DE1945208A1 - Tricycloundecane derivatives - Google Patents

Description

PATENT LAWYERS DR.-ING. BY KREISLER DR.-1NG. SCHONWALD DR.-ING. TH. MEYER DR. FUES D! PL.-CHEM. ALEK VON KREiSLER DIPL.-CHEM. CAROLA KELLER DR.-ING. KLDPSCH

COLOGNE 1, DEICHMANNHAUS

Cologne, August 18, 1969 AvK / Ax / Hz

EGG. du Pont de Nemours & Company _Λ
Wilmington, Delaware 19898 (V.St.A.).

Tricycloundecane derivatives

The invention relates to new tricycloundecane derivatives which are useful as antivirals. If compounds according to the invention are used in warm-blooded animals before infection by a pathogenic virus are administered, they protect the possible host from the virus. Of course, some of the Compounds according to the invention in warm-blooded animals for combating, alleviating or curing an existing viral infection administered. Warm-blooded animals are members of the animal kingdom that have a homeostatic mechanism.

The compounds according to the invention are preferred used to fight viral infections of the respiratory tract, e.g. influenza and rhino virus infections. In particular the compounds according to the invention are used for combating used by influenza virus infections.

The compounds according to the invention have the formula

R ₁

^{l (}} ^ t?

H ^ß 3

009612/1020

1145208

where η is O or 1, R _{1 is} a hydrogen atom or an alkyl group with 1 to 2 C atoms, R _{g is} a hydrogen atom or an alkyl group with 1 to 2 C atoms, R is a hydrogen atom, an alkyl group with 1 to 4 Carbon atoms, an alkenyl radical with 3 to 9 carbon atoms, a ^ -Methyl ^ -methylene - ^ - butenyl group, a cyoloalkenyl radical with 5 to 8 carbon atoms, an alkenyicycloalkyl radical with 6 to 9 carbon atoms, a cycloalkylalkenyl radical with 6 up to 9 carbon atoms, an alkynyl radical with 3 to 5 carbon atoms or a benzyl radical 1st and Eu stands for a hydrogen atom, an alkyl radical with 1 to 3 carbon atoms, an alkenyl radical with 3 to 5 carbon atoms or a propargyl radical, where however Ε and R ^ can also form a nitrogen-containing heterocyclic ring and in cases in which the substituent R and / or R ^ are unsaturated, the double bond or triple bond is not in the! position.

The invention also encompasses the pharmaceutically acceptable salts of these compounds.

Of the compounds defined above, preference is given to those of the formula (1) in which η has the value 1 and R ₁ , Rg 1 H and R ₂ ^ have the meanings given above, as well as the pharmaceutically acceptable salts of these compounds.

. Compounds of the formula (1) in which η has the value 1 and R ^, R ₂ and R ^ are each a hydrogen atom and R is a hydrogen atom or an alkenyl radical having 3 to 5 C are particularly preferred because of their excellent action as antiviral agents Atoms, and the pharmaceutically acceptable salts of these compounds.

The invention also encompasses novel compounds which can be found as Intermediates for the preparation of the compounds of the Formula (i) are suitable. These intermediates have the formula

(2)

/ id

The invention also relates to a method of combating of viral infections in warm-blooded animals, which is characterized by the fact that warm-blooded animals are given an antiviral effective amount of a compound of formula (1) administered.

The invention also includes pharmaceutical preparations which combine a compound of the formula (1) with suitable pharmaceutical carriers, auxiliary substances and containing modifying agents.

As mentioned earlier, the invention relates to antiviral agents effective compounds of the formula

(3)

wherein R ^, a hydrogen atom or alkyl radical with 1 to "2 carbon atoms, R ^ a hydrogen atom or alkyl radical with 1 to 2 carbon atoms, R, a hydrogen atom, an alkyl radical with 1 to 4 carbon atoms, an alkenyl radical with 3 to 9 carbon atoms, a 3-methyl-2-methylen-3-butenyl group, a cycloalkenyl group with 5 to 8 carbon atoms, an alkenylcycloalkyl group with 6 to 9 carbon atoms, a cycloalkylalkenyl group with 6 to 9 carbon atoms , an alkynyl radical with 3 to 5 carbon atoms or a benzyl radical and R ^, a hydrogen atom, an alkyl radical with 1 to 3 carbon atoms, an alkenyl radical with 3 to 5 carbon atoms or a propargyl radical, but where R _x and R ^ together can form a nitrogen-containing heterocyclic ring and in cases in which the substituent R and / or R ^ is unsaturated, the double bond or triple bond is not in the 1 position, the pharmaceutically acceptable salts' of these compounds and compounds of the formula

R _r?

H ^f

0 9 812/1920

where E ^ is a hydrogen atom or an alkyl radical with 1 to 2 carbon atoms, R _{6 is} a hydrogen atom, an alkyl radical with 1 to 4 carbon atoms, an alkenyl radical with 3 to 9 carbon atoms, a cyclo- '._ alkenyl radical with 5 up to 8 carbon atoms, an alkenylcycloalkyl radical with 6 to 9 carbon atoms, a cycloalkylalkenyl radical with 6 to 9 carbon atoms, an alkynyl radical with 3 to 5 carbon atoms or a benzyl radical and R ₁ -, a hydrogen atom, an alkyl radical with 1 to 3 carbon atoms, an alkenyl radical with 3 to 5 carbon atoms or a propargyl radical, where R, - and R- can together form a nitrogen-containing heterocyclic ring and in cases in which Eg and / or R "are unsaturated, the double bond or triple bond is not in the 1-position.

Pharmaceutically acceptable salts of compounds of the Formulas (3) ″ and (4) of course also fall within the scope the invention. Representative of these salts are the hydrochlorides, hydrobromides, sulfates, phosphates, acetates, " Nitrates, succinates, adipates, propionates, tartrates, cyclohexyl sulfamate, citrates, bicarbonates and pamoates. Of these The hydrochlorides are preferred for salts

A number of new compounds have also been found which can be used as intermediates for the synthesis of the invention Compounds with antiviral effects are suitable. These new compounds also fall within the scope of the Invention.

The invention thus comprises a group of new tricyclo- (4- »3» 1 »1 ) undecan derivatives. Certain compounds of this group, namely the compounds of the formulas (1), (3) and (4) are valuable pharmaceutical agents. Other connections of this group are advantageous starting materials for the preparation of various compounds of the formulas. (1), (3) and (4) as shown by the detailed description of the preparation of the compounds according to the invention will.

9012/19

As examples of compounds according to the invention are

called:

38
311

y (, 3,,) undecan-4-amine

Y »O

N-methyltricyclo (4,3,1,1 ') undecan-4-amine

, 3,1,1 ⁵¹⁸ ) undecan-4-amine

& yy (, 3 ,,)

JL Q

N-ethyl-N-methyltricyclo (4,3, 1,1 *) undecan-4-amine Ν, Ν-dimethyltricyclo (4,3,1,1 ^ ' ⁸ ) undecan-4-amine N, N-diethyltricyclo ( 4,3,1,1 ⁵ » ⁸ ) undecan-4-amine N-butyltricyclo (4 ·, 3» 1> 1 ') undecan-4-amine N- (5-hexenyl) tricyolo (4 _> 3,1, 1 ^ » ⁸ ) undecane-4-amine

JE Q

N- (3-cyclohexenyl) tricyclo (4 _l 3.1 »1 ') iindecan-4-amine N-Gyolohexylethylidentricyclo (4,3,1,1') undecan-4-amine

-2 Q

N- (3-methylenecyclobutyl) tricyclo (4,3,1,1 ^ ») undecan-4-amine

J »Q

lir-propargyltricyclo (4.3 »1 ₁ 1) undecan-4-amine N- (1-methyl-2-butynyl) tricyclo (4,3,1,1 ³ ' ⁸ ) undecan-4-a] nin

JE O

N-Benz - ^ - ltricyclo (4.3 ₁ 1 »1) undecan-4-amine 4-methyltricyclo (4,3,1,1 ^ *) undecan-4-amine N-methyl-4-methyltricyclo (4, 3 _> 1,1 ^ ») undecan-4-amine N, N-dimethyl-4-methyl.tricyclo (4,3,1,1 ^» ⁸ ) undecan-4-amine N-ethyl-N-methyl- 4-methyltricyclo (4,3,1,1 ^ ' ⁸ ) undecan-4-amine N, N-diethyl-4-methyltricyclo (4,3,1,1 ^ » ⁸ ) undecan-4-amine 4-ethyltricyclo (4,3,1,1 ^ ⁸ ) undecan-4-amine N-methyl-4-ethyltricyclo (4,3,1,1 ^ ' ⁸ ) undecan-4-amine N ^ -dimetliyl - ^ - ethyltricyolo ( 4,3,1,1 ^{5 TÖ)} undecane-4-amine NrIthyl-ir-metliyl-4-äthyltricyolo (4,3,1,1 ^{5 '8)} undecane-4-amine N-ltnyl-4-äthyltricyclo (4 , 3,1,1 ⁵ ' ⁸ ) undecan-4-amine N, N-diethyl-4-ethyltricyclo (4,3,1,1 ⁵ * ⁸ ) undecan-4-amine N-butyl-4-methyltricyclo (4 , 3,1,1 ^ ') undecan-4-amine N- (5-hexenyl) -4-methyltricyclo (4,3,1,1 ⁵ ' ⁸ ) undecan-4-amine N- (3-cyclohexenyl) - 4-methyltricyclo (4,3,1,1 ⁵¹⁸ ) undecan-4-amine

N-cyclohexylethylidene-4-methyltricyclo (4,3,1,1 ') -undecan-4-amine

4-Ethyl-N- (3-methylenecyclobutyl) tricyclo (4,3,1,1 ⁵ » ⁸ ) undecan-4-amine

JE Q

4-methyl-N-propargyltricyolo (4,3,1,1 *) undecan-4-amine

. iKi-methyl ~ 2 ~ butynyl) ~ 4-methyltricyclo (4 _t 3,1,1 ^ *) undecan-4-amine

009812/1920

N-benzyl-4-methyltricyclo (4.3, Ί, 1 ') undecane-4-amine 4-AminomethyltricycloC ^^ I, 1 ⁷ *) undecane N-methyl-4-aminomethyltricyclo (4-j3,1, "P ♦) undeean ^, N-dimethyl - ^ - aminomethyltricyclo ^, 3,1 »1 ') undecane

^ Z O

N.N-diethyl-4-aminoinetliyltricycloC ^^ "'! , 1 *) undecane N-ethyl-4-aminomethyltricycloC ^^ iiti) undecane

