NZ198879A - Tetra substituted benzene derivatives and pharmaceutical compositions - Google Patents

Tetra substituted benzene derivatives and pharmaceutical compositions

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Publication number
NZ198879A
NZ198879A NZ198879A NZ19887981A NZ198879A NZ 198879 A NZ198879 A NZ 198879A NZ 198879 A NZ198879 A NZ 198879A NZ 19887981 A NZ19887981 A NZ 19887981A NZ 198879 A NZ198879 A NZ 198879A
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New Zealand
Prior art keywords
hydroxy
methoxyphenyl
methoxy
phenyl
ethoxy
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NZ198879A
Inventor
N Shinma
M Fujiu
I Umeda
T Ohtsuka
H Ishitsuka
Y Suhara
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Hoffmann La Roche
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Application filed by Hoffmann La Roche filed Critical Hoffmann La Roche
Publication of NZ198879A publication Critical patent/NZ198879A/en

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    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
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    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/60—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/22—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and doubly-bound oxygen atoms bound to the same carbon skeleton
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    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
    • C07C323/40—Y being a hydrogen or a carbon atom
    • C07C323/42—Y being a carbon atom of a six-membered aromatic ring
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    • C07C327/00—Thiocarboxylic acids
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    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
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    • C07C45/54—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition of compounds containing doubly bound oxygen atoms, e.g. esters
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    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
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    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
    • C07C45/74—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups combined with dehydration
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    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
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    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
    • C07C65/24—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
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    • 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
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
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    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
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    • 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
    • C07D333/06—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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Description

New Zealand Paient Spedficaiion for Paient Number 1 98879 r 198879 Priority Dats(s): . $?P.J. ( Cons*T, cp?eifif«on ,.4 FEB isffl P.O. Journal Pec: '?&7 ct^LS! n is NEW ZEALAND PATENTS ACT, 1953 No.: Date: COMPLETE SPECIFICATION TETRA-SUBSTITUTED BENZENE DERIVATIVES Jl^We, F. HOFFMANN-LA ROCHE & CO. AKTIENGESELLSCHAFT, 124-184 Grenzacherstrasse, Basle, Switzerland, a Swiss company, hereby declare the invention for which H / we pray that a patent may be granted to flfife/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - (followed by la) aoop 79 i \j <./1 ' - la - The present invention relates to novel tetra-substituted benzene compounds, a process for the preparation thereof and antiviral agents containing same.
More particularly, the present invention relates 5 to novel tetra-substituted benzene compounds of the general formula wherein X represents an oxygen or sulphur atom or hydroxyimino; Y represents methylene or iraino; R1 represents hydroxy, phosphonooxy, glycosyloxy, acylated glycosvloxyj acvloxy or lower alkoxycarbonyl-2 oxy; R represents lower alkoxy, lower alkenyloxy or lower alkylthio; R^ represents lower alkoxv; 4 • R represents lower alkvl, p-lower-alkoxy-benzoyl or a substituted or unsubstituted phenyl, benzyl, pyridylmethvl, furfuryl, tetrahvdrofurfuryl, thenyl, tetrahydrothenyl , pyrrolvlmethyl,pyrrolinyimetnyl or pyrrolidinylnethyl group, with the proviso that 4 when R represents alkyl, phenyl, substituted phenyl, . 20 benzyl or p-hvdroxybanzyl , Y does not: represent a 19 387') methylene radical; and with the further proviso that 4 when R represents p-methoxybenzyl and Y represents 2 3 methylene, R and R Sire different, and pharmaceutically acceptable salts thereof.
» Preferred examples of glycosyloxy and acylated glycosyloxy are 3-D-glucopyranosyloxy and tetra-O-acetyl- 3-D-glucopyranosyloxy. The acyloxy radicals are preferably derived from aliphatic acids containing from 2 to 18 carbon atoms or from aromatic acids, preferred acyloxy radicals being lower alkanoyloxy radicals containing from 2 to 7 carbon atoms such as acetoxy, propionyloxy, butyryloxy and iso-butyryloxy, pivaloyloxy, stearoyloxy and benzoyloxy. The lower alkoxycarbonyloxy radicals contain preferably up to 7 carbon atoms, a preferred alkoxycarbonyloxy radical being ethoxycarbonyloxy.
The lower alkoxy radicals contain preferably from 1 to 6 carbon atoms, especially from 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy or butoxy. The lower alkylthio radicals contain preferably 1 to 6 carbon atoms especially from 1 to 4 carbon atoms, such as methylthio. The lower alkyl 20 radicals contain preferably from 1 to 6 carbon atoms, especially from 1 to 4 carbon atoms, such as methyl, ethyl, propyl and butyl. The lower alkenyloxy radicals contain preferably from 2 to 7 carbon atoms, especially from 2 to 4 carbon atoms, such as allyloxy and 3-methyl-25 2-proDenyloxy. Preferred examples of substituted phenyl, benzyl and pvridyimethyl radicals are lower alkoxy phenyl such as p-methoxyphenyl; benzyl which is substituted by N.Z. PATENT OFFICE ' 6 NOV 1984 RFrpiurr* 198879 one or more substituents such as hydroxyl, halogen, lower alkyl, lower alkoxy, lower alkylthio, amino, dialkylamino, allyloxy, benzyloxy and alkylenedioxy, especially p-hydroxybenzyl, m-hydroxy-p-methoxybenzyl, p-chloro-benzyl, p-methylbenzyl, p-methoxybenzyl, m-methoxybenzyl, m,p-dimethoxybenzyl, p-butoxybenzyl, p-(methylthio)benzyl, p-(dimethylamino)-benzyl, p-(allyloxy)benzyl, p-(benzyl-oxy)benzyl, and m,p-(methylenedioxy)benzyl. An exemplary pyridylmethyl radical is 4-pyridylmethyl. Preferred examples of substituted furfuryl, thenyl and pyrrolyl-methyl radicals and saturated derivatives thereof are furfuryl, 5-methylfurfuryl, tetrahydro-5-methylfurfuryl, 2-thenyl, tetrahydro-2-thenyl, and 2-pyrrolylmethyl.
A preferred group of compounds of formula I are 2 those wherein R is lower alkoxy or lower alkylthio and 13 4 R , R , R , X and Y are as defined above.
Also preferred are compounds of formula I wherein R^ is hydroxy, lower alkanoyloxy, benzoyloxy, phosphonooxy, 2 lower alkoxycarbonyloxy; R is lower alkoxy or lower 3 4 alkenyloxy; R is lower alkoxy; R is substituted phenyl; and X is a oxygen or sulfur atom and Y is methylene or imino, especially those wherein Y is imino. Compounds of particular interest are 4-ethoxy-2-hydroxy-6-methoxy-N- (p-methoxybenzyl)-benzamide, 2-[(p-anisylamino)carbony1]- -ethoxy-3-methoxyphenyl dihydrogen phosphate and the disodium salt thereof.
According to the process provided by the present invention, the novel tetra-substituted benzene compounds of formula I and their pharmaceutically acceptable salts are prepared by (a) hydrogenating a compound of the general formula 12 3 ^ wherein X, R , R , R and R" are as defined for formula I, in the presence of a catalyst in a solvent, or (b) reacting a reactive derivative of a carboxylic acid of the general formula 2 3 wherein R and R are as defined 11 for formula I and R represents a protected hydroxyl radical, with a compound of the general formula R4 - NH2 IV 4 j= wherein R is as defined tor formula I, and then removing the protecting moiety of the protected hydroxyl radical, or (c) reacting an acetophenone of the general formula 1 rno ""() 1 ; o o i ' 12 3 wherein R , R and R are as defined for formula I, with iodine in a tertiary 'amine and reacting a resulting salt with an amine of formula IV hereinbefore. or (d) subjecting an ester of the general formula VI -i- R' 2 3 4 wherein R , R and R axe as defined for formula I, to rearrangement in the presence of a base in a solvent, or (e) reacting a ketone of the general formula VII 2 3 4 wherein R , R and R are as defined for formula I, with a salt of hydroxylamine in a solvent, or OOQ j 'ju / _ .;,7 - (f) reacting a carbonyl compound of the general formula OH 0 2 3 4 wherein Y, R , R and R are as defined for formula If with phosphorus pentasulphide in the presence of a base in a solvent, or (g) reacting a phenol of the general formula IX N.Z. patenTr^P 16 NOV 1984 1 928 wherein Y, R2, R3 and R1* are as defined for formula I and X' represents an oxygen or sulphur atom, with an acylating agent in the presence of a base, 5 or (h) reacting a phenol of formula IX hereinbefore with phosphorus oxychloride or dibenzylphosphoro-chloridate in the presence of a base in a solvent followed by hydrolysis or hydrogenolysis as the case may require and, if necessary, converting a resulting compound into a salt, or (i) reacting a phenol of formula IX hereinbefore with a glycosyl halide,which may be acylated, in the presence of a catalyst in a solvent, followed, if necessary, by removal of the acyl radicals.
The hvdrogenation in accordance with embodiment (a) of the process can be carried out by treating a compound of formula II with hydrogen in the presence of a catalyst such as palladium black, palladium-on- charcoal and the like in a solvent such as chloroform. - .% - 198879 The reaction in accordance with embodiment (b) of the process can be effected by reacting a reactive derivative of a carboxylic acid of formula III with an amine of formula (IV) followed by removal of the 5 protecting moiety of the protected hydroxyl radical in the resulting compound. Preferred examples of such reactive derivatives of carboxylic acids of formula III are acyl halides such as acyl chlorides, acyl bromides and the like and active esters such as 10 the N-hydroxysuccinimide ester, p-nitrophenyl ester and the like. The removal of the protecting moiety of the protected hydroxy! radical can be performed by a method known per se.
