DE2635932A1 - GUANIDE DERIVATIVES - Google Patents

Description

PATENT LAWYERS

DR.-ING. H, FiNCKE Or PL.- IN GH BOHR DIPL.-ING .. S. STAE (SESR DR. Rer. Nat. R. KMEISSL

PA Dr. Hndce - Bohr - Sfacger. Dr. Knetssl - MüKersfr. 31 - EQOO Munich

August 10, 1976

a MONCHEM 5,

Müllerstrasse 31

Telephone: (689J * 2fiiaaa 2635932

Telegrams: Claims Munich Telex = 523903 claim d

Mop «No. 24071 - Dr.K

Please indicate in the answer

Case PH 28114-

TNPKRTAT, CHEMICAIi TJNBUSTBIES LTD. London, UK

Guanidine derivatives

Priority: August 11, 1975

The invention relates to new guanidine derivatives, which Have antiviral properties.

According to the invention, guanidine derivatives of the formula:

R-NH. C. NH-R ²

NH

709803/1215 ORIGINAL INSPECTEÖ

suggested, where R stands for a cyclohexyl-, adamantyl-,
Bicyclo [2.2.1] heptanyl-, bicyclo [2.2.1] hept-5-enyl-, sricyclo-

[2,2,1, O ² ' ⁶ ] heptanyl- or tetracyclo [4-, 3,0,0 ² ' \ o ⁵ ' ⁷ jnonanyl-

ρ
Radical stands - and R stands for a phenyl or pyridyl radical which is optionally substituted by 1 or 2 substituents, the
are selected from halogen atoms, alkyl and cyanoalkyl radicals having 1 to 6 carbon atoms, alkoxycarbonyl radicals having 2 to 6 carbon atoms, and amino radicals. According to the invention, the pharmaceutically acceptable acid addition salts of these derivatives are also proposed.

The formulas in 3-dimensional representation for adamantyl- (II), bicyclo [2,2,1] heptanyl- (III), bicycloL2,2,1Jhept-5-enyl- (IV), tricyclo [2,2,1, 0 ² » ⁶ ] heptanyl- (V) and ²⁴⁵

nonanyl (VI) radicals are as follows:

III

IV

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.ν

VI

The point of contact in radicals II, III, 17, V or VI can be in any of the numbered positions shown are present, some of which may be identical to one another. In addition, the connection point can be any of the possible stereochemical configurations. For example, in positions 2, 3, 5 or 6 in the 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 the formula VI, the bond is either the exo- or endq configuration, i.e. that they have cis and trans with respect to the bridge position (7 in formulas III, IV and V and 5 in formula VI) can be.

It can be seen that when R is a bicyclo [2,2,11 heptanyl-, bicyclo [2,2,1Jhept-5-enyl-, tricyclo [2,2, Λ , O ² * ⁶ ] heptanyl- or tetracyclo [4,3,0,0 '^, O ^' ^ jnonanyl radical and the molecule has no plane of symmetry, the guanidine derivative according to the invention contain an optically active center

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is and therefore separated into two optically enantiomeric forms can be. It should be noted that in such cases the invention can use the racemic form as well as both optically active enantiomers of such a derivative.

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

1
those where R is an adamantyl, bicyclo [2.2.1] hep-

tanyl, bicyclo [2,2, i] hept-5-enyl or tricyclo [2,2,1,0 ² * ⁶ ] -heptanyl radical;

those in which R is a cyclohexyl-, adamant-1-yl-, exo-bicyclo [2.2.1] heptan-2-yl-, endo-bicyclo L2.2, Λ \ heptan-2-yl-, exo -Bicyclo [2,2,1] hept-5-en-2-yl-, tricyclo [2,2,1, O ² ' ⁶ jheptan-3-yl- or tetracyclo [4,3,0,0 ² * \ o ^ '^] nonan-8-yl radical

ο
and R 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 where R is in the exo configuration;

ρ
those in which R has an optional substituent;

those where R is an exo-bicyclo [2,2, i] hept-5-en-2-yl- or exo-bicyclo [2,2,1] heptan-2-yl radical and R ^ for an optionally substituted phenyl radical; and

those where R is an exo-bicyclo [2,2,1] hept-5-en-2-yl radical and R is a phenyl radical bearing a single optional substituent, for example can be in the 4 position and for example a Can be fluorine, chlorine or bromine atom, stands.

Special compounds according to the invention are shown in the examples

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len described. Of these, 2-exo- [3-Cp-chlorophenyl) -guanidino] bicyclo [2,2,1Jhept-5-en preferred with its pharmaceutically acceptable acid addition salts.

