NO744537L - - Google Patents

Description

The present invention relates to a method for the production of new substituted carbazine alkyl esters which are used as antiviral compounds against various rhinoviruses.

In particular, the invention relates to the method for producing compounds with the formula:

where is hydrogen or lower alkyl (C^—), R~ is lower alkyl (C-^-Cg) and X is 2-naphthyl, 3-phenanthryl, 5-indanyl, 5,6,7,8-tetrahydro-2 -haftyl, 2-benzofuranyl, 5-chloro-2-benzofuranyl, 3,4-dimethoxybenzyl, 3-ethoxy-2-hydroxybenzyl or 3-biphenyl.

The method according to the invention can be illustrated graphically as follows:

where R 1 , R 2 and X are as previously defined. Among the special compounds that can be produced by the above method are, for example: 3-[1-(2-naphthyl)ethylidene]-carbazinic acid ethyl ester 3-[1-(2-naphthyl)ethylidene]-carbazinic acid methyl ester, 3- (2-Naphthylmethylene)-carbazinic acid ethyl ester, 3-[1-(2-Naphthyl)ethylidene]-carbazinic acid tert-butyl ester -(2-Naphthyl)propylidene]-carbazinic acid butyl ester, 3-[1-(3-phenanthryl)ethylidene]-carbazinic acid-ethyl-1-

ester , 3-[1-(3-phenanthryl)ethylidene]-carbazinic acid methyl ester, 3-[1-(3-phenanthryl)ethylidene]-carbazinic acid propyl ester, 3-[1-(3-phenanthryl)ethylidene]-carbazinic acid -t-Butyl Ester, 3-[1-(3-Phenanthryl)ethylidene]-Carbazic Acid Hexyl Ester, 3-[1-(5-Indanyl)-Ethylidene]-Carbazic Acid Ethyl Ester, 3-[1-(5,5, 7,8-Tetrahydro-2-Naphthyl)ethylidene]-Carbazic Acid Ethyl Ester, 3-[1-(5-Indanyl)-Ethylidene]-Carbazic Acid Propyl Ester, 3-[1-(5,6,7,8-Tetrahydro -2-Naphthyl)ethylidene]-carbazinic acid methyl ester and 3-[1-(5-indanyl)-ethylidene]-carbazinic acid hexyl ester, 3-[1-(2-benzofuranyl)-ethylidene]-carbazinic acid ethyl ester, 3- [1-(5-Chloro-2-benzofuranyl)-ethylidene]-carbazinic acid ethyl ester, 3-[1-(5-chloro-2-benzofuranyl)-ethylidene]-carbazinic acid propyl ester, 3-[1-(2- benzofuranyl)-ethylidene]-carbamic acid t-butyl ester, 3-(3-ethoxysalicylidene)-carbamic acid ethyl ester, 3-(a-ethylveratrylidene)-carbamic acid ethyl ester and 3-[1-(3-biphenyl)ethylidene]- carbamic acid ethyl ester.

The compounds produced according to the invention exhibit antiviral activity against various rhinoviruses. The following method is used to determine the antirhinovirus activity of the compounds, Confluent monolayer of a continuous cell array. such as "HeLa", "Hep-2", "KB" or "L-132" grown in plastic tissue culture dishes, were infected with one of the viruses that cause respiratory infections such as the common cold. These viruses include members of the picornavirus group including rhinoviruses, for example types IB, 2, 5, 14 or 23 and including enteroviruses such as Coxsackie A-15 or A-21. Protection of the tissues against the cytopathic effect of the viruses was determined by means of a plate inhibition test where the test compound was adsorbed on a piece of filter paper and placed on the agar used as an overlying layer on the infected cell monolayer, or by mixing in the aforementioned agar overlay. The agar overlay medium used for this purpose had the following composition:

"Minimum Essential Medium" (Eagles) containing "Earle's Salts" (Grand Island Biological Company, Grand Island, New York), to which was added:

The virus-infected cell monolayer plus test compound was incubated for 3 to 5 days in a humidified atmosphere with 5% carbon dioxide at either 33 or 37°C, depending on the virus. The ability of these compounds to protect tissue from destruction caused by viruses was demonstrated after staining the remaining, uninfected cells with 0.5% crystal violet in 20% ethanol.

