CH625207A5 - Process for the preparation of novel guanidine derivatives - Google Patents

Description

The invention relates to a process for the preparation of new guanidine derivatives which have anti-virus properties.

According to the invention, guanidine derivatives of the formula:

R'-NH • C • NH-R2 (I)

II

NH

prepared in which R1 is a cyclohexyl, adamantyl, bicyclo [2.2, l] heptanyl, bicyclo [2.2, l] hept-5-enyl, tricyclo [2,2,102,6] heptanyl or tetracyclo [4,3,0,02-4,03-7] nona-nyl radical and R2 represents a phenyl or pyridyl radical which is optionally substituted by 1 or 2 substituents consisting of halogen atoms, Alkyl and cyanoalkyl radicals with 1 to 6 carbon atoms, alkoxycarbonyl radicals with 2 to 6 carbon atoms and amino radicals are selected. According to the invention, the pharmaceutically acceptable acid addition salts of these derivatives are also produced.

The formulas in 3-dimensional representation for adamantyl- (II), bicyclo [2.2, l] heptanyl- (III), bicyclo [2.2, l] hept-5-enyl- (IV), tricyclo [2, 2, 1, 02'6] heptanyl (V) and tetracy-clo [4,3,0,02-4,03-7] nonanyl- (VI) radicals are as follows:

7

7

5

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30th

35

40

45

50

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65

3rd

625 207

I.

6

The point of attachment in radicals II, III, IV, V or VI can be at any of the numbered positions shown, some of which may be identical to one another. In addition, the point of attachment can be present in any of the possible stereochemical configurations. For example, in positions 2, 3, 5 or 6 in formula III, in positions 5 or 6 in formula IV, in positions 3 or 5 in formula V and in positions 8 or 9 in formula VI Binding have either the exo or endo configuration, ie that it can be ice or trans with respect to the bridge position (7 in formulas III, IV and V and 5 in formula VI).

It can be seen that when R1 is a bicyclo [2.2, l] heptanyl, bicyclo [2.2, l] hept-5-enyl, tricyclo [2.2, 1.02-6] heptanyl or tetracyclo [4,3,0,02'4,03'7] nonanyl radical and the molecule has no plane of symmetry, the guanidine derivative obtainable according to the invention will contain an optically active center and therefore be separated into two optically enantiomeric forms can be. It is pointed out that in such cases the invention encompasses both the racemic form and both optically active enantiomers of such a derivative.

Specific groups of compounds obtainable according to the invention within the above definition are the following:

those in which R1 is an adamantyl-, bicyclo [2.2, l] -heptanyl-, bicyclo [2.2, l] hept-5-enyl- or tricyclo [2.2, 1.02'6] heptanyl- Stands radical;

those wherein R1 is cyclohexyl-, adamant-l-yl-, exo-bicyclo [2.21] heptan-2-yl-, endo-bicyclo [2.2, l] heptan-2-yl, exo-bicyclo [2,2, l] hept-5-en-l-yl-, tricyclo [2,2,102,6] hep-tan-3-yl- or tetracyclo [4,3,0,02-4,03-7 ] nonan-8-yl radical and R2 represents a pyridyl radical or a phenyl radical which is optionally substituted by 1 or 2 fluorine atoms, by a chlorine or bromine atom or by a methyl, cyanomethyl, methoxycarbonyl or amino radical ;

those in which R1 is in the exo configuration;

those in which R2 has an optional substituent;

those in which R1 for an exo-bicyclo [2,2, l] hept-5-en-2-yl or exo-bicyclo [2,2, l] heptan-2-yl radical and Rz for an optionally substituted phenyl radical; and those in which R1 for an exo-bicyclo [2,2, l] hept-5-en-1-yl radical and R2 for a phenyl radical bearing a single optional substituent, for example in the 4-position can and which can be, for example, a fluorine, chlorine or bromine atom.

Specific compounds obtainable according to the invention are described in the examples. Of these, 2-exo- [3- (p-chlorophenyl) guanidino] bicyclo [2,2, l] hept-5-ene with its pharmaceutically acceptable acid addition salts is preferred.

