CA1178970A - Aryloxyalkyl containing compounds - Google Patents

Abstract

Abstract of the Disclosure Novel aryloxyalkyl- group containing substances are disclosed which have the ability to reduce the level of cholesterol and triglycerides in the blood. By varying the nature of the aryloxy group, the alkyl group and the moiety attached to the alkyl group, compounds of varying cholesterol-reducing activity can be obtained.
The moiety attached to the alkyl group can be a carboxyl group or a substituted carboxyl group, for example a carbamoyl, alkoxycarbonyl, tertiary aminoalkoxy carbonyl or pivaloyloxymethoxy group, in particular, or an olefin-ically unsaturated hydrocarbyl group. Processes for the production of the substances involve coupling phenols with organic halidce which contain the alkyl group and the entire said moiety. Alternatively, a phenol may be reacted with a ketone and a trihalogenated methane derivative to yield a carboxyl gorup-containing substance according to the invention for use as such or as a percursor of a more complex substance according to this invention.
Thiophenols may be used to produce thioanalogues of the eforenaid compounds.

Description

This invention .elates to novel aryloxyalkyl-group containing compounds having activity in reducing cholester-ol and triglyceride levels in blood and more particularly to processes ~or their production.
Aryloxy carboxylic acid esters have been proposed for use in the therapy of excessive cholesterol and triglycer-ide levels in the blood in British Patent Specification No. 860,303. One of the substances described in British Patent Specification No. 860,303, namely, the methyl ester of 2-(4'-chlorophenoxy)-isobutyric acid having the short name "Clofibrat" as recommended by World Health Organisation, has so far acquired considerable importance in the clinical treatment oi human beings. It has now been found that many of the ne~ compounds are superior to the Clofibrat in their cholesterol-reducing effect to a surprisingly high extent.
The present invention provides a process for the production of a compound having the general formula ~1 ~ CH2 ~ 12 A

wherein R~ is hydrogen or halogen;
A~ and A2 ~hich are the same or different are hydrogen or alkyl; and Z is amine, hydroxyj O M , M being an inorganic or organic cation, alkoxy, cyrlopentyl, pivaloyloxyalkoxy, 7-theophillinylalkoxy, pyridyl-C-alkGxy in which the alkoxy group contains ,rom 1 to 3 carbon atoms, 3-oxindolyl-oxy, N-methylpyrrolidinoxy, piperidinoxy, piperazinoxy or tertiar~ aminoal~o~y in which the tertiary

2 -- 1~ 7~9r70 amino group possesses the following general formula R3 \ CH ~

wherein R3 is lower alkyl and R4 is hydrogen or halogen, with the proviso that when A1 and A2 are both methyl, Z is not hydroxy or ethoxy, which process comprises conducting any of the following steps:
A: reacting a phenol of the general ~ormula R1 ~ CH2 ~ OH
r ~ , wherei~ R1 haæ the a~oresaid meaning or a corres-ponding alkali metal or alkaline earth metal phenolate . with a compound having the general formula Hal - C - COZ

ln which 'Iflal'' i~ a halogen atom and A , A2 and Z have the aforesaid meanings; or B: reacting an acid halide of the general ~ormula:

R1 ~ CN~ - ~ O - C - CO Nal wherein "Hal" is a halogen atom and R1, A1 and A2 have the aioresaid meanings with a compound of the general formula: `

~178970 Z - H
wherein Z is as defined hereinabove, or;
C: when Z in general formula I is a said tertiary aminoalkoxycarbonyl radical, reacting a compound of the general formula Rl ~ CH2 ~ 0 - C - CoOR5 Hal wherein Rl, Al, A2 and Hal have the aforesaid meanings and R5 denotes an alkylene group with a compound of general formula R3 CH2 ~

wherein R3 and R4 have the a$oresaid meanings, and isolating the compound obtained as such, as a racemate or optically active enantiomer when Al and A2 are different and/or as a pharmacologically acceptable acid addition salt when Z is a basic group.
A considerable variety of compounds according to the present invention can be obtained by varying, in particular, the substituents Rl, R2 and Z in the aforesaid general form-ula. Representative compounds according to this invention are set out in the Table and Examples which iollow.
The substituents Al and A2 which can be the same or different can represent hydrogen atoms-or alkyl groups pre-ferably containing from 1 to 4 carbon atoms. Of particular interest are those compounds in which Al and A2 contain a number of carbon atoms at least eq,ual to 3 and more partic-ularly in which Al and A2 are different alkyl groups. Part-icularly when Al and A2 are different alkyl groups, and Z
is alkoxy, compounds of particular therapeutic value are ~....
. ~ 4 --.. ~, ., 1~7~970 obtained.
As will be appreciated from the foregoing, the group COZ can be constituted by a considerable number of differ-ent types of groups. It can be a carboxyl group which can be in salt form with an organic or inorganic base, in amide form, that is Z constitutes an amine group, preferably of formula -NH2, or the carboxyl group can be esterified. In this latter connection, the esterifying group can be a sim-ple alkyl group or cyclopentyl group or can be a substituted alkyl group.
When Z represents a substituted alkoxy group, substitu-tion can take place in a number of ways to give radicals of varying complexity. Thus the alkoxy group can in turn be substituted by a tertiary amino group, a pivaloyloxy group, a pyridyl-C-alkoxy group, or a 7-theophyllinyl group. When the substituent is a tertiary amino group it possesses the formula 3 CH

wherein R3 is lower alkyl preferably containing from 1 to 3 carbon atoms and R4 is hydrogen or halogen.
Esterification of the group COZ can also be achieved by means of an azacyclohydrocarbyl group which contains a tertiary ring nitrogen atom. ~or this purpose, Z is a pyr-rolidinoxy-, piperidinoxy-, piperazinoxy-including 4-alkyla-tion derivatives thereof such as 4-methyl-piperazino or a

3-oxindolyloxy group.

117t~970 A number of basic preparative methods have been found to be particularly satisfactory for use in the pro-duction of compounds according to the present invention.
~n the first such method, a phenol or alkali metal or alkaline earth metal phenolate is reacted with a compound of general formula C(A )(A )(COZ)(Hal). The halogen atom in this latter compound is preferably chlorine or bromine.
Thus, for example, the compound 4-(4'-chlorobenzyl)-phenol can be condensed with the ethyl ester of 2-bromo-2-methyl butyric acid and the condensation product obtained can be subjected to hydrolytic cleavage of the ethyl group to form 2-[4-(4'-chlorobenzyl)-phenoxy]-2-methyl butyric acid. The reaction sequence may be terminated at this stage or if a reaction product in which Z is one of the more complex types described above is to be obtained, this acid can be reacted with thionyl chloride to form its acid chloride which can be esterified by reaction with a hydroxy alkylene terminated compound whose formula will depend upon the nature of the group Z which it is desired ~0 to introduce into the molecule; this procedure corresponds to the aforesaid step C. When the group Z is a tertiary aminoalkoxy group as mentioned hereinabove, it may be more convenient to introduce the group Z into the molecule in two stages, the latter of which constitutes the aforesaid step D. Thus, when esterification of the acid chloride is effected, a halo alcohol will be used to yield a compound having a terminal halogen atom at which reaction can then be effected with a basic compound, for example a secondary amine in order to enable a tertiary mab/ r ` !

