IE42425B1 - Aryloxy-and arythio-alkanoates having cholesterol-reducing properties - Google Patents

Aryloxy-and arythio-alkanoates having cholesterol-reducing properties

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IE42425B1
IE42425B1 IE2658/74A IE265874A IE42425B1 IE 42425 B1 IE42425 B1 IE 42425B1 IE 2658/74 A IE2658/74 A IE 2658/74A IE 265874 A IE265874 A IE 265874A IE 42425 B1 IE42425 B1 IE 42425B1
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group
compound
chlorobenzyl
hydrogen
methyl
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IE2658/74A
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IE42425L (en
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Siegfried Ag
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Priority claimed from CH1814473A external-priority patent/CH605557A5/en
Priority claimed from CH1814573A external-priority patent/CH601169A5/en
Priority claimed from CH435574A external-priority patent/CH605642A5/en
Priority claimed from CH1330274A external-priority patent/CH616909A5/en
Priority claimed from CH1532974A external-priority patent/CH617417A5/de
Priority claimed from CH1533074A external-priority patent/CH617420A5/en
Application filed by Siegfried Ag filed Critical Siegfried Ag
Publication of IE42425L publication Critical patent/IE42425L/en
Publication of IE42425B1 publication Critical patent/IE42425B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C321/00—Thiols, sulfides, hydropolysulfides or polysulfides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
    • C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
    • C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
    • C07C59/70—Ethers of hydroxy-acetic acid, e.g. substitutes on the ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Diabetes (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
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Abstract

1497266 Aryl-oxy- and -thio-alkyl compounds SIEGFRIED AG 24 Dec 1974 [27 Dec 1973 (2) 28 March 1974 3 Oct 1974 18 Nov 1974 (2)] 55755/74 Heading C2C The invention comprises novel compounds (I) wherein: R represents hydrogen, halogen, hydroxy; or alkyl or alkoxy containing from 1 to 4 carbon atoms; X represents hydrogen or a benzyl, benzyloxy or benzylthio group which is optionally substituted by a said group R; Y represents a sulphur or oxygen atom; Z represents a carboxyl group, an alkoxycarbonyl group, a cycloalkoxycarbonyl group, a carbamoyl group, an esterified carboxyl group in which the esterifying group contains an amino group, or a pivaloyloxymethoxy carbonyl group; and A1 and A2 which can be the same or different are hydrogen atoms or alkyl groups containing from 1 to 4 carbon atoms, and pharmacologically acceptable salts thereof with inorganic or organic acids or bases if they contain basic or acidic groups respectively and/ or optical isomers thereof, when A1 and A2 are different, with the proviso that, when Z represents a free carboxyl group or an alkoxycarbonyl group, either X represents benzyl, benzyloxy or benzylmercapto substituted by a halogen or X represents benzyl, benzyloxy or benzylmercapto and A1 and A2 together contain at least 3 carbon atoms, and with the proviso that when R is hydrogen, X is p-chlorobenzyl, Y is oxygen, Z is hydrogen, alkoxycarbonyl or dialkyl amino-alkoxycarbonyl, A1 and A2 are the same or different and are alkyl groups containing from 2 to 4 carbon atoms or hydrogen or one of A1 and A2 is methyl and the other is hydrogen or an alkyl group containing from 2 to 4 carbon atoms. The compounds are made by standard methods. Pharmaceutical preparations effective in lowering the cholesterol blood level contain (I) as active ingredient. Administration is orally or parenterally.

Description

This invention relates to novel aryloxyalkylgroup containing compounds, to their thio-analogues, to processes for their production and to pharmaceutical compositions comprising the same.
According to one aspect of the present invention, there is provided a compound of the general formula: wherein: R represents hydrogen, halogen, hydroxy; or lower 10 aklyl or lower alkoxy containing from 1 to 4 carbon atoms; X represents hydrogen or a benzyl, benzyloxy or benzylthio group which is optionally substituted by a said group R; Y represents a sulphur or oxygen atom; Z represents a carboxyl group, an alkoxycarbonyl group, a cycloalkoxycarbonyl group, a carbamoyl group, an esterified carboxyl group in which the esterify4242S - 3 ing group contains an amino group, or a pivaloyloxymethoxy carbonyl group? and 2 A and A 'which can be the same or different are hydrogen atoms or alkyl groups containing from 1 to 4 carbon atoms, and pharmacologically acceptable salts thereof with inorganic or organic acids or bases if they contain basic or acidic groups respectively and/or optical isomers thereof, when 1 2 A and A are different, with the first proviso that, when Z is carbamoyl any Y 1 2 is an oxygen atom, R, A and A are defined as aforesaid and X represents hydrogen or a benzyloxy or benzyl thio group which is optionally substituted by a said group R; with the second proviso that, when Z represents a free carboxyl group or an alkoxycarbonyl group, either X represents benzyl, benzyloxy or benzylthio substituted by a halogen or X represents benzyl, benzyloxy or 1 2 benzylthio and A and A together contain at least 3 carbon atoms; and with the third proviso that, when R is hydrogen, X is p-chlorobenzyl, Y is oxygen and Z is hydrogen, alkoxycarbonyl or dialkylaminoalkoxycarbonyl, then A1 and A are the same or different and are alkyl groups containing from 2 to 4 carbon atoms or hydrogen or one 1 2 of A and A is methyl and the other is hydrogen or an alkyl group containing from 2 to 4 carbon atoms.
According to a second aspect of the invention, there is provided a process for the production of a compound according to the present invention, wherein a phenol or thiophenol of the general formula: » 4242*.
