IE42406B1 - Diphenyl ether derivatives and processes for their preparation - Google Patents

Description

This invention is concerned with certain novel diphenyl other derivatives, with precesses for their preparation and with compositions containing them.

We have found that diphenyl ether derivatives of formula I: 2 wherein R is F, Cl or Dr, R is If or alkanoyl having 3-6 C atoms, and A is -CII(CHj)-CHg- or are well tolerated and possess valuable pharmacological properties. In particular, these compounds have antiinflammatory activity which can be demonstrated, for example, on rats by the adjuvant-arthritis test using NeWbould’s method (Brit. J. Pharmacol., volume 21 (1963), pages 127 - 136) . These compounds also have cholesterol level and triglyceride levol-roducing activity as shown in the serum of rats by the method of Levine et al., (Automation in Analytical Chemistry, Tochnicon Symposium 1967, Mediad, New York, pages 25 - 28) and by the method of Noble and Campbell (Clin, Chem., volume 16 (1970), pages l66 - 170), respectively. The compounds also have analgesic, antipyretic, fibrinolytic, enzyme-inducing and thrombocyte aggregation-inhibiting activities, all of which can be observed by methods which are current for these purposes.

The compounds of formula I can, therefore, bo used as medicaments in human and veterinary medicine and also as intermediates for the preparation of other compounds. For example, they can he converted by oxidation into the corresponding 3-(p-phenoxyphenyl)5 butyric acid derivatives or 3-(p-phenoxyphenyl)-2butenoic acid derivatives, which for their part are valuable plant protection agents.

The compounds of formula I are novel and constitute one aspect of the present invention.

In formula I, the H1 radical is preferably F or Cl, more preferably Cl. The II radical is preferably H or acetyl. Tho alkanoyl group having 1 to 6 C atoms is preferably acetyl, and may also he, for example, formyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, methylethylacetyl, triraetbylacetyl, caproyl, iaocaproyl or tort.-butylacetyl. The A radical is preferably -c(ch3)=ch-.

Preferred compounds according to the Invention are those compounds of formula I in which at least one of tho radicals mentioned has one of the preferred meanings indicated above. Some of the preferred groups of compounds can be expressed by the partial formulae Ia to Ih which follow and which correspond to formula I and in which the radicals not designated in greater detail have the meaning indicated in formula I, but in which in la R1 is F or Cl; in lb R1 is Cl; in Ic K2 is H; in Id R2 is H or acetyl; in Ie A is -C(CII3) aClI-; in If R1 is F or Cl and R2 is H or acetyl; in is R1 is F or Cl and R2 is H; and in Ih R1 is F or Cl, R2 is II and A is -C(CH3)=CH-.

In all cases, those compounds in which the R* radical is in the p-position are preferred.

The present invention also comprises a process for the preparation of the compounds of formula I, which comprises (i) reducing a compound of formula II: -A-E II V/ °Λ_/ wherein E is a free or functionally modified COOH or CHO group benzyloxy and R1 and A have the above-stated meanings, or or (ii, treating a compound of formula III: ,1 ' III wherein X is Cl, Br, I, Nil,, or a functionally modified 2 1 OH group other than OR , and Π and A have the abovestated meanings, with a solvolysing agent, or (iii) reacting a compound of formula IV; •A-CJk-OR4 Ct IV or a salt thereof, with a compound of formula V: or with a salt thereof, wherein one cf the groups or Q2 is OH and the other is Y, Y is Cl, Br, I, NH^, 2 Oil or a functionally modified OH group and R , R and A have the above-stated meanings, or (iv) treating a compound which in other respects corresponds to formula 1, but which contains a H atom instead of the R* radical, with a fluorinating, chlorinating or brominating agent, or (v) diazotising a compound which in other respects corresponds to formula I, but which contains an amino group instead of the radical, and then converting the resulting diazonium salt into the R^ radical.

Compounds of formula 1 in which Λ is —C(CII^) =CIi— can also be obtained by treating a compound of formula VI: CYtCH^)-CHgCHgOR* VI with an agent which splits off HY, for example by dehydration or dehydrohalogenation.

If desired, the R radical in a resulting compound of formula I may be converted by treatment with a solvolysing or acylating agent into another Π radical and/or the A radical -C(CH3)=CH- may be converted to the other A radical by treatment with a reducing agent.

The preparation of the compounds of formula I is, in other respects, carried out by methods which are known from the literature (for example, the standard works such as Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), George Thieme Verlag, Stuttgart) and, in particular, under the reaction conditions which are known and suitable for the reactions in question.

If desired, the starting materials for the preparation of compound I can be formed in situ in such a way that they are not isolated from the reaction mixture, but are immediately reacted further to form the compounds of formula I. The starting materials for the preparation of the compounds of formula I are also new; they can, however, be readily obtained by known methods.

The compounds of formula I are preferably obtained by reducing a compound of formula II. - 6 4240β Preferred starting materials for the reduction are: 3“(4-p-chlorophenoxy-phenyl)-butyric acid and 3(4-p-chlorophenoxyphenyl)-2-butenoie acid and the corresponding o- and ιη-chloro-, ο-, m~ and p-fluoro-, q-, m.- and j>-bromo- derivatives and the C^-Cg alkyl esters, particularly the methyl and ethyl esters, of these compounds: 3-(4-g-chlorophenoxy-phenyl)-butanal and 3-(4-j>-chlorophenoxy-phenyl)-2-butenal and the corresponding o- and m-chloro-, q-, ra- and p-fluoroand o-, m— and p-bromo-derivatives and the enol acylates, particularly the enol acetates, of these compounds; and l-benzyloxy-3-(4-p-chlorophenoxy-phenyl)-butane and 1benzyloxy-3-(4-p-chlorophenoxy-phenyl)-2-butene and the corresponding q- and is-ehloro-, ο-, ra- and p-fluoroand ο-, m- and p-bromo-derivatives. Other starting materials which can be used for the reduction are other functional derivatives of the acids mentioned, for example, the acid halides, the nitriles, the amides, the azides or the anhydrides, other ethers of the compounds of formula I which can be split by hydrogenolysis, for example, the diphenylmethyl ethers or triphenylmethyl ethers, and also compounds which have, on tho benzene rings, at least one substituent (for example, NII^) which can be removed by reduction. The alkyl esters mentioned can be obtained, for example, by tho reaction of corresponding acetophenone derivatives of the formula p-(R^-CgH^O)-CgH^COCH3 with zinc and bromoacetic alkyl esters to givo hydroxyestore of tho formula p-(R1-CgH4O)-C6H4-C(CH3)(0H)-CHoC00Alkyl and subsequent dehydration and/or reduction; they can be readily converted (for example, by saponification, amidation or reduction) into the other functional derivatives mentioned.