A suitable pharmaceutically acceptable acid addition salt of the guanidine derivatives according to the invention is, for example Hydrochloride, phosphate or sulfate or a citrate, acetate, succinate or fumarate.

The guanidine derivatives of the invention can be prepared by methods known in the art for the preparation of chemically analogous compounds are known, such as:

Ca) Implementation of a thiourea of the formula:

* 1 / τι ö ^ \ f TT

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

Cb) Implementation of a cyanamide of the formula R-NHCN or R-NHCN

2 1 with an amine of the formula R -NH ₀ or R -

Cc) Implementation of a carbodiimide of the formula:

R ¹ ^ = C = NR ² - VIII

with ammonia;

Cd) for those compounds in which R is a cyclohexyl or bicyclo [2,2,1] heptanyl radical, reduction of a compound of the formula:

R ³ -NH.C.NH-R ^{2 IX}

Ij

NH

where R ^ for a cyclohexenyl or bicyclo [2,2, i] heptenyl

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Radical; and

(e) for compounds which are optically active enantiomers, separation of the racemic compound of Formula I above by conventional measures or by using one of the methods (a) to (d), the starting material itself being a separate Is isomer.

Process (a) is preferably carried out in a diluent or solvent such as, for example, ethanol. A preferred catalyst for use in the process is a heavy metal oxide such as 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 temperature is lower. The use of 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:

^ -NH.C.NH-R ²

SR ⁴ .X

where R is an alkyl radical having 1 to 4 carbon atoms, such as a methyl radical, and X ^ is an anion, such as a halide anion, for example a chloride, bromide or iodide anion.

Process (b) can be carried out in the presence or absence of a diluent or solvent at a temperature between 50 and 250 ^° C., the upper limit being limited by the boiling point of any diluent or solvent used. A suitable optional diluent or solvent is, for example, n-butanol ”. The amine component of the reaction is preferred

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in the form of a salt, such as Hydrochloric !, used.

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

Process (d) can be carried out using hydrogen in a diluent or solvent such as ethanol, and in the presence of a catalyst such as a palladium on charcoal catalyst, for example a 5% (w / w) palladium on charcoal catalyst. Of the Hydrogen can have atmospheric pressure or a pressure up to 5 at.

The separation process (e) 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 (-) - rfendelic acid or (+) - 0,0-dibenzoyltartaric acid.

The starting material of formula VII for use in process (a) can be obtained by using an amine

2 1

of the formula R-HH ₀ or R -KH ₀ with an isothiocyanate of the formula

1 2
mel R -NCS or R -NCS. The isothiocyanate can itself

Λ 2 can be obtained by reacting an amine of the formula R -NE ^ or R -EELj with thiophosgene.

The starting material of the formula R -NHCN for use in process (b) can be obtained by using a compound de j
Thiourea

Reacts compound of the formula R-NCS with ammonia, the

R ¹ NH-C-NH ₂

is obtained, which is then mixed with yellow mercury (II) -ox ± d

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is used to manufacture the desired product. Another The possibility of production consists in the reaction of an amine of the formula R -NHp with cyanogen bromide.

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

The new compounds according to the invention have antiviral activity. In particular, they are specifically active against ehinoviruses which, for example, settle and multiply in the upper respiratory tract of warm-blooded animals, including humans. This activity is demonstrated by a tissue culture experiment on human embryonic lung cells, which shows that the compounds prevent the growth of at least 16 different ehinoviruses at concentrations which do not cause morphological abnormalities in the tissue culture cells. All of the compounds exemplified in this description are at concentrations of 5 ug / ml and below 50% active against rhinovirus type 2, with no morphological abnormalities occurring in the growing monolayers of the tissue culture parts at concentrations that are at least 4 times as high as the active one Can are. For example, the compound according to the invention 2-exo - [$ - (p-fluorophenyl) guanidino] bicyclo [2,2, ilhept-5-ene at a concentration of 0.02 μg / ml is 50 % active against ehinovirus type 2, while abnormalities only occur in 50% of the cells in the tissue culture layer at concentrations of 25 pg / ml, which means a therapeutic ratio of 1250.

The compounds according to the invention can be used as an active ingredient in a pharmaceutical composition for the purpose of Treatment of khinovirus infection in warm-blooded animals will. Due to the high selectivity of their antivirus

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The compounds according to the invention can also selectively cover a spectrum used in diagnostic studies and in hospital laboratories to prevent the growth of rhinoviruses, while other viruses such as the enteroviruses, the arborviruses, the myxoviruses and the DHA-containing viruses against which the Compounds according to the invention do not act normally in the tissue culture can multiply.

