DE2950518A1 - HEXAHYDRONAPHTOIMIDAZOTHIAZOLES AND PROCESS FOR PREPARING SAME - Google Patents

Description

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Hexahydronaphthoimidazothiazole and its derivatives, processes for their preparation and intermediates used therein

03060A / 0071

description

The invention relates to new compounds which can be used as human and veterinary medicaments and to a method their preparation, especially hexahydronaphthoimidazothiazole and its derivatives, which are found to be immunostimulatory or immunomodifying drugs for the medical treatment of cancer diseases or as remedies use for autoimmunogenic diseases, e.g. rheumatoid arthritis, as well as veterinary worming agents let, as well as a method for their preparation.

Tetramisole or 2,3,5,6-tetrahydro-6-phenylimldazo [2,1-b] -thiazole hydrochloride, is used as a veterinary anti-worm remedy. Levamisole, the left-hand spiral isomer des Tetramisole, probably because of its immunity-activating Puncture or immunization control Function as immunization therapeutic drug to fight cancer or as Remedies for autoimmune diseases, e.g. rheumatoid arthritis, are suitable. In fact, it is reported that levamisole is to some extent a cure for such diseases. However, its healing properties are not good still to be desired.

The invention was based on the object of providing compounds with respect to immunization activation and immunization control to create an improved effect compared to levamisole.

The invention was based on the knowledge that the task at hand with new compounds of a levamisole

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related structure can be solved.

The invention thus relates to hexahydronaphthoimida zothiazol and its derivatives of the formula:

.CH ₂ -CH ₂ -S

I \

CI]

wherein X represents a hydrogen or halogen atom, and m and n, which are different from each other, are each O and 1, respectively mean.

According to the invention, the hexahydronaphthoimidazothiazole is obtained and its derivatives of the formula I by reacting tetrahydronaphthoimidazoline-2-thione and its derivatives (3a, 4,5,9b-Tetrahydronaphtho [i, 2-d-jimidazoline-2-thione and its derivatives) of the formula:

CII]

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wherein X represents a hydrogen or halogen atom, with a compound of the formula:

Y-CH ₂ CH ₂ -Z [III]

wherein Y and Z, which can be the same or different, represent a halogen atom, an allene sulfonyloxy group or an alkanesulfonyloxy group.

The symbols A, B and C indicate the different rings. The rings B and C can be in trans or cis configuration.

The compounds tetrahydronaphthoimidazoline-2-thione and its compounds used as starting materials according to the invention Derivatives of the formula II are obtained by reacting a compound (1,2-diamino-i, 2,3,4-tetrahydronaphthalene or its derivatives) of the formula:

CIV]

wherein X is a hydrogen or halogen atom, with carbon disulfide and then removing the Hydrogen sulfide. In the compounds of the formula IV, the two amino groups can either be in trans or cis configuration.

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If in the formula I m »0 and η « 1, the compounds according to the invention are 5,6, 6a, 8, 9,11a-hexahydronaphtho- [1 ', 2 · i4,5] -imidazo [2, 1-b] thiazole and its derivatives of the formula:

wherein X represents a hydrogen or halogen atom. The symbols A, B and C in turn indicate the relevant Called rings.

If in formula I m '1 and η = O, it is the inventive compounds to 5,6,6a, 9,10,11 a -hex a hydronaphtho- [2', 1 ^f: 4 _t 5] - imidazo [2,1-b] thiazole and its derivatives of the formula:

CI "]

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wherein X represents a hydrogen or halogen atom.

Oils rings B and C of the Hexahydronaphthoimidazothiazols of the formulas I ¹ or I "may be either in _a tr ns or cis-configuration.

In the hexahydronaphthoimidazothiazole compounds according to the invention it can also be inorganic acid addition salts or organic acids. Suitable inorganic acids are, for example, hydrogen chloride, Hydrobromic, hydroiodic, sulfuric or phosphoric acid. Suitable organic acids are, for example Vinegar, propion, glycol, milk, pyot, oxal, malon, amber, malein, pumar, apple, wine, Lemon, benzoin, cinnamon, almond, methanesulfone, ethanesulfone, Hydroxyethane sulfone, benzenesulfone, p-toluenesulfone and salicylic acid.

Suitable halogen substituents are, for example, fluorine, chlorine or bromine atoms, which can be in the 1-, 2-, 3- or, preferably, 4-position.

If trans-3a, 4,5,9b-tetrahydronaphtho [i, 2-d] imidazoline-2-thione or its derivatives of the formula II are reacted according to the invention with compounds of the formula III, a mixture of trans-S ^^ a is obtained ^^ jHa-hexahydronaphtho- [1 ', 2 ·: 4,5] -imidazo [2,1-b] thiazole and its derivatives of the formula I ¹ and trans-5,6,6a, 9,10,11a-hexahydronaphtho - [2 ', 1': 4,5] -imidazo [2,1-b] thiazole and its derivatives of the formula I ". The individual compounds can be chromatographed from the mixture in pure form by any suitable measures, for example extraction , Around-

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ν * 3

crystallize and the like, separate or isolate.

If cis-3a, 4,5,9b-tetrahydronaphtho [1,2-d] imidazoline-2-thione or its derivatives of the formula II are reacted with compounds of the formula III, a mixture of the cis compound of the formula I ^{1 is obtained} and the cis compound of the formula I ". The individual compounds can be separated off or isolated in pure form from the mixture in the manner described.

In the compounds of the formula III, the radicals Y and Z can be identical to or different from one another and, for example, halogen atoms, allene sulfonyloxy groups or alkanesulfonyloxy groups represent. Preferred halogen atoms are chlorine, bromine and iodine atoms. Preferred examples of allene sulfonyloxy groups and alkanesulfonyloxy groups are benzenesulfonyloxy-, p-toluenesulfonyloxy-, α-naphthalenesulfonyloxy-, ß-naphthalenesulfonyloxy-, methanesulfonyloxy- and ÄthansulfonyloxygruppenV Examples of readily available compounds of the formula III are 1,2-dichloroethane, i-bromo-2-chloroethane, 1,2-dibromoethane, 1,2-diiodoethane, 2-chloroethyl-p-toluenesulfonate, 2-Bromoethyl-p-toluene sulfonate Ethylenedi-p-toluenesulfonate and 2-bromoethyl methanesulfonate.

When reacting compounds of the formula II with compounds of formula III per 1 mol of compound (s) of formula II are preferably 0.8 to 10 mol (s) of compound (s) of formula III used. If the compounds of the formula III are liquid at the reaction temperature, the compounds can of formula II allowed to react with the compounds of formula III in the absence of a solvent will. As a rule, however, the implementation in

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carried out in the presence of a suitable solvent. All solvents can be used as solvents, provided they do not interfere with the reaction. Examples of suitable solvents are alcohols such as ethanol, n-propanol, iopropanol or n-butanol, aromatic hydrocarbons such as benzene and toluene, ethers such as tetrahydrofuran and dioxane, acetonitrile and N, N-dimethylformamide. Of course, it is also possible to use solvent mixtures composed of two or more solvents. The reaction temperature ranges of the reaction system is usually from 5O ⁰ C to the boiling point. The reaction time can vary widely depending on the starting compounds, the reaction scale, the reaction solvents, the reaction temperature and the like. As a rule, it ranges from 30 minutes to 48 hours.

The reaction can also be carried out in the presence of a base, such as sodium hydrogen carbonate, Potassium hydrogen carbonate, sodium carbonate, potassium carbonate or sodium hydroxide will.

According to the invention, tetrahydronaphthoimidazoline-2-thione is obtained or its derivatives by reacting (reaction A) 1,2-diamino-1,2,3 »4-tetrahydronaphthalene or its Derivatives with carbon disulfide and (reaction B) removal of hydrogen sulfide.