Catalytically activated hydrogen or complex metal hydrides are preferably used as the reducing agents. Other conventional reducing agents, for example, metals in conjunction with acids or bases, can also be used.

Examples of catalysts which are suitable for catalytic hydrogenation.are noble metal catalysts, nickel catalysts or cobalt catalysts, and also mixed catalysts, such as copper-chromium oxide. Suitablo noble metuls include platinum and palladium, which can be present on supports (for example, charcoal, calcium carbonate or strontium carbonate), in tho form of oxides or in a finely divided form. Nickel catalysts and cobalt catalysts are preferably employed in the form of Raney metals. Hydrogenation can be carriod out at a pressure of from 1 to 100 atmospheres and at a temperature of from -80° to +150°C, more preferably from 20 to 100°C. Hydrogenation is preferably carried out in the presence of an inert solvent, for example an alcohol such as methanol, ethanol or isopropanol, a carboxylic acid, such as acetic acid, an ester, such as ethyl acetate, or ail other, such as tetrahydrofuran (THF) or dioxan. Mixtures of two or more solvents, for example mixtures containing water, can also be used. β 42406 Complex metal hydrides, such as I.iAlH^, NaBH^ and sodium aluminium-bis-(2-alkoxyethoxy) dihydrides, and diborane can also be used as reducing agents, if desired, with the addition of catalysts such as HF^t AlClj or LiDr. Suitable solvents in this case are, in particular, others, such as diethyl ether, TilF, dioxan, 1,2-dimethoxyethane or diglyme, and also hydrocarbons, such as benzene. Alcohols, such as methanol or ethanol, are preferably used as the solvent for reductions with NaBH^. The reduction is preferably carried out at a temperature of from -80° to +150°C, more preferably from 20° to 120°C. Unsaturated esters of tho formula p-(R1-CgH^-O)-CgH^-0(011^)= Cll-COOalkyl can be reduced by means of LiAlII^ (for example for the aldehydes of esters mentioned, brief reaction times (up to 30 minutes) to give the corresponding unsaturated alcohols of formula I (A = -C(CH^)=CII-); if, however, the mixture is heated (for example to its boiling point) and/or prolonged reaction times are used, saturated alcohols of formula I (A = -CH(ClIj)-CHQ-) are mainly obtained.

Another suitable method of reduction, for examplo for tho aldohydee or esters mentioned, is reaction with nascent hydrogen. The latter can be generated, for example, by treating metals with acids or bases. The systems zinc/acid, zinc/alkali metal hydroxide solution, iron/acid and tin/acid can, for example, be used. Examples of suitable acids are hydrochloric acid and acetic acid. Sodium or another alkali metal in an alcohol, such as ethanol, isopropanol. 42403 n-butanol, amyl alcohol or isoamyl alcohol or phonol, nnd also an aluminium-nickel alloy in an aqueous alkaline solution, if desired, with the addition of methanol, as well as sodium amalgam or aluminium amalgam in an aqueous alcoholic solution or aqueous solution are also suitable for generating nascent hydrogen. In this method, the reaction temperature ia preferably from 0° to 150°C, more preferably from 20° to 120°C.

Amino groups located on the aromatic rings can be removed by reduction, by first diazotising them and then reducing the resulting diazonium salts in situ, for example by boiling with ethanol, formic acid, H^POg or stannitc solutions.

Compounds of formula I can also be prepared by solvolysis of the compounds of formula II. In the latter, X can bo Cl, Br, 1, NH^ or a functionally modified OH group. The latter can be functionally modified, for example, in the form of an alcoholate, for example a magnesium alcoholate, such as are formed as reaction products in Grignard reactions, an ostor, for example a carboxylic acid ester, the carboxylic acid radical preferably having up to 7 C atoms (for example, benzoyl), an alkylsulphonic or arylsulphonic acid ester (wherein tho alkyl radical preferably contains 1 to 6 and the aryl radical preferably contains 6 to 10 C atoms), or an ether, for example an alkyl ether (wherein the alkyl group preferably contains up to 6 C atoms), an aryl ether (wherein the aryl group preferably contains 6 to 10 C atoms) or un aralkyl ethor (wherein tho aralkyl group preferably has 7 to 11 C atoms). Boric acid esters, which are formed as intermediates in oxidative hydroboronation, can also bo used. X is preferably Cl, Br, NH , an acyloxy group, such as benzoyloxy, a boric acid ester group or an alkoxy group having 1 to 3 C atoms, for example methoxy.

Compounds of formula XII wherein X is a ihagnesium alcoholate group, can be obtained, for example, by reacting a Grignard compound of the formula g-iR’-CgH^Oj-CgH^-ClKCHjJ-CHgMgHal (Hal = Cl, Br or I) with formaldehyde or reacting a Grignard compound of the formula g-i^-CgH^Oj-CgH^-CHiCH^-MgHal with ethylene oxide. Such compounds of formula III are preferably not isolated, but, after their formation, are hydrolysed ip situ by means of dilute acids, for example sulphuric acid or hydrochloric acid, or by means of aqueous ammonium chloride solution, the compounds of formula I being formed.