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

The compounds of the invention can be in the form of a pharmaceutical Composition used as an active ingredient / together with a pharmaceutically acceptable Contains diluents or carriers.

The pharmaceutical compositions according to the invention can take the conventional form of tablets, troches, capsules, aqueous or oily solutions or suspensions, emulsions, Contain nasal drops, sprays, aerosols (either wet or dry powder) or snuff. You can go through conventional techniques and contain conventional excipients.

The preferred compositions according to the invention are those those in the parts of the body where rhinoviruses normally grow, such as the mucous membranes of the nose, des Throat, mouth and bronchi, a virucidal level

/ a guanidine derivative according to the invention

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of the guanidine derivative according to the invention, the administration the compositions either act directly on these parts or else indirectly by maintaining an adequate blood level of the guanidine derivative after oral dosing.

Such preferred compositions for direct administration are for example lozenges that dissolve slowly in the mouth, around the mouth and the associated passages with a solution Rinse of the active ingredient, nasal sprays or wet aerosols in the form of a solution or suspension of the guanidine derivative in an inert pharmaceutically acceptable liquid, or a dry powder aerosol, which is an inventive Contains guanidine derivative in fine powder form, the latter being inhaled and into the fibrous and bronchial passages can be deposited there. Preferred compositions for oral dosages are, for example, tablets.

A suitable tablet or lozenge contains 25 to 100 mg of an antiviral compound according to the invention. The normal regimen for the prophylaxis or treatment of ehinovirus infection is 1 tablet 2 to 4 times a day.

Contains a suitable rabbit spray or aerosol 5 μg to 50 pg of an antivirus compound according to the invention each ml of solution or suspension. For the prophylaxis or treatment of bhinovirus infection, approximately 0.1 ml of such Solution 3 to 6 times per day through the patient into the nose injected.

The compositions of the invention may also contain other pharmaceutically useful compounds such as nasal decongestants, Antipyretics or antiseptics. Due to the highly selective nature of the antivirus spectrum of the invention. They are also used in hospitals and hospital laboratories for the selective inhibition of an ehinovirus

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Tissue culture growth useful so that other viruses that may be present can be more easily detected. For example, clinical samples from patients with diseases of the upper respiratory tract can be cultured in the presence of a compound of the invention. Ehinoviruses grow in the upper respiratory tract of humans, which is why bhinoviruses are often present in such samples. The growth of ehinoviruses during incubation is prevented, but other viruses that may be present, such as influenza viruses, adenoviruses and respiratory syncytial viruses, grow unaffected. Similarly, the growth of rhinoviruses can be suppressed in hospital laboratories, while other viruses, such as enteroviruses, arborviruses, ffyxoviruses and DNA-containing viruses, against which the compounds according to the invention are not effective, continue to multiply normally in tissue culture.

Finally, it follows from the fact that the invention Compounds selectively the growth of shinoviruses in Inhibiting the presence of other viruses, a diagnostic tool for the rapid identification of rhinoviruses in a mixed Virus population.

When used, a compound according to the invention is used as Suspension or solution in a suitable diluent or solvent, which is usually water or a Tissue culture medium is added to the tissue culture to be tested. The final concentration of the compound of the invention can be varied within a wide range, but is generally in the range of 0.04 to 45 µg / ml. The culture is then kept for an appropriate period of time incubated at a suitable temperature before testing for virus growth.

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For example, human embryonic lung cells that grew in Eagle medium in glass tubes measuring 51 x 13 mm were infected twice with 100 TCDn ₀ ⁸ ^ ¹ herpes simplex viruses of type 1 and 100 TCD, -q rhinoviruses of type 2, and at 33 ⁰ C incubated. Two days later it was seen that the cells were degenerating due to the growth of the viruses, and the culture media were then subjected to infectivity titrations and found to contain at least 100 times more of each virus than the original inoculum ..

In a parallel experiment, a culture medium was prepared which contained 2-exo- [3- (p-chlorophenyl) guanidine] bicyclo [2.2, Λ] hept-5-ene at a concentration of 2.5 µg / ml. This medium was added to the doubly 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 only contained a high concentration of herpes viruses, so that the growth of the rhinoviruses was suppressed.