X wherein X, Y and R having meanings set out herein, or a corresponding alkali metal or alkaline earth metal phenolate or thiophenolate is reacted with a compound of the general formula: Hal - C * Z 2 in which Hal is a halogen atom and A , A and Z have meanings set out' herein, and the said compound is recovered from the reaction mixture obtained, the compound being recovered as such or as a salt thereof with an inorganic or organic acid or base if the compound contains a basic or acidic group respectively.
According to a third aspect of the invention there is provided a method for the production of a compound according to the present invention, wherein a phenol or thiophenol 'of the general formula: 4242S wherein X, Ϊ and R have meanings set out herein, or a corresponding alkali metal or alkaline earth metal phenolate or thiophenolate is reacted in the presence of an at least trihalogenated methane derivative and in the presence of a strong base with a ketone of 12 formula A -CO-A (IV) in which A and A have meanings set out herein and, depending on the nature of Z in the aforesaid formula, (a) if necessary esterifying, either as such or as a reactive derivative thereof, a carboxyl group in the reaction product so obtained or obtained by alkaline hydrolysis of a reaction product so obtained, with a hydroxy-terminated compound Z'-OH in which the group Z'~ has a formila such that Z'-O-CO- in the product so obtained constitutes the group Z or reacting said carboxyl group reactive derivative thereof with an amine, ammonia, or inorganic base or salt; or (b) when the reaction product of the compound of general formula (II), the trihalogenated methane derivative and the ketone contains an alkoxycarbonyl group, subjecting the reaction product to ester exchange or to aminolysis with ammonia or an amine to yield a product respectively containing a group Z’~ 0C0- or Z CO-constiluting said group Z in which Z' is an alkylene-terminated radical and Z is an amino group, and recovering the compound formed from the reaction mixture, the compound being recovered as such or as a salt thereof with an inorganic or organic acid or base if the compound contains a basic or acidic group respectively.
According to a fourth aspect of the invention, there is provided a pharmaceutical composition which comprises a compound according to the present invention in association with a pharmacologically acceptable 43425 carrier therefor.
A considerable variety of compounds according to the present invention can be obtained by varying, in 1 2 particular the substituents A , A , R and Z in the aforesaid general formula. Of considerable interest are those compounds in which the radical X is a benzyl group. When a halogen atom is present in the benzene ring in the general formula (I) or in a benzyl or benzyloxy or benzylthio substituent therein, it is preferably a chlorine or bromine atom. Chlorine substituents are particularly preferred. By the term lower alkyl or alkoxy group as used herein is meant an alkyl or alkoxy group which contains from 1 to 4 carbon atoms, preferably from 1 to 3 carbon atoms. 2 The substituents A and A which can be the same or different, can represent hydrogen atoms or alkyl groups preferably containing from 1 to 4 carbon atoms.
Of particular interest are those compounds in which 12 A and A contain a total number of carbon atoms at least equal to 3. These carbon atoms may be spread 12 between the two groups A and A which are preferably different alkyl groups or all are present in a single 1 2 such group. Particularly when A and A are both alkyl groups and contain a total of at least 3 carbon atoms, the group Z- is preferably a tertiary amino alkoxy carbonyl group. .
As mentioned hereinabove, the group Z can be constituted by a considerable number of different types of group, it can be a carboxyl group which can be in salt form, in amide form, that is Z can constitute a carbamoyl group, preferably a group of formula CONH2, or ester form, Z then constituting an alkoxy carbonyl group, a cycloalkoxy carbonyl group, a pivaloyloxymethoxy-carbonyl group or an esterified carboxyl group comprising a basic group. 42423 When Ζ represents an alkoxy carbonyl group or 1 2 hydroxy, A and A are preferably different alkyl groups as aforesaid and X is preferably p-chlorobenzyl. The preferred cycloalkoxycarbonyl group Z is cyclopentoxycarbonyl.
When an amino group is present in the group Z, it is possible for it to be of the formula: R' ,1 CH.
R' ,2 wherein R^ is an alkyl group preferably containing 2 from 1 to 3 carbon atoms and R has the aforesaid meaning given for R. In such a case, X is preferably hydrogen and R is preferably chlorine. The group Z can also be a dialkylaminoalkoxy carbonyl group, for example a dimethylaminomethoxy carbonyl group, a dimethylamino- or diethylaminoethoxy carbonyl group, or a dimethylamino-, diethylamino-, di-n-propylaminoor di-isopropylaminopropoxy carbonyl group. Group Z can also be for example, a pyrrolidino-, piperidino-, piperazino-, 4-methylpiperazino- or morpholino-ethoxy carbonyl group. It is also possible for the tetriary amine moiety of the group Z to form part of a ring system containing one or more nitrogen atoms and one or more positions of unsaturation, the ring system being bonded to the carbonyl group of Z either directly or by way of an alkylene group. The ring system may be a pyridyl group, an oxindolyl group or a theophyllinyl group, or a 4-methylpiperidinyl group. The preferred group Z of this type is the 3-pyridylmethoxy-carbonyl group (3-nicotinyloxy carbonyl group). Insofar as Z • 48435 - δ may include a pyridylalkyl group therein, it should be understood that general references to such groups herein include the possibility that the group is a pyridyl-bisalkyl group esterifying two molecules of acid of general formula: Two basic preparative methods have been found to be particularly satisfactory for use in the production of compounds according to the present invention.
Xn the first such method, a phenol or thiophenol is reacted with a compound of general formula (III) hereinabove. The halogen atom in the compound of general formula (III) is preferably chlorine or bromine. Thus, for example, the compound 4-{4'-chlorobenzyl)15 phenol can be condensed with the ethyl ester of 2bromo-2-raethylbutyric acid and the condensation products obtained can be subjected to hydrolytic cleavage of. the ethyl group, to form the 2-/4-(4'chlorobenzyl)-phenoxy]-2-methylbutyric 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 to introduce into the molecule.
