CS255873B2 - Process for preparing derivatives of substituted 3-phenyliminothiazolidine - Google Patents

Abstract

The compounds of formula Ia, wherein R5 is independently hydrogen or C 1-4 alkyl, R halogen, C 1-4 alkyl, halomethyl, nitro-, amino-, hydroxy- C 1-4 alkoxy, carboxy or C 1-4 alkoxy carbonyl and n 0,1 or 2 are produced cyclizing the isothiocyanate of the formula II, wherein R1, R2, Ran are as defined above preferably in the presence of an acid, preferably Hydrogen chloride. Optionally, the product is converted to pharmaceutically acceptable addition salts with acid that have antidepressant, antiparkinsonian, antiepileptic a spasmolytic action.

Description

(54) A method for producing substituted 3-phenyliminothiazolidine derivatives

Compounds of formula (Ia) wherein R ^ and independently of one another are hydrogen or C1-4alkyl, R1 halogen, C1-4alkyl, halomethyl, nitro-, amino-, hydroxy-, C1-4alkoxy-, carboxy or C1-4alkoxycarbonyl and O, 1 or 2, are prepared by cyclizing an isothiocyanate of formula II wherein R 1, R 2, Ran are as defined above, in the presence of an acid, preferably hydrogen chloride. The product is optionally converted into pharmaceutically acceptable acid addition salts having antidepressant, antiparkinsonian, antiepileptic and spasmolytic activity.

The invention relates to a process for the preparation of novel substituted 3-phenyliminothiazolidine derivatives having pharmaceutical activity.

Hungarian patent specification 164 034 discloses 2-imino-1- (o-nitrophenyl) imidazolidines Hungarian patent specification 164 035 relates to a process for the preparation of 2-imino-1- (o-aminophenyl) imidazolidine derivatives. 3- (unsubstituted phenyl) thiazolidine and its light protection have been described by T. Huno et al (Chem. Pharm. Bull. (Tokyo) 14 (11), pages 1 201-1129 (1966)).

The present invention provides a process for the preparation of substituted 3-phenyliminothiazolidine derivatives of the general formula Ia

where it means

2

R and R independently of one another are hydrogen or alkyl of 1 to 4 carbon atoms,

R is halogen, C1-C4alkyl, halomethyl, nitro, hydroxy, C1-C4alkoxy, carboxy, C1-C4alkoxycarbonyl or amino, and is 0,1 or 2, and pharmaceutically acceptable acid addition salts thereof, characterized in that the isothiocyanate of the formula II

SCN (II)

Wherein R, R, Ran are as hereinbefore defined, cyclizes in the presence of an acid, and the compound of formula (Ia) obtained is optionally converted to its pharmaceutically acceptable acid addition salt.

Preferred compounds of formula (Ia) are derivatives wherein the nitro group is in the 2-position with respect to the phenyl carbon atom bonded to the thiazolidine nucleus.

2

In formula (Ia), preferably R and R are each hydrogen, n is zero or 1 and R is chlorine, trifluoromethyl, methoxy or amino.

The pharmaceutically acceptable acid addition salts of the derivatives of formula (Ia) may be inorganic or organic acid addition salts such as, for example, hydrochloride, hydrobromide, sulfate, nitrate, acetate, lactate, fumarate, maleate, tartrate, methanesulfonate, ethane sulfonate and the like.

The cyclization of the isothiocyanate of the formula II is preferably carried out in a protic dipolar solvent such as methanol or ethanol at elevated temperature, preferably at a temperature of 60 to 100 ° C, for example at the boiling point of the reaction mixture. The acid used is preferably hydrochloric acid or hydrogen chloride gas. However, other acids may also be used. The resulting product can be isolated from the reaction mixture by methods known per se, for example by cooling the mixture, evaporating the solvent, or adding a solvent such as an ether. Preferably, the product is isolated in the form of a crystalline salt.

The compound of formula (Ia) obtained can be reacted with inorganic or organic acids to obtain the corresponding acid addition salts. Similarly, the free bases can be liberated from the acid addition salts by reacting the acid addition salts with bases. These reactions can be carried out by methods known per se. For example, a compound of formula Ia is reacted in a suitable inert solvent with a stoichiometric amount or a slight excess of acid to give an acid addition salt of a compound of formula Ia.

The invention also relates to ^{: a} process for the preparation of all enantiomers, diastereomers and racemates of the compounds of the formula Ia.