The invention is further illustrated by the following examples in which the temperatures are expressed in C ^0.

example 1

A solution of 2 g of 2-exo- [3- (p-fluorophenyl) thioureido] -bicycloC2,2, i] hept-5-ene in 60 ml of saturated ethanolic ammonia was 16 hours long at room temperature with 1.74 g of yellow Mercury (II) oxide stirred. The reaction mixture was boiled on a steam bath for 15 min to remove excess ammonia drive off and around the fine particles of mercury (H) sulfide to cause coagulation. The solid was filtered off and washed twice with 10 ml of boiling ethanol each time, whereupon the combined filtrates were evaporated to dryness. The solid residue was recrystallized from ethyl acetate

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sated, where 2-exo- [3-Cp-fluorophenyl) guanidino] bicyclo- [2,2,1] hept-5-en, Pp 192-194 °.

The 2-exo- [3- (p-pluorophenyl) -thioureidojbicyclo used as starting material [2,2,1] hept-5-en was prepared as follows:

A solution of 2.6 g of p-fluoroaniline in 25 ml of chloroform was made to 3.0 g of 2-exo-isothiocyanatobicyclo [2,2,1Jhept-5-ene added, whereupon the mixture was stirred for 16 st at room temperature. The mixture was then refluxed for 5 hours to complete the reaction to bring it to an end, and then cooled, whereupon the solid The product was filtered off, washed with a little cold chloroform and dried. Recrystallization from toluene gave 2-exo-L3- (p-fluorophenyl) thiQureido] bicyclo [2,2,1Jhept-5-en, Pp

201-203 °.

Example 2

The procedure described in Example 1 was repeated, using appropriately substituted starting materials and the following compounds were obtained:

NHC-NH-NH

R ¹ R ² Pp (°) Cl H 206 Br H 214-215 H H 171 P. P. 187-188 *

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Recrystallized from toluene

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The starting materials for the above procedures were obtained by following that described in the second part of Example 1 Process using the correspondingly substituted aniline instead of p-fluoroaniline as starting material and using cyclohexane in place of chloroform as a solvent, the following Connections were obtained:

R. Ip (°) Eq
Br
H $ 18
145
164

Example ^

A solution of 0.5 g of 2-exo-C3- (p-fluorophenyl) guanidino] bicyclo [2,2, ilhept-5-ene in 25 ml of ethanol was at room temperature and room pressure in the presence of 0.05 g of 5% iger (w / w) palladium-on-charcoal hydrogenated until no more hydrogen uptake took place. The mixture was filtered and the solvent was evaporated in vacuo. The remaining solid was recrystallized from ethyl acetate, whereby 2-exof3- (pE ^l luorophenyl) guanidino] bicyclo [2.2.1] heptane, mp 186 °, was obtained.

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Example 4

The procedure described in Example 3 was repeated, wherein the correspondingly substituted starting material was used and the following compounds were obtained:

R ¹ R ² Fp (°) Cl *
F. H
F. 204
177

Example 5

A solution of 0.9 g of 1- (pJ ^l luorophenyl) -3- (2-exo-bicyclo-C2,2,1] hept-5-enyl) carbodiimide in 10 ml of saturated ethanolic ammonia was left to stand for 48 hours at room temperature . The solvent was evaporated from the suspension in vacuo and the solid obtained was crystallized from ethyl acetate, 2-exo- [3- (p-fluorophenyl) guanidino] bicyclo [2.2.1] hept-5-ene, mp 194 °, was obtained.

The 1- (p-fluorophenyl) -3- (2-exo-bicyclo [2,2, i] hept-5-enyl) carbodiimide used as starting material was obtained as follows:

To a solution of 1.55 g of 2-exo- [3- (p-fluorophenyl) thioureido] bicyclo [2.2.1] hept-5-ene in 6 ml of dry methylene chloride were 0.9 g of carbon tetrachloride, 0.58 g of triethyl

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amine and 1.8 g triphenylphosphine were added. The mixture was produced heated to 4-0 °. 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 washed 3 times with 10 ml of cold petroleum ether (Ep 60-80 °) extracted. After evaporation of the extract, the desired 1- (p-fluorophenyl) -3 - (2-exo-bicyclo [2,2, i} hept-5-enyl) carbodiimide was obtained obtained as a yellow oil which was determined by mass spectroscopy (mass ion 228) and infrared spectroscopy (N = C = N very strong absorption at 2100 cm ") identified and then was used without further purification.

Example 6

The procedure described in Example 1 was repeated using 1- (3-p-chlorophenylthioureido) adamantane as the starting material was used. In this way 1- [3- (p-chlorophenyl) guanidinojadamantan, Mp 196 °.