• ft a-Meth.yl-4-amiiiomethyltricyelo (4-, 3i1 »1) undecane

-ζ ο

α-Ethyl-4-aminomethyltricyclo (4-, 3 »1» 1) undecane

■ χ a

N-methyl-a-methyl-4-aminomethyltricyclo (4- _t 3,1,1 ^ ») undecane N-butyl-4-aminometliyltricyclo (4- _r 3,1,1 ^» ⁸ ) undecane N- (5- Hexenyl) -4-aminomethyltricyclo (4-, 3,1,1 ^ ») undecane N- (3-cyclohexenyl) -4- amino methyl (4-, 3>» 1) undecane N- (3-methylenecylol) utyl ) -4-aminomethyltricyclo (4-, 3,1,1 ^{5> 8} ) undecane
N-propargyl-4-aminomethyltricyclo (4-, 3,1, Ί ') undecane N- (1-methyl (2-butynyl) -4-aminomethyltri-eyeIo) - (4-, 3, Λ , 13, ö ^ undecane

N-Benzyl-4-aminomethyltricyclo (4-, 3 »1» 1 *) undecane N-Allyltricyclo / ?, 3,1,1 ^ »f7undecan-4-amine NjN-Diallyltricyclo ^^ jiji ^ 'fZundecan - ^ - amine

N-allyl-N-methyltricyclo / 5,3,1,1 ^ * f7undecan-4-amine N-allyl-4 ~ methyltricyclo / ?, 3,1,1 '^ »vendee an-4-amine N-allyl- N-methyl-4-methyltricyclo ^ f, 3 »1» 1_7undecan-4-amine iT-Allyl-4-aminomethyltricyclo _J / 4 ", 3» 1 »1 '_7iindecane Sr-allyl-N-methyl-4- aminomethyltricyclo ^, 3,1,1 ^ * vundecane N-AlIyla-methyl-4-amino methyl tricyelo / 4,3> 1 »1 '/ undecane

N-Allyl-N-methyl-a-methyl - ^ - aminome thyltricyclo / 4 ", 3,1,1» ^ undecan

In general, the compounds according to the invention can be prepared in the manner described below.

The intermediate compound tricyclo (4-, 3,1,1 *) undecan-4-one can be prepared by adding 2-aminomethyl-2-adamantanol with a source of nitrous acid in an aqueous one Medium is reacted until the ketone is precipitated. The source of nitrous acid can be in situ according to known Methods from materials such as a mixture. "

012/1920

a water-soluble nitrite salt and an acid such as glacial acetic acid.

The compounds of formula (1) in which η is 1, E ^. is a hydrogen atom or an alkyl radical and R ₂ , β, and R _- J, are hydrogen atoms can be prepared according to known processes for the preparation of amines by reducing suitable amine intermediates. These processes include the reduction of the corresponding nitrile, preferably carried out in the presence of ammonia, with a suitable reducing agent such as lithium aluminum hydride or Haney nickel and hydrogen, the reduction of the corresponding acid amide to the desired amine with a suitable reducing agent such as lithium aluminum hydride and the reduction of the corresponding azide under suitable conditions Reduction conditions, for example by catalytic hydrogenation or using reducing agents such as tin, tin (IV) chloride, lithium aluminum hydride, sodium borohydride and the like. The reduction reactions can be represented by the following equation:

R ₁ reduction

20 L / * ^^ JL conditions

(T ^ CH ₂ NH ₂

Herein is R _x . a hydrogen atom or an alkyl radical having 1 to 2 carbon atoms and A a group which can be reduced to the corresponding amine, for example
Q

₁ -C-HH ₂ and - ₂₅

Compounds of the formula (1) in which η is 1, R ^ is a hydrogen atom or an alkyl radical having 1 to 2 carbon atoms and Rp, R, and R ₂ are hydrogen atoms, can be obtained by reducing amination of the appropriate intermediate compounds are produced under known conditions «

009812/1920

BAG

194520Θ

Representative of suitable reducing amination reactions are the catalytic hydrogenation of a carbonyl compound in the presence of ammonia with suitable catalysts such as Raney nickel or the conversion of the corresponding alcohol into the desired amine by treating the Alcohol with ammonia in the presence of a catalyst such as ruthenium. The reducing amination reactions can can be represented by the following equations:

H ₂

catalyst
and

^ CH ₂ OH catalyst

Herein R ^ is a hydrogen atom or an alkyl radical with 1 to 2 carbon atoms.

The compounds of the formula (1) in which η is .1, R ,.

^ 5 a hydrogen atom or an alkyl radical with 1 to 2 carbon atoms is, can also by replacing a leaving group with an amine donor, optionally in the presence of a suitable Catalyst can be prepared under known conditions. Ammonia is usually used as the amine donor, however, in certain exchange reactions the 'amine' is given off by a group such as hydrazine. Representative examples for removable groups are halogen, benzenesulfonyl chloride, methanesulfonyl chloride and

009812/1920

A tricyclic phthalimide suitable as an intermediate can after the Gabriel phthalimide synthesis, which by Wagner and Zook in "Synthetic Organic Chemistry" (1955).

The exchange reaction is represented by the following equation:

+ Amine donor

Herein R ^ is a hydrogen atom or an alkyl radical with 1 to 2 carbon atoms and X is a removable group such as halogen, benzenesulfonyl chloride, methanesulfonyl chloride or

The compounds of the formula (1) in which η stands for 0 and R ^, R ₃ , and R ^, are water to ff atoms, can be prepared according to known processes for the preparation of amines by reducing suitable Aminzwi selenverbindungen · To these processes includes the reduction of the corresponding ketone oxime with a reducing agent such as lithium aluminum hydride, sodium in ethanol, rhodium or aluminum oxide in hydrogen or diborane.

The compounds of the formula (1) in which η is 0 and R ^, R ^ and R, are hydrogen atoms, can also be used by reducing Amination of the ketone with ammonia and hydrogen in the presence of a suitable catalyst such as Raney nickel or by hydrolysis of the corresponding formamido

2 $ interconnection can be established.

009812/1920

- ίο - ■

The compounds of formula (1) in which η is O, R ^. is an alkyl radical with 1 to 2 carbon atoms and iU and R ^ hydrogen Atoms are can be made by the Ritter reaction in which a 4-alkyl-4 - hydroxytricyclo- (4 · -, 3,1,1 '■) undecane with a mixture of acetic acid and Sodium cyanide is treated and then a treatment with sulfuric acid to form the corresponding Formamidö intermediate compound is made with v / ässriger Base is hydrolyzed to the desired product.

The compounds of the formula (1) in which η is 1, R ^ is a hydrogen atom or an alkyl radical having 1 to 2 carbon atoms, Ro is an alkyl radical having 1 to 2 carbon atoms , and R, and R ^ are hydrogen atoms can be prepared according to known processes for the preparation of amines by reducing suitable amine intermediate compounds, e.g. by reducing the corresponding ketone oxime with a suitable reducing agent, by reducing amination, for example, of the corresponding ketone with ammonia and hydrogen using a suitable catalyst or by hydrolysis of a suitable one Intermediate compound, for example the corresponding formamido intermediate compound.

'The compounds of the formula (1) in which η is O or 1 R ,, represents a hydrogen atom or an alkyl radical with 1 to 2 carbon atoms, Rq is a hydrogen atom or an alkyl radical with 1 to 2 carbon atoms and R- and R ^ are not for hydrogen can be prepared by known processes for the preparation of secondary and tertiary amines.

These connections can be made directly from the corresponding

Carbonyl compound by treating the carbonyl compound with a suitable amine in the presence of hydrogen and a suitable catalyst such as Raney nickel, ruthenium and the like. Of course, this process is not suitable for the preparation of compounds according to the invention in which the radicals R * or R ₁ . are unsaturated.

009812/1920 - -

The primary produced in the manner described above Amine can be obtained by treating the amine with an alkyl halide such as methyl iodide, ethyl bromide and the like in a solvent such as ethanol, benzene or carbon tetrachloride. * The reaction is triggered by the presence of a insoluble basic material such as sodium carbonate, calcium oxide and the like accelerated. However, such a base is not essential for the reaction. Mixtures of secondary and tertiary amines can be prepared by customary methods such as those described by Houben and Weyl "Methods of Organic Chemistry ", Volume 11/1, Section XI, pages 1026-1029 or by preparative gas chromatography will.

The primary manufactured in the manner described above Amine can be acylated and then reduced to give the N-alkyl compounds according to the invention. The products can also be made by reducing alkylation. To produce the desired product Suitable ketones, aldehydes and oximes can be used with the ducts desired tricyclic amine in the presence of a hydrogenation catalyst such as sodium borohydride in ethanol.

The compounds of the formula (1) in which one of the radicals R ₁ and Er is a hydrogen atom can be prepared by the method of Leuckart, the corresponding formamide being hydrolyzed with a base, or the corresponding formamide can be prepared with a suitable reducing agent how to reduce lithium aluminum hydride.

Of course, several of the methods described above can be combined to produce a desired secondary or to produce tertiary amine. Such a combination of methods also falls within the scope of the invention.

The salts of the amines prepared in the above manner are generally prepared by treating a solution of the

009812/1920

8AD ORIGINAL

Amine made with the acid of the desired salt. The solvent can be chosen to give a system in which the salt formed is insoluble and ' therefore can be easily separated from the solution * It is also possible to use a solvent system in which the Amine salts are soluble, and evaporate the solvent.

example 1

To a solution of 0.27 mol of 2-methylene adamantane in 1000 ml ' Ether is 0.29 mol of 85% m-chlorobenzoic acid within given by 2 hours. During the addition, the reaction mixture becomes held at -10 C. After this time it will Let the reaction mixture warm to room temperature, whereupon the mixture is stirred for a further 16 hours. After this time, the ethereal solution is transferred to a separating funnel.

.15 leads and with saturated sodium sulfite solution, saturated Extracted sodium bicarbonate solution and saturated sodium chloride solution. The ether layer is over anhydrous sodium sulfate dried. The ether is evaporated off under reduced pressure, whereby 45 g of crude spiro / oxirane ^^ '- tricyclo- (3,1,1,1 '' l / decane is obtained as a white solid.

This product is suitable for the next stage, but can be optionally crystallized from pentane at -70 ⁰ C to give a purified product is obtained of melting point 164-166 ⁰ C.

Elemental analysis: 16 ^0: 2 C. 40 9 H Calculated for C ^ -H 80, 65 9 , 82 Found example 79 ,8th

Su a well stirred solution of 0.1 mol of adamantanone in 75 ml of methanol are 0.30 mol of concentrated sulfuric acid added so that the solution is brought to reflux.

