DIARYL COMPOUNDS AND PHARMACEUTICAL FORMULATIONS CONTAINING THEM

Abstract: Known and novel compounds of formula (I) Ar - X - Y - Z - Ar (1) wherein Ar are the same or different and each is a substituted or unsubstituted phenyl group and Z is a bond, sulphur, -CHOH, or -C=O; and X is oxygen, sulphur, -CH₂ or -NH- when Y is -CH₂; or X is -CH₂ when Y is oxygen; or X - Y together is -CH=CN, are active against viruses, especially rhinoviruses. Methods for producing the com­ pounds are described, as are pharmaceutical formulations and methods for administering the compounds to cure or prevent rhinoviral infections.

Description: The present invention relates to certain benzene derivatives which are useful as medicaments. In particular which compounds are antiviral agents, and are especially suitable for the prevention and treatment of rhinoviral infections. The invention also relates to processes for the production of these compounds, to pharmaceutical formulations containing them and to methods of treatment employing them. In the majority of instances, the disease known as the " common cold" is caused by rhino viral infections, although "colds" may also be caused by infection of the upper respiratory tract by e.g. corona-and enteroviruses. Mankind throughout the world is prone to rhinoviral infections, which are a major cause of absence from work through illness. The prevention and treatment of such diseases is thus of great economic importance. Once infected by a rhinovirus, an individual retains immunity to that serotype, which may be enhanced by continual reinfection if the serotype is prevalent in the community. There is however, no cross-immunity between serotypes and thus a cold is usually experienced by an individual whenever a new rhinovirus serotype is encountered, on average about two or three times a year. Immunisation against rhinovirus is not practicable because there are about 120 known serotypes of rhinovirus and a vaccine against all these would overload the vaccinee's immune system. It would therefore appear that chemotherapy is the only suitable method for preventing or treating rhinoviral infections. Much research effort has been expended in recent years but no effective chemotherapeutic agent has yet emerged. it has now been found that certain biphenyl compounds have antiviral activity and are especially active against rhinoviruses and corona viruses. According to the present invention therefore, there is provided a compound of formula (I) Ar-X-Y-Z-Ar (I) as a medicament or in a pharmaceutically acceptable formulation, wherein the groups Ar are the same or different and each is a substituted or unsubstituted phenyl group, each of the substituents, when present, being selected from halo, (lower)alkyl, hydroxy(lower) alkyl, carboxy(lower)alkyl, (lower)alkoxy, amino, (lower)alkylamino, di(lower)alkylamino, EMI2.1 acylamino, nitro, cyano, trifluoromethyl, thiocarbamoyl, carbamoyl, carboxyl hydroxyl EMI2.2 Z is a bond, -C H2-, -CHOH-, or -C=O; and X is oxygen, sulphur, -CH2- or -NH- when Y is -CH2-; or X is -C H2- when Y is oxygen; or X-Y together is -CH=CH-. As used herein the expressions "(lower)alkyl" and "(lower)alkoxy" and cognate terms, mean straight or branched alkyl or alkoxy groups having from 1 to 5 carbon atoms; and "acylamino" means an amino group substituted with the residue of a carboxylic acid, in particular a (lower)alkyl, aryl(lower)alkyl or aryl carboxylic gird. Where a compound of formula (I) bears a hydroxyl, amino or carboxyl group or when X is a imino group, salts and esters may be formed, and these are encompassed within the present invention. It is preferred that these salts and esters be pharmaceutically acceptable,and a discussion of the properties and desirability of various salts is given in "pharmaceutical salts" by S.M.Berge et al, J.Pharm.Sci., 66, 1, (1977).Some of the compounds of formula (I) may also exist in various stereoisomeric forms, all of which are encompassed in the present invention. In particular, those compounds having a carbon-carbon double bond in the group XY