GB1565972A - M-substituted phenoxypropionic acid dervatives - Google Patents

M-substituted phenoxypropionic acid dervatives Download PDF

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GB1565972A
GB1565972A GB15777/76A GB1577776A GB1565972A GB 1565972 A GB1565972 A GB 1565972A GB 15777/76 A GB15777/76 A GB 15777/76A GB 1577776 A GB1577776 A GB 1577776A GB 1565972 A GB1565972 A GB 1565972A
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oc2h5
ch2o
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Priority to FR7710456A priority patent/FR2348182A1/en
Priority to DE19772716189 priority patent/DE2716189A1/en
Priority to AU24216/77A priority patent/AU2421677A/en
Priority to BE2055831A priority patent/BE853574A/en
Priority to DD7700198400A priority patent/DD129777A5/en
Priority to SE7704303A priority patent/SE7704303L/en
Priority to JP4402077A priority patent/JPS52136138A/en
Priority to NL7704174A priority patent/NL7704174A/en
Priority to ZA00772310A priority patent/ZA772310B/en
Priority to ES77457882A priority patent/ES457882A1/en
Publication of GB1565972A publication Critical patent/GB1565972A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • 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
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/27—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups
    • C07C205/35—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C205/36—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
    • C07C205/38—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system the oxygen atom of at least one of the etherified hydroxy groups being further bound to a carbon atom of a six-membered aromatic ring, e.g. nitrodiphenyl ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • 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
    • C07C59/76—Unsaturated compounds containing keto groups
    • C07C59/90—Unsaturated compounds containing keto groups containing singly bound oxygen-containing groups

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Description

(54) m-SUBSTITUTED PHENOXY-PROPIONIC ACID DERIVATIVES (71) We, SOCIETE DE RECHERCHES INDUSTRIELLES S. O. R. I., A French Body Corporate of 50, Avenue Des Champe Elysees, 75008 Paris, France, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which is is to be performed, to be particularly described in and by the following statement: The present invention concerns new m-substituted derivatives of phenoxy-propionic acids, and to a process for preparation of the derivatives, which are useful either in therapy, as hypolipidaemic, hypocholesterolaemic and hypotriglyceridaemic agents, or in agriculture as selective herbicides.
The invention provides a compound having the general formula:
in which: Xl, X2 and X3, which may be identical or different, each represent H, F, Cl, Br, NO2, CF3, C1-C4-alkyl or C1-C4-alkoxy, Z represents a -OCH2-, -CH2O-, -CH=CH-, -CH2CH2-, -COCH2-, -CH2CO-, -CH(OH)CH2-, -CH2CH(OH)-, -OCH2CO-, -COCH2O-, -OCH2CH(OH)-, -CH(OH )CH2O-, -O-, -S-, -SO-, -SOz- or -NH- group, R represents H or C,-C4-alkyl and Y represents OH, a Cl-Cl2-alkoxy group (whereof the hydrocarbon radical has a linear or branched chain), a C3-C8-cycloalkoxy group, a C1-C4-alkylthio group, a 2,3dihydroxypropoxy group, a 3-pyridylmethyleneoxy group, a 2-methyl-3-hydroxy-4hydroxymethylpyridyl-5-methyleneoxy group, or a NZ1Z2, NH(CH2)mNZlZ2, O(CH2)mNZlZ2, or O(CH2)mCONZlZ2 group (where m = 2, 3 or 4, and Z1 and I Z2, which may be identical or different, each represent H, a C1-C4-alkyl group or a CH2CH2OH group, or Z1 and Z2 together with the nitrogen atom to which they are bonded, represent an N-heterocyclic group of 5 to 7 ring members, which can contain a second hetero-atom and can be substituted), with the additional condition that where X1 = X2 = X3 = H, if Z = 0 and R = H or CH3, Y is different from OH and OC2H5, and if Z = CH2O and R = H, Y is different from OH, OCH3 and OQH5, and acid addition salts of the compound (I) if Y contains a basic group.
Amongst the Cl-C4-alkyl and C1-C4-alkoxy groups included in the definitions of Xl, X2 and X3, the preferred groups are methyl and methoxy groups.
If R represents a C1-C4-alkyl group, the preferred group is methyl.
Suitable Ci-Ciralkoxy groups included in the definitions of Y, include methoxy, ethoxy, isopropoxy, isobutoxy, tertiary butoxy, 2-pentoxy, 3-pentoxy, 1-cetyloxy and 1-dodecyloxy groups, the preferred alkoxy groups being OCH3, OC2H5, OCH(CH3), and OC(CH3)3.
