DE2101716A1 - Pharmaceutically active, substituted pyrrolidines - Google Patents

Description

Cologne, 8.1.1971 AvK / Ax

EGG. du Pont de Nemours and Company, Wilmington, Delaware 19898 (U.S.A.).

Pharmaceutically active, substituted pyrrolidines

The invention relates to pharmaceutically active compounds of the formula

(O

^Λ 1

wherein

R ₁ for hydrogen, methyl, ethyl, propyl, alkenyl with 3 to 5 carbon atoms, 3-methyl-2-methylen-3-butenyl, 3-methylenecyclobutylmethyl, 3-methylenecyclobutyl, cyclopropylmethyl, propargyl, phenyl, benzyl, halobenzyl or Methylbenzyl,

R ₂ for a hydrocarbon radical with up to 20 carbon atoms and

109831/2223

BATH ORIGINAL

R- for a water atom or a hydrocarbon residue with up to 22 carbon atoms,

where Rp and R _{5 are} linked to form a polymethylene ring, with the limitation that R ₂ and R together must contain at least 6 carbon atoms, but must not contain more than 22 carbon atoms.

The invention further relates to the control of viral infections in warm-blooded animals, the warm-blooded animals having an antivirally effective amount of a compound according to; the invention is administered before and / or during the time in which the warm-blooded animals are subject "of infection, and have been infected after k.

The invention also includes pharmaceutical preparations, the an antivirally effective amount of a compound according to the invention in combination with suitable pharmaceutical Carriers and modifying agents included.

As already mentioned, the invention is directed to the group of compounds of the formula (1), their pharmaceutical Efficacy as an anti-inflammatory agent has been established is.

The term "halobenzyl" used in the definition of the compounds means a benzyl radical which is substituted by ψ -one, two or three chlorine atoms, fluorine atoms or bromatoins or by several different halogen atoms.

The following hydrocarbon radicals are suitable as "hydrocarbon radicals with up to 22 carbon atoms": polymethylene radicals with 6 to 21 carbon atoms, alkyl radicals with 1 to 22 carbon atoms, alkenyl radicals with 3 to 22 carbon atoms, cycloalkyl radicals with 3 to 22 C atoms, alkylcycloalkyl radicals with 6 to 22 carbon atoms, cycloalkenyl radicals with 4 to 22 carbon atoms, cycloalkylalkyl radicals with 4 to 22 carbon atoms, cycloalkenylalkyl radicals with 5 to 22 carbon atoms, cycloalkyl

"'109831/2223

BATH ORIGINAL

-3- 2101718

alkenylreütfc r. with 5 to 22 carbon atoms, polycycloalkyl radicals with 8 to 22 carbon atoms, polycycloalkenyl radicals with 8 to 22 0-Aton.en, Polyeycloalkylalkylrestfc with 6 to 22 C-Atcmen, Polycycloalkenylalkylreote with 6 to 22 carbon atoms and Polycycloalkylalkenyl radicals with 6 to 22 carbon atoms.

In the context of the invention, compounds in which R- is an allyl radical or benzyl _{red, R 9} for decyl, decenyl and trie; clo / 4.3 · 1 · 1 .J ^ undecylirethyl and R-, stands for hydrogen and R _? and R ^ are linked to form a ring containing eleven saturated carbon atoms, preferred for their excellent anti-viral activity.

The following compounds according to the invention are particularly preferred because of their excellent antiviral activity:
1-allyl-3-n-decylpyrrolidine
i-Benzyl-3-n-decy! pyrrolidine
1-Allyl-3- (2-n-decen-1-yl) pyrrolidine 1'-Allyl spiro (cyclodoecane-1,3'-pyrrolidine) 1'-BenzylspiroCcyelododecane-1,3'-pyrrolidine) 1-Allyl-3 - (1-tricyclo / 4.3.1.1 ^3t f7undecylethyl) pyrrolidine

i-Aiiyi-3- (i-tricycio / 4,3.1.1 ³ 'f7 ^{undecvlmethvl} ) ^pyrrolidine 1-Benzyl-3- (i-tricyclo ^ j / JB. 1.1 * __ 7undecylethyl) pyrrolidine

Soi.1 '^ jundecylmethyl) pyrrolidine

Y / less preferred than the above-mentioned compounds, but still preferred within the general framework of the invention are compounds in which R _{1 is} an allyl radical, uenzyir radical or substituted benzyl radical and R ₂ and R ^ together a total of 9 to 16 carbon atoms or, if they are linked by a CC bond, contain a total of 7 to 13 methylene radicals. When R ^ is hydrogen, alkylcycloalkyl and polycycloalkyl are preferred as substituents at the Rp position.

103831/2223 ⁸ AD original

The pharmaceutically acceptable, non-toxic salts of the above compounds are of course also used preferred.

As "pharmaceutically acceptable non-toxic salts" can the salts of the compounds according to the invention in question, which are suitable for administration to Y / poor blood. Representative of these salts are the hydrochlorides, hydrobromides, sulfates, phosphates, acetates, nitrates, Succinates, adipates, propionates, tartrates, cyclohexylsulfamates, citrates, bicarbonates and pamoates. Of this the hydrochlorides are preferred

Ψ The compounds according to the invention can be prepared extremely easily by treating a substituted succinic anhydride with a suitable primary amine and heating the mixture to 100 to 260 ^° C. for 5 minutes to 24 hours, optionally in the presence of an inert solvent. The completeness of the imide formation can be monitored by taking small parts of the reaction mixture and recording the infrared spectrum.

- 1 - 1

is taken. Maxima between 1500 cm and 1650 cm disappear, while the maximum at 1700 cm "* becomes stronger. The residue is obtained by reaction with a complex metal hydride, for example lithium aluminum hydride or sodium bis (2-methoxyethoxy) aluminum hydride, in an inert solvent such as benzene, Diethyl ether, tetrahydrofuran or in dimethyl ether of diethylene glycol for 10 minutes to 48 hours at 30 to 15O ⁰ C reduced to the pyrrolidine.

In the production of compounds in which R ₁ is a hydrogen atom, the imide may be prepared 'by the succinic anhydride with urea is heated for 5 minutes to 5 hours to a temperature between 150 and 26O ⁰ C''

The compounds according to the invention can also be used according to The following process can be produced aj

109831/2223

BATH ORIGINAL

2101718.

Amides can be reduced with one of the complex metal hydrides mentioned above. Amides are used in coining of the formulas

R ₃

Il

-C-R

NO,

and

Rs-

NO,

the amide being of the former type when a carbonyl group is attached to the 1-position of the pyrrolidine ring. The end product generally corresponds to the above definition, except that it cannot contain any water atom, no alkenyl radicals with the double bond in the 2-position, no phenyl radical, methylene radical, cyclobutyl radical or propargyl radical as substituents in the 1-position. The amides having an oxygen atom at the 2- or 5-position on the pyrrolidine ring can be reduced to form all compounds according to the invention without any limitations or exceptions to the list of substituents. The above-mentioned imides and amides can also be reduced electrolytically. The conditions for the electrolytic reduction of compounds of this type are well known. Reference is made to the publication by PD Popp and HP Schultz in Chem. Review,, 62, 19 (1962) and the Japanese publication by! .Yamazaki and M.Nagata in Yakugaku Zasshi 23. * 1222-4 (1959). The Japanese publication is in CA. £ 4, 4596 (1960). The following conditions are typical for the electrolytic reduction of amides: A cell is provided with lead electrodes and a porous diaphragm between the anode and cathode. A

109831/2223

-6- 2101718

A typical catholyte consists, for example, of a solution of 5 g of the amide in 150 ml of acetic acid and 50 ml of sulfuric acid. 20% sulfuric acid is used as the anolyte. In general, current densities of 0.7 to 0.8 A / cm are used. The reduction is carried out at temperatures below 2O ⁰ C. After the reaction, the catholyte is removed and neutralized, and the product is extracted and purified using customary methods. The compounds according to the invention can also be prepared by alkylating pyrrolidines which contain a hydrogen atom in the 1-position and are substituted in the 3-position. These pyrrolidines react with organic halides of the general formula RX, wherein X is a halo- W genatom, preferably chlorine or bromine. The organic portion of the halide compound becomes a substituent on the pyrrolidine at the 1-position. The products of this reaction generally encompass the entire range of the compounds claimed here with the exception of those compounds which contain a hydrogen atom or a 2-methylene-3-methyl-3- "butenyl radical in the 1-position. The alkylation reaction proceeds in the opposite way an inert solvent and an acid acceptor, for example calcium carbonate or tertiary amines, Temperatures of 30 to 100 ^° C. are preferred. In general, the reaction times are 3 to 24 hours.