1~7~970 amino group-terminated compound to be obtained.
Although 2- or 3-stage preparative processes for the production of tertiary amino-terminated compounds according to the present invention have been described in the preceding paragraph, it is possible to use in place of an ethyl ester as indicated in the specific example, an ester of formula Z-OH where Z is a tertiary aminoalkyl group as aforesaid.
In the second aforesaid process for the production of compounds according to the present invention, a phenol or alkali metal or alkaline earth metalphe~late of general formula R ~ CH2 ~ OH

is reacted with an aldehyde or ketone of formula A1COA2 in the presence of an at least trihalogenated methane derivative. When the trihalogenated methane derivative is a simple halomethane for example chloroform or carbon tetrachloride, the reaction product will possess the general formula: A1 R1 ~ CH2 ~ O - C - COOH

When a substituted trihalogenated methane is used, the substituent will esterify the carboxyl group in the above formula. The product obtained in either case may be utilised as such as a compound according to the present invention. Alternatively, it may be ., .~

1789~70 converted to an alternative carboxyl derivative according LO the present invention.
In one procedure, a carboxyl group in the reaction product so obtained or obtained by alkaline hydrolysis of a reaction product so obtained, can be esterified, either as such or as a reactive derivative thereof, for example an acyl chloride obtained by reaction with for example thionyl chloride, with a hydroxy terminated compound Z-OH in the foregoing step B (1) or C. Alter-natively, the carboxyl group or reactive derivative thereof can be reacted with ammonia or an amine to form an amide or with an inorganic base or salt or with an organic salt to ab:~ain a compound of general formula I wherein Z is amine or O M (reaction step B (4)).
In an alternative reaction sequence applicable in the case when the trihalogenated methane derivative reacted with the phenol in the presence of the ketone and a strong base which can be sodium or potassium hydroxide contains a fourth substituent which is not a halogen atom and the product contains an alkoxy carbonyl group, the product of the first stage contains an alkoxy carbonyl group, the reaction product can be subjected then to aminol~sis with ammonia or an amine to obtain a compound of general formula I wherein Z is amine (reaction step B (5)).
Compounds of the general formula I have been found to be particularly effective agents for lowering the cholesterol level of blood. Although as mentioned above, aryloxy carboxylic acid esters have been proposed for use in mab/~ ' 1~7~3g~1J
the therapy of e~cessive cholesterol and triglyceride levels in the blood in British Patent Specification ~o.
860,303, in particular the compound Clofibrat, the com-pounds of this invention are generally more effective.
Results of tests carried out on animals are set out in the following Table, these results having been obtained with a representative selection of compounds according to this invention in comparison with Clofibrat.
In the Table which follows, column (1) of this table ~0 contains the identification number of the test substance in question. In columns (2) and (3) are set out data relating to the structure of the test subs~ances of the general formula:

R143 CR2 ~ O - C - Z (la) ~0 That part of the molecule which is situated in formula (la) on the left-hand side of the broken vertical line is represented by a symbol in column (2). The meanings of the symbols used for this purpose are as follows:
b = p-benzylphenvl c = p-(p'-chlorobenzyl)-phenyl Shown in column (3) is the partial structure which is situated in formula (la) on the right-hand side of the broken vertical line. The abbreviations "~et" and "Et" represent methyl and ethyl, respectively.
The numbers in the columns (4) and (5) relate to quantities of the test substance in mg/kg of body weight of the animal undergoing the test which were orally administered to the test animals in the respective tests.

g 7~ ~ ~

Indicated in column (4) is the acute toxicity LD 50 for the mouse. Column (5) shows the daily dose which lowers the serum cholesterol level in rats by 25% (ED 25).
Indicated in column (6) is the therapeutic index calcu-lated from the numerical values of the preceding columns,that is to say, the quotient of LD 50/ED 25.

_ 10 1~7~970 TABLE
.
(1) (2) (3) (4) (5) (6) No. _ LD50 ED25 Index .
32574 b OC(Met)(Et)COO Et ~ 2 6274 c OCH2COOH 2700 50 54 1374 - c OCH2COOEt 3000 25 120 18374 c OCH2COO ~ 3000 54 >65 22974 c OCH(Met)COOH 1700 29 59 2774 c OCH(Met)COOEt 2500 33 76 17474 c OCH(Et)COOEt 3000 54 >56 25974 c OC(Met)2COO ~~>3000 41 >73 24774 c OC(Met)(Et)COOEt10000 61667 25674 c OCH(Met)COO(CH2)2>3000 50 >60 N ~CH2 ~

7274 c OCH2COO(CH2)2- 3000 66 >45 CH2~
25874 c OC(Met)2COO(CH2)2)~300031> 97 N~CH2~
24874 c OCH(Met)COO ~ N-Met 2700 28 96 26074 c OC(Met)2COOCH2 ~ .HCl >3000 14>214 28374 c OC(Met)2COO ~~3300 >86 ~35 23174 c OC(Metd2cOo(cH2)2>~300020>150 . Met 15174 c OCrl2COOCH2OCO-C(Met)3,~300025 ~120 23574 c OCH(~5et)COOCH2OCO-C-~3000 17 >176 _ 11 --TABLE (continued) (1)(2) 1 (3) (4) (5) (6) No. l LD50 ED25 Index 24074 c OC(Met)2COOCH2O 3000 14 ~ 200 28274 c OC(Met)(Et)COOCH2O 3000 21 ~ 143 27874 c OCH2CONH2 ~ 3000~ 25 >~120 27774 c ¦ OC(Met)2CONH2 ~ 300019 > 158 Clofibrate: 2350160 In addition to possessing the strong hypocholesterol-aemic effect which can be seen from the table, the compounds of the present invention also lower considerably the tri-glyceride content oftheblood and a:re in this respect again several times better than the action of Clofibrat. By way of example, hypertriglyceridaemia produced in rats by add-ing fructose to their drinking water was lowered by Clofibrat administered in a dosage of 85 mg/kg by 25%, per oral administration whereas the dosages indicated in brack-ets in mg/kg were sufficient to achieve the same effect when using the following compounds of formula I, whose formulae are set out in the table: No. 24774 (4.5), No. 26074 (13) and No. 24074 (5.6).
For pharmaceutical purposes, the compounds of formula I can either be used as such or in the form of their salts.
If they comprise a free carboxy group, pharmacologically acceptable bases, such as basic sodium, potassium, calcium or aluminium compounds or ammonia or amines such as ethan-olamines, dimethylamine or morpholine can be used for the ~;

1~7~970 --formation of the salt. If the compounds comprise a basic group, inorganic or organic acids, such as hydrogen chloride, tartaric acid or malic acid can be used for forming the salt.
It will be appreciated that for therapeutic use, the ccmpounds of the invention can be made up, in accordance with well known pharmaceutical techniques, into compositions having as an essential active ingredient a compound of the invention in association with a pharmaceutical carrier therefor. If desired, the compositions can be made up in a dosage unit form suitable for the particular mode of administration, the quantity of active ingredient in each dosage unit being such that one or more units are required for each therapeutic administration. The dosage unit may exist, for example, in the form of a tablet, sugar coated pill, capsule or packaged power for oral administration, or in the form of a sterile injectable solution or suspen-sion, if desired contained in an ampoule, for parenteral administration. Each dosage unit preferably contains from 5 to 300 milligrams of active substance. The compounds of the present invention may also be incorporated in emulsions or solutions for oral administration. For a person of average build, it is expected that a dosage of from 0.02 to 1.5 gram per day will be suitable for therapeutic pur-poses.
The following Examples illustrate the invention.Although the examples only describe the preparation of representative members of classes of compounds according to the present invention, analogous processes may be employe~ for the production of analogues of the illustrated 1~78g7~

- coml~ounds. Compounds in the above Table whose production is not described in the Examples were prepared by analogous procedures to those described for compounds of lik~e type, in which the moiety in column 2 or 3 was replaced by a similar moiety. One such analogous procedure is referred to in Example 10.
Example 1