In reaction A, it is preferred to use 1,2-diamino-1,2,3,4-tetrahydronaphthalene and its derivatives per mole 1 to 1.3 moles carbon disulfide. The reaction is usually carried out in the presence of a suitable solvent. All solvents are used as solvents

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medium in question as long as they do not interfere with implementation. Examples of suitable solvents are alcohols, such as Methanol, ethanol, n-propanol, isopropanol or n-butanol, short-chain carboxylic acid esters such as ethyl acetate, halogenated hydrocarbons such as methylene chloride, chloroform or 1,2-dichloroethane, aromatic hydrocarbons such as benzene or toluene, and ethers such as ether, tetrahydrofuran or dioxane. Solvent mixtures can of course also be used from two or more solvents for one. sentence arrive. Provided the solvent is evenly mixed with water, the solvent can be used in a reaction system, in which there is so much water that the uniformity is not broken, can be used. The optimum reaction temperature can vary widely depending on the reaction solvent used. A suitable reaction temperature usually ranges from −10 ° C. to the boiling point of the system. The reaction time may vary depending on the starting compounds, the reaction scale, the reaction solvents, the reaction temperature and the like can vary widely, as a rule it ranges from 10 minutes to 48 hours.

The compounds obtained in reaction A are adducts of 1,2-diamino-1,2,3,4-tetrahydronaphthalene or its derivatives and carbon disulfide. In some cases the solubility of these compounds is lower than the solubility of the starting compounds. This depends on the reaction solvent used. In In the case mentioned, the adducts separate out of the reaction system in the form of the progress of the reaction of solid precipitation. Consequently, they can be isolated by filtration. Isolation can too

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take place by evaporation and solidification of the reaction mixture. The respective adduct of 1,2-diamino-i, 2,3,4-tetrahydronaphthalene or its derivatives and carbon disulfide is pure enough for the next reaction to take place Removal of hydrogen sulfide (reaction B) can be supplied.

Reaction B usually takes place in a suitable reaction solvent with heating. All solvents that do not interfere with the reaction are suitable as solvents. Examples of suitable solvents are alcohols such as methanol, ethanol, n-propanol, isopropanol or n-butanol, mixtures of the alcohols mentioned with water, and halogenated hydrocarbons such as chloroform and 1,2-dichloroethane. The optimum reaction temperature can be very different depending on the reaction solvent used, it usually ranges from 50 ⁰ C to the boiling point of the system. The reaction time can vary widely depending on the starting materials used in Reaction A, the reaction scale, the reaction solvent and the reaction temperature, and usually it ranges from about 10 minutes to 24 hours.

The separation and purification of the compounds obtained in reaction B, tetrahydronaphthoimidazoline-2-thione and its derivatives of the formula II from the reaction mixture can in the customary known manner, e.g. by filtration, Recrystallization, chromatographers and the like.

In reactions A and B, the following measures can be carried out: Those formed in reaction A

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After their isolation, adducts can be subjected to reaction B to remove hydrogen sulfide. the Reaction B can be carried out without isolating the respective adducts Reaction A can be followed. Furthermore, the reaction conditions under which the reaction B can be carried out will be adjusted as long as reaction A is still running. This is how reactions A proceed and B essentially as a single reaction rather than as separate reactions.

1,2-Diamino-i, 2,3, A-tetrahydronaphthalene and its derivatives of the formula IV, which are ultimately used as starting compounds, can be according to the most varied Process. For example, they can be prepared from 2-halo-3,4-dihydro-1 (2H) -naphthalenone and its derivatives, which in turn according to Koptyung and co-workers in "Zhurnal Obshchei Khimii", Volume 32, Page 1613 (1962) 3,4-dihydro-1 (2H) -naphthalenone and its derivatives are obtained can be produced. They are also obtained from 1,2-dihydronaphthalene and its derivatives, the according to that of Swift et al. in the Journal of Organic Chemistry ", Volume 32, page 511 (1967) can be prepared.

The following examples are intended to illustrate the invention in more detail.

example 1

831 mg (5.12 mmoles) of cis-1,2-diamino-i, 2,3,4-tetrahydronaphthalene are dissolved in 16 ml of ethanol, whereupon 8 ml of water are added. Then the obtained product is

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41

mix within 1 min with stirring at room temperature in a nitrogen atmosphere with 350 μl (5.84 mmoles) of carbon disulfide added and then heated to reflux temperature for 1.5 hours. When the reaction mixture cools down Crystals separate out in an ice bath. These are filtered off, washed with ether and dried in vacuo, 803 mg (3.93 mmol) of cis-3a, 4,5,9b-tetrahydronaphtho [1,2-d] imidazoline-2-thione in a 77% yield can be obtained. When the crude product obtained is recrystallized from acetone and ethanol, colorless needle-shaped crystals with a melting point of 237 ° to 237.5 ° C. are obtained. The reaction product possesses the following spectral characteristics:

IR spectrum (KBr tablet) cm " ¹ : 3190, 2930, 2900, 1530, 1475, 1441, 1291, 1255, 1204, 1186, 775, 748, 733, 692.

Nuclear magnetic resonance spectrum (CDCl,: dimethyl sulfoxide-dg = 5: 1) ο from TMS (ppm): 1.69 to 2.09 (2H, m, CH ₂ in 4-position), 2.58 to 3.04 (2H, m, CH ₂ in position 5), 4.44 (1H, dt, J - 10 Hz and 4 Hz, CH in position 3a), 5.05 (1H, d, J - 10 Hz, CH in 9b- Position), 7.15 to 7.38 (4H, m, H on the benzene ring), 7.79 (1H, broad s, NH), 8.03 (1H, broad s, NH).

Example 2

461 mg (2.84 mmoles) of trans-1,2-diamino-1,2,3,4-tetrahydronaphthalene are dissolved in 8 ml of ethanol, whereupon 4 ml of water are added. Thereafter, the resulting mixture with stirring at room temperature with 190ul (3.17 mmol) Carbon disulfide added and the whole thing for 4 hours

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Heated to reflux temperature. When the reaction mixture is cooled on an ice-cold water bath, crystals separate out. These are filtered off, washed with ether and dried in vacuo, 350 mg (1.71 mmol) of trans-3a, 4,5,9b-tetrahydronaphtho [1,2-d] imidazoline-2- thion can be obtained. The reaction product obtained has the following spectral characteristics:

IR spectrum (KBr tablet) cm " ¹ : 3170, 2950, 2880, 1508, 1458, 1429, 1337, 1330, 1235, 1218, 1197, 1177, 1157, 1126, 1110, 742, 713, 689.

Nuclear magnetic resonance spectrum (CDCl, ^ imethylsulfoxld-d ^ = 3: 2), 6 from TMS (ppm): 1.63 to 2.64 (2H, m, CH ₂ in 4-position), 2.90 to 3.67 ( 3H, m, CH in the 3a position and CH ₂ in the 5 position), 4.42 (1H, d, J = 13 Hz, CH in the 9b position), 7.13 to 7.50 (4H, m, H on benzene ring), 8.47 (1H, broad s, NH), 9.08 (1H, broad s, NH).

Example 3

(1) 810 mg (4.99 mmol) of cis-1,2-diamino-1,2,3,4-tetrahydronaphthalene are dissolved in 16 ml of benzene, whereupon 340 μl (5.64 mmol) of carbon disulfide are added with stirring. The mixture is then stirred for a further 2 hours at room temperature. Deposited crystals are filtered off, washed with benzene and dried in vacuo to give in 93% yield 2,3,4-tetrahydronaphthalene, 1.10 g (4.63 mmoles) of a adducts of cis-1,2-diamino-i, and Carbon disulfide can be obtained. The reaction product obtained has the following spectral characteristics:

Ö 3 0 6 0 4/0 0 7 1

IR spectrum (KBr tablet) cm * " ¹ : 2940, 1490, 1450, 1300, 962.

