DE2755750A1 - 2-ACYL FURANES AND THIOPHENES, METHOD FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS - Google Patents

Description

uZ: M 443
Case: M-863

RICHARD30N-MERREIL INC.
Wilton, Connecticut, V.St.A,

"2-Acyl-furans and -thiophenes, process for their preparation and medicines "

The invention relates to that characterized in the claims Object.

The group Rp-Y can be in the 3-, 4- or 5-position of the furan or thiophene ring. If Y means a bond, the group R-Y is in the 4- or 5-position.

The rest of Rp may be a straight or branched saturated hydrocarbon radical having 6 to 20 carbon atoms be, in this case, the group RY may be represented by the general For ^mel ^ q ^ 2a + 1 ~ ^{Y as an} d S ^e S ^{el:) s} are, in the Y denotes a bond, an oxygen or sulfur atom and q represents an integer with a value from 6 to 20. ' If the radical R denotes an unbranched or branched unsaturated hydrocarbon radical having 10 to 20 carbon atoms, this radical can contain 1 to 4 double bonds. When the Rp radical contains 6 to 9 carbon atoms, the radical can contain 1 or 2 double bonds. In this case the group RY has the general formula ^c _q ^H 2q-z ~ ^Y ' ^{in which Y represents} a bond, an oxygen or sulfur atom, q a

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is an integer with a value from 6 to 20 and ζ is the number 1, 3, 5 or 7, since the number of double bonds is from 1 to 4 varies when R contains 10 to 20 carbon atoms, and ζ is 1 or 3 when the number of double bonds is 1 or is 2 or when R contains 6 to 9 carbon atoms.

Specific examples of straight or branched saturated hydrocarbon _{radicals R 2} are decyl, undecyl, dodecyl, tridecyl, tetradecyl, 3,7-dimethyloctyl, 2,4-diethylnonyl, 1-methylundecyl, pentadecyl, hexadecyl -, heptadecyl - ^ - methyloctadecyl, nonadecyl, didecyl, nonyl, octyl, heptyl and hexyl groups.
15th

Specific examples of unbranched or branched unsaturated hydrocarbon radicals having 1 to 4 carbon atoms are the 10-undecenyl, 9,12-octadecyldienyl, 3,7,11-trimethyl-2,6,1O-hexadecyltrienyl, 3,7-dimethyl-2,6-octadienyl-, 5,9-dimethyl-2,4,8-decatrienyl-, 4,6-dimethyloct-3-enyl-, 1,2,5 * 9-tetramethyl-2,4,8-decatrienyl-, 11-didecenyl- and 2-hexenyl group.

Specific examples of straight or branched alkyl radicals with 1 to 4 carbon atoms are the methyl, ethyl, n-propyl, isopropyl, η-butyl and tert-butyl groups.

The compounds of the general formula I in which Y is an oxygen or sulfur atom, R. is an unbranched or branched alkyl radical with 1 to 4 carbon atoms and R _{2 is} an unbranched or branched saturated hydrocarbon radical with 10 to 20 carbon atoms or an unbranched or branched unsaturated hydrocarbon radical with 10 to 20 carbon atoms and 1 to 4 double bonds are new and preferred. Particularly preferred are the compounds of general formula I in which Y is an acid

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material atom and R ,, represents an unbranched alkyl radical. The furan derivatives are preferred over the thiophene derivatives. Furthermore, compounds are preferred in which the radical R _{P contains} 12 to 16 carbon atoms, in particular 14 carbon atoms.

The compounds of general formula I can be used to combat rhinovirus infections. To this end they are packaged as solid or liquid medicinal products.

