoted by boiling several times w½h /tetrahydrofuran. The combined tetrahydrofuran filtrates are evaporated, the residue is taken up in 40 cc of ether and the solution is extracted with a 2N tartaric solution. then acid/ The tartaric acid extract is/made alkaline with a 30$ sodium hydroxide solution, the precipitated base is taken up in ether, the ethereal solution is dried over potassium carbonate and the solvent is evaporated.

The residue is recrystallized several times from benzene. in -hydroxy- -[l-methyl-pyrrolidyl-(3) ] -9, 10-dihydro-4H- benzo[ ,53cyclohepta[l,2-b]thiophene melts at 155-159°. in c) -[1-meth 1-p rrolidylldene-(5) 3 - , 10-dihydro-4H- benzo[4, 5] cyclohepta[l 2-b] thiophene. 17 cc of concentrated hydrochloric acid are added to a solution of 3.8 g of 4-hydroxy-4-[l-methyl- in pyrrolidyl-(3) 3 -9, 10-dihydro-4H-benzo[4, 3cyclohepta [1, 2-b3 thiophene in 50 cc of glacial acetic acid, boiling is effected for one minute and evaporation to dryness is effected at 12 mm Hg. The residue is then taken up in 20 cc of ethanol, the solvent is evaporated and the residue is dissolved in acetone. After the addition of 1-2 cc of ether the hydrochloride crystallizes from the acetone solution in the form of a mixture of cis-and trans-isomers; this mixture is recrystallized several times from ethanol. Melting point 258-260° The 9, 10-dihydro-4H-benzo[4, 53 cyclohepta [l, 2-b]thiophen-4-one used as starting material is produced as follows: 2-[2-(2-thieriyl) -vinyl] -benzoic_acid g of powdered, well dried sodium methylate are added to a solution of 117 g of thenyl-diethyl-phosphonate (boiling point 120-124°/0.06 mm Hg) in 200 cc of freshly distilled dimethyl formamide, whereby the temperature of the solution rises to 45-50° . The flask is then placed in an ice bath and a solution of 80 g of o-phthalaldehydic acid in 200 cc of dimethyl formamide is added dropwise at such a rate that the temperature remains between 3 and 40° and stirring is then effected for 30 to 60 minutes at room tempera-ture. ΙβΟΟ cc of water (temperature 10-15°) are then added to the reaction solution whilst cooling well, whereby a red oil separates. The solution is then made alkaline with potassium carbonate, whereby the oil re-dissolves, the reddish brown solution is shaken out carefully three times with benzene and hydrochloric acid is/added at 10-15° to adjust the pH value of the aqueous solution to 4. After several hours in a refrigerator the precipitated acid is filtered off, dried and recrys-tallized from benzene. 2-[2-(2-thienyl) -vinyl] -benzoic acid has a melting point of 133-135° . The mother liquor is shaken out three times with methylene chloride, the organic phase is dried over sodium sulphate and evaporated at 15 mm Hg. The residue is crystallized 7.5 g of sodium are melted under anhydrous toluene, whereupon 375 g of pure mercury are added whilst shaking requently at such a rate that the toluene boils* The mixture is then heated to 120-140° whilst stirring and as soon as all the toluene is distilled off cooling is effected to 50°. A solution of 20 g of 2-[2- (2-thienyl) -vinyl] -benzoic acid in 150 cc of 9 $ efchanol is then poured onto the homogeneous amalgam and the mixture is shaken for half an hour.

The mercury is then separated, washed twice with ethanol and the combined ethanolic solutions are diluted with 1200 cc of water. The solution is filtered through highly purified diatomaceous earth, acidified with hydrochloric acid and cooled to 5°· After several hours the precipitated acid is filtered off and crystallized from chloroform hexane· Melting point 110-111° .

JbQBS*. 59 cc of an 8$ phosphoric acid and 8β g of phosphorus pentoxide are first stirred at 125-I300 for half an hour. 20 g of powdered 2-[ 2- (2-thienyl) -ethyl] -benzoic acid are then added at the same tempera-ture during the course of half an hour. The reaction mixture is stirred for a further 2 hours at 125-1300, poured into 1000 cc of water, the solution is filtered through highly purified diatomaceous earth and ex ganic phase is washed with a 2N sodium carbonate solution, dried over magnesium sulphate, the solvent is evaporated and the residue distilled in a high vacuum, whereby 9, lOrdihydro-4EB-benzo[ , 53cyclohepta[1, 2-b] thiophen-4-one distils over at 125-l40°/0.05 mm Hg in the form of a green oil.