A saturated aqueous solution containing 0.60 mol of sodium cyanide is added to this refluxed solution. The resulting solution is refluxed for 1 hour e-- »-»

009812/1920

. 10A52O8

and then stirred for a further 3 hours at room temperature. To During this time, 200 ml of ether are added to the solution. The ether solution is decanted from the precipitated salts and twice with 50 ^ l of saturated sodium chloride solution each time 'extracted. The ethereal solution is made with anhydrous magnesium sulfate dried. The solution is filtered and the ether is removed under reduced pressure, leaving a yellow-brown Solid is obtained. The solid is made from methyl cyclohexane recrystallized to give adamantancy anhydrin with a melting point of 257-259 ° C (decomp.).

Example 3

To a suspension of 0.13 mol of lithium aluminum hydride a solution of 0.028 mol of adamantanone cyanohydrin is added to 200 ml of ether with vigorous stirring at the reflux temperature given in 100 ml of ether, the mixture is 6 hours heated to reflux and then allowed to cool to room temperature. Then it is stirred over! To During this time, the mixture is cooled to -5 ° C. with an ice-acetone bath. To the cooled reaction mixture 30% aqueous sodium hydroxide is added until the salts are precipitated. The ethereal solution is filtered and dried over granulated potassium hydroxide. The ether is filtered and evaporated under reduced pressure, whereby 2-aminomethyl-2-adamantanol is obtained as a white solid. By recrystallizing the compound from cyclohexane white platelets with a melting point of 124-126 ° 0 er

keep. 0 H ■ κ Elemental analysis: : - 74.6 8.50 7.90 Calculated for C ^ ELgNOi 74.9 8.47 8.00 Found

The amine hydrochloride is made by dissolving 2-aminomethyl-2-adamantanol in a mixture of 505 & tetrahydrofuran each and 50% ether made. Anhydrous hydrogen chloride gas is then introduced into this solution, whereupon the amine hydrochloride is precipitated. The white precipitate becomes from methanol

009812/1920

-Ether recrystallized, leaving white platelets from melting point > 3OO ° Ö can be obtained.

Elemental analysis: G • 7 H 6th N Gl 3 Calculated for Ο ,,,, Η, _ia N0.HCl: 60 , 2 9.2 6th 16, O Found ¹ y
61 4th 9.6 16, example

In a 1300 ml stainless steel bomb, 45 g Spiro / öxiran-2,2'-tricyclo (3,3,1,1 ^ * ^ 27undecane, 800 ml given a 28% immonium hydroxide solution and 60 g of ammonia. The bomb is sealed and the reaction mixture is kept at 120 ° G with shaking for 3 hours. the The bomb is cooled and the contents decanted. The aqueous solution, which contains a yellow-brown solid, is with Water diluted to 2 liters and heated to reflux temperature. The boiling solution is filtered, concentrated to 800 ml and cooled to 0 C in an ice bath. The separating ones glittering white platelets are filtered off, pressed dry and recrystallized from cyclohexane, whereby 2-aminomethyl-2-adamantanol, which in all respects with the product obtained from adamantanone cyanohydrin is identical.

Example 5

A solution of 0.25 mol of adamantanone and 0.32 mol of nitromethane in 15 ml of ethanol is added to a solution of 0.3 mol of sodium in 200 ml of ethanol. The solution is held at 45 ° C during the addition or for about 5 minutes. It is left to cool to room temperature and stirred for 16 hours. After this time, the solution is ^{cooled to 10 °} C. and 0.35 mol of glacial acetic acid is added. The reaction mixture is stirred for 20 minutes, filtered, concentrated to 100 ml and then diluted with 600 ml of water. The semi-solid which separates out is extracted with ether and dried. After removing the ether, 2-hydroxy-2-nitromethyladamantane is obtained. 20 g are added to a solution of 0.63 mol of 2-nitromethyl-2-adamantanol in 250 ml of acetic acid

009812/1920 '

Given Raney Nickel. The solution obtained is in a appropriately sized bomb given and cooled with Pressed hydrogen to 4.2 atmospheres. The pressurized reaction mixture is shaken until hydrogen uptake stops, and then shaken for 2 more hours while keeping the temperature below 35 ° C will. The reaction mixture is removed from the bomb and filtered to remove the catalyst. The received The filtrate is concentrated to about half its volume under reduced pressure. The concentrate, the 2-amino-methyl-2-adamantanol contains, is suitable for the reaction described in Example 6.

Example 6

A solution of 1.24 mol of sodium nitrite in 174 ^{ml of water is added at 0} ° C. to a well-stirred solution of 0.5 ^ mol of 2-aminomethyl-2-adamantanol in 520 ml of glacial acetic acid and 1040 ml of water ^{Vigorously stirred for 1} hour at 0 ° C. and allowed to warm to room temperature with continued vigorous stirring. During this time, a white precipitate forms. The slurry is ^{cooled to 0 °} C. and made basic by adding solid sodium hydroxide. (P _H 9) · The cold slurry is filtered and the separated solid washed with water until the wash water is neutral, the solid is steam distilled in hexane to give tricyclo- (4.3 * 1 »1 ^ • ⁸ ) undecan-4-one . Melting point 258 to 260 ⁰ G (sealed tube). Molecular weight: calculated 164.1201, found 164.1206 (by mass spectrometry). IR ^CH 2 ^G1 2 3050, 1700, 1455, 1357, 1175, 1080 cm " ¹ .

IBflJC

Elemental analysis: G 6th 9 H Calculated for C ₁ ^ la ^^ ^ O: 80, 9 9 , 7 Found: 80, 7th , 7 example

To a solution of 0.05 moles of tricycle (4,3,1, i- ^ jundecan-4-

009812/1920

- ■ 16 - ■

on in 40 ml of ethanol. 0.12 moles of hydroxylamine hydrochloride given. The solution is refluxed for 2 hours. After this time the ethanol and pyridine will be removed under reduced pressure. The residue is added to ice water. The solid precipitate is filtered off, with Water washed well and dissolved in ether. The ether solution is dried with anhydrous magnesium sulfate and filtered. The ether is removed under reduced pressure,

2 Q

whereby tricyclo (4,3,1,1 ^v ) undecan-4-one oxime is obtained, which gives a white solid after recrystallization from ether-pentane. ♦

To a heated under nitrogen solution of 0.04 mol of tricycloO ^ I, ^ ") undecan-4-one oxime in 200 ml of butanol, 0.26 g-atom of sodium, which is cut into small pieces, are added within 2 hours. After this time the solution is cooled and concentrated under reduced pressure under nitrogen. The residue is distilled in hexane with steam under nitrogen. Anhydrous hydrogen chloride gas is passed into the hexane to precipitate the amine. The precipitate is filtered off and recrystallized from 3N hydrogen chloride solution to give 5 S tricyclo (4,3 '1,1') undecane-4-amine hydrochloride are obtained with a melting point> ⁰ C · 3QO

Elemental analysis: C Sä Si Calculated for C ₁₁ H ₁ QN 1 Cl: 65.7 9.4 6.9 17 »7 Found: 65.7 9.9 6.9 17.1

Example 8

A solution of 0.10 moles of tricyclo (4,3,1,1 *) undecan-4-amine (produced by neutralizing an aqueous solution of the hydrochloride, subsequent extraction with ether and Evaporation of the ether under nitrogen) and 50 ml of butyl formate is refluxed for 16 hours. The surplus Sige solvent is distilled off under reduced pressure lated to give 4-formamidotricyclo (4,3,1,1 ^ *) -undecane will.

009812/1920

Example 9

"To a solution of 0.10 mol of tricyclo (4.31" 1 ** ' ) undecan-4-amine in 200 ml of ethanol are added 0.20 mol of sodium carbonate. The resulting suspension is mixed with 0.10 mol of methyl iodide The suspension is refluxed for 18 hours with vigorous stirring, after which the suspension is filtered off, washed twice with 100 ml of water each time and concentrated under reduced pressure. The oily residue is then distilled with steam in hexane.

The solution is dried with anhydrous potassium carbonate, filtered and evaporated under reduced pressure. That as Residue remaining oil is fine cleaning by preparative Subjected to gas chromatography. The separated amine is dissolved in ether and with anhydrous hydrogen chloride treated, being N-methyl-tricyclo (4,3,1,1 ^ *) undecanamine hydrochloride is obtained.

Examples 10-13

The experiment described in Example 8 is repeated, however using an equivalent amount of the "amine" listed below in place of that used in Example 8 Iricyclo (4,3,1,1 ^ *) undecan-4-amines, the following being mentioned products are obtained.

^Βί 4 ~ amine product game .

10 4-aminomethyltricyclo- ^ -formamidomethyltricyclo- (4.3 / l, 1 ⁵ ' ⁸ ) undecane (4,3,1,15 »8

11 4-Methyl-4-aminomethyl-4-methyl-4-formajjnidomethyltricyclo (4,3,1, 15 »8) _ tricyclo {4,3,1,1.5» ⁸ ) undecane

undecatr

12 a-Methyl - ^ - aminomethyltri-Gi-Methyl ^ -formamidomethylcyclo (4,3,1, i3.8) _unaecane to? Icyclo (4,3,1, i5,8) undecane

13 N-Methyl ^ -methyl ^ -aminQ-N-iOrmainido-N-iaethyl - ^ -

methyltricyclo (4,3,1,1 ⁵ » ⁸ ) aminomethyltricyclo (4,3,1,1 undecane 3O)

"'535" Example 14

■ X Q

A solution of 0.1 mol of 0} ricyclo (4.3, ^/ l i1 ') undecan-4-amine

009812/1920

in 75 ml of dry pyridine, 0.1 mol of acetylochloride is so

ο
added so that the temperature does not exceed 30.degree. The resulting mixture is stirred for 16 hours. After this time the mixture is evaporated under reduced pressure to remove most of the pyridine. The residue is added to 500 ml of cold water. The precipitate formed is washed well with water and dried, N-acetamidotricyclo (4-, 3) 1,1 *) undecan-4-amine being obtained. ■

Examples 15-20

The experiment described in Example 14 is repeated, however, using an equivalent amount of the amines mentioned below instead of that used in Example 14- Tricyclo (4-, 3,1,1 *) undecan-4-amines, the ge. named products can be obtained.