The reaction in accordance with embodiment (c) 15 of the process is a novel reaction. In carrying out this reaction, an acetophenone of formula V is reacted with iodine in a tertiary amine such as pyridine, lutidine or the like at an elevated temperature and subsequently a resulting salt is reacted with an amine 20 of formula IV. 198879 The base-catalized rearrangement in accordance with embodiment (d) of the process can be carried out by subjecting an ester of formula VI to rearrangement in the presence of a base such as potassium carbonate, 5 sodium hydride, sodium amide or the like in a solvent such as benzene, toluene, tetrahydrofuran, dioxan or the like.
The oximation in accordance with embodiment (e) of the process can be effected by reacting a ketone of 10 formula VII with a salt of hydroxylamine in a solvent such as dimethyl sulphoxide.
The reaction in accordance with embodiment (f) of the process can be carried out by reacting a carbonyl compound of formula VIII with phosphorus pentasulphide 15 in the presence of a base such as triethylamine in a solvent such as carbon disulphide.
The acylation of the hydroxyl radical in a phenol of formula IX in accordance with embodiment (g) of the 198879 process can be carried out- in a manner known per se by treatment with an acylating agent such as acetic anhydride, ethoxycarbonyl chloride, stearic anhydride, benzoyl chloride or the like in the presence of a base such as sodium acetate, pyridine, triethylamine, 4-(dimethylamino)pyridine or the like.
The phosphorylation of the hydroxyl radical in a phenol of formula IX in accordance with embodiment (h) of the process can be effected in a manner known per se by treatment with phosphorus oxychloride or dibenzyl-phosphorochloridate in the presence of a base such as triethylamine, N,N-diisopropylamine or the like in a solvent such as benzene, toluene, triethylamine or the like. When phosphorus oxychloride is used, the resulting compound is hydrolyzed. When dibenzylphosphorochloridate is used, the resulting compound is subject to hydrogen-olysis. The phosphate of a compound of formula IX thus obtained may be converted into a salt by a process known per se. 198879 The glycosidation of the hydroxyl radical in a phenol of formula IX in accordance with embodiment (i) of the process can be carried out in a manner known per se by treatment with a glycosyl halide in which the hydroxyl radicals are protected by protecting radicals such as acetyl, benzyl and the like. Preferred glycosyls are glucosyl, mannosyl, glucosaminyl and the like.
The compounds of formula I provided by the present invention exhibit an antiviral activity and, in particular, inhibit the replication of human rhinoviruses in Hela cell culture at 0.001 to 2.7 ug/ml.
The present invention also relates to antiviral agents containing a compound of formula I or a pharmaceutically acceptable salt thereof. The compounds of formula I are particularly effective against certain viruses of the Picorna group. However, the following compounds have particularly strong antiviral activity: 198879 1-(4-Ethoxy-2-hydroxy-6-methoxyphenyl)-3-(4-methoxy-phenyl)-1-propanone, -ethoxy-3-methoxy-2-[3-(p-methoxypheny1)-propionyl]phenyl acetate, 5 i 4-ethoxy-2-hydroxy-6-methoxy-N-(p-methoxy benzyl) benzamide, 2-hydroxy-4,6-dimethoxy-N-[p-(methylthio)benzyl]-, benzamide, 2-{/ [p~(allyloxy)benzyl]amino_7carbonyl}-3,5--dimethoxyphenyl benzoate, 1-(4-ethoxy-2-hydroxy-6-methoxypheny1)-3-- (4-methoxyphenyl)-1-propanethione, -ethoxy-3-methoxy-2-[3-(4-methoxyphenyl)-propionyl]phenyl ethyl carbonate, 15 _ 2-[ (p-anisylamino)carbonyl]-5-ethoxy-3--methoxyphenyl dihydrogen phosphate^ disodium 2-[(p-anisylamino)carbonyl]-5-ethoxy--3-methoxyphenyl phosphate^ 2-hydroxy-6-methoxy-4-propoxy-N-(p-methoxybenzyl) 2 0 benzamide, 4-(allyloxy)-2-hydroxy-6-methoxy-N-(p-methoxybenzyl )benzamide, 2-hydroxy-6-methoxy-4-(3-methyl-2-butenyloxy)-N-(p-methoxybenzyl)benzamide and 25 disodium 2-[(p-anisylamino)carbonyl]-3-methoxy- -propoxyphenyl phosphate. _ 14 - 198879 Antiviral Activity 4 A suspension of HeLa cells (6 x 10 ) was mixed 3 with rhinovirus HGP (3 x 10 plaque-forming units, PFU) and was plated in a microtest plate containing the compounds to be tested serially diluted. The cells were then cultured with Eagle's minimum essential medium containing 2% calf serum, 1% tryptose phosphate broth, 100 ng/m£ of streptomycin and 20 units/ml of penicillin G. The viral C.P.E. (cytopathogenic effect) and cytotoxicity were observed by a microscope after 2 days culture at 33°C. The antiviral activity (IC^q) of the test compounds is expressed by the concentration inhibiting the viral C.P.E. by 50% when compared with the control culture. The cytotoxicity is expressed as the minimum concentration at which toxic symptoms were observed (cytotoxic dose).
The results are shown in Table 1 and demonstrate 198879 that the compounds provided by the present invention exhibit anti-rhinovirus activity at concentrations which are 10 to 10,000 times lower than their cytotoxic doses. -ethoxy-2-hydroxy-6-methoxypheny1)-3-(4-methoxyphenyl)--1-propanone (compound A) and 4-ethoxy-2-hydroxy-6--methoxy-N-(p-methoxybenzyl)benzamide (compound -B) against various serotypes of rhinovirus are shown in 10 Table 2.
In addition, the antiviral spectra of 1—(4— - ret - 19887 9 Table 1 Compound IC50 (ng/mJi) Cytotoxicity (|jg/m£ ) 1- (2-Hydroxy-4,6-dimethoxy-phenyl)-3-[3,4-(methylene-dioxy)phenyl]-1-propanone 0.03 - 0.1 >8 1- (2-Hydroxy-4,6-dimethoxy-phenyl)-3-[4-methylthio)-phenyl]-1-propanone 0.01 - 0.03 8 1- (2-Hydroxy-4,6-dimethoxy-phenyl)-3-(4-methylphenyl)--1-propanone 0.01 - 0.03 >8 1-(4-Ethoxy-2-hydroxy-6--methoxyphenyl)— 3—(4— -methoxyphenyl)-1-propanone 0.002 >8 -Ethoxy-3-methoxy-2-[3-(p--methoxypheny1)propionyl]-phenyl dihydrogen phosphate 0.3 - 0.8 >10 -Ethoxy-3-methoxy-2-[3-(p--methoxypheny1)propionyl]-phenyl acetate 0.001 >8 1-(2-Hydroxy-4,6-dimethoxy-phenyl)-3-(4-methoxyphenyl)--1-propanone oxime (Z-isomer ) 0.03 >10 1-(2-Hydroxy-4,6-dimethoxy- 1 phenyl)-3-(4-methoxyphenyl)- 0.3 - 0.9 -1-propanone oxime (E isomer) >10 2-Hydroxy-4,6-dimethoxy--N-(p-methoxybenzyl)-benzamide 0.002 8 3-(4-Chlorophenyl)-1-(2--hydroxy-4,6-dimethoxypheny 1)-1-propanone 0.1 198879 Table 1 (continued) Compound IC50 (ng/mJl) Cytotoxicity (ng/m2. ) 1- (2-Hydroxy-4,6-dimethoxy-phenyl)-3-(5-methyl-2-furyl) -1-propanone 0.9 >8 1- (2-Ethoxy-6-hydroxy-4--methoxypheny1)-3-(4--methoxypheny1)-1--propanone 0.01 - 0.03 0.9 1-(2-Hydroxy-4,6-dimethoxypheny l)-3- (4-methoxyphenyl) --1,3-propanedione 0.01 - 0.03 8 1-(2-Hydroxy-6-methoxy-4--propoxyphenyl)-3-(4--methoxypheny1)-1--propanone 0.004 - 0.01 2.7 1-(2-Hydroxy-4-isopropoxy--6-methoxyphenyl)-3-(4--methoxyphenyl)-1-propanone 0.03 - 0.1 8 4-Ethoxy-2-hydroxy-6--methoxy-N-(p-methoxybenzyl) benzamide 0.002 >10 1- (2-Hydroxy-4,6-dimethoxypheny 1)-3- (tetrahydro-5--methyl-2-furyl)-1--propanone 0.9 >8 2-Hydroxy-4,6-dimethoxy-N--(4-methoxyphenyl)benzamide 0.03 - 0.1 >10 N-Benzy1-2-hydroxy-4,6--dimethoxybenzamide 0.03 - 0.1 >8 198879 Table 1 (continued) Compound IC50 (ng/rm ) Cytotoxicity (ng/mji) 2-Hydroxy-4,6-dimethoxy--N-[m,p-(methylenedioxy)-benzyl]benzamide 0.003 - 0.01 >8 2-Hydroxy-4,6-dimethoxy--N-(m-methoxybenzyl)-benzamide 0.002 >8 2-Hydroxy-4,6-dimethoxy--N-(p-methylbenzyl)-benzamide 0.01 - 0.03 8 N-(p-Chlorobenzyl)-2--hydroxy-4,6-dimethoxy-benzamide 0.01 - 0.03 >2.4 N-Furfuryl-2-hydroxy-4,6--dimethoxybenzamide 0.03 - 0.1 >8 2-Hydroxy-4,6-dimethoxy-N--me thylbenzamide 0.9 >8 2-Hydroxy-N-(m-hydroxy-p--methoxybenzyl)-4,6--dimethoxybenzamide 0.1 - 0.3 2.7 N-(m,p-Dimethoxybenzyl)-2--hydroxy-4,6-dimethoxy-benzamide 0.3 8 2-Hydroxy-4,6-dimethoxy-N--[(4-pyridyl)methyl]-benzamide ! 