will exist as geometric isomers, denoted E and Z; and those having an asymmetric carbon atom, i.e. when Z is a CHOH group,will exist in enantiomeric forms. Of the various classes of compounds embraced by formula (I), those in which X is oxygen, -NH- or -CH2-, or in which X-Y is -CH=CH-, are preferred. Also preferred are those wherein Z is a bond or -CH2; and those wherein each phenyl ring bears no more than three substituents, more preferably one or two substituents, and most preferably a single substituent; for example substituents situated at the 3,4 and/or 5 positions of the phenyl ring of a group Ar and especially at the 4 position. Particularly preferred substituents are halo, amino, hydroxyl, methyl, ethyl, methoxy ethoxy, hydroxymethyl, cyano and trifluoromethyl groups. Compounds of formula (I) are more preferred as medicaments or in pharmaceutically acceptable formulations when they conform to formula (IA) EMI3.1 wherein Rl,R2,R3 and R4 are the same or different and each is selected from the class of substituents mentioned in the preceding paragraph; for example hydrogen and when R 1 and R3 are hydrogen atoms; or when R1 and R2 are hydrogen atoms; or when R3 and R4 are hydrogen atoms. The most preferred compounds of formula (I), as medicaments, or in pharmaceutically acceptable formulations, are compounds of formula (IA) in which R2 and R4, or R1 and R2, or R3 and R4 are both halo and the remaining pair of substituents are both hydrogen atoms. In a second aspect of the present invention there is provided a compound of formula (II) EMI4.1 wherein X Y and Z are as hereinbefore defined and R5, R6, R7 and R8 are substituents selected from the class defined hereinbefore with respect to the groups Ar, except that Z is not a > - - group when X is an oxygen atom or when X-Y is a group -CH=CH- provided that (a) when XYZ is a NH-CH2 moiety and three of R5 to R8 are hydrogen atoms, the remaining substituent is other than a chlorine atom or a methyl or methoxy group or(b) when XYZ is a NH-OH2 moiety and R5 and R7 are hydrogen atoms and R6 or R8 is a chlorine, bromine or iodine atom, the remaining substituent is other than a chlorine atom or(c) when XYZ is a NH-CH2 moiety and R5 and R7 are hydrogen atoms and one of R6 and R3 is a hydrogen atom the remaining substituent is other than a fluorine or bromine atom or a methyl group or(d) when XY is a CH=CH moiety and Z is other than a bond and R5 and R8 are both hydrogen atoms, R6 and R7 are not both chlorine atoms, or(e) when XY is a 0-C H2 moiety and Z is other than a bond, and three of R5 to R8 are hydrogen atoms, neither R6 nor R7 is a nitro group. or(f) when XYZ is a 0-C H2 moiety and three of R5 to R8 are hydrogen atoms, the remaining substituent is other than a methyl group or a halogen atom. or(g) when XYZ is a 0-OH2 moiety and R5 and R8 are hydrogen atoms, R6 and R7 are not both halogen atoms or(h) when XYZ is a 0-C H2 moiety and R6 is a methoxy group and R5 and R7 are both hydrogen atoms, R3 is other than a hydrogen or chlorine atom or a methoxy group or(i) when XYZ is a 0-C H2 moiety and R6 is a chlorine atom and R5 and R7 are hydrogen atoms, R8 is other than a halogen atom or(j) when XYZ is a -CH=CH- moiety and R5 and R8 are hydrogen atoms and R6 is a cyano group, R7 is other than a nitro or methoxy group or a halogen atom or(k) when X is a sulphur atom, or Y is an oxygen atom, at least one of R5 to R8 is other than a hydrogen atom and excluding the following compounds: : 1 -(4-methoxyphenyl)-2-phenylethane l ,3-bis-(4-chlorophenyl)-pro pane l, 3-bis-(4-chlorophenyl)-propanone N-(3,4-dimethoxybenzyl)aniline N-benzyl-3,4-dimethoxyaniline N-(3,4-dichlorobenzyl)aniline N-benzyl-3,4-dichloroaniline N=(3-ch iorobenzyl)-3-chloroaniline 4-chlorophenylaminomethyl 4-chlorophenyl ketone benzyl 3,4-dimethylphenyl ether 3-chlorobenzyl 4-methyiphenyl ether. 