(2) 820 mg (3.44 mmoles) of the adduct of cis-1,2-diamino-1,2,3,4-tetrahydronaphthalene and carbon disulfide are suspended in 10 ml of ethanol and 5 ml of water, whereupon the The resulting suspension is heated to reflux temperature for 4 hours. This removes hydrogen sulfide. At the When the reaction mixture cools, crystals separate out. These are filtered off, washed with ethanol and ether and dried in vacuo, 464 mg (2.27 mmol) of cis-3a, 4,5,9b-tetrahydronaphtho [1,2-d] imidazoline-2-thione in a 66% yield can be obtained. This compound has the same spectral characteristics as the compound of the Example 1.

Example 4

4.65 g (23.6 mmoles) of cis-1,2-diamino-6-chloro-1,2,3,4-tetrahydronaphthalene are dissolved in 70 ml of ethanol, whereupon the resulting solution is stirred at room temperature in nitrogen atmosphere with 1.6 ml (26.7 mmol) carbon disulfide is added. Right at the beginning of the addition of the carbon disulfide a white solid substance begins to deposit. After stirring for a further 10 minutes, 35 ml Water was added and the system was refluxed on an oil bath for 2 hours. After cooling down the reaction mixture and the addition of 50 ml of ethyl ether, the precipitated crystals are filtered off, washed with ether and dried in vacuo, with 3.99 g of cis-7-chloro-3a, 4,5,9btetrahydronaphtho (i, 2-d] imidazoline-2-thione in a 71% yield in form of a

Ö306Ö4 / 0Ö71

white solid matter can be obtained. This is recrystallized from acetone / acetonitrile to give colorless prisms, mp, 249 ° to 25O ⁰ C. These have the following spectral characteristics:

IR spectrum (KBR tablet) cm * " ¹ : 3180, 2920, 1599, 1533, 1482, 1438, 1300, 1267, 1250, 1202, 825.

Nuclear magnetic resonance spectrum (dimethyl sulfoxide-dg), Saus TMS (ppm): 1.54 to 1.84 (2H, m, CH ₂ in 4-position), 2.44 to 2.77 (2H, m, CH ₂ in 5- Position), 4.34 (1H, dt, J = 10 Hz, 5 Hz, CH in 3a-position), 4.97 (1H, d, J = 10 Hz, CH in 9b-position), 7.24 to 7.46 (3H, m, H on benzene ring), 8.36 (1H, broad s, NH), 8.70 (1H, broad s, NH).

Example 5

5.14 g (26.1 mmoles) of trans-1,2-diamino-6-chloro-1,2,3,4-tetrahydronaphthalene are dissolved in 60 ml of ethanol, whereupon the resulting solution at room temperature with stirring in a nitrogen atmosphere with 1.70 ml (28.4 mmol) of carbon disulfide is moved. A solid precipitate begins to separate out about 1 minute after the addition of carbon disulfide. The mixture is then stirred for a further 10 minutes at room temperature, whereupon 30 ml of water are added and the system Heated to reflux temperature for 2.5 hours. Will After cooling the reaction mixture on an ice bath for 1 hour, a solid precipitate separates out. This is filtered off, with about 150 ml of water, then with 20 ml of a 1: 2 volume mixture of ether and η-hexane and finally washed with 40 ml η-hexane and finally overnight in

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nt

Vacuum dried. This gives 4.86 g (20.4 mmol) of trans-7-chloro-3a, 4,5,9b-tetrahydronaphtho [i, 2-d] imidazoline-2-thione in a yield of 7896. This is recrystallized from methanol and acetonitrile to give colorless prisms, mp, 269 ° to 271 ⁰ C (with decomposition). The reaction product has the following spectral characteristics:

IR spectrum (KBr tablet) cm " ¹ t 3160, 2930, 2870, 1600, 1515, 1485, 1337, 1228, 1196, 1176, 1147, 1089, 881, 823, 792, 682.

Nuclear Magnetic Resonance Spectrum (dimethyl sulfoxide-d ^), h from TMS (ppm): 1.60 to 2.30 (2H, m, CH ₂ in 4-position), 2.87 to 3.17 (2H, m, CH ₂ in 5-position), 3.32 to 3.59 (1H, m, CH in 3a-position), 4.38 (1H, d, J = 13 Hz, CH in 9b-position), 7.17 to 7, 50 (3H, m, H on benzene ring), 8.73 (1H, broad s, NH), 9.18 (1H, broad s, NH).

Example 6

3.84 g (21.3 mmoles) of trans-1,2-diamino-6-fluoro-1,2,3,4-tetrahydronaphthalene are dissolved in 40 ml of ethanol, whereupon the resulting solution with 1.4 ml (23.4 mmol) of carbon disulfide is moved. The resulting white cloudy solution is stirred for a while, then 20 ml of water are added and finally at reflux temperature for 30 minutes heated. The reaction mixture is then cooled on an ice bath. The resulting solid precipitate is filtered off, first three times with 20 ml of water each time, then with 20 ml of ethyl ether and finally

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Washed with 50 ml η-hexane and dried in vacuo, with a yield of 82%, 3.88 g (17.4 mmol) of trans-7-fluoro-3a, 4,5,9b-tetrahydronaphtho [i, 2-dimidazoline-2- thion can be obtained in the form of a yellowish-gray solid substance. This is recrystallized from acetone and acetonitrile, pale yellow needles having a melting point of 256.5 ° to 257.5 ° C. (with decomposition) are obtained. The reaction product has the following spectral characteristics:

IR spectrum (KBr tablet) cm " ¹ : 3430, 3165, 1620, 1501, 1437, 1422, 1337, 1252, 1230, 120b, 1193, 1158, 1100, 878, 857, 802, 731, 708, 689.

Nuclear magnetic resonance spectrum (dimethyl sulfoxide-dg), 6 from TMS (ppm) 1.63 to 2.27 (2H, m, CH ₂ in 4-position), 2.87 to 3.57 (3H, m, CH ₂ in 5- Position and CH in position 3a), 4.35 (1H, d, J = 12 Hz, CH in position 9b), 6.83 to 7.51 (3H, m, H on the benzene ring), 8.66 ( 1H, broad s, HN), 9.13 (1H, broad s, NH).

Example 7

4.30 g (17.8 mmol) of cis-1,2-diamino-7-bromo-1,2,3,4-tetra- · hydronaphthalene are dissolved in 86 ml of ethanol, whereupon 1.2 ml (20 mmol) of carbon disulfide are added at room temperature with stirring in a nitrogen atmosphere. After stirring for an additional 10 minutes, 43 ml of water is added to the mixture, followed by 2.5 hours heated to reflux temperature in an oil bath. The reaction mixture is then worked up according to Example 4, whereby in 75 ^ iger yield 3.76 g (13i3 mmol) cis-8-bromo-3a, 4,5,9b-tetrahydronaphtho [i, 2-d] iniidazoline-

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ac -

2-thione obtained in the form of a light brown solid substance will. This is recrystallized from methanol and acetonitrile, with colorless prisms having a melting point of 247 ° to 248 ° C. can be obtained. The reaction product obtained has the following spectral characteristics

IR spectrum (KBr tablet) cm ~ ¹ : 3210, 2940, 1528, 1483, 1470, 1440, 1253, 1210, 1198, 1181, 831, 681.