^ The full range of compounds according to the invention can also be made from 1-4-dihalobutanes, which are at the 2-position are substituted by the radicals desired at the 3-position of the pyrrolidino. The dihalobutane is reacted with a primary amine which has the substituent on the 1-position of the pyrrolidine ring of the product contains the desired organic residue. After this reaction, all compounds according to the invention can getting produced. The reaction takes place in the presence of an inert solvent and an acid acceptor

109831/2223

tors, such as a tertiary amine or Calciuracarbonat, at a temperature of 10 to 100 ⁰ C. Preferably, temperatures of 10 to 50 ⁰ G ₀

Compounds according to the invention with saturated substituents at the 3-position of the pyrrolidine ring and with a phenyl radical, benzyl radical or substituted benzyl radical at the 1-position are prepared by reducing the double bonds of unsaturated substituents at the 3-position of a pyrrolidine ring which has a phenyl radical , Benzyl radical or substituted benzyl radical at the 1-position. This reduction is a catalytic hydrogenation which takes place at 10 to 20O ⁰ C and under a hydrogen pressure of 1 to 30 atmospheres. Palladium carbon, Raney nickel, platinum and the like are suitable as catalysts.

Compounds according to the invention which contain a 2-methylene-3-methyl-3-butenyl group as a substituent at the 1-position on the pyrrolidine ring can be obtained by reacting the desired pyrrolidine, which contains a hydrogen atom at the 1-position, with allene in Presence of a palladium catalyst and an inert solvent at 70 to 150 ° C can be prepared. A temperature of 120 ^° C. is preferably used. As a solvent is. Benzene preferred.

Salts of the compounds according to the invention are by concentrating solutions of the compounds in the presence of Acids that form pharmaceutically acceptable salts.

The succinic acids can be obtained from aldehydes or ketones by reaction with ethyl cyanoacetate, followed by treatment with potassium cyanide. and. subsequent acid hydrolysis of the adduct formed can be produced. The anhydride becomes from the acid by reaction with another anhydride such as acetic anhydride or by reaction with

109831/2223

an acid chloride such as acetyl chloride.

Another convenient route to succinic anhydrides is via the "en" reaction. In this reaction an olefin with a Y / aseerstoffatom in the 3-position to the double bond with maleic anhydride and an inert solvent such as benzene at 150 to 25O ⁰ O heated. The product of this reaction is an alkene succinic anhydride, the double bond of which has been shifted to a 2-position. The alkene succinic anhydride is formed by optional catalytic hydrogenation. Of course, this method is not suitable for the synthesis of spiroalkyl pyrrolidines.

example 1

0.1 Lioi n-Decylbernsteinsäureanhydrid is heated for 1 hour in a bath under nitrogen to 19O ⁰ C with 0.2 mol of allylamine. The product is distilled at 0.1 mm Hg to give N-allyl-n-decylsuccinimide. A mixture of 0.05 kol of N-allyl-n-decylsuccinimide and 0.2 kol of lithium aluminum hydride in 200 ml of anhydrous tetrahydrofuran is refluxed for 16 hours. The excess hydride is decomposed by careful addition of a saturated aqueous sodium sulphate solution. The pesticide is filtered off and the piltrate is concentrated under reduced pressure. The residue is taken up in diethyl ether. "The ether solution is dried over anhydrous potassium hydroxide and decanted. Hydrogen chloride is passed into the solution until the ether is strongly acidic. Water is added to dissolve the oil formed in the process. The ethereal layer is separated and discarded. The water is made strongly basic with 50% sodium hydroxide solution. The oil which separates out is extracted into ether. The ether is dried over anhydrous potassium hydroxide, decanted and concentrated. The residue is distilled at 0.1 mm Hg, 1-allyl-3-n-decylpyrrolidine being obtained.

109831/2223

Examples 2 to

The experiment described in Example 1 is repeated, where the following anhydrides instead of the according to Example 1 used n-decylsuccinic anhydride used and the amines mentioned are obtained.

example

Anhydride amine

2 n-dodecyl succinic anhydride

3 n-hexadecyl succinic anhydride

4 n-Oct-2-enylsuccinic anhydride

5 n-dec-2-enylsuccinic acid anhydride

6 n-Hexadec-2-enylsuccinic anhydride 1-allyl-3-n-dodecylpyrrolidine

i-Allyl-3-n-hexadecylpyrrolidine

1-Allyl-3-n - (- 2-octen-1-yl) pyrrolidine

1-Allyl-3-n - (-2-decen-1-yl) pyrrolidine

1-Ally1-3-n - (-2-hexadecen-1-yl) pyrrolidine

Examples 7 to

The experiment described in Example 1 is repeated, but using the amines mentioned below instead of the allylamines used in Example 1,
whereby the following products are obtained.

example

Amine product

7 3-methylenecyclobutyl-. Diethylamine

8 3-methylenecyclobutylamine

9 4-chlorobenzylamine

4-methylbenzylamine

aniline

1- (3-methylenecyclobutylmethyl) -3-n-deeylpyrrolidine

1- (3-methylenecyclobutyl) 3-n-decylpyrrolidine

1- (4-chlorobenzyl) -3-ndecylpyrrolidine

1- (4-methylbenzyl) -3-ndecylpyrrolidine

t-phenyl-3-n-decylpyrrolidine

109831/2223

Example Ί2 1- (3-Heth.yl-2-methylen-3-buten.yl) 3 - n- dec.ylp.yrrolidin

0.2 g of triphenylphosphine palladiura-maleic anhydride complex are added to a solution of 0.6 mol of 3-n-decylpyrrolidine in 100 ml of benzene. The solution is poured into a bomb. After adding 0.13 KoI Allen, the bomb is sealed. The bomb is ^{shaken at 120 °} C. for 6 hours. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The oil remaining as residue is distilled at 0.1 mm Hg, the desired compound being obtained.

Example 13 1-Allyl-3-n- (2-docosen-1-yl) pyrrolidine

0.1 mol n-docos-2-enylsuccinic is maintained with 0.2 mol of allylamine 1 hour under nitrogen in a bath at 19O ⁰ C. The reaction product is dissolved in 50 ml of anhydrous tetrahydrofuran and added to 0.3 kol of lithium aluminum hydride in 300 ml of tetrahydrofuran. The mixture is refluxed under nitrogen for 16 hours. The excess hydride is decomposed with saturated aqueous sodium sulfate solution and the pesticide obtained is filtered off. The filtrate is concentrated under reduced pressure. The residue is taken up in ether and dried over anhydrous potassium hydroxide. The ether solution is decanted. Anhydrous hydrogen chloride is passed into the ethereal solution until it is completely precipitated. The solid to give the desired 1-allyl-3-N- (2-docosene-1-yl) pyrrolidine hydrochloride ⁰ C is obtained of melting point 75-77 is filtered off and recrystallized from tetrahydrofuran.

109831/2223

2101718

Example H i-Benz.yl-3-n-decy! Pyrrolidine

0.1 mol n-Decylbernsteinsäureanhydrid is maintained with 0.1 mole of benzylamine 1 hour under nitrogen in a bath at 190 ⁰ C. The residue is distilled at 0.1 mm Hg, N-benzyl-n-decylsuccinic acid imide being obtained. A mixture of 0.05 moles of N-benzyl-n-decylsuccinimide, 0.2 moles of lithium-alumina hydride and 250 ml of anhydrous tetrahydrofuran is refluxed for 16 hours. The excess hydride is decomposed with saturated sodium sulfate solution = the pesticide is filtered off and the filtrate is concentrated under reduced pressure. The residue is taken up in ether. The ether solution is dried over anhydrous potassium hydroxide and decanted. Anhydrous hydrogen chloride is passed into the ether. The pesticide obtained is filtered off and recrystallized from acetone, the desired i-benzyl-3-n-decylpyrrolidine hydrochloride with a melting point of 124-126 ° C. being obtained.