The starting compounds used in the process according to the invention are known compounds or can be prepared by methods known per se.

The novel compounds of the formula Ia prepared by the process according to the invention have valuable antidepressant, antiparkinsonian, antiepileptic and spasmolytic properties associated with mild analgesic action. The activity of the compounds of the invention was verified by the following tests.

1) Acute toxicity in mice

Acute toxicity was determined using mice of both sexes (CFLP breed, body weight 18-22 g). Six mice were used to test each dose. The test compound is administered orally in a volume of 20 ml / kg body weight. After administration, mice are observed for seven days.

During this time, mice are alive with standard mouse food, with water being ad libitum. Toxicity values were determined by the Lichtfield-Wilcoxon method.

2) Antagonism of tetrabenazine ptosis in mice

The tetrabenzine ptosis antagonism of the compounds of formula Ia was tested in groups of ten mice. Mice are treated orally with various doses of test compounds by administering to the control group of mice the corresponding vehicle without the active compound of formula Ia. 30 minutes after drug or vehicle delivery, 50 mg / kg tetrabenazine, which is 3-isobutyl-9,10-dimethyl-1,2,3,4,6,7-hexahydrobenzo [a] quinolizine-2, is administered intraperitoneally. -he; and ptosis mice are counted 30, 60, 90 and 120 minutes after tetrabenazine administration. The mean ptosis value is then calculated for each group and the deviation from the mean value found for the control group (inhibition) is given as a percentage. Calculate Εϋ ^ θ from the values.

3) Antagonism of reserpine ptosis in mice

Each group of 10 mice is treated subcutaneously with 6 mg / kg reserpine. After 60 minutes, the mice are treated with the test compound of formula Ia, wherein the mice of the control group are treated with the vehicle alone without the active compound of formula Ia. Ptose mice are counted 60 and 120 minutes after administration of the test compound. Test evaluation is performed as described for Test 2).

4) Toxicity of yohimbine in mice

The test is carried out by the Quinton method. Each group, consisting of 10 mice, is treated with test compound and vehicle without active ingredient. After one hour, a sublethal dose of 20 ml / kg body weight of yohimbine is administered intraperitoneally to the test group. The number of dead mice is determined 1 hour and 24 hours after administration of yohimbine.

5) Inhibition of nicotine-induced convulsions

The test is performed on mice using the Ston method. One hour after oral treatment, a dose of 1.4 mg / kg of nicotine is injected intravenously and recorded seizures or deaths are recorded in both the test and control groups.

6) Inhibition of pentaterezole-induced convulsion

The test is carried out using a modified Banziger and Han method in mice. Each group, consisting of six mice, is treated orally with a test compound of formula Ia and a carrier without active compound of formula Ia. One hour after treatment, 125 mg / kg of pentatetrazole was administered intraperitoneally to each animal and the lower eyelid extension spasm was recorded.

7) Maximum electroshock inhibition

The test is performed on mice weighing 20-25 g by the Swinyard method. Corneal electrodes apply electroshocks with the following parameters: 50 Hz, 45 mA and 0.4 seconds. A perfect inhibition of the tonic spasm of the extensor of the lower eyelid is considered to be a criterion for anticonvulsant (anti-jerking) action. An hour before the electroshock, the animals are orally treated with test compounds of formula Ia and a carrier free of compounds of formula Ia.

8) Antiperistaltic effect on mice

The antiperistaltic activity of the compounds of formula (Ia) was tested using mice weighing 20-25 g by the method of Stickney et al. Each dose of the test compound of formula (Ia) is administered orally for 60 minutes by administering a 10% suspension of activated carbon. At the same time, the control group is treated in a similar manner using saline or other vehicle. 20 minutes after the administration of the activated carbon suspension, the mice are sacrificed and the total length of the small intestine and the length of the small intestine filled with activated carbon are determined. Inhibition was calculated as a percentage of the control group. The antiperistaltic effect is considered positive if the proportion of small intestine filled with activated carbon suspension does not exceed 50% of the total length of the small intestine. From the transformed values, Εβ ^ θ values are calculated.

9) Analgesic effect on mice (writhing test)

The test is performed on mice using the modified Newbould method. Mice are treated intraperitoneally with 0.75 acetic acid at 20 ml / kg and the characteristic writhing reactions are counted for 5 minutes starting at 5 minutes after initiating the reaction. Observe the number of writhes in both treated and control animals. The inhibition is evaluated as a percentage with respect to the control group.