Nuclear magnetic resonance spectrum (dimethyl sulfoxide-dg), S from TMS (ppm); 1.47 to 1.96 (2H, m, CH ₂ in 4-position), 2.35 to 2.77 (2H, m, CH ₂ in 5-position), 4.31 (1H, dt, J = 10 Hz, 5 Hz, CH in 3a position), 4.94 (1H, d, J = 10 Hz, CH in 9b position), 7.17 (1H, d, J = 8 Hz, H in 6- Position), 7.43 (1H, dd, J = 8 Hz, 2 Hz, H in 7-position), 7.59 (1H, d, J = 2 Hz, H in 9-position), 8.33 ( 1H, broad s, NH), 8.64 (1H, broad s, NH).

Example 8

A mixture of 723 mg (3.54 mmol) trans-3a, 4,5,9b-tetrahydronaphthoC1,2-d] imidazolin-2-thione, 1.77 g (β, 34 mmoles) of 2-bromoethyl-p-toluenesulfonate, 795 mg (7.50 mmoles) of sodium carbonate and 13 ml of isopropanol is heated to reflux temperature with stirring for 15 hours. Thereafter, the reaction mixture cooled to room temperature. A solid precipitate separates out, which is filtered off and is washed with methanol. The solvent is reduced under reduced pressure from the mixture of filtrate and washing liquid Distilled off under pressure, whereupon the distillation residue (to distribute its constituents in the various

Ö306CH / 0Q71

which solvents) 20 ml of methylene chloride, 10 ml of water and 10 ml of 1Obigen aqueous ammonia are added. The aqueous layer is extracted with methylene chloride. The obtained and combined methylene chloride solutions are washed with salt water and dried with anhydrous sodium sulfate. The distillation residue obtained after removal of the solvent by distillation is column chromatographed on silica gel (100 g of silica gel). Through the silica gel column 100 ml of benzene, 100 ml of a mixture of benzene and ethyl acetate (volume ratio: 4: 1), 400 ml of a mixture of benzene and ethyl acetate (volume ratio: 3: 2), 600 ml of a mixture of benzene and ethyl _a acetate (volume ratio: 2: 3) and 1.2 1 ethyl acetate run. Fractions weighing 17 g are collected. Fractions 25 to 42 are combined with one another. The solvent is distilled off from these under reduced pressure. The distillation residue is dissolved in methylene chloride and extracted with 4N hydrochloric acid. The hydrochloric acid layer is then made weakly basic with a saturated aqueous sodium hydrogen carbonate solution and extracted with methylene chloride. The extracted solution is washed with salt water and dried with anhydrous sodium sulfate. The distillation residue obtained after removal of the solvent by distillation is treated with a small amount of ether, trans-5,6,6a, 8,9,11a-hexahydronaphtho-Ci '^' ^^ J-imidazo ^ J-bJthiazole in the form colorless crystals is obtained. These are recrystallized from methylene chloride / n-hexane, colorless prisms with a melting point of 121.5 ° to 122.5 ° C. being obtained. The reaction product obtained has the following spectral characteristics:

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d »- U

IR spectrum (KBr tablet) cm " ¹ : 1558, 1309, 1196, 1136, 1010, 741.

Nuclear magnetic resonance spectrum (CDCl ·,), ο from TMS (ppm): 1.69 to 3.99 (9h, m), 4.86 (1H, d, J = 14 Hz), 7.01 to 7.22 (3H, m), 7.45 to 7.73 (1H, m).

Mass spectrum (70 eV), m / e: 230 (M ⁺ ).

Furthermore, the solvent is distilled off from the combined fractions 61 to 105 of the column chromatography under reduced pressure. The case incurred distillation residue is worked up in the described manner, trans-S ^ oa ^ iOjiia-Hexahydronaphtho-L'2 ', 1 ^l: 4,5] imidazo [2,1-bjthiazol colorless crystals is obtained in the form. These are recrystallized from methylene chloride / n-hexane, colorless prisms with a melting point of 127 ° to 128.5 ° C. being obtained. These have the following spectral characteristics:

IR spectrum (KBr tablet) cm " ¹ : 2825, 1565, 1322, 1289, 1279, 1246, 1237, 1167, 1143, 1123, 742.

Nuclear Magnetic Resonance Spectrum (CDCl3,), & from TMS (ppm): 1.59 to 4.19 (1OH, m), 7.17 (4H, s).

Mass spectrum (70 eV), m / e: 231 (4.596), 230 (24.590, M ⁺ ), 229 (25%), 202 (690, 128 (100%).

Elemental analysis (C ₁ , H ^ .NpS):

Calculated: C 67.79%, H 6.13%, N 12.16%, found: C 67.84%, H 6.90%, N 12.05%.

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Example 9

A mixture of 493 mg (2.41 mmol) trans-3ä, 4,5,9b-tetrahydronaphtho [i, 2-d] imidazolin-2-thione, 1.78 g (4.81 mmoles) of ethylene di-p-toluenesulfonate, 509 mg (4.80 mmoles) of sodium carbonate and 20 ml of isopropanol is heated to reflux temperature for 12 hours with stirring. The one after distilling off The distillation residue obtained from the solvent is distributed between 50 ml of benzene and 30 ml of water. The benzene Solution is separated, washed with salt water and dried with anhydrous sodium sulfate. After that, will the benzene solution is concentrated to such an extent that a solid substance is obtained. This is filtered off. The FiI kicked is further concentrated, whereupon the residue obtained in this way according to Example 8 on silica gel. column chromatographed will. This gives trans-5,6,6a, δ, 9,11a-hexahydronaphtho- [1 ', 2 *: 4,5] -imidazo [2,1-b] thiazole and trans-5,6,6a, 9,10,11a-hexahydronaphtho- [2 ', 1 »: 4,5] -imidazof2,1-bJ-thiazole.

Example 10

A mixture of 500 mg (2.45 mmol) trans-3a, 4,5,9b-tetrahydronaphtho [1,2-d] imidazoline-2-thione, 1,2-dibromoethane (8.98 mmoles), 924 mg (9.10 mmoles) sodium carbonate and 8 ml Isopropanol is stirred and refluxed for 17 hours. The one after the solvent has been distilled off The distillation residue obtained is divided between 50 ml of benzene and 40 ml of 10% aqueous ammonia. The benzene solution is separated, washed with salt water and dried with anhydrous sodium sulfate. Then the solvent is distilled off?

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The distillation residue is column chromatographed on silica gel according to Example 6, whereby trans-5,6,6a, 8,9, ii £ hexahydronaphtho- [1 ', 2': 4,5] -imidazo [2,1-b] thiazole and trans -5,6,6a, 9, T0,11a-Hexahydronaphtho- [2 ^l, 1 ': 4,5] imidazo [2,1-b] thiazole are obtained.

Example 11

A mixture of 5.00 g (24.5 mmoles) of cis-3a, 4,5,9b-tetrahydronaphtho [i, 2-d] imidazoline-2-thione according to Example 1, 13.00 g (46.6 mmol) of 2-bromoethyl-p-toluenesulfonate, 5.20 g (49.1 mmol) of sodium carbonate and 100 ml of isopropanol is heated to reflux temperature with stirring for 14 hours. Of the after heating to reflux temperature and distilling off the solvent under reduced pressure Distillation residue is used to divide its components between 60 ml of methylene chloride and 50 ml of water distributed. The aqueous layer is extracted with two times 30 ml of methylene chloride. The two methylene chloride fractions are washed with 50 ml of water and 30 ml of salt water and dried with anhydrous sodium sulfate. After drying, the solvent is distilled off, whereupon the distillation residue is column chromatographed on silica gel will. As columns A and B, 300 g of silica gel columns are used each. Each column is (in the given order) with 0.3 l of methylene chloride, 1 l of a mixture of methylene chloride and methanol (volume ratio: 49: 1), 0.6 1 of a mixture of methylene chloride and methanol (volume ratio: 97: 3), 0.8 1 a mixture of methylene chloride and methanol (volume ratio: 19: 1) and 0.4 l of a mixture of methylene chloride and methanol (volume ratio: 2: 3) eluted.