0.9 i 1 j ] 8 198879 Table 1 (continued) Compound IC50 (ng/ms,) Cytotoxicity (ng/mji) N- (p-Butoxybenzyl)-2--hydroxy-4,6-dimethoxy-benzamide 0.3 3 2-Hydroxy-N-(p-hydroxy-benzyl)-4,6-dimethoxy-benzamide 0.3 >8 N-[p-Dimethylamino)benzyl]--2-hydroxy-4,6-dimethoxy-benzamide 0.01 >8 2-Hydroxy-4,6-dimethoxy-N--[p-(methylthio)benzyl]-benzamide 0.002 >8 N"- [p- (Benzyloxy) benzyl] -2--hydroxy-4,6-dimethoxy-benzamide 0.3 - 0.9 >8 2-Hydroxy-4,6-dimethoxy-N--(2-thenyl)benzamide 0.03 8 N-[p-(Allyloxy)benzyl]-2--hydroxy-4,6-dimethoxy-benzamide 0.01 8 2-Hydroxy-4,6-dimethoxy-N--(tetrahydro-2-thenyl)-benzamide 0.004-0.01 8 2-Hydroxy-4,6-dimethoxy-N--C(2-pyrrolyl)methyl]-benzamide 2.7 >8 ' _ 19887 9 Table 1 (continued) Compound IC50 (Mg/mA) Cytotoxicity (ng/nU) 2-[(p-Anisyiamino)-carbonyl]-5-ethoxy-3--methoxyphenyl acetate 0.3 >8 2-[[[p-(Allyloxy)benzyl]-amino]carbonyl]-3,5--dimethoxyphenyl benzoate 0.002 2.7 2-{/"[g-(allyloxy)benzyl]-amino_/carbonyl}-3,5--dimethoxyphenyl octa-decanoate 0.3 >8 1-(4-Ethoxy-2-hydroxy-6--methoxypheny1)-3-(4-methoxyphenyl) 1-propanethione 0.002 r-• CM 4-Ethoxy-2-hydroxy-6-methoxy--N-(p-methoxybenzyl)thio-benzamide 0.01 >8 1-[2-Hydroxy-6-methoxy-4--(methylthio)phenyl]-3--(4-methoxyphenyl)-1--propanone 0.1 1 -Ethoxy-3-methoxy-2-[3-(4--methoxyphenyl)propionyl]-phenyl ethyl carbonate 0.002 8 -Ethoxy-3-methoxy-2-[3-(4--methoxyphenyl)propionyl]-phenyl octadecanoate ■ . 1 0.9 >8 i - /2i - >98879 Table 1 (continued) Compound 1CS0 (pg/m£) Cytotoxicity (ng/mil) -Ethoxy-3-methoxy-2-[3--(4-methoxyphenyl)-propionyl]phenyl benzoate 2-[(p-Anisylamino)carbonyl]--3,5-dimethoxyphenyl ethyl carbonate 2-C(p-Anisylamino)carbonyl]--3/5-dimethoxyphenyl benzoate 2—[(p-Anisylamino)carbonyl]-—3,5-dimethoxyphenyl octadecanoate 2-[(p-Anisylamino)carbonyl]--3,5-dimethoxyphenyl tetra-O;--acetyl 3-D-glucopyranoside 2-[(p-Anisylamino)carbonyl]--3,5-dimethoxyphenyl 0—D— -glucopyrano s ide -Ethoxy-3-methoxy-2-[3-(4--methoxyphenyl)propionyl]-phenyl 0—D-glucopyranoside Disodium 5-ethoxy-3-methoxy--2-[3-(4-methoxyphenyl)-propionyl]phenyl phosphate 0.01 0.1 0.03 0.3 - 0.9 2.7 2.7 2.7 0.03 - 0.1 >8 >8 >8 >10 >10 >10 >10 198879 Table 1 (continued) Compound IC50 (ng/nui) Cytotoxicity (Mg/m£) 2-C(p-Anisylamino)carbonyl]--3,5-dimethoxyphenyl dihydrogen phosphate 0.006-0.01 >8 2-C(p-Anisylamino)carbonyl]--5-ethoxy-3-methoxyphenyl dihydrogen phosphate 0.01 -0.03 >8 Disodium 2-[(p-anisylamino)-carbonyl]-5-ethoxy-3--methoxyphenyl phosphate 0.01 -0.03 >8 2-Hydroxy-6-methoxy-4-propoxy-N-(p-methoxybenzyl )benzamide 0.001-0.003 >2 0 4-(Allyloxy)-2-hydroxy-6-methoxy-N-(p-methoxybenzyl )benzamide 0.002 >8 2-Hydroxy-6-methoxy-4-(3-methyl-2-butenyloxy)-N-(p-methoxybenzyl)-benzamide 0.001-0.002 >8 Disodium 2-[(p-anisylamino)-carbonyl]-3-methoxy-5-propoxyphenyl phosphate 0.01 -0.02 >200 U 9887 Table 2 Virus Strain IC 50(ng/m£) Compound A Compound B Rhinovirus 1A 0.03 - 0.09 0.009 - 0.027 IB 0.03 - 0.09 0.003 - 0.009 2 0.001 0.001 9 0.012 - 0.037 0.003 14 0.1 - 0.3 0.009 - 0.027 16 - 0.003 21 <0.001 <0.001 23 0.004 - 24 0.01 - 0.03 - 0.01 - 0.09 - - 0.001 - 0.003 31 0.03 - 0.09 0.081 - 0.24 32 - 0.003 - 0.009 36 - 0.009 - 0.027 1 j 39 0.012 - 0.037 | 0.003 { 44 - j 0.003 46 0.037 - 0.11 1 | 47 [ - 0.003 1 i 50 l 0.004 - 0.012 0.01 55 - 0.009 Cytotoxic doses inhibiting HeLa cells growth by 50% are 60 ng/mJl (A) and 40 ng/mJl (B) , respectively. 198879 As mentioned earlier, the compounds of formula I and their pharmaceutically acceptable salts can be used as medicaments against viral diseases, especially in the common cold, in the form of pharmaceutical preparations.
The pharmaceutical preparations contain at least one of said antiviral compounds or pharmaceutically acceptable salts thereof in association with a compatible pharmaceutical carrier material and they may also contain other pharmaceutically active compounds such as a febrifuge, an anodyne, an anti-inflammatory, an anti-histamine, an interferon-inducer or the like. The pharmaceutical preparations include solid forms for oral administration such as tablets, capsules, pills, powders or granules, liquid forms for nasal or oral administration such as solutions, suspensions, syrups or elixers, forms for parenteral administration such as sterile solutions, suspensions or emulsions and forms for topical administration such as solutions, emulsions, micronized powders-, ointments, gargles, troches or aerosols. 198879 The pharmaceutical preparations can be administered so that the concentration of active ingredient is greater than the minimum inhibitory concentration for the particular viral infection being treated.
The dosage for treatment depends on the route of administration/ the age, weight and condition of the patient and the particular disease to be treated. In general, for adults a suggested dosage for use in the common cold is about 100 to 2,000 mg three to six times daily in the case of oral treatment and about 0.1 to 100 ng/cm three to six times daily in the case of topical administration. 198879 The following Examples illustrate the present invention: Example 1 A solution of 328 mg of 41-ethoxy-2'-hydroxy-4,61--dimethoxychalcone in 10 m£ of chloroform was hydrogenated in the presence of 30 mg of 10% palladium-on-charcoal at room temperature under atmospheric pressure for 3 hours. The catalyst was removed by filtration and washed with 30 m2 of chloroform. The filtrate and the washing were combined and evaporated under reduced pressure to give a crystalline residue. Recrystallization of the residue from methanol yielded 302 mg of 1-(4-ethoxy-2-hydroxy-6--methoxyphenyl)-3-(4-methoxyphenyl)-1-propanone as colourless needles of melting point 100.5° - 101°C.
Example 2 In a manner analogous to that described in Example 1, the products listed in Table 3 were obtained from the corresponding chalcones listed in Table 3. - 27 _ 198879 Table 3 Chalcones 2'-Hydroxy-4,4', 6 ' --trimethoxychalcone 2'-Hydroxy-4'-6'--dimethoxy-4-(methylthio)-chalcone 2'-Hydroxy-4',6'-dimethoxy--3,4-(methylenedioxy)-chalcone 2'-Hydroxy-4' , 6' --dimethoxy-4--methylchalcone 4-Chloro-2'-hydroxy--4',6'-dimethoxychalcone 2'-Ethoxy-61-hydroxy--4,4'-dimethoxychalcone Products 1-(2-Hydroxy-4,6-dimethoxy-phenyl)-3-(4-methoxyphenyl)-1--propanone; melting point 110°C (recrystallized from methanol) 1-(2-Hydroxy-4,6-dimethoxypheny 1) -3-[4-(methylthio)-phenyl]-1-propanone; melting point 84° - 85°C (methanol) 1-(2-Hydroxy-4,6-dimethoxy-phenyl)-3-[3,4-(methylenedioxy) • phenyl]-1-propanone; melting point 124.5°C (methanol) 1-(2-Hydroxy-4,6-dimethoxy-phenyl)-3-(4-methylphenyl)-1--propanone; melting point 128° - 129°C (methanol) 3- (4-Chlorophenyl)-1-(2-hydroxy--4,6-dimethoxyphenyl)-1--propanone; melting point 104.5°C (benzene/hexane) 1-(2-Ethoxy-6-hydroxy-4--methoxypheny1)-3-(4-methoxy-phenyl)-1-propanone; melting point 108° - 109°C (benzene/ hexane) 1 98879 Example 3 A solution of 400 mg of 2'-hydroxy-41,6'-dimethoxy--3-(5-methyl-2-furyl)acrylophenone in 25 ms, of chloroform was hydrogenated in the presence of 40 mg of 10% palladium-on-charcoal at room temperature under atmospheric pressure for 4 hours. After removal of the catalyst by filtration, the filtrate was evaporated to give an oily residue which was dissolved in a small amount of benzene. The solution was applied to a column of silica gel and the column was eluted with hexane/ethyl acetate (5:1, v/v), giving two fractions, A (Rf 0.29) and B (Rf 0.16), when monitored by silica gel thin-layer chromatography using cyclohexane/ethyl acetate (4:1, v/v). Removal of the solvent from fraction A and recrystallization from benzene/hexane gave 192 mg of 1-(2-hydroxy-4,6--dimethoxyphenyl)-3-(5-methyl-2-furyl)-1-propanone as colourless crystals of melting point 92° - 93°C.