Example 15 3-n-Dec.y! Pyrrolidine

0.1 mol of n-decylsuccinic anhydride is added to 0.5 mol of urea for 1 hour under nitrogen in a bath 190 G held. The residue is added to 150 ml of water. The mixture is extracted into ether. The ether solution is concentrated under reduced pressure and the residue distilled at 0.1 mm Hg to give n-decyl succinimide. A mixture of 0.05 moles of n-decyl succinimide, 0.2 moles of lithium aluminum hydride and 200 ml of tetrahydrofuran hydride is refluxed for 16 hours. The excess hydride is washed with a saturated sodium sulfate solution decomposed. The pesticide is filtered off and the piltrate is concentrated under reduced pressure. The residue is absorbed into ether. The ether is

10983 1/2223

BATH ORIGINAL

dried free potassium hydroxide and decanted. Of the Ether is removed in vacuo and the residue is "distilled at 0 | 1 mm Hg, 3n-decylpyrrolidine being the desired Product is obtained.

Example 16 i-Cyclopropylmethyl-ß-n-deoylpyrrolidine

A mixture of 0.5 Hol decylsuccinic anhydride, 0.054 moles of aminomethylcyclopropanoahydrochloride and 0.7 mol of triethylamine is heated to 190 ° C. in the course of 20 minutes and then at this temperature for 1 hour kept in a bath under nitrogen. The reaction products are taken up in a mixture of water and ether. The ether layer is separated and dried over anhydrous magnesium sulfate. The solvent will removed under vacuum and the residue distilled at 0.1 mm Hg ·, taking N-cyclopropylmethyl-n-decylsuccinimide is obtained. The imide is reduced to the procedure described in Example 1, i-Cyclopropylmethyl-3-n-decy! Pyrrolidine is obtained.

Example 17 i-propargyl-3-n-dec.ylpyrrolidine

A mixture of 0.05 moles of 3-n-decylpyrrolidine, 0.06 moles Propargyl bromide, 0.2 mol calcium carbonate and 100 ml ethanol is refluxed on the steam bath for 24 hours. The mixture is added to 500 ml of water. The water is extracted twice with 100 ml of ether each time. The ether becomes dried over anhydrous potassium hydroxide and evaporated to dryness. The residue is at 0.1 mm Hg distilled to obtain i-propargyl-3-n-decylpyrrolidine will.

109831/2223

Example 18 1-allyl-3t3-dipentylpyrrolidine

A mixture of 0.28 mol of 6-undecanone, 0.3 mol of ammonium acetate, 0.28 mol of ethyl cyanoacetate, 0.3 mol of glacial acetic acid and 400 ml of benzene is refluxed for 16 hours. Here the separating water with a Dean-Stark trap severed. The reaction mixture is cooled and washed three times with 200 ml of water each time. The benzene solution is dried over anhydrous magnesium sulfate. The pesticide is filtered off and the benzene is removed under vacuum. The residue is distilled at 0.1 mm Hg, whereby ethyl-ö-undecylidincyanacetat is obtained. A mixture of 0.2 mol of ethyl-6-undecylidine cyanoacetate, 0.4 mol of potassium cyanide as a solution in 100 ml of water / water and 375 ml of ethanol is sealed in a stopper Flask left for 4 days. The solvent is removed under vacuum. The residue is dissolved in 200 ml of glacial acetic acid dissolved and added to 800 ml of concentrated hydrochloric acid which is heated under reflux. The mixture will 16 hours, heated under reflux. The reaction mixture is concentrated in vacuo and the residue with 100 ml of Vfesoer and rub 200 ml of ether. The ether solution is separated off and dried over anhydrous magnesium sulfate. The ether is distilled off and the residue is added to 100 ml of acetyl chloride. The solution is refluxed for 1 hour "and then concentrated in vacuo. The residue is distilled at 0.1 mm Hg, taking 3,3-dipentylsuccinic anhydride is obtained. The 3,3-dipentylsuccinic anhydride is reacted with allylamine and the amide obtained is reduced in the manner described in Example 1, 1-allyl-3,3-dipentylpyrrolidine being obtained will.

109831/2223

-H-

Example 19
1'-allyl spiro / cyclooctane-1,3'-pyrrolidine /

A mixture of 0.28 mol of cyclooctanone, 0.3 mol of ammonium acetate, 0.28 Hol ethyl cyanoacetate, 0.3 mol bisacetic acid and 400 ml benzene is refluxed for 16 hours, wcbei the water which separates out is drawn off with a Dean-Stark trap. The reaction mixture is cooled and washed three times with 200 ml of water each time. The benzene solution is dried over anhydrous magnesium sulfate, the The solid is filtered off and the benzene is removed in vacuo. The residue is distilled at 0.1 mm Hg, whereby -Athylcyclooctylidincyanacetat is obtained.

A mixture of 0.2 mol of Ethylcyclooctylidincyanacetat, 0.4 mol of potassium cyanide as a solution in 100 ml of water and 375 ml of ethanol is kept in a stoppered "senen flask" for 4 days. The solvent is then removed under vacuum. The residue is dissolved in 200 ml of glacial acetic acid and added to 800 ml of concentrated hydrochloric acid, which is heated under reflux. The mixture is then refluxed for a further 16 hours. The reaction mixture is concentrated in vacuo and the residue with 100 ml of water and 200 ml The ether triturated The ether solution is separated off and dried over anhydrous magnesium sulfate. The ether is distilled off and the residue is added to 100 ml of acetyl chloride. The solution is refluxed for 1 hour and then concentrated in vacuo. The residue is at 0.1 mm Hg distilled to give spiro- ^ turan-2,5- (3H, 4H) (3.1 ^f ) cyclooctan7dione 0.1 mol of this compound is mixed with 0.2 mol of allylamine for one hour in a bath under nitrogen at 190 ⁰ O. The product is distilled at 0.1 mm Hg to give 1-allyl spiro-pyrrolidine-2,5- (3H, 4H) (3.1 ') cyclooctan-7-dione, a mixture of 0.05 mol this compound and 0.2 mol of idthium aluminum hydride in 200 ml of anhydrous tetr ahydrofuran is refluxed for 16 hours. That

109831/2223

Excess hydride is decomposed by carefully adding a saturated aqueous sodium sulfate solution. The solid is filtered off and the filtrate is concentrated in vacuo. The residue is taken up in diethyl ether and the ether solution is dried over anhydrous potassium hydroxide and then decanted. Anhydrous hydrogen chloride is passed into the ether until it is completely precipitated. The solid is filtered off and out! Recrystallized tetrahydrofuran, v / obei 1 '-Allylspiro / cyclooctane-1,3'-pyrrolidine / hydroehlorid ⁰ C is obtained, mp 172-174.,

Examples 20 to 25

The experiment described in Example 19 is repeated however, the ketones mentioned below are used in place of the cyclooctanone used according to Example 19 and the amine hydrochlorides mentioned below can be obtained.

example

A m i η

product

20 4-tert-butyl-cyclohexanone 21 4,4-dimethyley, clohexanone 22 Cyclodecanone 23 Cy clo / de canon 24 cyclopentadecanone

25 3,3,5,5-tetramethyl-cyclohexanone

1 "-Allyl -4-tert-butylspiro ^ yclohexane-1,3-pyrrolidine hydrochloride

1 "-Allyl-4,4-dimethylspiro / cyclohexane-1,3'-pyrrolidine 7 hydrochloride

i-allyl spiro / cyclodecane-1 »3'-pyrrolidine 7 hydrochloride j

1 '-Allylspiro / cVclo ^ iecan- ¹ »3'-pyrrolidine / hydrochloride

1'-Allylspiro / cyclopeirtadecane-1,3'-pyrrolidine / hydrochloride

1 «-Ally 1-3, 3j_5,5-t e tramethylspiro / cyclohexane ~ '-pyrrolidinThydro-

1098 3 1/2

SAD OBIGiNAL

Examples 26-30

The experiment described in Example 19 is repeated, but using the amines mentioned below instead of the allylamines used in Example 19, the products mentioned below being obtained.