The 1- [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 p-Chlorophenyl isothiocyanate in 10 ml of chloroform was mixed and stirred for 3 days at 20 °. The solvent was evaporated in vacuo and the remaining solid became recrystallized from toluene, with 1- [3- (p-chlorophenyl) thioureido] adamantane, Mp 185 °.

Example 7

The procedure described in Example 1 was repeated using appropriately substituted starting materials, whereby the following compounds were obtained:

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TY

R ¹ R ² r5 Ip (°) footnote H Cl H 1 CH, H H 208-209 1 H CH ₃ H 179-181 2 H H CH ₃ 160-162 2 CH ₂ CN H H 170 1 COOCH, H H I99-2OO 1 NH ₂ H H 204-205 3 H NH ₂ H 158-160 2

Footnotes

1. Recrystallized from ethyl acetate

2. Recrystallized from toluene

3. Hydrochloric!., Recrystallized from isopropanol / ethyl acetate

The starting materials for the above procedures were thereby obtained that the method described in the second part of Example 1 using the correspondingly substituted Aniline as a starting material instead of p-fluoroaniline and using cyclohexane in place of chloroform as a solvent, the following Connections were obtained:

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7 0 9 8 0 9/1215

If

R ^J

E ² R ⁵ Fp (°) footnote H Cl H 140-14-1 1 CH-. - H H 173 1 H CH ₃ H 125-128 2 H H CH 174-175 3 COOCH ^ H H 177-178 3 NH ₂ H H 158 1 H NH ₂ H - 4-

Footnotes

1. Recrystallized from toluene

2. Recrystallized from ether

3. Recrystallized from ethyl acetate

4. Used without further purification

Example 8

The procedure described in Example 1 was followed using of 2-exo- [3- (4 - pyridyl) thioureido] bicyclo [2,2,1] hept-5-ene hydrochloride instead of 2-exo- [3- (p-fluorophenyl) thioureido] bicyclo [2,2,1] hept-5-ene repeated. In this way became 2-exo- [3- (4-pyridyl) guanidino] bicyclo [2,2,1] hept-5-ene obtained, which converted into its dihydrochloride salt and recrystallized from a mixture of ethanol and ethyl acetate became. A product was obtained which melted at 282 ° with decomposition.

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The starting material was obtained by repeating the procedure described in the second part of Example 1 using 4-aminopyridine in place 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 200-20Ί ⁰ .

Example 9

The procedure described in Example 1 was used from. 2-endo- (3-phenylthioureido) bicyclo [2.2.1] heptane as Starting material instead of 2-exo- [3- (p-fluorophenyl) thioureido] bicyclo [2,2, i] hept-5-ene repeated. In this way, 2-endo- (3-phenylguanidino) bicyclo [2.2.1] heptane, m.p. 132-133 ° after recrystallization from toluene obtained.

The starting material was prepared as follows:

A solution of 2-endo-aminonorbornane in cyclohexane (prepared by extracting an alkaline solution of 1.5 g 2-endo-aminonorbornane hydrobromide in water using cyclohexane and subsequent drying over anhydrous magnesium sulfate) was added to a solution of 1.38 g of phenyl isothiocyanate in cyclohexane and the mixture was stirred at room temperature for 10 hours. The precipitated product was filtered off, washed with cyclohexane and then recrystallized from cyclohexane, whereby 2-endo- (3-phenylthioureido) bicyclo [2.2.1] heptane, mp 154 °, was received «

Example 10

2.0 g of 1-cyclohexyl-3- (p-chlorophenyl) thiourea was in 40 ml of absolute ethyl alcohol, which is saturated with ammonia was dissolved. 1.7 g of yellow mercury (II) oxide were added to this added, whereupon the mixture 16 st at room temperature

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was stirred. The mixture was then refluxed for 15 minutes in order 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 1-Cyclohexyl 5- (p-chlorophenyl) guanidine, Pp 187-19O ⁰ , was obtained.

The starting material was prepared as follows:

To a solution of 1.75 g of cyclohexylamine in 15 ml of chloroform a solution of 3.0 g of p-chlorophenyl isothiocyanate was added dropwise with stirring in 15 ml of chloroform at room temperature admitted. After stirring for 3 hours, the white solid was filtered off, washed with a little CHCl, and recrystallized from toluene, where 1-cyclohexyl-3- (p-chlorophenyl) thiourea, Ip 179-180 °.