A suitable pharmaceutically acceptable acid addition salt of the guanidine derivatives of the formula I is, for example, a hydrochloride, phosphate or sulfate or a citrate, acetate, succinate or fumarate.

According to the invention, the guanidine derivatives of the formula I are prepared by:

(a) reaction of a thiourea of the formula:

R'-NH • jj) • NH-R2 (VII)

S

or a thiouronium salt thereof with ammonia in the presence of a catalyst; or

(b) reaction of a carbodiimide of the formula:

RI-N = C = N-R2 (VIII)

with ammonia.

(c) Compounds of the formula obtained according to (a) or (b):

R3-NH ■ yy. NH-R2 (IX)

NH

where R3 is a bicyclo [2,2,1] hept-5-enyl radical, if desired by reduction into corresponding compounds of the formula:

R1'-NH-C-NH-R2 (I ')

II

NH

wherein R1 'stands for a bicyclo [2,2,1] heptanyl radical.

(d) Compounds which are optically active enantiomers can be obtained by separating the racemic compound of formula I by conventional means or by using one of the methods (a) to (c), the starting material itself being a separate isomer.

Process (a) is preferably carried out in a diluent or solvent, e.g. Ethanol. A preferred catalyst for use in the process is a heavy metal oxide, e.g. yellow mercury (II) oxide or lead oxide. The reaction is preferably carried out at a temperature between 0 and 100 ° C or at the boiling point of the diluent or solvent, whichever is lower. Using a temperature above room temperature may require constant addition of ammonia in the form of a gas stream. The thiouronium salt used as an optional starting material can have the formula:

R1-NH • Ç • NH-R2 (X)

i _ü ^ _ V ©

5

10th

15

20th

25th

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625 207

4th

wherein R4 is an alkyl radical of 1 to 4 carbon atoms, e.g. is a methyl radical, and X is an anion, e.g. a halide anion, for example a chloride, bromide or iodide anion.

Process (b) can be carried out under the same conditions as process (a), although of course no catalyst is then necessary.

Process (c) can be carried out using hydrogen in a diluent or solvent, e.g. Ethanol, and in the presence of a catalyst, e.g. a palladium-on-charcoal catalyst, for example a 5% (w / w) palladium-on-charcoal catalyst. The hydrogen can have atmospheric pressure or a pressure of up to 5 at.

The separation process (d) can be carried out, for example, by fractional crystallization of a salt of the racemic derivative of the formula I with an optically active acid, such as (+) - or (-) - mandelic acid or (+) - 0,0-dibenzoyl tartaric acid.

The starting material of formula VII for use in process (a) can be obtained by reacting an amine of the formula R2-NH2 or R1-NH2 with an isothiocyanate of the formula R'-NCS or R2NCS. The isothiocyanate can itself be obtained by reacting an amine of the formal R1-NH2 or R2-NH2 with thiophosgene

The starting material of formula VIII for use in process (b) can be obtained by reacting the compound of formula VII in the presence of carbon tetrachloride and triethylamine with triphenylphosphine.

By H.W. Geluk and co-workers [J. Med. Chem. 12 (1969), 712-715] are the preparation of compounds of the formula:

.R1

1-adamantyl-NH-C-N

NH

• R

and their activity against the influenza virus has already been described; in this formula R1 means hydrogen, methyl, ethyl, isopropyl, cyclohexyl, benzyl or 1-adamantyl and R2 means hydrogen or R1 and R2 together represent a radical of the formula:

-CH2CH2OCH2CH2-

In the studies in vivo, however, only the compound in which R1 and R2 represent hydrogen was found to be active.