Specific examples of compounds of the general formula I are ethyl 2- (5-tetradecylthio) furyl ketone, ethyl 2- (5-dodecylthio) furyl ketone, n-propyl 2- (4- decylthio) furyl ketone, isopropyl-2 - (3-undecylthio) furyl ketone, n-butyl 2- (4-tridecylthio) furyl ketone, tert-butyl 2- (5-octadecylthio) furyl ketone, methyl 2- (5-tetradecylthio) thienyl ketone, Ethyl 2- (5-dodecylthio) thienyl ketone, n-propyl 2- (4-decylthio) thienyl ketone, isopropyl 2- (5- "fcetradecylthio) -thienyl ketone, n-butyl-2- (3-pentadecylthio) thienyl ketone, tert-butyl 2- (4-heptadecylthio) thienyl ketone, methyl 2- (5-3ctadecylthio) thienyl ketone _t methyl 2- (5-hexylthio) furyl ketone, n-propyl 2- (4th -Octylthio) furyl ketone, butyl 2- (3-nonylthio) thienyl ketone, isopropyl 2- (5-heptylthio) thienyl ketone, ethyl 2- (3-octylthio) thienyl ketone, methyl 2- (5-hexyloxy) furyl ketone, ethyl 2- (3-tridecyloxy) furyl ketone, ethyl 2- (5-dodecyloxy) furyl ketone, methyl 2- (5-tetradecyloxy) furyl ketone, isopropyl 2- (4- octyloxy) furyl ketone , n-butyl-2- (4-undecyloxy) thienyl ketone, tert-butyl 2- (3-didecyloxy) thienyl ketone, ethyl 2- (5-dodecyloxy) thienyl ketone, methyl 2- (5-tetradecyloxy) thienyl ketone, n-propyl 2- (5 pentadecyloxy) thienyl ketone, methyl 2- (5-hexyl) furyl ketone, ethyl 2- (4-octyl) furyl ketone, isopropyl 2- (3-hexadecyl) furyl ketone, n-butyl 2- (3-fcridecyl) thienyl ketone, methyl 2- (5-tetradecyl) thienyl ketone, methyl 2- (5-tetradecyl) frryl ketone, ethyl 2- (5-dodecyl) furyl ketone, tert-butyl -2- (4-heptyl) thienyl ketone, methyl 4- (3,7-dimethyloctyl) -2-furyl-

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ketone, methyl 5- (2,4-diethylnonylthio) -2-thienyl ketone, Methyl 5- (9,12-octadecyldienyl) -2-furyl ketone, ethyl-5- (3.7, 11-trimethyl-2,6, iO-hexadecyltrienyloxy) -2-furyl ketone and Ethyl 5- (4,6-dimethyloct-3-enylthio) -2-furyl ketone.

The ketones of the general formula I can be obtained by reacting one equivalent of the corresponding carboxylic acid derivative made with two equivalents of an alkyllithium compound; see Fieser and Fieser, Reagents for Organic Synthesis,

J. V / iley and Sons, Inc., New York, p. 688 (1967). The reaction is preferably carried out in a solvent, such as diethyl ether, tetrahydrofuran, dioxane, diethylene glycol dimethyl ether or Dirnethoxyäthan, at temperatures from -10 ⁰ C to the reflux temperature of the reaction mixture during and

Ί5 carried out over a period of 30 minutes to 10 hours.

The ketones of the general formula I can also be prepared by reacting an alkyl! Magnesium bromide with the imidazolide of the thiophene or furancarboxylic acid can be produced. This reaction is preferably also in a solvent, for example Diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane or acetonitrile carried out. The reaction mixture is initially cooled to -10 ° C. The temperature is then increased to about 25 ° C. up to the reflux temperature of the solvent. The reaction time is 30 minutes to 10 hours.

The imidazolide is made by reacting the thiophene or furancarboxylic acid with Ν, Ν'-carbonyldiimidazole or by treatment of the thiophene or furancarboxylic acid chloride (produced by reacting the carboxylic acid with thionyl chloride) with two Equivalents of imidazole produced; see H.A. Staab, Angew. Chem. Internat. Edit., Vol. 1 (1962), p. 351.

The ketones of the general formula I in which the group is in the 5-position can also be obtained by Friedel-Crafts acylation of the correspondingly substituted thiophenes or furans with an acid halide of the general formula

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R ^ -CO-halogen are produced. R / j means unbranched or branched alkyl radical with 1 to 4 carbon atoms. The preferred halogen atom is the chlorine or bromine atom. This reaction is carried out in the presence of an acidic catalyst, for example boron trifluoride etherate, tin (IV ^ chloride, Zinc chloride, hydriodic acid or orthophosphoric acid, and optionally in the presence of a solvent, such as methylene chloride, nitromethane or benzene carried out. The reaction temperature can be in the range from -2O ° C to The reflux temperature of the solvent. The reaction time is about 30 minutes to 10 hours.

The R ^ -Y-substituted thiophene derivatives used according to the process of the general formula II, in which Y represents a sulfur atom, according to the method described by E. Profft, Chemiker-Zeitung, Vol. 82 (1958), p. 298 described method. When Y represents an oxygen atom, the compounds from 3-thiolen-2-one (R.P. Hawkins, Journal Heterocyclic Chemistry, Vol. 11 (197Ό, pp 291-294) with a corresponding Alkyl halide, alkyl mesylate or alkyl tosylate in the presence of a base such as sodium hydride, potassium amide, potassium tert-butoxide, metallic sodium or potassium, potassium carbonate, sodium carbonate, triethylamine or pyridine with formation of the 2-alkoxythiophene intermediate.