When the group Z contains a tertiary amino group as mentioned hereinabove, it may be more convenient to introduce the group Z into the molecule in two stages. 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 amino group terminated group compound to be obtained.
Although a multi-stage preparative process for a tertiary amino-terminated compound according to the present invention has 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 Z1 is a group which when combined in the final product in a group Z'-OCOconstitutes the group Z in the aforesaid general formula (I).
In the second aforesaid process for the production of the compounds according to the present invention, a phenol or thiophenol of general formula (II) is 1 2 reacted with a ketone of formula A -CO-A ln 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: A' A‘ X 43425 - 10 When a substituted trihalogenated methane such as acetone chloroform or chloral hydrate 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 converted to an alternative carboxyl-derivative according to 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 which the group Z' has a meaning as aforesaid. Alternatively the carboxyl group or reactive derivative thereof can be reacted with ammonia or an amine to form an amide.
In an alternative reaction sequence, applicable in the case when the trihalogenated methane derivative reacted with the phenol or thiophenol 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 to ester exchange with a corresponding ester or to aminolysis with ammonia or an amine depending upon the nature of the group Z In the final product.
Compounds of the general formula I have been found to be particularly effective agents for lowering the cholesterol level of blood. Although aryloxy carboxylic acid esters have been proposed for use in the therapy of excessive cholesterol and triglyceride - 11 levels in the blood in British Patent Specification No. 860,303 the compounds of this invention are generally more effective.
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 of human beings. It has now been found that many of the new compounds of formula I are superior to the Clofibrat in their cholesterolreducing effect to a surprisingly high extent.
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 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 substances of the general formula: 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: 4S435 - 12 a = p-chlorophenyl b = p-benzylphenyl c = p-(p'-chlorobenzyl)-phenyl <3 = o-(p1-chlorobenzyl)-phenyl e = o-benzyl-p-chlorophenyl 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 Met and Et represent methyl and ethyl, respectively.
The numbers in the colums (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. 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% (ED25). Indicated in column (6) is the therapeutic index calculated from the numerical values of the preceding columns, that is to say, the quotient of LD 50/ED 25.
In order to establish the values set out in column (5), dosage groups of 8 to 10 normally fed male rats were treated once a day and for 10 days with test substances suspended in gum arabic. The determinat25 ion of the total cholesterol content was effected according to RICHTERICH (Klinische Chemie, S.Kager Basle/new York 1965, page 232). From the percentage changes in the average values of the groups with the groups of preparations given in graduated doses and by comparison with control groups treated only with gum arabic, a dose efficiency curve was drawn on halflogarithmic coordinate paper, and the ED 25 was read off from the said curve.
Com- pound No. (1) No. (2) (3) (4) LD50 (5) ED25 (6) In- dex 1. 10574 a OCH (Met) COO (h~] >3000 90 >33 Met 2. 5674 a OCH(Met)COO(CIL·),N< .HCl >4000 140 >29 ch2O-ci Et 3. 1774 a OC(Met),C00(CH,),N< .HCl >3000 155 >19 4. 18474 a OC (Met) 2COOCH2 >>3000 170 >18 0C4h9 5. 10774 a SCH(Met)COO (jH >3000 «100 >30 6. 10674 a SCH2COO(CH2)3N(Et)2 »3000 100 >30 Met 7. 9374 a SCHnC00(CH„)oN< >>3000 60 >50 ch2O Met 8. 8074 a SCH(Met)COO(CH,),N ( 4000 125 32 CB.O-C1 9. 32574 b OC(Met)(Et)COO Et < 2 10. 6274 c och2cooh 2700 50 54 11. 1374 c OCH2COOEt 3000 25 120 12. 18374 c OCH2COO (h~~| >>3000 54 > 65 - 14 ' 43423 Com- pound No. (1) No. (2) (3) (4) LD50 (5) ED25 (6) In- dex 13. 22974 G OCH(Met)COOH 1700 29 59 14. 2774 C OCH(Met)COOEt 2500 33 76 15. 17474 C OCH(Et)COOEt »3000 54 >56 16. 25974 c OC (Met) 2C00 ^H~~[ >>3000 41 >73 17. 24774 c OC(Met)(Et)COOEt 10000 6 1667 Met 18. 25674 c OCH(Met)COO(CH2) 2N ( CH2-O Met >3000 50 >60 19. 7274 c 0CH2C00(CH2)2N < ·HClCH2~O >>3000 66 >45 Met 20. 25874 c OC (Met) 2C00 (CH2) 2N< ch2O »3000 31 >97 21. 24874 c OCH(Met)COO ( H - Met 2700 28 96 22. 23. 26074 28374 c OC (Met) 2c00CH2 “ · HC.X >3000 »3300 14 >86 >214 >35 oc(Met)2coo -jpQ; 0 H 24. 23174 c 0C(Met)2C00(CH2)2- N-X _ >>3000 20 >150 1 ° Met Com- pound No. (1) No. (2) (3) (4) LD50 (5) ED25 (6) In- dex 25. 15174 c OCH2COOCH2OCO-C(Met)3 >>3000 25 -120 26. 23574 c OCH(Met)COOCH2OCO-C(Met)3 >3000 17 >176 27. 24076 c OC (Met) 2COOCII2OCO-C (Met) 3 >>3000 15 >200 28. 28274 c OC(Met)(Et)COOCH2OCO-C(Met)3 >>3000 21 >143 29. 27874 c och2conh2 >>3000 <25 >>120 30. 27774 c OC(Met)2CONH2 >>3000 19 >158 31. 2874 d OCH(Met)COOEt >>3000 >100 > 30 32. 22074 e OCH2COOEt >>3000 58 > 52 33. Clofil irat: 2350 160 15 42423 - 16 In addition to possessing the strong hypocholesterolaemic effect which can be seen from the table, the compounds of the present invention also lower considerably the triglyceride content of.the blood and are in this respect again several times better than the action of Clofibrat. By way of example, hypertriglyceridemia produced in fats by adding 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 brackets 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.8674 (15), No.24774 (4.5), No.26074 (13), No.24074 (5.6) and tfo.21974 (15).