The new compounds obtainable according to the invention have antivirus activity. In particular, they are specifically active against rhinoviruses, which, for example, colonize and multiply in the upper respiratory tract of warm-blooded animals, including humans. This activity is demonstrated by a tissue culture test on human embryonic lung cells, whereby it can be shown that the compounds prevent the growth of at least 16 different rhinoviruses at concentrations that do not cause any morphological abnormalities in the tissue culture cells. All of the compounds given by way of example in this description are active against rhinovirus type 2 at concentrations of 5 ^ g / ml and below, with no morphological abnormalities occurring in growing monolayers of the tissue culture cells at concentrations which are at least 4 times as large as the active dose . For example, the compound 2-exo- [3- (p-fluorophenyl) guanidino] bicyclo [2,2,1] hept

5-s

5 50% active against rhinovirus type 2 at a concentration of 0.02 jug / ml, while abnormalities only occur in 50% of the cells in the tissue culture layer at concentrations of 25 / ig / ml, which means a therapeutic ratio of 1250.

The compounds can be incorporated as an active ingredient in a pharmaceutical composition for the purpose of treating a rhinovirus infection in warm-blooded animals. Due to the high selectivity of their antivirus spectrum, the compounds according to the invention can also be used selectively for diagnostic studies and in hospital laboratories in order to prevent the growth of rhinoviruses, while other viruses, such as e.g. the enteroviruses, the arborviruses, the myxoviruses and the DNA-containing viruses, against which the compounds do not act, can normally multiply in the tissue culture.

When used in warm-blooded animals to achieve the desired effect, a daily oral dose of 1 to 15 mg / kg of the compound is desirable. When used in humans, this corresponds to a daily dose between 70 mg and 1 g. In humans, a daily dose between 70 and 250 mg administered in single doses is preferred. In humans, a daily nasal dose of 1 to 125 µg and preferably 1 to 25 µg is desirable.

The compounds can be used in the form of a pharmaceutical composition which, as an active ingredient, contains a guanidine derivative of the formula I together with a pharmaceutically acceptable diluent or carrier.

The pharmaceutical compositions can have the conventional form of tablets, troches, capsules, aqueous or oily solutions or suspensions, emulsions, nasal drops, sprays, aerosols (either wet or as dry powder) or snuffing agents. They can be made by conventional techniques and contain conventional excipients.

The preferred compositions are those found in the parts of the body where rhinoviruses normally grow, e.g. the mucous membranes of the nose, throat, mouth and bronchial tubes produce a virucidal level of the Gu-45 anidine derivative, the compositions being administered either directly to these parts or indirectly by providing adequate blood levels of the guani derivative after oral dosing is produced.

Such preferred compositions for direct administration are, for example, lozenges that slowly dissolve in the mouth to rinse the mouth and the associated passages with a solution of the active ingredient, nasal sprays or aerosols in the form of a solution or suspension of the guanidine derivative in one Inert pharmaceutically acceptable liquid, or a dry powder aerosol, which contains the guanidine derivative in fine powder form, the latter being inhaled into the nasal and bronchial passages and being deposited there. Preferred compositions for oral dosages are, for example, tablets. 60 A suitable tablet or troche contains 25 to 100 mg of the antivirus compound. The normal posology for the prophylaxis or treatment of a rhinovirus infection is 1 tablet 2 to 4 times a day.

A suitable nasal spray or aerosol 65 contains 5 to 50 fi g of the antivirus compound per ml of solution or suspension. For the prophylaxis or treatment of a rhinovirus infection, approximately 0.1 ml of such a solution is injected into the nose 3 to 6 times a day by the patient.

5

625 207

The compositions may also contain other pharmaceutically useful compounds such as e.g. Nasal decongestants, antipyretics or antiseptics. Because of the highly selective nature of the compounds' antivirus spectrum, they are also useful in hospitals and hospital laboratories for the selective inhibition of rhinovirus growth on tissue cultures so that other viruses that may be present can be more easily detected. For example, clinical samples from patients with diseases in the upper respiratory tract can be cultivated in the presence of a compound of the formula I. Rhinoviruses grow in the upper respiratory tract of humans, which is why rhinoviruses are often present in such samples. The growth of rhinoviruses during the incubation is prevented, but other viruses that may be present, e.g. Influenza viruses, adenoviruses and respiratory syn-cytial viruses grow unaffected. Similarly, the growth of rhinoviruses can be suppressed in hospital laboratories, while other viruses, e.g. Enteroviruses, arborviruses, myxoviruses and viruses containing DNA, against which the new compounds do not work, continue to multiply normally in tissue culture.

