CA1104574A - Antirhinovirus agents - Google Patents
Antirhinovirus agentsInfo
- Publication number
- CA1104574A CA1104574A CA290,375A CA290375A CA1104574A CA 1104574 A CA1104574 A CA 1104574A CA 290375 A CA290375 A CA 290375A CA 1104574 A CA1104574 A CA 1104574A
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- CA
- Canada
- Prior art keywords
- carbon atoms
- straight
- methyl
- solvent
- branched
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/58—One oxygen atom, e.g. butenolide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/32—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Abstract
ABSTRACT OF DISCLOSURE Compounds of the following general structure are use-ful as antirhinovirus agents: wherein Y Is a bond, oxygen or divalent sulfur; X is oxy-gen or sulfur; R is a straight or branched hydrocarbon chain having from 6 to 20 carbon atoms and is saturated or unsaturated having from 1 to 4 double bonds when R has from 10 to 20 carbon atoms and l or 2 double bonds when R has from 6 to 9 carbon atoms; and R, is hydrogen or a straight or branched alkyl group of from 1 to 4 carbon atoms; with the proviso that when Y is a bond the R-Y group is attached at the 4- or 5- position of the hetero-cycltc ring.
Description
r-~ ~
;
FIELD OF INVENTION ` :i~
Th;s invention relates to substituted furan and thio- ;
phene aldehydes and alkyl ketones and ~their use as~ anti- :
rhinovirus agents.
SUMMARY OF INVENTION : :
Compounds of the followlng general Formula I are use- ;
ful as antirhinovirus agents:
~, ~ C-RI Formul a In the above general Formula I:Y is a bondJ oxygen or 10 ~ divalent sulfur; X is oxygen or divalent sulfur;;R is a ;~
straight or branched saturated hydrocarbon chain;having `:
from 6 to 20 carbon atoms or a straight or branched un~
saturated hydrocarbon chain having from 6 to 20 carbon atoms and from 1 to 4 double bonds when R has from 10 to :: 15 ~ 20 carbon atoms and 1 or 2 double bonds when R has from ~ -~ 6 to 9 carbon atoms; and R1 is hydrogen or a straight or ; : branched iower alkyl group of from 1 to 4 carbon atoms;
with the proviso that when Y is a bond the R-Y- group is attached at the ~- or 5- positlon of the heterocyclic ring.
: :DETAILED DESCRIPTION OF INVENTION
It is evident from the above general Formula I that the compounds employed in the present inventlon are sub- ~
- : ; .:
-1- ~ . ~
~ M-863 stituted thiophenecarboxaldehydes and alkyl ketones as represented by the following general Formula ll, and sub-stituted furancarboxaldehydes and alkyl ketones as repre-sented by the following general Formula lll:
Y ~ C-R1 Formula ll R^Y- ~ C-R1 Formula lll In the above general Formulas ll and lll the various symbols R, Y and R1 have the meanings defined in general ~ormula l~ and the substituent group represented as R~Y : -may be attached at any of the positions ~-, 4- or 5- of the Furan or thiophene ring except when Y is a bond the . ~;
R-Y group is attached at the 4- or 5- position.
In the above general Formulas I to lll the substi-tuent R is a straight or branched saturated hydrocarbon chain having from 6 to 20 carbon atoms in which case the R-Y- group may be represented as CqH2-q+l ~- wherein Y is a bond, oxygen or divalent sulfur, and q is an integer of from 6 to 20g and the hydrocarbon chain Is straight or branched; or R is a straight or branched unsaturated hydrocarbon chain having from 6 to 20 carbon atoms and from 1 to 4 double bonds when R has from 10 to 20 carbon atoms and 1 or 2 double bonds when R has from 6 to ~ .
1~4~ 1 ~1 M-863 carbon ato~ms in which case the ~-Y- group may be repre-sented as CqH2q z Y- wherein Y is a bond, oxygen or diva-lent sulfur, q is an integer of from 6 to 20 and z ;s the integer 1, ~, 5 or 7 as the number of double bonds varies from 1 to 4 respectively when R has from 10 to 20 carbon ~;
atoms and z is 1 or ~ as the number of double bonds varies from 1 to 2 respectively when R has from 6 to 9 carbon atoms, and the hydrocarbon chain is straight or branched~
Illustrative examples of straigh~ or branched satura-ted hydrocarbon chains which R may represent are, for example, decyl, undecyl, dodecyl 3 tridecyl, tetradecyl, ~,7-dimethyloctylJ 2,4-diethylnonylg 1-methylundecyl, pen~adecyl, hexadecyl, heptadecyl, 3-methyloctadecyl, nonadecyl, didecyl, nonyl, octyl, heptyl and hexyl. ;
Illustrative examples of straight or branched unsat-urated hydrocarbon chains containing from 1 to 4 double bonds which R may represent are, for example, 10-undec-enyl~ g~l2-octadecyldienyl~ 377,11-trimethyl-2,6,10-hexadecyltrienyl~ 3,7-dimethyl-2,6-octadienyl, 5,9~di- ;
methyl-2,4,8-decatrienyl, 4,6-dimethyloct-3-enyl, 1,2,5,9-tetramethyl-2,4J8-decatrienyl, 11-didecenyl and 2-hexenyl.
lllustrative examples of straight or branched lower alkyl groups of from 1 to 4 carbon atoms which Rl may represent are methyl, ethyl, n-propyl, isopropyl, n-butyl and tert-butyl.
The compounds of general Formula I wherein Y is oxygen or divalent sulfur~ R1 is a straight or branched alkyl group of from 1 to 4 carbon atomsg and R îs a straight or branched saturated hydrocarbon chain having from 10 to ~0 carbon atoms or a straight or branched . . .
unsaturated hydrocarbon chain having from 10 to 20 carbon atoms and from 1 to 4 double bonds are novel compounds and represent a preferred embodiment oF the present invention.
The novel compounds of this invention are represented by the following general Formula IV:
R2y ~jl 11 ~ X~~~C-R3 Formula IV
In the above general Formula IV X is oxygen or divalent sul~ur; Y' is oxygen or divalent sulfur; R2 is a straight or branched saturated hydrocarbon group having ~rom 10 to 20 carbon atoms or a straight or branched unsaturated hydrocarbon group having from 10 to 20 carbon atoms and from 1 to 4 double bonds, illustrative examples of which are se~ forth hereinabove, and R3 is a straight or branched lower alkyl group of from 1 to 4 carbon atoms such as methyl, ethylj n-propyl, isopropyl and n-butyl. The substituent group R2Y'- may be attached at positions 3-4- or 5- of the furan or thiophene ring.
The compounds of general Formula IV represent a preferred embodiment of this invention. Of the compounds of general Formula IV those wherein Y is oxygen are more preferred. Also, the compounds of general Formula IV
wherein R9 is a straight chain alkyl are preferred over the branched chain alkyl derivatives. Compounds wherein R3 is methyl are particularly preferred. The furans of general Formula IV, ~hat is3 compounds wherein X is oxy-~en are preferred over the thiophene compounds wherein X
.
57~
is divalent sulfur. Also, the compounds wherein R2 has from 12 to 16 carbon a-toms are preferred with 14 carbon atoms being most preferred.
Another preferred embodiment of this invention is the use of compounds of general Formula I as antirhinovirus agents. The use of compounds of general Formula I where- -;
in Rl is a straight chain alkyl group are preferred with Rl as methyl being more preferred. Another preferred em-bodiment is the use of compounds of general Formula I as antirhinovirus agents wherein R has from 12 to 16 carbon atoms with a 14 carbon atom chain length being more pre-ferred. The use oE compounds oE general Formula I wherein ~ is oxygen or sulfur is another preferred embodiment with Y as oxygen being more preferred. The use of compounds of general Formula I as antirhinovirus agents wherein X is '~
. ~ . , oxygen is preferred over the use of the compounds wherein X is divalent sulfur.
: , , .
The compounds of general Formulas I to III wherein R
is hydrogen, Y is divalent sulfur or oxygen, and R is a straight or branched saturated hydrocarbon chain having from 10 to 20 carbon atoms or a straight or branched un-saturated hydrocarbon chain having from 10 to 20 carbon atoms and from 1 to 4 double bonds are disclosed in U.S.
patent No. 4,011,334, wherein the use of said compounds as hypolipidemic agents is described.
The compounds of general Formula II wherein Rl is methyl, Y is divalent sulfur or oxygen and R is a straight or branched saturated hydrocarbon chain having i ~ - 5 -,.
from 10 to 20 carbon atoms or a strai~ht or branched un-saturated hydrocarbon chain having from 10 to 20 carbon atoms and from 1 to 4 double bonds are described as inter-mediates for the preparation of hypolipidemi.c agents in U.S. patent No. 4,032,647.
The compounds of general Formula III wherein Rl is methyl, Y is divalent sulfur or oxygen, and R is a ~
straight or branched hydrocarbon chain having from 10 to .
20 carbon atoms or a straight or branched unsaturated hydrocarbon chain having from 10 to 20 carbon a-toms and from 1 to 4 double bonds are described as intermediates for the preparation of hypolipidemic agents in U.S. patent No. 4,032,647.
Illustrative examples of compounds of general For-mula I are the following~
5-decylthio-2-furancarboxaldehyde, :
5-tetradecylthio-2-furancarboxaldehyde, ~.
5-dodecylthio-2-furancarboxaldehyde, 4-hexadecylthio-2-furancarboxaldehyde, 4-tetradecylthio-2-furancarboxaldehyde.
3-didecylthio-2-furancarboxaldehyde, .
methyl 2-(5-tetradecylthio)furyl ketone, ~ ~:
ethyl 2-(S-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, ~ ~ ' I ~ , - 6 -' : - , .
: ~
~ ~ 4 ~ M-86~ ;
ethyl 2-(5-dodecylthio)thienyl ketone, n-propyl 2-(4-decylthio)thienyl ketone, isopropyl 2-(5-tetradecylthio)thienyl l<etone n-butyl 2-(3-pentadecylthio)thienyl ketone~
tert-butyl 2-(4-heptadecylthio)thienyl ketone, methyl 2-(5-octadecylthio)thienyl ketone, methyl 2-(5-hexylthio)furyl ketone, n-propyl 2 (~-octylthio)furyl ketone, butyl 2-(~-nonylthio)thienyl ketone, ~ I
isopropyl 2-(5-heptylthio)thienyl ketone, :~ ~.
ethyl 2-(~-octylthio)~hienyl ketone, :
5-hexylthio-2-thiophenecarboxaldehyde, 4-decylthio-2-thiophenecarboxaldehyde, ~ ~:
5 dodecylthio-2-thiophenecarboxaIdehyde, 5-tetradecylthio-2-thiophenecarboxaldehyde, 3-ortadecylthio-2-thiophenecarboxaldehyde, 5-hexyloxy-2-thiophenecarboxaldehyde, -4-LIndecyloxy-2-thiophenecarboxaldehyde~
5-dodecyloxy-2-thiophenecarboxaldehyde, ZO 5-tetradecyloxy-2-thiophenecarboxaldehyde, 3-heptadecyloxy-2-thiophenecarboxaldehyde, 4-nonadecyloxy-2-thiophenecarboxald~hyde, 5-heptyloxy-2-furancarboxaldehydeJ
4-nonyloxy-2-furancarboxaldehyde, 5-dodecyloxy-2-furancarboxaldehyde, 5-tetradecyloxy-2-furancarboxaldehyde, 3-hexadecyloxy-2-furancarboxaldehyde, 5-didecyloxy-2-furancarboxaldehyde, 5-octyl-2-thiophenecarboxaldehyde, ~ M-86 5-dodecyl-2-thiophenecarboxaldehyde, 5-tetradecyl-2-thiophenecarboxaldehyde, 4-(~7-dime~hyloctyl)-2-thiophenecarboxaldehyde, ~-octyldecyl-2 thiophenecarboxaldehyde, 5-dodecyl-2-furancarboxaldehyde, 5-tetradecyl-2-furancarboxaldehyde, ~-hexyl-2-furancarboxaldehyde, ~-nonadecyl-2-furancarboxaldehyde, methyl 2-(5-hexyloxy)furyl ketone, ethyl 2-(~-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-(~-didecyloxy)thienyl ketoneJ ~:
ethyl 2-(5-dodecyloxy)thienyl ketone, ~:
methyl 2-(5-tetradecyloxy)thienyl ketoneJ
n-propyl 2-(5-pentadecyloxy)thienyl ketone, :.
methyl 2-(5-hexyl)furyl ketone, ethyl 2-(4-octyl)furyl ketone, isopropyl 2~ hexadecyl)furyl ketone, n-butyl 2-(3-tridecyl)thienyl ketone, methyl 2-(5-tetradecyljthienyl ketoneJ
methyl 2-(5-tetradecyl)furyl ketone, ethyl 2-(5-dodecyl)furyl ketone, tert-butyl 2-~4-heptyl)thienyl ketone, methyl 4-(~,7-dimethyloctyl)-2-furyl ketone, ~ `
ethyl 5-(2,4-diethylnonyl)-2-thienyl ketone~
5~ methylundecyl)-2-furancarboxaldehyde, ~0 5-(3 methyloctadecyloxy)-2-thiophenecarboxaldehyde, ~ , i i~ 4574 M-86 3-(3,7-dimethyloctyloxy)-2-furancarboxaldehyde, 5-(3-methyloctadecylthio)-2-furancarboxaldehyde, methyl 5-(2J4-diethylnonylthio)-2-thienyl ketone, 5-(10-undecenyloxy)-2-thiophenecarboxaldehyde, ;~
methyl 5-( 9J 12-octadecyldienyl)-2-furyl ketone, 5-(3,7~11-trime~hyl-2,6,10-hexadecyltrienyloxy)-2- furyl ketone, ~-(3J7-dimethyl-2,6-octadienylthio)-2-furancarboxaldehydeJ
~-(5,9-dime~hyl~2~4,8-decatrienyl)-2-thiophenecarbox-aldehyde, and ethyl 5-(4,6-dimethyloct-~-enylthio)-2-furyl ketone.
The compounds o~ general Formulas I to IV are useful as antirhinovirus agents. The rhinovirus genus which is a member of the picornavirus family, contains over 100 different antigenic typesJ and is known to be responsible for many of the symptoms attendant respiratory infections.