Compounds of formula III wherein X is Cl, Br, I or an acylated OH group, are proforably saponified in an aqueods or aqueous alcoholic solution or suspension, if desired with the addition of a solubiliser, for example an alcohol, glycol or glycol ether. Alkali metal hydroxides, such as NaOH or KOH, alkaline earth motal hydroxides, such ns Ca(0H)_ or Ha(01I)„, and also suspensions of Pb(0H)2 or AgOlI, are preferably used as the saponifying agent. Alcohols, such as methanol, ethand, and isopropanol, and mixtures thereof with water are preferably used as the solvent. The sapon11 ification ia preferably carried out at a temperature of from 20° to 100°C, more preferably from 60° to 100°C.

Halogen atoms in compounds of formula IX 5 (X = Cl, Dr or I) can also bo converted into tho corresponding acyloxy groups by treatment with salts of fatty acids, for example, potassium acetate or heavy metal acetates, in an inert solvent, such as dimethylformamide (DMF) and at a temperature of from ° to 100°C. .. .

Etherified OH groups are preferably split by treatment with hydrogen halide acids, such as HBr or HI, and it is preforablo to carry out the reaction in acetic acid or aqueous acetic acid at a tomperaturo of from 60°C to tins boiling point, more proforably at the boiling point. Tho halogen compounds formed are, in general, subsequently hydrolysed with alcoholic alkali as indicated above.

Compounds of formula I can also be obtained by reacting a Compound of formula IV , or a salt thoroof, with a Compound of formula V, or a salt thereof. The starting materials of formula TV can be obtained, for example, by reaction of a p-Q -acetophonone with bromoace tic acid ethyl ester and zinc and subsequent dehydration and/or reduction. The starting materials of formula V are, in general, known.

A phenol of formula TV = OH) can either ο be reacted with a compound of formula IV (Q = Y) or a compound of formula χν (Q* = Y) can be reacted with a ο phenol of formula V (Q = OH). In this reaction the phonol is preferably present in the form of a corresponding phenolate, more preferably the corresponding sodium or potassium phenolate. The reaction is preferably carried out in tho presence of an inert solvent, such M DMF or hexamothylphosphoric acid triamide (IC-1PT) , and in the presence of a catalyst, such as copper powder, at a temperature of from 5θ° to 200°C, more preferably from 80° to 130°C.

Compounds of formula I £A = -0(01¾)=CH~2 can also be obtained by elimination of HY (for example, dehydration or dehydrohalogenation) from compounds of formula VI. The dehydration of compounds of formula V (Y = OH) is preferably carried out by troutment with an acid catalyst, such as sulphuric acid or a sulphonic acid, such as p-toluenesulphonic acid, in an inert solvent, for example a hydrocarbon, such as benzene or toluene, at a temperature of from 0° to 200°C, more preferably from 80° to 110°C, and also by heating for several hours in a high-boiling solvent, such as HMPT, proforably nt a temperature of from 150° to 200°C.

The dehydrohalogonation of compounds of formula V (Y a Cl, Br or I) may be carried out, for example, by treatment with an inorganic or organic base, proferably a tertiary amine such as triethylamine, preferably in tho presence of an inert solvent and at a temperuture of from 0° to 100°C.

Tho diphenyl ether derivatives of formula I can also be obtained by halogenation of a corresponding compound which contains an H atom instead of tho radical, for example by direct reaction with elementary chlorine or bromino in un inert solvent, such no ether, totrachloromethane or acetic acid, preferably in the presence of a catalyst, for example iron filings, iodine or AlClj, and at a temperature of from -30° to 100°C.

Compounds of formula 1 can also be obtained by diazotising a corresponding compound which contains an amino group instead of the R* radical, and subsequently converting the resulting diazonium compound into the desired compound of formula I.

The starting materials for this method of preparation can be obtained, for example, by reducing the corresponding butyric acid ester which contains a nitro group instead of the it* radical; if desired, the nitro group can be reduced to the amino group and the ester group to the hydroxymethyl group, in one stage.

Diazotisation is suitably carried out at a temperature of from -20° to +10°C, for oxomplc in an aqueous solution of hydrochloric or hydrobromic acid, by adding an inorganic nitrite, preferably NaNO . The diazonium group is replaced by chlorine or bromino, preferably in a hot aqueous solution in the presence of CUgClg or Cu^Br^. In order to introduce a fluor25 ine atom, diazotisation is carried out, for example in anhydrous hydrofluoric acid, and the mixture is then warmed, or the diazonium salt is reacted with IIUP^ to give the sparingly soluble diazonium tctrafluoboratc, which can be isolated and converted into tho desired fluorine compound by heating, for exumple in an inert - 1¾ 43406 solvent.

If desired, the R radical in a resulting compound of formula I can be converted into another ll radical by treatment with a solvolyaing or acylating agent.

Thus, an ester of formula I (Il = alkanoyl having 1 to 6 C atoms) can be converted into the corresponding alcohol of formula I (Il = II) by solvolysie, preferably hydrolysis. The solvolysis is preferably carried out by tho methods described above; the ester is preferably saponified by reaction with a base, such as NaOH or KOH.

Conversely, it is possible to acylate an 2 alcohol of formula I (It = H) by methods which are described in the literature, to give the corresponding alkanoic acid ester of formula I (It = alkanoyl having 1 to 6 C atoms). The acylating agents which are preferably used are fatty acids having 1 to 6 C atoms or their reactivo derivatives, in particular their halides (for example, acetyl chloride or acetyl bromide) and their anhydrides (for example, acetic anhydride). The acylation is preferably carried out in the presence of an acidic or basic catalyst. Examples of suitable acid catalysts are mineral acids, such as hydrochloric acid or sulphuric acid, and also organic sulphonic acids, such as p-tolucnesulphonic acid. Examples of suitable basic catalysts are alkalis, «ucli as NaOH or KOH, alkali metal carbonates, such as Ma„C0_ or K CO , and organic buses, such as pyridine. If desired, an inert solvent, for example benzene, can also bo present.