A summary of the results obtained in the tested areas is shown in the following table.

The following examples describe in detail the preparation according to the invention of representative active compounds.

Example 1

Preparation of 3-[1-(2-naphthyl)ethylidene]-carbamic acid ethyl ester

A mixture of 5.0 g of 2-acetonenaphtho, 3.12 g of ethyl carbazate and 2 drops of concentrated hydrochloric acid in 100 ml of 95% ethanol is heated at reflux for 1.5 hours and then cooled to room temperature. The precipitate formed is collected by filtration, dissolved in methylene chloride and passed through a column of acidic magnesium silicate. The effluent from the reflux is treated with hexane until crystallization. The product is collected and dried to give 2.16 g, melting point 133.5-134.5°C.

Analysis: Calculated for C]_5Hi5<N>2°2<:><C>' 70'29'H'6'29»N>10.93

Found: C, 70.14, H, 6.25, N, 10.91.

Example 2

Preparation of 3-[1-(2-naphthyl)ethylidene]-carbamic acid ethyl ester

A mixture of 8.5 g of 2-acetonenaphtho and 4.5 g of methylcarbazate in 25 ml of absolute ethanol containing 2 drops of concentrated hydrochloric acid is heated under reflux for 1.5 hours and then cooled. The precipitate is washed with hexane and then with water, dried, dissolved in methylene chloride and passed through a column of acid magnesium silicate. The reflux effluent is treated with hexane until crystallization. The product is collected and dried, whereby 9.6 g with a melting point of 130.5-131.5°C are obtained.

Analysis: Calculated for ci4H]_4<N>2°2: C'69'40'H'5.83, N, 11.56

Found: C, 69.24, H, 5.80, N, 11.45.

Example 3

Preparation of 3-(2-naphthylmethylene)-carbamic acid ethyl ester

A mixture of 15 g of /3-naphthaldehyde and 10.4 g of ethyl carbazate in 100 ml of absolute ethanol containing 2 drops of concentrated hydrochloric acid is heated on a steam bath for 0.75 hour, cooled and filtered. The precipitate is washed with ethanol and water. The precipitate is dissolved in methylene chloride and passed through one column of acidic magnesium silicate. The effluent from the reflux heating is treated with hexane to achieve crystallization. The product is collected by filtration, washed with hexane and dried. 12.0 g is obtained which melts at 136.5-137.5°C.

Analysis: Calculated for ci4Hi4N2°2: C'69'40'H'5'83, N/11.56

Found: C, 69.26, H, 6.04, N, 11.58.

Example 4

Preparation of 3-[1-(2-naphthyl)ethylidene]-carbamic acid tert-butyl ester

A mixture of 8.5 g of 2-acetonenaphtho and 6.6 g of tert-butyl carbazate in a solution of 94 ml of absolute ethanol and 6 ml of glacial acetic acid is heated on a steam bath for 2 hours and cooled. The precipitate is collected, dissolved in methylene chloride and passed through a column of acidic magnesium silicate. The effluent from reflux heating is treated with hexane to achieve crystallization. The product is collected, washed with hexane and dried. 8.2 g is obtained which melts at 178-180°C.

Analysis: Calculated for ci7<H2>oN2°2<:>C'71.80,H'7'09'N'9.85

Found: C, 72.21, H, 7.38, N, 9.99.

Example 5

Preparation of 3-[1-(3-phenanthryl) ethylidene]- carbamic acid ethyl ester

A mixture of 4.4 g of 3-acetylphenanthrene, 2.1 g of ethyl carbazate and 2 drops of concentrated hydrochloric acid in 100 ml of 95% ethanol is heated on a steam bath for 1 hour, cooled to room temperature and filtered. The precipitate is dissolved in methylene chloride and passed through a column of acidic magnesium silicate. The effluent from the reflux treatment is treated with hexane to achieve crystallization. The product is collected and dried. 4.0 g is obtained which melts at 164-165°C.

Analysis: Calculated for ClgH18N202: S, 74.49, H, 5.92, N, 9.15

Found : C, 74.59, H, 5.91, N, 9.11.