30604/0071

The first 900 ml of eluate are discarded, the rest of the eluate is collected in the form of fractions weighing 20 g. the Fractions 15 to 30 from column A and 19 to 35 from column B provide 5,6,6a, 8,9,11a-hexahydronaphtho- [1 ·, 2 ': 4,5] -imidazo [2,1-b] thiazole in the form of colorless crystals. These are recrystallized from a mixture of methylene chloride and η-hexane, with colorless prisms having a melting point of 96 ° to 97.5 ° C can be obtained. The reaction product obtained has the following spectral characteristics:

IR spectrum (KBr tablet) cm " ¹ : 2930, 2830, 1596, 1235, 1218, 1182, 1162, 1155, 742.

Nuclear Magnetic Resonance Spectrum (CDCl,), 6 from TMS (ppm): 1.72 to 2.00 (2H, m, CH ₂ in 6-position), 2.25 to 3.64 (6H, m, CH ₂ in 5- , 8 and 9 positions), 3.85 (1H, dt, J = 9 Hz and 5 Hz, CH in 6a position), 5.37 (1H, d, J = 9 Hz, CH in 11a position ), 6.9 "to 7.54 (4H, m, H in the 1- to 4-position).

Mass spectrum (M ⁺ ):

theoretical value: 230.0878 determined value: 230.0909 - 0.0069.

A mixture of fractions 60 to 111 from column A and 70 to 122 from column B is reduced by distillation Pressure released from its solvent. The distillation residue is worked up in the manner described, where cis ^ iöjöa ^ fiOjHa-hexahydronaphtho- [2 ', 1': 4,5] -imidazo [2,1-b] thiazole is obtained in the form of colorless crystals. These are made from methylene chloride and η-hexane recrystallized, with colorless needles of a mp

030604 / 0Ö71

be obtained from 100 ° to 101 ⁰ C. The reaction product obtained has the following spectral characteristics:

IR spectrum (KBr tablet) cm " ¹ : 2950, 2840, 1596, 1262, 1224, 1170, 1150, 1047, 763, 746, 660.

Nuclear magnetic resonance spectrum (CDCl,), h from TMS (ppm): 1.70 to 2.07 (2H, m, CH ₂ in 6-position), 2.58 to 3.65 (6H, m, CH ₂ in 5- , 9- and 10-position), 4.42 (1H, d, J = 9 Hz, CH in 11a-position), 4.70 (1H, dt, J = 9 Hz, 5Hz, CH in 6a-position) , 6.99 to 7.30 (4H, m, H in the 1- to 4-position).

Elemental analysis (C ₁ , H ₁ ^ N ₂ S):

Calculated: C 67.79% H 6.13% N 12.16% Found: C 67.56% H 5.94% N 12.06%.

Example 12

190 mg of cis-5,6,6a, 8,9 _f 11a-hexahydronaphtho- [i ', 2': 4,5] -imidazo [2,1-b] thiazole according to Example 11 are dissolved in 40 ml of benzene, whereupon gaseous hydrochloric acid is passed in at room temperature. The solution is then bubbled with nitrogen gas to remove excess hydrochloric acid gas. The solvent is distilled off under reduced pressure. The resulting distillation residue is crystallized from methanol and ether. The crystals obtained are filtered off, washed with methanol and ether and dried, whereby cis-5,6,6a, 8,9,11a-hexahydronaphtho-ti ', 2 *: 4,5I-imidazo [2,1-b] thiazole hydrochloride is obtained. This

0 3 0 6 0 4/0071

is recrystallized from methanol and acetonitrile, whereby colorless plates having a Pp of 232 ° to 235 ° C. can be obtained. The reaction product obtained has the following spectral characteristics:

IR spectrum (KBr tablet) cm " ¹ : 2920, 2750,. 2640, 1598, 1528, 1487, 1449, 1435, 1237, 743.

Nuclear magnetic resonance spectrum (dimethyl sulfoxide-dg), <5 from TMS (ppm) 1.57 to 2.31 (2H, m, CH ₂ in 6-position), 2.40 to 2.84 (2H, m, CH ₂ in 5 Position), 3.63 to 4.12 (4H, m, CH ₂ in 8- and 9-position), 4.44 to 4.80 (1H, m, H in 6a-position), 5.74 ( 1H, d, J = 10 Hz, CH in 11a-position), 7.17 to 7.53 (4H, m, H in 1- to 4-position), 12.03 (1H, broad).

Trans-5,6,6a, 8,9,11a-hexahydronaphtho- [i ·, 2 ': 4,5] -imidazo- [2,1-b] thiazole according to Example 8 is converted into its hydrochloride in the manner described. After crystallization from methanol and acetonitrile, colorless prisms with a melting point of 254 ° to 259 ° C. (with decomposition) are obtained. The reaction product obtained has the following spectral characteristics:

IR spectrum (KBr tablet) cm " ¹ : 2650, 2600, 1527, 1499, 1490, 1452, 1331, 1240, 1233, 1220, 1202, 825, 754.

Nuclear magnetic resonance spectrum (methanol-d ^), £> from TMS (ppm): 1.84 to 4.31 (9H, m, methylene in 5-, 6- »8- and 9-positions and methine in 6a-position) , 5.29 (1H, d, J = 14 Hz, methine in 11a-position), 7.15 to 7.34 (4H, m, hydrogen in 1- to 4-position).

030604/0071

Example 15

210 mg of cis-5,6,6a, 9,10,11a-hexahydronaphtho- [2 ^l , 1 ·: 4,5] -imidazo [2,1-b] thiazole according to Example 11 are dissolved in 6 ml of benzene, whereupon 2 ml of isopropanol saturated with hydrochloric acid are added. After stirring for one hour, the solvent is distilled off under reduced pressure. 6 ml of ether and 2 ml of methanol are added to the distillation residue obtained. The crystals thus formed are filtered off, whereby cis-5,6,6a, 9,10,11a-hexahydronaphtho- [2 ·, 1 ': 4,5] -imidazo [2,1-b] thiazole hydrochloride is obtained. This is recrystallized from methanol and acetonitrile, colorless prisms having a melting point of 268 ° to 273 ° C. (with decomposition) being obtained. The reaction product obtained has the following spectral characteristics:

IR spectrum (KBr tablet) cm " ¹ : 2750, 1594, 1517, 1432, 1270, 1194, 774, 754.

Nuclear magnetic resonance spectrum (dimethyl sulfoxide-dg), 6 from TMS (ppm): 1.57 to 2.23 (2H, m, CH _£ in 6-position), 2.40 to 2.85 and 3.02 to 4.03 ( 6H, m, CH ₂ in 5-, 9- and 10-positions), 5.11 (1H, dd, J = 10 Hz, 3 Hz, CH in 6a-position), 5.27 (1H, d, J = 10 Hz, CH in position 11a), 7.23 to 7.45 (4H, m, H in position 1 to 4).

Elemental analysis (C., H ^, -ClNpS):

Calculated: C 58.53% H 5.67% N 10.50% Found: C 58.36% H 5.72% N 10.87%.