An excess of the base, for example pyridine, can also be used as the solvent. In a preferred pro2 ceduro, an alcohol of formula I (R = II) is reacted with the acid chloride or acid anhydride concerned, in pyridine at room temperature.

Esterification can also be effected using ketenes, preferably in an inert solvent, such as ether, benzene or toluene, and with the addition of one of tho acid catalysts mentioned. The acylation is preferably carried out at a temperature of from 0° to l40°C, more preferably from 20° to 100°C.

' An unsaturated diphenyl ether of formula I (A = -C(Cltj)=CH-) can also be reduced to the corresponding saturated compound of formula I (A = -011(011^)-011^-), preferably by catalytic hydrogenation under the conditions indicated above, for example in tho presence of a Pd catalyst.

The compounds of formula I £A = - Cli(CII^) - Oil,,-J possess a centre of asymmetry. They are therefore obtained in the form of racemates or, if optically active starting materials are used, in an optically active form. If desired, a racemate can be resolved into its optical antipodes by mechanical or chemical means according to conventional methods. It. is preferred to form diastereomers from the racemate by reaction with an optically active resolving agent.

Examples of suitable resolving agents are optically active acids with which diastereomeric ostors are formed. It is also possible to form acid esters of the raceinato I, for example the acid phthulic acid - 16 42406 esters, which may then bo converted by means of optically active bases into diastereomoric salts, from which tho optically active acid esters can be obtained and, by the saponification thereof, the optical antipodes of the compounds of formula 1 can be obtained.

The compounds of formula I are used as medicaments in human or veterinary medicine in admixture with solid, liquid and/or semi-liquid medicinal inert, physiologically acceptable carriers or oxcipients. Suitable carriers are organic or inorganic substances which are suitable for enteral or parenteral administration or topical application and which do not react'with the compounds of formula I, such as, for example, water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatine, lactose, starch, magnesium stearate, talc or petroleum jelly. Compositions in the form of tablets, dragees, capsules, syrups, elixirs or suppositories are, for example, suitable for enteral administration. Solutions, preferably oily or aqueous solutions, and also suspensions, emulsions or implants, are preferably used for parenteral administration, while ointments, creams or powders are proforably used for topical application. Such compositions may bo sterilised and/or may additionally contain adjuvants, such as preservatives, stabilisers, lubricants and/or wetting agents, salts for controlling the osmotic pressure, buffer subst.incus, dyestuffs, flavourings and/or aroma substances. If desired, they can also contain ono or more other active - 17 42406 compounds.

The compounds of formula I ere generally administered in tho same way aa known anti-inflammatory agents, such as Indomothacin. Suitable daily dosages are from 0.2 to 20 mg/kg of body weight. Oral administration is preferred. When compositions according to the invention are formulated in dosago unit form, they preferably contain from 10 to 1,000 mg, more preferably from 30 to 300 mg of the active compound(s) per dosage unit.

All tho compounds of formula I mentioned in the Examples which follow are particularly suitable for tho production of pharmaceutical compositions.

In order that tho invention may bo inoro fully 15 understood, the following Examples are given by way of illustration only. In these Examples, all tomperaturea are in degrees Centigrade; the expression ’’worked up in conventional manner or working up in conventional manner” is used to mean: water is added to the reaction mixture, the resulting mixture is extracted with chloroform, methylene chloride or ether, the phases ars separated, the organic phase is dried over sodium sulphate, filtered and evaporated and the product is purified by chromatography and/or crystallisation.

Example 1 A solution of 31·7 g of 3-(A-p-chloropnenoxyphenyl)-2-butenoic acid ethyl ester ^obtainable by reacting p-(p-chlorophenoxy)-acetophenone with bromo30 acetic acid ethyl ester and Zn and subsequently dehydrating the resulting 3-hydroxy-3-(4-p-chlorophonoxyphenyl)-butyric acid ethyl esterJ in 300 ml of TIIF is added dropwise, while stirring, to a solution of 6.8 g of LiAlH^ in 400 ml of THF. The mixture is boiled for 90 minutes and then cooled and a mixture of 20 ml of THF and 5 ml °f water ie added, followed by 5 ml of 32J5 aqueous sodium hydroxide solution, and the mixture is worked up with chloroform and water to give 3-(4-p20 chlorophenoxy-phenyl)-butan-l-ol, an oil, 1.5756» Examples 2 to 9 The following are obtained, analogously to Example 1, from tho corresponding 3-pbenoxyphonyl-2butonoic acid estors by reduction with LiAlil^ at tho boiling point! 2. 3-(4-q-Kluorophenoxy-phonyl)-butan-l-ol. 3» 3-(4-jm-Fluorophenoxy-phenyl)-butan-l-ol. 4. 3-(4-p-Fluorophenoxy-phenyl)-butan-l-ol, n“ 1.5485· 5» 3-(4-q-Chlorophenoxy-phonyl)»butan-l-ol. 6. 3-(4-m-Chlorophenoxy-phenyl)-butan-l-ol. 7. 3-(4-2-Bromophenoxy-phenyl)-butan-l-ol. 8. 3-(4-m-Broraophenoxy-phenyl)-butan-l-ol. 9· 3-(4-p-Bromophenoxy-phenyl)-butan-l-t>l.