Similar working-up of fraction B gave 25 mg of 1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(tetrahydro-5--methyl-2-furyl)-1-propanone as colourless needles of 198879 melting point 67.5°C (recrystallized from petroleum ether).
Example 4 85 mg of 2'-hydroxy-4/6'-dimethoxy-41--propoxychalcone were hydrogenated in a manner analogous to that described in Example 1. There were obtained 69 mg of 1-(2-hydroxy-6-methoxy-4-propoxyphenyl)-3--(4-methoxyphenyl)-1-propanone as colourless needles of melting point 85° - 86°C.
The 21-hydroxy-4,6'-dimethoxy-41-propoxychalcone used as the starting material was prepared as follows: A mixture of 182 mg of 2', 41-dihydroxy-61--methoxyacetophenone, 187 mg of propyl iodide and 276 mg of anhydrous potassium carbonate in 5 mJl of acetone was heated under reflux for 16 hours. After cooling, the mixture was diluted with 30 mi, of water and extracted three times with 30 mil of dichloromethane each time. 198879 The combined dichloromethane extracts were washed with water, dried over sodium sulphate and evaporated to give crude 21-hydroxy-61-methoxy-4'-propoxyacetophenone as a pale yellow oil.
The foregoing oil was dissolved in 5 mJl of ethanol containing 120 mg of p-methoxybenzaldehyde, to which 4 mil of 15% aqueous sodium hydroxide were added. After stirring at room temperature for 2 days, the mixture was adjusted to pH 5 - 6 with hydrochloric acid and extracted with three 30 mil pprtions of ethyl acetate. The combined ethyl acetate extracts were washed with water, dr.ied over sodium sulphate and evaporated to give , an oily residue. Recrystallization of the residue from methanol gave 110 mg of 21-hydroxy-4,61-dimethoxy-4'-propoxychalcone as yellow needles of melting point 95° - 96°C. p .Example 5 In a manner analogous to that described in Example 1, from 21-hydroxy-4'-isopropoxy-4,61-dimethoxychalcone there was obtained 1-(2-hydroxy-4-isopropoxy-6-methoxy-phenyl)-3-(4-methoxyphenyl)-1-propanone of melting point 96.5°C (recrystallized from methanol). 31 _ 198879 The starting material was prepared in a manner analogous to that described in Example 4, except that isopropyl iodide was used instead of propyl iodide.
Example 6 120 mg of 2'-hydroxy-4,61-dimethoxy-4'-(methylthio)-chalcone were dissolved in 10 mil of chloroform. The solution was hydrogenated in the presence of 180 mg of 10% palladium-on-charcoal at room temperature under atmospheric pressure for 33 hours. After removal of the catalyst by filtration, the filtrate was evaporated to give a pale yellow residue which was recrystallized from methanol. There were obtained 103 mg of l-[2--hydroxy-6-me thoxy-4-(methylthio)phenyl]-3-(4-methoxy-phenyl)-1-propanone as cream coloured needles of melting point 127° - 127.5°C.
The starting material was prepared as follows: To a solution of 120 mg of 21-hydroxy-61-methoxy- - ?? - 198879 -4 1 - (methylthio) acetopheno'ne and 92 mg of p-methoxy-benzaldehyde in 6 mil of ethanol were added 4 ml of 15% aqueous sodium hydroxide. After stirring at room temperature for 24 hours, the mixture was diluted 5 with 10 mil of water and acidified with IN hydrochloric acid. The resulting crystalline precipitate was collected by filtration, washed with a small amount of 50% methanol and recrystallized from methanol to give 144 mg of 2'-hydroxy-4,61-dimethoxy-4(methylthio) -10 chalcone as yellow needles of melting point 145° - 147°C, Example 7 1 g of 2-(benzyloxy)-4,6-dimethoxybenzoic acid was dissolved in 5 mil of thionyl chloride and the solution was stirred at room temperature for 1 hour. Removal of 15 excess thionyl chloride by repeated evaporation with the aid of benzene gave, an oil which dissolved in 5 mil of benzene. The solution was added dropwise to an ice-cold solution of 1.8 ml of p-methoxybenzyl amine in 5 mil of — 33" - II 9887 9 benzene. After stirring at room temperature for 17 hours, the mixture was diluted with 50 m£ of ethyl acetate, washed successively with dilute hydrochloric acid and water, dried over sodium sulphate and evaporated under reduced pressure to give 1.66 g of an oil.
The foregoing oil was dissolved in 2 mS, of benzene and the solution was applied to a column of silica gel (60 g in hexane). The column was eluted with 600 m£ of hexane/ethyl acetate (1:1, v/v). Removal of the solvent from the eluate followed by recrystallization from ethyl acetate gave 700 mg of 2-(benzyloxy)-4,6--dimethoxy-N-(p-methoxybenzyl)benzamide as colourless needles of melting point 123° - 124°C.
A solution of 700 mg of the foregoing benzamide in 20 m£ of chloroform.was hydrogenated for 4.5 hours in the presence of 140 mg of 10% palladium-on-charcoal at room temperature under atmospheric pressure. Removal of the catalyst by filtration followed by evaporation of the - 34;y - 198879 filtrate gave a crystalline residue. Recrystallization of the residue from methanol yielded 475 mg of 2-hydroxy--4,6-dimethoxy-N-(p-methoxybenzyl)benzamide as colourless needles of melting point 108° - 109°C.
The 2-(benzoyloxy)-4,6-dimethoxybenzoic acid used as the starting material was prepared as follows: To a stirred suspension of 39.75 g of methyl 2--hydroxy-4,6-dimethoxybenzoate and 207 g of anhydrous potassium carbonate in 2000 mil of acetone was added dropwise a solution of 22.3 mil of benzyl bromide in 300 mil of acetone. After stirring at room temperature for 78 hours, the mixture was filtered. The filtrate was evaporated under reduced pressure to give an oil which was dissolved in 500 mil of chloroform. The solution was washed with 400 mil of water, dried over sodium sulphate and-evaporated to give 78.7 g of crude methyl 2-(benzyloxy)-4,6-dimethoxybenzoate as a colourless oil. _ 19887 9 78.7 g of the foregoing crude ester were dissolved in 2200 m$, of dioxan/methanol (4:1, v/v). To this solution were added 900 mi of 2.4N sodium hydroxide, the mixture was heated under reflux for 16 hours, cooled 5 and then acidified with hydrochloric acid. The resulting crystalline precipitate was collected by filtration and washed with ethyl acetate to yield 48 g of 2-(benzyloxy)--4,6-dimethoxybenzoic acid as colourless needles of melting point 167° - 168°C.
Example 8 In a manner analogous to that described in Example 7, the products listed in Table 4 were obtained from 2--(benzyloxy)-4,6-dimethoxybenzoic acid (prepared as the starting material in Example 7) and the respective amines 15 listed in Table 4. - 36j - 1198879 Table 4 Amines p-Methoxyaniline Benzylamine m,p-(Methylenedioxy) benzylamine m-Methoxybenzylamine p-Methylbenzylamine p-Chlorobenzylamine i 2-(Aminomethyl)furan Methylamine Products 2-Hydroxy-4,6-dimethoxy-N-(4--methoxypheny1)benzamide; melting point 131° - 132°C (recrystallized from methanol) N-Benzyl-2-hydroxy-4,6-dimethoxy-benzamide; melting point 96°C (methanol) 2-Hydroxy-4,6-dimethoxy-N-(m,p--methylenedioxybenzy1)benzamide; melting point 116° - 117°C (methanol) 2-Hydroxy-4,6-dimethoxy-N-(m--methoxybenzyl)benzamide; melting point 95° - 96°C (methanol) 2-Hydroxy-4,6-dimethoxy-N-(p--methylbenzyl)benzamide; melting point 100° - 100.5°C (methanol) N-(p-Chlorobenzyl)-2-hydroxy--4,6-dimethoxybenzamide; melting point 131° - 132°C (methanol) N-Furfuryl-2-hydroxy-4,6--dimethoxybenzamide; melting point 74° - 75°C(methanol) 2-Hydroxy-4,6-dimethoxy-N--methylbenzamide; melting point 144° - 145.5°C (methanol) - 37, - 198879 Table 4 (continued) Amines Products m-(Benzyloxy)-p--methoxybenzylamine 2-Hydroxy-N-(m-hydroxy-p-methoxy-benzyl)-4/6-dimethoxybenzamide; melting point 144° - 145°C (methanol) m,p-Dimethoxybenzy1-amine 2-Hydroxy-4,6-dimethoxy-N--(m,p-dimethoxybenzyl)benzamide; melting point 115° - 116°C (methanol) p-Butoxybenzylamine N-(p-Butoxybenzy1)-2-hydroxy--4,6-dimethoxybenzamide; melting point 88° - 89°C (methanol) p-Hydroxybenzylamine 2-Hydroxy-N-(p-hydroxybenzyl)--4,6-dimethoxybenzamide; melting point 170° - 171°C (methanol) p-(Dimethylamino)-benzylamine N-[p-(Dimethylamino)benzyl]-2--hydroxy-4,6-dimethoxybenzamide; melting point 79° - 82°C (methanol) p-(Methylthio)-benzylamine 2-Hydroxy-4,6-dimethoxy-N-[p--(methylthio)benzyl]benzamide; melting point 119° - 120°C (methanol) p- (Benzyloxy)-benzylamine N-[p-(Benzyloxy)benzyl]-2--hydroxy-4,6-dimethoxybenzamide; . melting point 109° - 110°C (methanol) 2-Theny1amine 2-Hydroxy-4,6-dimethoxy-N-(2--theny1)benzamide; melting point 60°C (methanol) Tetrahydro-2--thenylamine 2-Hydroxy-4,6-dimethoxy-N--(tetrahydro-2-thenyl)benzamide; melting point 81° - 82°C (methanol) #98 87 9 Example 9 To a cooled suspension of 2-(benzyloxy)-4,6--dimethoxybenzoic acid ( 1 g), prepared as the starting material in Example 7, and 400 mg of N-hydroxysuccinimide in 20 nu of dioxan were added 858 mg of dicyclohexyl-carbodiimide. The mixture was stirred at room temperature for 19 hours and then filtered. Removal of the solvent from the filtrate gave an oil which was chromatographed on 50 g of silica gel eluting with hexane - ethyl acetate (4:1, v/v). The eluate was evaporated to give a syrup which upon standing in a cool place solidified as_a crystalline mass. 225 mg of the solid obtained according to the preceding paragraph were dissolved in 5 ms, of dimethyl-formamide. To the resulting solution were added 88 mg of p-methoxybenzylamine and the mixture was stirred at room temperature. After 18 hours, the mixture was diluted with 20 mil of IN hydrochloric acid and extracted twice with 50 mil of ethyl acetate each time. The 1 O o Q I ? o U - 39. - combined ethyl acetate extracts were washed with water, dried over sodium sulphate and evaporated to give a crystalline residue. Recrystallization of the residue from ethyl acetate/hexane yielded 228 mg of 2-(benzyloxy)--4 , 6-dimethoxy-N-(p-methoxybenzyl) benzamide as colourless needles of melting point 123° - 124°C.