Finally, the fact that the compounds selectively inhibit the growth of rhinoviruses in the presence of other viruses results in a diagnostic tool for the rapid identification of rhinoviruses in a mixed virus population.

In use, the compound is added as a suspension or solution in a suitable diluent or solvent, which is usually water or a tissue culture medium, to the tissue culture to be tested. The final concentration of the compound can be varied within a wide range, but is generally in the range of 0.04 to 45 mg / ml. The culture is then incubated for a suitable period of time at a suitable temperature before testing for virus growth.

For example, human embryo lung cells that grew in Eagle medium in 51x13 mm glass tubes were infected twice with 100 TCDS0 of type 1 herpes simplex viruses and 100 TCD5o rhinoviruses of type 2 and incubated at 33 ° C. Two days later, the cells were seen to degenerate due to the growth of the viruses, and the culture media were subjected to infectivity titrations to determine that they contained at least 100 times more virus than the original inoculum.

A culture medium was produced in a parallel experiment

2-exo- [3- (p-chlorophenyl) guanidino] bicyclo [2.2, 1] -

hept-5-ene with a concentration of 2.5 contained. This medium was added to the double infected cell cultures which were incubated for 2 days at 33 ° C as above. Again, the cells were seen to degenerate due to virus growth. However, the culture media contained only a high concentration of herpes viruses, so that the growth of the rhinoviruses had been suppressed.

The invention is illustrated by the following examples, in which the temperatures are expressed in ° C.

example 1

A solution of 2 g of 2-exo- [3- (p-fluorophenyl) thiourei-do] bicyclo [2,2, l] hept-5-ene in 60 ml of saturated ethanolic ammonia was mixed with 1.74 at room temperature for 16 hours g of yellow mercury (II) oxide stirred. The reaction mixture was boiled on a steam bath for 15 minutes to drive off excess ammonia and to remove the fine particles of

To induce mercury (II) sulfide to coagulate. The solid was filtered off and washed twice with 10 ml of boiling ethanol, whereupon the combined filtrates were evaporated to dryness. The solid residue was recrystallized from 5 ethyl acetate, giving 2-exo- [3- (p-fluorophenyl) guanidino] bicyclo [2.2, 1] -

hept-5-en,

Mp 192-194 °.

The 10 2-exo- [3- (p-fluorophenyl) thioureido] bicyclo [2,2, l] -hept-5-ene used as the starting material was prepared as follows:

A solution of 2.6 g of p-fluoroaniline in 25 ml of chloroform was added to 3.0 g of 2-exo-isothiocyanatobicyclo [2.2, 1] hept-5-ene 15, and the mixture was stirred at room temperature for 16 hours. The mixture was then refluxed for 5 hours to complete the reaction and then cooled, after which the solid product was filtered off, washed with a little cold chloroform and dried. Recrystallization from toluene gave

2-exo- [3- (p-fluorophenyl) thioureido] bicyclo [2.2, l] -

hept-5-en mp 201-203 °.

Example 2

25 The procedure described in Example 1 was repeated using appropriately substituted starting materials and obtaining the following compounds:

R1 R2 Fp (°)

Cl H 206

Br H 214-215

40 H H 171

F F 187-188 *

* Crystallized from toluene

45 The starting materials for the above processes were obtained by repeating the process described in the second part of Example 1 using the appropriately substituted aniline instead of p-fluoroaniline as the starting material and using cyclohexane instead of 50 as chloroform as the solvent, the following connections were obtained:

625 207

6

Example 3

A solution of 0.5 g of 2-exo- [3- (p-fluorophenyl) guanidi-no] bicyclo [2,2, l] hept-5-ene in 25 ml of ethynol was added at room temperature and room pressure in the presence of 0. 05 g of 5% (w / w) palladium-on-charcoal hydrogenated until no more hydrogen was taken up. The mixture was filtered and the solvent was evaporated in vacuo. The remaining solid was recrystallized from ethyl acetate, whereby

2-exo- [3- (p-fluorophenyl) guanidino] bicyclo [2,2, l] -heptane, mp 186 °, was obtained.