3,4-dichlorobenzyl phenyl thioether In particular aspects the present invention provides the following compounds: trans-I (4-cyanophenyl)-2-(4-chlorophenyl)ethylene 1 ,2-bis(4-methoxyphenyl)ethane l,2-bis(3-methoxyphenyl)ethane 3-(3,4-dichlorophenyl)-l-phenylpropanone l,3-bis(4-chlorophenyl)-propanol 3-(3, 4-dichlorophenyl)- I -phenyipropanol 3-(3, 4-dichlorophenyl)- l-phenylpropane N-(3,4-dichlorobenzyl)aniline 4-chloro-N-(3,4-methylenedioxybenzyl)aniline 4-nitro-N-benzylaniline 4-methyl-N-(4-methylbenzyl)aniline 2-(3,4-dichloroanilino)-l -phenylethanol 2-(4-chloroanilino)- 1 -(4-chlo rophenyl)ethanol 2-(3,4-dichloroanilino)-l-phenylethane benzyl 4-hydroxyphenyl ether benzyl 3-methyl-4-chlorophenyl ether benzyl 3-nitrophenyl ether 2,4-dichlorobenzyl phenyl ether benzyl 3,4-dichlorophenyl ether 4-chlorobenzyl 3,4-dimethylphenyl ether 4-chlorobenzyl 4-ethylphenyl ether 4-chlorobenzyl 4-t-butylphenyl ether benzyl 3-ethylphenyl ether 4-chlorobenzyl 2-hydroxymethyiphenyl ether 3, 4-dichlorobenzyl 3,4-dichlorophenyl ether benzyl 3-trifluoromethylphenyl ether 4-chlorobenzyl 4-cyanophenyl ether 4-methylbenzyl 4-methylphenyl ether 4-chlorobenzyl 4-carboxyphenyl ether and its methyl ester. 3,4,5-trichlorobenzyl phenyl ether 4-chlorobenzyl 3,4-dichlorophenyl ether 2-(3,4-dichlorophenyl)-1-phenylethane 1 ,3-bis(4-chlorophenyl)prop-l -en-3-ol l-(3,4-dichlorophenyl)-3-phenylprop-I-en-3-ol 3-(3, 4-dich lorophe nyl)- 1 -phenylprop-l -ene Compounds of formula (I) and (II) may be produced by a variety of processes which are well known in the art of organic chemistry. In particular, those compounds having oxygen, nitrogen or sulphur as part of the X-Y moiety will be readily produced by condensation reactions. Thus, for instande, benzyl phenyl ethers are formed by condensation of a phenol with a benzylchloride derivative; and benzyl anilines are produced from benzylchloride derivatives by interaction with an aniline. Those compounds of formula (I) and (II) wherein X-Y is a hydrocarbon moiety are conveniently produced by forming an unsaturated compound and then (if necessary) reducing the double bond. The 1,3-diphenyl propanes and propenes are produced by first making the corresponding chalcone (by Knoevenagel condensation of acetophenone with benzaldehyde or derivatives thereof) and then reducing either the double bond (to form saturated ketones) and/or reducing the ketone function to provide the alcohol or alkene or alkane. A few of these reactions are illustrated in the Examples hereinbelow. Further details can be obtained from standard chemical texts. While it is possible for the'compounds of formula (I) or (II) or, where appropriate, pharmaceutically acceptable salts thereof (hereinafter referred to as the "active compounds") to be administered as the raw chemical it is preferred that the active compound is presented in the form of a pharmaceutical composition. In a further aspect of the invention there is therefore provided a pharmaceutical formulation comprising the active compound together with a pharmaceutically acceptable carrier there for. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Such carriers are solid, liquid or gaseous material recommended for the purpose of administering the medicament. These pharmaceutical compositions may be administered orally or parenterally (including subcutaneous, intramuscular and intravenous injection) or as a suppository or pessary or may be applied topically or as an ophthalmic solution, or may be inhaled. It is preferred that the compositions are administered orally or inhaled. For oral administration the pharmaceutical compositions may be presented as a draught in water or in a syrup, in capsules, cachets, boluses or tablets, as an aqueous or oleaginous solution or suspension or in suspension in a syrup, such suspensions optionally including suspending agents or as an oil-in-water or water-in-oil emulsion. Where desirable or necessary flavouring, sweetening, preserving,- thickening or emulsifying agents may be included in the formulation. Tablets may contain the active compound as a powder or granules optionally mixed with binders, lubricants or inert diluents or surface-active or dispersing agents and may be formed by compression or by moulding in an inert liquid diluent. Such tablets may be optionally scored