4-(4'-chlorobenzyl)-phenoxyacetic acid ethyl ester 9.0 g (0.18 mol) of sodium hydride in the form of a 55 to 60% emulsion in mineral oil were introduced into 40 ml of dimethylformamide (DMF). To the mixture was slowly added a solution of 39.3 g (0.18 mol) of g'-chloro-4-hydroxydiphenylmethane in 90 ml of DMF. The mixture as obtained wasstirred for 15 minutes at 70C, whereafter a solution of 30.0 g (0.18 mol) of ethyl bromacetate in 90 ml of DMF was added and stirring took place for 7 hours at 130C. The solvent was thereafter removed in a B~chi rotary evaporator. The residue was treated with water and then thoroughly extracted with dichloromethane. After being dried over magnesium sulphate, the extract was con-centrated by evaporation under reduced pressure. After chromatography over 20 g of A12O3, elution with 200 ml of benzene and distillation, the residue yielded 23.0 g of pure product, of boiling point 156 - 160C (0.03 mm).
C17H17ClO3 (304.8) Calculated C 66.98 H 5.62 Cl 11.64 Found C 66.51 H 5.80 Cl 11.85 - 1'1 -Example 2 4-(4'chlorobenzyl)-phenoxyacetic acid N-benzyl-N-methyl aminoethyl ester hydrochloride A solution of 21.0 g (0.07 mol) of 4-(4'-chlorobenzyl)-phenoxyacetyl chloride in 140 ml of anhydrous xylene was added dropwise and while stirring to a solution of 11.55 g (0.07 mol) of N-benzyl-N-methyl-2-aminoethanol in 70 ml of anhydrous pyridine. The reaction mixture was heated for 24 hours at reflux temperature, whereupon the solvent was evaporated in a B~chi rotary evaporator under reduced pressure, the residue was taken up in 10% aqueous KHC03 solution and extracted with dichloromethane. The organic phase was washed with water and dried over anhydrous magnesium sulphate. 27.0 g of brown resin were obtained 1~ therefrom by evaporation. This resin was dissolved in ben-zene and filtered over 35.0 g of A12O3. By combining the three first fractions, each of 50 ml, and concentration by evaporation, 25.0 g of a light brown resin were obtained.
After dissolving in ether and adding ethereal hydrogen chloride, solid hydrochloride precipitated after tritura-tion. Recrystallization from acetone/ether yielded 13 0 g of product in the form of lustrous white crystals of melting point 120 - 122C.
C25H26ClN03 . HCl (460.3) Calculated: C 65.22 H 5.91 N 3.04 Cl 15.40 Found: C 65.41 H 5.96 N 3.20 Cl 15.63 Example 3 4-(4'-Chlorobenzyl)-phenoxyacetic acid-4(N-methyl)-piperidyl ester hydrochloride A solution of 6.0 g (0.02 mol) of 4-(4'-chlorobenzyl)-l;) 1~7~9'70 phenoxyacetyl chloride in ~0 ml of anhydrous xylene was added as in Example 2 to a solution of 2.30 g (0.02 mol) of 4-hydroxy-N-methylpiperidine in 20 ml of anhydrous pyridine, whereafter the mixture was kept at reflux temperature for 24 hours while stirring. Working up in the same way as in Example 2 and filtration of the solution in benzene through 10 g of Al2O3 yielded 8.5 g of brown resin, and this resin, after being dissolved in ether and after addition of HCl/ether, could be caused to solidify by trituration. The crude hydrochloride (5.8 g) was dis-solved in acetone and boiled for 3 minutes with active carbon. By recrystallization from acetone/ether, 3.5 g of hydrochloride were obtained with a melting point of 170 -C21H24ClNO3 . HC1 (410.3) Calculated: C 61.47 H 6.14 N 3.41 Cl 17.28 Found: C 61.36 H 6.14 N 3.43 C1 17.54 Example 4 4-(4'-Chlorobenzyl)-phenoxyacetic acid (3-pyridyl)-methyl ester A solution of 6.0 g (0.02 mol) of 4-(4'-chlorobenzyl)-phenoxyacetyl chloride in 50 ml of anhydrous benzene was added to a solution of 2.18 g (0.02 mol~ of 3-hydroxymethyl pyridine in 20 ml of anhydrous pyridine. The mixture was stirred for 45 minutes at room temperature and thereafter heated for 6.5 hours at reflux temperature. ~orking up in the same way as in the preceding Examples 2 and 3 yielded a residue, from which 4.0 g of product in the form of white lustrous needles and a melting point of 77 - 78C

could be recovered by recrystallization from ether/

, - lG --',.
~ . .....

li~9~

petroleum ether.

C21~18ClN3 (367.5) Calculated: C 68.57 H 4.90 N 3.81 Cl 9.66 Found: C 68.31 H 4.52 N 3.41 Cl 10.24 Example 5 Bis-[4-(4'-chlorobenzyl)-phenoxyacetic acid] (2,6-pyridyl)-dimethyl diester A solution of 6.0 g (0.02 mol) of p_(p~-chlorobenzyl)-phenoxy-acetyl chloride in 50 ml of anhydrous toluene was added to a solution of 1.39 g (0.01 mol) of 2,6-bis-(hydroxymethyl)-pyridine in 15 ml of anhydrous pyridine.
After boiling for 24 hours under reflux and working up in a similar manner to that used in the preceding Examples 2 to 4, a residue was obtained which yielded 4.0 g of product in the form of lustrous white crystals of melting point 78C
after recrystallization from dichloromethane/ether/petroleum ether .
C37H31Cl2NO6 (656.5) Calculated: C 67.68 H 4.76 N 2.13 Cl 10.80 Found: C 67.67 H 4.84 N 1.77 Cl 11.14 Although general formula I set out hereinabove indicates the presence of only one group of general formula:
Al R~ ~ CH2 4~ A2 that is Z is monovalent, it is possible for Z to be divalent particularly when it is (2,6-pyridyl)-dimethyl group in which case two of the aforesaid acyl groups will be present.
The aforesaid general formula I is to be considered as including within its ambit those compounds in which Z denotes a single valency and the residue of a divalent group to which .
.. .......

7~ ~ 0 the single valency belongs.
Example 6 4-(4'-Chlorobenzyl)-phenoxyacetic acid 2-(7-theophyllinyl)-ethyl ester A solution of 6.0 g (0.02 mol) of 4-~4~-chldrobenzyl)-; phenoxy-acetyl chloride in 50 ml of anhydrous xylene was added to a solution of 4.48 g (0.02 mol) of 7-(2-hydroxy-ethyl)-theophylline in 25 ml of anhydrous pyridine. The mixture was heated for 20 hours while stirring to reflux temperature and the residue worked up as in the preceding Examples 2 to 5. Crystallization from dichloromethane/
methanol yielded 6.5 g of product in the form of white lustrous needles of melting point 134 ~ 135Co C24H23ClN405 (482.9) Calculated: C 59.69 H 4.80 N 11.60 Cl 7.34 Found: C 59 ~ 35 H 4.97 N 11.51 Cl 7.84 Example 7 2-Methyl-2-~g -(4'-chlorobenzyl)-phenoxy]-butyric acid ethyl ester ~ ~ CH2 ~ ~H3 8~.0 g (0.4 mol) of 4-chloro-4 ' -hydroxydiphenylmethane are heated together with 27.0 g (0.2 mol) oi anhydro~s pot-assium carbonate in 350 ml of anhydrous xylene for 30 minutes to reflux temperature, u~her~after a solution of B3~5 g (0.4 mol) of 2-bromo-2-ethyl-2-methyl acetic acid ethyl ester in 50 ml of anhydrous xylene is added. The mixture is kept for 24 hours and ~ith vigorous stirring at reflux temperature.
After filtering off the precipitated potassium bromide and 1~7897(J

evaporating the solvent in a BUchi rotary evaporator, the residue is taken up in ether and extracted with normal sodium hydroxide solution. The ether extracts are washed with water, dried over MgSO4 and concentrated by evaporation.
The brown oil (82.0 g) thereby obtained is dissolved in n-hexane and filtered through a column of 200 g of basic A1203. After evaporating the solvent and distillation at reduced pressure, 34.7 g of pure product are obtained with the boiling point 200 - 204C/0.01-0.1 mm Hg.
C20H23C13 (346.8) Calculated: C 69.25 H 6.68 O 13.84 Cl 10.22 Found: C 69.16 H 6.66 O 13.84 Cl 10.27 The analogous product without chloride substituent shows a boiling point of 154 - 162C@0.03 mm Hg ("Sgd 32574").
Example 8 2-Methyl-2-[4-(4'-chlorobenzyl)-phenoxy]-valeric acid ethyl ester Cl--~r CH2 ~,~ o - c - coo - C2H5 8.7 g (0.04 mol) of 4-chloro-4'-hydroxydiphenylmethane and 2.76 g (0.02 mol) of K2CO3 are brought over a period of 30 minutes to reflux temperature in 40 ml of anhydrous mesit-ylene-(1,3,5-trimethylbenzene), whereafter a solution of 8.9 g (0.04 mol) of 2-bromo-2-methyl-2-propyl acetic acid ethyl ester in 10 ml of anhydrous mesitylene is added and kept for another 24 hours and while stirring at reflux temperature. By working up in a manner similar to that ind-icated in the preceding Example 7 4.0 g of product are obtained as an oil with a boiling point of 177 - 179C/