:
The name rhinovirus is indicative of the prominent nasal involvement seen in infections with these viruses resulting in syndromes charac~erist7cs of the common cold. Rhino-viruses have been classified as serotypes 1 to 89 andsubtypes 1A(88~89J90) with at least 20 more types to be added to the classification. Experimental studies indi-cate nasal mucosa is more susceptible to rhinovirus than -is the lower respi ratory tract. The symptoms of rhino-virus infection have also been produced experimentally by dropping sma71 amounts of the virus on the conjunctiva, indicating that the eye is another susceptible infectious site~ Developed rhinovirus infection is characterized by hyperemia and edema of the mucous membrane with exudation .; , . , . .
1 ~ 4 ~ M-863 of ser-ous and mucinous fluid. The nasal cavities are nar-rowed by thickening of the membrane and engorgement of the turbinates.
The compounds described herein have been found to be effective antiviral agents agalnst numerous types of rhinovirus rendering said compounds useful in treating -~
the symptoms of a rhinovirus infection in hosts susceptible to said infections including humans and certain anthropoid apes such as the chimpanzee. It is known in the art that several test systems can be employed to measure antiviral activity against rhinovirus. for example, antirhinovirus activity can be measured using a plaque assay or tube test wherein the activity of the compound against virus chal-lenge in a cell system is measured. Using a variety of test sys~ems it was found that compounds of general Formula I are effective antirhinov;rus agents ~hen the te~t con~
pound is glven prior to/ concurrently with or subsequent to virus challenge. The utility of the compounds described herein as antirhinovirus agents has been demonstrated in a variety of test systems. For example, using HeLa cell cultures to which a rhinovirus challenge of from 30 to 100 TCID50 is added concurrently with test compounds at a concentration of 4, 20 or 100 ~g/ml after which the cell cultures are incubated for 48 hours it was found upon microscopic examination of the cell cultures that com-pounds of general Formula I markedly inhibit the cyto-pathic effect of the virus when compared to cell cultures containing virus challenge. For example, when the com pound of Example 1 at a concentration of 4 ~g/ml was added to cell cul~ures together with a rhinovirus challenge of ~ M-~6~
100 TCID50 the cytopathic effect of virus was inhibited by ~7~ when compared to control. In a tube test system using ~ ~;
HeLa cells it was found tha-t the tissue culture ED50 of the compound of Example 1 is 0.~ ~g/ml.
In the treatment of symptoms of rhinovirus infection the compounds of general Formulas I to IV can be adminis-tered orally, topically, ~or example~ intranasa11y, and parenteral 1YJ for exampleJ intramuscularly. Topical ad-ministration is preferred. The compounds are administered preferably in the form o~ a pharmaceutical preparation to a host susceptible to rhinovirus infection either prior to or aFter invasion oF virus or after onset of the infection.
For prophylactic treatment it is contemplated that an anti-rhinovirus effective amount of compound be administered for from about 1 to 5 days prior to anticipated exposure to virus and from about ~ to 10 days subsequent to exposure or from about 5 to about 15 days subsequent to exposure to rhinovirus. It is known that rhinovirus is readily trans-mitted from one susceptible host to another as commonly occurs, for example, among family members, in classrooms and in military popula~ions. The compounds of general Formula ~ are also useful therapeutically in treating rhinovirus infections ;n that said compounds are effec-tive in diminishing or blocking replication of the virus.
For prophylactic or therapeutic treatment of rhino-virus infection any antirhinovirus effective amount of a compound of general Formula I may be employed. Fcr thera-peutic treatment the amount of compound administered will vary depending primarily on the severity of the infection.
For therapeutic or prophylactis treatment the amount of compound administered will vary from about 0.1 mg/kg to -~1- ;.' ~ M-863 15 mg/kg of body weigh~ of the patient~ that is) susceptible host. Preferably the amount of compound admlnistered will vary from about 1 mg/kg to about 3 mg/kg. Typica11y a unit dose containing about 25 mg of cornpound administered -from 1 to 6 times daily will achieve the desired effect.
The compounds of general Formula I together with suit-able pharmaceutical carriers can be in the form of solid unit dosage forms such as tablets~ capsules, powders, or in the form of a suppository. The powders can be adminis-tered orally or by insufflation. In the preparation ofsolid unit dosage Forms it may be desirable to micronize the compound to be employed. In solid unit dosage forms the compounds can be combined with conventional carriers, for example, binders, such as acaciaJ corn starch or gelatin, disintegrating agents, such as, corn starch, potato starch or alginic acid, lubricants, such as, stearic acid or magnesium stearate, and inert fillers, such as, lac~ose, sucrose or corn starch.
The compounds of general Formula I may also be ad-ministered as liquid suspensions or solutions using a sterile liquid~ such as, an oil, or water with or without ~
the a~dition of a pharmaceutically suitable surfactant or ~-emulsifying agent for oral, topical or parenteral admin- ~ -. - - , istration, A particularly suitable mode of administration is a liquid formulation of the compounds applied directly to the nasal cavity, for example, in the form of a nose drop. For liquid preparations the compounds can be suit-ably formulated wlth fixed oils, such as~ peanut oil~
sesame oil, cottonseed oil or olive oil Peanut oil and ~0 sesams oil are particularly useful in preparation of .
M-8~
formulations for intramuscular injection~ Such oils can a1SQ b~ employed in the preparation of formula~ions of the soft gelatin type and suppositories, In general, waterJ
salin0, aqueous dextrose and rela~ed sugar solu~ions and glycerolsJ such as, polyethyleneglycol may be employed in the preparation of li~uid ~ormulations which may sui~ab!y eontain suspending agents, such as, methyl cellulose, hydroxypropyl cellulose or carboxymethyl cellulose as well as buff~rs and preservatives.
Illustrative examples o~ switable pharmac~utieal formulat70ns ar~ set for-th hereinbelow.
The ketone compounds of general Formula 1, that is, compounds wherein R1 is a straight or branched alkyl group of from 1 to 4 carbon atoms may be prepared by treating one equiYalent of the corresponding carboxylic acid deri-vatives wtth two equivatents of an appropriat~ alkyl-lithium as generally described by Fieser and Fieser, R~ nt$ for Orqan7c Synthesis9 J, Wiley and Sons~ Inc., New York, p, 688 (1967). This reaction ts suitably carried out in solvents, such as, ether, t~trahydrofuran9 p-dToxane~ dim~thoxyethane or diethyleneglycol dimethyl~
ether at ~emperatures of from -10C to the reflux temp- ~:
~rature of the solvent ~or from 1/2 hour to 10 hours.
The ketone compounds of g~neral Formula I may also be prepared by ~he reaction of alkyl magnesium bromide wherein the alkyl moiety is straight or branched and has from 1 to ~ carbon atoms, and ~he imidazolide deriva~ive of an appropria~ely R-Y substituted thiophene or furan-.
.. ..
f~ , carboxylic acid derivative wherein R and Y have the mean- -ings defined in general Formula 1. This reaction is carried out in solvents such as e~her, tetrahydrofuran, dioxane, dimethoxyethane, or acetonitrile. The reaction mixture is initially cooled to -10C after which the temperature is elevated to from about 25C to the reflux temperature of the solvent, and the reaction time varles from about 1/2 hour to 10 hours. The imidazolide deriva-tive is obtained by treating an appropriately R-Y- sub-stituted thiophene or furan carboxylic acid derivativewith N,N'-carbonyldiimidazole or by treatment of the R-Y~
substituted thiophene or furancarboxylic acid chloride, obtained by treating the substituted carboxylic acid with thionyl chloride, with two equivalents of imidazole as generally described by H. A, Staab, Angew Chem. Internat.
Edit, 1 351 ~1962 ) .
The ketone compounds of general Formula I wherein the R-Y substituent group is attached at the 5- position oF
the furan or thiophene ring may also be prepared by a Friedel-~rafts acylation of an appropriately R-Y- sub-stituted thiophene or furan, wherein R and Y have the meanings defined in general Formula 1, with an acyl halide oF the formula R4-C-halo wherein halo is halogen, prefer-ably chlorine or bromine, and R~ is a straight or branched alkyl group of from 1 to 4 carbon atoms. This reaction is carried out in the presence of an acid catalyst, For example, borontrifluoride-etherate, stannic chloride~
zinc chlorideJ hydriodic acid or orthophosphoric acid and optionally in the presence oF a solvent, for example~
~ M-863 methyl~ne chloride, nitromethane or benzene. Suitable temperatures for this reaction vary from -20C to the reflux temperature oF the solvent) and ~he reaction time varies from about 1/2 hour to 10 hours.
The compounds of general Formula I wherein R1 is hydro-gen and R is a straight or branched saturated hydrocarbon chain having from 6 to 20 carbon atoms may be prepared by chemical or catalytic reduction of the corresponding R-Y-substituted carboxylic acid halide or tertiary amide by methods generally described in J. March,Advanced Orqanic Chemistry. Reactions, Mechanism and Structure, McGraw-Hill, pp. 351 and 352 (1968). Reduction of the corresponding carboxylic acid halides J for example, the acid chloride using a catalytic hydrogenation method to give the aldehyde compounds is known as the Rosenmund reduction and i5 the most common way to prepare the aldehydes. A suitable cata- ~
lyst for this reaction is p~lladium-BaSO4 in a ratio of 1'`
part catalyst to 5 to 10 parts of acid chloride. This reaction may be carried out with or without a regulator such as quinoline sulfur. Suitable solvents for this reaction are dry solvents selected from aromatic hydro-carbons, such as, benzene~ toluene and xylene, non-aromatic hydrocarbons, such as, decalin and ethers, such as, di~
ethyl ether. This reaction may be carried out at tempera-tures of from about 25~ to the reflux temperature of the solvent and the reaction time may vary from about 15 minu~es to 24 hours. The compounds of general Formula I
wherein R1 is hydrogen and R is a straight or branched unsaturated hydrocarbon chain having from 6 to 20 carbon ~0 atoms may be prepared by reduc~ion of the tertiary carbox-~ M-86~
amide or acid halide using a metal hydride reducing agent.
This reaction is carried out in ether solvents, such asJ
diethylether, te~rahydrofuran, dioxane and dimethoxyethane, or aromatic hydrocarbon solvents, such asJ benzene and toluene. The reaction temperature may vary from 0C to the reflux temperature of the solvent, and the reaction time may vary from abou~ 15 minutes to 24 hours. The carbox~
ylic acid halides and carboxamide derivatives can be `~
prepared from the corresponding acid by procedures generally known in the art.
The thiophene carboxaldehydes described herein wherein the R-Y- substituent is attached to the 5- position of the thTophene ring may also be prepared by ~reating an appro~
priately R-Y- subst7tuted th70phene derivative with N-methylforman31ide and phosphorus oxychloride followed by ;~
water hydrolysis as generally described, for example3 in F;eser and Fieser, Advance~ anic Chemistry, Reinhold Publishing Corp., New York (1961).
The R-Y- substituted thiophene derivatives employed herein wherein Y represents sulfur can be obtained in the manner described by E. Profft, Chemiker-Zeitung, 82 298 (1958) and wherein Y represents oxygen can be prepared from the ~-thiolene-2-one ~R.P, Hawkins, Journal Hetero~
cyclic Chemistry, 11 (3) 291-4 (1974)) with a suitable alkyl halide~ alkyl mesylate or a1kyl tosylate in th~
presence of a base, for example, sodium hydride, potassium amide, potassium tert-butylate, sodium or potassium metal, potassium carbonate, sodium carbonate, triethylamine or pyridine ~o yield the 2-alkoxythiophene intermediate.
~0 This reaction may be carried out with or without a solvent.
-~6-. .
~ ,7~ M-86~
Suitable solvents include pyridineJ benzene~ xylene, chlorobenzeneJ ethers~ for example, bis(2-methoxyethyl)-ether or anisoleJ dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide. The alkyl halide may beJ
for exampleJ alkyl chloride, alkyl bromide or alkyl iodide The alkyl moiety in the alkyl halideJ the alkyl mesyla~e or the alkyl tosylate is a hydrocarbon radical containing from 6 to 20 carbon atoms which is straight or branched and which is saturated or unsaturated in which case the.
hydrocarbon radical contains from 1 to 4 double bonds when said radical has from 10 to 20 carbon atoms ancl 1 or
;
FIELD OF INVENTION ` :i~
Th;s invention relates to substituted furan and thio- ;
phene aldehydes and alkyl ketones and ~their use as~ anti- :
rhinovirus agents.
SUMMARY OF INVENTION : :
Compounds of the followlng general Formula I are use- ;
ful as antirhinovirus agents:
~, ~ C-RI Formul a In the above general Formula I:Y is a bondJ oxygen or 10 ~ divalent sulfur; X is oxygen or divalent sulfur;;R is a ;~
straight or branched saturated hydrocarbon chain;having `:
from 6 to 20 carbon atoms or a straight or branched un~
saturated hydrocarbon chain having from 6 to 20 carbon atoms and from 1 to 4 double bonds when R has from 10 to :: 15 ~ 20 carbon atoms and 1 or 2 double bonds when R has from ~ -~ 6 to 9 carbon atoms; and R1 is hydrogen or a straight or ; : branched iower alkyl group of from 1 to 4 carbon atoms;
with the proviso that when Y is a bond the R-Y- group is attached at the ~- or 5- positlon of the heterocyclic ring.
: :DETAILED DESCRIPTION OF INVENTION
It is evident from the above general Formula I that the compounds employed in the present inventlon are sub- ~
- : ; .:
-1- ~ . ~
~ M-863 stituted thiophenecarboxaldehydes and alkyl ketones as represented by the following general Formula ll, and sub-stituted furancarboxaldehydes and alkyl ketones as repre-sented by the following general Formula lll:
Y ~ C-R1 Formula ll R^Y- ~ C-R1 Formula lll In the above general Formulas ll and lll the various symbols R, Y and R1 have the meanings defined in general ~ormula l~ and the substituent group represented as R~Y : -may be attached at any of the positions ~-, 4- or 5- of the Furan or thiophene ring except when Y is a bond the . ~;
R-Y group is attached at the 4- or 5- position.
In the above general Formulas I to lll the substi-tuent R is a straight or branched saturated hydrocarbon chain having from 6 to 20 carbon atoms in which case the R-Y- group may be represented as CqH2-q+l ~- wherein Y is a bond, oxygen or divalent sulfur, and q is an integer of from 6 to 20g and the hydrocarbon chain Is straight or branched; or R is a straight or branched unsaturated hydrocarbon chain having from 6 to 20 carbon atoms and from 1 to 4 double bonds when R has from 10 to 20 carbon atoms and 1 or 2 double bonds when R has from 6 to ~ .