and/or coated. Capsules and cachets may contain the active compound alone or in admixture with one or more accessary ingredients. Capsules may also contain the active compound in aqueous or oleaginous solution suspension or emulsion, optionally in association with accessory ingredients. For administration as a suppository or pessary the active compound may be presented in admixture with a suitable carrier such as cocoa butter and other material commonly used in the art, the formulation conveniently being shaped by moulding. For administration in discrete dosage forms such as the tablets, capsules, suppositories and pessaries described above, the active compound is preferably presented at 0.lmg to 100mg most preferably 1 mg to l0mg per tablet, capsule, suppository or pessary. For parenteral administration the active compound may be presented in sterile solutions or suspensions in aqueous or oleaginous vehicles, which may also contain preservatives and materials for rendering the solution or suspension isotonic with the blood of the intended recipient. Such formulations may conveniently be presented in unit-dose or multi-dose sealed containers. For topical administration the composition may be presented in ointments,creams,lotions, pastes, jellies, sprays, aerosols and bath oils. Ointments and creams may have oleaginous, absorption and colloidal clay bases and may contain thickening agents such as gum tragacanth or sodium alginate and other pharmaceutically acceptable accessory ingredients such as humectants, preservatives, buffers and antioxidants which are useful in such formulations. For administration as eye drops, the active compound is presented in sterile water with excipients such as antimicrobical agents and antioxidants, as a dilute solution. For administration orally in liquid form or parenterally or as eye drops the active compound is preferably presented in solution or suspension or emulsion at a concentration of from 0.1 to 10%, more preferably 0.2to 5% w/v in unit or multi-dose forms. When presented in unit dose form it is preferred that each dose unit contains 0.lmg to 100mg, preferably I mg to lOmg of active compound. For inhalation the active compound may be presented in association with volatile excipients, as a cream, lotion, paste or ointment or as a finely divided dry powder or in solution for inhalation through a nasal spray, atomiser or insufflator. All the above formulations are produced by processes which comprise bringing into association the active compound and one or more carriers. According to the present invention there is therefore provided a process for producing a pharma ceuticai formulation of a compound of formula (I) comprising bringing into association a compound of formula (I) and a pharmaceutically acceptable carrier therefor. Compounds of formula (I) may be administered to human beings and to other mammals to treat or prevent viral diseases, especially rhinoviral infection. The dosage administered obviously depends on the activity of the active compound and also on the speed with which it is absorbed into the body and on other well-known pharmacological considerations; however it is recommended that the active compound is administered at from 2 jug to 10mg/kg of animal body weight per day, preferably from 25g to lmg/kg/day and most preferably about 0.1 to 0.3mg/kg/day. The active compound may be administered once or severaltimes daily to achieve the required daily dose. In a further aspect of the present invention there is therefore provided a method for treating or preventing viral infections comprising the administration to a mammal in an effective dosage of a non-toxic dose of a compound of formula (T) or a pharmaceutical formulation thereof. The invention will now be illustrated with reference to the following Examples, which are not intended to limit the invention in any way. Temperatures are given hereunder in degrees Celsius. Pressures are given hereunder in millimeters of mercury ("mmHg").