Bei- amine product

game - ~ - ~ - "™" ™ "™" ™ "™"

15 U-methyltricyclo- N-acetamido-N-methyl-

(4,3, "I> i3» ⁸ ) undecan-4-tricyclo (4,3,1, i5 » ⁸ ) undecanamine 4-amine

16 N-methyl-4-aminomethyl-N-acetamido-N-methyl-4-tricyclo (4-, 3 »1 »1 ') - aminomethyltricycloundecane (^ -, 3,1,15» 8) undecane

■ 17 α-Methyl-4-aminomethyl-N-acetamido-α-methyl-4-tricycloC ^ -jJji , i5j8) _ aminomethyltricyclo-

undecane _s (4,3,1, i3 »8) undecane

18 4-Ethyl-N-methyl tricycle-H-acetamido-N-methyl-A - (4 _? 3 »1, i5» ⁸ ) undecane-4-ethyltricyclo (4,3,1, I ⁵

amine undecane-4-amine

19 N-Benzyl-4-aminomethyl-If-Acetamido-H-benzyl tricyclo (4,3,1,1 ') ~' aminomethyltricyclo-

undecane (4,3,1,13 »8) _{un (} i _ecan

20 N- (3-0yclohexenyl) -4- F-acetamido-N- (3-cyclohexeaminomethyltricyclonyl) -4-aminomethyltricyclo- (4-, 3.1, i3.8) undecane (4,3,1,1> » ⁵ ) undecane

Example 21

- To a well stirred suspension of 0.20 mol of lithium aluminum hydride in 100 ml of ethylene glycol dimethyl ether is added 0.10 mol of 4 -]? Ormamido-tricyclo (4,3,1,1 ^{:? L} ) undecane. . "

009812/1920

The mixture is held at 75 ° for 16 hours, cooled to 10 ° C and washed carefully with 30% sodium hydroxide solution to remove the excess lithium aluminum hydride destroy. The mixture is washed three times with 100 ml of ether each time. The ether extracts are combined and twice with 50 ml of water each and washed over, solid potassium hydroxide dried. The ether is removed under reduced pressure and the residue is distilled with steam in hexane. The hexane solution is mixed with anhydrous hydrogen chloride gas treated, whereby N-methyltricyelo (4-, 3,1,1 ^ ») undecan-4 ~ amine hydrochloride is obtained.

Examples 22-33

The experiment described in Example 21 is repeated, but using an equivalent amount of the following

* ^ R

4-A.cylamido-tricyclo (^, 3 _l 1 »'1) undecan' instead of the 4_Formamidotri- used in Example 21

• X Q

cyclo (4.3 »1i1 ') undecane, with those mentioned below Products are obtained.

Bei- ^ -Acylamido-tricyclo- (iT3B

22 ^ -Acetamidotricyclo- N -ethyltricyclo (4,3,1,1 (4 »3» 1 »1 *) undeean ·) undecan-4-aminhydro-

chloride

23 A-Acetamido-H-methyl-N-Ethyl-H-methyltricyclotricyclo (^, 3,1,1 ⁵ ' ⁸ ) - (4,3,1,1 ⁵ ' ⁸

uiidecan amine hydrochloride

y A-ethyl-N-methyltricyclo-

tricyclo (4,3,1,1 ³ ' ⁸ ) - (4,3,1,1 ⁵ ' ⁸ ) undecane - ^ - undecane amine hydrochloride

25 ^ acetamido-N-methyl - ^ - N-iithyl-H-methyl - ^ - ethyl-Utliyltricyclo (4,3,1,1 ³¹⁸⁾ tricyclo (4,3,1,1 ^{5 '8)} -undecane undecan-A-amine hydro chloride

26 α-Iaethyl-4-formamido-H-methyl-α-methyl-4-aminomethyltricyclo (4 _f 3,1,1 ⁵¹⁸ ) methyltricyclo (4,3,1,1 ⁵¹⁸ ) undecane undecane hydrochloride

009812/1920

27

28

29

4-formamidomethyltri-

3,1,1 ⁵ ') undecane

30th

31

32

33

4-methyl-4-formamidomethyltricyclo- (4,3,1,1 ⁵ⁱ⁸ ) undecane

N-formamido-N-methyl-4-amiiiome thyl tri eye Io -

N-Ac et amido-JT-methyl-4-aminomethyltrieyelo- (4,3,1,1 ^5,18 ) wndecane

N-acetamido-armethyl 1-4-aminomethyltricyclo- (4,3,1,1 ⁵ * ⁸ ) undecane

N-acetamido-N-benzy1-4-aminomethy! Tricycle- (4 _s 3,1,1 ³ ' ⁸ ) undecane

N-acetamido-N- (3-cyclohexenyl) -4-aminomethyltricyclo (4,3,1,1 ³ ' ⁸ ) undecane

N-Methyl-4-aminomethyltricyclo (4,3,1,1 ³ ' ⁸ ) -und c anhydrochloride N-methyl-4-methy1-4-aminomethyltricyclo (4,3,1 »1 ³ ' ^ tmdecane hydrochloride

II-ethyl-N-methyl-4-methyl-4-aminomethyltricyclo- (4,3,1,1 ^ » ⁸ ) undecane hydrochloride

IT-ethyl-N-methyl-4-aminomethyltricycIo (4,3,1,1 ^{3 r8} ) undec anhydro chloride

N-ethyl-a-methyl-4-amino-

methyltricycloC4,3,1,1 ⁵ ' ⁸ ) undecane hydrochloride

KB enzyl-N-ethyl-4-aminomethyltricyclo (4,3,1,1 ⁵ * ⁸ ) undecane hydrochloride

IT- (3-Cyclohexenyl) -4-amino

methyltricyclo (4,3,1,1 ⁵ ' ⁸ ) undecane hydrochloride

example

0.1 mol of tricyclo (4,3,1,1 ³ ' ⁸ ) undecan-4-amine in 100 ml of carbon tetrachloride is added 0.1 mol of sodium hydroxide in 100 ml of water. 0.1 Liol allyl bromide is carefully added to the mixture with vigorous stirring so that the temperature of the reaction mixture remains at 35 to 40.degree. To

When the allyl bromide has been added, the reaction mixture becomes Stirred for 16 hours at room temperature. After this time, the carbon tetrachloride layer is separated off and washed twice with 100 ml of water each time. The carbon tetrachloride is evaporated under reduced pressure and that

• <

0 0 9812/1920

«AD

21 -

remaining oil by steam distillation in hexane over- ' leads. The hexane solution is dried with potassium carbonate and filtered. The hexane is removed under reduced pressure. The oil remaining as residue is dissolved in ether and precipitated with anhydrous hydrogen chloride. The precipitate is recrystallized, with N-AlIyItricyclo-

■ 2 Q

(4-, 3 | 1j1 ') undecan-4-amine hydrochloride is obtained.

Examples 35 to 39

The experiment described in Example 34 is repeated, however, using an equivalent amount of the amines listed below in place of that used in Example 34 Tricyclo (4,3,1 »1 ') undecan-4-amines, the the following products can be obtained

At- Ατηί η product

game

35 4-aminomethyltricyclo-N-allyl-4-aminomethyltri- ^{58 8}

yy (4,3,1,1 ^{5> 8} ) undecane

36 4-methyltricyclo-

cyclo (4,3,1,1 ^ ' ⁸ ) undecane hydrochloride

N-allyl-4-methyltricyclo-

(4,3,1,1 ⁵ ' ⁸ ) undecane-4- (4,3,1,1 ⁵ⁱ⁸ ) undecane-4-amine-

hydrochloride

aiin

37 a-methyl-4-amiho methyl- lT-allyl-a-methyl-4-aminotricyclo (4,3,1,1 ^{3> 8} ) -methyltricyclo (4,3,1,1 ^{3> 8} )

undecan

undecan

N-allyl-N-methyltricycIo-

38 N-methyltricyclo-

(4,3,1,1 ⁵ ' ⁸ ) undecane-4- (4,3,1,1 ⁵ ' ⁸ ) undecane-4-amine-

amine

hydrochloride

39 N-Allyltricyclo (4,3,1,1 N, N-Diallyltricyclo (4,3,1,1 ^ ¹ ) undecan-4-amine * ■) undecan-4-aminhydro-

chloride

Example 40

-7 Q

To a solution of 0.10 moles of tricyclo (4,3,1,1 ^ ') undecan-4-amine in 0.5 mol of 98% formic acid there are 39 »^ 6 one

003812/1920

37% formalin solution given. The solution will take 16 hours Stirring heated to reflux. After this time the solution is cooled, diluted with 200 ml of water and strong made basic. The mixture obtained is evaporated by water vapor s tillation converted into hexane. The hexane solution will treated with anhydrous hydrogen chloride, with N, N-dimethyl tri eye Io (4-, 3 »1,1 *) undecan-4-amine hydrochloride as Precipitation is obtained.

Examples 4-1 through 44

The experiment described in Example 40 is repeated, but using an amount equivalent to that below named amines instead of the tricyclo (4.3 | 1.1) undecan-4-amines used in Example 40, the mentioned products are received «

Ji Ai product

41 4-Ethyltricyelo (4,3,1,1 ⁵ » ⁸ ) ~ N, N-dimethyl-4-ethyltriundecan-4-amine cyclo (4.3» 1 »1 ■) undecane

4-amine hydrochloride

42 4-aminomethyltricyclo- U, IT-dimethyl-4-amino- (4,3,1,1 ^{5> 8} ) undecane methyltricyclo (4,3,1,1 ⁵

-undecane hydrochloride

43 α-methyl ~ 4- aminomethyltri- N, N-dimethyl-a ~ methyl-4-eyclo (4.3 »1» 1 ^f ) undecane aminomethyltricyclo- (4,3,1,1 ³ⁱ⁸ ) undecane

hydrochloride

44 ^ -Methyl- ^ - aminomethyl- ^, Nyy

tricyclo (4,3,1,1 ³ ») - aminome thyltri cyclo-

undecane (4,3,1,1 ^ ») undecan-

amine hydrochloride

Example 45

^{0.10 mol of tricyclo (4,3,1,1 5f8} ) undecan-4-one in 100 ml of benzene is added to a solution of 0.16 mol of lithium ethyl in 150 ml of hexane so that the temperature of the solution does not exceed 10.degree increases. After the addition, the solution becomes

009812/1920

left to warm to room temperature and stirred for a further 16 hours. ^{The solution is cooled to 0} ° C. with a bath of ice and acetone, and 200 ml of water are added so that the temperature does not exceed 10 ° C. The solution is decanted and the hexane-ether layer is washed twice with 50 ml of water each time. The organic phase is dried with anhydrous magnesium sulfate. After filtration and removal of the solvent, 4-ethyl-4-hydroxytrieyeIo- ( ^/ * - »3» 1 _ί 1 ') undecane is obtained.

Example 4β

In the experiment described in Example 45, tricyclo- (4.3 »1.1 *) undecan-4-one in 4-hydroxy-4-methyl ^ lOyalC- (4.3 »1» 1 ') Undecane converted by replacing the lithium ethyl with an equivalent amount of lithium methyl.