The tests were carried out with the following compounds of formula Ia:

= 3- (4-chloro-2-nitrophenyl) -2-iminothiazolidine hydrochloride

6 = 3- (2-nitro-4-trifluoromethylphenyl) -2-iminothiazolidine hydrochloride = 3- (5-chloro-nitrophenyl) -2-iminothiazolidine = 3- (2-nitrophenyl) -2-iminothiazolidine = 3- (4-methoxy -2-nitrophenyl) -2-iminothiazolidine hydrobromide 15 = 3- (4-amino-2-nitrophenyl) -2-iminothiazolidine

The test results are summarized in the following tables.

Table I

Compound ^LD 50 Antagonism tetrabenazine ptoses number mg / kg ED ₅₀ , mg / kg Therapeutic index 11 650 40 16.3 amitriptyline 225 12 18.7

Table II

Compound number 11 amitriptyline bulka III ^LD 50 mg / kg 650,225 Antagonism of reserpine ptosis ED ₅₀ mg / kg 40 65 Terepeutic index 16.3 3.5 Compound ^LD _n Inhibition of lethality by nicotine number 5 U mg / kg ED ₅₀ mg / kg Therapeutic index 5 1 100 9 122.0 10 700 50 24.0 11 650 45 14.4 trihexylphenidyl 365 40 9.1 bulka IV Compound ^LD 50 Inhibition of pentatetrazole spasm C1S1O mg / kg ^e D ₅₀ > mg / kg Therapeutic index 5 1 100 66 16.60 11 650 34 19.11 trimethadione 2 050 490 4.30 bulka V Compound ^LD 50 Inhibition of intestinal peristalsis number mg / kg ^ED 50 ' ^m 9 ^{/ k} 9 Therapeutic index 6 800 8 100.00 9 700 18 38.90 10 700 140 5.00 11 650 105 6.20 15 Dec 1 200 130 12.00 papaverine 380 185 2.01 bulka VI Compound ^LD 50 Analgesic effect (twitch test) number mg / kg ED ₅₀ mg / kg Therapeutic index 9 700 54 13.0 10 700 40 17.5 15 Dec 1 200 115 10.4 paracetamol 510 180 2.9

Pharmaceutical compositions containing as active ingredient a compound of formula (Ia) or a pharmaceutically acceptable acid addition salt thereof may be prepared by known methods for preparing pharmaceutical compositions.

These pharmaceutical compositions are preferably in the form of orally administrable compositions such as tablets, capsules, coated tablets, solutions, suspensions and the like, or parenterally administrable compositions such as sterile solutions or suspensions.

Orally administrable pharmaceutical compositions generally include carriers such as gelatin, sorbitol, latose, sugar, starch, calcium phosphate, polyvinylpyrrolidone, magnesium stearate, talc, polyethylene glycol, silica, sodium lauryl sulfate, and the like.

Formulations for parenteral administration include conventional carriers for such type of formulations as sorbitol, sugar solutions, glycerin, propylene glycol, ethanol, and the like.

The daily dose of the compound of formula Ia is generally 0.1 to 1000 mg / kg and preferably 1 to 100 mg / kg.

The invention is illustrated by the following non-limiting examples.

Example 1

Preparation of 2-inino-3- (2-nitrophenyl) thiazolidine hydrochloride

Hydrogen chloride gas is introduced into a solution of 0.4 g (0.018 mol) of 2-nitro-N- (2-thiocyanatoethyl) aniline in 50 ml of ethanol for 30 minutes while boiling the solution. After cooling, the separated crystals were filtered off, washed with ether and dried.

3.9 g (83% of theory) of 2-imino-3- (2'-nitrophenyl) thiazolidine hydrochloride are obtained in the form of a yellow crystalline powder. Melting point 286 ° C (dec.) (Ethanol-ether).

Analysis for C _g H ₁₀ ClN ₃ O ₂ S (MW 259,8) calculated: Cl 13.66% N 16.17% S 12.34% Found: Cl 13.54% N 16.23% S 12 The base is released as follows:

A solution of 1.3 g (0.005 mol) of the above hydrochloride was basified with 40% aqueous sodium hydroxide solution to pH 9. The precipitated crystals were collected by filtration, washed with water and recrystallized from ethyl acetate / petroleum ether.