(lmm Hg= 133.322Pa). EXAMPLE 1 Preparation of N-3,4-dichlorobenzylaniline hydrochloride A mixture of aniline (0.93 g) and 3,4-dichlorobenzaldehyde (1.75g ) in ethanol (10 ml) was heated on the steam bath for ten minutes and the resultant solution was allowed to cool to room temperature. The crystalline Schiff's base so formed was filtered, washed with ethanol, dried, and a portion (0.46 g) in ethanol (10 ml) was treated with sodium borohydride (0.17 g). The mixture was stirred at room temperature for 1 hr, evaporated in vacuo and the residue was partitioned between water and ether. The ether extract was dried over anhydrous sodium sulphate and evaporated to give an oil which was treated with lOM hydrochloric acid (0.83 ml) and evaporated to dryness in vacuo. The resultant solid was recrystallised from ethanol to give N -3,4-dichlorobenzylaniline hydrochloride, m.pt 2030-2120. EXAMPLE 2 Preparation of 4-chlorobenzyl 2-nitrophenyl ether A mixture of 2-nitrophenol (6.95 g,) and 4-chlorobenzylchloride (4.03g) in ethanol (40 ml) was treated with 10M-aqueous sodium hydroxide (5.5 ml,) and heated at reflux on the steam-bath for 2 hour. The reaction mixture was evaporated in vacuo to removed the ethanol and the residue was partitioned between water (50 ml) and ether (50 ml). The ether layer was separated and washed 5 times with 2M aqueous sodium hydroxide (50, 50, 50, 25, 25 rnl) to remove umeacted 2-nitrophenol. The ethereal solution was dried over anhydrous sodium sulphate and evaporated in vacuo. The resulting solid was recrystallised from ethanol to give 4-chlorobenzyl 2-nitrophenyl ether as pale yellow crystals, m.pt 74q750. EXAMPLE 3 to 11 The following compounds were produced by a method exactly analogous to that used in Example 2. Example No Compound m.pt 3 4-Chlorobenzyl 4-ethylphenyl ether, 88.5-89.50 4 4-Chlorobenzyl 3-t-butylphenyl ether, 43. -44 5 3,4-Dichlorobenzyl 3,4-dichlorophenyl ether, 99-100 6 Benzyl 3-trifluoromethylphenyl ether, 65-660 7 4-Chlorobenzyl 4-cyanophenyl ether, 101-102t 8 4-Methylbenzyl 4-methylphenyl ether, 76-78 9 4-Chlorobenzyl 4-carboxyphenyl ether 225-2290 10 3,4,5-Trichlorobenzyl phenyl ether, 71-73 11 4-Ohlorobenzyl 3,4-dichlorophenyl ether, 78-80 EXAMPLE 12 Preparation of 1-(3,4-dichlorophenyl)-3-phenylpropane 3-(3,4-Dichlorophenyl)-1-phenylpropan-1-one (1.8g),hydrazine hydrate (1.2 ml) and powdered potassium hydroxide (0.53 g) in ethane-1,2-diol (13.4 ml) were heated to 210-2200 under reflux for 12' hours. Some (5 ml) of the diol was distilled off from the mixture and heating was continued for a further 8 hours. The mixture was poured into water (100 ml) and extract with ether (3 x 50 ml). The ethereal extract was dried over anhydrous sodium sulphate, evaporated under reduced pressure and the residual oil was subjected to column chromatography on silica gel (50 g). Elution with petroleum ether b.pt. 60 -80 gave pure 1-(3,4-dichlorophenyl)-3-phenyl- propane as a colourless oil. EXAMPLE 13 Preparation of 1,3-bis-(4-chlorophenyl)propan-1-ol Sodium borohydride (0.34 g) was gradually added to a stirred mixture of 1,3-bis-(4-chlorophenyl)propan-1-one (2.5g) in ethanol (40 ml) and stirring was continued for a further hour at room temperature. Ethanol was removed in vacuo and the residue was partitioned between water and ether. The ether extract was separated, dried over anhydrous sodium sulphate and evaporated in vacuo. The resulting solid was recrystallised from ethanol to give 1,3-bis-(4-chlorophenyl)propan-1-ol, m.pt. 63 -64 . EXAMPLE 14 Preparation of 3-(3,4-dichlorophenyl)-l -phenylpropan-1-ol 3-(3,4-Dichlorophenyl)-l-phenylpropan-1-ol, (m.pt.550) was prepared by a method exactly analogous to that used in Example 13. EXAMPLE 15 Preparation of 3-(3,4-dichlorophenyl)-1-phenylpropan-1-one 3-(3,4-Dichlorophenyl)-1-phenylprop-2-en-1-one (6 g) in dry ethyl acetate (37.5 ml) was hydrogenated at ambient temperature and pressure using Raney Nickel (0.75 g) as catalyst. Hydrogen absorption ceased after 6 hours by which time 690 ml had been absorbed. The reaction solution was filtered and the solvent removed under reduced pressure to give a solid which was recrystallised from a