03060A / 007 1

-tS'.i ·: 4,5] -imidazo- (2,1-b-thiazole according to Example 8 is converted into its hydrochloride in the manner described. If this is made from methanol and acetonitrile recrystallized, colorless prisms with a melting point of 232 ° to 235 ° C. are obtained. The received Reaction product has the following spectral characteristics:

IR spectrum (KBr tablet) cm " ¹ : 2920, 2750, 2640, 1588, 1528, 1487, 1449, 1435, 1273, 743.

Nuclear magnetic resonance spectrum (dimethyl sulfoxide-dg), S from TMS (ppm): 1.57 to 2.31 (2H, m, methylene in 6-position), 2.40. to 2.84 (2H, m, methylene in the 5-position), 3.63 to 4.12 (4H, m, methylene in the 8- and 9-position), 4.44 to 4.80 (1H, m, Methine in 6a-position), 5.74 (1H, d, J = 10 Hz, methine in 11a-position), 7.17 to 7.53 (4H, m, H in 1- to 4-position), 12 .03 (1H, broad s, proton of hydrochloric acid).

Example 14

A mixture of 3.00 g (12.6 mmol) of cis-7-chloro-3a, 4,5,9btetrahydronaphtho [1,2-d] imidazoline-2-thione, 7.01 g (25.1 mmoles) of 2-bromoethyl-p-toluenesulfonate, 1.50 g (14.2 mmoles) anhydrous sodium carbonate and 100 ml of isopropanol Heated to reflux temperature for 17.5 hours with stirring. The reaction mixture is then cooled to room temperature. The resulting solid precipitate is filtered off and washed with 40 ml of water and 50 ml of methylene chloride. The filtrate and wash liquids are combined with one another, whereupon the solvent is distilled off from the mixture under reduced pressure.

030604/0071

The distillation residue obtained in this way is mixed with 30 ml of methylene chloride, 50 ml of water and 10 ml of a saturated aqueous sodium hydrogen carbonate solution for fractional precipitation. The aqueous layer is extracted once with 40 ml and once with 20 ml, for a total of 60 ml of methylene chloride. The methylene chloride layers obtained are washed first with a saturated aqueous sodium hydrogen carbonate solution and then with saturated salt water and finally dried with anhydrous sodium sulfate. After the solvent has been distilled off under reduced pressure, 4.12 g of a very brown oily substance are obtained. This is column chromatographed on silica gel. It is eluted first with 0.3 l of methylene chloride and then with 2 l of a mixture of methanol and methylene chloride (volume ratio: 2: 90). The first 900 ml of eluate are discarded, the remainder is collected in a fraction collector in the form of fractions weighing 20 g. The solvent is distilled off under reduced pressure from a mixture of fractions 12 to 19, with cis ^ -Cailor-Stojea.e ^ iia-hexahydronaphtho- [1 ^I , 2 ': 4,5] -imidazo [2,1-b] thiazole is obtained in the form of light yellow crystals. When the solvent is distilled off under reduced pressure from a mixture of fractions 30 to 56, cis-3-chloro-5,6,6a, 9,10,11ahexahydronaphtho- [2 ', 1': 4.5] -imidazo [2 , 1-b] thiazole in the form of a light yellow oily substance.

The former reaction product is made from methylene chloride and hexane recrystallized, colorless needles having a melting point of 95.5 ° to 96.5 ° C. being obtained. The reaction product has the following spectral characteristics:

030604/0071

-H-

IR spectrum (KBr tablet) cm " ¹ : 1590, 1471, 1213, 1208, 1180, 1157, 1148, 872, 828, 802, 761.

Nuclear Magnetic Resonance Spectrum (CDCl,), S from TMS (ppm): 1.75 to 2.03 (2H, m, methylene in 6-position), 2.26 to 3.72 (6H, m, methylene in 5-, 8th position) - and 9-position), 3.90 (1H, dt, J = 9 Hz, 5 Hz, methine in 6a-position), 5.40 (1H, d, J β 9 Hz, methine in 11a-position) , 7.13 to 7.57 (3H, m, hydrogen in the 1- to 4-position).

The spectral characteristics of the latter reaction product are the following:

IR spectrum (blank) cm " ¹ : 2930, 2840, 1690, 1600, 1480, 1438, 1280, 1266, 1223, 1190, 1170, 1090, 881, 678.

Nuclear Magnetic Resonance Spectrum (CDCl,), S from TMS (ppm): 1.67 to 2.19 (2H, m, CH ₂ in 6-position), 2.57 to 2.87 (2H, m, CH ₂ in 5- Position), 3.02 to 3.63 (4H, m, CH ₂ in 9- and 10-position), 4.45 (1H, d, J = 9 Hz, CH in 11a-position), 4.78 ( 1H, dt, J = 9 Hz, 5 Hz, CH in 6a-position), 7.02 to 7.41 (3H, m, H in 1- to 4-position).

Example 15

mg of cis-3-chloro-5,6,6a, 9,10,11a-hexahydronaphtho- [2 ^f , 1 ': 4,5] -imidazof2,1-bJthiazole according to Example 14 are dissolved in 10 ml of dry benzene, whereupon in the solution placed in an ice bath for 15 minutes while stirring gas-

030604/0071

Fönnige hydrochloric acid is introduced. Gaseous nitrogen is then passed in for 20 minutes. After the solvent has been distilled off under reduced pressure, the resulting distillation residue is brought to crystallization from ether, whereby 013-3-ChIOr-SjO ₁ Oa ^ jIOjIIahexahydronaphtho- [2 ', 1': 4,5] -imidazo [2,1-b ] thiazole hydrochloride is obtained. This is recrystallized from methanol and acetonitrile, colorless prisms having a melting point of 263 ^° to 269 ^° C. (with decomposition) being obtained. The reaction product has the following spectral characteristics:

IR spectrum (KBr tablet) cm ~ ¹ : 2960, 2920, 2840, 2770, 1582, 1517, 1483, 1272, 1192, 818.

Nuclear magnetic resonance spectrum (dimethyl sulfoxide-dg), b from TMS (ppm): 1.5 to 2.2 (2H, m, CH ₂ in 6-position), 2.5 to
2.8 (2H, m, CH ₂ in the 5-position), 3.2 to 4.3 (4H,
ι, CH ₂ in 9- and 10-position), 5.09 to 5.52 (2H, ι, 6a, CH in 11a-position), 7.33 to 7.66 (3H, m, H in 1- up to 4 position).

Cis-3-chloro-5,6,6a, 8,9,11a-hexahydronaphtho- [i ', 2': 4,5] -imidazo [2,1-b] thiazole according to Example 14 is in the manner described in transferred its hydrochloride. This is recrystallized from methanol and acetonitrile, colorless prisms having a melting point of 234 ° to 239 ° C. (with decomposition) being obtained. The reaction product possesses
the following spectral characteristics:

IR spectrum (KBr tablet) cm " ¹ : 2920, 2730, 2670, 2630, 1590, 1524, 1439, 1278, 1204, 872, 811.

030604/0071

Nuclear magnetic resonance spectrum (dimethyl sulfoxide-dg), ^ from TMS (ppm): 1.56 to 2.34 (2H, m, methylene in 6-position), 2.44 to 2.84 (2H, m, methylene in 5-position), 4.65 (1H, dt, J = 10 Hz, 4 Hz, methine in 6a position), 5.81 (1H, d, J · = 10 Hz, methine in 11a position), 7.29 to 7.64 (3H, m, hydrogen in the 1- to 4-position, -12.1 ppm (1H, broad peak, HCl).