1.0 g (90% of theory) of 2-imino-3- (2'-nitrophenyl) thiazolidine is obtained as a yellow crystalline powder. Melting point: 127 ° C.

Example 2

Preparation of 2-imino-3- (4'-methyl-2'-nitrophenyl) thiazolidine hydrochloride

2.0 g (0.008 4 mol) of 4-methyl-2-nitro-thiocyanatoethyl) aniline is boiled in 50 ml of ethanol for one hour while hydrogen chloride gas is introduced into the solution. At the end of the reaction, the heterogeneous reaction mixture becomes homogeneous. The solution is evaporated to half its volume and the crystals precipitated by cooling are filtered off, washed with a small amount of ethanol, then washed with ether and dried. .

1.8 g (78% of theory) of 2-imino-3- (4'-methyl-2'-nitrophenyl) thiazolidine hydrochloride are obtained in the form of a yellow crystalline powder. Melting point: 287-289 ° C.

The base is filled as follows:

1 g of the above prepared hydrochloride is stirred vigorously in a mixture of 20 ml of saturated aqueous potassium carbonate solution and 25 ml of chloroform. The phases are separated, the aqueous phase is extracted twice with 10 ml of chloroform each. The combined organic phases were dried over anhydrous magnesium sulfate and evaporated.

0.78 g (90% of theory) of 2-imino-3- (4-methyl-2'-nitrophenyl) thiazolidine is obtained in the form of a pale yellow crystalline powder. Melting point: 132-134 ° C (etherpetrol ether).

Analysis for ^{C H} l 3 ^N ° 2 ^S (molecular weight 237.3): Calculated: C, 50.62% H, 4.67 and N, 17.71% S and 13.51 Found: C 50.52% H 4, 59% N 17.89% S 13.69%

Example 3

Preparation of 2-imino-3- (4'-methoxycarbonyl-2'-nitrophenyl) thiazolidine hydrochloride

To a mixture of 0.5 g (0.001 8 mol) of methyl 3-nitro-4-N- (2-thiocyanatoethyl) aminobenzoate and 10 ml of anhydrous methanol was added dry hydrogen chloride gas for one hour at reflux.

The solution obtained is evaporated to approximately one third of its volume and ether is added to induce crystallization. After cooling, the crystals were removed by filtration, washed with ether and dried

0.4 g (71% of theory) of 2-imino-3- (4'-methoxycarbonyl-2'-nitrophenyl) thiazolidine hydrochloride is obtained. Melting point 242 ° C (dec.) (Methanol-ether).

The base is released as follows:

1 g of the above prepared hydrochloride is stirred vigorously in a mixture of 20 ml of saturated aqueous sodium carbonate solution and 30 ml of dichloromethane. The phases are separated, the aqueous phase is extracted twice with 10 ml of dichloromethane each time. The organic solutions were combined, dried and evaporated.

0.8 g (80% of theory) of 2-imino-3- (4'-methoxy-2'-nitrophenyl) thiazolidine are obtained. Melting point 156 ° C.

Analysis for ^{C H} beta N ° 4 ^N 3 ^S (molecular weight 281.3): Calculated: C 46.97% H 3.94% N 14.34% Ξ 11.40% Found: C, 47.02% N, 4 16% N 14.07% S 11.30%

TLC (toluene-ethyl acetate 1: 1) = 0.25.

Example4

Preparation of 2-imino-3- (2'-nitro-4'-trifluoromethylphenyl) thiazolidine hydrochloride

To a solution of 5 g (0.017 mol) of 2-nitro-4-trifluoromethyl-N- (2-thiocyanatoethyl) aniline in 30 ml of ethanol was added dry hydrogen chloride gas under reflux for one hour.

At the end of the reaction, crystals precipitate. After cooling, the crystalline mass was collected by filtration, washed with ether and dried.

4.5 g (81% of theory) of 2-imino-3- (2'-nitro-4'-trifluoromethylphenyl) thiazolidine hydrochloride are obtained in the form of a pale yellow crystalline powder. Mp 295 ° C (dec. (Ethanol)) ·

Analysis for C ^ %HgClF ^NjOjS (MW 327.8) calculated: C 10.83% N 12.82% S 9.78% found: C 10.98% N 12.78% S 9.57 i

Example 5

Preparation of 2-imino-3- (4'-methoxy-2'-nitrophenyl) thiazolidine hydrochloride

To a suspension of 2.5 g (0.01 mole) of 4-methoxy-2-nitro-N- (2-thiocyanatoethyl) aniline in 60 mL of anhydrous ethanol was added dry hydrogen chloride gas for one hour at reflux.