E amgle_2_: a) 7-chloro-4-hydroxy-4-[l-methyl-2-oxopyrroli<^l-(5) ] - 9.10-dihydro-4H-benzo[4,53oyolohepta[l,2-b3thiophene.

Approximately 0.03 g of ferric nitrate are added to 100 cc of liquid ammonia, subsequently 0.49 g of lithium are added portionwlse and the resulting dark blue mixture is stirred at -35° for half an hour. 4u56 g of l-methyl-pyrrolidone-(2) are then added to the resulting gray 11thiifln amide suspension. After stirring the mixture at -350 for half an hour a solution of 5.8 g of 7-chloro-9,10-dihydro-4H-benzo[4,53cyclohepta [1, 2-b]thiophen-4-one in βθ cc of absolute ether is added dropwise and stirring is then effected for a further 2 hours. 4.2 g of ammonium chloride and 50 cc of ether are then added portionwlse to the reaction mixture. After evaporating the ammonia, whereby the temperature rises to +10°, the reaction mixture is sti red with 300 cc of ice water and 100 cc of dichloromethane. The organic layer is separated, dried over sodium sulphate and evaporated. The residue is recrysta!lized from isopropanol and methanol. Melting point 165-Ιβ7°. - 11 - 1949 * b) 7-ohloro-4-hydroxy-4-[l-methyl-pyrrolidfrl-(3) 3- 9J10-dihydro"4H-benzo[4.53cyclohepta[lJ2-b]thlophene. 8o cc of a 0.661 molar ethereal lithium aluminium hydride solution are added dropwise to a solution of 11.5 S of the compound obtained in a) above i 60 cc of absolute tetrahydrofuran at 5°· The reaction mixture is subsequently stirred for half an hour at room temperature, cooled to 5° and 10 cc of saturated sodium sulphate solution are added dropwise whilst cooling. The resulting precipitate is filtered and washed several times with tetrahydrofuran. The combined tetrahydrofuran filtrates are evaporated, the residue is taken up in 120 cc of ether and the solution is ex- solution. tracted with a 2N sulphuric acid/ The sulphuric acid extract is then adjusted to a pH value of 11 with a 30$ sodium hydroxide solution and the precipitated base is taken up in methylene chloride. After drying the methylene chloride solution over sodium sulphate and evaporating the solvent the base is recrystallized from benzene. Melting point 90-94°. in c) 7-chloro-4-[l-methyl-pyrrolidylidene-(3) 3-9.10- dihydro-4H-benzo[4, 53eyelohe ta[112-b3 thiophene. 16 cc of concentrated hydrochloric acid are added to a solution of 4.0 g of the compound obtained in b) above in 0 cc of glacial acetic acid, heating is effected to 100° for 5 minutes and evaporation to dryness is effected at 12 mm Hg. The residue is then taken up in 20 cc of ethanol, the solvent is evaporated and the residue is triturated with 10 cc of acetone. from ethanol. Melting point 235-2370 (decomposition) (mixture of cis- and trans-isomers) .

The 7-chloro-9, 10-dihydro-4H-benzo[4, 5] cyclohepta[l, 2-b] thiophen-4-one used as starting mate-rial is produced as follows: 3-bromo -5;Chloro-phthalide.

A mixture of 72.5 g of 5-chloro-phthalide, 76.6 g of N-bromo-succinimide and 0.25 g of dibenzoyl peroxide is heated to the boil, whilst stirring for 22 hours, in 300 cc of absolute carbon tetrachloride. After cooling the reaction mixture filtration is effected and the filtrate is evaporated to dryness at reduced pressure and at 50° . After recrystallization from acetone the pure 3-bromo-5-chloro-phthalide, having a melting point of 108-110°, is obtained from the crystalline residue. 59.1 g of 3-bromo -5-chloro-phthalide are suspended in 600 cc of water and the suspension is heated to 100° for 8 hours whilst stirring well. Cooling is then effected to 0°, the 4-chloro-phthalaldehydic acid is filtered off and washed with ice cold water until neutral. Pure 4-chloro-phthalaldehydic acid, having a melting point of 184-186°, is obtained without fur-ther purification.