Example 16

A mixture of 3.00 g (12.6 mmoles) of trans-7-chloro-3a, 4,5,9-tetrahydronaphtho [1,2-d-jimidazoline-2-thione according to Example 5, 7.00 g (25.1 mmol) of 2-bromoethyl-p-toluenesulfonate, 1.50 g (14.2 mmol) anhydrous sodium carbonate and 100 ml isopropanol is heated to reflux temperature with stirring for 29.5 h. Then the mixture is according to the example 14 worked up, whereby trans-3-chloro-5,6,6a, 8,9,11ahexahydronaphtho- [1 ', 2': 4,5I-imidazo [2,1-b] thiazole and trans -3-chloro-5,6,6a, 9,10,11a-hexahydronaphtho- [2 ·, 1 ': 4.5 I-imidazo [2,1-bjthiazole can be obtained.

The first compound is recrystallized from methylene chloride and hexane, colorless plates having a melting point of 171.5 ° to 173 ° C. are obtained. The reaction product has the following spectral character! stika:

IR spectrum (KBr tablet) cm " ¹ : 2830, 1563, 1469, 1311, 1274, 1204, 1198, 1182, 1139, 887, 828, 771.

Nuclear Magnetic Resonance Spectrum (CDCl,), 6 from TMS (ppm): 1.76 to 2.38 (2H, m, methylene in 6-position), 2.54 to 3.10 (2H, m, methylene in 5- and 9 - position (or

030604/0071

J *

in the 8-position)), 3.22 to 4.01 (3H, m _t methylene in the 8-position (or 9-position), methine in the 6-position), 4.83 ppm (1H, d, J >> 13 Hz, methine in position 11a), 7.13 to 7.67 (3H, m, hydrogen in position 1 to 4).

The latter reaction product has the following spectral characteristics:

Nuclear Magnetic Resonance Spectrum (CDCI,), S from TMS (ppm): 1.73 to 4.44 (1OH, m), 7.19 (3H, s).

Example 17

The introduction of hydrochloric acid in 906 mg (3.42 mmoles) trans -3-chloro-5,6,6a, 9,10,11a-hexahydronaphtho- [2 ', 1': 4.5] -imida2o [2,1-b] thia2ol according to example 16 takes place according to example 12, whereby 1.02 g of trans-3-chloro-5,6,6a, 9,10,11a-hexahydronaphtho- [2 ·, 1 ': 4,5] -imida20- [2, 1-bJthiazole hydrochloride can be obtained. The reaction product is recrystallized from methanol and acetonitrile, colorless needles are obtained. These gradually begin at a temperature of 269 ° C to decompose. The reaction product has the following spectral characteristics:

IR spectrum (KBr tablet) cm " ¹ : 2950, 2890, 2850, 2750 to 2700, 2670, 1601, 1544, 1488, 1366, 1338, 1264, 1167, 1128, 883, 824, 658.

Nuclear magnetic resonance spectrum (dimethyl sulfoxide-d ^), ί from TMS (ppm): 1.87 to 2.40 (2H, m, CH ₂ in 6-position), 2.94 to

030604/0071

3.17 (2H, m, CH ₂ in the 5-position), 3.52 to 4.64 (5H, m, CH ₂ in the 9- and 10-positions and CH in the 6a-position), 4.77 (1H , d, J β 14 Hz, CH in 11a-position), 7.27 to 7.74 (3H, m, H in 1- to 4-position).

Trans-3-chloro-5,6,6a, 8,9,1ia-hexahydronaphtho-11 ·, 2 ': 4,5 J-imidazo [2,1-b] thiazole according to Example 16 is also used in the manner described in transferred its hydrochloride. This is brought from methanol and acetonitrile to crystallize to give colorless needles are obtained, mp 275 ° to 280 ⁰ C (with decomposition). The reaction product has the following spectral characteristics:

IR spectrum (KBr tablet) cm " ¹ : 2700, 2620, 1572, 1548, 1487, 1379, 1339, 1193, 1162, 828, 803.

Nuclear magnetic resonance spectrum (dimethyl sulfoxide-d, -), & from TMS (ppm): 1.74 to 2.43 (2H, m, methylene in 6-position), 2.96 to 3.17 (2H, m, methylene in 5th position) Position), 3.31 to 4.24 (5H, m, methylene in 8- and 9-position and methine in 6a-position), 5.34 (1H, d, J = 14 Hz, methine in 11a-position ), 7.27 to 7.67 (3H, m, hydrogen in the 1- to 4-position).

Example 18

A mixture of 2.00 g (9.00 mmoles) of trans-7-fluoro-3a, 4,5,9-tetrahydronaphtho [1,2-djimidazoline-2-thione according to Example 6, 5.02 g (18.0 mmol) of 2-bromoethyl-p-toluenesulfonate, 1.05 g (9.90 mmol) of anhydrous sodium carbonate and 70 ml of isopropanol are refluxed for 38 hours with stirring heated. Thereafter, the reaction mixture

030604/0071

Jt

worked up in the same way as in Example 14, with trans-3-fluoro-516,6a, 8,9,11a-hexahydronaphtho- [1 ', 2': 4,5] -imidazo [2,1-b] thiazole and trans-3-fluoro-5,6,6a, 9,10,11a-hexahydronaphtho- [2 ', 1 · : 4,5] -imdazo [2,1-b] -thiazole.

The first compound has the following spectral characteristics:

IR spectrum (KBr tablet) cm " ¹ : 3420, 2940, 2835, 1613, 1565, 1489, 1474, 1438, 1419, 1342, 1310, 1274, 1240, 1201, 1172, 1136, 1120, 1094, 1013, 907, 892, 810, 772.

Nuclear Magnetic Resonance Spectrum (CDCl,), S from TMS (ppm): 1.90 to 2.37 (2H, m, methylene in 6-position), 2.54 to 3.72 (7H, m, methylene in 5-, 8th position) - and 9-position and methine in 6a-position), 4.80 (1H, d, J = 12 Hz, methine in 11a-position), 6.74 to 7.72 (3H, in, hydrogen in 1- to 4 position).

The latter compound has the following spectral characteristics ;; :

IR spectrum (KBr tablet) cm " ¹ : 2950, 2860, 1615, 1575, 1492, 1346, 1322, 1278, 1254, 1219, 1168, 1149, 1121, 1068, 921, 912, 867.

Nuclear Magnetic Resonance Spectrum (CDCl,), S from TMS (ppm): 1.77 to 2.59 (2H, m, CH ₂ in 6-position), 2.73 to 4.10 (8H, m, CH ₂ in 5- , 9- and 10-position and CH in 6a and 11a-position), 6.73 to 7.18 (3H, m, H in 1- to 4-position).

030604/007 1

Example 19

The introduction of hydrochloric acid in 340 mg (1.43 mmoles) of trans-3-fluoro-5,6,6a, 9,10,11a-hexahydronaphtho- [2 ', 1 ^f: 4,5] imidazo [2,1 -b] thlazole according to Example 18 is carried out according to Example 12, with trans-3-fluoro-5,6,6a, 9,10,11a-hexahydronaphtho-f2 ', 1 · ι4,5! -imidazole, 1-bJthiazole hydrochloride is obtained. This is recrystallized from methanol and acetonitrile, 250 mg (0.874 mmol) of colorless needles being obtained. The reaction product has the following spectral characteristics:

IR spectrum (KBr tablet) cm " ¹ : 2940, 2880, 2825, 2705, 2655, 1616, 1586, 1549, 1493, 1459, 1418, 1362, 1337, 1268, 1231, 1175, 1159, 1128, 880, 817, 788, 659.

Nuclear Magnetic Resonance Spectrum (dimethyl sulfoxide-d ^), 6 from TMS (ppm) 1.97 to 2.50 (2H, m, CH ₂ in 6-position), 3.02 to 4.73 (8H, m, CH ₂ in 5 -, 9- and 10-positions and CH in 6a and 11a-positions), 6.88 to 7.15 (2H, m, H in 2- and 4-positions), 7.35 to 7.60 (1H , m, H in 1-position).