Suitable N-heterocyclic NZ1Z2 groups of 5 to 7 ring members, which can contain a second hetero-atom and can be substituted, include pyrrolidino, morpholino, piperidino, 4methylpiperazino, 4-(p-chlorophenyl)-piperazino and hexamethyleneimino groups.
Amongst the groups Y which contain at least one nitrogen atom, the preferred groups for Y = NZlZ2 are the N(CH3)2, N(C2H5)2, N(n-C4H9)2, piperidino and morpholino groups; the preferred groups for Y = NH(CH,)mNZlZ2 are the -dimethylaminoethylamino and ss-diethylaminoethylamino groups; and the preferred groups for Y = O(CH2)mNZ1Z2 are the ss-hexamethyleneiminoethoxy, ss-morpholinoethoxy, ss-piperidinoethoxy, ssdimethylaminoethoxy and ss-diethylaminoethoxy groups.
Suitable acid addition salts include those obtained by reaction of the base with inorganic and organic acids, preferably with hydrochloric, oxalic, fumaric or maleic acid.
A preferred group of the compounds (I) in question comprises those wherein Z is OCH2 Or CH2O, R is H or CH3, and Y is OH, C1-C12 alkoxy, or NZ1Z2, NH(CH2)2NZ1Z2, O(CH2)2NZ1Z2, or
where m is 2 or 3 and Z1 and Z2 are independently H or C1-C4 alkyl or jointly with the N atom are said heterocyclic group.
The synthesis of the compounds of the formula I is illustrated by the reaction mechanisms of diagram I given below, in which R1 represents the
x2t group. x R1-Z 6, Acetone Hoc(c3) Acetone H or O} O , + CHC13 / CaH3, \HC13 BrC(R)-COY < 0 CH3 i R1-Z - R1-Z- Cif Y -C02lt 13 -C-COY esterifAcatton anidificaLon amides escers The synthesis scheme described by diagram I is applicable directly to the phenol substituted in the meta-position by the R1-Z group if Z is -OCH2-, -CH2O-, -CH=CH-, -CH2CH2-, -COCH2-, -CH2CO-, -OCH2CO-, -COCH2O-, -O-, -S-, -SO-, -SO2-, or -NH-.
If Z is -CH(OH)CH2-, -CH2CH(OH)-, -CH(OH)CH2O- and -OCH2CH(OH)-, two variants are employed: (i) the OH group of Z is blocked before reaction with HOC(CH3)2COY,
or a mixture of acetone + chloroform, and the said OH group is then regenerated; or (ii) the m-substituted phenol starting material, in which Z represents -COC2-,-CH2CO-, -COCH2O- and -OCH2CO- respectively, is reacted with one of the three reagents, and the resulting product is then subjected to a reduction, especially by means of KBH4, to give the compound of the formula I in which :Z represents -CH(OH)CH2-, -CH2CH(OH)-, -CH(OH)CHl/4O- and -OCH2CH(OH)- respectively.
Of course it is possible, if necessary, when applying the reaction mechanisms of diagram I, to convert an acid of the formula I (Y = OH) to the corresponding ester or amide, by reacting a halide of the said acid (especially the chloride) with an alcohol or an amine.
Furthermore, if necessary, it is also possible to convert a lower alkyl ester of the formula I (Y = especially OCH3 or OC2H5) to the corresponding acid by hydrolysis, or to the corresponding ester and amide by trans-esterification and amidification, respectively.
The process proposed according to the invention is characterised in that an m-phenol of the formula:
(in which X1, X2 and X3 are defined as above and Zo represents a -OCH2-, -CH2O-, -CH=CH-, -CH2CH2-, -COCH2-, -CH2CO-, -OCH2CO-, -COCH2O-, -O-, -S-, -SO-, and -SO,- or -NH- group) is reacted with HOC(CH3)2COY,
(where R and Y are as defined above), or a mixture of acetone and chloroform; a product compound of the formula (I) where R = CH3 and Y = OH obtained by reaction with a mixture of acetone and chloroform is converted, where appropriate, to a compound (I) where Y is different from OH by esterification or amidification; and a product compound of the formula (I) where Z is -COCHr, -CH2CO-, -OCH2CO-, or -COCH2O-, is subjected, if desired, to a reduction reaction to give a compound of the formfula (I) where Z is -CH(OH)CH2-, -CH2CH(OH)-, -OCH2CH(OH)-, or -CH(OH)CH2O-.
One of the preferred embodiments of this process consists of (i) preparing a compound of the formula:
where X1, X2, X3, R and Z0 are defined as above and Y' represents OH, OCH3 and OC2H5), (ii) converting, where appropriate, the compound Io, where Zo contains a carbonyl group and Y' is OCH3 or OC2H5, to a compound
[where X1, X2, X3 and R are defined as above, Y" is OCH3 or OQH5 and Z'O is -CH(OH)CH2-, -CH2CH(OH)-, -OCH2CH(OH)- and -CH(OH)CH2O-] and (iii) converting, where appropriate, the groups Y' and Y" of 1o and Iso to a group Y in accordance with one of the techniques given above.