Example amine product

26 Dimethallylamine 1 • -Dimethylallylspiro / cyclooc .--

tan-1,3'-pyrrolidine / hyärochlc " rid

27 methallylamine 1'-methallyl spiro / cyclooctane

1 »3'-pyrrolidine T-hydrochloride

28 Cyclopropyl-1'-Cyclopropylmethylspiromethylamine / cyclooctane-1,3'-pyrrolidine / "-

k hydrochloride

29 Benzylamine 1 • -Benzylspiro / cyclooetan-i, 3'-.

pyrrolidine / hydrochloride

30 aniline 1'-phenylspiro / cyclooctane-i, 3-

pyrrolidiny hydrochloride

/ Example 31

1-Ally 1-3 - (-2-c.Yclododecene-1-.vl) pyrrolidine

A mixture of 0.10 mole Cyclonecanon, 0.11 Koi maleic anhydride and 15 ml of benzene is placed into a tube, sealed the 24 hours is maintained at 200 ⁰ C. The reaction product is concentrated to remove the benzene and the residue is distilled at 0.1 mm Hg to remove the cyclododec-2-enylsuccinic acid anhydride desired as product w from the starting materials and polymers. The cyelododec-2-serous acid anhydride can be reacted with allylamine as well as the n-decylsuccinic anhydride in Example 1, whereby 1-allyl-3- (2-cyclododecen-1-yl) pyrrolidine is obtained.

109831/2223

Example 32
4-tricyclo / 4.3.1.1 '_7undecylethyl methyl ketone

A mixture of 0.1 Lioi 4-tricyclo / 4 \ 3.1.1 'f / ¹¹¹ ^ ^{130}' 1} -methyltoluolsulfonat, 0.2 mol Batriumcyanid and 200 isl dimethyl sulfoxide is heated 48 hours, 90 to 95 ⁰ C. The reaction mixture is poured into 1 l of water. The water is extracted three times with 250 ml of pentane each time and backwashed twice with 100 ml of Y / ater each time. The pentane is removed in vacuo and the residue is distilled at 0.1 min Hg, 4-trieyclo / 4.3.1.1 ./undecylacetonitrile being obtained. A solution of 0.3 mol ^ oi ^ nesium-

bromide is added to 0.1 mol of 4-tricyclo ^ 4.3.1 d * f7 ^undec y ^lace ' ^bo nitrile in 500 ml of tetrahydrofuran. The mixture is refluxed for 20 hours and then hydrolyzed with aqueous sulfuric acid. The acid layer is extracted with ether. The ether and tetrahydrofuran components are combined and concentrated in vacuo. The residue is distilled at 0.1 mm Hg to give the desired compound.

Example 33
4-ethylene tricyclo </4,3.1.1 ³ '^ / undecane

0.25 mol of potassium tert-butyl alcoholate is added under nitrogen to a suspension of 0.28 mol of methyltriphenylphosphonium bromide in 500 ml of dry dirnethoxyethane. The suspension is stirred at 40 ° C. for 2 hours. After this time, 0.12 mol TricycloA.3.1.1 ^ ⁱ are _yundecan-4-carboxaldehyde was added to the mixture at 30 C with vigorous stirring. The suspension is stirred for 24 hours at room temperature. After this time, the reaction mixture is added to 3 l of water and extracted three times with 300 ml of pentane each time. The pentane solution is dried with anhydrous magnesium sulfate, filtered and evaporated under reduced pressure, 4-ethylene tricyclo / 4.3.1.1 '^ / undecane being obtained.

109831/2223

Examples β4 to 3S

The experiment described in Example 33 is repeated, except that the ketones mentioned are used instead of tricyclo / 4.3.1.1 ³ⁱ ^ / undecane-4-carboxaldehyde and the products mentioned below are obtained.

At-

game ketone product

34 I-acetyltricyclo- 1-isopropenyltricyclo-

/ 1 .3.1.1 ³ '! / - decan β .3.1.1 ³ ' ¹ Yes ecan

35 4-acetyltricyclo- 4-isopropenyltricyclo-

/4\3.1.1 ³ »^ / - unde- /4.3.1.1 ^3> ^ / undeean can

36 i-acetyl-4-methylbi- i-isopropenyl-4-methylbicyclo / 2.2.27octane - ■ cyclo / i ^ .Syoctane

37 4-tricyclic ^: - 4 (2-methylprop-1-enyl) tri-

/4.3.1.1 ^3> ^ / - undecylcyclo / 4.3.1.1 ^3> ^ 7undecane methyl ethyl ketone

38 8-Ketotricyclo- e-Methylentricyclo / B ^. 1.0 /5.2.1.0 ^2f l / -decane decane

Example 39

A mixture of 0.1 mol of 4-Methylentricyclo / w undecane 4.3.1.1 ^3, 0.11 mol Ilaleinsäureanhydrid and 15 ml of benzene is placed into a tube, sealed the 24 hours is maintained at 200 ⁰ C. The reaction product is concentrated to remove the benzene. The residue is distilled at 0.1 mm Hg, 4-tricyclo / 4.3.1.1 ^{3> 8} ./-undec-4-enylmethylsuccinic anhydride being removed as the desired product.

Examples 40 to 46

The experiment described in Example 39 is repeated, but with the following reactants instead of the 4-ethylene tricyclo / 4 "used according to Example 39 .3.1.1 '"/ -UndecanB used and the mentioned

109831/2223

Succinic anhydrides are obtained < >

play reaction participants succinic anhydride

40 4- ^r Xricyclo / 4.3.1.1 ³ ' ⁸ / - 4-tricyclo / 4.3 .1.1 ³ ' ⁸ / "- undecylethane undecylidinethyl amber-

stinic anhydride

41 1-isopropenyltricyclo- 2- (1-tricyclic-

/3.3.1.1 ^{3> 7} 7decane /3.3.Ί.1 ³ ' ⁷ _ / deeyl) prop ~ 1-

eny! succinic anhydride

42 4- (2-l;: ethylprop-1-enyl-) tri- 3- (4-tricyclo / 4.3.1.1 ³ ' ⁸ ./

cyclo / 4.3.1.1 _ / undecane undecyl) -2-methylprop-2-

eny! succinic anhydride

43 4-Isopropenyltricyclo- 4-Tricyclo / 4.3.1.1 'y ~ ^un "/ I ^ 1 ΐ ^{3) 8} 7ηηΛρ ^ η decylidinisopropyl-

/4.3.1.1 yundeean succinic anhydride

44 Isopropenyl-4-diethylbi- a-methylene-1- (4-methylbicyclo / 2.2.2 / octane cyclo / 2.2.2 / octyl amber

stinic anhydride

45 ß-pinene u-pinenylsuccinic acid

anhydride

46 e-L'ethylentricyclo- e-Tricyclo / B ^. 1 .0 ² ' ^S J-

/ E ο 1 0 ² » ⁶ 7decane dec-8-enylmethylbern-

/^.^.i.ü Vdccan stinic anhydride

Example 47

A Genisch of 250 ml _n ietrahydrofura, 0.05 mol of 4-tricyclo / 4.3.1.1 '"/ undec-4-enylmethy! Succinic anhydride and 5 g of 5 $ igerPalladiunkohle 16 hours at room temperature under a hydrogen atmosphere having a pressure of 3, 2 kg / cm, shaken. The catalyst is filtered off and the piltrate is concentrated under reduced pressure. The residue is distilled at 0.1 mm Hg, 4-tricyclo / 4.3.1.1 ./undecylmethylsuccinic anhydride being obtained.

BAD ORlGINAL, 109831/2 223

2101718

Examples 4S -Ms

The Versracfe level in Example 47 is extracted, but using the below-mentioned bermic acid anhydrides instead of the 3 1 * y used according to Example 47

fcei n acid an-

hydrids used and those below; mentioned. Fradulcte will be preserved «

example

Bernatelpaätir anhydride

4-3TrIeJClOiI ^. TT ³ * ^a J- UEdeeYlidinathylfeernstein-Bäare achy dräd 2- (1 -Tricycle ^. 3. T. T ³ ' ⁷ J- decjl2l% ate i

3-

- 3-aiethylprQp - 2-

y drid

2- (4-tricyelo / 4.3. T undecylidinlpropyli a te insäureanhydrict

α-He thy len-1 - (4-methy lb ± - cy clxi / 2. "2" _2 ^ octylethyl- farest insäureanhydride

a-Fineny! succinic anhydride 8-Tricyclo25.2 .1.0 ² * tZ ~ d ec-Swenyimethylsuccinic anhydride

1 ^{3 f B} J-

a-

2-Ct-Trieyclo-

f_

-2 n-

säuar

.3 11

Iienuaiie mail ure-

Mey. cül® / 2m 2

y t y Ίϊ ~

y ^ 2 · T. O ² '^

dieeylmatJiy Iüeiriiat el n-

55 big TQ:

The verse described in leiapiel 1 & t wir *; repeated, JedoGli geanteir the nacnateaead. BemiatelnaäureaH-liydride used in place of the geiaäS example Ti v "3! We3i £ n-Decylsernsteiiisäureaiihydrida: and: dtüe standheöd called Pya ^ rolidiae earhaltßni wearäem.,

10983T / 2223

BAD ORJGINAL

Example

Succinic anhydride Pyrrolidine

4-Tricyclo / 4 ".3.1.1 ^ * _ / unde Cylidinethsuccinic anhydride

4-TrICyCIo ^. 3 -1.1 ³ 'V-undecylethylsuccinic anhydride

(y ^ / decyl) prop-1-enylsuccinic acid anhydride

2- (l-Trioyclo / 3 «3« 1.1 ^{3> 7} 7-decylpropylsuccinic anhydride

3_ (4-TrICyClO ^ O.! .I ³ ' ⁸ I-undecyl) -2-methylprop-2-enyl-amic acid anhydride

1- (4-TrICyCIo, /?. 3.1.1 ³ » ⁸ I-undecyl) -2-methylpropy1-succinic anhydride.

decylidine-isopropy / succinic anhydride

2- (4-tricyclo / 4.3.1.1 ^{3> 8} y-

undecyl) propylsuccinic anhydride.