This reaction can be carried out in the presence of a solvent will. Examples of solvents that can be used are pyridine, benzene, xylene, chlorobenzene, ethers, such as bis (2-methoxyethyl) ether or anisole, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide. Examples of usable Alkyl halides are alkyl chlorides, bromides and iodides. The alkyl radical in the alkyl halide, alkyl mesylate or Alkyl tosylate can contain 6 to 20 carbon atoms. The remainder can be straight or branched and saturated or unsaturated be. When the radical contains 1 to 4 carbon atoms, the alkyl radical can contain 10 to 20 carbon atoms, and if the alkyl radical contains 1 or 2 double bonds, the alkyl radical can contain 6 to 9 carbon atoms.

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The R ₂ -Y-substituted furan and thiophene derivatives used according to the process, in which Y is a bond, can be obtained by reacting 2-lithiofuran or 2-lithiothiophene (prepared from furan or thiophene with butyllithium) with an alkyl halide of the general formula Ro -halogen, in which Rp has the meaning given above.

The method employed in accordance with Rp-Y-substituted furan derivatives wherein Y is an oxygen or sulfur atom, may be prepared by decarboxylation of a are prepared according Rp-Y-substituted 2-furancarboxylic acid by heating at temperatures above 150 ^0C.

The Rp-Y-substituted furanic and thiophenecarboxylic acids used according to the process, in which Y is an oxygen or Means sulfur atom can be prepared by aromatic nucleophilic substitution according to the following reaction scheme.

1) base

2) Acid \

Rp, X and Y have the meanings given above and L means a leaving group such as a nitro group, a fluorine, chlorine, bromine or iodine atom. The preferred leaving Group is the chlorine atom. The substituent L can be in the 3- » 4- or 5-position of the ring. The one described above The reaction can be carried out in the presence of a solvent will. Examples of solvents that can be used are benzene, xylene, toluene, chlorinated hydrocarbons, such as Chlorobenzene, ethers such as bis (2-methoxyethyl) ether, 1,2-dimethoxyethane or anisole, dimethylformamide, dimethylacetamide, 1-methyl-2-pyrrolidone and pyridine. The preferred solutions with tel are xylene and dimethylacetamide. If necessary, the

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Γ Π

Reaction in the presence of metallic copper or a copper salt, such as copper (I) chloride, can be carried out. Examples Bases that can be used are metallic sodium or potassium, sodium hydride, potassium amide, potassium tert-butoxide or other strong bases, such as potassium carbonate, potassium hydroxide, sodium hydroxide, and sodium carbonate. The reaction temperature can range from about 25 ° C to reflux temperature of the solvent. The reaction time is about 1 hour to 7 days. When the implementation is complete, the resulting Salt of the carboxylic acid treated with an inorganic or organic acid and the free furan or thiophenecarboxylic acid set in freedom.

The thiophenecarboxylic acid derivatives of the formula given above, in which X is a sulfur atom, can be after several Methods are prepared as described in Chemistry of Heterocyclic Compounds, Thiophenes and Its Derivatives, H.D. Hartough, Interscience Publishers, Inc., New York 1952, pp. 379-381. The furancarboxylic acids of general Formula I, in which X is an oxygen atom, can also be prepared by several methods, the in The Furans, A.P. Dunlop and F.N. Peters, Reinhold Publishing Corp., 1953, pp. 80-169.

The Ro-Y-substituted furan used according to the process and thiophenecarboxylic acids in which Y is a bond can be obtained by reacting a compound of the general formula III

R 30 2

^LLi (III)

in which R ₂ and X have the meaning given above and the radical R2 is in the 4- or 5-position, can be produced with dry ice (solid carbon dioxide) and then with water. The compounds of the general formula III are prepared by metallizing the corresponding Rp-substituted furan or thiophene with butyllithium.

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The preparation of the Rp-substituted furans and thiophenes in which R i represents _n der5-position, described above. The! ^ - substituted thiophenes in which R2 is in the 4-position are prepared by reacting one equivalent of 3-iodothiophene with one equivalent of one Rp-iodide in the presence of two equivalents of metallic sodium. The Rp-substituted furans, where Rp is in the 4-position are (prepared by reaction of 3-Jodfuran with butyllithium at -7O ⁰ C) by reaction of 3-lithiofuran with an R ₂ halide produced.