Example 10 A solution of 3 g of 3-(4-p-fluorophenoxyphenyl)-2-butenoic acid ethyl ester in 30 ml of THF is added dropwise at 5 - 10° and while stirring, to a solution of Ο.38 g of LiAlil^ in 30 ml of THF. After stirring for 10 minutes at 5°, the mixture is worked up with aqueous THE and concentrated aqueous sodium hydroxide to give 3-(4-p-fluoraphenoxy-phcnyl)-2buten-l-ol, m.p. 52 - 54°.

Examples 11 - 18 The following are obtained, analogously to Example 10, from tho corresponding 3-pbenoxyphenyl-2butenoic acid eaters by reduction with I.iAlIl^ at 5 10°: 11. 3-(4-o-Fluorophenoxy-phenyl)-2-butcn-l-ol. 12. 3-(4_in-Fluorophonoxy-phcnyl)-2-buten-l-ol. . 3-(4-o-Chlorophenoxy-phenyl )-2-buton-l-ol. 1¾. 3-( 4-m-Chlorophenoxy-phenyl) -2-buton-l-ol. . 3-(4-p-Chlorophenoxy-phonyl)-2-buten-l—ol, m.p. 77-78 16. 3-( 4-o-Broniophonoxy-phonyl) -2-buten-1 -ol.

I?. 3-(4-m-Bromophenoxy-phonyl)-2-buten-l-ol. 18. 3-( 4-p-Broitiophcnoxy-phenyl)-2-buton-l-ol, m.p. 86-87° Example 19 3-(4-p-Chlorophejioxy-phenyl)-butyric acid (obtainable by saponifying the corresponding ethyl ester) is reduced with LiAlII^, analogously to Example 1, but with boiling for 8 hours. 3-(4-p-Chlorophenoxy20 phenyl)-butan-l-ol is obtained; ιιθ 1.5756.

Example 20 33.4 ml of a 70% solution of NaAltuCgil^OOH^).,Ho in benzene arc added dropwise, while stirring, 1-) a mixture of 30*3 fi of 3-(4-p-chlorophenpxy-phonyl)-2-butenoic acid methyl ester and 90 ml of benzene and the mixture ie then stirred at 80° overnight. The mixture is poured into 130 ml of 20% aqueous Ii^SO^ stirr°d for one hour. The phasas are separated nnd the benzene phase is washed with water, separated off and evaporated to give 3-(4-p-chlorophenoxy-phenyl)-2buten-l-ol, m.p. 77 - 78° (from cyclohexane).

Example 21 2.76 g of 3-(4-p-fluorophenoxy-phenyl)-l,3butanediol are dissolved in 30 ml of acetic acid and hydrogenated at 20° and 1 atmosphere in the presence of 0.5 g of 10% Pd/C until hydrogen absorption has ceased. After filtration and evaporation, 3-(4-pfluorophenoxy-phenyl)-butan-l-ol, ηθ 1.5485, is obtained.

Example 23 Λ solution of 2.75 g of 3-(4-p-cblorophenoxyphonyl)-butanal (obtainable by hydrogenating tho corresponding acid chloride) in 12 ml of ethanol is added dropwise to a solution of 0.6 g of NaBH^ in 15 ml of ethanol. The mixture is stirred for two hours at ° and worked up in conventional manner to give 3-(420 p-cblorophenoxy-phenyl)-butan-l-ol, n^ 1.5756.

Example 23 g of l-ben3jyloxy-3-(4-p-fluorophenoxy-phenyl)butane ^obtainable from l-bromo-3-(4-p-fluorophrhox/phenyl)-butane and Na benzylatej are dissolved in 50 ml of methanol, the mixture is hydrogonatod in tho presence of 0.5 g of 5% I’d/C catalyst at 20° and normal pressure until hydrogen absorption has ceasod, and 3-(4-p_fluoro20 phenoxy-phenyl)-butan-l-ol, 1.5485, is obtained.

Example 24 5 A Grignard solution is prepared from 31.2 g of 4-(1-broinoethyl)-4‘-chloro-diphenyl ether (obtainable by bromineting 4-etbyl-4'-chloro-diphenyl ether with N-bromosuccinimide) and 2.43 S of magnesium in 350 ml of other, a solution of 4.4 g of ethylene oxide in ml of other is added and tho mixture is boated in an autoclave for 3 hours nt 100°. After cooling, the product of the formula p-Cl-C^H^-O-ip-CgH^J-CHiCH^)CHCH OMgBr which is formed is decomposed with water i5 and worked up In conventional manner to givo 3-(4-p20 chlorophonoxy-phenyl)-butan-l-ol, . 1.5756« Example 25 2.42 g of 3-(4-p-fluorophenoxy-pbenyl)-l20 butene ^obtainable from 2-(4-p-fluorophenoxy—phlinyl)propanal and tri.phenylphosphine-metliylenoJ are dissolved in 5 ml of diglyme, 3 ml of a 1 tnolai solution of Nulllli( in diglyme are added and n solution of Ο.56 g of 1111¾ othorate in 1.2 ml of diglyme is addod dropwise under 2’5 Ng. 0.7 ml of water is then added and 1.4 ml of 3 N NaOH and 1.4 ml of JO-i H^Og are then added dropwise at 80 - 100°. The mixture is cooled, treated with ice water and worked up in conventional manner (tho boric acid ester which is intermediately formed being hydro30 lysed) to give 3-(4-p-fluorophonoxy-phenyl)-butan-l-ol, «ρ 1.5685.

Example 26 3.38 g of l-bromo-3-(6-p-chlorophenoxyphonyl)-2-butene [(obtainable by brominating 2-(6-pchlorophonoxy-phenyl)-2-buteno(] are dissolved in a mixturo of 15 ml of acetone and 15 ml of water, 1 drop of sulphuric acid is added and the mixture is warmed for 6 hours nt 65° and worked up in conventional manner to give 3-(6-p-chlorophenoxy-phenyl)-2-buton-l-ol, m.p. - 78°.