<x-methylene-1- (4-methylbi-

cyclo / 2.2.27ethylsuccinic anhydride

α-methyl-1- (4-methylbicyclo / 2.2.27octyl) ethyl succinic anhydride

α-pinene succinic anhydride

Pinayl succinic anhydride

1-Ally1-3- (4-tricy clo / 4.3.!. 1 ³⁸ yy lidinethyl) pyrrolidine.

1-Ally1-3- (4-tricyclo-Z4.3.1.1 ^{3> 8} 7undecylethyl) pyrrolidine

y {

cyclo / 5.3.1.1 ^3> T / -

decyl) prop-l-enyl}

pyrrolidine

1-Ally1-3- {2- (l-tricyclo / 3.3.1.l ^{3> 7} 7-decyl) propyl} pyrrolidine

1-Allyl-3 {3- (4-tricy clo / 4.3.1.1 ^{3 t8} Jun decyl) -2-methylprop-2-enyl} pyrrolidine

1-Ally1-3 {1- (4-tricy clo / 4.3.1.13 ^> 8_ / undecyl) -2-methylpropyl} pyrrolidine

1-allyl-3 (4-tricyclo- ³

.3.1.1

³ '

/ 43fyy dinisopropyl) pyrrolidine

1-Ally1-3 {2- (4-tri-

cyclo / 4.3.1.1 ^{3> 8} 7-undecyl) propyl} pyrrolidine

1-A! Lyl-3 {u-methylene-1- (4-methylbicyclo- / 2 ".2.2 / octyl) methyl} pyrrolidine

1-Allyl-3- {a-methyl-1- (4-methylbicyclo- £ 2.2.2jo cty 1) ethy ψ -pyrrolidine

1-Allyl-3 - («- pinenyl) pyrrolidine

1-allyl-3-pinanyl pyrrolidine

109831/2223

Example

Succinic anhydride Pyrrolidine

! Ericyclo / 5.2o1.0 ² ' ⁶ _ / dec-8-enylmethylsuccinic acid anhydride

8 ~ tricyclo / 5.2.1.0 ² 'l7-decylmethyl amber-

1-Allyl-3- (8-tricyelo ely ^ it ^ l) pyrrolidine

1-allyl-3- (8-tricyclo ⁶

4-TrICyCIo /?. 3.1.1 ^{3> 8} 7-undee-4-enylmethylbern

4-tricyclo / 4.3.1.1 ^{3> 8} 7-

1-Ally1-3- (4-tricyclo /4.3.1.1 yundec-4-enylmethyl) pyrrolidine 1-allyl-3- (4-tricyclo

Example 71

0.1 mol of 4-tricyclo / 4.3.1.1 '_7undecylmethylsuccinic anhydride is dissolved in methylene chloride. 0.1 mol of benzylamine are added dropwise to the solution. The solvent is removed under vacuum and one hour in \ the residue kept under nitrogen at a bath 19O ⁰ C. The residue is taken up in 250 ml of anhydrous tetrahydrofuran, whereupon 0.4 pounds of lithium aluminum hydride are added. The mixture is refluxed for 16 hours. The excess lithium aluminum hydride is decomposed with a saturated sodium sulfate solution. The pesticide is filtered off, the piltrate is concentrated in vacuo and the residue is taken up in ether. The ether is dried over potassium hydroxide granules and then decanted. Anhydrous hydrogen chloride is introduced into the ether until it is completely precipitated. The pesticide is filtered off and the hydrochloride is recrystallized from ethanol-ether, 1-Benzy 1-3- (4-tricyclo / 4.3.1.1 "* ' ⁸ I-undecylmethyl) pyrrolidine hydrochloride being obtained.

If 4-chlorobenzylamine is used in place of benzylamine in the reaction described above, 1- (4-chlorobenzyl) -3- (4-tricyclo / 4.3.1.1 ³ '^ 7undecylmethy ^ - pyrrolidine hydrochloride is obtained

109831/2223

2Ί0Ί716

Tain instead of benzylamine in, the reaction before Example 7ΐ is 1 :-( 4- £ iet]: ayll3enzyl) -3 ~ C4 ~ tri-, 3% 1 · 1 *

obtain"

Examples 72 Ma 7 8

eat example Tt feesicirrieftene. Try repeated t ,, wo / feei Jedöea each of the following

instead of <ies according to Example 7't
3 * ΐ1 '*

used and obtained the namedeti pyrrolidines

game Bern & teinsaiireanhydrlde ^ pyrrolidine

ΊΖ 4> TTloyeiQ / 4 * 3 * 1 * I * vWdeoyläthy. Ibernstt inslittreanhy drid

uitde cyiätoy 1) pyrrtalidinhy d ro cjhlo.r id

deey; l} pro / pylbernateinsäiice- + »ίΛ ,, _η ι _Λ Λ α ι

lidinhydroehlorld

and ecy 1), ^ 3-methyl— feutyl) pyrrolidine hydrochloride

3 * 1U1 ^3r ^ / ~ i-Benzyl-3 {2 (4-tri-

serious in- "" -. _n π , _Λ Λ ₁ 8 _τ _

drid ^^^^ »3.1.1

ypy | py rrolidijany dro enlo ~ rid

ay, 1.-3— ¹ Cw- ^ »a ^ iTootyl ^ atfeyl- t- (4""

Hydride

y
rid

1-Banz ^ l-3-pinany1 lidift

BAD OBtGtNAi

y 2.1.O ² ' ⁶ / -

decylmethy! succinic acid anhydride

^ 5t / y

methyl) pyrrolidine
hydrochloride

example

A mixture of 0.10 Lioi 1 '--Allylspiro (cyclooctane - 1,3' -pyrrolidine) and 0.1 koi 48 $ hydrogen bromide acid v / IRj evaporated under reduced pressure at 6O ⁰ C. The obtained salt, 1'-AllylspircCcyclooctan-1,3'-pyrrolidine) hydrobromide, is dried under reduced pressure at 6O ⁰ C.

Examples 80 to

The experiment described in Example 79 is repeated, but in each case using an equivalent amount of the following mentioned acids is used instead of the hydrobromic acid used according to Example 79 and the ^ the salts mentioned below can be obtained.

example

acid

salt

80 85% phosphoric acid

sulfuric acid

82 tartaric acid 83 perchloric acid 84 maleic acid 85 acetic acid 8-6 citric acid 87 succinic acid

1-Allylspiro (cyclooctane-1-3-pyrrolidine) dihydrogen phosphate

1-Allyl spiro (cyclooctane-1-3-pyrrolidine) hydrogen sulfate

1-Allylspiro (cyclooctane-1-3-pyrrolidine hydrogen tartrate

1-Allyl spiro (cyclooctane-1-3-pyrrolidine) perchlorate

1-Allyl spiro (cyclooctane-1-3-pyrrolidine) maleate

1-Allyl spiro (cyclooctane-1-3-pyrrolidine) acetate

1-Allylspiro (cyclooctane-1-3-pyrrolidine) dihydrogen citrate

1-Allylspiro (cyclooctane-1-3-pyrrolidine) succinate

109831 /? 223

BATH ORIGINAL

88 mandelic acid I-allylspiroicyelooctane-I-B-

pyrrolidine) mandelate

89 Lactic acid 1-Allylspiro (cyclooctane-1-3-

pyrrolidine) lactate

Of course, following the method described above for the preparation of the various pharmaceutical harmless, non-toxic salts also include the desired salts other than those in the method described above • specially used compounds according to the invention -be placed.