Trans-3-fluoro-5,6,6a, 8,9 _f 11ahexahydronaphtho- ( 1 ·, 2 ·: 4.5 I-imidazo [2 , 1-bjthiazole] obtained according to Example 18 is converted into its hydrochloride in the manner described This has the following spectral characteristics:

IR spectrum (KBr tablet) cm " ¹ : 2865, 2755, 2575, 1617, 1529, 1495, 1461, 1421, 1376, 1331, 1229, 1213, 1164, 1133, 1102, 1073, 875, 840, 830.

030604/0071

Nuclear magnetic resonance spectrum (dimethyl sulfoxide-d ^), 6 from TMS (ppm) 1.76 to 2.54 (2H, m, methylene in 6-position), 2.97 to 4.96 (7H, m, methylene in 5-, 8- and 9-position and methine in 6a position), 5.30 (1H, d, J = 13 Hz, methine in 11a position), 6.95 to 7.83 (3H, m, Hydrogen in the 1- to 4-position).

Example 20

This example illustrates the immunization-activating effect of cis-5,6,6a, 8,9,11a-hexahydronaphtho- [1 ', 2': 4,5I-imidazo [2,1-bJthiazole hydrochloride (agent A) and trans- 5,6,6a, 8,9,11a-hexahydronaphtho- [1 ', 2': 4,5 I-imidazo [2,1-b-thiazole hydrochloride (agent B) according to Example 12 and cis-5,6,6a , 9,10,11a-Hexahydronaphthiols ¹ , 1 ': 4,5I-imidazo [2,1-bJthiazole hydrochloride (agent C) and trans-5,6,6a, 9,10,11a-hexahydronaphtho- [2nd ', 1': 4,5jimidazo [2,1-bJthiazole hydrochloride (agent D) according to Example 13.

(1) Influence of humoral antibody formation:

Experiment 1: Male, 8-week-old ICR mice or male, 8-week-old CDF ₁ mice are administered intraperitoneally 10 red blood cells from sheep as antigens. Twenty-four hours after antigen administration, the various mice received intraperitoneal administration of each agent. 4 days after the administration of the antigen, the antibody-producing cells in the spleen of the mice are determined according to the method described by AJ Cunningham and A. Czenberg in "Immunology", Volume 14, pages 599 to 600 (1969). To comparison

030604/0071

For the purposes of this, experiments are also carried out with mice to which no agents were administered and to which the known agent levamisole was administered instead of the agent according to the invention. The results of these experiments can be found in the following table I. The experiments carried out with the ICR mice are called experiment 1a, the _{experiments carried out with CDF 1} mice are called experiment 1b.

Experiment 2: Male, 17 week old C3H / He mice are injected intravenously with 5 x 10 sheep red blood cells as Antigens administered. 24 hours after the administration of the antigen, the various agents become hypodermic in the inquinal Part of the mice administered. 4 days after the administration of the antigen, the antibodies will form according to experiment 1 Cells in the spleen of the mice were determined. As in experiment 1, experiments without the agents according to the invention or carried out with the known agent levamisole. The results of these experiments can also be found in Table I.

030604/0071

Table I.

middle dosage
(mg / mouse) number
attempt the antibody-forming cell
1a experiment 1b 930 i ■ ■ - 90 Len / 10 ~ spleen cells
Attempt 2 140 Blind test O 1500 - 170 1180 i 120 750 i 420 Levamisole 0.1 3530 ί 260 1040 i 160 1410 i 130 Il 0.4 1490 - 140 1220 - 100 860 i Means A 0.1 - 860 i 60 - Il 0.4 - 1100 i 100 - Medium B 0.1 - 1500 t 200 - Il 0.4 - - - 170 O
u> Middle C 0.1 1800 ± 150 1000 i 200 O ti 0.4 1610 - 180 1265 i 0 4/007 Medium D
ti 0.1
0.4 2440 -
2580 i 160
220 -

From Table I it can be seen that the agents according to the invention the number of antibody-producing cells of mice increase significantly, i.e. they have an excellent effect in terms of activating immunization.

(2) Influence on cellular immunity:

The influence or the effect of the means on the cellular Immunity is measured via an index of delayed hypersensitivity detected red blood cells from sheep injected as antigen in the balls of the hind paws of mice (See that of P.H. Lagrange, G.B. Mackaness and T.E. Mille procedures described in "Journal of Experimental Medicine", Volume 139, pages 1529-1539 (1974)).

8th
10 red blood cells from sheep blood, which are suspended in 0.05 ml of a phosphate-buffered physiological saline solution, are injected hypodermically into the balls of the hind paws of male, 12-week-old ICR mice. The mice are then given the various agents intraperitoneally. Four days after the administration of the agents, 10 red blood cells from sheep blood are hypodermically injected into the other ball of the hind paw, ie into the ball of the hind paw which has not previously received an anti-gene injection. 24 hours after the injection, the thickness of the ball of the hind paw is measured using a commercially available disc caliper. Here, the increase in the thickness of the ball of the hind paw in comparison to the ball of the hind paw which has not received an injection is determined. For comparison purposes, the experiments are repeated with mice, which no agent or instead of an invention

030604/0071

the known agent levamisole were administered according to the agent repeated. The results of the various experiments can be found in the following table II.

A. Tabel II middle dosage Increase in the thickness of the hind B. (mg / mouse; pad of paw in mm O 0.28 i 0.04 C. 0.1 0.33 0.04 0.4 From 0.29 to 0.04 Blind test D. 0.1 0.41 i 0.04 Levamisole 0.4 0.44 0.06 dd 0.1 0.57 to 0.03 middle 0.4 0.42 0.04 0.1 0.37 i 0.05 middle 0.4 0.38 t o, O5 ti 0.1 0.37 ± 0.06 middle 0.4 .39 to .04 11 middle Il

From Table II it can be seen that the compositions according to the invention swell the balls of the hind paws of mice, i.e. that they increase cellular immunity at least as much as levamisole.

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Claims (7)

Claims 1/. Hexahydronaphtholmidazothiazole and its derivatives of the formula: wherein X is a hydrogen or halogen atom and m and n, which are different from each other, either O or 1 mean. 2. Hexahydronaphthoimidazothiazole and its derivatives according to claim 1, characterized in that they are the Formula: wherein X is a hydrogen or halogen atom, correspond. 030604/0071 3. Hexahydronaphthoimidazothiazole and its derivatives according to claim 1, characterized in that they the Formula: Ci-3 wherein X is a hydrogen or halogen atom, correspond. 4. hexahydronaphthoimidazothiazole according to claim 1 in the form of an acid addition salt of a compound of the formula I with an inorganic or organic acid. 5. A process for the preparation of hexahydronaphthoimidazothiazole or a derivative thereof according to claim 1, characterized in that a tetrahydronaphthoimidazoline-2-thione or a derivative of the same of the formula: [II] 030604/0071 wherein X stands for a hydrogen or halogen atom, with a compound of the formula: Y-CH ₂ CH ₂ -Z Cm] where T and Z, which can be the same or different, represent a halogen atom, an allene sulfonyloxy group or an alkanesulfonyloxy group. 6. Tetrahydronaphthoimidazoline-2-thione and its derivatives the formula: [II] wherein X represents a hydrogen or halogen atom. 7. Process for the preparation of tetrahydronaphthoimidazoline-2-thione and its derivatives according to Claim 6, characterized in that a compound of Formula: [IV] 030604/0071 .-each - ■ '- ■' - ■ it wherein X stands for a hydrogen or halogen atom, reacted with carbon disulfide and then removed the hydrogen sulfide. 030604/0071