Example 27 2.78 g of l-chloro-3-(6-p-fluorophonoxy-phenyl)butano [(obtainable by roacting 6-(3-chloropropionyl)-6'fluoro-diphenyl other with CH^Mgl, with subsequent hydrolysis and reduction(] are boiled for 3 hours with a solution of 2 g of Ba(OII),, in 60 ml of methanol and the mixturo is worked up in conventional manner to give 20 3-(6-p-fluoropbonoxy-phenyl)-butan-l-ol: n“ 1.5685· Example 28 2.78 g of l-chloro-3-(6-p_fluorophenoxy-phenyl)butane are diseolvod in 20 ml of DMF, 3 g of anhydrous potassium acetate are added and the mixture is stirred for 3 hours at 60°. Working up in conventional manner gives 1-acotoxy-3-( 6-p-f luoroplienoxy-phenyl)-but.ine.

Example 29 1—Bromo-3-(6-p—chlorophenoxy-phenyl)-2-butene is reacted with potassium acetate analogously to Example Ζβ to give l-acctoxy-3-(4-p-chlorophcnoxy-phenyl)-2ΟΛ butene, njj 1*5662.

Example 30 5 A solution of 1 g of NaNOg in 5 ml of water is added, while cooling in ice, to a solution of 2.74 g of l-amino-3-(4-p-chlorophenoxy-phenyl)-2-butene [^obtainable from 3-(4-p-Chlorophenoxy-phenyl)-210 butanoic acid amide by means of LiAlH^J in 50 ml of % aqueous acetic acid. The mixture is Warmed at 80° for 1 hour and worked up in conventional manner to give 3-(4-p-chlorophenoxy-phonyl)-2-buten-l-ol, m.p. 77 - 73°· Example 31 2*90 g of l-methoxy-3-(4~p-chloroplionoxy-phenyl) butane ^obtainable by rencting l-methoxy-3-(4-g-chlorophonoxy-phenyl)-3-propanone with CH^Mgl, with subsequent hydrolysis and reductionJ are boiled for 2 hours with a mixture of 5 ml of 48% aqueous HDr and 5 ml of acetic acid, 10 ml of 10% methanolic K011 aro added and the mixture io ugain boiled for 2 hours and worked up with water and chloroform to give 3-‘(4-p-cJilorophonoxy-pb».'ityl) butan-l-ol, η“θ 1.5682.

Example 32 A mixture of 2.22 g of p-iodofluorobenzene and 1.83 g of tho sodium salt of 3-p-hydroxyphenyl-butnn-l4-. ol (obtainable by reducing 3-P-hydroxyphonylbutyric acid ethyl ester) is warmed at 90° for 8 hours in the presence - 24. 42406 of 1 g of Cu powder in 10 ml of IIMPT and is then worked up in conventional manner to give 3-(4-p20 fluorophenoxy-phenyl)-butnn-l-ol, ηθ 1.5485.

Example 33 A solution of 2.74 g of 3-P-iodophenyl-2buten-l-ol (obtainable by reducing 3-p-iodophenyl-2butenoic acid ethyl ester) and 1.5 g of sodium g-chlorophenolate in 20 ml of DMF is warmed at 130° for 8 hours, forking up in conventional manner gives 3-(4-p-chlorophenoxy-phenyl)-2-buten-l-ol, m.p. 77 - 7®°· Example 34 2.93 g of 3-(4-p-chlorophenoxy-phenyl)-l,3butane-diol {^obtainable by reducing 3-(4-ji-chlorophenoxyphenyl)-3-hydroxy-butyric acid ethyl ester with LiAlH^T in 3° wl of IIMPT are heated at 180° for 8 hours and tho mixture is cooled and 'worked up in conventional manner to give 3-(4-p-chlorophonoxy-phonyl)-2-buten-l-ol, m.p. 77 - 78°.

Example 35 3.56 S 3-bromo-3-(4-p-chlorophenoxy-phenyl)butan-l-ol [^obtainable by brominating 3-(4-p-chlorophenoxy-phenylj-butan-l-ol^ and 1.02 g of triethylamine nre dissolved in 60 ml of tolueno and the mixture is stirred for 10 hours at 60° and worked up in conventional manner to give 3-(4-p-chlorophcnoxy-phenyl)-2-buten-Ιοί, m.p. 77 - 78°. 4240 6 Example 36 2.4 g of 3-p-phenoxyphenyl-butan-l-ol are dissolved in 20 ml of acetic acid, a solution of 0.8 g of chlorine in 20 wl of ucotic acid is added dropwise, while stirring, at 20° and the mixture is stirred for a further hour and evaporated. Working up in conventional manner with water and chloroform gives 3~(4-p20 chloroplienoxy-phenyl)-butan-l-ol, n^ 1.5756.

Example 37 A solution of 0.7 g of NaNO in 2 ml of wator is added dropwise at 0° to a solution of 2.57 g of 3-(4nminoplionoxy-pbenylj-butan-l-ol ^obtainable by hydrogenating 3-(4-p-nitrophonoxy~phonyl)-butyric acid ethyl ester over CuCrgO^]] in 25 ml of 15% aqueous hydrochloric acid. 1.2 ml of a 40% solution of IIBF^ are thon added dropwise. The diazonium totrafluoborate is filtered off, washed with water, dried and introduced in portions into 20 ml of boiling xylene. After the decomposition is complete, the mixture is evaporated and worked up in conventional manner to give 3-(4-p-fluorophenoxy-phenyl) on butan-l-ol, 1.5485· Example 38 2.55 g of 3-(4-£-aminophenoxy-phenyl)-2-butonl-ol ^obtainable from 3-(4-p-nitrophenoxy-phenyl)-2butonoic acid ethyl ester and LiAllIj J arc dissolved in ml of 10% hydrochloric acid, 0.7 g of NaNO in 2 ml d of water is added nt 0 - 5°, the resulting solution is slowly added dropwise to a hot solution of CuoCla (obtained by reducing 2.1 g of copper sulphate with SOg in 13 nl of water in the presence of 2.6 g of NaCl) and tho mixture is heated at 90 - 95° for a further 30 minutes, cooled and worked up in conventional manner to give 3-(i*-P~chlorophenoxy-phenyl)-2-buten-l-ol, m.p. - 70°.