Removal of the benzyl group from the foregoing benzamide by hydrogenolysis following the procedure described in Example 7 yielded 2-hydroxy-4,6-dimethoxy--N-(p-methoxybenzyl)benzamide of melting point 108° -109°C.
Example 10 To a solution of 980 mg of 2'-hydroxy-4',6'--dimethoxyacetophenone in 2 mil of pyridine were added 1.27 g of iodine. The mixture was heated at 100°C for 1 hour to give a solid mass. After cooling, the solid was washed successively with 50 ml of ether and a small amount of cold water and then dried under reduced pressure - 4o: - 198879 to give 2 g of crude 1-[(2-hydroxy-4,6-dimethoxybenzoyl)-methyl]pyridinium iodide as a brown powder. 1 g of the foregoing pyridinium salt was added to 514 mg of p-methoxybenzylamine and the mixture was heated at 80°C for 72 hours. After cooling, the mixture was poured into 20 mil of IN hydrochloric acid. The resulting suspension was extracted twice with 100 mil of dichloromethane each time. The combined dichloromethane extracts were washed with water, dried over sodium sulphate and evaporated to give 945 mg of an oily residue which was purified by silica gel chromatography using hexane/ethyl acetate (3:1, v/v) for the elution.
Removal of the solvent from the eluate followed by recrystallization of the residue from methanol gave 316 mg of 2-hydroxy-4,6-dimethoxy-N-(p-methoxybenzyl)-benzamide of melting point 108° - 109°C.
Example 11 In a manner analogous to that described in Example 10, the products listed in Table 5 were obtained from the 198879 pyridinium salt prepared in Example 10 and the respective amines listed in Table 5.
Table 5 Amines Products 4-(Aminomethyl)pyridine p-(Allyloxy)benzylamine 2-(Aminomethyl)pyrrole 2-Hydroxy-4,6-dimethoxy-N-[(4--pyridyl)methyl]benzamide; melting point 114° - 115°C (recrystallized from ether) N-[p-(Allyloxy)benzyl]-2--hydroxy-4,6-dimethoxybenzamide; melting point 93° - 94°C (methanol) 2-Hydroxy-4,6-dimethoxy-N-(2--pyrrolylmethyl)benzamide; melting point 116° - 117°C (ether) Example 12 A solution of 9.8 g of 41-ethoxy-21-hydroxy-61--methoxyacetophenone and 12 g of iodine in 22 m£ of pyridine was heated at 100°C for 1 hour. The resulting 1 o o 1 / u _ 42. _ slurry was cooled, triturated. and again heated at 100°C for 1 hour. After cooling, the mixture was filtered and the solid residue was washed successively with 100 m£ of ether and 100 mi of water and then dried at 60°C for 3 hours under reduced pressure. There were obtained 18.2 < of 1-[ (4-ethoxy-2-hydroxy-6-methoxybenzoyl) methyl] pyridinium iodide as a pale brown solid. .4 g of the foregoing pyridinium salt were added to 10 mi, of p-methoxybenzy lamine and the stirred mixture was heated at 80°C for 18 hours under nitrogen. After cooling, the mixture was treated with 200 m£ of ethyl acetate and 150 m£ of water. The ethyl acetate phase was separated and the aqueous phase was extracted with 150 m£ of ethyl acetate. The combined ethyl acetate solutions were washed successively with two 150 m.1 portions of dilute hydrochloric acid, 150 ml of aqueous sodium bicarbonate and brine, dried over sodium sulphate and then evaporated to give 15 g of an oil which was purified by silica gel chromatography using hexane/ethyl acetate for the elution. Removal of the solvent from the eluate 198879 followed by recrystallization of the residue from methanol yielded 6.3 g of 4-ethoxy-2-hydroxy-6-methoxy-N-(p--methoxybenzyl)benzamide as colourless needles of melting point 87° - 88°C.
Example 13 A mixture of 336 mg of 2-acetyl-3,5-dimethoxyphenyl--4-methoxybenzoate and 735 mg of anhydrous potassium carbonate in 5 mi of toluene was heated at 100°C for 17 hours, cooled and then filtered. After washing with benzene, the filtered cake was treated with 50 mi of dichloromethane and 50 mi of water. The dichloromethane phase was separated, dried over sodium sulphate and evaporated to give a crystalline residue. Recrystallization of the residue from methanol gave 77 mg of 1-(2-hydroxy--4,6-dimethoxyphenyl)-3-(4-methoxyphenyl)-1,3-propanedione as yellow prisms of .melting point 136° - 136.5°C. 198879 Example 14 To a stirred suspension of 580 mg of 1-(2-hydroxy--4,6-dimethoxypheny1)-3-(4-methoxyphenyl)-1-propanone, obtained as described in Example 2, and 482 mg of sodium 5 acetate in 9 m£ of dimethyl sulphoxide were added 204 mg of hydroxylamine hydrochloride. The mixture was heated at 80°C for 15.5 hours, cooled, diluted with 30 mil of ethyl acetate, washed successively with dilute hydrochloric acid and water, dried over sodium sulphate and then 10 evaporated to give 710 mg of a yellow oil which was dissolved in 1 mil of benzene.
The solution obtained according to the preceding paragraph was applied to a column of 25 g of silica gel and the column was eluted with hexane/ethyl acetate 15 (3:1, v/v) with fractionation (each fraction 15 mJl) .
Fractions 5 to 8 were combined and evaporated to give 435 mg of a pale yellow oily residue. Recrystallization of the residue from ethyl acetate/hexane yielded 301 mg of the E isomer of 1-(2-hydroxy-4,6-dimethoxyphenyl)-3-20 -(4-methoxyphenyl)-1-propanone oxime as colourless crystals of melting point 82° - 83.5°C. 198879 - .45 - The corresponding Z isomer of the oxime was also obtained as colourless crystals (melting point 102° -104°C) from fractions 20 to 30 after removal of the solvent and subsequent recrystallization from ethyl 5 acetate/hexane (yield 95 mg).
Example 15 A mixture of 500 mg of 4-ethoxy-2-hydroxy-6-methoxy--N-(p-methoxybenzyl)benzamide, obtained as described in Example 12, 673 mg of phosphorus pentasulphide and 259 mg of 10 triethylamine in 10 mi of carbon disulphide was stirred at room temperature for 3 days. There were then added 100 mi, of ethyl acetate and 100 mi of water and the mixture was shaken. The ethyl acetate phase was separated and the aqueous phase was extracted with 100 mi of ethyl acetate. 15 The combined ethyl acetate solutions were washed with brine and evaporated. The residue was chromatographed on silica gel using benzene/ethyl acetate (10:1, v/v) for the elution. Removal of the solvent from the eluate and recrystallization from methanol yielded 4-ethoxy-2-20 -hydroxy-6-methoxy-N-(p-methoxybenzyl)thiobenzamide as - 4'6 - J 9887 9 pale yellow needles of melting point 98° - 99°C.
Example 16 In a manner analogous to that described in Example 15 but using 1-(4-ethoxy-2-hydroxy-6-methoxypheny1)-3-(4-5 -methoxypheny1)-1-propanone (obtained as described in Example 1) in place of 4-ethoxy-2-hydroxy-6-methoxy-N-- (p-methoxybenzyl)benzamide, there was obtained l-(4--ethoxy-2-hydroxy-6-methoxypheny1)-3-(4-methoxyphenyl)-1--propanethione as orange needles of melting point 69° -10 70°C (recrystallized from methanol).
Example 17 A mixture of 165 mg of 1-(4-ethoxy-2-hydroxy-6--methoxypheny1)-3-(4-methoxyphenyl)-1-propanone, 0.2 m£ of acetic anhydride-.and 5 mg of sodium acetate in a sealed 15 tube was heated at 140°C for 3 hours. After cooling, the mixture was poured into 20 mS, of water. The mixture was extracted with 50 m£ of chloroform and the extract was _ 47 - 198879 washed with water, dried over sodium sulphate and evaporated to give 178 mg of an oily residue. Recrystallization of the residue from methanol gave 138 mg of 5-ethoxy-3-methoxy-2-[3-(4-methoxyphenyl)-propionyl]phenyl acetate as colourless needles of melting point 58° - 59°C.