Example 47

To a well stirred solution of 0.10 mol of 4-ethyl-4-

■ z a

hydroxytricyclo (4.3.1.1 ^{? t} ) undecane in 100 ml of glacial acetic acid are given 0.22 mol of potassium cyanide. A solution of 50 ml of glacial acetic acid in 100 ml of concentrated sulfuric acid at 50 to 60 ° C. is added to the suspension obtained, with thorough stirring. The solution is left to warm to room temperature and stirred for a further 16 hours, after which time the reaction mixture is added to 1000 ml of ice water and adjusted to p = 12 with solid potassium hydroxide. The suspension obtained is extracted three times with 200 ml of ether each time. The ether is dried with anhydrous magnesium sulfate. Filtration of the ether and removal under reduced pressure gives K-formamido-4-ethyltricyclo (4,3,1,1 *) undecan-4-amine.

A mixture of 0.1 mol of N-formamido-4-ethyltricyclo- (4,3,1,1 - '* ) undecan-4-amine, 450 ml of water and 1, ü mol Sodium hydroxide is refluxed for 24 hours. To At this time, the reaction mixture is converted directly into hexane by steam distillation. Through treatment

009812/1920

_ 24 - '

treatment of the hexane solution with anhydrous hydrogen chloride gas

JE O

becomes 4-ethyl% ricyclo- (4,3,1,1 ') undecan-4-amine hydrochloride received as a precipitate. ',

If an equivalent amount of ^ hydroxy - ^ - methyltricyclo- (4,3,1,1 ^f ) undecane is used in place of the 4-ethyl-4-hydroxytricyclo (4,3,1,1 ') undecane used in Example 47, 4-methyltricyclo (4,3,1,1 ⁵ * ^& ) -undecan-4-amine hydrochloride with a melting point of> 300 ° C. is obtained as the product.
Example 48

^{0.1 mol of a? Ricyclo (4.3 »1.1 5f &} ) -undecan-4-one in 200 ml of ether is added to a well-stirred suspension of 0.2 mol of lithium aluminum hydride in 500 ml of ether so that the temperature is 20 ° C not exceeded. The resulting mixture is stirred for 16 hours at room temperature. After this time, the solution is ^{cooled to Q 0} C in a bath of ice and acetone and saturated ammonium chloride solution is added until the inorganic salts are precipitated. The ether layer is decanted and washed with saturated sodium chloride solution. The ether solution is dried with anhydrous magnesium sulfate and filtered. Removal of the ether under reduced pressure gives tricycle (4,3,1,1 ^ ¹ ) -undecan-4-ol.

Example 49

■ ζ ο

0.215 g atom of bromine are added at 55 ° C. to a solution of 0.1 mol of tricyclo (4,3,1,1 ⁵ ') undecan-4-ol and 0.107 hol triphenylphosphine in 100 ml of dimethylformamide, with stirring. The solution is cooled to room temperature and added to 500 ml of water. The aqueous mixture is converted into hexane by steam distillation. The hexane solution is dried with anhydrous magnesium sulfate and filtered. Removal of the hexane under reduced pressure gives 4-bromotricyclo (4,3,1,1 * jundecane.

009812/1920

Example 50

0.28 mol of methyltriphenylphosphonium bromide and 0.25 mol of anhydrous potassium tert-butoxide are added to 500 ml of glyme. The solution is kept at 40 ° C. for 2 hours. During this time the solution will turn deep yellow. 0.12 mol of tricycle- (4,3,1,1 - **) undecan-4-one are added to this solution with vigorous stirring at 30 ^{0 O.} Allowing the temperature of the solution to 40 C _t rise and the reaction mixture 24 hours at room temperature is stirred. After this time, the reaction mixture is added to 3 l of water and then extracted three times with 300 ml of pentane each time. The pentane extract is concentrated under reduced pressure and the remaining oil is converted into hexane by steam distillation. The hexane solution is dried, filtered and concentrated,

■ χ η whereby 4-methylentricyclo (4.3 _> 1 »1) undecane is obtained.

IR _{max #} 3050, 2930, 1615, 1430, 1110, 890, 875 cm "" ¹ , (pure liquid)
Example 51

100 ml of a 1a-diborane solution in tetrahydrofuran are added to a solution of 0.12 mol of 4-methylentricyclo (4,3,1,1 **) -undecane in 300 ml of ether. The solution is kept at 45 ° C. under nitrogen for 5 hours. After this time, the solution is ^{cooled to 0} ° C. and carefully mixed with 30 ml of a 20% strength sodium hydroxide solution, whereupon 30 ml of a 30% strength hydrogen peroxide solution are slowly added carefully at ⁰ ° C. The reaction mixture is allowed to warm to room temperature and stirred for a further hour. After this time a trace of platinum oxide is added in order to decompose excess hydrogen peroxide, whereupon the mixture is stirred vigorously overnight. To

• 30 this time the organic layer is separated, with 200 ml of ether are added and washed neutral with water. the Ether solution is dried with anhydrous magnesium sulfate and filtered. The solvent is removed under reduced pressure to give a crystalline solid . will. By recrystallizing the solid from hexane at

009812/1920

-20 O becomes ^ hydroxymethyltricycloCA ^ ji, 1 ') undecane of the melting point. 61 to 62 ⁰ G obtained. ,.

To a solution of 0.11 mol ^ ^^ -HydroxymethyltricycloC, 1.1 ^ ^»8) undecane in 200 ml of acetone are added mole Ghromtrioxyd a standard solution at 1O ⁰ O- 0.14. The reaction mixture is stirred for 30 minutes and after this time added to 1 liter of ether. The ether solution is extracted with water until the wash water is no longer green. The ether-acetone solution is dried with anhydrous magnesium sulfate. The organic phase is filtered and evaporated under reduced pressure. The remaining solid is dissolved in a warm 5% lgev sodium hydroxide solution and extracted with ether. The aqueous phase is separated off, heated to 60 ° C. to remove excess ether, cooled and strongly acidified with concentrated hydrochloric acid.

The precipitate obtained is filtered off and extracted from nitromethane

-7 Q

recrystallized, whereby tricyclo (4-, 3.1 »1 ') undecane-4- carboxylic acid of melting point 130 to 132 ° C. is obtained.

Example 32

7 O

Ground to 0.1 mole of tricyclo (4,3,1,1 ') undecane-4-carboxylic acid 100 ml of chemically pure thionyl chloride and 2 drops of dimethylformamide given. The resulting solution is refluxed for 1 hour. After this time the thionyl chloride becomes removed at reduced pressure. To that as a return The remaining oil is given to dry heptane. The heptane is removed under reduced pressure. That as Remaining oil is dissolved in ether and washed with anhydrous Treated ammonia until the solution becomes strongly basic. The ether solution is washed with 5% sodium hydroxide dried with anhydrous magnesium sulfate, filtered and evaporated under reduced pressure, whereby a pale yellow solid is obtained. The solid will turn out Nitromethane and then recrystallized from heptane, with tri-

3 fl
cyclö (4,3,1 »1 *) undecane-4-carboxylic acid amide of melting point

159 to 161 ⁰ G is obtained. Γ

009812/1920

Examples 55 to 58

The experiment described in Example 52 is used the amines mentioned below in place of the example 52 used ammonia repeatedly, the named Carboxamides are obtained.

Example

53

55

56

57 58

Amine allylamine

Dimethallylamine 3-lethylene azetidine

3-methylenecyclobutylmethylamine

LIethallylamine

5-kethylene cyclobutylamine

Carboxamide

N-Allyltricyclo (4-, 3,1,1 ^3f8 ) -undecane-4-carboxamide

N- (1,1-dimethallyl) tricyclo- (4.3 »1 | 1 ' ) -4-carboxamide

3-methylene-1 / tricyclo (4,3,1,1 ^ ') undecane-4-carboxamide 7-

azeti'din

N- (3-methylenecyclobutylmethyl-

^ ⁸

carbonic acid amide

N- (2-methallyl) tricyclo (4 _L 3.1, 1 x) undecane-4-carboxylic acid amide

N- (3-methylenecyclobutyl) tricyc-

■ T Q

10 (4.3Ii i1) undecane ^/ i-carboxamide

Example 59

8 g of lithium aluminum hydride are added to 300 ml of dry tetrahydrofuran under nitrogen. A solution of 0.05 UoI of tricyclo (4,3,1,1 ^ ') undecane-4-carboxamide in 150 ml of anhydrous tetrahydrofuran is added to the mixture with stirring over the course of 1 hour. The resulting mixture is heated and stirred under nitrogen for 24 hours. Hach this time, the mixture is neutralized by adding a 20> strength at liatriumhydroxydlösung 0 ⁰ G is carefully added, all bit salts are precipitated. The tetrahydrofuran solution is decanted and then evaporated under reduced pressure. The remaining as residue Ul is through

009812/1920

8AD

Steam distillation converted into hexane under nitrogen. The hexane solution is dried with anhydrous potassium carbonate and filtered. Anhydrous hydrogen chloride is added to the dried solution, 4-aminomethyl-tricyclo (4,3,1,1 *) undecane hydrochloride with a melting point of> 5OO ^G C being precipitated.

Examples 60 to 65

The experiment described in Example 59 is repeated, however using an equivalent amount of the below mentioned carboxamides in place of the example

59 used tricycle (4, 3, 1 * 1) undecane-4-carboxylic acid- amids ,. whereby the named products are obtained

^e ^ "~ _T carboxylic acid amjjd product game

60 N-Al IyI tricycle- K-Allyl-4-aminomethyltri- (4,3, ^ »1: ⁵ * ⁸ ) undecancyclo (^, 3,1t'l ⁵ » ⁸ > undecaii-.

4-carbon acid amide hydrochloride

61 N- (1,1-Dime thallyDtri- N- (1,1-Mmethallyl) -4-aminocycloC iji ^^^ ^ '^ ^ carbonmethyltricycloC, 3,1,1 ^{5 »8)} -säureamid undec anhydro chloride

62 3-I.Iethylene-1- ^ tricycle- 3- ^ ethylene-i- ^ tricyclo-

^(/ "-I3,1, ^{'1 $ i8)} undecane-4- (4,3,1,1 ^{5' 8)} undec an-4-methyl ylcarbonsäureamid7azetidin / azetidine hydrochloride

63 N- (2-methallyl) tricyclo N- (2-iiethallyl) tricyclo (4,3,1,1 ^5tö) undecane-4- (4,3,1,1 ^{5 '8)} undecane-4-methyl -

carboxamide amine

64 N ^ -iKethylencyclobutyl- N- (3-Methylencyclobutytmethyl) tricyclo (4,3,1,1 methyl) tricyclo (4,3,1,1 ^{5 '8)} - XQ

^y * ) undecane-4-carbon-undecane-4-methylaminhydro acid amide chloride

65 li- (3-I <ethylene cyclobuty! 0- N- (3-I ^ ethylenecyclobutyl) -

tricyclo (4,3,1,1 ⁵ ' ⁸ ) - tricyclo (4,3,1,1 ^5f8 ) undecanundecane-4-carboxylic acid-4-methylamine hydrochloride arid

• ·

009812/1920

Example 66

3i | 1 »1) undeean-4-carboxamide (0.1 mol) is in a mixture of 150 ml (thionyl chloride and 150 ml Benzene dissolved. The resulting solution is refluxed for 4 hours heated, whereupon the solvent under reduced Pressure is removed. Additional benzene is added and removed under reduced pressure. All of the raw product is converted into hexane by steam distillation. the Hexane solution is dried over anhydrous magnesium sulfate and filtered. After removing the hexane, 4-cyantricyclo (4,3,1,1 ') undecane is obtained.