Example 6

Preparation of 3-[1-(3-phenanthryl)ethylidene]-carbamic acid methyl ester

A mixture of 11.0 g of 3-acetylphenanthrene and 9.0 g of methylcarbazate in 50 ml of a solution of 4% glacial acetic acid in absolute ethanol. heated under reflux for 2 hours and cooled in a refrigerator. The precipitate is washed with 95% ethanol and then with water. The precipitate is dissolved in methylene chloride and passed through a column of acidic magnesium silicate. The effluent from the reflux treatment is treated with hexane to provide crystallization. The product is collected and dried. 12.1 g is obtained which melts at 176-178.5°C. Analysis: Calculated for C]_8H16<N>2°2<:><C>' 73.95,H'5.52'N'9.58

Found: C, 74.05, H, 5.57, N, 9.55.

Example 7

Preparation of 3-[1-(5-indanyl)ethylidene]-carbamic acid ethyl ester

A mixture of 5.7 g of 5-acetylidene and 3.18 g of ethyl carbazate in 200 ml of 95% ethanol containing 2 drops of concentrated hydrochloric acid is heated under reflux for 1 hour and evaporated to dryness. Water is added and a crystalline solid is formed. This solid is dissolved in methylene chloride and passed through a column of acidic magnesium silicate. The outlet from the reflux treatment is treated with hexane so that crystallization occurs. The product is collected and dried to give 6.0 g which melts at 109-109.5°C. Analysis: Calculated for ci4Hi8N2°2<:>C# 68.27, H' 7'37' N' 11'37

Found: C, 68.54, H, 7.47, N, 11.59.

Example 8

Preparation of 3-[1-(5,6,7,8-tetrahydro-2-naphthyl)ethylidene]-carbamic acid ethyl ester

A mixture of 8.71 g of 6-acetyltetralin and 5.0 g of ethyl carbazate in 25 ml of absolute ethanol containing 2 drops of concentrated hydrochloric acid is heated under reflux for 2 hours on a steam bath and cooled. The precipitate is dissolved in methylene chloride and passed through a column of acidic magnesium silicate. The effluent from the reflux treatment is treated with hexane so that crystallization occurs. The product is collected and dried and gives

.7.65 g which melts at 118.5-120°C.

Analysis: Calculated for ci5<H2>o<N>2°2: C'69'20'H'7'74 >N'IO,76

Found: C, 69.40, H, 7.89, N, 10.93.

Example 9

Preparation of 3-[1-(2-benzofuranyl)ethylidene]-carbamic acid ethyl ester

A mixture of 4.0 g of 2-acetylbenzofuran and 4.0 g of ethyl carbazate in 200 ml of a mixture of 4% glacial acetic acid in absolute ethanol is heated on a steam bath for 2 hours, cooled to room temperature and filtered. The precipitate is dissolved in methylene chloride and passed through a column of acidic magnesium silicate. The outlet from the reflux heating is treated with hexane so that crystallization occurs. The product is collected and dried to give 3.6 g which melts at 173-174°C.

Analysis: Calculated for C]_3Hi4N2°3 : c>63'40, H, 5.73, N, 11.38

Found: C, 63.21, H, 5.83, N, 11.41.

Example 10

Preparation of 3-[1-(5-chloro-2-benzofuranyl)ethylidene]-carbamic acid ethyl ester

A mixture of 1.94 g of 5-chloro-2-acetylbenzofuran, 1.04 g of ethyl carbazate and 1 drop of concentrated HCl in 25 ml of 95% ethanol is heated on a steam bath for 1 hour, cooled and filtered. The precipitate is dissolved in methylene chloride and passed through a column of acidic magnesium silicate. The outlet from the reflux heating is treated with hexane so that crystallization occurs. The product is collected, dried and yields 2.5 g which melts at 202-203°C. Analysis: Calculated for ci3H]_3ClN203: C' 55'61'H'4'66'N'9'98»

Cl, 12.63

Found : C, 56.06, H, 4.73, N, 10.10,

Cl, 12., 39.

Example 11

Preparation of 3-(o-ethylveratryl)-carbamic acid ethyl ester

A mixture of 5.0 g of 3,4-dimethoxypropiophenone, 2.71 g of ethyl carbazate and 2 drops of concentrated hydrochloric acid in 100 ml of 95% ethanol is heated under reflux on a steam bath for 1 hour. The mixture is cooled overnight and evaporated to dryness to give an oil. The oil is triturated with hot hexane so that a crystalline product is obtained. This product is dissolved in methylene chloride and passed through a column with aqueous, acidic magnesium silicate. Hexane is added to the outlet from the reflux treatment until crystallization occurs. The product is collected by filtration and dried.