Example 18 To a solution of 200 mg of 4-ethoxy-2-hydroxy-6--methoxy-N-(p-methoxybenzyl)benzamide, obtained as described in Example 12, in 2 m£, of pyridine was added 0.07 mz of acetic anhydride. The mixture was stirred at room temperature for 18 hours and then evaporated under reduced pressure to give an oily residue. Recrystallization of the residue from methanol gave 60 mg of 2-[(p--anisylamino)carbonyl]-5-ethoxy-3-methoxyphenyl acetate as colourless needles of melting point 121° - 122°C. - 4:8.« _ 198879 Example 19 To a solution of 317 mg of 2-hydroxy-4,6-dimethoxy--N-(p-methoxybenzyl)benzamide, obtained as described in Example 7, 0.14 mil of triethylamine and 24 mg of 4-5 - (dimethylamino) pyridine in 20 mil of dichloromethane was added 0.1 mil of ethoxycarbonyl chloride. The mixture was stirred at room temperature for 1 hour, washed successively with dilute hydrochloric acid and water, dried over sodium sulphate and then evaporated to give 10 480 mg of a yellow oil. The oil was chromatographed on silica gel using hexane/ethyl acetate (3:1, v/v) for the elution. Removal of the solvent from the eluate and recrystallization from ether/petroleum ether gave 110 mg of 2-[(p-anisylamino)carbonyl]-3,5-dimethoxyphenyl ethyl 15 carbonate as colourless crystals of melting point 123° -124.5°C.
Example 20 In a manner analogous to that described in Example 19, but using 1-(4-ethoxy-2-hydroxy-6-methoxyphenyl)-3-20 -(4-methoxyphenyl)-1-propanone in place of 2-hydroxy-4,6- 198879 49 - -dimethoxy-N-(p-methoxybenzyl)benzamide, there was obtained 5-ethoxy-3-methoxy-2-[3-(4-methoxyphenyl)propionyl]- l phenyl ethyl carbonate; H-nmr spectrum (in CDCL3): 6 1.38 (3H), 1.40 (3H) , 3.00 (4H) , 3.76 (6H), 4.02 (2H) , 4.34 (2H), 6.32 (2H), 6.80 (2H) and 7.13 ppm (2H).
Example 21 To a solution of 200 mg of 2-hydroxy-4,6-dimethoxy--N-(p-methoxybenzyl)benzamide, obtained as described in Example 7, in 5 mi of pyridine were added 347 mg of stearic anhydride. The mixture was heated at 60°C for 22.. 5 hours and then evaporated under reduced pressure to give an oily residue which was dissolved in 30 m£ of ethyl acetate. The solution was washed successively with dilute hydrochloric acid and brine, dried over sodium sulphate and evaporated. Recrystallization of the residue from ethyl acetate yielded 92 mg of 2-[(p--anisylamino)carbonyl]-3,5-dimethoxyphenyl octadecanoate as colourless needles of melting point 88° - 89°C. - 5 "0 ; - 198879 Example 22 In a manner analogous to that described in Example 21, but using N-[p-(allyloxy)benzyl]-2-hydroxy--4,6-dimethoxybenzamide in place of 2-hydroxy-4,6--dimethoxy-N-(p-methoxybenzyl)benzamide, there was obtained 2-{/~[p-(allyloxy)benzyl]amino_7carbonyl}-3,5--dimethoxyphenyl octadecanoate as colourless crystals of melting point 88° - 89°C (recrystallized from ethanol/ hexane).
Example 23 In a manner analogous to that described in Example 21, but using 1-(4-ethoxy-2-hydroxy-6-methoxy-phenyl)-3-(4-methoxyphenyl)-1-propanone in place of 2-hydroxy-4,6-dimethoxy-N-(p-methoxybenzyl)benzamide, there was obtained 5-ethoxy-3-methoxy-2-[3-(4-methoxyphenyl) propionyl] phenyl octadecanoate of melting point 40° - 41°C (recrystallized from methanol). 198879 - 51 _ Example 24 In a manner analogous to that described in Example 19/ but using benzoyl chloride in place of ethoxycarbonyl chloride/ there was obtained 2-[(p-anisylamino)carbonyl]--3/5-dimethoxyphenyl benzoate as colourless crystals of melting point 124.5° - 125.5°C (recrystallized from ethyl acetate/hexane).
Example 25 In a manner analogous to that described in Example 19, but using N-[p-(allyloxy)benzyl]-2-hydroxy-4,6--dimethoxybenzamide (obtained as described in Example 11) and benzoyl chloride in place of 2-hydroxy-4,6-dimethoxy--N-(p-methoxybenzyl)benzamide and ethoxycarbonyl chloride, respectively, there was obtained 2-{/ [p-(allyloxy)benzyl]-amino_/carbonyl}-3,5-dimethoxyphenyl benzoate as colourless crystals of melting point 105° - 106°C (recrystallized from methanol). 198879 - 52 ~ Example 26 In a manner analogous to that described in Example 19/ but using 1-(4-ethoxy-2-hydroxy-6-methoxy-phenyl)-3-(4-methoxyphenyl)-1-propanone and benzoyl chloride in place of 2-hydroxy-4,6-dimethoxy-N-(p--methoxybenzyl)benzamide and ethoxycarbonyl chloride, respectively, there was obtained 5-ethoxy-3-methoxy-2--[3-(4-methoxyphenyl)propionyl]phenyl benzoate, nmr spectrum: 6 1.42 (3H), 2.65 3.35 (4H), 3.75 (3H), 3.80 (3H) , 4.06 (2H), 6.40 (2H) , 6.75 (2H) , 7.11 (2H) and 7.42 - 7.70 ppm (3H).
Example 27 To a solution of 990 mg of 1-(4-ethoxy-2-hydroxy--6-methoxypheny1)-3-(4-methoxyphenyl)-1-propanone, obtained as described in Example 1 and 2 mA of N,N--diisopropylethylamine in 20 mil of toluene were added in one portion 10 m£ of phosphorus oxychloride. The mixture was stirred at room temperature for 1.5 hours and then evaporated under reduced pressure at a bath temperature of below 40°C to give an oily residue which was dissolved in 10 m£ of toluene. After removal of the solvent by evaporation under reduced pressure, the resulting oily residue was dissolved in 40 mi, of tetra-hydrofuran/water (1:3, v/v). The solution was vigorously stirred at room temperature for 50 minutes and concentrated under reduced pressure at a bath temperature of 30° - 40°C to an aqueous solution which was then extracted three times with 50 mi, of chloroform each time. The combined chloroform extracts were washed with a small amount of water, dried over sodium sulphate and evaporated to give an oily residue which was dissolved in 100 m2, of 0.1N potassium carbonate. The solution was washed twice with 30 ml of ethyl acetate each time, acidified with hydrochloric acid and extracted three times with 50 ma of ether each time. The combined ether extracts were washed with a small amount of water, dried over sodium sulphate and evaporated to give an oily residue. Recrystallization of the residue from ether 198879 yielded 930 mg of 5-ethoxy-3-methoxy-2—[3-(4-methoxyphenyl) propionyl]phenyl dihydrogen phosphate as colourless needles of melting point 122° - 125°C (decomposition) .
Example 28 410 mg of 5-ethoxy-3-methoxy-2-[3-(4-methoxyphenyl)-propionyl]phenyl dihydrogen phosphate, obtained as described in Example 27, were dissolved in 15 mS, of 0.1N sodium hydroxide. After carefully adjusting the pH to 8.0 with 0.IN sodium hydroxide, the solution was lyophilized to give a white solid. Recrystallization of the solid from water/acetonitrile yielded 380 mg of disodium 5-ethoxy-3-methoxy-2-[3-(4-methoxyphenyl)-propionyl]phenyl phosphate as colourless needles of melting point 138° - 139°C.
Example 29 To a stirred solution of 380 mg of dibenzyl-phosphorochloridate in 10 m£ of benzene was added a 1 solution containing 350 mg of 4-ethoxy-2-hydroxy-6--methoxy-N-(p-methoxybenzyl)benzamide, obtained as described in Example 12, and 51 mg of 60% sodium hydride in 10 ml of dimethylformamide. After stirring at room temperature for 14.5 hours, the mixture was diluted with 50 mi of ethyl acetate, washed three times with 50 mil of water each time, dried over sodium sulphate and evaporated to give 1.25 g of a yellow oil. The oil was chromatographed on 37.5 g of silica gel using ethyl acetate/hexane (1:1, v/v) for the elution. Removal of the solvent from the eluate gave 237 mg of dibenzyl 2- [ (p-anisylamino)carbonyl]-5-ethoxy-3-methoxyphenyl phosphate as a colourless syrup which was dissolved in 20 mil of chloroform.
The solution obtained according to the preceding paragraph was hydrogenated for 34 hours in the presence of 47 mg of 10% palladium-on-charcoal at room temperature under atmospheric pressure. Removal of the catalyst by filtration followed by evaporation of the filtrate gave 94 mg of a white residue. Recrystallization of the • 15 - 56 ~ 198879 residue from methanol yielded 79 mg of 2-[(p-anisylamino)-carbonyl]-5-ethoxy-3-methoxyphenyl dihydrogen phosphate as colourless crystals of melting point 162° - 163.5°C.
The compound thus obtained was converted into disodium 2-[(p-anisylamino)carbonyl]-5-ethoxy-3-methoxyphenyl phosphate of melting point 126° - 127°C in a manner analogous to that described in Example 28.