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 ethanolamine, dimethylamine or morpholine can be used for the 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 compounds 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 composition 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 48435 - 17 in bhe form of a tablet, sugar coated pill, capsule or packaged powder for oral administration, or in the form of a sterile injectable solution or suspension, 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.θ2 to 1.5 gram per day will be suitable for therapeutic purposes.
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 employed for the production of analogues of the illustrated compounds. In particular, in the main, compounds of the aforesaid general formula (I) are produced in which the group Y is oxygen. By use of corresponding thio-analogues as starting materials, the Examples may be repeated readily to produce the corresponding thio-products. Compounds in the above Table whose production is not described in the Examples were prepared by analogous procedures to those described for compounds of like type, in which the moiety in column 2 or column 3 was replaced by a similar moiety.
One such analogous procedure is referred to in Examp]c 7.
Example 1 4-(41-Chlorobenzyl)-phenoxy acetic 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 41-chloro-4-hydroxydiphenylmethane in 90 ml of DMF. The mixture as obtained was stirred for 15 minutes at 70 C, - 18 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 130°C. The solvent was thereafter removed in a Buchi rotary, evaporator. The residue was treated with water and then thoroughly extracted with dichloromethane. After being dried over magnesium sulphate, the extract was concentrated by evaporation under reduced pressure. After chromatography over 20 g of A^O^, elution with 200 ml of benzene and distillation, the residue yielded 23.0 g of pure product, of boiling point 156 - 1600C (0.03 mm).
C17H17C1O3 (304·θ) Calculated C 66.98 H 5.62 Cl 11.64 Found C 66.51 H 5.80 Cl 11.85 Example 2 4-(4'-Chlorobenzyl)-phenoxyacetic acid-N-benzyl-Nmethylaminoethyl 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-2aminoethanol in 70 ml of anhydrous pyridine. The reaction mixture was heated for 24 hours at reflux temperature, whereupon the solvent was evaporated in a Buchi rotary evaporatoe under reduced pressure, the residue was taken up in 10% aqueous KHCOg 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 therefrom by evaporation. This resin was dissolved in benzene and filtered over 35.0 g of A^Og. 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 - 19 hydrogen chloride, solid hydrochloride precipitated after trituration. Recrystallisation from acetone/ether yielded 13.0 g of product in the form of lustrous white crystals of melting point 120 - 122°C.
C25H26C1NO3 Calculated: . HCl (460. .3) C 65.22 H 5.91 N 3.04 Cl 15.40 Found: C 65.41 H 5.96 N 3.20 Cl 15.68 Example 3 4-(4'-Chlorobenzylj-phenoxyacetic acid 4-(N-methyl) piperidyl ester hydrochloride A solution of 6.0 g (0.02 mol) of 4-(4’-chlorobenzyl)-phenoxyacetyl chloride in 40 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 A^O-j 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 dissolved in acetone and boiled for 3 minutes with active carbon. By recrystallisation from acetone/ether, 3.5 g of hydrochloride were obtained with a melting point of 170 - 171°C.C21H24C1NO3 . HCl (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 Cl 17.54 - 20 4843B Example 4 4-(41-Chlorobenzyl)-phenoxyacetic acid 3-pyridyl methyl ester A solution of 6.0 g (0.02 mol) of 4-(4'-chloro5 benzyl)-phenoxy-acetyl 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. Working up in the same way as 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 - 78°C could be recovered by crystallisation from ether/petroleum ether.
C21H18C1NO3 (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 2,6-bis-/3-(4'-chlorobenzyl)-phenoxy-acetoxymethyl/20 pyridine A solution of 6.0 g (0.02 mol) of 4-(4'-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 78°C after recrystallisation from dichloromethane/ether/petroleum ether. - 21 48425 C37H31C12NO6 (656.5) Calculated: C 67.68 H 4.76 N 2.13 Cl 10.8' Found: C 67.67 H 4.84 N 1.77 Cl 11.14 Example 6 4-(4'-Chlorobenzyl)-phenoxyacetic acid 7-fcheophillinylethyl ester A solution of 6.0 g (0.02 mol) of 4-(41-chlorobenzyl) -phenoxy-acetyl chloride in 50 ml of anhydrous xylene was added to a solution of 4.48 g (0.02 mol) of 7-(8-hydroxyethyl)-theophylline in 25 ml of anhydrous pyridine. The mixture was heated for 24 hours while stirring to reflux temperature and the residue was worked up as in the preceding Examples 2 to . Crystallisation from dichloromethane/methanol yielded 6.5 g of product in the form of white lustrous needles of melting point 134 - 135°C.