1~4~ 1 ~1 M-863 carbon ato~ms in which case the ~-Y- group may be repre-sented as CqH2q z Y- wherein Y is a bond, oxygen or diva-lent sulfur, q is an integer of from 6 to 20 and z ;s the integer 1, ~, 5 or 7 as the number of double bonds varies from 1 to 4 respectively when R has from 10 to 20 carbon ~;
atoms and z is 1 or ~ as the number of double bonds varies from 1 to 2 respectively when R has from 6 to 9 carbon atoms, and the hydrocarbon chain is straight or branched~
Illustrative examples of straigh~ or branched satura-ted hydrocarbon chains which R may represent are, for example, decyl, undecyl, dodecyl 3 tridecyl, tetradecyl, ~,7-dimethyloctylJ 2,4-diethylnonylg 1-methylundecyl, pen~adecyl, hexadecyl, heptadecyl, 3-methyloctadecyl, nonadecyl, didecyl, nonyl, octyl, heptyl and hexyl. ;
Illustrative examples of straight or branched unsat-urated hydrocarbon chains containing from 1 to 4 double bonds which R may represent are, for example, 10-undec-enyl~ g~l2-octadecyldienyl~ 377,11-trimethyl-2,6,10-hexadecyltrienyl~ 3,7-dimethyl-2,6-octadienyl, 5,9~di- ;
methyl-2,4,8-decatrienyl, 4,6-dimethyloct-3-enyl, 1,2,5,9-tetramethyl-2,4J8-decatrienyl, 11-didecenyl and 2-hexenyl.
lllustrative examples of straight or branched lower alkyl groups of from 1 to 4 carbon atoms which Rl may represent are methyl, ethyl, n-propyl, isopropyl, n-butyl and tert-butyl.
The compounds of general Formula I wherein Y is oxygen or divalent sulfur~ R1 is a straight or branched alkyl group of from 1 to 4 carbon atomsg and R îs a straight or branched saturated hydrocarbon chain having from 10 to ~0 carbon atoms or a straight or branched . . .
unsaturated hydrocarbon chain having from 10 to 20 carbon atoms and from 1 to 4 double bonds are novel compounds and represent a preferred embodiment oF the present invention.
The novel compounds of this invention are represented by the following general Formula IV:
R2y ~jl 11 ~ X~~~C-R3 Formula IV
In the above general Formula IV X is oxygen or divalent sul~ur; Y' is oxygen or divalent sulfur; R2 is a straight or branched saturated hydrocarbon group having ~rom 10 to 20 carbon atoms or a straight or branched unsaturated hydrocarbon group having from 10 to 20 carbon atoms and from 1 to 4 double bonds, illustrative examples of which are se~ forth hereinabove, and R3 is a straight or branched lower alkyl group of from 1 to 4 carbon atoms such as methyl, ethylj n-propyl, isopropyl and n-butyl. The substituent group R2Y'- may be attached at positions 3-4- or 5- of the furan or thiophene ring.
The compounds of general Formula IV represent a preferred embodiment of this invention. Of the compounds of general Formula IV those wherein Y is oxygen are more preferred. Also, the compounds of general Formula IV
wherein R9 is a straight chain alkyl are preferred over the branched chain alkyl derivatives. Compounds wherein R3 is methyl are particularly preferred. The furans of general Formula IV, ~hat is3 compounds wherein X is oxy-~en are preferred over the thiophene compounds wherein X
.
57~
is divalent sulfur. Also, the compounds wherein R2 has from 12 to 16 carbon a-toms are preferred with 14 carbon atoms being most preferred.
Another preferred embodiment of this invention is the use of compounds of general Formula I as antirhinovirus agents. The use of compounds of general Formula I where- -;
in Rl is a straight chain alkyl group are preferred with Rl as methyl being more preferred. Another preferred em-bodiment is the use of compounds of general Formula I as antirhinovirus agents wherein R has from 12 to 16 carbon atoms with a 14 carbon atom chain length being more pre-ferred. The use oE compounds oE general Formula I wherein ~ is oxygen or sulfur is another preferred embodiment with Y as oxygen being more preferred. The use of compounds of general Formula I as antirhinovirus agents wherein X is '~
. ~ . , oxygen is preferred over the use of the compounds wherein X is divalent sulfur.
: , , .
The compounds of general Formulas I to III wherein R
is hydrogen, Y is divalent sulfur or oxygen, and R is a straight or branched saturated hydrocarbon chain having from 10 to 20 carbon atoms or a straight or branched un-saturated hydrocarbon chain having from 10 to 20 carbon atoms and from 1 to 4 double bonds are disclosed in U.S.
patent No. 4,011,334, wherein the use of said compounds as hypolipidemic agents is described.
The compounds of general Formula II wherein Rl is methyl, Y is divalent sulfur or oxygen and R is a straight or branched saturated hydrocarbon chain having i ~ - 5 -,.
from 10 to 20 carbon atoms or a strai~ht or branched un-saturated hydrocarbon chain having from 10 to 20 carbon atoms and from 1 to 4 double bonds are described as inter-mediates for the preparation of hypolipidemi.c agents in U.S. patent No. 4,032,647.
The compounds of general Formula III wherein Rl is methyl, Y is divalent sulfur or oxygen, and R is a ~
straight or branched hydrocarbon chain having from 10 to .
20 carbon atoms or a straight or branched unsaturated hydrocarbon chain having from 10 to 20 carbon a-toms and from 1 to 4 double bonds are described as intermediates for the preparation of hypolipidemic agents in U.S. patent No. 4,032,647.
Illustrative examples of compounds of general For-mula I are the following~
5-decylthio-2-furancarboxaldehyde, :
5-tetradecylthio-2-furancarboxaldehyde, ~.
5-dodecylthio-2-furancarboxaldehyde, 4-hexadecylthio-2-furancarboxaldehyde, 4-tetradecylthio-2-furancarboxaldehyde.
3-didecylthio-2-furancarboxaldehyde, .
methyl 2-(5-tetradecylthio)furyl ketone, ~ ~:
ethyl 2-(S-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, ~ ~ ' I ~ , - 6 -' : - , .
: ~
~ ~ 4 ~ M-86~ ;
ethyl 2-(5-dodecylthio)thienyl ketone, n-propyl 2-(4-decylthio)thienyl ketone, isopropyl 2-(5-tetradecylthio)thienyl l<etone n-butyl 2-(3-pentadecylthio)thienyl ketone~
tert-butyl 2-(4-heptadecylthio)thienyl ketone, methyl 2-(5-octadecylthio)thienyl ketone, methyl 2-(5-hexylthio)furyl ketone, n-propyl 2 (~-octylthio)furyl ketone, butyl 2-(~-nonylthio)thienyl ketone, ~ I
isopropyl 2-(5-heptylthio)thienyl ketone, :~ ~.
ethyl 2-(~-octylthio)~hienyl ketone, :
5-hexylthio-2-thiophenecarboxaldehyde, 4-decylthio-2-thiophenecarboxaldehyde, ~ ~:
5 dodecylthio-2-thiophenecarboxaIdehyde, 5-tetradecylthio-2-thiophenecarboxaldehyde, 3-ortadecylthio-2-thiophenecarboxaldehyde, 5-hexyloxy-2-thiophenecarboxaldehyde, -4-LIndecyloxy-2-thiophenecarboxaldehyde~
5-dodecyloxy-2-thiophenecarboxaldehyde, ZO 5-tetradecyloxy-2-thiophenecarboxaldehyde, 3-heptadecyloxy-2-thiophenecarboxaldehyde, 4-nonadecyloxy-2-thiophenecarboxald~hyde, 5-heptyloxy-2-furancarboxaldehydeJ
4-nonyloxy-2-furancarboxaldehyde, 5-dodecyloxy-2-furancarboxaldehyde, 5-tetradecyloxy-2-furancarboxaldehyde, 3-hexadecyloxy-2-furancarboxaldehyde, 5-didecyloxy-2-furancarboxaldehyde, 5-octyl-2-thiophenecarboxaldehyde, ~ M-86 5-dodecyl-2-thiophenecarboxaldehyde, 5-tetradecyl-2-thiophenecarboxaldehyde, 4-(~7-dime~hyloctyl)-2-thiophenecarboxaldehyde, ~-octyldecyl-2 thiophenecarboxaldehyde, 5-dodecyl-2-furancarboxaldehyde, 5-tetradecyl-2-furancarboxaldehyde, ~-hexyl-2-furancarboxaldehyde, ~-nonadecyl-2-furancarboxaldehyde, methyl 2-(5-hexyloxy)furyl ketone, ethyl 2-(~-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-(~-didecyloxy)thienyl ketoneJ ~:
ethyl 2-(5-dodecyloxy)thienyl ketone, ~:
methyl 2-(5-tetradecyloxy)thienyl ketoneJ
n-propyl 2-(5-pentadecyloxy)thienyl ketone, :.
methyl 2-(5-hexyl)furyl ketone, ethyl 2-(4-octyl)furyl ketone, isopropyl 2~ hexadecyl)furyl ketone, n-butyl 2-(3-tridecyl)thienyl ketone, methyl 2-(5-tetradecyljthienyl ketoneJ
methyl 2-(5-tetradecyl)furyl ketone, ethyl 2-(5-dodecyl)furyl ketone, tert-butyl 2-~4-heptyl)thienyl ketone, methyl 4-(~,7-dimethyloctyl)-2-furyl ketone, ~ `
ethyl 5-(2,4-diethylnonyl)-2-thienyl ketone~
5~ methylundecyl)-2-furancarboxaldehyde, ~0 5-(3 methyloctadecyloxy)-2-thiophenecarboxaldehyde, ~ , i i~ 4574 M-86 3-(3,7-dimethyloctyloxy)-2-furancarboxaldehyde, 5-(3-methyloctadecylthio)-2-furancarboxaldehyde, methyl 5-(2J4-diethylnonylthio)-2-thienyl ketone, 5-(10-undecenyloxy)-2-thiophenecarboxaldehyde, ;~
methyl 5-( 9J 12-octadecyldienyl)-2-furyl ketone, 5-(3,7~11-trime~hyl-2,6,10-hexadecyltrienyloxy)-2- furyl ketone, ~-(3J7-dimethyl-2,6-octadienylthio)-2-furancarboxaldehydeJ
~-(5,9-dime~hyl~2~4,8-decatrienyl)-2-thiophenecarbox-aldehyde, and ethyl 5-(4,6-dimethyloct-~-enylthio)-2-furyl ketone.
The compounds o~ general Formulas I to IV are useful as antirhinovirus agents. The rhinovirus genus which is a member of the picornavirus family, contains over 100 different antigenic typesJ and is known to be responsible for many of the symptoms attendant respiratory infections.
:
The name rhinovirus is indicative of the prominent nasal involvement seen in infections with these viruses resulting in syndromes charac~erist7cs of the common cold. Rhino-viruses have been classified as serotypes 1 to 89 andsubtypes 1A(88~89J90) with at least 20 more types to be added to the classification. Experimental studies indi-cate nasal mucosa is more susceptible to rhinovirus than -is the lower respi ratory tract. The symptoms of rhino-virus infection have also been produced experimentally by dropping sma71 amounts of the virus on the conjunctiva, indicating that the eye is another susceptible infectious site~ Developed rhinovirus infection is characterized by hyperemia and edema of the mucous membrane with exudation .; , . , . .
1 ~ 4 ~ M-863 of ser-ous and mucinous fluid. The nasal cavities are nar-rowed by thickening of the membrane and engorgement of the turbinates.
The compounds described herein have been found to be effective antiviral agents agalnst numerous types of rhinovirus rendering said compounds useful in treating -~
the symptoms of a rhinovirus infection in hosts susceptible to said infections including humans and certain anthropoid apes such as the chimpanzee. It is known in the art that several test systems can be employed to measure antiviral activity against rhinovirus. for example, antirhinovirus activity can be measured using a plaque assay or tube test wherein the activity of the compound against virus chal-lenge in a cell system is measured. Using a variety of test sys~ems it was found that compounds of general Formula I are effective antirhinov;rus agents ~hen the te~t con~
pound is glven prior to/ concurrently with or subsequent to virus challenge. The utility of the compounds described herein as antirhinovirus agents has been demonstrated in a variety of test systems. For example, using HeLa cell cultures to which a rhinovirus challenge of from 30 to 100 TCID50 is added concurrently with test compounds at a concentration of 4, 20 or 100 ~g/ml after which the cell cultures are incubated for 48 hours it was found upon microscopic examination of the cell cultures that com-pounds of general Formula I markedly inhibit the cyto-pathic effect of the virus when compared to cell cultures containing virus challenge. For example, when the com pound of Example 1 at a concentration of 4 ~g/ml was added to cell cul~ures together with a rhinovirus challenge of ~ M-~6~
100 TCID50 the cytopathic effect of virus was inhibited by ~7~ when compared to control. In a tube test system using ~ ~;
HeLa cells it was found tha-t the tissue culture ED50 of the compound of Example 1 is 0.~ ~g/ml.
In the treatment of symptoms of rhinovirus infection the compounds of general Formulas I to IV can be adminis-tered orally, topically, ~or example~ intranasa11y, and parenteral 1YJ for exampleJ intramuscularly. Topical ad-ministration is preferred. The compounds are administered preferably in the form o~ a pharmaceutical preparation to a host susceptible to rhinovirus infection either prior to or aFter invasion oF virus or after onset of the infection.
For prophylactic treatment it is contemplated that an anti-rhinovirus effective amount of compound be administered for from about 1 to 5 days prior to anticipated exposure to virus and from about ~ to 10 days subsequent to exposure or from about 5 to about 15 days subsequent to exposure to rhinovirus. It is known that rhinovirus is readily trans-mitted from one susceptible host to another as commonly occurs, for example, among family members, in classrooms and in military popula~ions. The compounds of general Formula ~ are also useful therapeutically in treating rhinovirus infections ;n that said compounds are effec-tive in diminishing or blocking replication of the virus.
For prophylactic or therapeutic treatment of rhino-virus infection any antirhinovirus effective amount of a compound of general Formula I may be employed. Fcr thera-peutic treatment the amount of compound administered will vary depending primarily on the severity of the infection.