Example 4

The procedure described in Example 3 was repeated using the appropriately substituted starting material and obtaining the following compounds:

The l- [3- (p-chlorophenyl) thioureido] adamantane used as the starting material was obtained as follows:

Separate solutions of 0.9 g of 1-aminoadamantane and 0.9 g of p-chlorophenyl isothiocyanate in 10 ml of chloroform were mixed and stirred at 20 ° for 3 days. The solvent was evaporated in vacuo and the remaining solid was recrystallized from toluene to give l- [3- (p-chlorophenyl) thioureido] adamantane, mp 185 °.

Example 7

The procedure described in Example 1 was repeated using appropriately substituted starting materials to give the following compounds:

/ T \ -

vu

R1

R2

Fp (°)

a

F

H F

204 177

Example 5

A solution of 0.9 g of l- (p-fluorophenyl) -3- (2-exobicyclo [2,2, l] hept-5-enyl) carbodiimide in 10 ml of saturated ethanolic ammonia was at room temperature for 48 hours ditched. The solvent was evaporated in vacuo from the suspension and the solid obtained was crystallized from ethyl acetate, giving 2-exo- [3- (p-fluorophenyl) guanidino] bicyclo [2.2, 1] -

hept-5-en,

Mp 194 °, was obtained.

The l- (p-fluorophenyl) -3- (2-exo-bicyclo [2,2, l] hept-5-enyl) - used as the starting material

carbodiimide was obtained as follows:

0.9 g of carbon tetrachloride was added to a solution of 1.55 g of 2-exo- [3- (p-fluorophenyne) thioureido] bicyc! O [2,2, l] hept-5-ene in 6 ml of dry methylene chloride , 0.58 g of triethylamine and 1.8 g of triphenylphosphine were added. The mixture was heated to 40 °. A clear solution had formed after 20 minutes. After a further 1.5 hours at 40 ° the solution was cooled. The solvent was removed by evaporation and the residue was extracted 3 times with 10 ml of cold petroleum ether (bp 60-80 °). After evaporating the extract, the desired l- (p-fluorophenyl) -3- (2-exo-bicyclo [2,2, l] hept-5-enyl) -carbodiimide was obtained as a yellow oil, which by mass spectroscopy (mass ion 228) and infrared spectroscopy (N = C = N very strong absorption at 2100 cm31) and then used without further purification.

Example 6

The procedure described in Example 1 was repeated using 1- (3-p-chlorophenylthioureido) adamantane as the starting material. In this way l- [3- (p-chlorophenyl) guanidino] adamantane, mp 196 °, was obtained.

R1

R2

R3

Fp (°)

Footnote

25 h cl h

154

1

ch3

h h

208-209

1

h ch3

H

179-181

2nd

h h

ch3

160-162

2nd

ch2cn h

H

170

1

30 cooch3

h h

199-200

1

nh2

h h

204-205

3rd

h nh2

H

158-160

2nd

Footnotes 35 1. Crystallized from ethyl acetate

2. Recrystallized from toluene

3. Hydrochloride, recrystallized from isopropanol / ethyl acetate

The starting materials for the above processes were obtained by repeating the procedure described in the second part of Example 1 using the appropriately substituted aniline as the starting material instead of p-fluoroaniline and using cyclohexane instead of chloroform as the solvent, whereby the following compounds were obtained:

R-

55

60

R1

R2

R3

FpO

Footnote h

Cl h

140-141

1

ch3

h h

173

1

h ch3

H

125-128

2nd

h h

ch3

174-175

3rd

cooch3

h h

177-178

3rd

nh2

h h

158

1

h nh2

H

-

4th

Footnotes

1. Recrystallized from toluene

2. Recrystallized from ether

3. Recrystallized from ethyl acetate

4. Used without further cleaning

7

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Example 8

The procedure described in Example 1 was carried out using

2-exo- [3- (4-pyridyl) thioureido] bicyclo [2,2, l] hept-5-en-

hydrochloride instead of

2-exo- [3- (p-fluorophenyl) thioureido] bicyclo [2,2, l] -

hept-5-en repeated. That way

Obtained 2-exo- [3- (4-pyridyl) guanidino] bicyclo [2,2, l] -hept-5-ene, which was converted into its dihydrochloride salt and recrystallized from a mixture of ethanol and ethyl acetate. A product was obtained which melted at 282 ° with decomposition.

The starting material was obtained by repeating the procedure described in the second part of Example 1 using 4-aminopyridine instead of p-fluoroaniline, maintaining the reflux for 3 days rather than 5 hours. The product was isolated as its hydrochloride salt and had a melting point of 200-201 °.

Example 9

The procedure described in Example 1 was carried out using

2-endo- (3-phenylthioureido) bicyclo [2,2, l] heptane as starting material instead of

2-exo- [3- (p-fluorophenyl) thioureido] bicyclo [2,2,1] -

hept-5-en repeated. In this way 2-endo- (3-phenylguanidino) bicyclo [2,2, l] heptane,

Mp 132-133 ° after recrystallization from toluene. The starting material was produced as follows:

A solution of 2-endo-aminonorbornane in cyclohexane (prepared by extraction of an alkaline solution of 1.5 g of 2-endo-aminonorbornane hydrobromide in water using cyclohexane and subsequent drying over anhydrous magnesium sulfate) became a solution of 1.38 g of phenyl -isothiocyanate in cyclohexane added and stirred for 10 hours at room temperature. The precipitated product was filtered off, washed with cyclohexane and then recrystallized from cyclohexane, giving 2-endo- (3-phenylthioureido) bicyclo [2,2, l] heptane, mp 154 °.

Example 10

2.0 g of l-cyclohexyl-3- (p-chlorophenyl) thiourea was dissolved in 40 ml of absolute ethyl alcohol saturated with ammonia. 1.7 g of yellow mercury (II) oxide were added and the mixture was stirred at room temperature for 16 hours. The mixture was then refluxed for 15 minutes to coagulate the fine precipitate of mercury (II) sulfide, which was then filtered off. The clear filtrate was then evaporated to dryness. The residue was recrystallized from toluene. This gave l-cyclohexyl-3- (p-chlorophenyl) guanidine, mp 187-190 °.

The starting material was produced as follows:

A solution of 3.0 g of p-chlorophenyl isothiocyanate in 15 ml of chloroform was added dropwise to a solution of 1.75 g of cyclohexylamine in 15 ml of chloroform with stirring at room temperature. After stirring for 3 hours, the white solid was filtered off, washed with a little CHC13 and recrystallized from toluene, giving l-cyclohexyl-3- (p-chloro-rophenyl) thiourea, mp 179-180 °.

Example 11

To a solution of 0.25 g of 3- [3- (p-chlorophenyl) thiou-reido] tricyclo [2.2, 1.02-6] heptane in 10 ml of ethanol saturated with ammonia was added 0.2 g of yellow mercury (II) oxide were added and the mixture was stirred for 16 hours at room temperature. The solids were filtered off and the clear filtrate was evaporated to dryness. The remaining solid was recrystallized from toluene. Da-5 was at

3- [3- (p-chlorophenyl) guanidino] tricyclo [2.2, 1.02'6] -

heptane,

Mp 204-205 °.

The thiourea used as the starting material was prepared as follows:

21 g of 3-aminotricyclo [2.2, 1.02'6] heptane (prepared according to GB-PS 1 051 319) were dissolved in 25 ml of chloroform and slowly below 10 ° to a stirred solution of 22 g of thiophosgene in 20 ml of chloroform admitted. After the addition had ended, the mixture was allowed to adjust to room temperature and stirred for a further 2 hours. The chloroform solution was washed successively with 20 ml portions of water, n NaOH and again water, dried over anhydrous MgSO4 and filtered, after which the chloroform was evaporated in vacuo. The remaining oil was fractionally distilled in vacuo to give 3-isothiocyanatotricyclo [2.2, 1.02-6] heptane, bp 70-76 ° at 0.4 mm Hg pressure.