Example 67

^{0.1 mol of 4-bromotricyclo (4,3,1,1 9} ') undecane in 75 ml of dimethyl sulfoxide is added at 75 ° G to 0.2 mol of sodium cyanide in 300 ml of dimethyl sulfoxide with stirring. The reaction mixture is stirred at 75 ° C. until the reaction, which is monitored by gas chromatography, has ended. After this time

water
the reaction mixture is poured into 1 l and extracted three times with 400 ml of ether each time. The ether is washed well with water to remove the dimethyl sulfoxide and dried with anhydrous magnesium sulfate. The ether is filtered and removed under reduced pressure to give 4-cyanantricyclo (4,3,1 »1 ') undecane.

Example 68

To a well stirred suspension of 0.26 mol of lithium aluminum hydride in 300 ml of tetrahydrofuran, 0.1 mol of 4-0yantricyclo (4 _t 3.1.1 ^ ^{> 8} ) undecane in 100 ml of tetrahydrofuran is added under nitrogen. The mixture is refluxed with stirring for 18 hours. After this time, the excess lithium aluminum hydride is carefully decomposed ^{with 30% strength sodium hydroxide solution at 0 ° C.} The tetrahydrofuran solution is decanted from the precipitated salts and the tetrahydrofuran is removed under reduced pressure under nitrogen. The oil remaining as a residue is through

3-5 · Steam distillation converted from a strongly basic aqueous solution into hexane. The hexane solution is mixed with water

009812/1920

washed, dried over anhydrous potassium carbonate and filtered. By removing the hexane from part of the Filtrate is obtained ^ -ÄminomethyltricycloC ^, 3,1,1 ') undecane. The Hest of the hexane solution is with anhydrous Treated hydrogen chloride gas, with 4-aminomethyltricyclo- (4-j3 >> 1i1 ) undecane hydrochloride is obtained as a precipitate.

Example 69

-Z Q

0.1 mol of butyllithium is added at 0 to 10 ° G to 0.1 mol of ^ -aminomethyltricycloC ^ - ^ ii, 1 ') undecane in 200 ml of benzene. 0.1 mol of propargyl bromide is added to the mixture at 0 to 10 ° C. with vigorous stirring. The mixture is stirred for 2 hours at 0 to 10 ^° C. and then left to warm to room temperature, whereupon it is stirred for a further 6 hours. The mixture is then carefully washed twice with 100 ml of water each time. The benzene solution is dried with anhydrous potassium carbonate. The potassium carbonate is removed by filtration and the solution is concentrated under reduced pressure. The oil remaining as residue is converted into hexane by steam distillation. The hexane solution is dried with anhydrous potassium carbonate, filtered, treated with COp, filtered again and concentrated under reduced pressure. The oil remaining as a residue is dissolved in ether, whereupon anhydrous hydrogen chloride is carefully passed through the. I / o solution is passed, whereby N-propargyl-4- aminomethyltricycle (4,3,1,1 ') undecane hydrochloride is precipitated. ■

Example 70

To a well stirred solution of 0.3 mole of methyl magnesium bromide in 100 ml of ether under nitrogen _o 0.1 mol of 4-Cyaiitricyclo (4, 3,1,1 ^{5 '8)} undecane in 100 ml of ether at 0 to 5 ° C . The reaction mixture is allowed to warm to room temperature, whereupon an additional 16 hours. is stirred. After this time, the solution is ^{cooled to O 0} C and the excess methyl magnesium bromide with

009812/1920

saturated ammonium chloride solution decomposed. The ethereal solution is decanted from the precipitated salts. The ether is removed under reduced pressure and the residue in Dissolved methanol and 10 L-minutes with% hydrogen chloride solution heated under reflux, the solution is neutralized and evaporated under reduced pressure and by steam distillation converted into hexane. The hexane solution is dried and concentrated under reduced pressure, whereby

• X Q

i »iethyl-4-tricyclo (4-, 3» 1 »1 ') undecyl ketone is obtained.

Example 71

To a well stirred solution of 0.3 mole of methyl magnesium bromide in 100 ml of ether under nitrogen is added 0.1 mole of 4-Gyantricyclo (4.3 _t 1 '1') undecane in 100 ml of ether was added at 0 to 5 ⁰ C. The reaction mixture is allowed to warm to room temperature and stirred for a further 16 hours. After this time, the solution is ^{cooled to 0} ° C. and the excess imethylmagnesium bromide is decomposed with saturated ammonium chloride solution. The ether solution is decanted from the precipitated mats and dried. The ether solution is filtered and added to a suspension of lithium aluminum hydride and ether. The mixture is refluxed with stirring overnight. The reaction mixture is then cooled and neutralized with 2Q sodium hydroxide solution. The ether is removed under reduced pressure and the oil remaining as residue is converted into hexane by steam distillation under nitrogen. The hexane solution is dried with potassium carbonate and filtered. The iriitrate is treated with anhydrous hydrogen chloride, whereby a-Lethyl-A-aminomethyltricycloC ^^ ji, ^1-7 I) undecane hydrochloride is precipitated.

Example 72

The experiment described in Example 7 is repeated, but using 0.1 ml of ethyl-4-tricyclo (4,3,1,1 - * ») undecyl ketone instead of the 0.05 mol of 4 used in Example 7 -Iricyclo (4,5, I ₁ I ⁹ ') undecan-4-one, where a-.iethyl-

009812/1920

ORIGINAL

■ τ Cf

zj.-aminoinethyltricyclo (4,, 3, ^/ 1,1 *} undecane hydrochloride 'is obtained *

Example 73 '

A solution of 0.1 mol of 4-methyltrieyelo (4-, 3 »1» 1 *) undecan-4 ~ -ol in 65 ml of formic acid is added to 650 ml of concentrated sulfuric acid at such a rate that the temperature does not exceed 0 ⁰ C. the reaction mixture is stirred vigorously during the addition and held for 1 hour at O ⁰ G and then quilted 1 additional hour at 10 ⁰ G »the solution is added to 2 1 of ice and stirred vigorously. A

solid precipitate separates out and is filtered off. the . crude acid is dissolved in methylene chloride and the solution with "Dried anhydrous magnesium sulfate. The methylene chloride is filtered and removed at reduced pressure »whereby a mixture of 4-methyltricyclo (4.3 »1» 1 *) undecane-4-carboxylic acid and 4-methyltricyclo (4.3 »1» 1 *) undecane-1-carboxylic acid is received *

0.1 mol of the mixed acids is added to 200 ml of thionyl chloride and 6 drops of dimethylformamide. The solution is refluxed for 12 hours. The thionyl chloride is removed under reduced pressure. The crude acid chlorides are added to 200 ml of a solution of 20 g of triethylamine in 300 ml of methanol. The solution is stirred for 16 hours, and the methanol and excess of triethylamine at 25 w verminder- system pressure are removed. The residue is dissolved in 300 ml of ether and washed with water until the wash water is neutral. The ether solution is dried with anhydrous magnesium sulfate. The ether is filtered and removed under reduced pressure, a mixture of methyl 4-methyltricyclo (4.3 »111 *) undecane-4-carboxylate and methyl

7 O -

* 4-methyltricyclo (4,3,1,1 *) undecane-1-carboxylate obtained will.

Kethyl 4-methyltricyclo (4.3 »1» 1) undecane-4-carboxylate is cleaned by preparative gas chromatography. Of the The above-mentioned ester is used in ethanolic "potassium hydroxide

009812/1920

SAD ORIGINAL

solution hydrolyzed and acidified, with 4-methyltricyclo- ■ , (4-, 3JIjI) undecane-4-carboxylic acid is obtained. The acid. ·. Chloride is prepared in the manner described above, dissolved in chloroform and treated with anhydrous ammonia. The salts are filtered off and the chloroform is removed, with 4-methyltricyclo (4-, 3 j1 j1 *) undecane-4-carboxamide is obtained.

By reducing the carboxamide with lithium aluminum hydride in ethylene glycol dimethyl ether is 4-methyl-4-aminomethyltricyclo {4,3,1j1 *) received undecah. The Gemi-see is purified by steam distillation in hexane. By Addition of anhydrous hydrogen chloride to the hexane becomes 4-methyl-4-aminomethyltricyclo (4,3j1,1 *) undecane hydrochloride obtain·

Example 74

0.1 mol of p-toluenesulfonyl chloride is added to a solution of 4-hydroxymethyltricyclo (4,3,1,1 *) -undecane in 100 ml of pyridine. The solution is left to stand for 2 days and then added to 500 ml of ice and 500 ml of water. The solid which separates out is filtered off, washed well with water and recrystallized from hexane, 4-hydroxymethyltricyclo (4,3j1j1 *) undecane-p-toluenesulfonate being obtained. 0.12 mol of sodium azide are added to a solution of 0.1 mol of the above-mentioned ester in 250 ml of dimethyl sulfoxide. The mixture is stirred for 24 hours and then added to 1 l of ice water. The mixture is extracted three times with 200 ml of ether each time. The separated ether layer is washed three times with 100 ml of water each time. The Atherschicht is dried with anhydrous magnesium sulfate, filtered and dried at reduced pressure and a temperature of not more than 25 ⁰ C and evaporated to give 4-Azidomethyltricyclo obtained -undecane (4,3,1,1 ^{5 »8).} 2 g of platinum oxide are added to a solution of the above azide in 200 ml of ethanol. The mixture is hydrogenated at a pressure of 2.8 kg / cm in a Parr shaker until hydrogen uptake ceases. The catalyst is filtered off and the obtained

009812/1920

solution concentrated under reduced pressure. The oil remaining as residue is converted into hexane by steam distillation. The hexane solution is dried with anhydrous potassium carbonate. The solution is filtered and treated with anhydrous hydrogen chloride, 4-aminomethyltricyclo (4 _r 3,1,1 '_ ») undecanhydric chloride being precipitated.