mixture of ethanol and water to give 3-(3,4-dichlorophenyl)-1-phenylpropan-1-one, m.pt. 47.50. EXAMPLE 16 Preparation of 3-(3,4-dichloro phen yl)-1 phenylpro pene A mixture of 3-(34-dichlorophenyl)-1-phenylpropan-1-ol (0.65 g) and polyphosphoric acid (0.9 ml) was heated to 140 for 3 hours. The cooled mixture was treated with water (50 ml) and extracted three times with ether. The combined extract was dried over anhydrous sodium sulphate, evaporated under reduced pressure and purified by chromatography on a silica gel (50 g) column, eluting with petrol, b.p. 60-80 3-(3,4-dichlorophenyl)-l-phenylpropene was obtained as a colourless oil homogeneous by t.l.c. on silica-gel eluting with petroleum ether, b.pt. 60800 as solvent. EXAMPLE 17 Preparation of 3-(3, 4-dichlorophenyl)-l -phenylpropr2-en-l -ol A suspension of 3-(3,4-dichlorophenyl)-1-phenylprop-2-en-1-one (2.0 g) in ethanol (60 ml) was treated with sodium borohydride (0.17 g) and the mixture was stirred at room temperature for one hour. Water (200 ml) was then added and the mixture was extracted three times with ether. The combined extract was dried over sodium sulphate and evaporated under reduced pressure. The residue was recrystal lised from a mixture of ether and hexane to give 3-(3,4-dichlorophenyl)-1-phenylprop 2-en-l-ol, m.pt. 520-';90 EXAMPLE 18 Preparation of 1 ,3-bis-(4-chlorophenyl)prop-2-en-1 -ol 1,3-Bis-4(-chlorophenyl)prop-2-en-1-ol (m.pt. 68o69.50) was prepared by a method exactly analogous to that used in Example 17. EXAMPLE 19 Preparation of 2-(4-chlorophenoxy)-1 -(4-chlorophenyl)ethanol A suspension of 1-(4-chlorophenoxy)-2-(4-chlorophenyl)ethanone (2.5g) in ethanol (5Cml) was treated witll sodium borohydride (0.34 g) and stirred at room tempera-tulc for 1 hr. The solution was treated with water until a solid was precil)itated and the mixture was extracted three times with ether. The combined ether extract was dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was recrystallised from a mixture of ethanol and water to give 2-(4-chlorophenoxy)-I (4-chlorophenyl)ethanol, m.pt. 7 1 0 EXAMPLE 20 Preparation of 2-(3,4-dichlorophenoxy)-l -phenylethanol 2-(3,4-Dichlorophenyl)-l-phenylethanol, a crystalline solid, (m.pt. 70.50- 71.50), was prepared by a method exactly analogous to that used in Example 19 EXAMPLE 21 Preparation of 4-(4-chlorobenzyloxy)benzenecarbothicamide A solution of 4-chjorobenzyl 4-cyanophenyl ether (2.43 g) in dry pyridine (90 ml) and triethylamine (12 ml) was treated with a steady stream of gaseous hydrogen sulphide for lT hours. The solution was treated with an excess of water and the resultant solid was filtered, washed with water and recrystallised from ethanol to give 4-(4-chlorobenzyloxy)benzenecarbothioamide, m.pt 2000-2050. EXAMPLE 22 Preparation of 4-(4-chlorobenzyloxy)benzamide A mixture of 4-chlorobenzyl 4-cyanobenzyl ether (2.43 g), 10M aqueous sodium hydroxide (0.24 ml) and hydrogen peroxide solution (4 ml) in ethanol (30 ml) was stirred at 500 for 3 hours. The mixture was cooled and filtered and the solid was recrystallised from chloroform to give 4-(4-chlorobenzyloxy)benzamide, m.pt. 212 -217 . EXAMPLE 23 Preparation of 4-chlorobenzyl 3-hydroxymethylphenyl ether A solution of 3-(4-chlorobenzyloxy)benzaldehyde (1.23 g) in ethanol (25 ml) was treated with sodium borohydride (0.19 g) and the mixture was stirred at room temperature for 30 minutes. The solution was treated with water until a solid precipitated out. The solid was filtered, washed with a mixture of water and ethanol, dried and recrystallised from ethanol to give 4-chlorobenzyl 3-hydroxymethylphenyl ether, m.pt. 820. EXAMPLE 24 Preparation of 2-(4-chloroanllino)-l -(4-chlorophenyi)ethanoi A suspension of 2-(4-chloroanilino)-l-(4-chlorophenyl)ethanone (1 g) in ethanol (50 ml) was treated with sodium borohydride (0.19 g) and the mixture was stirred at room temperature for one hour during which time the solid dissolved. Most of the ethanol was removed in vacuo and the residue was partitioned between water and ether. The ether solution was dried over anhydrous