Example 39 A solution of 3·θ2 g of l-acetoxy-3-(4-j>10 fluorophonoxy-phenyl)-butane and 2 g of NaOH in 3θ ml of 80% aqueous ethanol is boiled for 3 hours. Water is added, the mixture is extracted with chloroform and the extract is evaporated to givo 3-(4-p-fluorophenoxy-phcnyl)butan-l-ol, njj° 1.5435.

Example 40 3.17 g of l-acetoxy-3-(4-p-chlorophenoxy-phenyl)2-butene are boiled for 2 hours with 2 g of KOH in jO ml of methanol, water and chloroform are added and the mixture is worked up to give 3-(4-p-chlorophenoxy-phcnyl)2-buten-l-ol, m.p. 77 - 78°.

Example 4i Λ mixture of 2.77 S of 3-(4-p-chlorophenoxy25 phonyl)-2-buten~l-ol, 5 ml of acetic anhydride and 8 ml of pyridine is allowed to stand at 20° for 15 hours and is poured into ico water and worked up with chloroform and Water to give l.-acetoxy-3-(4-p-chlorophenoxy-jshenyl)Οθ 2-butene, ίθ Examples 42 - 58 The following arc obtained, analogously to Example 4l, by acetylating the corresponding alcohols: 42. l-Acetoxy-3-(4-o-fluorophenoxy-phenyl)-butane. 3. 1-Ace toxy-3-(4-m-fluorophenoxy-phenyl)-butane . 44. l-Acetoxy-3-(4-p-fluorophenoxy-phenyl)-butane. 45· l-Acotoxy-3-(4-o-chlorophenoxy-phenyl)-butane, 46. 1-Aco toxy-3-(4-m-chloropheiioxy-phenyl)-butane. 47. 1-Acotoxy-3-(4-p-chlorophenoxy-phenyl)-butane. 48. l-Aco toxy-3-(4-o-bromophonoxy-phenyl)-butane. 49. 1-Ace toxy-3-(4-jn-bromoplienoxy-phenyl)-butane. 50. 1-Acc toxy-3-(4-p-bromophenoxy-phenyl)-butane. 51. 1-Aco toxy-3- ( 4-o-fluorophenoxy-phenyl) -2-butene . 52. 1-Acetoxy-3-(4-m-fluoroplionoxy-phenyi)-2-butene. 53. l-Acetoxy-3-(4-p-fluorophenoxy-phenyl)-2-butene. 54. 1-Acetoxy-3-(4-o-chlorophenoxy-phenyl)-2-butene. 55· 1-Ace toxy-3-(4-m-chlorophenoxy-phenyl)-2-butene. 56. 1-Acotoxy-3-(4-q-bromophenoxy-phenyl)-2-butene. 57. 1-Acetoxy-3-(4-nb-bromophenoxy-phenyl)-2-butene. 58. l-Acetoxy-3-(4-£_-bromophonoxy-phenyl) -2-butene, m.p. 48°.

Examples 59 to 67 Using the corresponding anhydrides, the corr25 osponding propionates, butyrates, isobutyrates, valerates iaovalerates, trimethylacetates, caproatos, isocaproates and tert.-butylacetates, are obtained, analogously to Example 41: 59· l-Propionyloxy-3-(4-p-chlorophenoxy-phenyl)-2-butene 30 60. l-Butyryloxy-3-(4-p-chlorophenoxy-phenyl)-2-butene. 61. l-Isobutyryloxy-3-(6-p-chlorophenoxy-phenyl)-2-butene. 62. l-Valeryloxy-3-(6-p-chlorophenoxy-phenyl)-2-butone. 63· l-Isovaleryloxy-3-(6-p-chlorophenoxy-phenyl)-2-butene. 66. l-Trimethylacetoxy-3-(6-p-chlorophenoxy-phenyl)-2butene. 65. 1-C aproyloxy-3-(6-p-chlorophenoxy-phenyl)-2-butene. 66. l-Isocaproyloxy-3-(6-p-chlorophenoxy-phenyl)-2butene. 67. l-Tert.-butylacetoxy-3-(6-j>-chlorophenoxy-phenyl)2-butene.

Example 68 2.77 S of 3-(6-p-chlorophenoxy-phenyl)-2-butenl-ol and 15 ml of formic acid are warmed at 80° for 2 hours and the mixture is cooled and worked up in conventional manner to give 1-formyloxy-3-(6-g-chlorophenoxy-phenyl) -2-butene .

Examples 69 to 85 The following are obtained, analogously to Examplo 68, from the corresponding alcohols: 69. l-Formyloxy-3-(6-0-fluoroplienoxy-phenyl)-butane. 70. l-Formyloxy-3-(6-m-fluorophenoxy-phenyl)-butane. 71· 1-Formyloxy-3-(6-p-fluorophenoxy-phenyl)-butane . 72. 1-F ormyloxy-3-(6-o-chlorophenoxy-phenyl)-butane . 73· l-Formyloxy-3-(6-m-chlorophenoxy-phenyl)-butane . 76. 1-Formyloxy-3-(A-p-chlorophenoxy-phenyl)-butane . 75· l-Formyloxy-3-(6-o-bromophenoxy-phenyl)-butane . 76. l-Formyloxy-3-(6-m-bromophenoxy-phonyl)-butane, 77· 1-Formyloxy-3-(6-p-bromophenoxy-phenyl)-bu tane. 2$ 42406 78. i-Formyloxy-3-(4-o-fluorophenoxy-phenyl)-2-butene. 79· l-Formyloxy-3-(4-m-fluorophenoxy-phenyl)-2-butene. 80. l-Formyloxy-3-(4-p-fluorophenoxy-phenyl)-2-butene. 81. l-Formyloxy-3-(4-o-chlorophenoxy-phenyl)-2-butene. 82. l-Formyloxy-3-(4-m-chlorophenoxy-phonyl)-2-butene. 83. l-Formyloxy-3-(4-o-bromophenoxy-phonyl)-2-butene. 84. l-Forinyloxy-3-(4-m-bromophenoxy-phenyl)-2-butene. 85. l-Formyloxy-3-(4-p-bromophonoxy-phenyl)-2-butono.