Analysis: Calculated for c14H2oN2°4: C'59'48'H' 7'19' N' 9'99

Found C, 59.70, H, 7.52, N, 10.00.

Example 12

Preparation of 3-(3- ethoxysalicylidene)- carbamic acid ethyl ester

A mixture of 4.98 g of 3-ethoxysalicylaldehyde, 3.12 g of ethyl carbazate and 2 drops of concentrated hydrochloric acid in 150 ml of 95% ethanol is heated on a steam bath for 1 hour and evaporated to dryness. The product is recrystallized from acetone-hexane twice whereby 5.75 g is obtained which melts at 143-1<!>4'4°C.

Analysis: Calculated for ^c12Hi6N2°4: C'57'13'H, 6.39, N, 11.11

Found: C, 57.25<,>H, 6.34, N, 10.97.

Example 13

Preparation of 3-[1-(3-biphenylyl)ethylidene]-carbamic acid ethyl ester

A mixture of 2.5 g of 3-acetylbiphenyl and 2.5 g of ethyl carbazate in 10 ml of absolute ethanol containing 2 drops of concentrated hydrochloric acid is heated on a steam bath for 3 hours. Water is added and a gum is formed. This gum is dissolved in methylene chloride and passed through a column of acidic magnesium silicate. The effluent from the reflux heating is treated with hexane to

crystallization occurs. The methylene chloride acid magnesium silicate-hexane treatment is repeated. The product is collected by filtration, recrystallized from acetone-hexane and dried. 1.30 g is obtained which melts at 107-107.5°C.

Claims (6)

1. Procedure for preparing a compound of the formula: where is hydrogen or lower alkyl (C^ -Cg ), is lower alkyl (C^ -Cg ) and X is 2-naphthyl, 3-phenanthryl, 5-indanyl, 5,6,7,8-tetrahydro-2-naphthyl , 2-benzofuranyl, 5-chloro-2-benzofuranyl, 3,4-dimethoxybenzyl, 3-ethoxy-2-hydroxybenzyl or 3-biphenyl, characterized in that a compound of the formula: where R^ and X are as defined above, is reacted with a carbazine acid ester of the formula: where R2 is as defined above, in an organic solvent at reflux temperature and that the product is isolated therefrom. 2. Process for the preparation of a /3-riaphthyl- alkylidene-carbazinic acid ester with the formula: where is hydrogen or lower alkyl (C^ -C^ ) and R 2 is lower alkyl (C^ -C^ )/characterized in that a compound with the formula: where R^ is as defined above, is reacted with a compound of the formula: where R2 is as indicated above. 3. Procedure for the preparation of a compound of the formula: .. where R1 is lower.alkyl (C^-Cg), characterized in that a compound with the formula: is reacted with a compound with the formula: NH2 NHCOOR1 where R^ is as indicated above, in the presence of HCl as a catalyst in an organic solvent, that said mixture is heated at reflux temperature from 1 to 2 hours and that said product is isolated therefrom. 4. Procedure for the preparation of a compound of the formula: where R 2 is lower alkyl (C 2 -C 8 ) and X is 1 or 2, characterized in that a compound with the formula: where X is as indicated above, is reacted with a compound of the formula: where R2 is as stated above, in the presence of HCl and ethanol and that said reaction mixture is heated at reflux temperature for 1 to 2 hours and that said product is isolated therefrom. 5. Procedure for the preparation of a compound of the formula: where R is hydrogen or chlorine and R2 is alkyl (C^-C^) / characterized in that a compound with the formula: where R is as indicated above, is reacted with a compound of the formula: where R2 is as stated above, in the presence of ethanol and hydrochloric acid at reflux temperature for 1 to 2 hours and that said product isolated from there. 6. Procedure for the preparation of a compound of the formula: where" R4 is hydrogen or methoxy, R^ is methoxy, ethoxy, or phenyl, R^ is hydrogen or hydroxy and R^ is hydrogen, methyl or ethyl, characterized in that a compound with the formula: where R^ , R1-, Rg and R^ are as indicated above, is converted to a