Example 11

To a solution of 0.25 g of 3- [3- (p-Qhlorophenyl) thioureido] -tricycloL2,2,1,0 1 heptane in 10 ml ethanol, saturated with ammonia, were added 0.2 g of yellow mercury * ( II) oxide was added, whereupon the mixture was stirred for 16 hours at room temperature. The solids were filtered off and the clear precipitate was evaporated to dryness. The remaining solid was recrystallized from toluene. This gave 3- [3- (p-chlorophenyl) guanidinoltricyclo [2.2.1, O ² ' ⁶ ] heptane, melting point 204-205 °.

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

21 g of 3-aminotricyclo [2,2,1,0 ² '! 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

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Thiophosgene in 20 ml of chloroform was added. 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, η NaOH and again water, over anhydrous MgSO. dried, filtered and the chloroform evaporated in vacuo. The remaining oil was fractionally distilled in vacuo to give 3-isothiocyanatotricyclo [2.2.1.0 ² ' ⁶ ] heptane, b.p. 70-76 ° at 0.4 mm Hg pressure.

1.2 g of this isothiocyanate was dissolved in 30 ml of chloroform, to which 2.1 g of p-chloroaniline was added. The latter dissolved quickly, whereupon the mixture was refluxed for 3 hours. The cooled solution was extracted with 10 ml of 2 HCl, washed with 10 ml of water and dried over anhydrous rigSO ^. After filtration, the solvent was evaporated in vacuo and the solid residue was recrystallized from toluene. This gave 3- [3- (p-chlorophenyl) thioureido] trieyclo [2.2.1.0 ² ' ⁶ jheptane, Ip 164-166 °.

Example 12

0.30 g of 8- [3- (p-chlorophenyl) thioureido] tetracyclo [4,3,0,0 ² ' ^Zi ', O ^ ononane were dissolved in 100 ml of ethanol, which was saturated with ammonia, at room temperature and 6 st stirred with 0.43 g of yellow mercury (II) oxide. The mixture was then boiled for 15 minutes to remove excess ammonia and filtered and the filtrate was evaporated to dryness. The solid residue was recrystallized from a 1: 2 volume mixture of toluene and cyclohexane, 8- [3- (p-chlorophenyl) -guanidino] tetracyclo [4,3,0,0 ^{2) 4} ", 0 ⁵ ' ^] nonane, m.p. 170-171%.

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

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0.5 g of 8-aminotetracyclo [4,4,0,0 '^, O ^' ^ nonane hydrochloride (prepared according to GB-PS 1 180 749) was dissolved in a mixture of 25 ml of chloroform and 0.33 g of triethylamine . 0.5 S of p-chlorophenyl isothiocyanate was added to this solution, and the mixture was refluxed for 16 hours. After cooling, the chloroform solution was washed successively with 10 ml portions of 2 η HCl, V / water and saturated sodium chloride solution and then _{dried over anhydrous MgSO 2} ^. After filtration, the solvent was evaporated in vacuo and the residue was crystallized from a 1: 2 volume mixture of toluene and cyclohexane. This gave 8- [3- (p-chlorophenyl) thioureido] tetracyclo [4,3,0,0 ²ⁱ⁴ , 0 ^ ^> ^] - nonane, mp 168-170 °.

Example 13

0.96 g of 2-endo-aminobicyclo [2.2, i] heptane hydrobromide were intimately mixed with 0.76 g of p-chlorophenylcyanamide and heated to 200-220 ° for 15 minutes. The mixture quickly became fluid and was stirred occasionally. It was allowed to cool and then treated with 10 ml of ethyl acetate and 5 ml of water to dissolve the residue. The organic phase was extracted 3 times with 5 ml of water each time. The aqueous phases were combined and made alkaline with 10 η aqueous NaOH. The precipitated solid was filtered off, washed with water and dried. According to thin-layer chromatography, it consisted of pure guanidine. According to thin-layer chromatography, the ethyl acetate layer still contained the desired guanidine. It was therefore extracted 3 times with 5 ml of 2η NaOH, _{dried over anhydrous K 2} CO-T, filtered and evaporated. The residue was recrystallized from toluene. This gave 2-endo- [3- (p-chlorophenyl) guanidino] bicyclo [2.2.1] heptane, melting point 179-181 °.