Example 30 In a manner analogous to that described in Example 29, but using 2-hydroxy-4,6-dimethoxy-N-(p--methoxybenzyl)benzamide in place of 4-ethoxy-2-hydroxy--6-methoxy-N-(p-methoxybenzyl)benzamide, there was obtained 2-[(p-anisylamino)carbonyl]-3,5-dimethoxyphenyl dihydrogen phosphate as colourless crystals of melting point 160.5° - 162.5°C. 19887 Example 31 To a stirred solution of 300 mg of 2-hydroxy-4,6--dimethoxy-N-(p-methoxybenzyl)benzamide, obtained as described in Example 7, and 50 mg of 60% sodium hydride in 3 m£ of dimethylformamide were added 600 mg of 2,3,4,6--tetra-0-acetyl-a-D-glucopyranosyl bromide. The mixture was stirred at room temperature for 18 hours and then treated with 50 m£ of ethyl acetate and 30 m£ of water. The ethyl acetate phase was separated, washed with water, dried over sodium sulphate and evaporated to give an oily residue. The residue was chromatographed on 10 g of. silica gel using ethyl acetate for the elution.
Removal of the solvent from the eluate followed by recrystallization from methanol gave 135 mg of 2-[(p--anisylamino)carbonyl]-3,5-dimethoxyphenyl tetra-0--acetyl-0-D-glucopyranoside as colourless crystals of melting point 73° - ,76°C. - 5.8 - 198879 Example 32 To a suspension of 100 mg of 2-[(p-anisylamino)-carbonyl]-3,5-dimethoxyphenyl tetra-O-acetyl-0-D--glucopyranoside, obtained as described in Example 31, in 30 m£ of methanol were added 0.09 m£ of water and 0.09 m£ of triethylamine. After stirring at room temperature for 3 days, the mixture was evaporated to give a solid residue. The residue was chromatographed on 10 g of silica gel using ethyl acetate/methanol (10:1, v/v) for the elution. Removal of the solvent from the eluate followed by recrystallization from ethanol/hexane yielded 40 mg of 2-[(p-anisylamino)-carbonyl]-3,5-dimethoxyphenyl 0-D-glucopyranoside as colourless needles of melting point 132° - 133°C.
Example 33 To a stirred solution of 330 mg of 1-(4-ethoxy-2--hydroxy-6-methoxyphenyl)-3-(4-methoxyphenyl)-1-propanone, obtained as described in Example 1, and 44 mg of 60% 198879 - 59: - sodium hydride in 5 ml of dimethylformamide was added tetrayO-acetyl-a-D-glucopyranosyl bromide. The mixture was stirred at room temperature for 18 hours, diluted with 30 ml of cold water and extracted with three 30 ml portions of ethyl acetate. The combined extracts were washed with water, dried over sodium sulphate and evaporated to give 700 mg of crude 5-ethoxy-3-methoxy--2- [3-(4-methoxyphenyl)propionyl]phenyl tetra-O-acetyl--0-D-glucopyranoside.
The foregoing crude material was purified by silica gel chromatography using hexane/ethyl acetate (3:1, v/v) for the elution and then saponified following the procedure described in Example 32 to give 5-ethoxy-3-methoxy-2-[3- -(4-methoxyphenyl)propionyl]phenyl 0-D-glucopyranoside; l H nmr: 6 1.35 (3H) , 2.6 - 3.2 (4H), 3.2 - 4.6 (6H), 3.72 (3H) , 3.78 (3H), 4.05 (2H), 4.87 (1H), 6.26 (1H), 6.45 (1H) , 6.78 (2H). and 7.15 ppm (2H) .
Example 34 198879 In a manner analogous to that described in Example 12 but using 2' -hydroxy^' -methoxy-4 '-propoxyacetophenone in place of 4'^ethoxy-2'-hydroxy-6'-methoxyacetophenone, there was obtained 2-hydroxy-6-methoxy-4-propoxy-N-(p-methoxybenzyl) benzamide as colourless crystals of melting point 96,5° -97.5°C (recrystallized from methanol). 'n Example- 35 In a manner analogous to that described in Example 12 but using 2 ' -hydroxy-6 ' -methoxy-4 (2-!-propenyloxy)_acetophenone in place of 4'-ethoxy-2 ' ^-hydroxy^-61-methoxyacetophenone, there was obtained 4-(.allyloxy) ^2-hydroxy-6-methoxy^N^-(p-methoxybenzyl)benzamide as colourless crystals of melting point 69..5° - 7Q°C (recrystallized from methanol)., ' Example 36 In a manner analogous to that described in Example 12 but using 2 '-hydroxy-6 1 -methoxy-4 '^ (3^methyl-2T-Butenyloxy)_ acetophenone in place of 4'-ethoxy-2'-hydroxy-6'-methoxyacetophenone, there was obtained 2-hydroxy-6-methoxy-4-(3-methyl-2-butenyloxy)-N-(p-methoxybenzyl)benzamide as colourless crystals of melting point 48.0° - 48.5°C (recrystallized from petroleum ether). - 61 — 1988 7 9 Example 37 In a manner analogous- to that described in Example 29 but using 2-hydroxy-6-methoxy-4-propoxy-N-(p-methoxybenzyl) benzamide, obtained as described in Example 37, in place of 4-ethoxy-2-hydroxy-6-methoxy-N-(p-methoxybenzyl)benzamide, there was obtained disodium 2-[(p-anisylamino)carbonyl]-3-methoxy-5-propoxyphenyl phosphate as colourless crystals of melting point 116° - 119°C (recrystallized from ethyl acetate). #98879 Example a Tablets containing the following ingredients can be prepared by conventional procedures: Active ingredient (i.e. a compound of formula I) 300 mg Dried lactose 200 mg Cellulose (microcrystalline) 30 mg Polyvinylpyrrolidone 5 mg Magnesium stearate 4 mg Example B Drops for intranasal administration containing the following ingredients per 1 m£ can be prepared using methods known per se: Active ingredient (i.e. a compound of formula I) 0.1 mg Surfactant 0.05 mg Propyleneglycol/water (1:1/ v/v) q.s. ad 1 m£ 198879 An acceptable range of concentration of the active ingredient is 0.001 to 1 mg/nu.
Example c- Troch^s containing the following ingredients can 5 be prepared using methods known per se: Active ingredient (i.e. a compound of formula I) 0.1 g Powdered sucrose 1.6 g Acacia 0.2 g Dextrin 0.1 g Flavor 0..001 g 1 r no •') I OO I '

Claims (24)

WHAT WE CLAIM IS:
1) Compounds of the general formula 10 15 wherein X represents an oxygen or sulphur atom or hydroxyimino; Y represents methylene or imino; R^" represents hydroxy, phosphonooxy, glycosyloxy, acylated glycosyloxy, acyloxy or lower alkoxycar-2 bonyloxy; R represents lower alkoxy, lower alkenyloxy or lower alkylthio; R"^ represents lower 4 alkoxy; R represents lower alkyl, p-lower-alkoxy-benzoyl or a substituted or unsubstituted phenyl, benzyl, pyridylmethyl , furfuryl, tetrahydrofurfuryl, thenyl,tetrahydrothenyl, pyrrolylmethylj pyrrolinyl-methyl or pyrrolidinylmethyl group, with the 4 proviso that when R represents alkyl, phenyl, substituted phenyl, benzyl or p-hydroxybenzyl, Y does not represent a methylene radical; and with 4 the further proviso that when R represents p-methoxy- 2 3 benzyl and Y represents methylene, R and R are 20 different, and pharmaceutically acceptable salts thereof. n.z. PATENT OFFICE*" 16 NOV 1984 - 65 - A c O Q ') i ; J O I y
2) Compounds of formula I given in claim 1, wherein X represents an oxygen or sulphur atom or hydroxyimino; Y represents methylene or imino; R* represents hydroxy, phosphonooxy, glycosyloxy, acylated glycosyloxy, acyloxy 2 5 or lower alkoxycarbonyloxy; R represents lower alkoxy, 3 4 or lower alkylthio; R represents lower alkoxy; R represents lower alkyl, p-lower-alkoxy-benzoyl or a substituted or unsubstituted phenyl, benzyl, pyridyl- methyl, furfuryl, tetrahydrofurfuryl, thenyl, tetrahydro- 10 thenyl, pyrrolylmethyl, pyrrolinylmethyl or pyrrolidinyl- 4 methyl group, with the proviso that when R represents alkyl, phenyl, substituted phenyl, benzyl or p-hydroxybenzyl, Y does not represent a methylene radic.al; and 4 with the further proviso that when R represents p-methoxy- 2 3 15 benzyl and Y represents methylene, R and R are different.
3) Compounds as in claim 1 wherein R1 is hydroxy, lower alkanoyloxy, benzoyloxy, phosphonooxy, lower alkoxy- 2 carbonyloxy; R is lower alkoxy or lower alkenyloxy; 3 4 R is lower alkoxy; R is substituted phenyl; and X is an 20 oxygen or sulfur atom and Y is methylene or imino.
4) Compounds as in claim 3 wherein Y is imino.
5) 4-Ethoxy-2-hydroxy-6-methoxy-N-(p-methoxybenzyl)-benzamide. 1Sft&Gty 1&B879 i i - 66 - Eg 44f0/
6) 2-[(p-Anisylamino)carbonyl]-5-ethoxy-3-methoxyphenyl dihydrogen phosphate and the disodium salt thereof.
7) 1-(4-Ethoxy-2-hydroxy-6-methoxyphenyl)-3-(4-methoxyphenyl )-1-propanone. 5
8) 5-Ethoxy-3-methoxy-2-[3-(p-methoxyphenyl)-propionyl]-phenyl acetate.
9) 2-Hydroxy-4,6-dimethoxy-N-[p-(methylthio)benzyl]-benzamide.
10 ) 2-j£/" [p-( Allyloxy) benzyl] amino _7carbonyl3"-3 ,5-dimethoxy-10 phenyl benzoate.
11) 1-(4-Ethoxy-2-hydroxy-6-methoxyphenyl)-3-(4-methoxy-phenyl)-1-propanethione.
12) 5-Ethoxy-3-methoxy-2-[3-(4-methoxyphenyl)-propionyl]-phenyl ethyl carbonate. 15
13) 2-Hydroxy-6-methoxy-4-propoxy-N-(p-methoxybenzyl)-benzamide.