For therapeutic or prophylactis treatment the amount of compound administered will vary from about 0.1 mg/kg to -~1- ;.' ~ M-863 15 mg/kg of body weigh~ of the patient~ that is) susceptible host. Preferably the amount of compound admlnistered will vary from about 1 mg/kg to about 3 mg/kg. Typica11y a unit dose containing about 25 mg of cornpound administered -from 1 to 6 times daily will achieve the desired effect.
The compounds of general Formula I together with suit-able pharmaceutical carriers can be in the form of solid unit dosage forms such as tablets~ capsules, powders, or in the form of a suppository. The powders can be adminis-tered orally or by insufflation. In the preparation ofsolid unit dosage Forms it may be desirable to micronize the compound to be employed. In solid unit dosage forms the compounds can be combined with conventional carriers, for example, binders, such as acaciaJ corn starch or gelatin, disintegrating agents, such as, corn starch, potato starch or alginic acid, lubricants, such as, stearic acid or magnesium stearate, and inert fillers, such as, lac~ose, sucrose or corn starch.
The compounds of general Formula I may also be ad-ministered as liquid suspensions or solutions using a sterile liquid~ such as, an oil, or water with or without ~
the a~dition of a pharmaceutically suitable surfactant or ~-emulsifying agent for oral, topical or parenteral admin- ~ -. - - , istration, A particularly suitable mode of administration is a liquid formulation of the compounds applied directly to the nasal cavity, for example, in the form of a nose drop. For liquid preparations the compounds can be suit-ably formulated wlth fixed oils, such as~ peanut oil~
sesame oil, cottonseed oil or olive oil Peanut oil and ~0 sesams oil are particularly useful in preparation of .
M-8~
formulations for intramuscular injection~ Such oils can a1SQ b~ employed in the preparation of formula~ions of the soft gelatin type and suppositories, In general, waterJ
salin0, aqueous dextrose and rela~ed sugar solu~ions and glycerolsJ such as, polyethyleneglycol may be employed in the preparation of li~uid ~ormulations which may sui~ab!y eontain suspending agents, such as, methyl cellulose, hydroxypropyl cellulose or carboxymethyl cellulose as well as buff~rs and preservatives.
Illustrative examples o~ switable pharmac~utieal formulat70ns ar~ set for-th hereinbelow.
The ketone compounds of general Formula 1, that is, compounds wherein R1 is a straight or branched alkyl group of from 1 to 4 carbon atoms may be prepared by treating one equiYalent of the corresponding carboxylic acid deri-vatives wtth two equivatents of an appropriat~ alkyl-lithium as generally described by Fieser and Fieser, R~ nt$ for Orqan7c Synthesis9 J, Wiley and Sons~ Inc., New York, p, 688 (1967). This reaction ts suitably carried out in solvents, such as, ether, t~trahydrofuran9 p-dToxane~ dim~thoxyethane or diethyleneglycol dimethyl~
ether at ~emperatures of from -10C to the reflux temp- ~:
~rature of the solvent ~or from 1/2 hour to 10 hours.
The ketone compounds of g~neral Formula I may also be prepared by ~he reaction of alkyl magnesium bromide wherein the alkyl moiety is straight or branched and has from 1 to ~ carbon atoms, and ~he imidazolide deriva~ive of an appropria~ely R-Y substituted thiophene or furan-.
.. ..
f~ , carboxylic acid derivative wherein R and Y have the mean- -ings defined in general Formula 1. This reaction is carried out in solvents such as e~her, tetrahydrofuran, dioxane, dimethoxyethane, or acetonitrile. The reaction mixture is initially cooled to -10C after which the temperature is elevated to from about 25C to the reflux temperature of the solvent, and the reaction time varles from about 1/2 hour to 10 hours. The imidazolide deriva-tive is obtained by treating an appropriately R-Y- sub-stituted thiophene or furan carboxylic acid derivativewith N,N'-carbonyldiimidazole or by treatment of the R-Y~
substituted thiophene or furancarboxylic acid chloride, obtained by treating the substituted carboxylic acid with thionyl chloride, with two equivalents of imidazole as generally described by H. A, Staab, Angew Chem. Internat.
Edit, 1 351 ~1962 ) .
The ketone compounds of general Formula I wherein the R-Y substituent group is attached at the 5- position oF
the furan or thiophene ring may also be prepared by a Friedel-~rafts acylation of an appropriately R-Y- sub-stituted thiophene or furan, wherein R and Y have the meanings defined in general Formula 1, with an acyl halide oF the formula R4-C-halo wherein halo is halogen, prefer-ably chlorine or bromine, and R~ is a straight or branched alkyl group of from 1 to 4 carbon atoms. This reaction is carried out in the presence of an acid catalyst, For example, borontrifluoride-etherate, stannic chloride~
zinc chlorideJ hydriodic acid or orthophosphoric acid and optionally in the presence oF a solvent, for example~
~ M-863 methyl~ne chloride, nitromethane or benzene. Suitable temperatures for this reaction vary from -20C to the reflux temperature oF the solvent) and ~he reaction time varies from about 1/2 hour to 10 hours.
The compounds of general Formula I wherein R1 is hydro-gen and R is a straight or branched saturated hydrocarbon chain having from 6 to 20 carbon atoms may be prepared by chemical or catalytic reduction of the corresponding R-Y-substituted carboxylic acid halide or tertiary amide by methods generally described in J. March,Advanced Orqanic Chemistry. Reactions, Mechanism and Structure, McGraw-Hill, pp. 351 and 352 (1968). Reduction of the corresponding carboxylic acid halides J for example, the acid chloride using a catalytic hydrogenation method to give the aldehyde compounds is known as the Rosenmund reduction and i5 the most common way to prepare the aldehydes. A suitable cata- ~
lyst for this reaction is p~lladium-BaSO4 in a ratio of 1'`
part catalyst to 5 to 10 parts of acid chloride. This reaction may be carried out with or without a regulator such as quinoline sulfur. Suitable solvents for this reaction are dry solvents selected from aromatic hydro-carbons, such as, benzene~ toluene and xylene, non-aromatic hydrocarbons, such as, decalin and ethers, such as, di~
ethyl ether. This reaction may be carried out at tempera-tures of from about 25~ to the reflux temperature of the solvent and the reaction time may vary from about 15 minu~es to 24 hours. The compounds of general Formula I
wherein R1 is hydrogen and R is a straight or branched unsaturated hydrocarbon chain having from 6 to 20 carbon ~0 atoms may be prepared by reduc~ion of the tertiary carbox-~ M-86~
amide or acid halide using a metal hydride reducing agent.
This reaction is carried out in ether solvents, such asJ
diethylether, te~rahydrofuran, dioxane and dimethoxyethane, or aromatic hydrocarbon solvents, such asJ benzene and toluene. The reaction temperature may vary from 0C to the reflux temperature of the solvent, and the reaction time may vary from abou~ 15 minutes to 24 hours. The carbox~
ylic acid halides and carboxamide derivatives can be `~
prepared from the corresponding acid by procedures generally known in the art.
The thiophene carboxaldehydes described herein wherein the R-Y- substituent is attached to the 5- position of the thTophene ring may also be prepared by ~reating an appro~
priately R-Y- subst7tuted th70phene derivative with N-methylforman31ide and phosphorus oxychloride followed by ;~
water hydrolysis as generally described, for example3 in F;eser and Fieser, Advance~ anic Chemistry, Reinhold Publishing Corp., New York (1961).
The R-Y- substituted thiophene derivatives employed herein wherein Y represents sulfur can be obtained in the manner described by E. Profft, Chemiker-Zeitung, 82 298 (1958) and wherein Y represents oxygen can be prepared from the ~-thiolene-2-one ~R.P, Hawkins, Journal Hetero~
cyclic Chemistry, 11 (3) 291-4 (1974)) with a suitable alkyl halide~ alkyl mesylate or a1kyl tosylate in th~
presence of a base, for example, sodium hydride, potassium amide, potassium tert-butylate, sodium or potassium metal, potassium carbonate, sodium carbonate, triethylamine or pyridine ~o yield the 2-alkoxythiophene intermediate.
~0 This reaction may be carried out with or without a solvent.
-~6-. .
~ ,7~ M-86~
Suitable solvents include pyridineJ benzene~ xylene, chlorobenzeneJ ethers~ for example, bis(2-methoxyethyl)-ether or anisoleJ dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide. The alkyl halide may beJ
for exampleJ alkyl chloride, alkyl bromide or alkyl iodide The alkyl moiety in the alkyl halideJ the alkyl mesyla~e or the alkyl tosylate is a hydrocarbon radical containing from 6 to 20 carbon atoms which is straight or branched and which is saturated or unsaturated in which case the.
hydrocarbon radical contains from 1 to 4 double bonds when said radical has from 10 to 20 carbon atoms ancl 1 or
2 double bonds when said rad7cal has from 6 to 9 carbon .
atoms.
R-Y substituted furan and thiophene derivatives : .
employed herein wherein Y is a bond can be obtained by the reaction of 2-lithiofuran or 2-lithiothiophene, pre-pared by treating respectively furan or thiophene with butyllithium, with an R-halide wherein R has the meaning defTned in general Formula I by procedures generally known in the art.
The R-Y- substituted furan derivatives employed herein wherein Y is oxygen or divalent sulfur can be obtained by thermo ~150C) decarboxylation of an ~:
appropriately R-Y- substituted furoic acid by procedures `
known in the art~
The R-Y- substituted furan and thiophene carboxylic acid derivatives used herein wherein Y is oxygen or di-valent sulfur can be prepared by aromatic nucleophilic substitution as generally described in the above cited ~ f~ M-86 March reference at page 500 as outlined below.
R-Y "~ ~ L ~
X C~OH
structure 1 1) base ~ ~ 2~ ac;d R-Y' ~ C-OH
structure 2 In the above general reaction R and X have the meanings de~ined in general Formula 1, Y' is oxygen or divalent sulfur and L represents a leavTng groupJ such as, nitroJ
fluoro~ chloroJ bromo, or iodl), the preferred leaving group being chloro. The substituent group L on compounds of structure 1 and the R-Y' group on compounds of structure 2 may be attached at the 3-, 4- or 5- position o~ the thiophene or furan ring.
The above reaction may be carried out with or without a solvent. Suitable solvents ~or the reaction include benzene, xylene, toluene, chlorinated hydrocarbon solvents, such as, chlorobenzene, ethers, such as, bis(2-methoxy-ethyl)etherJ 132-dimethoxyethane or anisole, dimethyl-formamide, dimethylacetamide, 1-methyl-2-pyrrolidone or pyridine. Preferred solvents are xylene and dimethyl-acetamide. Copper metal or a salt such as cuprous chloride may be optionally added to the reaction. Suitable ZO bases for the reaction include sodium or potassium metal, sodium hydride, potassium amide, potassium tert-butylate or other strong bases, such as, potassium carbonate, potassium hydroxide, sodium hydroxide and sodium carbonateO
The temperature of the reaction varies from about 25C to the reflux temperature of the solvent, and the reaction time varies from about 1 hour to about 7 days. Following completion of the reaction the carboxylate salt derivative is treated with a mineral or organic acid to give compounds of structure 2.
Alcohols as represented by R-Y'H which find use in the above general reaction are commercially available or may be prepared by reductlon of the corresponding carboxylic lQ acid or aldehyde.
The thiophene carboxylic acid derivatives as repre-sented by compounds of structure 1 wherein X is sulfur may be prepared by several methods as described in the Chemistry of_Heterocyclic Compounds, Thiophene and Its :~
Derivatives, by H.D. Hartough, Interscience Publishers, Inc., New York pp. 379-~81 (1952). The furoic acid derivatives as represented by compounds of structure 1 where;n X is oxygen may be prepared by several methods as described in The Furans, by A,P, Dunlop and F.N, PetersJ
Reinhold Publishing Corp., pp. 80 - 169 (195~).
The R-Y- substituted furan and thiophene carboxylic acid derivatives employed herein wherein Y is a bond can be prepared by treating a compound of the structure R ~ Li structure 3 wherein R and X have the meanings defined in general Formula I~ and R is attached at the 4- or 5- position of the furan or thiophene ring with dry ice followed by the ~ ' ~ ~ M-863 addition of water by procedures known in the art. The com-pounds of structure ~ are obtained by metaliza~ion of the appropriately R- substituted furan or thiophene with butyl-lithium. The preparation of the R- substituted furan and ;~
thiophene derivatives wherein R is attached to the 5-position of the heterocyclic ring is described above. The R- substituted thiophene derivatives wherein R is attached ~ ;~
to the 4- posi~ion of the thiophene ring are o~tained by reaction of 1 equivalent of 3-iodothiophene with 1 equiva-len~ of R-iodine wherein R has the meaning defined in general Formula I in the presence of 2 equivalents of sodium metal. The R- substituted Furan der7vatives wherein R is attached to the 4- position of the furan ring are obtained by the reaction of 3-lithiofuran~ obtained by re-action of ~-iodofuran with butyllithium at -70C with R-halide wherein R has the meaning defined in general Formula 1.
The following specific Examples further illustrate -~
the invention.
_AMPLE 1 Methyl 2-(5-tetradecyloxy~furyl ketone (A) A mixture of 125.0 9 (0.552 mole) of 5-bromo-2-furoie acid, 210.0 9 (o.9T8 mole) of 1-tetradecanol, 1~3 0 9 (1.630 mole) of potassium tert-butoxide and 2500 ml of di-methylacetamide is heated with stirring. The tert-butanol formed ;n the reaction is allowed to distill off, then the mixture is heated to reflux with stirring for 48 hours.
To the cooled mixture is added 6 liters of ice-water, and the mixture is acidified with malonic acid. The resulting prec;pitate is collected, dried and recrystallized twice ~ M-86~ ;
from methanol to give 82.0 g (29~) of 5~(tetradecyloxy)-2 furoic acid, M.P. 112-115C (dec.).
(B) A mixture of 82.0 9 (0.25~ mole) of 5-(-tetradecyl-oxy)-2-fwroic ac;d, 41.0 g (0.25~ mole) of N,N'-carbonyldi-imidazole and 800 ml tetrahydrofuran is stirred at roomtemperature during which time carbon dioxîde gas is evolved. The reaction mixture is cooled to 0C to give N-[5-(tetradecyloxy)-2-furoyl]imidazole. The N-substituted imidazole, 50.0 g (0.1~4 mole) in 500 ml tetrahydrofuran ~;
is cooled in an ice bath. An equivalent amount of methyl magnesium bromide (50 ml oF a 3 M solution in ether) is slowly added over a 2 hour period to the stirred mixture.