0.01 mm Hg, 11785~7~

C21H25C13 (360.8) Calculated: C 73.89 H 6.98 Cl 9.83 Found: C 70.00 H 7.23 Cl 9.37 Example 9 2-~lethyl-2-~4-(4' chlorobenzyl)-phenoxy]-butyric acid-(3-oxymethylpyridine)-ester hydrochloride ~ ~ ~ O - C - COO - CH2 ~ . HCl 78 g (0.232 mol) of 2-methyl-2-[4-(4'-chlorobenzyl)-phenoxy]-butyryl chloride are dissolved in 300 ml of anhydrous benzene and 200 ml of anhydrous pyridine and then a solution of 27 g (0,247 mol) of 3-hydroxymethyl pyridine in 20 ml of anhydrous benzene is added. The mixture is heated for 5 hours and while stirring at reflux temperature and is thereafter concentrated by evaporation in a B~chi rotary evaporator. The brown residue is taken up in ether, the solution is extracted with water, dried over MgS04 and again evaporated under reduced pressure. The residue is dissolved in cyclohexane and filtered through a column of 250 g of basic A12O3. The light brown oil which is obtained by distilling off the cyclohexane is dissolved in ether and treated with a solution of hydrogen chloride in ether. The crystalline precipitate, after being recrystallized from dichloromethane/ether, yields 40.0 g of hydrochloride as white lustrous crystals of melting point 111 - 114C.
C24H24ClNO3 . HCl (446.3) Calculated: C 64.58 H 5.65 N 3.14 O 10.75 Cl 15.89 Found: C 64.95 H 5.65 N 2.98 O 10.46 Cl 16.00 ~1.78970 The 2-methyl-2-[4-(4'-chlorobenzyl)-phenoxy]-butvryl chloride used as starting substance can be obtained from the ethyl ester obtained as product in accordance with Example 7 being saponified with alcoholic caustic potash solution and by the free acid which is formed being con-verted with thionyl chloride into the acid chloride.
Example 10 2-Methyl-2-[4-(4'-chlorobenzyl)-phenoxy]- butyric acid 2-(7-theophyllinyl)-ethyl ester Cl ~ C~2 ~ I COO C~2CH2 ~ CH3 29 g (0.086 mol) of 2-methyl-2-[4-(4'-chlorobenzyl)-phenoxy]-butyryl chloride are dissolved in 200 ml of anhyd-rous xylene and 50 ml of anhydrous pyridine and a solution of 19.35 g (0.086 mol) of 7-(2-hydroxethyl)-theophylline in 50 ml of anhydrous xylene and 50 ml of anhydrous pyrid-ine is added. The mixture is heated for 24 hours and while stirring at reflux temperature and is thereafter concentrat-ed by evaporation in a B~chi rotary evaporator. The residue is extracted with dichloromethane, and the organic base is washed with water, dried over MgS04 and concentrated by evaporation under reduced pressure. The solid residue which is thereby obtained yields 28.5 g of product of melt-ing point 105 - 106C after being recrystallized from methanol.
C27H29clN4O5 (525.0) Calculated: C 61.77 H 5.57 N 10.67 0 15.24 Cl 6.75 Found: C 61.83 H 5.59 N ~0.57 O 15.15 Cl 6.94 _ 1 --1~7~

Example 11 Cl ~\ ~ CH2 ~ o -cr;2-coo-c~2-oco-c(c~3)3 4-(4'-Chlorobenzyl)-phenoxy acetic acid-(pivaloyloxymethyl) ester To a solution of 8.3 g (0.06 mol) of 4-(4'-chlorobenzyl)-phenoxy acetic acid in 50 ml of dimethylformamide are added 6.0 g (0.06 mol) of triethylamine, whereafter the mixture is stirred for 30 minutes at room temperature and, after adding 9.0 g (0.06 mol) of chloromethyl pivalate, is heated for 6 hours in an oil bath at 85 - 90C. The residue which is obtained by concentration by evaporation at reduced pressure in a B~chi rotary evaporator is washed with water and extracted with ether. The ethereal solution is once agàin washed with water, dried over anhydrous magnesium sulphate and concentrated by evaporation in the B~chi rotary evaporator, an oil being obtained which quickly solidifies. By recrystallization from ether/n-hexane, 9.5 g of product are obtained in the form of white crystals with the melting point 54 - 55C.
C21H23C15 (390.8) Calculated: C 64.53 H 5.93 Cl 9.07 Found: C 64.57 H 5.88 Cl 9.67 Example 12 Cl ~ ~ C~2 ~ O-CH Coo-cH2-oco-c(cH3)3 1~7~970 2-[4-(4'-Chlorobenzyl)-phenoxy]-propionic acid-(pivaloyloxy-methyl)-ester To a solution of 43.5 g (0.15 mol) of a-~4-(4'-chloro-benzyl)-phenoxy]-propionic acid in 250 ml of dimethylform-amide are added 30.0 g (0.3 mol) of triethylamine and,after stirring for half an hour at room temperature, 45.0 g (0.3 mol) of chloromethyl pivalate. The reaction mixture is heated in the oil bath for 6 hours at 90C and is there-after worked up in accordance with the procedure described in Example 11, there being obtained 50.0 g of white needles which, on recrystallization from n-hexane, once again produce white needles of melting point 65C.

C22H25C15 (404.8) Calculated: C 65.26 H 6,22 Cl 8.76 ~ound: C 65.27 H 6.23 Cl 8.29 _ ample 13 Cl ~ CH2 ~ ~O-C-COO-CH2-OCO-C(CH3)3 2-[4-(4'-Chlorobenzyl)-phenoxy]-isobutyric acid-(pivaloyloxy-methyl)-ester -To a solution of 27.4 g (0.09 mol) of 4-(4'-chlorobenzyl)-phenoxyisobutyric acid in 150 ml of dimethylformamide are added 18.0 g (0.18 mol) of triethylamine and, after stirring for half an hour at room temperature, 27.0 g (0.18 mol) of chloromethyl pivalate are added. After heating for 6 hours ~5 at 90C and working up in the manner indicated in the preced-ing examples, a liquid is obtained which, after distillation~
yields 26.0 g of a light yellow liquid product; boiiing point 204 - 209C/0.02 mm Hg.

C23H27C15 (418.9) Calculated: C 65.94 H 6.50 Cl 8.46 Found: C 66.34 H 6.56 Cl 8.42 The a-[4-(4'-chlorobenzyl)-phenoxy]-a-methyl-butyric acid-(pivaloyloxymethyl)-ester, obtained by a similar procedure using a-[p-~p'-chlorobenzyl)phenoxy~-a-methyl-butyric acid, shows a boiling point of 213 - 214C/O.Ol mm Hg.

11~7~97~

SUPPLEMENTARY DISCLOSURE
Further compounds have been prepared having similar or even enhanced therapeutic activity over that of the compounds referred to earlier herein. These compounds belong to the same classes of compounds as those described earlier herein and are accordingly prepared by the process described herein.
One preferred type of compound is a compound of the aforesaid general formula I
wnerein Z is alkoxy containing 1 to 4 carbon atoms, preferably 3 or 4 carbon atoms and A1 and A2 are alkyl groups prèferably containing a total of up to 5 to 10 carbon atoms and A1 and A2 being different. Particularly preferred compounds W~ich exhibit good therapeutic activity ~5 are those compounds of the aforesaid general formula I
in which ~1 is p-chloro- Z is alkoxy containing 3 or 4 carbon atoms and A and A2 are different alkyl ~roups containing a total of 5 to 10 carbon atoms.
Insofar as it has been postulated earlier herein that Z can be a group of formula O M+, compounds having suitable therapeutic activity have now been prepared wherein M is a catlon of groups I, II and III of the Periodic System of the Elements~ for example, sodium, potassium or lithium, magnesium, calcium, strontium or barium, or aluminium. Insofar as the elements may yield polyvalent cations, it should be appreciated that what is meant by M is in fact one half M or one third M+++ depending upon the valency of the metal M. M ma~ also be a cation of an -~178970 organic base or ammonia. Examples of such cations are piperidinium, methylthiazolinium, morpholinium, diethyl-hydroxyethylammonium, diethylammonium, diethanolammonium and ammonium. Other new compounds which have been found to possess particularly enhanced therapeutic activity are those compounds of general formula I in which Z denotes a 3-pyridylalkoxy group, particularly those in which Al and A are different alkyl groups containing a total of not more than 10 carbon atoms. The compounds possessing greatest therapeutic activity are those in which Rl is p-chloro.
Insofar as Z may be basic in nature, a compound of the invention containing such a radical Z may be isolated in the form of a pharmacologically acceptable acid addition or quaternary ammonium salt. Such acid addition salts can be derived from a variety of organic and inorganic acids, such as sulphuric, phosphoric, hydrobromic, hydroiodic, sulphonic, citric, lactic, oleic, succinic, tartaric, cimamic, acetic, benzoic, gluconic, ascorbic and related acids. Similarly, the quaternary ammonium salts can be derived from a variety of organic esters of sulphuric and aromatic sulphonic acids and from various organic halides.
Among these quaternization agents are methyl chloride and bromide, ethyl chloride, propyl chloride, butyl chloride, isobutyl chloride, benzyl chloride and bromide, phenethyl-bromide, naphthyl ethyl bromide, dimethyl sulphate, ethyl benzene sulphonate, ethyl toluene sulphonate, ethylene chlorohydrin, propylene chlorohydrin, methallyl bromide and crotylbromide.
Results of tests carried out on animals with specific compounds of the present invention additional to î~ mab/ ^-, 117~97~