Example 86 2.58 g of 3-(4-j>-fluorophonoxy-phenyl)-2buton-l-ol are dissolved in 50 ml of ethanol and hydrogenated in the presence of 1 g of 5% Pd/C at 20° and normal pressure until hydrogen absorption ceases.

Filtration and evaporation gives 3-(4-p-fluorophenoxy20 phenyl)-butan-l-ol, nn oil, ηβ 1.5485.

The following Examples describe pharmaceutical compositions- containing a compound of formula I and are given by way of illustration only: Example A: Tablets A mixture consisting of 1 kg of 3-(4-p-chlorophonoxy-phenyl)-2-buten-l-ol, 4 kg of lactose, 1.2 kg of wheat starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is pressed into tablets in conventional manner so as to form tablets, each containing 100 mg of active compound.

Example B: Dr’agoes Tablets are pressed in the same way ns in Example A and are then coated in conventional manner with a coating consisting of sucrose, wheat starch, talc and tragacanth.

Example Ci Capsules 5 kg of 3-(4-p-chlorophenoxy-phenyl)-2-butenl-ol nre filled into hard gelatine capsules in conventional manner so as to form capsules, each containing 250 mg of active compound.

Tablets, dragees and capsules containing one or more of the other active compounds of formula I can bo obtained analogously.

Claims (22)

1. CLAIMS:1. Diphenyl other derivatives of formula I 1 2 wherein R is F, Cl or Dr, R is H or alkanoyl having 1 - 6 C atoms and A is -CHiCH^j-CHg- or -CiCIl^)=CH-.

2. . 3-(4-p-Fluorophenoxy-phenyl)-butan-l-ol.

3. 3-(4-p-Fluorophenoxy-phenyl)-2-buten-l-ol.

4. 3-(4-p-Chlorophenoxy-phenyl)-butan-l-ol.

5. 3-(4-p-Chlorophenoxy-pIienyl)-2-buten-l-ol.

6. 3-(4-o-Chlorophonoxy-phenyl)-butan-l-ol. 10

7. 3-(4-p-Bromophenoxy-phenyl)-2-buton-l-ol.

8. l-Acetoxy-3-(4-p-chlorophenoxy-phenyl)-2buteno.

9. 1-Ace toxy-3-(4-p-broinoplienoxy-phenyl) -2-butene

10. Λ process for the preparation of a diphenyl 15 ether derivative of formula I specified in claim 1, which comprises reducing a compound of formula II: where E is a free or functionally modified COOH or CHO group or benzyloxy and P.^ and A have the meanings specified in claim 1.

11. A process for the preparation of a diphenyl ether derivative of formula I specified in claim 1, which comprises treating a compound of formula III: wherein X is Cl, Br, I, NH 2 or a functionally modified 2 1 OH group other than OR , and R and A have the meanings specified in claim 1, with a solvolysing agent.

12. A process for the preparation of a diphenyl ether derivative of formula I specified in claim 1, which comprises reacting a compound of formula IV: q1 ”C # A “ cHr ° R2 iv or a salt thereof, with a compound of formula V: 1 2 or a «alt thereof, wherein one of the groups Q or Q is OH and tho other in Y, Y in Cl, Hr, I, NH,,, OH or 1 2 a functionally inodifiod OH group and R , R and A have the meanings spocified in claim 1. 5

13. A process for the preparation of a diphenyl ether derivative of formula I specified in claim 1, which comprises treating a compound which in other respects corresponds to formula I, but which contains an H atom instead of the R^ radical, with a fluorinating, chlorinating or brominating agent.

14. A process for tlie preparation of a diphenyl ether derivative of formula I specified in claim 1, which comprises diazotising a compound which in other respects corresponds to formula I, but which contains 15. An amino group instead of the R^ radical, and then converting the resulting diazonium salt into the radical.

15. A process for the preparation of a diphenyl other derivative of formula I spocified in claim 1, in 20 which A is -0(011^)=011-, which comprises treating a compound of formula VI: claim 12, with an agent which splits off HY. - 34 42406

16. A process according to any one of claims o 10 to 15, in which when the It radical in the compound of formula I obtained is II, it is converted to an R radical which is an alkanoyl group having 1 to 6 carbon atoms by treatment with an acylating agent.

17. A process according to any one of claims ο 10 to 15, in which when the R radical in the compound of formula I obtained is an alkanoyl group having 1 to 6 carbon atoms, it is converted to the II radical which is II by treatment with a solvolysing agent.

18. A process according to any one of claims 10 to 17, in which when tho A radical in the compound of formula I obtained is -C(CH^)=CH-, it is converted to the A radical which is by treatment with a reducing agent.

19. · A process for tho preparation of a diphenyl ether derivative of formula I specified in claim 1, substantially as herein described in any of Examples 1 to 86.

20. A pharmaceutical composition comprising at least one compound as claimed in any one of claims 1 to 9 and an inert, physiologically acceptable carrier.

21. A composition according to claim 20 which is in dosage unit form, each dosage unit containing from 30 to 300 mg of said compound(s).

22. A pharmaceutical composition substantially ns herein described in any of Examples A to C.