The reaction is s~irred for an addi~ional ~ hours then excess (500 ml) of 2N HCl is added and the product ex-tracted into ether. The ether extract is separated,washed with water) dried over sodium sulfate, filtered and evaporated to dryness to give methyl 2-(5-tetradecyl-oxy)furyl ketone, M.P. 70-72C.
Methyl ~-(cis~-octadecen 1-yloxy)-2-furyl ketone A mixture of 57.2 (0.300 mole) of 5-bromo-2-furoic acid, 121oOg (0.45 molej of cis-9-octadecenol, 18.0 9 (0.750 mole) of sodium hydride and 2 liters of P-xylene -are heated ~o reflux for 48 hours. The mixture is allowed to cool, then is acidifiPd w;th acetic acid and diluted wi~h 2 li~ers of wa~er. The organic layer is separated, dried, evaporated to dryness, and the residue recrystal-lized from hexane to give 5-(cis-9-octadecen-1-yloxy)-?-furoic acid.
-When in the procedure of Example 1(B) an appropriate amount of 5-(cis-g-octadecen-l-yloxy)^2-furoic acid is substituted for 5-(tetradecyloxy) 2-furoic acid, methyl 5-(cis-9-octadecen-1-yloxy)-2-Furyl ketone is obtained, Ethyl ~-(9,12,15-octadecatrien-1-yloxy)-2-furyl ketone A mixture of 57,0 g (0.300 mole) of 5-bromo-2-furoic acid, 119.0 g (0.450 mole) of 9,12J15-octadecatrienol, and 84 9 (0.750 mole) o~ potassium tert-butox7de in dry tolu-ene is stirred with heating. The tert-butanol formed in the reaction is allowed to distill off, and the mixture is refluxed at 110C with stirring for 48 hours. The mixture is allowed to cool, then is actdified with acetic acid and diluted with ice-water. The toluene organic layer is ;~
separated, washed with water, then extracted~three times with 5~ sodium bicarbonate solution. The combined aqueous extracts are cooled and acidified with 10% HCl solution to give 5-(9,1~,15-octadecatrien-1-yloxy)-2-furoic acid.
When in the procedure of example 1(B) an appropriate amount of 5-(9~12,15-octadecatrien-1-yloxy)-2-furoic acid is substituted for 5-(tetradecyloxy)-2-fLIroic acidj and an appropr7ate amount of ethyl magnesium bromide is sub-stituted for methyl magnesium bromide, ethyl 5-(9,12,15-octadecatrien-1-yloxy)-2-furyl ketone is obtained.
Methyl 2-(5-tetradec ~oxy)thienYl ketone ~A) A mixture of 214 9 (1.0 mole) of 1-tetradecanol, `~
59 g (1046 mole) of sodiu~ hydr7de (59.5~ in oil) and 3 I.
of dried xylene is heated to reflux with stirring for two hours~ then allowed to cool after which 75 ~ (o.46 -22~
:
~ M-863 mole) of 5-chloro-2-thiophene carboxylic acid is added The mixture is refluxed for 64 hours after which it is cooled and poured into a water-ice mixture, acidlfied with acetic acid and extracted with the addition of ether.
The e~her is evaporatedg and the xylane: layer extracted five times wi~h water:strong ammonia solution (1:1). The combined aqueous extract is acidi~ied with acetic acid.
The solid obtained is crystallized twice from hexane to give 2-(5-tetradecyloxy)thiophene carboxylic acid, M.P.
~5-96C.
(B) A mixture of 86.1 g (0.25~ mole) of 2-(5~tetra-ciecyloxy)~hiophene carboxylic acid, 41.0 9 (0.25~ mole) oF N,N'-carbonyldiimidazole and tetràhydrofuranJ is stirred at room temperature during which time carbon dioxide is evolved, then cooled to give N-~5-(tetra-decyloxy)-2-thenoyl]imidazole The N-substituted imid-azole, 52.3 9 (0.134 mole) in tetrahydrofuran is cooled in an ice bath. An equivalent amount of methyl magnesium bromide (50 ml of a 3 molar solution o~ ether) is slowly added over two hours to ~he stirred mixture. The reaction is stirred for an additional three hours, then excess ~500 ml) of 2N HCl is added and the product extracted into ether. The ether layer is separated, washed with wa~er~ dried over sodium sulfate, filteredg and evaporated to dryness to give 5-(te~radecyloxy)-2-thienyl methyl ke~one.
When in the procedure of Example 4(A) an appropriate amount of cis-9-octadecanol is substituted for 1-tetra-~ ]~7~ M 863 decanol, 5-(cis-9-octadecenyloxy)-2-thiophene carboxylic acid is obtained. When an appropriate amount of the thus obtained acid is substltuted for 5-tetradecyloxy-2-thio-phenecarboxylic acid and an appropriate amount of n-propyl magnesium bromide is substituted for methyl ma~nesium bromide in the procedure o~ Example 4(B), n-propyl 5-(cis-9-octadecenyloxy)-2wthienyl ketone is obtained.
Methyl 2-(5-tetradecylthio~thienyl ketone A mixture of 18.6 g (0.090 mole) of 2-(5-bromo)thio-phene carboxylic acid, 25.0 9 (0.109 mole) of 1-tetra-decanethiol and 500 ml of dried dtmethylacetam7de Is stirred at room temperature after which 10.8 9 (0.200 mole) of sodium methoxide is added. The mixture is heated, and the met~anol formed is allowed to spill off. The mixture is refluxed for 24 hours after which the mixture is cooled and poured into a water-ice mixture, acidified with 10~ aqueous hydrochloric acid, filtered and the ;
precipita~e washed with water and dried The solid ob tained is crystallized from methanol then recrystallized from hexane to give 2-(5-tetradecylthio)thiophene carbox-ylic acid, M.P. 106-108C -To 17.8 g (0.05 mole) of 2-(5-tetradecylthio)thio-phene carboxylic acid in tetrahydrofuran cooled in an ice bath is added ~.3 y (0 15 mole) of methyl lithium. The mixture is allowed to warm up to room temperature, then ;
trea~ed with saturated ammonium chloride solution until ~ ~
neutral to litmus paper to give methyl 5-(tetradecylthio)- ~ -2-thienyl ketone.
, ~ ~ ',' M-86~
~ ~ .
n-Butyl 2~(5-te~radecyloxy)thiPnyl ketone A mixture of 20.0 ~ (0.2 mole) of ~-thiolen-2-one [R,T. Hawkins, J. Heterocyclic Chem., 11 291-4 ( 1974) ] : ;
65.5 9 (0.2 mole) of 1-bromo-9~12,15-octadecatriene, and 4.8 9 ~0.2 mole) of sodium hydride in benzene is refluxed with stirring for 24 hours after which the solvent is removedg and the product distilled ~o give 2-(9,12315-octadecatrienyloxy)thiophene, To 6.o 9 of sodium amalgam in 100 ml of anhy~rous ether at reflux temperature (36-~9C) under slight ni~ro-gen pressure ts added 34.7 g (0.10 mole) of 2-(9J12~15-octadecatrienyloxy)thiophene in 50 ml of anhydrous ether over a four hour period. The mixture is refluxed an additional two hours. The mixture is cooled to room $empera~ure and carbonated by adding freshly crushed dry ice after which 20 ml of ethanol is added dropwise Followed by the addition of 50 ml of water. The aqueous solution is separated from the ether layerJ filtered and acid7fied with hydrochloric acid to precipitate 5-(9,12,-15-octadecatrien-1-yloxy)-2-thiophene carboxylic acid.
To ~6.3 9 (0.10 mole) of 5-(9,12,15-octadecatrien-1 yloxy)-2-thiophene carboxylic acid in anhydrous tetra-hydrofuran is added 17.4 9 (O.lQ7 mole) of N,N'-carbonyl-dTImidazole, The mixture is stirred at room temperature until the evolution of carbon dioxide gas ceases after which the mixture is evaporated to dryness, and the resi-due extracted with anhydrous ether. The ether extract is evaporated to dryness to give N-[5-(9,12,15-octadecatrien-~ ~C~ M-863 1-yloxy)-2-thenoyl]imidazole.
When an appropriate amount o~ the thus obtained imidazole is substituted for N-[5-(tetradecyloxy)-2-furoyl]imidazole and an ~ppropriate amount of n-butyl mag-nesium bromide is substituted for methyl magnesium bromidein the procedure of Example 1(B), n-butyl 2-(5-tetradecyl-oxy)thienyl ketone is obtained.
5-Hexadecyloxy-2-thiophenecarboxaldehyde 10(A) A mixture oF 20 g (0.2 mole) of 3-thiolen-2-one [R,T. Hawkins, J. Heterocyclic Chemistry 11, 291-4 (1974)], 61.1 g (0.2 mole) of 1-bromohexadecane, and 9.6 g (002 mole) o~ sodium hydride (50~ in oil) in dry benzene is refluxed with stirring for 24 hours after which the solvent is removed and the product is distilled to give 2-hexadecyloxythiophene.
(B) To a cooled mixture of 27 g of N-methylform- -~
anilide in 27 g (0.176 mole) of phosphorusoxy chloride is added 32.5 g (0.1 mole) of 2-hexadecyloxythiophene.
The mixture is warmed to 70C under vacuum (10 mm Hg).
The mixture is allowed to stand at 60 to 70C for 7 hours then overnight at room temperature after which the mix~
ture is stirred in~o 100 g of ice. The mixture is ex~
tracted into benzene, washed with waterJ dried over sodium~ - -sulfate and distilled in vacuo to give 5-hexadecyloxy-2-thiophenecarboxaldehyde, ~ ,.
.
5-~,7711,15-Tetramethylhexadecyloxy)-2-furancarboxaldehyde (A~ A mix~ure of 59.8 g (0.2 mole) of 3J7,11,15-~0 tetramethyl-l-hexadecanol and 19.2 g (0.4 mole) of sodium :`:
.
~:
~ ~ ~ M-863 hydride (50~ in oil) in 1 li~er of toluene is refluxed with stirring for 2 hours then cooled to room temperatureO
To the mixture 29.~ 9 (0.2 mole) oF 5-chloro-2-furoic acid is added and the mixture is reFluxed with stirring for 24 hours~ Upon cooling to rocm temperature the mix-ture is acidified with glacial acetic acid and water is added. The toluene layer is evaporated and allowed to crystallize to give 5-(~,7,11,15-tetramethylhexadecyloxy)-2-furoic acid.
(B) A mixture of ~7.2 9 (0.1l~ mole) of 5-(~,7,11,15 tetramethylhexadecyloxy)-2-fuoric acid in 300 ml of thionyl chloride is heated to reFlux for 1 hourJ and the excess thionyl chloride is removed by distillation to give 5-(3,7,11,15-tetramethylhexadecyloxy)-2-furanearbox-ylic acid chloride which is combined with 2.8 9 of 2~
palladium-BaS04 catalyst, o.6 g of quinoline-sulfur in 800 ml of xylene. A slow stream of hydrogen gas is passed through the mixture until hydrogen chloride is no longer evolved (about 8 hours). After cooling, the catalyst is removeci by centrifuging, and the solvent is removed under reduced pressure. The residue is dis-tilled to give 5-(3,7,11,15-tetramethylhexadecyloxy)-2-furancarboxaldehyde.
~. .
5-(Dodecyl~hio~-2-thiophenecarboxaldehyde (A) A mixture oF 40.5 9 (0.2 mole) of 1-dodecane-thiol (laurylmercaptan) in 19.2 9 (0.4 mole) of sodium hydride (50~ in oil) in :L liter of toluene îs reFluxed with s~irring for 1 hour ~hen cooled to room temperature.
7f~ M-863 To the mixture 32.5 g (0.2 mole) of 5-chloro-2-thiophene~
carboxyl;c acid is added and the mixture is refluxed with stirring ~or 24 hours after which the mixture is cooled to room temperature and acidified with 5~ aqueous hydr chloric acid. Water is added, and the toluene layer is separated, dried over sodium sulfate and evaporated to give 5-(dodecylthio~-2-thiophenecarboxylic acid.
(B) A mixtwre of ~2.8 g (0.1 mole) of~5-~dodecyl~
thio)-2-thiophenecarboxylic acid in 500 ml oF tetrahydro-furan is stirred in an ice bath. To the cooled mixture . ~ .
is slowly added 19.5 9 (0,12 mole) of 1,1'-carbonyldi-imidazole. The reaction mixture is reluxed for 2 hours, then cooled in an ice bath. Ether and ice water are ;;
. .. .
added to the mixture and the layers separated. The ether ;`
layer is washed with ice water~and 5~aqueous~sodium bi-carbonate then dried over sodium sulfate and evaporated `~
to dryness to give 1-C5-(dodecylthio)-2-thienylcarbonyl]~
1-H-imidazole. T the imidazole in 500 ml of tetrahydro~
~ . .
furan cooled to -20C is slowly added 0.95 9 (0.25 mole) of lithium alum7num hydride in 100 ml of ether. After 1 hour 100 ml of 5% aqueous hydrochloric acid is added dropwise with stirring after which the~mixture is warmed to room temperature, diluted with water and ether and ~, , extracted. The ether layer is washed with~5% aqueous hydrochloric acid,~water and 5~ aqueous sodium bicar-. , bonate then dried over sodium sulfate and evaporated ~to dryness to give 5-(dodecylthio)-~-thiophenecarbox- ~;
aldehyde.
., : :
., ~ .
~ 4 ~ -~ M-86~ ;
Solution Methyl 2-(5-tetradecyloxy)furyl ketoneo~85 9 Alcohol 78.9 ml Isopropyl Myristate 5.0 g Polyethylene Glycol 400 10,0 9 Purified Water qs ad 100 ml Combine the alcoholt isopropyl myrista~e and polyethylene glycol 400 and dissolve the drug substance therein. Add 10 sufficient puri-fied water to give 100 ml.
Tablet For 1~,000 __ .
Methyl 2-(5-dodecyloxy)furyl ketone 75 g Lactose 1,216 Kg Corn Starch o,3 Kg Mix ~he active ingredient, the lactose and corn starch uniformly. Granulate with 10% starch paste. Dry to a moisture content of about 2.5~. Screen through a No. 12 mesh screen. Add and m;x the following:
Magnesium Stearate 0.015 Kg Corn Starch qs ad 1.725 Kg -Compress on a suitable tablet machine to a weight of 00115 g/tablet.