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Example 14-

1.25 S p -chloroaniline hydrochloride was dissolved in 10 ml of n-butanol and heated to reflux. A cold solution of 1.07 liters of 2-exo-cyanamidobicycloC2,2,1] hept-5-ene in 10 ml of butanol was slowly added dropwise so that the mixture remained at reflux. One hour after the addition was complete, the mixture was cooled, the butanol was evaporated in vacuo and the residue was dissolved in 10 ml of ethyl acetate. The organic phase was extracted 4 times with 5 ml of water each time. The combined aqueous phases were brought to pH 7 with aqueous Na ^ CO ^ solution and extracted with ether. This removed unreacted p-chloroaniline. The remaining aqueous phase was brought to pH 12 with aqueous 10 η NaOH, as a result of which pure product precipitated. It was filtered off, washed with water and dried and recrystallized from ethyl acetate. This gave 2-exo- [3- (p-chlorophenyl) guanidinoJbicyclo [2,2, ilhept-5-ene, mp 206-207 °.

The 2-exo-gyanamidobicyclo [2,2,1] hept-5-ene used as the starting material was made as follows:

50 g of 2-exo-isothiocyanatobicyclo [2,2, i] hept ~ 5-en were in Dissolved 200 ml of ethanol, whereupon 10 ml of concentrated aqueous ammonia (SG 0.88) were added. The mixture was on Maintained reflux, whereupon another 50 ml of concentrated aqueous. Ammonia was added dropwise over 30 minutes. To After a total reflux time of 3 hours, the solution was cooled, whereupon the desired product crystallized out. There were 50.35 g of 2-exo-thioureidobicyclo [2,2, i] hept-5-ene, m.p. 158 up to 159.5 °.

1.0 g of this thiourea was dissolved in 50 ml of absolute ethanol dissolved at room temperature, whereupon 1.29 g of freshly prepared yellow mercury (II) oxide were added. The mixture

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9βΟ97 1215

was stirred for 24 hours at room temperature, after which a further portion of 1.29 g of HgO was added. Compartment to another The solids were filtered off and stirred for 48 hours washed well with ethanol. The filtrate was evaporated to dryness on a rotary evaporator, the temperature being so was kept as low as possible. The 2-exo-cyanamidobicyclo [2,2, i] hept-5-ene obtained in this way is very pale brown Gum, which is dissolved in 10 ml of cold n-butanol and taken immediately was used on it.

Example <15

0.5 g of 2-exo-L3- (p-chlorophenyl) thioureido] bicyclo [2.2.1] hept-5-ene were dissolved in 10 ml of ethanol, followed by the addition of 0.255 g of iodomethane. * The mixture was refluxed for 3 hours held, during which the thiourea was completely converted into the S-methyltniouronium iodide. The mixture was cooled and then saturated with ammonia gas. The mixture was refluxed for 10 hours with a constant flow of ammonia was passed through, whereupon it was cooled to room temperature, saturated again with ammonia and allowed to stand for 3 days became.

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 10 η RaOH, and the precipitate was filtered off, washed with water and dried. After recrystallization from ethyl acetate, 2-exo- [3- (p-chlorophenyl) guanidino] bicyclo [2.2, i] hept-5-ene, melting point 202-203 °, was obtained.

709809/1215

Example 16

A solution of 6.1 g of 2-exo- [3- (p-chlorophenyl) guanidino3bicyclo- [2,2,13hept-5-ene in 75 ml of hot ethanol was stirred, during which a solution of 3 ^ 54- 6 (+ ) -Mandelic acid in 25 ml of hot ethanol was added dropwise. The mixture was allowed to cool slowly over 16 hours, after which the precipitate was filtered off, stirred with a 10 ml portion of ethanol and filtered again. The two filtrates were combined and saved. The filtered solid was recrystallized 3 times from ethanol and then had a melting point of 159-162 °. This solid was stirred for 15 min with 20 ml of 2η NaOH, the free base of the unseparated guanidine being obtained, 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) guanidinoj bicyclo [2,2,13 hept-5-en, mp 205-20 °, [a] | ¹ = + 73 ° (c, 1.0 in methanol).

The retained filtrates of the (+) - mandelate salt were evaporated to dryness in vacuo, and the base was set free by stirring with 20 ml of cold 2η NaOH. The base was filtered off, washed with water and dried to give 3.0 g of solid. This was hot in 45 ml Dissolved ethanol, whereupon a solution of 1.75 S (-) - mandelic acid in 20 ml of hot ethanol was added. The mixed ones Solutions were allowed to cool slowly for 16 hours. The precipitate was filtered off, washed with 10 ml of ethanol and then recrystallized 2 times from ethanol. A salt with melting point 159.5-162 ° was obtained.

The base was set free as above, and after crystallization from ethyl acetate, (-) - 2-exo- [3- (p-chlorophenyl) guanidino] bicyclo [2.2.1] hept-5-ene, mp 205 -207 °, [a] ^ ¹ = -73 ° (c, 1.0 in methanol).