The compounds of formula (1) 'can be used in pharmaceutical Preparations according to the invention in dosage forms suitable for oral, parenteral or topical Application are suitable to be used. In these preparations, the active ingredient is usually always in an amount of at least 0.5 wt .- ^ and no more as 90% by weight based on the total weight of the preparation. In addition to the active ingredient included the antiviral agents according to the invention provide a solid or liquid non-toxic carrier for the active ingredient and, where appropriate, suitable pharmaceutical excipients or modifying agents.

As a medicine for. oral administration Tablets, capsules, solutions, emulsions, suspensions and the like.

Suitable pharmaceutical preparations for parenteral administration are, for example, sterile solutions, Suspensions, powders for solutions or suspensions and granules for implantation.

Solutions, suspensions, ointments, jellies and the like come in as pharmaceutical preparations for topical use Question.

109831/2223

- do -

According to one embodiment, a pharmaceutical Preparation according to the invention is in the form of a gelatin capsule for oral administration which is about 1 to 90 of a compound according to the invention, e.g., 1-allyl-3-ndecylpyrrolidine, and about 99 to 10 of a suitable one pharmaceutical carrier contains. According to another embodiment, the active ingredient is with or without Tablets excipients. In these capsules and tablets, the active ingredient generally makes up about 5 to 99 wt .- $, preferably 25 to 90 wt .- ^ of the finished Preparation.

According to a further embodiment, the medicament Preparation according to the invention is in the form of a sterile solution for parenteral administration. It contains 0.05 to 10% by weight, preferably 0.1 to 5% by weight Compound according to the invention, e.g. 1-allyl-3-n ~ decylpyrrolidine hydrochloride dissolved in sterile water. Sterile oils are also suitable as pharmaceutical carriers, e.g., peanut oil, soybean oil, mineral oil, and sesame oil.

In general, water, saline, aqueous dextrose and related sugar solutions and glycols, e.g. Propylene glycol and polyethylene glycol, preferred as liquid carriers for injection solutions when the salts of the active ingredients are to be administered. When a parenteral dosage form of the free base, particularly of Compounds according to the invention which do not readily form pharmaceutically acceptable salts is desired, the aforementioned oils are particularly preferred as pharmaceutical carriers.

The active ingredient can be incorporated into a suitable suspension or syrup for oral administration , wherein it is generally about 0.5 to preferably 2 to 10 wt .- $ of the preparation. Suitable pharmaceutical carriers for such accessories are

109831/2223

preparations aqueous carriers, e.g. aromatic water, syrups or pharmaceutical mucilages "

The active ingredient can be used for topical application in a suitable solution, suspension, liquid emulsion, ointment, Paste or jelly can be incorporated, in which it is generally about 0.5 to 10% by weight of the preparation matters. Suitable pharmaceutical carriers for these topical preparations are v / ater, organic Solvents such as glycerine, emulsions or ointment bases, e.g. petrolatum, hydrophilic ointments and Jelly"

Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E. Ίί, Kart in, a well known textbook in the field.

The invention is illustrated by the following further examples.

Example 90

A large number of unit capsules for oral administration are manufactured by conventional two-part Gelatin capsules with 100 mg powder * 1-benzyl-3-n-decyl-pyrrolidine hydrochloride, 125 mg of lactose, 1 mg of finely divided silica "Cab-o-sil", 5 mg of magnesium stearate and 20 mg of talc can be filled.

Example 91

A large number of tablets are produced by conventional methods so that the dosage unit consists of 150 mg 1-Allylspiro (cyclodecane-1-3-pyrrolidine) hydrochloride, 15 mg gelatin, 5 mg hagensium stearate, 100 mg lactose and • consists of 25 mg of corn starch.

BATH ORIGINAL

1 0 9 ί? "ι / 2 2 2 3

Example 92

A preparation suitable for injection is made, by 0.25 wt .- # 1-33enzyl-3- (1-tricyclo / 4.3 .1. 1 ^ ' undecylmethyl) pyrrolidine mixed with saline solution and the resulting solutions sterilized «

Example 93

A solution suitable for use as a nasal spray is prepared by adding 0.05% by weight of 1-benzyl-3-n-decylpyrrolidine hydrochloride Dissolved in an aqueous solution, the benzalkonium chloride ($ 0.02), monobasic Potassium phosphate, sodium chloride and sodium hydroxide for Contains setting to p ™ 6.5.

A variety of preparations according to the invention can thus easily be prepared by adding other compounds according to the invention including those specifically mentioned above, but not limited to, as \ Active ingredients are used. The connections will be earthen The amounts mentioned are used according to procedures that are well known and described in the above-mentioned manual of E.W. Martin are described.

As already mentioned, the invention encompasses a method of combating virus and llycoplasma infections Warm-blooded animals. The term "combating" virus and micoplasma infections includes prophylaxis, healing and / or amelioration of these infections in warm-blooded animals. Under "warm blooded animals" are members of the animal kingdom understand that have a homeoetic mechanism. Mammals and birds belong here.

_: "The compounds according to you! Invention are suitable for combating one, largely Zafrl Ton virus infections by members of the following groups of viruses: Pookenvü-ua, Picorn * vir ¹ uaV% xoTirus and Arbovirua. They are also useful for fighting infections

1ÖMH / 2223

BAt> OFUQlNAL

The antiviral activity was observed in tissue cultures against the vaccine virus, rhinovirus and influenza virus. The activity against Hycoplasraen was observed in vitro. The observed activity against the vaccine virus shows that the compounds are also effective against other smallpox viruses such as variola, alastrim, and cowpox Orf (contagious bulb-shaped dermatitis). The observed activity against rhinoviruses shows that the compounds according to the invention also against other picorna viruses such as poliomyelitis viruses, coxsackie viruses, Echoviruses and the like can be effective. The observed activity against influenza Α virus shows that the compounds according to the invention can also be effective against other hyxoviruses. The observed effectiveness against "yellow fever virus" indicates that the compounds can also be effective against other group B arboviruses according to the invention.

In view of the observations described above, it is evident that the compounds are similar Invention exhibit a wide spectrum of potent antiviral activity. It is expected that the connections according to the invention, particularly valuable for combating infections of the upper respiratory tract in arm-blooded animals, caused by microorganisms such as influenza, parainfluenza, rhinovirus and micoplasma, as well as other infections are.

The compounds according to the invention can be used in antiviral treatment can be administered according to the invention in any way in which the active ingredient corresponds to the location of the virus infection is supplied in the body of a warm-blooded animal. This of course includes the administration before infection as well as after infection.

BAD OR (GINAl

109831/2223

The Doais administered depends of course on the fight ~ cn Virus, from age, health status and weight deo Recipient, extent of infection, type of one any concurrent treatment, the frequency of treatment and the type of effect desired. When the compounds are administered orally or parenterally, the daily dose of active ingredients is generally about 0.1 to 50 ng / kg. Preferably will ■ the connection in a length of 1 to 10 ng, kg ei ^ r.al administered daily or in several doses per day. Of course, the above areas are only Clues, i.e. the exact dose for a particular | Recipient can be higher or lower than stated above. With local application of the connections they are in the carrier in a range of 0.1 to 25% by weight or more available.

It has been observed that the influenza virus A2 / Japan / 3O5 / 57 grown on chick embryo cells has been, by 1'-Allylspiro / cyclooctan-i, 3'-pyrrolidin ^ hydrochloride is inhibited.