Soft Gelatin Cal~le Methyl 2-(5-tetradecyloxy)furyl ketone 0.25 Kg Polysorbate 80 0.25 Kg Corn Oil qs ad 25.0 Kg Mix and fill into 50,000 sof~ gelatin capsules.
_~9_ :
~ M-86 , !M I ~ ections A~ Oil Type:
5-Tetradecyloxy-2-furancarboxaldehyde 25 mg BHA, BHT aa 0.01~ w/v Peanu~ Oil or Sesame Oil qs 1.0 ml :
B Suspension Type:
Methyl 2-(5-tetradecyloxy)thienyl 25 mg ;
ketone micronized Sodium Carboxymethylcellulose 0.5~ w/v Sod;um Bisulfite 0.02~ w/v Water ~or Injection, qs 1.0 ml EXAMPLE 1~ :
Powder ~ w/w .~;'. ;~
Methyl 2-(5-tetradecyloxy)furyl ketone 1 : .
15 Silicon dioxide, anhydrous ; 0.5 Corn starchJ lactose, fine powder aa qs 4-Octyloxy-2 When in the procedure of Example 9(A) appropriate amounts of 1-octanol and 4-chloro-2-furoic acid are sub-stituted respectively for 3~7311,15-tetramethyl-1-hexa-decanol and 5-chloro-2-furoic acid 4-octyloxy-2-furoic acid is obtained. When in the procedure of Example g(B) an appropriate amount of 4-octyloxy-2-furoic acid is substituted for 5-(~J7,11315-tetramethylhexadecyloxy)~
2-furoic acid, 4-octyloxy-2-furancarboxatdehyde is obtained.
,. :
~ M-863 Methyl 2-(3-decylthio)thienyl ketone ~;~
When in the procedure oF Example 4(A) appropriate amounts of 1-decanethiol and 3-chloro-2-thiophene carbox-ylic acid are substituted respectively for 1-tetradecanol ~ -and 5-chloro-2-thiophene carboxylic acid 2-(3-decylthio)-thiophene carboxylic acid is obtained When in the pro-cedure of Example 4(B) an appropriate amount oF 2-(3-decylthio)thiophene carboxylic acid is substituted For 2-(5-tetradecyloxy)thiophene carboxylic acid~ methyl 2-(3-decylthio)thieny~ ke~one is obtained, When in the procedure of Example 9(B) an appropriate amount oF an acid listed in the following Table I is substituted ~or 5-(397,11,15-tetramethylhexadecyloxy)-2-furoic acid the respective products listed in Table I -- ;
are obtained.
TABLE I
. ,~.~, .
ACID PR~DUCT
5-(trans-trans-~,7J11-tri- 5-(trans-trans-3,7,11-~ri-methy~l-2,6,10-dodecatrienyl- methyl-2,~ dodecatrienyl-oxy)-2-thiophenecarboxylic oxy)-2-thiophenecarboxalde-acid hyde 5-(cis-cis-9,12-octadecadi- 5-(cis-cis-9J12-octadecadi~
enylthi~~2-thiophenecarbox- enylthi~l~2-thiophenecarbox-ylic acid aldehyde 5-tetra~ecyloxy-2-thiophene- 5-tetradecyioxy--2-thioohene-carboxylic acid,M.P. 95-96C carboxaldehyde 5-tetradecylthio-2-thiophene- 5-tetradecylthio 2-thiophene-lco8bcOxylic acid~ M P. 106- carboxaldehyde 5-(~rans~,7-dimethyl-2,6- 5-(trans-3,7-dimethyl-2,6~
octadienyloxy)-3-furoic acid octadienyloxy)-3-furancar-boxaldehyde 5-(10-undecenylthio) 2-fur- 5-(10-undecenylthio)-2-oic acid ~urancarboxaldehyde .
~'' ~ ~g~ 7~ M-86 TABLE l (contlnued) ACID PRODUCT
5-tetradecylthio-2-furoic 5-~etradecylthio-2-furan-acid, M.P, 84~86C carboxaldehyde 5-octadecyloxy-2-furoic acid, 5-octadecy10xy-2-furancar-M~P. 117-118C boxaldehyde 5-dodecyloxy-2-furolc acid~ 5-dodecyloxy-2-~urancarbox-M.P. 122-123C aldehyde 5-deeyloxy-2-furoic acid, 5-decyloxy-2-furancarbox-M.P. 124-126C aldehyde 5-~cis-9-octadecenylox )-2- 5-(cis-9-octadecenyloxy)-furoic acid, M.P. 93-9~ C 2-Furancarboxaldehyde 5-tetradecyloxy-2-furoic 5-tetradecyloxy^2-~urancar-acid J M.P. 112-115C boxaldehyde EXA
Methyl 2-(5-hexyl)furyl ketone A mixture of 68.1 g (1.0 mole) o~ furan and 500 ml of anhydrous ether is s~irred at -20C af~er which 1.1 moles (458 ml of a 2.4 molar hexane solution) oF butyl-lithium is added slowly with stirring. The reaction mixture is stTrred for 1 hour then 198.1 9 (1.2 moles) of 1-bromohexane is added. The reaction mixture is stirred at room temperature for 4 hours after which it is poured ;nto a saturated ammonium chloride solution. The organic layer is separated and washed with water and brine, dried over sodium sulfate and distilled under reduced pressure to give 2-hexylfuran.
A solution of 30.4 g (0.2 moles) of 2 hexylfuran jn 300 ml of anhydrous ether is stirred at -20C after which 0.22 moles (g2 ml of a 2.4 molar hexane solution) of butyllithium is added slowly with stirring The reaction - mixture is stirred for 1 hour then poured over ~00 g of ~2-.
~ 5 ,74 M-863 crushed dry ice (solid C02) after which the mixture ;s allowed to stand for 1 hour prior to dilution wi~h a sat- `
urated ammonium chloride solution. The organic layer is ' separated, washed with water and brine, dried over sodium sulfate and evaporated to give 5 hexyl-2-furancarboxylic acid. The thus obtained acid in 500 ml of anhydrous ether is stirred at room temperature during which time 200 ml of a 2 molar solution of methyllithium in ether is added slowly. The reaction mtxture is allowed to stand at room temperature for 2 hours after which it is poured into a ~`
saturated ammonium chloride solution. The organic layer ~, is separated and washed with water and brineJ dried over `, sodium sulfate and evaporated to dryness to give methyl 2-(5-hexyl)furyl ketone.
_~ .
A solution of 30.8 9 (0.1 mole) of 5-tetradecyl-2-furancarboxylic acid in 300 ml of tetrahydrofuran is stirred in an ice bath. To the cooled mixture is slowly ' added 19.5 9 (0.12 mole) of 1,1'-carbonyldiimidazole.
The reaction mixture i5 refluxed for 2 hours then cooled in an ice ba,th. Ether and ice-water are added to the mixture and the layers separated. The ether layer is washed with ice-water and 5~ aqueous sodium bicarbonate then dried over sodium sulfate and evaporated to dryness to give 1-~5-(tetradecyl)-2 furylcarbonyl]-1-H-imidazole. ~' To the imidazole in 500 ml of tetrahydrofuran cooled to -20C is slowly added 0.95 g (0,25 mole) of lithium aluminum hydride in 100 ml of ether. After 1 hour 100 ml .
~ M-86~ ~
~ ~, or 5~ aqueous hydrochloric acid is added dropwlse with stirring after which the mixture is warmed to room temp~
erature then diluted with water and ether and e~tracted.
,; , ~
The ether layer is washed with 5~ aqueous hydrochloric acid and 5~ aqueous sodium bicarbonate then dried over sodium sulfate and evaporated to dryness to give 5-tetra~
decyl-2-furancarboxaldehyde.
.:
- ~;
~ ' ..
,:
.
. ~ :: : :
.
:~: -: ~
-74~
.
; ;~
: , , _ _ _ . _ . ,_ . , _ .. . .. .. _, .__ .. . . . .. .
atoms.
R-Y substituted furan and thiophene derivatives : .
employed herein wherein Y is a bond can be obtained by the reaction of 2-lithiofuran or 2-lithiothiophene, pre-pared by treating respectively furan or thiophene with butyllithium, with an R-halide wherein R has the meaning defTned in general Formula I by procedures generally known in the art.
The R-Y- substituted furan derivatives employed herein wherein Y is oxygen or divalent sulfur can be obtained by thermo ~150C) decarboxylation of an ~:
appropriately R-Y- substituted furoic acid by procedures `
known in the art~
The R-Y- substituted furan and thiophene carboxylic acid derivatives used herein wherein Y is oxygen or di-valent sulfur can be prepared by aromatic nucleophilic substitution as generally described in the above cited ~ f~ M-86 March reference at page 500 as outlined below.
R-Y "~ ~ L ~
X C~OH
structure 1 1) base ~ ~ 2~ ac;d R-Y' ~ C-OH
structure 2 In the above general reaction R and X have the meanings de~ined in general Formula 1, Y' is oxygen or divalent sulfur and L represents a leavTng groupJ such as, nitroJ
fluoro~ chloroJ bromo, or iodl), the preferred leaving group being chloro. The substituent group L on compounds of structure 1 and the R-Y' group on compounds of structure 2 may be attached at the 3-, 4- or 5- position o~ the thiophene or furan ring.
The above reaction may be carried out with or without a solvent. Suitable solvents ~or the reaction include benzene, xylene, toluene, chlorinated hydrocarbon solvents, such as, chlorobenzene, ethers, such as, bis(2-methoxy-ethyl)etherJ 132-dimethoxyethane or anisole, dimethyl-formamide, dimethylacetamide, 1-methyl-2-pyrrolidone or pyridine. Preferred solvents are xylene and dimethyl-acetamide. Copper metal or a salt such as cuprous chloride may be optionally added to the reaction. Suitable ZO bases for the reaction include sodium or potassium metal, sodium hydride, potassium amide, potassium tert-butylate or other strong bases, such as, potassium carbonate, potassium hydroxide, sodium hydroxide and sodium carbonateO
The temperature of the reaction varies from about 25C to the reflux temperature of the solvent, and the reaction time varies from about 1 hour to about 7 days. Following completion of the reaction the carboxylate salt derivative is treated with a mineral or organic acid to give compounds of structure 2.
Alcohols as represented by R-Y'H which find use in the above general reaction are commercially available or may be prepared by reductlon of the corresponding carboxylic lQ acid or aldehyde.
The thiophene carboxylic acid derivatives as repre-sented by compounds of structure 1 wherein X is sulfur may be prepared by several methods as described in the Chemistry of_Heterocyclic Compounds, Thiophene and Its :~
Derivatives, by H.D. Hartough, Interscience Publishers, Inc., New York pp. 379-~81 (1952). The furoic acid derivatives as represented by compounds of structure 1 where;n X is oxygen may be prepared by several methods as described in The Furans, by A,P, Dunlop and F.N, PetersJ
Reinhold Publishing Corp., pp. 80 - 169 (195~).
The R-Y- substituted furan and thiophene carboxylic acid derivatives employed herein wherein Y is a bond can be prepared by treating a compound of the structure R ~ Li structure 3 wherein R and X have the meanings defined in general Formula I~ and R is attached at the 4- or 5- position of the furan or thiophene ring with dry ice followed by the ~ ' ~ ~ M-863 addition of water by procedures known in the art. The com-pounds of structure ~ are obtained by metaliza~ion of the appropriately R- substituted furan or thiophene with butyl-lithium. The preparation of the R- substituted furan and ;~
thiophene derivatives wherein R is attached to the 5-position of the heterocyclic ring is described above. The R- substituted thiophene derivatives wherein R is attached ~ ;~
to the 4- posi~ion of the thiophene ring are o~tained by reaction of 1 equivalent of 3-iodothiophene with 1 equiva-len~ of R-iodine wherein R has the meaning defined in general Formula I in the presence of 2 equivalents of sodium metal. The R- substituted Furan der7vatives wherein R is attached to the 4- position of the furan ring are obtained by the reaction of 3-lithiofuran~ obtained by re-action of ~-iodofuran with butyllithium at -70C with R-halide wherein R has the meaning defined in general Formula 1.
The following specific Examples further illustrate -~
the invention.
_AMPLE 1 Methyl 2-(5-tetradecyloxy~furyl ketone (A) A mixture of 125.0 9 (0.552 mole) of 5-bromo-2-furoie acid, 210.0 9 (o.9T8 mole) of 1-tetradecanol, 1~3 0 9 (1.630 mole) of potassium tert-butoxide and 2500 ml of di-methylacetamide is heated with stirring. The tert-butanol formed ;n the reaction is allowed to distill off, then the mixture is heated to reflux with stirring for 48 hours.
To the cooled mixture is added 6 liters of ice-water, and the mixture is acidified with malonic acid. The resulting prec;pitate is collected, dried and recrystallized twice ~ M-86~ ;
from methanol to give 82.0 g (29~) of 5~(tetradecyloxy)-2 furoic acid, M.P. 112-115C (dec.).
(B) A mixture of 82.0 9 (0.25~ mole) of 5-(-tetradecyl-oxy)-2-fwroic ac;d, 41.0 g (0.25~ mole) of N,N'-carbonyldi-imidazole and 800 ml tetrahydrofuran is stirred at roomtemperature during which time carbon dioxîde gas is evolved. The reaction mixture is cooled to 0C to give N-[5-(tetradecyloxy)-2-furoyl]imidazole. The N-substituted imidazole, 50.0 g (0.1~4 mole) in 500 ml tetrahydrofuran ~;
is cooled in an ice bath. An equivalent amount of methyl magnesium bromide (50 ml oF a 3 M solution in ether) is slowly added over a 2 hour period to the stirred mixture.
The reaction is s~irred for an addi~ional ~ hours then excess (500 ml) of 2N HCl is added and the product ex-tracted into ether. The ether extract is separated,washed with water) dried over sodium sulfate, filtered and evaporated to dryness to give methyl 2-(5-tetradecyl-oxy)furyl ketone, M.P. 70-72C.
Methyl ~-(cis~-octadecen 1-yloxy)-2-furyl ketone A mixture of 57.2 (0.300 mole) of 5-bromo-2-furoic acid, 121oOg (0.45 molej of cis-9-octadecenol, 18.0 9 (0.750 mole) of sodium hydride and 2 liters of P-xylene -are heated ~o reflux for 48 hours. The mixture is allowed to cool, then is acidifiPd w;th acetic acid and diluted wi~h 2 li~ers of wa~er. The organic layer is separated, dried, evaporated to dryness, and the residue recrystal-lized from hexane to give 5-(cis-9-octadecen-1-yloxy)-?-furoic acid.