sodium sulphate and evaporated to give material which was purified by column chromatography on silica gel (45 g). The product was eluted with chloroform and recrystallised from a mixture of isopropanol and water to give 2-(4-chloroanilino)-l-(4-chlorophenyl)ethanol, m.pt. 58 -61 . EXAMPLE 25 Assay of activity of compounds of formula (I) Activity may be detected by the plaque inhibition (PI) test and measured by the plaque reduction (PR) test. Both assays involve the formation of a monolayer cell culture in a petri dish followed by infection with a virus suspension, and then overlaying the culture with nutrient agarose in the form of a gel. This gel ensures that there is no spread of virus throughout the culture and thus areas of localised cell destruction or plaques are formed. In the plaque inhibition test a filter paper disc which holds 0.01 ml when impregnated with il solution of a compound is placed on top of the agarose gel. The compound may then diffuse throughout the gel so that its greatest concentration will be around the disc and its lowest concentration towards the periphery of the petri dish. The efficacy of the compound may be detected by observing the zone of inhibition of plaque formation. Detectable activity is measured with the plaque reduction assay. A range of concentrations of compounds of known molarity are incorporated in the nutrient agarose overlay. Plaque suppression is proportional to compound concentration. Plaque numbers are expressed as percentages of a control, and a dose response curve may be drawn. From this curve 50% of the effective dose (ED50) may be estimated. RESULTS Compound of Example No. PR(ED50/M) 1 0.17 2 1.20 3 0.72 4 1.90(5.0) 5 0.47 6 0.66(1.7) 7 0.22 8 0.56 9 1.60 10 1.60 11 0.33 12 0.068 13 1.30 14 0.66 15 0.235 16 0.19 17 1.20 18 1.35 19 1.50 20 2.5 21 0.60 22 0.43 23 0.53 24 3.00 EXAMPLE 25 Intranasal Administration- Simulation in vitro Petri dishes were prepared, as for the plaque inhibition test and the confluer sheet of cells was covered with a layer of agarose gel. The compound, of Example 12 (l,ug) was dissolved in ethanol, and applied to the lids of the petri dishes. When the ethanol had evaporated, leaving the compound spread over the inside of the lids, these were replaced on the petri dishes. Sufficent compound penetrated the agarose layer to cause total inhibition of plaque formation. EXAMPLE 26 to 77 The following compositions were prepared according to the techniques known in the art of pharmacy. EXAMPLE 26 An inhalant for use in an insufflator was prepared frorn the following ingredients Compound of Example 12 0.6g isopropyllnyristate 10 g Tween 80 0.5g Span 60 O.5g methyl-p-hydroxybenzoic acid 0.1 g Water to 100ml EXAMPLE 27 A suspension for use as nose drops was prepared from the following ingredients Compound of Example 12 0.6g Keltrol O.lg Sodium Chloride 0.5g Sodium lauryl sulphate 0.1g Methyl-p-hydroxybenzoic acid 0.1g Water to 100 ml. EXAMPLE 28 Capsule 1 Compound of Example 12 6g Spray-dried lactose 300g. Gelatin capsules (size O) were each filled with 500mg. of the formulation, affording lOmg. of active ingredient per capsule. EXAMPLE 29 Capsule2 Compound of Example 12 6g Spray-dried lactose 208g Maize starch 20.8 g Polyvinylpyrollidine 5.2g Gelatin capsules (size I) were each filled with 400 mg. of the formulation, affording 10 mg. of the active ingredient per capsule. EXAMPLE 30 Tablet of the compound of Example 12 A tablet formulation containing a mixture of the compound (10 mg), lactose (90 mg), maize starch (10 mg) and magnesium stearate (1 mg) is prepared by wet granula EXAMPLE 31 to 53 Tablet formulations, each containing one of the flavan derivatives of Examples 1 to 11 and 13 to 24 are prepared by a method exactly analogous to Example. 30 EXAMPLE 54 Oil formulation of l-(3,4-dichlorophenyl)-3-phenylpropane olive oil B.P. Ig The compound was dissolved in olive oil for use by oral administration. EXAMPLES 55 to 77 Oil formulations of the compounds of Examples 1 to 11 and 1 to 24 were prepared by a method exactly analogous to that of Example 54.