It was observed that cenus embryo cells were grown on Pseudorabies, Aujeszky, by administering the following Connections is inhibited:

* 1'-Allylspiro / cyelooetan-1,3'-pyrrolidine / hydrochloride 1 ^l -Allyl-4,4-dimethylspiro / cyclohexane- ^{1,3 l} -pyrrolidine / hydrochloride

i-Allyl-3-decylpyrrolidine

1-Ally1-3- (2-octen-1-yl) pyrrolidine 1-Allyl-3- (2-decen-1-yl) pyrrolidine

It was found that rhinovirus-2 / HGrP cultured on Heia cells susceptible to beta-virus by the following Connections is inhibited:

BATH ORIGINAL ■■■■ "■ -'- fc-i 0983 1/2223

- 31 -

1 "-Allylspiro / cyclooetan-1,3'-pyrrolidine / hydrochloride 1'-Allyl-A ^ -dimethylspiro / cyclohexane-1,3'-pyrrolidine / hydrochloride

1'-Allyl ^ -tert.-butylspiro / cyclohexane-1,3'-pyrrolidine / hydrochloride

1'-AllyIspiro / cyclodecane-1,3'-pyrrolidine / hydrochloride

1-Ally1-3-decylpyrrolidine

1 »-Hethallylspiro / cyclooctan-i, 3 • -pyrrolidine / hydrochloride 1 »-Allylspiro / cyclodecan-i, 3 • -pyrrolidine / hydrochloride 1-Allyl-3- (2-octen-1-yl) pyrrolidine, 1-allyl-3- (2-decen-1-yl) pyrrolidine 1-Allyl-3 - (2-docosen-1-yl) pyrrolidine hydrochloride i-Allyl ^ - ^ - hexadecen-i-y ^ pyrrolidine

1-Benzy1-3-decylpyrrolidine hydrochloride

It has been observed that chick intravenous cells cultured Yellow fever virus 17D is inhibited by the following compounds:

1 * -Allyl-4f4-diKethylspiro ^ cyclohexane-1,3'-pyrrolidine / hydrochloride

1-allyl-3-decylpyrrolidine

1-Ally1-3- (2-O et en-1-y1) pyrrolidine 1-Allyl-3- (2-decen-1-yl) pyrrolidine

It was observed that Mycoplasma arthriditis (ATGC 13388} and Bycoplasma gallisepticum (A0? CG 15302) grown on EPLO agar were completely inhibited by the following compounds «

1-Ally1-3- (2-decen-1-y1) pyrrolidine 1-Benzy1-3-decylpyrrolidine hydrochloride 1-Allyl-3- (4-tricyclo / 4.3-1.1 ³ * ^ / undecylethy1) pyrrolidine hydrochloride

3-deeyl pyrrolidine

1-Bensyl-3- (4-tricyclo / 4,3,1,1 ³ »? 7undecylethyl) pyrroliaine hydrochloride

1-Allyl-3f1- (4-tricyclo / 4.3.1.1 ^{3 f} ? / Undecyl-2-methylpropyl} pyrrolidine hydrochloride. '

BATH ORIGINAL

10'9831 / 222-3

i-Cyclopropylmethyl ^ -decylpyrrolidine 3- (2-decen-i-yl) pyrrolidine

1-Benzyl-3- (4-tricyclo / 4.3.1.1 '_, 7undecylmethyl) pyrroli ~ dinhydroehlorid

1-Allyl-3- (4-tricyclo / 4.3.1 «1 ^3> ^ ⁷ undecylmethyl) pyrrolidine hydrochloride

l-Benzyl-3- {2- (l-tricyclo / ^. 3.1. P'ydecyl) propel] pyrrolidine hydrochloride.

It has been observed that Lederle vaccine virus grown on chicken embryo cells is caused by the following "Connections is inhibited:

t «-Ally1-4,4-dimethylspiro / cyclohexane ~ 1,3'-pyrrolidine / hydrochloride

1-allyl-3-decylpyrrolidine

1-Allyl-3- (2-octen-1-yl) pyrrolidine t -allyl-3- (2-decen-1-yl) pyrrolidine

It has been observed, the grown on rabbit kidney cells Virus Herpes simplex (I) H4 -that by 1 ^{f-allyl-4-tert-butylspiro} / öyclohexan-1,3'-pyrrolidin / hydrochloride \ is inhibited.

The antiviral effects of the compounds according to the invention have also been demonstrated in test animals at Stundardiects. If, for example, 1 • -Allyl -. 'Tj ^ -dimethylsyiro- / cyclohexane-1,3 ^f -pyrrolidine hydrochloride llüusen is administered orally in a dose of 40 mg / kg before infection (each mouse is given an LDqQ-Doois des Virun Influenza A2 / Bethesda / iO) and the administration is continued by adding 0.5 mg of the compound per chew in the drinking water for 72 hours after infection, the number of surviving animals is significantly higher in the treated mice than in the mice that get infected but don't get the leased line.

The experiment described above was also carried out with the following compounds, which had good effects against influenza viruses show:

BAD ORIGINAL -..-_—

109831/2223

1 • -Methallylspiro / cyclooctane-t'jß · -pyrrolidine / hydrochloride 1'-allyl spiro / cyclodecane-1,3 · pyrrolidine / hydrochloride 1-Allyl-3- (2-hexadecen-1-yl) pyrrolidine

BATH ORIGINAL

1098 31/2223

Claims (1)