-When in the procedure of Example 1(B) an appropriate amount of 5-(cis-g-octadecen-l-yloxy)^2-furoic acid is substituted for 5-(tetradecyloxy) 2-furoic acid, methyl 5-(cis-9-octadecen-1-yloxy)-2-Furyl ketone is obtained, Ethyl ~-(9,12,15-octadecatrien-1-yloxy)-2-furyl ketone A mixture of 57,0 g (0.300 mole) of 5-bromo-2-furoic acid, 119.0 g (0.450 mole) of 9,12J15-octadecatrienol, and 84 9 (0.750 mole) o~ potassium tert-butox7de in dry tolu-ene is stirred with heating. The tert-butanol formed in the reaction is allowed to distill off, and the mixture is refluxed at 110C with stirring for 48 hours. The mixture is allowed to cool, then is actdified with acetic acid and diluted with ice-water. The toluene organic layer is ;~
separated, washed with water, then extracted~three times with 5~ sodium bicarbonate solution. The combined aqueous extracts are cooled and acidified with 10% HCl solution to give 5-(9,1~,15-octadecatrien-1-yloxy)-2-furoic acid.
When in the procedure of example 1(B) an appropriate amount of 5-(9~12,15-octadecatrien-1-yloxy)-2-furoic acid is substituted for 5-(tetradecyloxy)-2-fLIroic acidj and an appropr7ate amount of ethyl magnesium bromide is sub-stituted for methyl magnesium bromide, ethyl 5-(9,12,15-octadecatrien-1-yloxy)-2-furyl ketone is obtained.
Methyl 2-(5-tetradec ~oxy)thienYl ketone ~A) A mixture of 214 9 (1.0 mole) of 1-tetradecanol, `~
59 g (1046 mole) of sodiu~ hydr7de (59.5~ in oil) and 3 I.
of dried xylene is heated to reflux with stirring for two hours~ then allowed to cool after which 75 ~ (o.46 -22~
:
~ M-863 mole) of 5-chloro-2-thiophene carboxylic acid is added The mixture is refluxed for 64 hours after which it is cooled and poured into a water-ice mixture, acidlfied with acetic acid and extracted with the addition of ether.
The e~her is evaporatedg and the xylane: layer extracted five times wi~h water:strong ammonia solution (1:1). The combined aqueous extract is acidi~ied with acetic acid.
The solid obtained is crystallized twice from hexane to give 2-(5-tetradecyloxy)thiophene carboxylic acid, M.P.
~5-96C.
(B) A mixture of 86.1 g (0.25~ mole) of 2-(5~tetra-ciecyloxy)~hiophene carboxylic acid, 41.0 9 (0.25~ mole) oF N,N'-carbonyldiimidazole and tetràhydrofuranJ is stirred at room temperature during which time carbon dioxide is evolved, then cooled to give N-~5-(tetra-decyloxy)-2-thenoyl]imidazole The N-substituted imid-azole, 52.3 9 (0.134 mole) in tetrahydrofuran is cooled in an ice bath. An equivalent amount of methyl magnesium bromide (50 ml of a 3 molar solution o~ ether) is slowly added over two hours to ~he stirred mixture. The reaction is stirred for an additional three hours, then excess ~500 ml) of 2N HCl is added and the product extracted into ether. The ether layer is separated, washed with wa~er~ dried over sodium sulfate, filteredg and evaporated to dryness to give 5-(te~radecyloxy)-2-thienyl methyl ke~one.
When in the procedure of Example 4(A) an appropriate amount of cis-9-octadecanol is substituted for 1-tetra-~ ]~7~ M 863 decanol, 5-(cis-9-octadecenyloxy)-2-thiophene carboxylic acid is obtained. When an appropriate amount of the thus obtained acid is substltuted for 5-tetradecyloxy-2-thio-phenecarboxylic acid and an appropriate amount of n-propyl magnesium bromide is substituted for methyl ma~nesium bromide in the procedure o~ Example 4(B), n-propyl 5-(cis-9-octadecenyloxy)-2wthienyl ketone is obtained.
Methyl 2-(5-tetradecylthio~thienyl ketone A mixture of 18.6 g (0.090 mole) of 2-(5-bromo)thio-phene carboxylic acid, 25.0 9 (0.109 mole) of 1-tetra-decanethiol and 500 ml of dried dtmethylacetam7de Is stirred at room temperature after which 10.8 9 (0.200 mole) of sodium methoxide is added. The mixture is heated, and the met~anol formed is allowed to spill off. The mixture is refluxed for 24 hours after which the mixture is cooled and poured into a water-ice mixture, acidified with 10~ aqueous hydrochloric acid, filtered and the ;
precipita~e washed with water and dried The solid ob tained is crystallized from methanol then recrystallized from hexane to give 2-(5-tetradecylthio)thiophene carbox-ylic acid, M.P. 106-108C -To 17.8 g (0.05 mole) of 2-(5-tetradecylthio)thio-phene carboxylic acid in tetrahydrofuran cooled in an ice bath is added ~.3 y (0 15 mole) of methyl lithium. The mixture is allowed to warm up to room temperature, then ;
trea~ed with saturated ammonium chloride solution until ~ ~
neutral to litmus paper to give methyl 5-(tetradecylthio)- ~ -2-thienyl ketone.
, ~ ~ ',' M-86~
~ ~ .
n-Butyl 2~(5-te~radecyloxy)thiPnyl ketone A mixture of 20.0 ~ (0.2 mole) of ~-thiolen-2-one [R,T. Hawkins, J. Heterocyclic Chem., 11 291-4 ( 1974) ] : ;
65.5 9 (0.2 mole) of 1-bromo-9~12,15-octadecatriene, and 4.8 9 ~0.2 mole) of sodium hydride in benzene is refluxed with stirring for 24 hours after which the solvent is removedg and the product distilled ~o give 2-(9,12315-octadecatrienyloxy)thiophene, To 6.o 9 of sodium amalgam in 100 ml of anhy~rous ether at reflux temperature (36-~9C) under slight ni~ro-gen pressure ts added 34.7 g (0.10 mole) of 2-(9J12~15-octadecatrienyloxy)thiophene in 50 ml of anhydrous ether over a four hour period. The mixture is refluxed an additional two hours. The mixture is cooled to room $empera~ure and carbonated by adding freshly crushed dry ice after which 20 ml of ethanol is added dropwise Followed by the addition of 50 ml of water. The aqueous solution is separated from the ether layerJ filtered and acid7fied with hydrochloric acid to precipitate 5-(9,12,-15-octadecatrien-1-yloxy)-2-thiophene carboxylic acid.
To ~6.3 9 (0.10 mole) of 5-(9,12,15-octadecatrien-1 yloxy)-2-thiophene carboxylic acid in anhydrous tetra-hydrofuran is added 17.4 9 (O.lQ7 mole) of N,N'-carbonyl-dTImidazole, The mixture is stirred at room temperature until the evolution of carbon dioxide gas ceases after which the mixture is evaporated to dryness, and the resi-due extracted with anhydrous ether. The ether extract is evaporated to dryness to give N-[5-(9,12,15-octadecatrien-~ ~C~ M-863 1-yloxy)-2-thenoyl]imidazole.
When an appropriate amount o~ the thus obtained imidazole is substituted for N-[5-(tetradecyloxy)-2-furoyl]imidazole and an ~ppropriate amount of n-butyl mag-nesium bromide is substituted for methyl magnesium bromidein the procedure of Example 1(B), n-butyl 2-(5-tetradecyl-oxy)thienyl ketone is obtained.
5-Hexadecyloxy-2-thiophenecarboxaldehyde 10(A) A mixture oF 20 g (0.2 mole) of 3-thiolen-2-one [R,T. Hawkins, J. Heterocyclic Chemistry 11, 291-4 (1974)], 61.1 g (0.2 mole) of 1-bromohexadecane, and 9.6 g (002 mole) o~ sodium hydride (50~ in oil) in dry benzene is refluxed with stirring for 24 hours after which the solvent is removed and the product is distilled to give 2-hexadecyloxythiophene.
(B) To a cooled mixture of 27 g of N-methylform- -~
anilide in 27 g (0.176 mole) of phosphorusoxy chloride is added 32.5 g (0.1 mole) of 2-hexadecyloxythiophene.
The mixture is warmed to 70C under vacuum (10 mm Hg).
The mixture is allowed to stand at 60 to 70C for 7 hours then overnight at room temperature after which the mix~
ture is stirred in~o 100 g of ice. The mixture is ex~
tracted into benzene, washed with waterJ dried over sodium~ - -sulfate and distilled in vacuo to give 5-hexadecyloxy-2-thiophenecarboxaldehyde, ~ ,.
.
5-~,7711,15-Tetramethylhexadecyloxy)-2-furancarboxaldehyde (A~ A mix~ure of 59.8 g (0.2 mole) of 3J7,11,15-~0 tetramethyl-l-hexadecanol and 19.2 g (0.4 mole) of sodium :`:
.
~:
~ ~ ~ M-863 hydride (50~ in oil) in 1 li~er of toluene is refluxed with stirring for 2 hours then cooled to room temperatureO
To the mixture 29.~ 9 (0.2 mole) oF 5-chloro-2-furoic acid is added and the mixture is reFluxed with stirring for 24 hours~ Upon cooling to rocm temperature the mix-ture is acidified with glacial acetic acid and water is added. The toluene layer is evaporated and allowed to crystallize to give 5-(~,7,11,15-tetramethylhexadecyloxy)-2-furoic acid.
(B) A mixture of ~7.2 9 (0.1l~ mole) of 5-(~,7,11,15 tetramethylhexadecyloxy)-2-fuoric acid in 300 ml of thionyl chloride is heated to reFlux for 1 hourJ and the excess thionyl chloride is removed by distillation to give 5-(3,7,11,15-tetramethylhexadecyloxy)-2-furanearbox-ylic acid chloride which is combined with 2.8 9 of 2~
palladium-BaS04 catalyst, o.6 g of quinoline-sulfur in 800 ml of xylene. A slow stream of hydrogen gas is passed through the mixture until hydrogen chloride is no longer evolved (about 8 hours). After cooling, the catalyst is removeci by centrifuging, and the solvent is removed under reduced pressure. The residue is dis-tilled to give 5-(3,7,11,15-tetramethylhexadecyloxy)-2-furancarboxaldehyde.
~. .
5-(Dodecyl~hio~-2-thiophenecarboxaldehyde (A) A mixture oF 40.5 9 (0.2 mole) of 1-dodecane-thiol (laurylmercaptan) in 19.2 9 (0.4 mole) of sodium hydride (50~ in oil) in :L liter of toluene îs reFluxed with s~irring for 1 hour ~hen cooled to room temperature.
7f~ M-863 To the mixture 32.5 g (0.2 mole) of 5-chloro-2-thiophene~
carboxyl;c acid is added and the mixture is refluxed with stirring ~or 24 hours after which the mixture is cooled to room temperature and acidified with 5~ aqueous hydr chloric acid. Water is added, and the toluene layer is separated, dried over sodium sulfate and evaporated to give 5-(dodecylthio~-2-thiophenecarboxylic acid.
(B) A mixtwre of ~2.8 g (0.1 mole) of~5-~dodecyl~
thio)-2-thiophenecarboxylic acid in 500 ml oF tetrahydro-furan is stirred in an ice bath. To the cooled mixture . ~ .
is slowly added 19.5 9 (0,12 mole) of 1,1'-carbonyldi-imidazole. The reaction mixture is reluxed for 2 hours, then cooled in an ice bath. Ether and ice water are ;;
. .. .
added to the mixture and the layers separated. The ether ;`
layer is washed with ice water~and 5~aqueous~sodium bi-carbonate then dried over sodium sulfate and evaporated `~
to dryness to give 1-C5-(dodecylthio)-2-thienylcarbonyl]~
1-H-imidazole. T the imidazole in 500 ml of tetrahydro~
~ . .
furan cooled to -20C is slowly added 0.95 9 (0.25 mole) of lithium alum7num hydride in 100 ml of ether. After 1 hour 100 ml of 5% aqueous hydrochloric acid is added dropwise with stirring after which the~mixture is warmed to room temperature, diluted with water and ether and ~, , extracted. The ether layer is washed with~5% aqueous hydrochloric acid,~water and 5~ aqueous sodium bicar-. , bonate then dried over sodium sulfate and evaporated ~to dryness to give 5-(dodecylthio)-~-thiophenecarbox- ~;
aldehyde.
., : :
., ~ .
~ 4 ~ -~ M-86~ ;
Solution Methyl 2-(5-tetradecyloxy)furyl ketoneo~85 9 Alcohol 78.9 ml Isopropyl Myristate 5.0 g Polyethylene Glycol 400 10,0 9 Purified Water qs ad 100 ml Combine the alcoholt isopropyl myrista~e and polyethylene glycol 400 and dissolve the drug substance therein. Add 10 sufficient puri-fied water to give 100 ml.
Tablet For 1~,000 __ .
Methyl 2-(5-dodecyloxy)furyl ketone 75 g Lactose 1,216 Kg Corn Starch o,3 Kg Mix ~he active ingredient, the lactose and corn starch uniformly. Granulate with 10% starch paste. Dry to a moisture content of about 2.5~. Screen through a No. 12 mesh screen. Add and m;x the following:
Magnesium Stearate 0.015 Kg Corn Starch qs ad 1.725 Kg -Compress on a suitable tablet machine to a weight of 00115 g/tablet.
Soft Gelatin Cal~le Methyl 2-(5-tetradecyloxy)furyl ketone 0.25 Kg Polysorbate 80 0.25 Kg Corn Oil qs ad 25.0 Kg Mix and fill into 50,000 sof~ gelatin capsules.
_~9_ :
~ M-86 , !M I ~ ections A~ Oil Type:
5-Tetradecyloxy-2-furancarboxaldehyde 25 mg BHA, BHT aa 0.01~ w/v Peanu~ Oil or Sesame Oil qs 1.0 ml :
B Suspension Type:
Methyl 2-(5-tetradecyloxy)thienyl 25 mg ;
ketone micronized Sodium Carboxymethylcellulose 0.5~ w/v Sod;um Bisulfite 0.02~ w/v Water ~or Injection, qs 1.0 ml EXAMPLE 1~ :
Powder ~ w/w .~;'. ;~
Methyl 2-(5-tetradecyloxy)furyl ketone 1 : .