The compounds of general formula I are suitable for combating of rhinovirus infections. In the subgroup of Rhinoviruses, which belong to the group of picornaviruses, have so far been able to detect over 100 different serotypes. These viruses can cause colds in adults and children. The rhinoviruses were classified as serotypes 1 to 89 and subtypes 1A (88,89,90), with there being at least 20 other types are there. Using various test systems, it was found that compounds of the general Formula I can be used effectively to combat rhinovirus infections if the drug occurs at the same time as or following a virus load. The compounds of general formula I inhibit cytopathic ones Effects of the virus. To treat the symptoms of rhinovirus infections you can use the compounds of general Formula I can be given orally, locally, for example intranasally, or parenterally, for example intramuscularly. Local application is preferred. The preferred form of packaging are solid or liquid preparations. These Preparations can be the usual additives, auxiliaries and / or Contain carriers, such as binders, for example gum arabic, corn starch or gelatin, disintegrants, such as Corn starch, potato starch or alginic acid, lubricants such as stearic acid or magnesium stearate, and inert fillers, such as lactose, sucrose or corn starch.

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For the production of liquid preparations, sterile liquids, such as oils or water, optionally together with a wetting agent or emulsifier, can be used. Examples of liquid preparations are nasal drops. Come as oils for example peanut oil, sesame oil, cottonseed oil or olive oil in question. Peanut oil and sesame oil are preferred for making injectables.

The examples illustrate the invention.

example 1

Ethyl 5- (9 »12,15-octadecatrien-1-yloxy) -2-furyl ketone A mixture of 57.0 g (0.300 mol) 5-bromo-2-furancarboxylic acid, 119.0 g (0.450 mol) 9, 12,15-octadecatrienol and 84 g (0.750 mol) of potassium tert-butoxide in anhydrous toluene are heated under reflux and stirred. The generated during the reaction of tert-butanol is removed by distillation and the mixture heated for 48 hours at 110 ⁰ C under reflux and stirred. The reaction mixture is then cooled, acidified with acetic acid and diluted with ice water. The toluene solution is separated off, washed with water and extracted three times with 5 percent aqueous sodium bicarbonate solution. The aqueous extracts are combined, cooled and acidified with 10 percent hydrochloric acid. The 5- (9,12,15-octadecatrien-1-yloxy) -2-furanearboxylic acid is obtained. This compound is reacted with ethylmagnesium bromide to give the title compound.

Example 2 n-Propyl-5- (cis-9-octadecenyloxy) -2-thienyl ketone cis-9-octadecanol is anhydrous with sodium hydride Xylene converted into the sodium salt. 5-chloro-2-thiophenecarboxylic acid is then added to the sodium salt obtained. The mixture is refluxed for 64 hours, then cooled and poured into ice water, acidified with acetic acid and extracted with diethyl ether. The ether is distilled off and the remaining xylene solution five times with a

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Extracted mixture of equal parts by volume of water and concentrated aqueous ammonia solution. The aqueous extracts are combined and acidified with acetic acid. It becomes 5- (cis-9-octadecenyloxy) -2-thiophenecarboxylic acid obtain. This compound becomes the title compound with n-propyl magnesium bromide implemented.

Example 3 n -Butyl-2- (5-tetradecyloxy) thienyl ketone A mixture of 20.0 g (0.2 mol) of 3-thiolen-2-one (R.T. Hawkins, J. Heterocyclic Chem., Vol. 11 (1974), pp. 291-294), 65.5 g (0.2 mol) of 1-bromo-9,12,15-octadecatriene and 4, Sg (0.2 mol ) Sodium hydride in benzene is refluxed for 24 hours and stirred. The solvent is then distilled off and the product is distilled. It becomes 2- (9> 12,15-octadecatrienyloxy) thiophene obtain.

6.0 g of sodium amalgam in 100 ml of anhydrous diethyl ether are under a slight nitrogen pressure at 36 to 39 ° C under Heated to reflux. A solution of 34.7 g (0.10 mol) of 2- (9,12,15-0ctadecatrienyloxy) thiophene is then added over the course of 4 hours registered in 50 ml of anhydrous diethyl ether. That The mixture is refluxed for a further 2 hours, then cooled to room temperature and covered with freshly crushed dry ice offset. Then 20 ml of ethanol and then 50 ml of water are added dropwise. The aqueous solution is of the Separated ether solution, filtered and acidified with hydrochloric acid. The 5- (9,12,15-octadecatrien-1-yloxy) -2-thiophenecarboxylic acid falls here which is filtered off.