C24H23C1N4O5 (482.9) Calculated: C 59.69 H 4.80 N 11.60 Cl 7.34 Pound: C 59.35 H 4.97 N 11.51 Cl 7.84 Example 7 2-Methyl-2-/4-(4'-chlorobenzyl)-phenoxy7~butyric acid ethyl ester CH, % // CH, C2H5 Cl 87.0 g (0,4 mol) of 4-chloro-4'-hydroxydiphenylmethane are heated together with 27.0 g (0.2 mol) of anhydrous potassium carbonate in 350 ml of anhydrous xylene for 30 minutes to reflux temperature, whereafter a solution of 83.5 g (0.4 mol) of 2-bromo-2-ethyl-2methyl acetic acid ethyl ester in 50 ml of anhydrous xylene is added. The mixture is kept for 24 hours and with vigorous stirring at reflux temperature. After filtering off the precipitated potassium bromide and 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 MgSO^ 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 AlgOj. After evaporating the solvent and distillation at reduced pressures, 34.7 g of pure product are obtained with the boiling point 200 - 2O4°C/O.02-0.1 mm Hg, C20H23C103 (346.8) Calculated: C 69.25 H 6.68 0 13.84 Cl 10.22 Found: C 69.16 H 6.66 0 13.84 Cl 10.27 The analogous product without chlorine substituent shows a boiling point of 154-162°C/0.03 mm Hg $3gd 32574).
Example 8 2-Methyl-2-/3-(41-chlorobenzyl)-phenoxy7~valeric acid ethyl ester 8.7 g (0.04 mol) of 4-chloro-4'-hydroxydiphenylmethane and 2.76 g (0.02 mol) of K2C03 are brought over a period of 30 minutes to reflux temperature in 40 ml of anhydrous mesitylene-(1,3,5-trimethylbenzene), whereafter a solution of 8.9 g (0.04 mol) of 2-bromo-2methyl-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 indicated in the preceding Example 7 4.0 g of product are obtained as an oil with a boiling point of 177 - 179°C/0.01 mm Hg.
C21H25C1O3 (360. 8) 15 Calculated: C 69.89 H 6.98 Cl 9.83 Found: C 70.00 H 7.23 Cl 9.37 Example 9 2-Methyl-2-/3-(4'-chlorobenzyl)-phenoxy7~butyric acid 3-pyridylmethyl ester hydrochloride Cl * HCl - 24 78 g (0.232 mol) of 2-methyl-2-/4-(4'chlorobenzyl)phenoxy7~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 Buchi rotary evaporator. The brown residue is taken up in ether, the solution is extracted with water, dried over MgSO4 and again evaporated under reduced pressure. The residue is dissolved in cyclohexane and filtered through a column of 250 g of basic A^Og. The light brown oil which is obtained by distilling off the oyclohexane is dissolved in ether and treated with a solution of hydrogen chloride in ether. The crystalline precipitate, after being recrystallised from diehloromethane/ether, yields 40.0 g of hydrochloride as white lustrous crystals of melting point 111 - 114 °C.
C24H24C1NO3 . HCl (446.3) Calculated: C64.58 H 5.65 N 3.14 0 10.75 Cl 15.89 Found: C64.95 H 5.65 N 2.98 0 10.46 Cl 16.00 The 2-methyl-2-/4-(4'-chlorobenzyl)-phenoxy7butyryl 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 converted with thionyl chloride into the acid chloride.
Example 10 2-Methyl-2-/4-(4'-chlorobenzyl)-phenoxy7~butyric acid 7-theophillinylethyl ester 4242S Cl Ο - C - COO - CH2CH2—N '3 g (0.086 mol) of 2-methyl-2-/?-(4'-chlorobenzyl)phenoxy7-butyryl chloride are dissolved in 200 ml of anhydrous xylene and 50 ml of anhydrous pyridine and a solution of 19.35 g (0.086 mol) of 7-2-hydroxyethyl)theophylline in 50 ml of anhydrous xylene and 50 ml of anhydrous pyridine is added. The mixture is heated for 24 hours and while stirring at reflux temperature and is thereafter concentrated by evaporation in a Buchi rotary evaporator. The residue is extracted with dichloromethane, and the organic phase is washed with water, dried over MgSO^ and concentrated by evaporation under reduced pressure. The solid residue which is thereby obtained yields 28.5 g of product of melting point 105 - 106°C after being recrystallised from methanol. (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 10.57 0 15.15 Cl 6.94 Example 11 - ch2 - COO - ch2 - oco -c(ch3)3 Cl - 26 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 dimethyl5 formamide 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 - 90°C. The residue which is obtained by concentration by evaporation at reduced pressure in a Buchi rotary evaporator is washed with water and - extracted with ether. The ethereal solution is once again Washed with water, dried over anhydrous magnesium sulphate and concentrated by evaporation in the Buchi rotary evaporator, an oil being obtained which quickly solidifies. By recrystallisation from ether/n-hexane, 9.5 g of product are obtained in the form of white crystals with the melting point 54 - 55°C.
C21H23C1O5 (390.8) Calculated: C 64.53 H 5.93 Cl 9.07 Cl 9.67 COO - ch2 oco - c(ch3)3 2-/4-(4'-Chlorobenzyl)-phenoxy7~propionic acid25 (pivaloyloxymethyl)-ester - 27 To a solution of 43.5 g (0.15 mol) of 2-/4-(4'chlorobenzyl)-phenoxx7“P^opionic acid in 250 ml of dimethylformamide 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 90°C and is thereafter worked up in accordance with the procedure described in Example 11, there being obtained 50.0 g of white needles which, on recrystallisation from n-hexane, once again produce white needles of melting point 65°C.
C22H25C1O5 (404. 8) Calculated: C 65.26 H 6.22 Cl 8.76 Found: C 65.27 H 6.23 Cl 8.29 Example 13 CH, Cl C - COO - CH, - OCO - C(CH3)3 CH, 2-Methyl-2-/3-(4'-Chlorobenzyl)-phenoxy7~propionic acid(pivaloyloxymethyl)-ester To a solution of 27.4 g (0.09 mol) of 2-Methyl-220 /4- 4'-chlorobenzylphenoxy7-propionic 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 at 90°C and working up in the manner indicated in the Examples .· 43 42 5 - 28 11 and 12, a liquid is obtained which, after distillation, yields 26.0 g of a light yellow liquid product; boiling point 204 - 2O9°C/O.O2 mm Hg.