Example 75

A solution of 0.1 mole of tricyclo (4.3 »1 * 1 ') undeean- * 4-one in 200 ml of ethanol is placed in a 1000 ml bomb. Of the 5 S Raney Kickel are added to the solution * The bomb is

closed and pressed with anhydrous ammonia to 21 kg / cm. The bomb is heated for 2 hours with shaking to 125 ° C, then cooled, pressed with hydrogen to 105 kg / cm ² and maintained for 8 hours with shaking at 100 ⁰ C. The bomb is cooled in it and the solution poured out. The solution is filtered and then concentrated under reduced pressure. The oil remaining as residue is converted into hexane by steam distillation under nitrogen.

The hexane solution is dried with anhydrous potassium carbonate and filtered * The solution is treated with anhydrous chlorine

• Hydrogen treated, with 4-Aminötricyclo (4,3,1,1 ^ ») -undecane hydrochloride is precipitated.

"1

Example 76

To a solution of 0.1 mol of 4-hydroxymethyltrieyeIo (4,3,1,

* 1. ■ ») undecane in 200 ml of purified dioxane produces 5 g of one Catalyst, which consists of 10% euthenium on carbon ?, given. The mixture is filled into a bomb and with a 1: 1 mixture of ammonia and hydrogen up to 35 kg / cm printed. The mixture is then held at 250 ° C. for 12 hours. After this time the solution is cooled and poured out and filtered. The organic solvent is reduced at Pressure removed. The oil remaining as residue is converted into hexane by steam distillation. The; Hexane solution is dried with anhydrous potassium carbonate

009812/1920

and filtered The solution is washed with anhydrous chlorinated water

Jt O

treated substance, with 4 — ÄminomethyltricycloC ^^ jiji- '») -undecane hydrochloride is precipitated.

Example 77

0.2 mol of calcium oxide and 0.1 mol of diallylamine are added to 0.1 mol of ^ - hydroxymethyltricyclo ^^ i, 1 ') undecane-p-toluenesulfonate. The reaction mixture is kept at 170 ° G for 16 hours * After this time, the solution is cooled, filtered and reduced at reduced. Pressure evaporated. The oil remaining as residue is dissolved in 3N hydrogen chloride solution and then extracted with ether. The aqueous phase is heated to remove residual ether and then made strongly basic with sodium hydroxide granules. The aqueous mixture is extracted with ether and the ether layer is concentrated under reduced pressure. The Cl remaining as residue is distilled at 0.1 mm Hg at a temperature between 80 and 120 ^{° C.} The distillate is dissolved in ether and then treated with anhydrous hydrogen chloride. The precipitate formed is recrystallized from ethanol-ether to give lI, N-DiaHlyltricyclo (4,3,1,1 ^{5 »8)} undecane-4-methyl amine hydrochloride of melting point 143-144 ° C is obtained.

Example 78

To a solution of 0.6 liol of 4-aminomethyltricycloC ^^ ji i1 Jt ο

? t °) undecane in 100 ml of benzene are added to 200 mg of a triphenylphosphine-palladium-maleic anhydride complex. The solution is placed in a bomb, which is sealed after adding 0.13 mol of allene. The bomb is shaken at 120 ° 0 for 6 hours. After this time, the reaction mixture is decanted, filtered and then concentrated under reduced pressure. The remaining as a residue Gl is distilled at 0.1 mm HSS and a temperature between 120 and 140 ⁰ C. The distillate is then dissolved and treated with form of hydrogen chloride in an amount sufficient to render the solution neutral

009812/1920 BAD ORSQtNM,

te solid is recrystallized with ethanol-ether _f wherein N- (3-methyl-2-methylene-3-butenyl) tricyc; obtained lo (4, 3,1,1 ^{5 '8)} undecanhydro chloride of melting point 248-249 ° C

will.
Example 79

A mixture of 0.10 mole of tricyclo _(4-r ^ 3,1,1 ') undecani-4-amine and 0.10 mole of acid of 48% strength hydrogen bromide is evaporated under reduced pressure at 60 ⁰ G. The salt obtained, TricyclQ (4-, 3 »1 j1 *) undecane hydrobromide, is min-. 10 dertem pressure dried at 60C.

Examples 80 to 89

The experiment described in Example 79 is repeated, but using an amount equivalent to that below Reaction participants mentioned in place of those mentioned in at-15 game 79 named reactants, the named salts being obtained.

Amine

■ At game

N-Benzyl-H-ethyl-4-aminomethyltricyclo (4-, 3,1,1 ³ ' ⁸ ) -undecane

N-allyl-4-aminomethyltricyclo-

82

acid

85%

Phosphorus-

acid

sulfuric acid

Κ, Ν-diallyltricyclo- wine-

-Z Q

(4,3, I ₁ I ') undecanoic acid 4-amine

H, Η-dimethyl- ³⁸

undecane-4-ainine

By-

chlorine-

acid

84

W-Allyl-H-methyl-maleic tricyclo (4,3,1,1 ^ » ⁸ ) - acid undec an-4-amine

salt

K-Benzyl-N-ethyl-4-aminome thy1tri cyclο- ( ^/ * -i3,1, ^/ l ⁵ ' ⁸ ) undecandihydrogenpho sphat

IT-Al Iy 1-4-aminome thy 1-tricyclo (4,3,1, ^/ l ⁵ⁱ⁸ ) -undec anhydrogen sulfate

Ν, Ιί-diallyltricyclo- (4,3,1,1 ⁵ » ⁸ ) undecanhydro gent artrat

N, N-dimethyl

(* »3,1,1 ⁵ ' ⁸ ) undecan-

4-amine perchlorate

N-AlIy1-N-methyltricycloC4,3,1,1 ³ ' ⁸ ) -, undecan-4-amine hydrogen maleate

009812/1920

! 945208

-Undecane N, N-dimethyl-4-aminomethyl thyltricyclo (4, 3,1,1 ^{3 »8)}

₄ 4-aminomethyltri-

cyclo (4,3,1,1 ³ ' ⁸ ) undecane

4 ~ aminomethyltricyclo (4-, 3,1,1 ³ ' ⁸ ) -undecane

oc-methyl-4-aminomethyltricyclo-

O> 3.1.1 ³ ' ⁸ ) undecane

N-methyl-oc-methyl-4-aminomethyltricyclo (4-, 3,1,1,3 ^{> 8} ) -undecane

Vinegar-U, H-dimethyl-4-amino acid methyltricyclo-

acetate

Citric 4-aminomethyltricycle ■ acid (4,3,1,1 ⁵ * ⁸ ) undecanedihydrogen citrate «

Undecansuccinat Bernhard 4-Aminomethyltricyclostein- (4 _l 3,1,1 ^5r8)

acid

Mandelic acid

Lactic acid

α-Me thy 1-4- aminome thy 1-

tricyclo (4,3,1,1? ' ⁸ ) -

undecan almond

H "-Methyl-α-methyl-4-aminomethyltricyclo- (4,3,1,1 ³ ' ⁸ ) undecane lactate

As already mentioned, the invention is in one aspect contributes to a method of combating viral infections Directed to warm-blooded animals. Under the "fight" against viral infections is prevention, cure, and / or relief understand these viral infections in warm-blooded animals. "Warm-blooded animals" are members of the animal kingdom who have one exhibit homeostatic mechanism. This includes mammals and birds.

The compounds according to the invention are particularly suitable and valuable for combating viral infections of the upper respiratory tract in warm-blooded animals, e.g. by influenza viruses, parainfluenza viruses, syncytial viruses of the respiratory tract (respiratory syncytial), rhinoviruses and the like.

The compounds according to the invention can be used in any suitable manner for the antiviral treatment according to the invention To be administered in a manner by which the active substance is brought to the site of the viral infection in the body of warm-blooded animals

009812/1920

will. This of course includes the site prior to infection as even after infection. For example, the treatment parenterally, i.e. subcutaneously, intravenously, intramuscularly or intraperitoneally. As an alternative or at the same time oral administration can be used.

The dosage depends on the virus to be controlled Age, health and weight of the recipient, the extent of the infection, the nature of any concurrent Treatment, the frequency of treatment and the desired th effect. In general, the daily dose of active ingredient is between about 1 and 50 mg / kg of body weight, however larger amounts can also be used. Usually 1 to 20 mg, preferably 1 to 10 mg / kg / day, given all at once or spread over the day, get the results you want.

The antiviral effectiveness of the compounds according to the invention can be demonstrated by using the test compound Mice in the drinking water orally at 0.5 mg / ml from 24 hours before infection to 48 hours after infection with Influenza A2 / Bethesda / 10/63 is administered.

The consequence of this is that the possibility of infection is significantly reduced.

The effectiveness of the test compound in controlling and combating viral infections is decreased by the Mortality of experimental animals to which the compounds administered versus mice infected but not treated in the same manner have been. The results of experiments carried out in the manner described are as follows Called table.

Mortality is checked 7 days after infection.

009812/1920

Treated group comparison group

«■" ν · λ Infi- survivors Infi- survivors

connection adorned animals adorned animals

Animals number% Animals number %

Tricyclo (4,3,1,1

3 »8) undecane-4- 18 .15 83 108 19 18 amine hydrochloride

N- (3-methylene

cyclobutyDtri- ^{18 12} 66 108 19 18

cyclo (4,3,1,1 ⁵ » ⁸ ) undecane-4-methylamine hydrochloride

3 ₌ methylene-1-

/ tricyclo (4,3,1,1
5, B) ₁₁₁₁ CLeC __4_ I ₈ 15 83 108 18 17

ylmethyl / azetidine hydrochloride

N-allyl tri cyclo-

(4,3,1,1 ⁵ » ⁸ ) unde-18 10 55 108 15 13 can-4-methylamine hydrochloride

The effectiveness of the compounds according to the invention against rhinovirus is determined as follows: monolayers of HeLaC cells are infected with the HPG strain of rhinovirus. i.a paper disk containing the desired amount of Contains compound, is placed on the liono layer. To On a suitable incubation site, the IUo no layers of cells stained and examined for courtyards caused by the destruction of cells by the virus. Are effective Compounds that create a zone around the disc that is free of cells (cell destruction) by inhibiting the virus. the The following connections form a courtyard-free zone for the one described above read: H- (3-liethylenecyclo-

'- ^ ft

butylmethyl) tricyclo (4,3,1,1- ») undecane-4-methylamine hydro-

chloride, K- (2-methallyl (tricyclo (4,3,1,1 ⁵ⁱ⁶ ) undecane-4-methylamine hydrochloride, N- (5-i «etliylenecyclobutyl) tricyclo- (4,3,1,1 ^ *) undecane-4-methylamine hydrochloride, 3-ethylene-1- / tricyclo (4,3,1,1 ^ »^ undec ^ -ylmethyljazetidine hydrochloride, II- (1,1-dimethallyl) tricyclo (4,3,1,1 ⁵ » ⁸ ) undecane-4-methylanine hydrochloride, N-allyltricyclo (4, $, 1,1 ⁵ *) undecane-4-methylamine hydrochloride.