36.3 g (0.10 mol) of 5- (9,12,15-0ctadecatrien-1-yloxy ^ -thiophenecarboxylic acid in anhydrous tetrahydrofuran are with

17.4 g (0.107 mol) of Ν, Ν'-carbonyldiimidazole were added. The mixture is stirred at room temperature until the evolution of carbon dioxide has subsided. Thereafter, the reaction mixture evaporated to dryness and the residue with water-

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extracted free diethyl ether. The ether extract becomes Evaporated to dryness. It becomes N- / 5-C9,12,15-octadecatrien-1-yloxy ) -2-thenoyl7-imidazole.

When implementing this connection with the appropriate Amount of n-butyl magnesium bromide will give the title compound.

35, ■ '

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Claims (11)

V (ETSSIUS VOSSIUS HILIl- TAUCHNE =? HEUNEMANN -, PATENT LAWYERS 7 7 ^ 5750 • j SI E BE RTSTRASSE ■ * ■ 8OOO MÖNCHEN 86 ■ PHONE: (Ο88) 4 7 4Ο7Ο CABLE: BEN ZOLPATENT MÖNCHEN ■ TELEX B-29 453 VOPAT D uZ: M 443 (Vo / H)
Case: M-863 RICHARDSON-MERREII, INC;
Wilton, Connecticut, V.St.A. 5 ■ γ * -ν? "2-Acyl-furans and -thiophenes, process for their preparation and medicines " Priority: December 20, 1976, V.St.A., No. 751 I39 Claims 1. 2-acyl-furans and -thiophenes of the general formula I. 2 ■ in which X is an oxygen or sulfur atom, Y is an oxygen or sulfur atom, R .. is an unbranched or branched one Co ^ -alkyl radical and R ~ an unbranched or branched saturated hydrocarbon radical with 10 to 20 carbon atoms or an unbranched or branched one unsaturated hydrocarbon radical with 10 to Means 20 carbon atoms and 1 to 4 double bonds. 2. Compounds according to claim 1 of the general formula I, in which X is an oxygen atom. 3. Compounds according to claim 1 of the general formula I, in which Y is an oxygen atom. 809825/0853 4. Compounds according to claim 1 to 3 of the general formula I, in which H _{2 is} an alkyl radical having 12 to 16 carbon atoms. 5. Compounds according to claim 4 of the general formula I, in which R "denotes an alkyl radical with 14 carbon atoms.
6. Compounds according to claim 1 of the general formula I, in which the group R ₂ Y is in the 5-position. 10 7 · 2-acetyl-5-tetradecyloxyfuran. 8. 2-acetyl-5-dodec; ylox; yfuran. 9. Process for the preparation of the compounds according to claim 1, characterized in that either a) one equivalent of a furan or thiophenecarboxylic acid of the general formula ^R ₂ M -COOH in which X, Y and Rp have the meaning given in claim 1, with two equivalents of an alkyllithium compound of the general formula R ,, - Li in an ether as a solvent for 30 minutes to 10 hours at temperatures from -10 ⁰ G to Converts the reflux temperature of the reaction mixture or b) an alkyl magnesium bromide of the general formula R ^ MgBr, in which R ^ denotes an unbranched or branched alkyl radical with 2 to 4 carbon atoms, with the imidazolide of the furanic or thiophenecarboxylic acid of the general formula II in an ether or acetonitrile for 30 minutes to 10 hours at temperatures from -10 ⁰ C to the reflux temperature of the reaction mixture. 809825/0853 10. Medicines to fight hhinovirus infections, characterized by a content of a 2-acyl furan or thiophene of the general formula I-a O
CR ₁ in which Y is a bond, an oxygen or sulfur atom, X is an oxygen or sulfur atom, Ro is an unbranched or branched saturated hydrocarbon radical with 6 to 20 carbon atoms or an unbranched or branched unsaturated hydrocarbon radical with 6 to 20 carbon atoms and 1 to 4 double bonds, if R _{2 contains} 10 to 20 carbon atoms, and 1 or double bonds when R _{2 contains} 6 to 9 carbon atoms, and R ^. represents an hydrogen atom or a straight or branched alkyl radical having 1 to 4 carbon atoms, with the proviso, when Y represents a bond, the group RY is in the 4- or 5-position. 11. Medicaments for combating rhinovirus infections, containing a 2-acyl furan or thiophene according to claim 10 of the general formula Ia _r in which X is an oxygen or sulfur atom, Y is an oxygen or sulfur atom, R is an unbranched or branched C _{1- 4} alkyl radical and R ₂ denotes a straight or branched saturated alkyl radical with 10 to 20 carbon atoms or a straight or branched unsaturated alkyl radical with 10 to 20 carbon atoms and 1 to 4 double bonds. 809825/0853