those set OUt earlier herein are set out in the following Table, these results being compared with those obtained with Clofibrat. In the Table which follows, the various columns are given reference numerals which have the following meanings:-(1) Sets out the identification number ofthe test substance in question;
(2) Indicates the nature of the group etherifying a hydroxy alkanoic acid or ester or salt thereof;

(3) and (4) Denote the alkyl groups linked to the carbon atom which links the ether oxygen atom to the group -COZ;
_ ...
(~) Denotes the nature of the symbol "Z";
(6) Denotes the quantities of the test substance in mg/kg of body weight of the animal - rat (a) or mouse (,b)'which were orally administered to the test animals in tests to determine the acute toxicity LD50 therefor;
(7) Sho~Js the quantities of the test substance , in mg/kg of body weight of rats undergoing tests which were orally administered thereto to determine the daily dose which lowers the serum cholesterol level by 25~
(ED25). Indicated in columns (8) and ( 9) are the thera-peutic index values calculated from the numerical values of the preceding columns, that is to say that the LD50r t 2~ ED25 t and LD50 oUse/ED25ra, ratios respectively.
In column 2 the meanings of the symbols employed are as follows:
c = p-benzylphenyl " _ _ - -~17~g70 ~ = p-(p'-chlorobenzyl)-phenyl To determine the LD50 values, tests were carried out using male animals. Arter a single administration of the test substances, the animals were observed, their body weight being monitored, for at least seven days until toxic symptoms had faded. The volume of substances injected amount to 10 ml/kg.
To determine the ED25 values set out in the Table, male rats weighing 100-200 g were given the test substance once daily orally, emulsified in 3% gum arabic in a volume of 1 ml/100 g body weight. Administration was usually carried out on a Monday and continued up to and including Thursday of a second week. The final treatment on a q'hursday was given at about 16.00 hours.
Then the rats, which throughout the experiment had been kept in dosage groups of 8 to 10 in size 3 Makrolon cages, were kept fasting. On the Friday morning, the animals were sacrificed by carotid section under ether narcosis.
After centrifugation of the blood obtained in this way, the total cholesterol content of the serum was determined on a Beckman or DBG spectrophotometer by the method of Richterich, R. (Clinical Chemistry, S. ~arger, New York 1965, p. 232). The average group values of the Table were compared with those from a simultaneously investigated control group.

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_ 30 --1~7~970 The followin~ further Examples illustrate tne invention:

~1 1~7897(~
Exam~le 14 2-Methyl-2-[4-(4'-chlorobenzvl)Dhenoxy~butYric acid 20.80 9 (0.095 mol) of 4'-chloro-4-hydroxy-diphenyl-methane are dissolved in 400 9 (5.55 mol) of ethyl methyl ketone and stirred. 61.5 9 tl.10 mol) of potassium hydroxide are added to the clear, colourless solution which is then stirred for 10 minutes. While the suspension o~tained is under~oing stirring, 35.0 9 (0.29 mol) of chloroform are added dropwise thereto. The temperature of the suspension increases from 24 to 26C. After completion of addition of chloroform, stirring is continued for 5 minutes. The suspension becomes denser but more finely divided. The suspension is then heated to 50C. and stirred for 4 hours at this temperature, the highest temperature recorded being 54C.--The suspension becomes dense and yellow.
The suspension is totally evaporated on a BUchi rotation evaporator at 50C. using a water jet vacuum. The compact yellow residue is dissolved in 250 ml water. The 2~ dark solution obtained is mixed with 1 gram of active carbon and stirred for 10 minutes. The suspension obtained is filtered over Decalite. This brown, aqueous solution is acidified with 2N - Y.Cl and extracted twice with 250 ml quantities of ether. The ethereal ?hase is then extracted twice with 200 ml samples of 10% sodium carbonate solution.
The two alkaline phases are 3urified, acidified with 2N
HCl and extracted twice with 250 ml batches of ether. The ethereal extracts are dried over magnesium sulphate, filtered and completely eva?orated on a BUchi rotation evaporator over a bath having a temperature of 40C. 25 9 .

1~7~970 of a dark brown very viscous oil are obtained. This crude product is dissolved in 10 ml of n-hexane and the solution is subjected to column chromatography using a column con-taining 75 g of silica gel (r~oelm: activity III/30 mm)~
the column having a diameter of 20 mm. Elution is effected using n-hexane in 250 ml quantities. Four fractions are obtained in this way, the first being colour-less, the second yellow, and the third and fourth being colourless. Fractions 1, 2 and 4 are purified and com-pletely evaporated on a suchi rotation evaporator at abath temperature of 50C. 15 gram of a yellow oil are obtained representing a 46.6~ yeild. Analysis showed the product obtained to be 2-methyl-2-[4-(4'-chlorobenzyl) phenoxy]butyric acid.
Example 15 2-Methyl-2-[4-(4'-chlorobenzyl)-phenoxy]-valeric acid-3 .
pyridylmethyl -ester hydrochlorlde Cl ~ CH ~ , C3H7 ~ . HCl 262 g (0.75 ml) of 2-methyl-2-[4-(4'-chloro-benzyl)phenoxy~-valero,yl chloride are dissolved in 900 ml of anhydrous benzene and 250 ml oE anhvdrous pyridine and then a solution of 87 g (0.80 ml) of 3-hydroxymethyl pyridine, in 200 ml anhydrous benzene is added. The mixture is heated under reflux for one hour and is thereafter con-centrated by evaporation in a Buchi rotary evaporator. The brown residue is stirred with saturated sodium bicarbonate solution, and extracted with methylene dichloride in water.
The organic phase is dried with magnesium sulphate and again evaporated li7~970 under reduced pressure. The residue is dissolved in cyclohexane and filtered through a column of 900 9 of basic Al20~. The light brown oil obtained by distilling off the cyclohexane is dissolved in ether and treated with a solution of hydrogen chloride in ether. The crystalline deposit yields, after recrystallisation from methylene dichloride/ether, 190 ~ of hydrochloride as white crystals melting at 112-114C. Elemental analysis of this product gave the following result:
C25H27ClN03.HCl Calculated: C 65.22 H 5.91 N 3.04 O 10.43 Cl 15.40 Found: C 65.21 H 5.94 N 2.69 O 10.41 Cl 15.74 The 2-methyl-2-[4-(4'chlorobenzyl)phenoxy]-valeroyl chloride used as starting material can be obtained in a procedure in which t7~ corresponding ethyl ester is hydrolysed with alcoholic potassium hydroxide solution, the corresponding free acid obtained then being reacted with thionyl chloride.
ExamDle 16 2-MethYl-2-[4-(4'-chlorobenzvl)-phen~vlbutvramide Cl ~ CH2 ~ C 3 Ammonia gas was bubbled into a solution of dl-2-methyl-2-[4-(4'-chlorobenzyl)phenoxy]-butyryl chloride (509) in 500 ml dried ether for ~ hour. The reaction mixture was treated several times with water, dried over anhydrous magnesium sulphate and the organic layer was evaporated in vacuo. The resulting residue was purified by column chromatographv in a column containing 200 9 ,,"~ .