A solution of a mixture of 36.9 g of 4-chloro-phthalaldehydic acid and 47.0 g of 2-thenyl-diethyl- dropwise whilst stirring to a suspension of dry sodium methylate, produced from 10.4 g of sodium in 110 cc of dimethyl formamide. The dropwise addition is effected at such a rate that the internal temperature always remains at 3 - 5°. Stirring is subsequently effected for a further 15 minutes at room temperature and the mixture is then poured into 6000 cc of water. Dilute hydrochlorio acid is carefully added to acidify the alkaline aqueous solution to a pH value of 3. The precipitated material is filtered off and after recrystallization of the crude product from ethanol pure -chloro-2-[2-(2-thienyl) -vinyl] -benzoic acid, having a melting point of 198-200°, is obtained.

A suspension of l8.5 g of -chloro-2-[2- (2-thienyl) -vinyl] -benzoic acid in 350 cc of 95$ ethanol at 50° is added at once/to sodium amalgam, produced from 7,0 g of sodium and 520 g of mercury. Stirring is aifcscquently effected for 3 hours at room temperature and the ethanolic solution of the reaction product is then separated from the mercury. Evaporation to dryness is effected at 60° and reduced pressure and the residue is then dissolved in 1000 cc of water. The solution is filtered and the filtrate is acidified with concentrated hydrochloric acid. The reaction product is extracted with ether, the extracts are dried over sodium sulphate and the solvent is evaporated at reduced pressure and 300. The crystalline residue is re- 2-[2-(2-thienyl) -ethyl] -benzoic acid, having a melting point of 127-128°. thiophen-4-one. 104 g of phosphorus pentoxide and 74 cc of an 8c phosphoric acid are mixed and the mixture is heated to 140° whilst stirring for half an hour.

Subsequently 25.7 g of 4-chloro-2-[2-(2-thienyl) -ethyl] -benzoic acid are added at the same temperature and stirring is effected for a further 3 hours at l4o°.

The hot reaction mixture is then poured into 1400 cc of water. Extraction is effected several times with ether, the combined extracts are dried over sodium sulphate and the solvent is evaporated at 30° and reduced pressure. The viscous residue is distilled in a hot air bath at a strongly reduced pressure. Boiling point 170-l80°/0.1 mm Hg. The distillate is made to crystallize from a mixture of ether and petroleum ether.

Pure 7-chlor0-9, 10-dihydro-4H-benzo[4,5] cyclohepta [l,2-b]thiophen-4-one melts at 63-β4°.

Example 3: _= in a) 6-chloro-4-hydroxy-4-[l-methyl-2-oxopyrrolidyl-(3) ] - 9.10-dihydro-4H-benzo[4J53oyclohepta[1.2-b]thiophene.

This compound is obtained from 5.8 g of 6-chloro-9, 10-dihydro-4H-benzo[4,5]cyclohepta[l, 2-b] thiophen-4-one in 35 cc of absolute tetrahydrofuran in a manner analogous to that described in Example 2, a) .

Melting point 114-115° from carbon tetrachloride. in b) 6-ohloro- -hydroxy-4-[l-methyl-pyrrollo¾-l-(3) 3 -9.10- dlhydro-4H-benzo[4, 53 oycloheptaCl, 2-b] thiophene.

This compound is obtained in a manner analogous to that described in Example 2, b). Melting point 169-171° from acetone (mixture of diastereo-isomers) . in c) 6-chloro-4-[1-methy1-pyrrolid^lidene-( ) 3 -9.10- dihydro-4H-benzo[4, 3oyolohepta[lJ 2-b3 thiophene. 1 mol of water is split off from the compound obtained in b) above in a manner analogous to that described in Example 2, c). The resulting residue is then dissolved in ethanol, the solvent is evaporated and the residue is recrystallized first from isopropa-nol and then from ethanol. Melting point of the hydrochloride: 3OO-3050 (decomposition, mixture of cis-and trans-isomers) .

The 6-chloro-9, 10-dihydro-4H-benzo[4, 53 cyclohepta[l,2-b3thiophen-4-one used as starting material is produced as follows: A mixture of 60 g of β-chloro-phthalide, 6l.5 g of N-bromo-succinimide and 0.15 g of benzoyl peroxide in 4000 cc of anhydrous carbon tetrachloride is heated to the boil whilst stirring for 22 hours.