After cooling, the precipitated crystals are filtered off, washed with ether and dried.

2.1 g (73% of theory) of 2-imino-3- (4'-methoxy-2-nitrophenyl) thiazolidine hydrochloride are obtained in the form of a yellowish-white crystalline powder. Mp 288-290 ° C (dimethylformamide ether).

Calculated: Cl 12.25% N 14.50% S 11.06% Found: Cl 12.43% N 14.23% S 10.91%

The corresponding base is liberated with a 40% aqueous sodium hydroxide solution and is in the form of a red crystalline powder. Melting point: 108 ° C (ethyl acetate / petroleum ether).

Example 6

Preparation of 2-imino-3- (4'-chloro-2'-nitrophenyl) thiazolidine hydrochloride

Dry hydrogen chloride was added to a suspension of 5.15 g (0.02 mol) of 4-chloro-2-nitro-N- (2-thiocyanatoethyl) aniline in 50 ml of anhydrous ethanol for one hour.

During the reaction, the color of the crystalline mass changes from orange to pale yellow. After cooling, the crystals were filtered off, washed with ether and dried.

5.5 g (93% of theory) of 2-imino-3- (4'-chloro-2'-nitrophenyl) thiazolidine hydrochloride are obtained. Melting point: 295-296 ° C (decomposition) (ethanol).

Analysis for C 8 H 8 Cl 3 N 4 S (molecular weight 295.0) calculated: Cl 24.04% N 14.24% S 10.87% found: Cl 24.08 N 13.88% S 10.61%

Example 7

Preparation of 2-imino-3- (5'-chloro-2'-nitrophenyl) thiazolidine hydrochloride

Dry hydrogen chloride gas was introduced into a suspension of 11.5 (0.045 mol) of 5-chloro-2-nitro-N- (2-thiocyanatoethyl) aniline in 100 ml of anhydrous ethanol for 30 minutes. The reaction mixture is evaporated in vacuo to approximately half its volume. After cooling, the crystals were filtered off, washed with ether and dried.

11 g (83% of theory) of 2-imino-3- (5'-chloro-2'-nitrophenyl) thiazolidine hydrochloride are obtained in the form of a pale yellow crystalline powder. Melting point: 279-281 ° C (dec.) (Methanol-ether).

Analysis for C _g H _g Cl ₂ N ₃ O ₂ S (MW 295,0) calculated:% C124,04 Nl4,24% S10,87% Found: Cl 23.92% N 14.43% S 1-1 , 20%

Example 8

Preparation of 2-imino-5-methyl-3- (4'-chloro-2'-nitrophenyl) thiazolidine hydrochloride

12 g (0.044 mol) of 4-chloro-2-nitro-N- (2-methyl-2-thiocyanatoethyl) aniline are suspended in 150 ml of anhydrous ethanol and dry hydrogen chloride gas is introduced into the suspension for two hours under reflux. After 30 minutes a homogeneous solution is obtained, then crystals develop. After cooling, the crystals were filtered off, washed with ethanol, then with ether and dried.

There was thus obtained 2-imino-5-methyl-3- (4'-chloro-2'-nitrophenyl) thiazolidine hydrochloride (11.5 g, 85%) as a pale yellow crystalline powder. Melting point: 281-283 ° C (ethanol).

Analysis for (MW 308.3) calculated: C 38.96% H 3.59% S 10.40%. .

Found: C 37.75% H 3.30% S 10.72%

Example 9

Preparation of 2-imino-3- (2'-chloro-6'-nitrophenyl) thiazolidine hydrochloride

a) 19.5 g (0.09 mol) of 2- (2-chloro-6-nitroaniline) ethanol are dissolved in 60 ml of pyridine and 9.7 ml (0.12 mol) of methanesulfonyl chloride are added dropwise.

During this addition, the temperature of the mixture was maintained at 5 ° C with ice cooling. The mixture was stirred for two hours, then poured into 300 ml of ice water. The red oil formed is removed, the aqueous solution is extracted three times with 30 ml of dichloromethane each time, the organic phases are combined, dried over anhydrous magnesium sulphate and evaporated in vacuo.