1.2 g of this isothiocyanate were dissolved in 30 ml of chloroform 25, to which 2.1 g of p-chloroaniline were added. The latter dissolved quickly, whereupon the mixture was refluxed for 3 hours. The cooled solution was extracted with 10 ml of 2N HCl, washed with 10 ml of water and dried over anhydrous MgSO4. After filtration, the solvent was evaporated in vacuo and the solid residue was recrystallized from toluene. It was

3- [3- (p-Chlorophenyl) thioureido] tricyclo [2.2, 1, 02'6] -heptane, mp 164-166 °.

35 Example 12

0.30 g of 8- [3- (p-chlorophenyl) thioureido] tetracy-clo [4,3,0,02'4,03-7] nonane was dissolved in 100 ml of ethanol saturated with ammonia at room temperature and stirred for 6 hours with 0.43 g of yellow mercury (II) oxide. The Ge-40 was then boiled for 15 minutes to remove excess ammonia and filtered, after which the filtrate was evaporated to dryness. The solid residue was recrystallized from a 1: 2 vol. Mixture of toluene and cyclohexane, where

45 8- [3- (p-chlorophenyl) guanidino] tetracyclo [4,3,0,02-403'7] nonane,

Mp 170-171 °, was obtained.

The thiourea used as the starting material was prepared as follows: 0.5 g of 8-aminotetracyclo [4,4,0,02'4,03,7] nonane hydrochloride (prepared according to GB-PS 1 180 749) was mixed dissolved from 25 ml of chloroform and 0.33 g of triethylamine. 0.5 g of p-chlorophenyl isothiocyanate was added to this solution, and the mixture was kept at reflux for 16 hours. After cooling, the chloroform solution was washed successively with 10 ml portions of 2N HCl, water and saturated saline, and then dried over anhydrous MgSO4. After filtration, the solvent was evaporated in vacuo and the residue was crystallized from a 1: 2 vol. Mixture of toluene and cyclohexane. It was

8- [3- (p-chlorophenyl) thioureido] tetracyclo [4.3.0,02,4,03-7] -

nonane mp 168-17 °, obtained.

65 Example 13

A similar procedure can also be used to obtain 2-endo- [3- (p-chlorophenyl) guanidino] bicyclo [2,2,1] heptane, mp 179-181 ° after recrystallization from toluene.

625 207

8th

Example 14

0.5 g of 2-exo- [3- (p-chlorophenyl) thioureido] bicyclo [2.2, 1] hept-5-ene was dissolved in 10 ml of ethanol and 0.255 g of iodomethane was added. The mixture was refluxed for 3 hours during which time the thiourea was completely converted to the S-methylthiouronium iodide. The mixture was cooled and then saturated with ammonia gas. The mixture was refluxed for 10 hours, passing a constant stream of ammonia, after which it was cooled to room temperature, saturated again with ammonia and left to stand for 3 days.

The solvent was evaporated and the residue was dissolved in 10 ml of ethyl acetate. An insoluble part (ammonium iodide) was filtered off and the organic phase was extracted 4 times with 10 ml of water each time. The combined aqueous extracts were made alkaline with 10N NaOH and the precipitate was filtered off, washed with water and dried. After recrystallization from ethyl acetate, 2-exo- [3- (p-chlorophenyl) guamdino] bicyclo [2.2, 1] -

hept-5-en,

Mp 202-203 °, obtained.