The hot solution is filtered and the filtrate is evaporated at 15 mm Hg. The crude 3-bromo-6-chloro-phthalide is subsequently heated to 100° with AOO cc of water for 8 hours and the solution is filtered through precipitated acid is filtered off, the diatomaceous to the boil earth is heated/once more for several hours together with the mother liquor, the hot solution is filtered and evaporated to a small extent at reduced pressure, whereby a further portion of acid is obtained. After drying in a vacuum at 90° the acid melts at I36-I380. 1 to 2 cc of a solution of 70 g of 5-chloro-phthalaldehydic acid and 89 g of 2-thenyl-diethyl-phosphonate in 135 cc of dimethyl formamide are added dropwise to a suspension of 5.6 g of sodium methylate in 135 cc of dimethyl formamide, whereby the temperature of the mixture rises to 35-40° · The flask is then placed in an ice bath and the remainder of the solution of 5-chloro-phthalaldehydic acid and 2-thenyl-diethyl-phosphonate is added dropwise as rapidly as possible and at such a rate that the internal temperature remains at 35-40°. The reaction mixture is then stirred for a further 30 minutes at room temperature. 300 cc of water are slowly added to the reaction solution at 10-15° whilst cooling well and the aqueous solution is shaken out with 300 cc of benzene. 2N hydro chloric acid solution is then carefully added to adjust the pH value of the aqueous solution to 3 to 4. After several hours the precipitated acid is filtered off and dried. Melting point 152-153° .from benzene.

I8.8 g of sodium are melted under anhydrous dropwise whilst shaking frequently, at such a rate that the toluene boils. The mixture is then heated to 120-140° whilst stirring and as soon as all the toluene is distilled off cooling is effected to 60° . The homo-geneous amalgam is covered with a solution of 50 g of -chloro-2-[2-thienyl-(2) -vinyl] -benzoic acid in 350 cc of 9 $ ethanol and the mixture is vigorously shaken for 1 V2 to 2 hours. The mercury is then separated, washing is effected three times with ethanol and the combined ethanolic solutions are diluted with 5000 cc of water. The solution is filtered through highly puri- solution fied diatomaceous earth and a 2 hydrochloric acid/ is slowly added whilst stirring and cooling to adjust the pH value to 1. After several hours the precipitated acid is filtered off and recrystallized from ethanol. Melting point 13 -13 ° . thiophen-4-one . 90 cc of an 8 $ phosphoric acid and 126 g of phosphorus pentoxide are first stirred at 125-130° for half an hour. 30 g of finely powdered 5-chloro-2-[2-thienyl- (2) -ethyl] -benzoic acid are then added at the same temperature during the course of half an hour.

The reaction mixture is then stirred for a further hour at 125-130°, poured into 1500 cc of ice water, the solution is filtered through highly purified diatomaceous earth and extracted three times with methylene chloride. The organic phase is first washed with a 2N sodium sulphate, the solvent is evaporated and the residue is distilled in a high vacuum, whereby 6-chloro-9, 10 dihydro-4H-benzo[4,5]cyclohepta[l, 2-b] thiophen-4-one distils over at 185-195°/0.1 mm Hg in the form of an oil which crystallizes. Melting point 107-108° from ether.

Claims (1)

1. particularly and ascertained the nature of our in what manner the mm to that what claim A process for the production of derivatives of formula in which signifies a lower l each of and signifies a hydrogen atom or one of them signifies a hydrogen atom and the other a halogen atom of atomic number greater than 9 but smaller than and their acid addition characterized in that water is split off from a compound of formula in which when an acid addition salt is the resulting compound of formula I is reacted with an organic or inorganic A process according to Claim in which the compound of formula V is obtained in such a way that a compound of formula in which and have the meaning stated in Claim is reduced to give a compound of formula A process according to Claim in which the compound of formula IV is obtained in such a way that a of formula in which and have the meaning stated in Claim is reacted with a derivative of formula in which has the meaning stated in Claim in the presence of an alkali metal amide or an alkali metal A process for the production of the compounds of formula I stated in Claim 1 and their acid addition salts substantially as herein described with reference to any one of the The compounds of formula I stated in Claim 1 and their acid addition salts whenever produced by the process claimed of formula I stated in Claim 1 and their acid addition acid addition salts of the compounds claimed in any one of Claims 8 and Pharmaceutical compositions in addition to a physiologically a compound of formula I an acid addition salt For the Applicants insufficientOCRQuality