There was thus obtained 2-chloro-N- (mesyloxyethyl) -6-nitroaniline (21.0 g, 93%) as a red oil.

N, 9.51%; S, 10.88%. Found: N, 9.28%, S, 11.19%.

b) A mixture consisting of 25 g (0.1 mol) of 2-chloro-N- (mesyloxyethyl) -6-nitroaniline, 16 g (0.16 mol) of potassium rhodanide and 300 ml of ethanol is stirred for 12 hours under reflux condenser. The mixture was evaporated under reduced pressure and the residue was poured into 500 ml of water. After cooling, the crystals were filtered off, washed with water and dried.

20.5 g (79.5% of theory) of 2-chloro-6-nitro-N- (2-thiocyanatoethyl) aniline are obtained in the form of an orange-red crystalline powder. Melting point: 92-94 ° C.

(ethanol).

N, 16.30%. Found: Cl, 13.88%. N, 16.51%, S, 12.87%.

c) 3 g (0.011 7 mol) of 2-chloro-6-nitro-N- (2-thiocyanatoethyl) aniline are suspended in 50 ml of ethanol and the suspension is saturated with refluxing with hydrogen chloride gas.

The solvent was evaporated, the crystalline residue was treated with ether, filtered, washed with ether and dried.

2.9 g (84% of theory) of 2-imino-3- (2'-chloro-6'-nitrophenyl) thiazolidine hydrochloride are obtained in the form of a pale yellow crystalline powder. Melting point: 279-280 ° C (ethanol-ether).

Analysis for C _g H _g Cl ₂ N ₃ O ₂ S Calculated: Cl 24.04% N 14.24% S 10.87% Found: Cl 23.57% N 14.17% S 10.98%

Example 10

Preparation of 2-imino-3- (2'-chloro-4'-nitrophenyl) thiazolidine hydrochloride

Suspend 6 g (0.023 4 mol) of 2-chloro-4-nitro-N- (2-thiocyanatoethyl) aniline in

100 ml of ethanol and the resulting suspension were saturated with hydrogen chloride gas for one hour at boiling.

After cooling, the crystals formed are filtered off, washed with ether and dried.

5.6 g (82%) of 2-imino-3- (2'-chloro-4'-nitrophenyl) thiazolidine hydrochloride are obtained in the form of yellow crystals. Melting point: 194-196 ° C (ethanol).

Analysis for C ₉ H _g Cl ₂ N ₃ O ₂ S Calculated: Cl 24.04 N 14.24% S and 10.87% Found: Cl 24.27% N, 14.30 A and 11.02%

Example 11

Preparation of 2-imino-3- (2 ', 4', 6'-trinitrophenyl) thiazolidine

Dry hydrogen chloride gas was introduced into 1.2 g (0.003 8 mol) of 2,4,6-trinitro-N- (2-thiocyanatoethyl) aniline in 120 ml of anhydrous ethanol for 5 hours while the mixture was heated to reflux. The solvent was then distilled off, the residue was boiled for 10 minutes with 30 ml of ethyl acetate, and the warm mixture was filtered. The insoluble material is shaken with 30 ml of ethyl acetate and 20 ml of 10% aqueous sodium carbonate solution. The phases were separated and the aqueous solution was extracted twice with 10 ml of ethyl acetate each time. The organic phases were combined, dried over anhydrous magnesium carbonate and evaporated.

0.084 g (7% of theory) of 2-imino-3 (24 ', 6'-trinitrophenyl) thiazolidine is obtained. Mp 160-162 ° C (ethyl acetate).

Claims (2)

SUBJECT OF THE INVENTION A process for the preparation of a substituted 3-phenyliminothiazolidine derivative of the general Formula Ia wherein R 12 is 12 R and R independently of one another are hydrogen or alkyl of 1 to 4 carbon atoms, R < 1 > halogen is C1-C4alkyl, halomethyl. nitro, hydroxy, C 1 -C 4 alkoxy, carboxy, C 1 -C 4 alkoxycarbonyl or amino, and n or O or 2, and pharmaceutically acceptable acid addition salts thereof, characterized in that: isothiocyanate of formula II SCN (II) Wherein R, R, Ran are as defined above, cyclizes in the presence of an acid, and optionally converting the compound of Formula Ia to a pharmaceutically acceptable acid addition salt thereof. 2. The process of claim 1 wherein the isothiocyanate of formula II is cyclized in the presence of hydrogen chloride.