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Claims (13)

PATENT CLAIMS: 1. / Guanidine derivatives of the formula: R ¹ -NH.C.NH-R ² NH - where R stands for a cyclohexyl, adaciantyl, bicyclo [2.2, i] -heptanyl-, bicyclo [2.2.1] liept-5-enyl-, iricyclo [2.2.1, O ² ' ⁶ ] -heptanylode r Te tracyc1ο [A, 3,0,0 ² '^, O ^ »^] nonanyl radical ^% 2
and R stands for a phenyl or pyridyl radical which is optionally substituted by 1 or 2 substituents selected from halogen atoms, alkyl and cyanoalkyl radicals with 1 to 6 carbon atoms, alkoxycarbonyl radicals with 2 to 6 carbon atoms and amino radicals, as well as pharmaceutical permissible acid addition salts thereof. 2. guanidine derivatives according to claim 1, characterized in that R is an adamantyl, bicyclo [2.2.1] heptanyl, bicyclo [2.2.1] hept-5-enyl or tricyclo [2.2, Λ , O ² ' ⁶ ] heptanyl radical. 3. guanidine derivatives according to claim 1, characterized in that R is a cyclohexyl, adamant-1-yl, exo-bicyclo [2.2.1] heptan-2-yl, endo-bicyclo [2.2, i] heptan-2-yl-, exo-bicyclo [2,2,1] hept-5-en-2-yl-, tricyclo [2,2,1,0 ² ' ⁶ ] heptan-3-yl- or Tetracyclo [4,3,0,0 ² » ⁴ , 0 ⁵ » ^] nonan-8-yl radical and R stands for a pyridyl radical or a phenyl radical, possibly by 1 or 2 ITluoratome, by a chlorine or Bromine atom or by a methyl, cyanomethyl, methoxycarbonyl- or amino radical substituted. - 26 - 709809/1215 4. guanidine derivatives according to claim 2, characterized in that 1 " that R is in the exo configuration. 5. guanidine derivatives according to one of claims 2 or 4, characterized 2
characterized in that the radical R carries an optional substituent. 6. guanidine derivatives according to claim 2, characterized in that that R is an exo-bicyclo [2,2, iJhept-5-en-2-yl or exo-bicyclo [2,2, i] heptan-2-yl radical and R stands for an optionally substituted phenyl radical. 7. guanidine derivatives according to claim 6, characterized in that that R ^{1 is} an exo-bicyclo [2,2,1] hept-5-en-2-yl radical 2
and R has a single optional substituent. 8. guanidine derivatives according to claim 7 * characterized in that that the only optional substituent is in the 4-position is located. 9. guanidine derivatives according to one of claims 7 or 8, characterized in that the optional substituent from consists of a fluorine, chlorine or bromine atom. 10. The guanidine derivative 2-exo- [3- (p-chlorophenyl) guanidino] - ■ bicyclo [2,2, i] hept-5-en and the pharmaceutically acceptable ones Acid addition salts thereof. 11. A method for producing a guanidine derivative according to claim 1, characterized in that: (a) a thiourea of the formula:, - 27 - 709809/1215 ". or a thiouronium salt thereof with ammonia in the presence a catalyst converts; 1 ? (b) a cyanamide of the formula R-UHCN or R-NHCN with a Converts amine of the formula R ² -NH ₂ or R -HH ₂ ; (c) a carbodiimide of the formula: R ¹ ^ = C = NR ² VIII Reacts with ammonia; (d) for those compounds in which R is a cyclohexyl or bicyclo [2,2,1] heptanyl radical, a Compound of the formula: R ³ -NH.C.NH-R ² _IX NH wherein Br is a cyclohexenyl or bicyclo [2,2,1] heptenyl radical, reduced; or (e) for those compounds which are optically active enantiomers, a racemic compound of formula I from claim 1 by conventional rfe.messungen or separates in any of the above processes (a) to (d) uses a starting material which is itself a separate isomer. 12. Pharmaceutical compositions, characterized in that they contain a guanidine derivative according to any one of claims 1 to 10 together with a pharmaceutically acceptable diluent or carrier. 13. Compositions according to claim 12, characterized in that that they are in a form suitable for intranasal or oral administration. wTut * dr.-tng. H. fincke, dipl.-inq. hi βθη D1PU.ING. S. STAEGER. DR. Fir. nit. R. KNEi - 28 - 709809/1215