Patent claims Q /, compounds of the formula ^R 2 in the R. = hydrogen, methyl, ethyl, propyl, alkenyl with 3 to 5 carbon atoms, 3-methyl-2-methylen-5-butenyl, 3-methylenecyclobutylmethyl, 3-methylenecyclobutyl, Cyclopropylmethyl, propargyl, phenyl, benzyl, halo- ^ benzyl or methylbenzyl, Rp = a hydrocarbon radical with 1 to 22 carbon atoms and R, = hydrogen or a hydrocarbon radical with 1 to 22 carbon atoms, where Rg and R ^, be connected to a poly me thy lenr ing \ can, with the restriction that Rp and R ^, together Contain at least 6 carbon atoms but not more than 22 carbon atoms, and the non-toxic pharmaceutically acceptable ones Salts of these compounds. 2. Compounds according to claim 1 with the formula mentioned in claim 1 in which R ₁ = hydrogen, alkenyl with 3 to 5 carbon atoms, 3-methyl-2-methylen-3-butenyl, 3-methylenecyclobutylmethyl, 3-methylenecyclobutyl, cyclopropylmethyl, propargyl, phenyl, benzyl, halobenzyl or methylbenzyl, R ₂ = alkyl with 1 to 22 carbon atoms, alkenyl with 3 to 22 carbon atoms, cycloalkyl with 3 to 22 carbon atoms, alkylcycloalkyl with 6 to 22 carbon atoms, cycloalkenyl with 4 to 22 carbon atoms, cycloalkylalkyl with ^J r up to 22 carbon atoms, cycloalifenylalkyl with 5 to 22 carbon atoms, cycloalkylalkenyl with 5 to 22 carbon atoms, polycycloalkyl with 8 to 22 carbon atoms, polycycloalkenyl with 8 bin ? 2 C- 109831/2223 BATH ORIGINAL Atoms, polycycloalkylalkyl with 6 to 22 carbon atoms, polycycloalkenylalkyl with 6 to 22 carbon atoms, Polycycloalkylalkenyl with 6 to 22 carbon atoms, R = Y / hydrogen, alkyl with 1 to 22 carbon atoms, alkenyl with 3 to 22 carbon atoms, cycloalkyl with J to 22 carbon atoms, alkylcycloalkyl with 6 to 22 carbon atoms, cycloalkenyl with 4 to 22 carbon atoms Atoms, cycloalkylalkyl with k to 22 carbon atoms, cycloalkenylalkyl with 5 to 22 carbon atoms, cycloalkylalkenyl with 5 to 22 carbon atoms, polycycloalkyl with 8 to 22 carbon atoms, polycycloalkenyl with 8 to 22 carbon atoms, polycycloalkylalkyl with 6 up to 22 carbon atoms, polycycloalkenylalkyl with 6 to 22 carbon atoms, polycycloalkylalkenyl with 6 to 22 carbon atoms or polycycloalkylalkenyl with 6 to 22 carbon atoms with the restriction that R ₂ and R together at least 6 carbon atoms, however contain no more than 22 carbon atoms, where Rg and R ^, can be linked to form a polymethylene ring with 6 to 22 carbon atoms, and the pharmaceutically acceptable, non-toxic salts of these compounds. Compounds according to claim 2 with the formula mentioned in claim 1, in which R _{1 is} an alkenyl radical with 5 to 5 carbon atoms and R ₂ and R-, which have the meanings mentioned in claim 2, and the pharmaceutically acceptable, non-toxic salts of these compounds. Compounds according to claim 2 having the formula mentioned in claim 1, in which R- is a benzyl radical and R ₂ and R-, which have the meanings mentioned in claim 2, and the pharmaceutically acceptable, non-toxic salts of these compounds. BAD Oj = UGINAL 109831/2223 5. Compounds according to claim 2 jnit the formula mentioned in claim 1, in which R _{1 is} an alkyl radical or benzyl radical, R _{2 is} a decyl radical, decenyl radical or tricyclo ^ T.3 · 1 ·! _7-undeeylmethylrest and R- * is a hydrogen atom, and the pharmaceutically acceptable unsuitable salts of these compounds. 6, l-Allyl-3-n-decylpyrrolidine and its pharmaceutically acceptable, non-toxic salts. 7 · 1-Benzyl-3-n-decylpyrrolidine and its pharmaceutical harmless, non-toxic salts. 8.1-Allyl-3-n-deeenylpyrrolidine and its pharmaceutical harmless, non-toxic salts. 9. 1'-Allylspiroicyclododecane-1,3 * -pyrrolidine and its pharmaceutically safe, non-toxic salts. 10. I ¹ -Benzylspiro- (cyclod <> decane-1,3 · -pyrrolidine) and its pharmaceutically acceptable, non-toxic salts. 11. l-Allyl ^ -il-tricyclo / ^ O. 1. l ^ / undecylmethyl) pyrrolidine ^x and its pharmaceutically acceptable, non-toxic salts. 12. l-Allyl-3- (l-tricyclo ^ T.3 x 1 x 1-7undecylethyl) pyrrolidine and its pharmaceutically acceptable non-toxic salts. 13 · 1-Benzyl-3- {1-tricyclo ^ 4.3 · i · 1] _ / undecylmethyl) pyrrolidine and its pharmaceutically acceptable non-toxic salts. 14. l-Benzyl-3- (i-tricyclo ^ r.3-l ·! ^ J7undecylethyl) pyrrolidine and its pharmaceutically acceptable unsuitable salts. 15. Pharmaceutical preparations, consisting of a pharmaceutical effective amount of a compound according to claim 1 to 14 as an active ingredient in combination with inejri non-toxic pharmaceutical carrier for the Wlricefcoff. 16. Use of compounds according to claims i to 14 as active ingredients for the production of vxm
Preparations. BATH ORIGINAL 109831/2123 17. Process for the preparation of compounds of the formula Ra
Rs - in the R. = hydrogen, methyl, ethyl, propyl, alkenyl with 3 to 5 carbon atoms, 3-methyl-2-methylen-3-butenyl, 3-methyleneyclobutylmethyl, 3-methylenecyclobutyl, Cyclopropylmethyl, propargyl, phenyl, benzyl, halobenzyl or methylbenzyl, R ₂ = a hydrocarbon radical with 1 to 22 carbon atoms and R, = hydrogen or a hydrocarbon radical with 1 to 22 carbon atoms, where'R ₂ and R ^ can be joined to form a polymethylene ring with the restriction that R ₅ and R together have at least 6 carbon atoms but not more than 22 Contain carbon atoms, and the pharmaceutically acceptable salts of these compounds, characterized in that imides of the formula . Ra - Rs- NR _n or half-amides of the formulas
Rs NO, Rs or 'S η NO wherein R ^, R ₂
reduced. R- * have the meanings given above, 109831/2223 18. Process for the preparation of pre-compounds of the formula] R ₂
R ₃ - NR ₄ in the Rp = a hydrocarbon radical with 1 to 22 carbon atoms, R may be hydrogen or a hydrocarbon radical having 1 to 22 carbon atoms and R ₂ and R, connected to a Polymethylenrinc with the Einghränkung, da2 Rp and R, together at least 6 carbon atoms but not r.:ehr than 22 Contain carbon atoms, and R ₂ ^ = methyl, ethyl, propyl, alkenyl with 3 to 5 carbon atoms, the double bond not being in the 2-position, 5-methyl-2-methylen-3-butenyl, cyclopropylmethyl, benzyl, halobenzyl or methylbenzyl and the pharmaceutically acceptable non-toxic salts of these compounds, characterized in that there are compounds of the formula Ra. It KCR ₅ W is reduced in the R ₂ and R, have the meanings given above and Rk a Wasserst off atom, methyl, ethyl, alkenyl, cyclopropyl, phenyl, halophenyl, or methylphenyl having 2 to 4 ^ C-atoms, 1,2-Dimethylenpropyl, . 109831/2223 19. Process for the preparation of compounds of the formula in the Rp = a hydrocarbon radical with 1 to 22 carbon atoms, B, = hydrogen or a hydrocarbon radical with 1 to 22 carbon atoms and R ₂ and R-, can be linked to form a polymethylene ring, with the restriction that R ₂ and R , together contain at least 6 carbon atoms but not more than 22 carbon atoms, and Rg - methyl, ethyl, propyl, alkenyl with 3 to 5 carbon atoms, ^ -Methylene cyclobutylmethyl, 3-methylenecyclobutyl, cyclopropylmethyl, propargyl, phenyl, benzyl, halobenzyl or pie thy 1 benzyl, and the pharmaceutically acceptable, non-toxic salts of these compounds, characterized in that Compounds of the formula HH in which R ₂ and R-, have the meanings given above, with BAt) ORIQlNAt 409831/2223 a compound of the formula R ₆ X in the Rg has the meaning given above and X is a chlorine atom, bromine atom or iodine atom is alkylated. 20. Process for the preparation of compounds of the formula MR ₁ in the R ₁ = hydrogen, methyl, ethyl, propyl, alkenyl with 3 to 5 carbon atoms, J-methyl ^ -methylene-J-butenyl, 3-methylenecyclobutylmethyl, 3-methylenecyclobutyl, cyclopropylmethyl, propargyl, phenyl, benzyl, halogen- benzyl or methylbenzyl, R2 = a hydrocarbon radical with 1 to 20 carbon atoms and R, = hydrogen or a hydrocarbon radical with 1 to 22 carbon atoms and R ₂ and R ^ can be linked to form a polymethylene ring with the restriction that R ₂ and R together at least 6 carbon atoms but not more than 22 carbon atoms and the pharmaceutically acceptable, non-toxic salts of these compounds, characterized in that 2,2-disubstituted 1,4-dihalobutanes of the formula R ₂ R, CX CX in which R ₂ and R have the meanings given above and X is a chlorine atom or a bromine atom, with a compound of the formula R ₁ NH ₂ ,
in which R _{1 has} the meaning given above. 109831/2223 21. Process for the preparation of compounds of the formula NO ₇ in which R _{7 is} a phenyl radical, a benzyl radical or substituted benzyl radical, Rg is a saturated hydrocarbon radical with 2 to 22 carbon atoms and R _{0 is} a hydrogen atom or a saturated hydrocarbon radical with 1 to 22 carbon atoms and Rg and Rq form a polymethylene ring may be connected with the restriction that Rg and R ^ together contain at least 6 but not more than 22 carbon atoms, characterized in that compounds of the formula 10 - N - ¹ V in which R- has the meaning given above, R, a hydrogen atom or a hydrocarbon radical with 1 to 22 carbon atoms and R, _{Q is} an unsaturated hydrocarbon radical with 2 to 22 carbon atoms and R * _Q and R- , can be linked to form an unsaturated polymethylene ring, with the restriction that Rq and R together contain at least 6 but not more than 22 carbon atoms, reduced. 22. Process for the preparation of salts of compounds of the formula Ra in the Rj «hydrogen, methyl, ethyl, propyl, alkenyl with 3 to 5 carbon atoms, J-methyl ^ -methylene - ^ - butenyl, 3-methylenecyclobutylmethyl, 3-methylenecyclobutyl, Cyclopropy! Methyl, propargyl, phenyl, benzyl, halogen 109831/2223 benzyl or methylbenzyl, R ₂ = a hydrocarbon radical having 1 to 22 carbon atoms and R ^. = Hydrogen or a hydrocarbon radical with 1 to. 22 carbon atoms and R ₂ and R, can be linked to form a polymethylene ring, with the restriction that Rg and Rz together contain at least 6 carbon atoms but not more than 22 carbon atoms, characterized in that compounds of the above formula are converted into pharmaceutically acceptable ones with acids Converts salts. 23. Process for the preparation of compounds of the formula Ra H ₂ CH ₂
- C - C C = CH ₂ CHa in the R ₂ = a hydrocarbon radical with 1 to 22 carbon atoms and R ^ = hydrogen or a hydrocarbon radical with 1 to 22 carbon atoms and R ₂ and R, can be linked to form a polymethylene ring, with the restriction that Rg and R, together contain at least 6 carbon atoms but not more than 22 carbon atoms, and the pharmaceutically acceptable, non-toxic salts of these compounds, characterized in that one Compounds of the formula R _n > ■ in which R ₂ and R, which have the abovementioned meanings, are catalytically reacted with all of them. 109831/2223