Example 15

A solution of 6.1 g of 2-exo- [3- (p-chlorophenyl) guanidi-no] bicyclo [2,2, l] hept-5-ene in 75 ml of hot ethanol was stirred, while a solution of 3, 54 g (+) - mandelic acid in 25 ml of hot ethanol was added dropwise. The mixture was allowed to cool slowly for 16 hours after which the precipitate was filtered off with a 10 ml portion

Ethanol was stirred and filtered again. The two filtrates were combined and saved. The filtered solid was recrystallized 3 times from ethanol and then had an mp of 159-162 °. This solid was stirred for 15 min with 20 ml of 2N NaOH to give the free base of the undivided guanidine, which was filtered off, washed with 10 ml of water and dried. The solid was recrystallized from ethyl acetate, whereby

(+) - 2-exo- [3- (p-chlorophenyl) guanidino] bicyclo [2,2, l] -lo hept-5-ene,

Mp 205-207 °, [a] D21 = + 73 ° (c, 1.0 in methanol).

The retained filtrates of the (+) - mandelate salt were evaporated to dryness in vacuo and the base 15 was released by stirring with 20 ml of cold 2N NaOH. The base was filtered off, washed with water and dried to give 3.0 g of a solid. This was dissolved in 45 ml of hot ethanol, whereupon a solution of 1.75 g of (-) - mandelic acid in 20 ml of hot ethanol was added. The mixed solutions were allowed to cool slowly for 16 hours. The precipitate was filtered off, washed with 10 ml of ethanol and then recrystallized twice from ethanol. A salt with mp 159.5-162 ° was obtained.

25 The base was liberated as above, and after crystallization from ethyl acetate, (-) - 2-exo- [3- (p-chlorophenyl) guanidino] bicyclo [2,2, l] -hept-5-ene,

Mp 205-207 °, [a] D21 = -73 ° (c, 1.0 in methanol).

s

Claims (6)

625 207 2. The method according to claim 1 for the preparation of optically active guanidine derivatives of the formula I, characterized in that a racemic compound obtained is separated or an optically active thiourea of the formula VII or a thiouronium salt thereof is used as the starting material. 2nd PATENT CLAIMS 1. Process for the preparation of guanidine derivatives of the formula: R -NH • C • NH-R2 (I) II NH wherein R1 for a cyclohexyl, adamantyl, bicyclo [2.2, l] heptanyl, bicyclo [2.21] hept-5-enyl, tricyclo [2.2, 1.02-6] heptanyl or tetracyclo [4,3,0,02'4,03,7] nonanyI-Radial and R2 represents a phenyl or pyridyl radical which is unsubstituted or substituted by 1 or 2 substituents consisting of halogen atoms, alkyl and cyanoalkyl radicals 1 to 6 carbon atoms, alkoxycarbonyl radicals with 2 to 6 carbon atoms and amino radicals are selected, and their pharmaceutically acceptable acid addition salts, characterized in that a thiourea of the formula: R '-NH • C • NH-R2 (VII) II S or reacting a thiouronium salt thereof with ammonia in the presence of a catalyst. 3. The method according to claim 1 for the preparation of guanidine derivatives of the formula: R1 '-NH-C-NH-R2 (I') II NH wherein R1 'represents a bicyclo [2,2, l] heptanyl radical and R2 has the meaning given above, as well as their pharmaceutically acceptable acid addition salts, characterized in that a guanidine derivative obtained of the formula: R3 — NH-C-NH-R2 (IX) II NH where R3 stands for a bicyclo [2,2,1] hept-5-enyl radical. 4. A process for the preparation of guanidine derivatives of the formula I given in claim 1 and their pharmaceutically permissible acid addition salts, characterized in that a carbodiimide of the formula: R1-N = C = N-R2 (VIII) reacted with ammonia. 5. The method according to claim 4 for the preparation of optically active guanidine derivatives of the formula I, characterized in that a racemic compound obtained is separated or an optically active carbodiimide of the formula VIII is used as starting material. 6. The method according to claim 4 for the preparation of guanidine derivatives of the formula I 'given in claim 3, and their pharmaceutically acceptable acid addition salts, characterized in that a guanidine derivative obtained of the formula: R3-NH-C-NH-R2 (IX) II NH where R3 stands for a bicyclo [2,2,1] hept-5-enyl radical.