14) 4-(Allyloxy)-2-hydroxy-6-methoxy-N-(p-methoxybenzyl)-benzamide. - 67 - ES 443 198879
15) 2-Hydroxy-6-methoxy-4-(3-methyl-2-butenyloxy)-N-(p-methoxybenzyl)-benzamide.
16) Disodium 2-[p-anisylamino)-carbonyl]-3-methoxy-5-propoxyphenyl phosphate
17) A compound as claimed in claim 1 selected from 1-(2-hydroxy-4,6-dimethoxyphenyl)-3-[3,4-(methylenedioxy)-phenyl]-1-propanone, 1-(2-hydroxy-4,6-dimethoxyphenyl)-3—[4—(methylthio)phenyl]-1-propanone, 1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(4-methylphenyl)-1-propanone, 1-(4-ethoxy-2-hydroxy-6-methoxyphenyl)-3-(4-methoxyphenyl)-1-propanone, 5-ethoxy-3-methoxy-2-[3-(p-methoxyphenyl)-propionyl]phenyl dihydrogen phosphate, 1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(4-methoxyphenyl)-1-propanone oxime (Z isomer), 1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(4-methoxyphenyl)-1-propanone oxime (E isomer), 2-hydroxy-4,6-dimethoxy-N-(p-methoxybenzyl)benzamide, 3-(4-chloro-phenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)-1-propanone, 1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(5-methyl-2-furyl)- 1-propanone, 1-(2-ethoxy-6-hydroxy-4-methoxyphenyl)-3- (4-methoxyphenyl)-1-propanone, 1-(2-hydroxy-4,6-dimethoxyphenyl )-3-(4-methoxyphenyl)-1,3-propanedione, 1-(2-hydroxy-6-methoxy-4-propoxyphenyl)-3-(4-methoxyphenyl)-l-propanone, 1-(2-hydroxy-4-isopropoxy-6-methoxyphenyl)-3-(4-methoxyphenyl)-1-propanone, 1-(2-hydroxy-4,6-dimethoxyphenyl )-3-(tetrahydro-5-methyl-2-furyl)-1-propanone, 2-hydroxy-4,6-dimethoxy-N-(4-methoxyphenyl)benzamide, - 68 - ES 443 N-benzyl-2-hydroxy-4,6-dimethoxybenzamide, 2-hydroxy-4,6-dimethoxy-N-Cm,?-(methylenedioxy)benzyl]benzamide, 2-hydroxy-4,6-dimethoxy-N-(m-methoxybenzyl)-benzamide, 2-hydroxy-4,6-dimethoxy-N-(p-methyl-benzyl)benzamide, N-(p-chlorobenzyl)-2-hydroxy--4,6-dimethoxybenzamide, N-furfury1-2-hydroxy-4,6--dimethoxybenzamide, 2-hydroxy-4,6-dimethoxy-N--methylbenzamide, 2-hydroxy-N-(m-hydroxy-p-methoxy-benzyl)-4,6-dimethoxybenzamide, N-(m,p-dimethoxy-benzyl)-2-hydroxy-4,6-dimethoxybenzamide, 2-hydroxy--4,6-dimethoxy-N-[(4-pyridyl)methyl]benzamide, N-(p-butoxybenzyl)-2-hydroxy-4,6-dimethoxybenzamide, 2-hydroxy-N-(p-hydroxybenzy1)-4,6-dimethoxybenzamide, N-[(p-dimethylamino)benzyl]-2-hydroxy-4,6-dimethoxybenzamide , N-[p-(benzyloxy)benzyl]-2-hydroxy-4,6-dimethoxybenzamide, 2-hydroxy-4,6-dimethoxy-N-(2-thenyl)-benzamide, N-[p-(allyloxy)benzyl]-2-hydroxy-4,6-dimethoxybenzamide , 2-hydroxy-4,6-dimethoxy-N-(tetrahydro-2-thenyl)benzamide, 2-hydroxy-4,6-dimethoxy-N-[(2-pyrrolyl)-methyl]benzamide, 2-[p-anisylamino)carbonyl]-5-ethoxy- 3-methoxyphenyl acetate, 2-{£ [p-(allyloxy)benzyl]aminoJ carbonylJ"-3,5-dimethoxyphenyl octadecanoate, 4-ethoxy-2-hydroxy-6-methoxy-N-(p-methoxybenzyl)thiobenzamide, 1-[2-hydroxy-6-methoxy-4-(methylthio)phenyl]-3-(4-methoxy-phenyl)-1-propanone, 5-ethoxy-3-methoxy-2-[3-(4-methoxyphenyl )propionyl ]-phenyl octadecanoate, 5-ethoxy-3-methoxy- 2-[3-(4-methoxyphenyl)propionyl]phenyl benzoate, 2-[(p- - 69 - -BS- 4430/17 198879 -anisylamino)carbonyl]-3,5-dimethoxyphenyl ethyl carbonate, 2-[(p-anisylamino)carbonyl]-3,5--dimethoxyphenyl benzoate, 2-[(p-anisylamino)-carbonyl]-3,5-dimethoxyphenyl octadecanoate, 5 2- [ (p-anisylamino)carbonyl]-3,5-dimethoxyphenyl tetra-O-acetyl-0-D-glucopyranoside, 2-[(p-anisylamino)- I carbonyl]-3,5-dimethoxyphenyl 0-D-glucopyranoside, 5-ethoxy-3-methoxy-2-[3-(4-methoxyphenyl)propionyl]-phenyl 0-D-glucopyranoside, disodium 5-ethoxy-3-10 -methoxy-2-[3-(4-methoxyphenyl)propionyl]phenyl phosphate, 2- [(p-anisylamino)carbonyl]-3,5-dimethoxyphenyl dihydrogen phosphate.
18) Compounds of formula I given in claim 1 and pharmaceutically acceptable salts thereof for use as antiviral 15 agents.
19) A process for the preparation of the compounds of formula I given in claim 1 and of pharmaceutically acceptable salts thereof, which process comprises (a) hydrogenating a compound of the general formula - 70 - wherein X, R1 , R2, R3 and R^ are as defined in claim 1, in the presence of a catalyst in a solvent, or (b) reacting a reactive derivative of a carboxylic acid of the general formula wherein R2 and R3 are as defined in claim 1 and R1 ' represents a protected hydroxyl radical, with a compound of the general formula Rk - NH2 IV wherein R^ is as defined in claim 1, N.2. PATfiWv <;i\ • ;C 16 NOV 1984 - 71 - U"3t< 'J and then removing the protecting moiety of the protected hydroxyl radical, or (c) reacting an acetophenone of the general 5 formula wherein R1 , R2 and R3 aire as defined in claim 1, with iodine in a tertiary amine and reacting a resulting 10 salt with an amine of formula IV given earlier in this claim, or (d) subjecting an ester of the general formula i r Q I - ^ -12- wherein R2 , R3 and R1* are as defined in claim 1., to rearrangement in the presence of a base in a solvent, or (e) reacting a ketone of the general formula wherein R2, R3 and R4 are as defined in claim 1T with a salt of hydroxylamine in a solvent, or (f) reacting a carbonyl compound of the general formula - 73 - 1 VIII wherein Y, R2, R3 and R^ are as defined in claim 1, with phosphorus pentasulphide in the presence of a 5 base in a solvent, or (g) reacting a phenol of the general formula OH X' IX 10 wherein Y, R2, R3 and R^ are as defined in claim 1, and X1 represents an oxygen or sulphur atom, I - 74 - 19GG7V with an acylating agent in the presence of a base, or (h) reacting a phenol of formula IX given earlier in this claim with phosphorus oxychloride or dibenzyl-5 phosphorochloridate in the presence of a base in a solvent followed by hydrolysis or hydrogenolysis as the case may require and, if necessary, converting a resulting compound into a salt, or 10 (i) reacting a phenol of formula IX given earlier in this claim with a glycosyl halide,which may be acylated, in the presence of a catalyst in a solvent, followed, if neqessary, by the removal of the acyl radicals.
20) A pharmaceutical composition containing as the 15 active ingredient at least one compound of formula I given in claim 1 or a pharmaceutically acceptable salt thereof. N.Z. PATENT Q.cp (Qg 16 NOV 1984 1 c n ^ ') 1 , o ^ ' J - 75 -
21) The use of a compound of formula I given in claim 1 or a pharmaceutically acceptable salt thereof in the treatment of viral infections in non-human warm-blooded animals.
22) A process for the preparation of the compounds of formula I given- in cla.im 1 and of pharmaceutically acceptable salts thereof, substantially as hereinbefore described with particular reference to any one of the foregoing Examples 1 to 37.
23) Compounds of formula I given in claim 1 or a pharmaceutically acceptable salt thereof when prepared according to the process of claim 19 or claim 22.
24) A pharmaceutical composition containing, as the active ingredient, at least one compound of formula I — ^ -• _ ^ . T—.. ^—. t i,, . u i yivcn xii ^ _lcj._l.iu x wx a ^iiaxiuac.cuux^axx^ auwc^/uajjic salt thereof, substantially as hereinbefore described with particular reference to any one of the foregoing Examples A, B and C. OATH* I-
NZ198879A 1980-11-12 1981-11-05 Tetra substituted benzene derivatives and pharmaceutical compositions NZ198879A (en)

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CH653670A5 (en) * 1983-03-03 1986-01-15 Hoffmann La Roche BENZAMIDE DERIVATIVES.
US5098613A (en) * 1987-01-12 1992-03-24 Eli Lilly And Company Anti-inflammatory agents
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IL122591A0 (en) 1997-12-14 1998-06-15 Arad Dorit Pharmaceutical compositions comprising cystein protease inhibitors
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US9988405B2 (en) 2014-01-23 2018-06-05 Neopanora Bio-Technology (Zhuhai) Ltd. O-phenyl chalcone compounds and uses thereof

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