C23H27C1O5 (418.9) Calculated: C 65.94 H 6.50 Cl 8.46 Found: C 66.34 H 6.56 Cl 8.42 The a-/5-(4'-ehlorobenzyl)-phenoxy7-a-methylbutyric acid-(pivaloyloxymethyl)-ester, obtained by a similar procedure, using α-/ρ-(ρ'-ehlorobenzyl)phenoxy7~ a-methylbutyric acid, shows a boiling point of 213 214°C/O.O1 mm Hg.
Example 14 2-Methyl-2-/4-(4'ehlorobenzyl)-phenylthio7~butyric acid CHn C-COOH c2h5 suspension in oil) 3.1 g of sodium hydride (60% are suspended in 60 ml of dimethylformamide (DMF). A solution of 11.8 g of 4-(4'-ehlorobenzyl)-thiophenol in 12 ml of DMF is then slowly added dropwise and while 20 stirring, the mixture becoming heated. After continuing stirring for 1 hour, a solution of 15.7 g of 2-bromo2-methyl-butyric acid ethyl ester in 16 ml of DMF is added dropwise and stirring is continued for another 2 hours at 70°C. The solvent is then distilled off under 25 reduced pressure. The residue is treated with normal - 29 NaOH and the insoluble ester is extracted with ether. Concentration of the etheral solution by evaporation provides a crude yield of 17.7 g (97.5%). The 2-methyl2-/4-(4'-chlorobenzyl)-phenylthio7-butyric acid ethyl ester thus obtained as intermediate product is boiled for 1 hour under reflux in the unpurified state and for the purpose of saponification with 25 ml of methanolic KOH solution (25%) for 1 hour further. The solvent is then distilled off and the residue is dissolved in water and treated with active carbon. After filtration, acidification is carried out with dilute hydrochloric aeid and extraction is effected with ether. The residue concentrated by evaporation yields 13.7 g of crude product (80%), from which the pure acid of melting point 88 - 89°C is obtained after reerystallisation from petroleum ether.
C18H19C1O2S (334.9) Calculated: C 64.56 H 5.72 0 9.55 Cl 10.59 S 9.58 Found: C 64.69 H 5.44 0 9.44 Cl 10.61 S 9.50 The 4-(4'-chlorobenzyl)-thiophenol used as starting substance can be prepared in a manner indicated in the instructions given in J. Org. Chem. 31, 3980 (1966).
Example 15 2-Methyl-2-4-Chlorophenoxy)-propionic acid-N-methyl-Nbenzylaminoethyl ester hydrochloride A mixture of 29.8 g of N-methyl-N-benzylaminoethanol, 42.0 g of 2-Methyl-2-(4-chlorophenoxy)-propionic acid chloride, 13.7 g of potassium carbonate and 400 ml of xylene was kept for 20 hours at reflux temperature. After separating out the insoluble fractions and ' 43423 - 30 evaporating the filtrate, 77 g of brown oil were obtained as residue. In order to isolate the product as hydrochloride, this residue was dissolved in 10 parts of ether, purified by treatment with active carbon and a saturated solution of hydrogen chloride in ethyl acetate was added. The oil which separated out was caused to crystallise by trituration over a relatively long period, 52.7 g of crude product of melting point 96 -104°C being obtained. From this product, by recrystallisation from isopropanol and with renewed purification with active carbon, it was possible to recover 35.7 g of pure hydrochloride of melting point 113 - 115°C.
Found: C2OB24C1NO3 * HC1 {398> Calculated C 60.30 H 6.28 C 60.23 H 6.28 N 3.52 fl 3.21

Claims (56)

1. CLAIMS;1. A compound of the general formula: A’ 42435 R A' wherein: R represents hydrogen, halogen, hydroxy; or lower alkyl or lower alkoxy containing from 1 to 4 carbon atoms; X represents hydrogen or a benzyl, benzyloxy or benzylthio group which is optionally substituted by a said group R; Y represents a sulphur or oxygen atom; Z represents a carboxyl group, an alkoxycarbonyl group, a cycloalkoxycarbonyl group, a carbamoyl group, an esterified carboxyl group in which the esterifying group contains an amino group, or a pivaloyloxymethoxy carbonyl group; and A and A which can be the same or different are hydrogen atoms or alkyl groups containing from 1 to 4 carbon atoms, and pharmacologically acceptable salts thereof with inorganic or organic acids or bases if they contain basic or acidic groups respectively and/or optical isomers there1 2 of, when A and A are different, With the first proviso that, when Z is carbamoyl and Y 1 2 is an oxygen atom, R, A and A are defined as aforesaid and X represents hydrogen or a benzyloxy or benzylthio • 48425 - 32 group which is optionally substituted by a said group R; with the second proviso that, when Z represents a free carboxyl group or an alkoxycarbonyl group, either X 5 represents benzyl, benzyloxy or benzylthio substituted by a halogen or X represents benzyl, benzyloxy or 1 7 benzylmercapto and A and A together contain at least 3 carbon atoms; and with the third proviso that, when R is hydrogen, 10 X is p-chlorobenzyl, Y is oxygen, Z is hydrogen, alkoxy1 2 carbonyl or dialkylamino-alkoxycarbonyl, A and A are the same or different and are alkyl groups containing from 2 to 4 carbon atoms or hydrogen or one of A 1 · and A is methyl and the other is hydrogen or an alkyl 15 group containing from 2 to 4 carbon atoms.
2. A compound as claimed in claim 1, wherein X represents hydrogen and R represents halogen.
3. A compound as claimed in claim 1, wherein X represents benzyl, benzyloxy or benzylthio substituted 20 by a halogen atom in the benzene ring.