. . . ;

1~78~70 of neutral alumina using n-hexane as the eluant. The colourless oil thus obtained in a yeild of 40.0 g showed one spot when subjected to silica gel thin layer chromato-graphy.
C18H20ClNO2. n-hexane (339 35) Calculated: C 69.01 H 6.98 N 4.13 Cl 10.45 Found: C 69.36 H 6.98 N 3.69 Cl 10.50 Example 17 ~4-(4'-chloro~enzyl)phenoxy]acetamide The procedure of Example 16 was repeated using, however, as acid chloride starting material 21.08 g of [4-(4'-chlorobenzyl)phenoxy]acetylchloride. The corres-ponding amide was obtained which when crystallized from dichloromethane gave shiny white crystals of melting point 133 - 134C.
Cl5Hl4clNO2 (275.7) ! Calculated: C 65.34 H 5.12 N 5.08 Cl 12.86 Found: C 65.36 H 5.13 N 4.78 Cl 13.17 Exampl e 18 2-Methyl-2-[4-(4'-chlorobenz~l)phenoxy]propionamide The procedure of Example 16 was again repeated using on this occasion as acid chloride starting material 20.0 g of 2-methyl-2-[4-(4'-chlorobenzyl)phenoxy]propionyl-chloride. The corresponding amide was obtained which was crystallized from dichloromethane as white crystals of melting point 95 - 96C.
Cl7Hl8clNO2 (303.80) Calculated: C 67.21 H 5.97 N 4.61 Cl 11.67 Found: C 67.42 H 6.03 N 4.31 Cl 11.87 Additional compounds which have been prepared mab/'~

1~78970 by ?rocedures referred to in the foregoing Examples the compounds having different groups Z of general formula I, were as follows:
I Methyl-2-~4-(4'-chlo.obenzyl)phenoxy]propionate II Ethyl 2-isopropyl-2-[p-(p'-chlorobenzyl)phenoxy~acetate III Isopropyl 2-[p-(p'-chlorobenzyl)phenoxy]propionate IV 2-methyl-2-(4-benzylphenoxy)butyramide V Ethyl 2-methyl-2-(p-benzylphenoxy)valerate VI Ethyl 2-methyl-2-~o-methyi-p-(pl-chlorobenzyl)phenoxy]
butyrate (boiling point 184-1~C/0.001 mm Hg) VII Ethyl 2-methyl--~-[m-methyl-p-(p'-chlorobenzyl)phenoxy]-butyrate (boiling point 154C/0.01 mm.Hg) VIII Ethyl 2-methyl-2-[p-(p'-chlorobenzyl)phenoxy]hexanoate (boiling point: 180-18SC.) 15 IX n-Propyl 2-methyl-2-Cp-(p'-chlorobenzyl)phenoxy]
butyrate (boiling point: 172-190C~/0.001 mm.Hg~
X Methyl 2-methyl-2-tp-(p'-chlorobenzyl)phenoxy]butyrate (boiling point 173-185C./0.01 mm.Hg) XI n-Butyl 2-methyl-2-[p-(p'-chlorobenzyl)phenoxy~butyrate (boiling point: 175C./0.001 mm.Hg) Y.II t-Putyl 2-methyl-2-]p-(p'-chlorobenzyl)phenoxy~utyrate ~melting point 52-54C.) XIII Isopropyl 2-methyl-2-[p-(p'-chlorobenzyl)phenoxy]butyrate (boiling point 19~-18C./0.01 mm.Hg) 5 XIV The sodium salt of 2-methyl-2-[p-(p'-chlorobenzyl) phenoxy]butyric acid .

_ 3G_ 1 1 78 ~ ~

XV 2-methyl-2-[4-benzylphenoxy]valeric acid-(3-pyridyl methyl)-ester XVI 2-methyl-2-[4-(4~-chlorobenzyl)phenoxy]valeric acid-(3-pyridylmethyl)-ester~
S XVII 2-methyl-2-[4-(4'-chlorobenzyl)phenoxy]-propionic acid-(3-pyridylmethyl)-ester hydrochloride In the cases of each of the aforesaid compounds, the structure of the product obtained was confirmed both by elemental analysis and by spectrographic analysis.
Compounds I to III and V to XIII were prepared by the procedure of the foregoing Example 7, Compound IV
was prepared by the procedure of the foregoing Example 16, Compounds XV and XVI were prepared by the procedure of _ .
the foregoing Example 4 and Compound XVII was prepared by the procedure of the foregoing Example 15. In the case of compound XIV, the ethyl ester of 2-methyl-2-[4-(4'-chlorobenzyl)phenoxy]butyric acid prepared in Example 7 was hydrolysed in the presence of sodium hydroxide.

Claims (53)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the production of a compound having the general formula I
wherein R1 is hydrogen or halogen;
A1 and A2 which are the same or different are hydrogen or alkyl; and Z is amine, hydroxy, O-M+, M+ being an inorganic or organic cation, alkoxy, cyclopentoxy, pivaloyl oxyalkoxy, 7-theophillinylalkoxy 7 pyridyl-C-alkoxy in which the alkoxy group contains from 1 to 3 carbon atoms, 3-oxindolyloxy, pyrrolidin-oxy, N-methylpiperidinoxy, piperazinoxy or tertiary aminoalkoxy in which the tertiary amino group possesses the following general formula wherein R3 is lower alkyl and R4 is hydrogen or halogen, with the proviso that when A1 and A2 are both methyl, Z is not hydroxy or ethoxy, which process comprises conducting any of the follo~ing steps:
A: reacting a phenol of the general formula wherein R1 has the aforesaid meaning or a corresponding alkali metal or alkaline earth metal phenolate with a compound having the general formula in which "Hal" is a halogen atom and A1, A2 and Z have the aforesaid meanings; or B: reacting an acid halide of the present general formula:
wherein "Hal" is a halogen atom and R1, A1 and A2 have the aforesaid meanings with a compound of the general formula:
Z - H
wherein Z is as defined hereinabove; or C: when Z in general formula I is a said tertia.y aminoalkoxycarbonyl radical, reacting a compound of the general formula:

wherein R1, A1, A and Hal have the aforesaid meanings and R5 denotes an alkylene group with a compound of general formula:
wherein R3 and R have the aforesaid meanings, and isolating the compound obtained as such, as a race-mate or optically active enantiomer when A1 and A2 are different and/or as a pharmacologically acceptable acid addition salt when Z is a basic group.

2. A process as claimed in claim 1, wherein R1 is a chlorine atom.

3. A process as claimed in claim 2, wherein the reactants are so chosen that there is produced a compound of general formula:

wherein R3 is a lower alkyl group.

4. A process as claimed in claim 1, wherein R1 is chlorine and Z is 7-theophillinylethoxy, 3-pyridyl methoxy or a group of formula:

5. A process as claimed in claim 19 wherein the reactants are so chosen that there is produced a compound of general formula:
wherein A1 and A2 have the meanings set out in claim 1.

6. A process as claimed in claim 1, wherein A1 and A2 are different alkyl groups and Z is hydroxy, amine, alkoxy or O-M+.

7. A process as claimed in claim 6, wherein the reactants are so chosen that there is produced a compound of general formula:
wherein A1 and A2 are different alkyl groups and R6 is methyl or ethyl.

8. A process for thepreparation of 4-(4'-chlorobenzyl)-phenoxyacetic acid ethyl ester, which comprises reacting 4'-chloro-4-hydroxydiphenylmethane with ethyl bromoacetate.

9. A process for the preparation of 4-(4'-chloro-benzyl)-phenoxyacetic acid N-benzyl-N-methyl-aminoethyl ester hydrochloride, which comprises reacting 4-(4'-chlorobenzyl)-phenoxyacetyl chloride with N-benzyl-N-methyl-2-aminoethanol and reacting the reaction product obtained with hydrogen chloride.

10. A process for the preparation of 4-(4'-chloro-benzyl)-phenoxyacetic acid-4-(N-methyl)-piperidyl ester hydrochloride, which comprises reacting 4-(4'-chlorobenzyl)-phenoxyacetyl chloride with 4 hydroxy-N-methylpiperidine and reacting the reaction product obtained with hydrogen chloride.