Claims: CLAIMS 1. A compound of the formula ), Ar-X-Y-Z-Ar (I) as a medicament, characterised in that the groups Ar are the same or different and each is a substituted or unsubstituted phenyl group, each of the substituents, when present, being selected from halo, (lower)alkyl, hydroxy(lower)alkyl, carboxy(lower)alkyl, (lower)alkoxy, amino, (lower)alkylamino, di(lower)alkylamino, acylamino, nitro, cyano, trifluoromethyl, thiocarbamoyl, carbamoyl, carboxyl and hydroxyl; Z is a bond, -CH2-, -CHOH-, or -C=O; and X is oxygen, sulphur, -OH2- or -NH- when Y is -CH2; or X is -OH2- when Y is oxygen; or X-Y together is -CH=CH-; or a salt or an ester of such a compound. 2. A compound as claimed in claim 1 characterised in that at least one Ar group is substituted in the 3- and 4- position or in the 3-, 4- and 5- position. 3. A compound as claimed in claim 1 characterised in that both Ar groups are substituted in the 4-position or both groups are substituted in the 3- and 4-positions. 4. A compound as claimed in claim 1 characterised in that one Ar group is substituted by 3,4-dichloro, 4-carbamoyl, 3,4-methylenedioxy, 4-chloro or is unsubstituted; the other Ar group is substituted by 3,4-dichloro, 4-chloro or is unsubstituted; provided that taken together the two Ar groups have a total of at least two substituents; X is -NH-, oxygen or -OH2-, Y is CH2, or X-Y together is -CH=CH-; and Z is a bond, -C=O. 5. A compound as claimed in claim 4 characterised in that one Ar group is substituted by 4-C1 and the other Ar group is substituted by 4-C1 or 3,4dichloro. 6. A compound of the formula (I), Ar-X-Y-Z-Ar (I) characterised in that the groups Ar are each a phenyl group, one Ar group is substituted by 3,4-dichloro, 4-carbamoyl, 3,4-methylenedioxy, 4-chloro or is unsubstituted; the other Ar group is substituted by 3,4-dichloro, 4-chloro or is unsubstituted; provided that taken together the two Ar groups have a total of at least two substituents; X is -NH-, oxygen or -CH2-, Y is CH2, or X-Y together is -CH=CH-; and Z is a bond, -C=O; together with salts thereof. 7. A compound selected from: N-3,4-dichlorobenzylaniline, 3,4-dichlorobenzyl 3 ,4-dichlorophenyl ether, 4-chlorobenzyl 4-cyanophenyl ether, 4-chlorobenzyl 3,4-dichlorophenyl ether, 1 (3,4-dichlorophenyl)-3-phenyl propane, 3-(3,4-dichlorophenyl)-1-phenylpropan-1-one, 3-(3,4-dichlorophenyl)-1-phenylprop-2-ene, 2-(4-chlorophenoxy)-1-(4-chlorophenyl)ethanol 4-(4-chlorobenzyloxy)benzamide, 4-chloro-N-(3, 4-methy lenedioxybenzyl)aniline, and salts thereof. 8. A compound selected from: 3-(3,4-dichlorophenyl)- 1-phenylprop-2-ene, and 2-(4-chlorophenoxy)-1-(4-chlorophenyl)ethanol. 9. A pharmaceutical formulation characterised in that it comprises a compound of formula (I) as defined in any one of claims 1 to 8 in association with a pharmaceutically acceptable carrier. 10. A formulation as claimed in claim 9 characterised in that it is in the form of an orally ingestible tablet or capsule. 11. A formulation as claimed in claim 9 characterised in that it is in the form of nose drops.

Inventors: HODSON, HAROLD FRANCIS, LEAVER, CATHERINE MARY, SELWAY, JOHN WILLIAM TALBOT
Applicants: THE WELLCOME FOUNDATION LIMITED
Application year: 1980
Main classification: C07C79
IPC codes: A61K31, C07C205, C07C201, A61K9, C07C235, C07C327, C07C43, C07C17, C07C255, C07C27, C07C211, C07C45, C07C67, C07C237, C07C233, C07C209, C07C215, A61P31