4. A compound as claimed in claim 1, 2 or 3, wherein the halogen is chlorine or bromine.
5. A compound as claimed in claim 4, wherein X represents p-chlorobenzyl. 25
6. A compound as claimed in any one of the preceding claims, wherein a said alkyl or alkoxy group contains from 1 to 3 carbon atoms.
7. A compound as claimed in any one of the preceding elaims,wherein A 1 and A 2 are different alkyl 30 groups and Z is carboxyl or alkoxycarbonyl.
8. A compound as claimed in claim 7, wherein X - 33 is benzyl or p-chlorobenzyl and Y is oxygen.
9. A compound as claimed in any one of claims 1 to 6, wherein, subject to said first proviso Z represents a -CONH 2 group. 5 10. A compound as claimed in any one of claims 1 to 6, wherein Z is a tertiary aminoalkoxy carbonyl group of formula: - COO - CH 2 CH 2 - N 1 2 wherein R is a lower alkyl group and R has one of
10. The meanings given in claim 1 for R.
11. A compound as claimed in claim 10, wherein 1 2 R is methyl and R is hydrogen.
12. A compound as claimed in claim 10 or 11, wherein X represents hydrogen and Y represents oxygen. 15 13. A compound as claimed in claim 1, wherein
R has the meaning given in claim 1, X represents benzyl or benzyl substituted by a said group R, Y represents oxygen, Z represents an esterified carboxyl group in which the esterifying group contains an amino group. 20
14. A compound as claimed in claim 1 or 13, in which Z represents a dialkylaminoalkoxycarbonyl group.
15. A compound as claimed in claim 1 or 13, wherein Z represents a methylbenzylaminoethyl group.
16. A compound as claimed in claim 1 or 13, wherein the amino group of Z forms part of a hetero25 4342® - 34 cyclic ring.
17. A compound as claimed in claim 16, in which Z represents a pyrrolidino-, piperidino-, piperazino-, 4-methylpiperazino-or morpholino-ethoxy carbonyl group. 5
18. A compound as claimed in claim 1 or 13, in which Z includes a saturated or unsaturated heterocyclic ring, system containing one or more tertiary amino nitrogen atoms, which ring system is bonded to the carbonyl group or Z either directly or by way of an alkylene 10 group.
19. A compound as claimed in claim 18, wherein the heterocyclic ring system is a pyridyl group, an oxindolyl group, a theophyllinyl group or a 4-methylpiperidinyl group. 15 20. A compound as claimed in any one of claims
13. To 19, wherein X is a p-chlorobenzyl group.
21. A compound as claimed in claim 19 or claim 20 when appended to claim 19, wherein Z is a 3~pyridylmethoxycarbonyl group. 20
22. A compound as claimed in any one of claims 1 and 3 to 6, wherein Z represents a pivaloyloxymethoxy-carbonyl group.
23. A compound as claimed in any one of claims 1 to 6, wherein Z represents a cyclopentoxycarbonyl group. 25
24. 4-(4'-chlorobenzyl)-phenoxyacetic acid methyl ester.
25. 2-Methyl-2-(4-chlorophenoxy)-propionic acid benzylaminoethyl ester or a pharmacologically acceptable acid addition salt thereof. 30
26. 4-(4'Chlorobenzyl)-phenoxyacetic acid-Nbenzyl-N-methyl-aminoethyl ester or a pharmacologically acceptable acid addition salt thereof.
27. 4-(4'-Chlorobenzyl)-phenoxyacetic acid 4-(Nmethyl)-piperidyl ester or a pharmacologically acceptable acid addition salt thereof.
28. 4-(4'-chlorobenzyl)-phenoxyacetic acid 3-pyridiylliKthyl ester or a pharmacologically acceptable acid addition salt thereof.
29. 2,6-bis-/4-(4'-chlorobenzyl)-phenoxyacetoxymethyl7-pyridine or a pharmacologically acceptable acid addition salt thereof.
30. 4-(4-Chlorobenzyl)-phenoxyacetic acid 7theophyllinylethyl ester, or a pharmacologically acceptable acid addition salt thereof.
31. 2-Methy1-2-/4-(4'-chlorobenzyl)-phenoxy_7butyric acid ethyl ester.
32. 2-Methyl-2-/4-(4 1 -chlorobenzyl)phenylthio/butyric acid.
33. 2-Methyl-2-/4-(4'-chlorobenzyl)-phenoxy/valeric acid ethyl ester.
34. 2-Methy1-2-/4-(4'-chlorobenzyl)-phenoxy/butyric acid 3-pyridylmethyl ester or a pharmacologically acceptable acid addition salt thereof.
35. 2-Methyl-2-/4-(4'-chlorobenzyl)-phenoxy/butyric acid 7-theophillinyl ethyl ester or a pharmacologically acceptable acid addition salt thereof.
36. 4-(4'-Chlorobenzyl)-phenoxy acetic acid(pivaloyloxymethyl) ester.
37. 2-/4-(4'-Chlorobenzyl)-phenoxy/-propionic acid-(pivaloyloxy-methyl)-ester).
38. 2-Methyl-2-/4-(4'-chlorobenzyl)-phenoxy/propionic acid-(pivaloyloxy-methyl)-ester.
39. 2-Methyl-2-/4-benzylphenoxy/-butyric acid ethyl ester.
40. A process for the production of a compound as claimed in claim 1, wherein a phenol or thiophenol - 36 of the general formula: R or a corresponding alkali metal or alkaline earth metal phenolate or thiophenolate is reacted with a compound of the general formula: A 1 r Hal - C - Z III ι in which Hal is a halogen atom, and the said compound is recovered from the reaction mixture obtained, the compound being recovered as such or as a 10 salt thereof with an inorganic or organic acid or base if the compound contains a basic or acid group 1 2 respectively, X, Y, Z, A , A and R in said general formulae II and III having the meanings given therefor in any one of claims 1 to 23.