11. A process for the preparation of 4-(4'-chloro-benzyl)-phenoxyacetic acid (3-pyridyl)-methyl ester, which comprises reacting 4-(4'-chlorobenzyl)-phenoxyacetyl chloride with 3-hydroxymethyl pyridine.

12, A process for the preparation of bis-[4-(4'-chlorobenzyl)-phenoxyacetic acid] (2,6-pyridyl)-dimethyl diester, which comprises reacting 4-(4'-chlorobenzyl)-phenoxyacetyl chloride with 2,6-bis-(hydroxymethyl)-pyridine

13. A process for the preparation of 4-(4'-chloro-benzyl)-phenoxyacetic acid 2-(7-theophillinyl)-ethyl ester, which comprises reacting 4-(4'-chlorobenzyl) phenoxyacetyl chloride with 7-(2-hydroxyethyl)-theophylline.

14. A process for thepreparation of 2-methyl-2-[4-(4'-chlorobenzyl)-phenoxy]-butyric acid ethyl ester which comprises reacting 4-chloro-4'-hydroxydiphenylmethane v;ith 2-bromo-2-methylbutyric acid ethyl ester.

15. A process for the preparation of 2-methyl-2-[4-(4'-chlorobenzyl)-phenoxy] aleric acid ethyl ester, which comprises reacting 4-chloro-4'-hydroxydiphenylmethane with 2-bromo-2-methyl-valeric acid ethyl ester.

16. A process for the preparation of 2-methyl-2-[4-(4'-chlorobenzyl)-phenoxy]-butyric acid-(3-oxymethyl-pyridine)-ester hydrochloride, which comprises reacting 2-methyl-2-[4-(4'-chlorobenzyl)-phenoxy]-butyryl chloride with 3-hydroxymethyl pyridine and reacting the reaction product obtained with hydrogen chloride.

17. A process for the preparation of 2-methyl-2-[4-(4'-chlorobenzyl)-phenoxy]-butyric acid 2-(7-theo-phillinyl) ethyl ester, which comprises reacting 2-methyl-2-[4-(4'-chlorobenzyl)-phenoxy]-butyryl chloride with 7-(2-hydroxyethyl)-theophylline.

18. A process as claimed in claim 5, which comprises reacting an acid of formula:
wherein A1 and A2 have the meanings set out in claim 17, with chloromethyl pivalate.

19. A compound having the general formula:
wherein R1, A1, A2 and Z have the meanings set out in claim 1, and pharmacologically acceptable acid addition salts of said compound when containing basic groups and/or optically active enantiomers of said compound when A1 and A are different, whenever produced by the process of claim 1 or by an obvious chemical equivalent.

20. 4-(4'chlorobenzyl)-phenoxyacetic acid elhyl ester whenever prepared by the process of claim 8 or by an obvious chemical equivalent.

21. 4-(4'-chlorobenzyl)-phenoxyacetic acid N-benzyl-N-methyl-aminoethyl ester hydrochloride whenever prepared by the process of claim 9 or by an obvious chemical equivalent.

22. 4-(4'-chlorobenzyl)-phenoxyacetic acid-4-(N-methyl)-piperidyl ester hydrochloride, whenever prepared by the process of claim 10 or by an obvious chemical equivalent.

23. 4-(4'-chlorobenzyl)-phenoxyacetic acid (3-pyridyl)-methyl ester, whenever produced by the process of claim 11 or by an obvious chemical equivalent.

24. Bis-[4-(4'-chlorobenzyl)-phenoxyacetic acid]
(2,6-pyridyl)-dimethyldiester whenever produced by the process of claim 12 or an obvious chemical equivalent.

25. 4-(4'-chlorobenzyl)-phenoxyacetic acid 2-(7-theophillinyl)-ethyl ester, whenever produced by the process of claim 13 or an obvious chemical equivalent.

26. 2-methyl-2-[4-(4'-chlorobenzyl)-phenoxy]-butyric acid ethyl ester, whenever produced by the process of claim 14, or an obvious chemical equivalent.

27. 2-methyl-2-[4-(4'-chlorobenzyl)-phenoxy]-valeric acid ethyl ester, whenever produced by the process of claim 15, or an obvious chemical equivalent.

28. 2-methyl-2-L4-(4'-chlorobenzyl)-phenoxy]-butyric acid-(3-oxymethylpyridine)-ester hydrochloride, whenever produced by the process of claim 16 or an obvious chemical equivalent.

29. 2-methyl-2-[4-(4'-chlorobenzyl)-phenoxy]-butyric acid (7-theophillinyl)-ethyl ester, whenever produced by the process claimed in claim 17 or an obvious chemical equivalent.
CLAIMS SUPPORTED BY THE SUPPLEMENTARY DISCLOSURE

30. A process for the preparation of 2-methyl-2-[4-(4'-chlorobenzyl)phenoxy]butyric acid, which comprises reacting 4-chloro-4-hydroxy-diphenylmethane uith ethyl methyl ketone in the presence of a strong base and a trihalogenated methane derivative.

31. A process as claimed in claim 30, wherein the trihalogenated methane derivative is chloroform.

32. A process for the production of 2-methyl-2-[4-(4'-chlorobenzyl)-phenoxy]-valeric acid 3-pyridyl--methyl-ester or the hydrochloride salt thereof which comprises reacting 2-methyl-2-[4-(4'-chlorobenzyl)-phenoxy]-valeroyl chloride with 3-hydroxymethyl pyridine and optionally reacting the reaction product obtained with hydrogen chloride.

33. A process for the production of 2-methyl-2[4-(4'-chlorobenzyl)'-phenoxy]butyramide which comprises reacting 2-methyl-2-[4-(4'-chlorobenzyl)phenoxy]butyryl chloride with ammonia.

34. A process for the production of [i-(4'-chloro-benzyl)phenoxy]acetamide which comprises reacting 4-(4'-chlorobenzyl)phenoxyacetyl chloride with ammonia.

35. A process for theproduction of 2-methyl-2-[4-(4'-chlorobenzyl)phenoxy]propionamide which comprises reacting 2-methyl-2-[4-(4'-chlorobenzyl)phenoxy] propionyl chloride with ammonia.

36. A process as claimed in claim 1, wherein reactants are employed to yield a compound of general formula I wherein R1 is hydrogen, A1 and A2 are both alkyl groups and Z is alkoxy containing from 1 to 4 carbon atoms.

37. A process as claimed in claim 36, wherein A1 and A2 are different alkyl groups containing a total of from 5 to 10 carbon atoms.

38. A process as claimed in claim 1, wherein reactants are employed to yield a compound of general formula I wherein R1 is chlorine, A1 and A2 are different alkyl groups containing a total of from 5 to 10 carbon atoms and Z is alkoxy containing from 1 to 4 carbon atoms.

39. 2-methyl-2-t4-(4'chlorobenzyl)phenoxy]
butyric acid, whenever prepared by the process of claim 30 or an obvious chemical equivalent.

40. 2-methyl-2-[4-(4'-chlor'obenzyl)-phenoxy]-valeric acid 3-pyridylmethyl ester or the hydrochloride hereof, whenever prepared by the process of claim 32 or an obvious chemical equivalent.

41. 2-methyl-2-[4-(4'-chlorobenzyl)-phenoxy]butyramide whenever prepared by the process of claim 33 or an obvious chemical equivalent.

42. [4-(4'-chlorobenzyl)phenoxy]acetamide whenever prepared by the process of claim 34 ox an obvious chemical equivalent.

43. 2-methyl-2-[4-(4'-chlorobenzyl)phenoxy]
propionamide whenever prepared by the process of claim 35 or an obvious chemical equivalent.

44. A compound of the general formula:
wherein A1 and A2 are both alkyl and Alk denotes alkyl containing from 1 to 4 carbon atoms whenever produced by the process of claim 36 or by an obvious chemical equivalent.

45. A compound of the general formula wherein A1 and A2 are different alkyl groups containing a total of from 5 to 10 carbon atoms and Alk denotes alkyl containing from 1 to 4 carbon atoms and optically active enantiomers of said compound, whenever produced by the process of claim 37 or by an obvious chemical equivalent.