009812/1920

- 40 - ■

The active ingredients according to the invention can be used in preparations such as tablets, capsules, powders or liquid solutions, suspensions or elixirs for oral administration or in 'liquid solutions for parenteral use and in certain cases in suspensions for parenteral use (except intravenous). These preparations contain the active ingredient usually in an amount of at least 0.5 wt. -Jo and at most 90 wt .-%, based on the total weight of the preparation.

In addition to the active ingredient according to the invention, the antiviral preparations contain a solid or liquid non-toxic pharmaceutical carrier or excipient for the active ingredient.

In one embodiment of a pharmaceutical preparation according to the invention, the solid carrier consists of a capsule, which can consist of ordinary gelatin. The capsule contains about 30 to 60% by weight of a compound of the Formulas (1) and (2) and 70 to 40% of a carrier. At a In another embodiment, the active ingredient is tabletted with or without an excipient. It is also possible to use the active ingredient to be incorporated into a powder and used as a powder. These capsules, tablets and powders usually make about up to 95% "preferably 25 to 90% by weight". They contain preferably about 5 to 500 mg of active ingredient, with about 25 to 250 mg are particularly preferred.

Suitable pharmaceutical carriers are sterile liquids, for example water and oils obtained from petroleum or of animal, vegetable or synthetic origin, for example peanut oil, soybean oil, mineral oil and sesame oil. In general, water, salt solutions and aqueous dextrose solutions (glucose) and similar sugar solutions and glycols such as propylene glycol or polyethylene glycol are preferred as liquid carriers, especially for injection solutions. The sterile injection solutions, including salt solutions usually contain preferably about 1 to 10 wt% about 0.5 His 25 »-.% Of the active ingredient.

V 0 09812/1920

Already mentioned., Oral application can take place in a suspension or in a syrup, in which the active substance usually amounts to about 0.5 to 10/0, preferably about 2 to 5 wt .- #>. In these preparations, pharmaceutical carriers can be used. aqueous carriers ζ, B ₀ aromatic water, syrups or pharmaceutical mucilages can be used. Suitable pharmaceutical carriers v / ground E "W _e Martin,"Remington's Pharmaceutical Sciences ", a well-known manual on this field, described"

The invention is further illustrated by the following examples explained »

Example 90

A large number of unit capsules are produced using the usual two-part hard gelatin capsules, each weighing about 50 mg, each containing 50 g of powdered 4 ~ aminotricyclo- (4 · »3» 1 »1 ') undecane hydrochloride _i 125 mg of lactose and 1 mg of silica under the trade name "Oab-o-sil" are filled.

Example 91

Instead of the hard gelatin capsules mentioned in Example 90 soft gelatin capsules are used. In addition, the powdery 4 ~ aminotricyclo (4,3j1 »1 ') undecane is previously in Soybean oil dissolved.

Example 92

In accordance with the usual procedures, a great number of i ^ will lead manufactured, the 50 mg each active ingredient, 5 mg gelatin, Contains 1.5 mg magnesium stearate and 100 mg lactose. Pills or tablets with sustained release of the active ingredient can also be prepared by applying suitable coatings · A sugar coating can be applied to make the tablets more palatable.

Example 93

A parenteral injectable preparation is shown by Mi- " of 5% by weight ^ -AminotricycloC ^^ ti, 1 ') undecanhydro-

0 09812/1920

Chloride prepared with sterile aqueous 0.9% saline solution.

The most varied of preparations according to the invention can thus easily be made using other compounds according to the invention, including those specifically above but are easily produced without being limited to will be presented. The compounds are used in the stated amounts used in accordance with well known procedures described in the Martin manual referred to above.

The compounds according to the invention are antiviral agents for domestic animals and animals. For example, the compounds falling under formulas (1) and (2) are effective against viruses of the respiratory tract, for example swine influenza, equinfluenza and wing influenza. One embodiment of the invention is thus the control of these infections by adding a compound according to the invention to the feed of the infected animals. For most purposes, the active ingredient is used in such an amount that its proportion of the total feed consumed is about 0.0001 to 0, 1 % by weight. Preferably 0.001 to 0.2 & e.w, - ^. used. '.

The invention creates new and valuable preparations and preparations available which contain at least one active ingredient according to the invention mixed with an animal feed Suitable feeds are in the book "Feeds and Feeding" by Frank ", Morrison (Morrison Publishing Company of Ithaca, New Xork 194-8, 21st edition). The V / ahl of the respective feed is of course left to the expert and depends on the animals, the economy, the available ones natural substances, local conditions and the desired effect.

Is particularly important under this aspect of the invention a concentrate that is used to make and sell at Farmers or ranchers to add to forage ^ suitable. These concentrates usually contain about 0.5 to

00.9812 / t920

95 wt -. ° / o of the active ingredients with susamineii ex ^ f ss solid, preferably flour such as wheat flour, corn flour, cottonseed meal and Scgabohnenmehl. Depending on the animal to be treated, ground grain, charcoal, fuller's earth, ground mussel shells and the like can be used as solid auxiliaries. Finely divided attapulgite and bentonite, which at the same time act as solid dispersants, are also suitable.

The feed and the concentrates described above can of course add further components to feed concentrates or contain cattle feed. Proteins, carbohydrates, fats, vitamins, Minerals, antibiotics, etc. in question.

009812/1920

βΑΟ ORIGINAL

Claims (1)

- ■ 44 - Claims 1 · Compounds of the formula € r T2 .R, -N ' • R in which η stands for O or 1, R _x for a hydrogen atom or an alkyl radical with 1 to 2 carbon atoms, Ro for a hydrogen atom or an alkyl radical with 1 to 2 carbon atoms, R ^ a hydrogen atom, an alkyl radical with 1 to 4 carbon atoms, an alkenyl radical with 3 "to 9 carbon atoms, a 3-methyl-2-methylen-3-butenyl group, a cycloalkenyl radical with 5 to 8 carbon atoms, an alkenylcycloalkyl radical with 6 to 9 Carbon atoms, a cycloalkylalkenyl radical with 6 to 9 carbon atoms, an alkynyl radical with 3 to 5 carbon atoms or a benzyl radical, R ^ is a hydrogen atom, an alkyl radical with 1 to 3 carbon atoms, an alkenyl radical with 3 dis 5 carbon atoms -Atoms or a propargyl radical, where R, and R ^, together can form a nitrogen-containing heterocyclic ring and in cases in which the substituent R and / or R ^, is unsaturated, the double bond or triple bond is not in the 1-position , and the pharmaceutically acceptable salts of these compounds » 2. Compounds of the formula - where R _x , a hydrogen atom or alkyl radical with 1 to 2 carbon atoms, Rp a hydrogen atom or an alkyl radical with 1 to 2 carbon atoms, R, a hydrogen atom, an alkyl radical with Λ to 4 carbon atoms, an alkenyl radical with 3 up to 9 carbon atoms, a 3-methyl-2-methylene-3-butenyl group, a cyclo- 009812/1920 alkenyl radical with 5 "to 8 carbon atoms, an alkenylcysIoalkylrest with 6 to 9 carbon atoms, a cycloalkylalkenyl radical with 6 to 9 carbon atoms, an alkynyl radical with 3 to 5 carbon atoms or a Benayl radical, and R ^ for a V. / water atom, an alkyl radical with 1 to 3 carbon atoms, an alkenyl radical with 3 to 5 carbon atoms or a propargyl radical, where R ₇ and IL together can form a nitrogen-containing heterocyclic sing and in cases where the substituent R ^ and / or R ₂ ^ is unsaturated, the double bond or triple bond is not in the 1-position, and the pharmaceutically acceptable salts of these compounds. 3 · Compounds of the formula R _{2 R} H ^R 3 where R ^ is a hydrogen atom, Rp is a hydrogen atom, R ₇ . a hydrogen atom or an alkenyl radical with 3 to 5 carbon atoms and R ^, a hydrogen atom, and the pharmaceutically acceptable salts of these compounds, 4, compounds of formula wherein R ^ is a hydrogen atom or an alkyl radical with 1 to 2 carbon atoms, Rg is a hydrogen atom, an alkyl radical with 1 to 4 carbon atoms, - an alkenyl radical with 3 to 9 carbon atoms, a 3-methyl-2-methylene -3-butenyl group, a cycloalkenyl group with 5 to 8 carbon atoms, an alkenylcycIoalkyl group with 6 to 9 carbon atoms, a cycloalkylalkenyl group with 6 to 9 carbon atoms, an alkynyl group with 3 to 5 carbon atoms or a benzyl group, and R ₁ -, for a hydrogen atom, one 009812/1920
ORIGINAL Alkyl radical with 1 "to 3 carbon atoms, an alkenyl radical with 3 to 5 carbon atoms or a propargyl radical, where Eg" and En can together form a nitrogen-containing heterocyclic ring and in cases in which the substituent Rc; tmcL / or E ₁ , is unsaturated, the double bond or triple bond is not in the 1-position, and the · pharmaceutically acceptable salts of these compounds » . -T Q _s Trieye Io (4,3 ₉ .1,1 ^ *) undec an-4- amin. 6 / Pharmaceutically harmless Salse of Tricycle (4.5 »Ί» Ί ') undecan ~ 4-amine in ITor of hydrochloride, hydrobromide, sulfate, phosphate, acetate, nitrate, succinate, adipate, propionate, tartrate, citrate, cyclohexylsulfamate _s Bicarbonates and Pamoats «, 7 «Tricyclo (4,3i ^/ l _s 1 * Oundecan ^ l-amine hydrochloride. 8p F-Allyl« -4-aminomethyltricyclo (4,3 _s 1,1 ^ » ⁸ 9e N-Allyl-4-aminomethyltricyclo (4.3 _> 1 »^) undecane hydrochloride. 10 x 4-aminomethyltricyclo (4,3,1, '1') undecane. 11. 4-aminomethyltricyclic o (4 _i 3 _t ^/ l >> 1 *) undecane hydrochloride. 12 Pharmaceutical preparations containing a pharmaceutical > Zeutischen carrier and a compound according to claim 1 to 13 »Use of compounds according to claims 1 to 11 for pharmaceutical preparations. -. '■ / ■ 14. methods of combating viral infections in warm-blooded animals, characterized in that one is the warm-blooded animals an antivirally effective amount of a compound according to claim 1 to 11-administered. ₍ 15 Compound of the formula OH 0981271920