15 Silicon dioxide, anhydrous ; 0.5 Corn starchJ lactose, fine powder aa qs 4-Octyloxy-2 When in the procedure of Example 9(A) appropriate amounts of 1-octanol and 4-chloro-2-furoic acid are sub-stituted respectively for 3~7311,15-tetramethyl-1-hexa-decanol and 5-chloro-2-furoic acid 4-octyloxy-2-furoic acid is obtained. When in the procedure of Example g(B) an appropriate amount of 4-octyloxy-2-furoic acid is substituted for 5-(~J7,11315-tetramethylhexadecyloxy)~
2-furoic acid, 4-octyloxy-2-furancarboxatdehyde is obtained.
,. :
~ M-863 Methyl 2-(3-decylthio)thienyl ketone ~;~
When in the procedure oF Example 4(A) appropriate amounts of 1-decanethiol and 3-chloro-2-thiophene carbox-ylic acid are substituted respectively for 1-tetradecanol ~ -and 5-chloro-2-thiophene carboxylic acid 2-(3-decylthio)-thiophene carboxylic acid is obtained When in the pro-cedure of Example 4(B) an appropriate amount oF 2-(3-decylthio)thiophene carboxylic acid is substituted For 2-(5-tetradecyloxy)thiophene carboxylic acid~ methyl 2-(3-decylthio)thieny~ ke~one is obtained, When in the procedure of Example 9(B) an appropriate amount oF an acid listed in the following Table I is substituted ~or 5-(397,11,15-tetramethylhexadecyloxy)-2-furoic acid the respective products listed in Table I -- ;
are obtained.
TABLE I
. ,~.~, .
ACID PR~DUCT
5-(trans-trans-~,7J11-tri- 5-(trans-trans-3,7,11-~ri-methy~l-2,6,10-dodecatrienyl- methyl-2,~ dodecatrienyl-oxy)-2-thiophenecarboxylic oxy)-2-thiophenecarboxalde-acid hyde 5-(cis-cis-9,12-octadecadi- 5-(cis-cis-9J12-octadecadi~
enylthi~~2-thiophenecarbox- enylthi~l~2-thiophenecarbox-ylic acid aldehyde 5-tetra~ecyloxy-2-thiophene- 5-tetradecyioxy--2-thioohene-carboxylic acid,M.P. 95-96C carboxaldehyde 5-tetradecylthio-2-thiophene- 5-tetradecylthio 2-thiophene-lco8bcOxylic acid~ M P. 106- carboxaldehyde 5-(~rans~,7-dimethyl-2,6- 5-(trans-3,7-dimethyl-2,6~
octadienyloxy)-3-furoic acid octadienyloxy)-3-furancar-boxaldehyde 5-(10-undecenylthio) 2-fur- 5-(10-undecenylthio)-2-oic acid ~urancarboxaldehyde .
~'' ~ ~g~ 7~ M-86 TABLE l (contlnued) ACID PRODUCT
5-tetradecylthio-2-furoic 5-~etradecylthio-2-furan-acid, M.P, 84~86C carboxaldehyde 5-octadecyloxy-2-furoic acid, 5-octadecy10xy-2-furancar-M~P. 117-118C boxaldehyde 5-dodecyloxy-2-furolc acid~ 5-dodecyloxy-2-~urancarbox-M.P. 122-123C aldehyde 5-deeyloxy-2-furoic acid, 5-decyloxy-2-furancarbox-M.P. 124-126C aldehyde 5-~cis-9-octadecenylox )-2- 5-(cis-9-octadecenyloxy)-furoic acid, M.P. 93-9~ C 2-Furancarboxaldehyde 5-tetradecyloxy-2-furoic 5-tetradecyloxy^2-~urancar-acid J M.P. 112-115C boxaldehyde EXA
Methyl 2-(5-hexyl)furyl ketone A mixture of 68.1 g (1.0 mole) o~ furan and 500 ml of anhydrous ether is s~irred at -20C af~er which 1.1 moles (458 ml of a 2.4 molar hexane solution) oF butyl-lithium is added slowly with stirring. The reaction mixture is stTrred for 1 hour then 198.1 9 (1.2 moles) of 1-bromohexane is added. The reaction mixture is stirred at room temperature for 4 hours after which it is poured ;nto a saturated ammonium chloride solution. The organic layer is separated and washed with water and brine, dried over sodium sulfate and distilled under reduced pressure to give 2-hexylfuran.
A solution of 30.4 g (0.2 moles) of 2 hexylfuran jn 300 ml of anhydrous ether is stirred at -20C after which 0.22 moles (g2 ml of a 2.4 molar hexane solution) of butyllithium is added slowly with stirring The reaction - mixture is stirred for 1 hour then poured over ~00 g of ~2-.
~ 5 ,74 M-863 crushed dry ice (solid C02) after which the mixture ;s allowed to stand for 1 hour prior to dilution wi~h a sat- `
urated ammonium chloride solution. The organic layer is ' separated, washed with water and brine, dried over sodium sulfate and evaporated to give 5 hexyl-2-furancarboxylic acid. The thus obtained acid in 500 ml of anhydrous ether is stirred at room temperature during which time 200 ml of a 2 molar solution of methyllithium in ether is added slowly. The reaction mtxture is allowed to stand at room temperature for 2 hours after which it is poured into a ~`
saturated ammonium chloride solution. The organic layer ~, is separated and washed with water and brineJ dried over `, sodium sulfate and evaporated to dryness to give methyl 2-(5-hexyl)furyl ketone.
_~ .
A solution of 30.8 9 (0.1 mole) of 5-tetradecyl-2-furancarboxylic acid in 300 ml of tetrahydrofuran is stirred in an ice bath. To the cooled mixture is slowly ' added 19.5 9 (0.12 mole) of 1,1'-carbonyldiimidazole.
The reaction mixture i5 refluxed for 2 hours then cooled in an ice ba,th. Ether and ice-water are added to the mixture and the layers separated. The ether layer is washed with ice-water and 5~ aqueous sodium bicarbonate then dried over sodium sulfate and evaporated to dryness to give 1-~5-(tetradecyl)-2 furylcarbonyl]-1-H-imidazole. ~' To the imidazole in 500 ml of tetrahydrofuran cooled to -20C is slowly added 0.95 g (0,25 mole) of lithium aluminum hydride in 100 ml of ether. After 1 hour 100 ml .
~ M-86~ ~
~ ~, or 5~ aqueous hydrochloric acid is added dropwlse with stirring after which the mixture is warmed to room temp~
erature then diluted with water and ether and e~tracted.
,; , ~
The ether layer is washed with 5~ aqueous hydrochloric acid and 5~ aqueous sodium bicarbonate then dried over sodium sulfate and evaporated to dryness to give 5-tetra~
decyl-2-furancarboxaldehyde.
.:
- ~;
~ ' ..
,:
.
. ~ :: : :
.
:~: -: ~
-74~
.
; ;~
: , , _ _ _ . _ . ,_ . , _ .. . .. .. _, .__ .. . . . .. .
Claims (8)
1. A process for the preparation of a compound selected from the formula wherein X is oxygen or divalent sulfur; Y' is oxygen or divalent sulfur; R3 is a straight or branched lower alkyl group having from 1 to 4 carbon atoms; and R2 is a straight or branched saturated hydrocarbon group having from 10 to 20 carbon atoms or a straight or branched unsaturated hydrocarbon group having from 10 to 20 carbon atoms and from 1 to 4 double bonds which comprises (a) treating one equivalent of the corresponding carboxylic acid derivative with two equivalents of an alkyl lithium reagent in an ether solvent at about -10°C to the reflux temperature of the solvent for about 0.5 hour to 10 hours, or (b) react-ing an alkyl magnesium bromide compound wherein the alkyl moiety is straight or branched and has from 1 to 4 carbon atoms with the imidazolide derivative of an R2Y' - substi-tuted thiophene- or furancarboxylic acid wherein R2 and Y' have the meanings defined hereinabove in an ether sol-vent or acetonitrile at a temperature of from about -10°C
to the reflux temperature of the solvent for about 0.5 hour to 10 hours.
to the reflux temperature of the solvent for about 0.5 hour to 10 hours.
2. A compound of the formula wherein R2, Y', X and R3 have the meanings defined in claim 1 when prepared by the process of claim 1.
3. A process for the preparation of a compound of the formula wherein R2 is a straight or branched saturated hydrocar-bon group having from 10 to 20 carbon atoms or a straight or branched unsaturated hydrocarbon group having from 10 to 20 carbon atoms and from 1 to 4 double bonds, and R3 is a straight or branched lower alkyl group having from 1 to 4 carbon atoms which comprises (a) treating one equi-valent of the corresponding carboxylic acid derivative with two equivalents of an alkyl lithium reagent in an ether solvent at about -10°C to the reflux temperature of the solvent for about 0.5 hour to 10 hours, or (b) react-ing an alkyl magnesium bromide compound wherein the alkyl moiety is straight or branched and has from 1 to 4 carbon atoms with the imidazolide derivative of an R2O- substi-tuted furancarboxylic acid wherein R2 has the meaning de-fined hereinabove in an ether solvent or acetonitrile at a temperature of from about -10°C to the reflux tempera-ture of the solvent for about 0.5 hour to 10 hours.
4. A compound of the formula wherein R2 and R3 have the meanings defined in claim 3 when prepared by the process of claim 3.
5. A process for the preparation of methyl 2-(5-tetradecyloxy)furyl ketone which comprises treating one equivalent of the corresponding carboxylic acid derivative with two equivalents of methyl lithium in an ether solvent at about -10°C to the reflux temperature of the solvent for about 0.5 hour to 10 hours.
6. Methyl 2-(5-tetradecyloxy)furyl ketone when pre-pared by the process of claim 5.
7. A process for the preparation of methyl 2-(5-tetradecyloxy)furyl ketone which comprises reacting methyl magnesium bromide with the imidazolide derivative of 5-(tetradecyloxy)-2-furoic acid in an ether solvent or ace-tonitrile at a temperature of about -10°C to the reflux temperature of the solvent for about 0.5 hour to 10 hours.
8. Methyl 2-(5-tetradecyloxy)furyl ketone when pre-pared by the process of claim 7.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US75113976A | 1976-12-20 | 1976-12-20 | |
| US751,139 | 1976-12-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1104574A true CA1104574A (en) | 1981-07-07 |
Family
ID=25020661
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA290,375A Expired CA1104574A (en) | 1976-12-20 | 1977-11-07 | Antirhinovirus agents |
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| Country | Link |
|---|---|
| JP (1) | JPS5377055A (en) |
| AU (1) | AU512654B2 (en) |
| BE (1) | BE862066A (en) |
| CA (1) | CA1104574A (en) |
| DE (1) | DE2755750A1 (en) |
| DK (1) | DK564977A (en) |
| ES (1) | ES465093A1 (en) |
| FR (1) | FR2374319A1 (en) |
| GB (1) | GB1539636A (en) |
| IE (1) | IE45905B1 (en) |
| IL (1) | IL53386A0 (en) |
| NL (1) | NL7713825A (en) |
| NZ (1) | NZ185688A (en) |
| SE (1) | SE436878B (en) |
| ZA (1) | ZA776821B (en) |
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| JPH0213066U (en) * | 1988-07-12 | 1990-01-26 | ||
| US4980371A (en) * | 1988-12-21 | 1990-12-25 | Merrell Dow Pharmaceuticals | Antiretroviral furan ketones |
| US4977185A (en) * | 1988-12-21 | 1990-12-11 | Merrell Dow Pharmaceuticals | Antiretroviral aryloxy substituted furan ketones |
| AU621434B2 (en) * | 1988-12-21 | 1992-03-12 | Merrell Dow Pharmaceuticals Inc. | Antiretroviral furan ketones |
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| US2746973A (en) * | 1955-05-27 | 1956-05-22 | Du Pont | 5-alkylmercapto-2-heterocyclic aldehydes and ketones |
| US4000164A (en) * | 1973-04-02 | 1976-12-28 | Richardson-Merrell Inc. | Hypolipidemic agents |
-
1977
- 1977-11-07 CA CA290,375A patent/CA1104574A/en not_active Expired
- 1977-11-14 IE IE2306/77A patent/IE45905B1/en not_active IP Right Cessation
- 1977-11-15 IL IL53386A patent/IL53386A0/en unknown
- 1977-11-15 ZA ZA00776821A patent/ZA776821B/en unknown
- 1977-11-15 NZ NZ185688A patent/NZ185688A/en unknown
- 1977-11-23 AU AU30867/77A patent/AU512654B2/en not_active Expired
- 1977-12-09 JP JP14733277A patent/JPS5377055A/en active Granted
- 1977-12-14 NL NL7713825A patent/NL7713825A/en not_active Application Discontinuation
- 1977-12-14 SE SE7714210A patent/SE436878B/en not_active IP Right Cessation
- 1977-12-14 DE DE19772755750 patent/DE2755750A1/en not_active Ceased
- 1977-12-15 GB GB52182/77A patent/GB1539636A/en not_active Expired
- 1977-12-15 ES ES465093A patent/ES465093A1/en not_active Expired
- 1977-12-19 DK DK564977A patent/DK564977A/en not_active Application Discontinuation
- 1977-12-19 FR FR7738319A patent/FR2374319A1/en active Granted
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Also Published As
| Publication number | Publication date |
|---|---|
| JPS622565B2 (en) | 1987-01-20 |
| JPS5377055A (en) | 1978-07-08 |
| BE862066A (en) | 1978-04-14 |
| ZA776821B (en) | 1978-09-27 |
| IE45905B1 (en) | 1982-12-29 |
| IE45905L (en) | 1978-06-20 |
| DE2755750A1 (en) | 1978-06-22 |
| IL53386A0 (en) | 1978-01-31 |
| SE7714210L (en) | 1978-06-21 |
| DK564977A (en) | 1978-06-21 |
| AU3086777A (en) | 1979-05-31 |
| GB1539636A (en) | 1979-01-31 |
| NL7713825A (en) | 1978-06-22 |
| AU512654B2 (en) | 1980-10-23 |
| SE436878B (en) | 1985-01-28 |
| FR2374319A1 (en) | 1978-07-13 |
| NZ185688A (en) | 1980-09-12 |
| ES465093A1 (en) | 1978-12-01 |
| FR2374319B1 (en) | 1980-10-17 |
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