14. 15 41. A method for the production of a compound as claimed in claim 1, wherein a phenol or thiophenol of the general formula: R or a corresponding alkali metal or alkaline earth metal 20 phenolate or thiophenolate is reacted in the presence of an at least trihalogenated methane derivative and in the presence of. a strong base with a ketone of formula 42438 - 37 1 2 A -CO-A (IV) and, depending on the nature of Z in the desired product, (a) if necessary esterifying, either as such or as a reactive derivative thereof, a carboxyl group in the reaction product so obtained or obtained by alkaline hydrolysis of a reaction product so obtained, with a hydroxy-terminated compound Z'-OH in which the group Z' has a formula such that Z'-0-C0 in the product so obtained constitutes the group Z or reacting said carboxyl group reactive derivative thereof with an amine, ammonia or inorganic base or salt; or ; (b) when the reaction product of the compound of general formula (II), the trihalogenated methane derivative and the ketone contains an alkoxycarbonyl group, subjecting the reaction product to ester exchange or to aminolysis with ammonia or an amine to yield a product respectively containing a group Z'-OCO- or ZCO- constituting said group Z in which Z' has the aforesaid meaning and Z is an amino group, and recovering the compound formed from the reaction mixture obtained, the compound being recovered as such or as a salt thereof with an inorganic or organic acid or base if the compound contains a basic or acidic 1 2 group respectively, X, Y, A , A and R in said general formulae II and IV having the meanings given therefor in any one of claims 1 to 23.
42. A method as claimed in claim 41, wherein the trihalogenated methane derivative is chloroform, acetone chloroform, chloral hydrate, or carbon tetrachloride .
43. A method as claimed in claim 41 or 42, wherein said carboxyl group is converted to an acyl chloride before undergoing esterification. 43425 - 38
44. A method for the production of a compound as claimed in claim 1, substantially as described in the foregoing Example 1.
45. A method for the production of a compound 5 as claimed in claim 1, substantially as described in any one of the foregoing Examples 2 to 6.
46. A method for the production of a compound as claimed in claim 1, substantially as described in any one of the foregoing Examples 7 to 10. 10
47. A method for the production of a compound as claimed in claim 1, substantially as described in any one of the foregoing Examples 11 to 13.
48. A method for the production of a compound as claimed in claim 1, substantially as described in 15 the foregoing Example 14.
49. A method for the production of a compound as claimed in claim 1, substantially as described in the foregoing Example 15.
50. A compound as claimed in claim 1, whenever prepared fay a process as claimed in any one of claims 20 40 to 49.
51. Any one of the compounds 1 to 8, 10 to 16, 15. 18, 20 to 24 and 28 to 32 disclosed in the foregoing Table.
52. A pharmaceutical composition, which comprises 25 a compound as claimed in any one of claims 1 to 39, 50 and 51 in association with a pharmacologically acceptable carrier.
53. A composition as claimed in claim 52, which is in dosage unit form containing from 5 to 300 mg of 30 said compound. 43433 - 39
54. A composition as claimed in claim 52 or 53, which is in the form of a capsule, tablet or sugar coated pill.
55. A composition as claimed in claim 52, which 5 is in the form of an emulsion or solution.
56. claim 52, A pharmaceutical composition as claimed in substantially as hereinbefore described.
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CH1330274A CH616909A5 (en) 1974-10-03 1974-10-03 Process for the preparation of aromatically substituted olefins
CH1532974A CH617417A5 (en) 1973-12-27 1974-11-18
CH1533074A CH617420A5 (en) 1974-11-18 1974-11-18 Process for the preparation of novel pivaloyloxymethyl esters

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US4214095A (en) * 1979-01-25 1980-07-22 Siegfried Aktiengesellschaft Chlorobenzyl phenoxy alkoxylates
FR2481702A1 (en) * 1980-04-30 1981-11-06 Anvar CYCLIC AMINOUS SUBSTITUTED PHENOXYACETATES, PROCESS FOR OBTAINING THE SAME, APPLICATIONS AS MEDICAMENTS AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME
DE3037391A1 (en) * 1980-10-03 1982-05-19 King Consult GmbH, 5000 Köln ESTERS OF 7-HYDROXYALKYL-1,3-DIMETHYLXANTHINES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A LIPID-REDUCING AGENT
ATE14584T1 (en) * 1981-03-11 1985-08-15 Merckle Kg Chem Pharm L PROCESS FOR THE PREPARATION OF PHENOXYALCANCARBONIC ACID ESTERS OF HYDROXYAETHYLTHEOPHYLLINE.
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DK157005C (en) 1990-03-26
NL7416412A (en) 1975-07-01
DE2461069C3 (en) 1981-07-23
DE2461069A1 (en) 1975-07-17
AU7690274A (en) 1976-07-01
JPS5934695B2 (en) 1984-08-24
DE2463001C2 (en) 1988-11-24
SE7416163L (en) 1975-06-30
IE42425L (en) 1975-06-27
LU71561A1 (en) 1975-08-20
GB1497266A (en) 1978-01-05
DK157005B (en) 1989-10-30
FR2255891A1 (en) 1975-07-25
SE426582B (en) 1983-01-31
FR2255891B1 (en) 1978-11-10
DK670274A (en) 1975-09-08
JPS50105621A (en) 1975-08-20
SU612619A3 (en) 1978-06-25
DE2461069B2 (en) 1980-10-02
BE823904A (en) 1975-06-27

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