46. A compound of the general formula wherein A1 and A2 are different alkyl groups containing a total of from 5 to 10 carbon atoms and Alk denotes alkyl containing from 1 to 4 carbon atoms and optically active enantiomers of said compound, whenever produced by the process of claim 38 or by an obvious chemical equivalent.

47. A process for the production of a compound having the general formula Ia wherein R2 is hydrogen or alkyl containing from 1 to 4 carbon atoms and R1, A1, A2 and Z are as defined in claim 1, which comprises conducting any of the following steps:
A: reacting a phenol of the general formula wherein R1 and R2 have the aforesaid meaning or a corresponding alkali metal or alkaline earth metal phenolate with a compound having the general formula in which "Hal" is a halogen atom and A1, A2 and Z have the aforesaid meanings; or B: reacting a phenol of the general formula:
wherein R1 and R2 have the aforesaid meanings, or a corres-ponding alkali metal or alkaline earth metal phenolate in the presence of an at least trihalogenated methane derivative and in the presence of a strong base, with an aldehyde or ketone of general formula A1 - CO - A2 wherein A1 and A2 have the aforesaid meanings to obtain an intermediate reaction product, followed by:

(1) esterifying either as such or as a reactive derivative thereof, a carboxyl group in the intermediate reaction product thus obtained or obtained by alkaline hydrolysis of the said intermediate reaction product with a hydroxy terminated compound Z1 - OH in which Z1 denotes alkyl, cyclopentyl, pivaloyloxyalkyl, 7-theophillinyl-alkyl, pyridyl-C-alkyl in which the alkyl group contains from 1 to 3 carbon atoms, 3-oxindolyl, pyrrolidino, piperidino, piperazino or tertiary aminoalkyl, in which the tertiary amino group possesses the following general formula wherein R3 and R4 have the aforesaid meanings to obtain a said compound of general formula Ia wherein Z is alkoxy, cyclo-pentoxy, pivaloyloxyalkoxy, 7-theophillinyl-alkoxy tertiary-aminoalkoxy, pyridyl-C-alkoxy 3-oxindolyloxy, pyrrolidinoxy, piperidinoxy, piperazinoxy or said tertiaryaminoalkoxy; or (2) when the said intermediate reaction product contains an alkoxy carbonyl group, subjecting the intermediate reaction product to ester exchange with a hydroxy-terminated compound of formula Z1-OH wherein Z1 has the aforesaid meaning, Z1, when alkyl, yielding an alkoxy carbonyl group different to that in the intermediate reaction product; or (3) isolating said intermediate reaction product when it contains a carboxyl group or an alkoxycarbonyl group and Z in general formula Ia is carboxyl or said alkoxycarbonyl group; or (4) reacting either as such or as a reactive derivative thereof a carboxyl group in the said intermediate reaction product or obtained by alkaline hydrolysis thereof, with ammonia, an amine or an inorganic base or salt or an organic salt, to obtain a said compound of general formula Ia wherein Z is amine or O-M+, M+ having the aforesaid meaning; or (5) when the said intermediate reaction product contains an alkoxy carbonyl group, subjecting the intermediate reaction product to aminolysis with ammonia or an amine, to obtain a said compound of general formula Ia wherein Z is amino;
or C: reacting an acid halide of the general formula:
wherein "Hal" is a halogen atom and R1, R2, A1 and A2 have the aforesaid meanings with a compound of the general formula:

wherein Z1 is as defined hereinabove, or;
D: when Z in general formula I is a said tertiary aminoalkoxy-carbonyl radical, reacting a compound of the general formula:
wherein R1, R2, A1, A2 and Hal have the aforesaid meanings and R5 denotes an alkylene group with a compound of general formula:
wherein R3 and R4 have the aforesaid meanings, and isolating the compound obtained as such, as a recemate or optically active enantiomer when A1 and A2 are different and/or as a pharmacologically acceptable acid addition salt when Z
is a basic group.

48. A process for the production of a compound having the general formula Ia wherein R1 is hydrogen or halogen;
R2 is hydrogen or alkyl containing from 1 to 4 carbon atoms; A1 and A2 which are the same or different are hydrogen or alkyl; and Z is amine, hydroxy, O-M+, M+ being an inorganic or organic cation, alkoxy, cyclopentoxyl pivaloyloxy-alkoxy, 7-theophillinylalkoxy, pyridyl-C-alkoxy in which the alkoxy group contains from 1 to 3 carbon atoms, 3-oxindolyloxy, pyrrolidinoxy, piperidinoxy, piperazinoxy or tertiary amino-alkoxy in which the tertiary amino group possesses the following general formula wherein R3 is lower alkyl and R4 is hydrogen or halogen, with the proviso that when A1 and A2 are both methyl, Z is not hydroxy or ethoxy, which comprises reacting a phenol of the general formula:
wherein R1 and R2 have the aforesaid meanings, or a corres-ponding alkali metal or alkaline earth metal phenolate in the presence of an at least trihalogenated methane derivative and in the presence of a strong base, with an aldehyde or ketone or general formula A1 - CO - A2 wherein A1 and A2 have the aforesaid meanings to obtain an intermediate reaction product, followed by:
(1) esterifying either as such or as a reactive derivative thereof, a carboxyl group in the intermediate reaction product thus obtained or obtained by alkaline hydrolysis of the said intermediate reaction product with a hydroxy terminated compound Z1 - OH in which Z1 denotes alkyl, cyclopentyl, pivaloyloxya, l,7-theophillinyl-alkyl, pyridyl-C-alkyl in which the alkyl group contains from 1 to 3 carbon atoms, 3-oxindolyl, pyrrolidino, piperidino, piperazino or tertiary aminoalkyl, in which the tertiary amino group possesses the following general formula wherein R3 and R4 have the aforesaid meanings to obtain a said compound of general formula Ia wherein Z is alkoxy, cyclopentoxy, pivaloyloxyalkoxy, 7-theophillinyl-alkoxy tertiaryaminoalkoxy, pyridyl-C-alkoxy 3-oxindolyloxy, pyrrolidinoxy, piperidinoxy, piperazinoxy or said tertiary-aminoalkoxy; or (2) when the said intermediate reaction product contains an alkoxy carbonyl group, subjecting the intermediate reaction product to ester exchange with a hydroxy-terminated compound of formula Z1-OH wherein Z1 has the aforesaid meaning, Z1, when alkyl, yielding an alkoxy carbonyl group different to that in the intermediate reaction product; or (3) isolating said intermediate reaction product when it contains a carboxyl group or an alkoxycarbonyl group and Z in general formula Ia is carboxyl or said alkoxycarbonyl group; or (4) reacting either as such or as a reactive derivative thereof a carboxyl group in the said intermediate reaction product or obtained by alkaline hydrolysis thereof, with ammonia, an amine or an inorganic base or sali or an organic salt, to obtain a said compound of general formula Ia wherein Z is amine or O-M+, M+ having the aforesaid meaning; or (5) when the said intermediate reaction product contains an alkoxy carbonyl group, subjecting the intermediate reaction product to aminoylsis with the ammonia or an amine, to obtain a said compound of general formula Ia wherein Z is amine.

49. A compound of the general formula Ia:
wherein R1, R2, A1, A2 and Z are as defined in claim 1 and 47, whenever prepared or produced by the process defined in claim 1, 47 or 48 or by the obvious chemical equivalent.

50. A process as claimed in claim 48, wherein R1 is a chlorine atom.

51. A process as claimed in claim 48, wherein A1 and A2 are different alkyl groups and Z is hydroxy.

52. A process for the preparation of a compound of the formula (I) (I) wherein R1 is haloyen, R2 is hydrogen or alkyl of 1 to 4 carbon atoms, R3 and R4 are hydrogen or alkyl, R5 is NH2, OH, O-Cation+, or OR6, wherein R6 is alkyl; which comprises reacting a compound of the formula (II) (II) wherein R1 and R2 are as defined above, or a corresponding alkaki metal or alkaline earth metal salt thereof, with a compound of the formula (III) (III) wherein R3, R4 and R5 are as defined above and R7 is halogen.

53. A compound of formula (I) (I) wherein: R1, R2, R3, R4 and R5 are as defined in claim 52, whenever prepared by the process defined in claim 52 or by the obvious chemical equivalent.