The compounds of the formula II can be prepared in accordance with a method which is in itself known, by application of previous conventional reaction principles.
Of course it is also possible to prepare the compounds of the formula I in accordance with reaction mechanisms equivalent to those of diagram I. FOR EXAMPLE, IF Z is -OCH2-, -CH2O-, -OCH2CO-, -COCH2O-, -O-, -S-, -SO-, -SO2- and -NH-, it is possible to employ one of the following two reactions:
(where R, R1 and Y are defined as above, X represents a halogen atom, preferably Cl or br, and M represents a metal atom, especially Na).
Equally, the compounds of the formula I, where Z is CH=CH, can be prepared by the Wittig method [cf. Merck Index (1968), 8th edition, pages 1,226 and 1,227]. The compounds of the formula I, where Z is CH2CH2, can be prepared from the corresponding ethylenic derivatives (CH=CH).
In Table I below, a certain number of compounds of the formula I which have been obtained in accordance with the process of the invention have been listed by way of example.
The compounds of the formula I according to the invention can be utilised in thereapy and in agriculture. In therapy, they are useful as hypolipidaemic, hypocholesterolaemic and hypotriglyceridaemic agents in the treatment of cardiovascular diseases and arterial diseases, especially those which are associated with the pathology of the cardio-vascular system.
For this purpose, the invention proposes a therapeutic composition characterised in that it contains at least one compound of the formula I or one of its addition salts with non-toxic acids, in association with a physiologically acceptable excipient or diluent.
The compounds of the formula I can be administered to man orally, by injection or by implantation. The preferred method of administration of the esters and the amides is oral administration. The acids are preferably administered by injection in the form of a metal salt (especially Na, K, Mg, Zn and Al).
In Table II below has been summarised a part of the pharmacological tests which have been carried out on normal rats, the products to be tested being administered orally at a dose of 50 mg/kg in the case of the acids (Y = OH) and at a dose of 100 mg/kg in the case of the esters and the amides (Y * OH). The working procedure, which was employed to determine the variations in the content of cholesterol and of total lipids in the blood, is that proposed by R. SORNAY et al., Arzneimittel-Forschung (Drug Research) (1976), 26, 885-889.
Furthermore, in Table III below, a certain number of clinical cases are given by way of example, and relate to experiments carried out using the compound of Example 2.
Furthermore, the compounds of the formula I are useful in agriculture as herbicidal agents which are selective, especially towards adventitious plants.
The properties of selective herbicides containing compounds of the formula I together with a suitable carrier or diluent were assessed especially with regard to adventitious graminaceae. For this purpose, seeds of cultivated plants (wheat and barley) and adventitious graminaceae (foxtail and wild oats) were sown in pots and raised in a greenhouse. When the plants have three to four leaves, they are watered with aqueous solutions or suspensions of compounds of the formula I and of a known comparison product, namely 2-(2,4-dichlorophenoxy)-propionic acid, each substance being administered at a rate of application of the order of 0.80 to 1.20 kg/ha. It is found that the products according to the invention after several weeks (4 weeks, for example) of treatment do not destroy the cereals but destroy the two adventitious graminaceae used for the tests, namely foxtail and wild oats.
In agriculture, the compounds according to the invention can be administered in the usual forms, especially as a wettable powder, as an emulsion and/or as granules.
Specific embodiments of the invention are described in the following preparations, which are given by way of illustration.
Preparation I Synthesis of 2-[3- (4-chlorobenzyloxy) -phenoxy] -2-methyl-propionic acid (product of Example 19)
Code No. 667 The starting material used is 3-(4-chlorobenzyloxy)-phenol, prepared by condensing para-chlorobenzyl chloride with the monopotassium salt of resorcinol.
A mixture of 23.5 g of the phenol mentioned above, 24 g of sodium hydroxide and 250 cm3 of acetone is heated under reflux in a 1 litre flask; when the salt has been produced, the source of heat is removed and a mixture of 36 g of chloroform in 50 cm3 of acetone is added dropwise; the addition must be regulated so that refluxing is maintained for 2/3 of this addiction; at the end, the source of heat is returned and refluxing is continued for 2 hours after the end of the addition; thereafter, the acetone is evaporated in vacuo, the oily residue is taken up in 300 cm3 of water and this basic aqueous phase is extracted with ether; the aqueous phase is acidified and the acid which precipitates is then re-extracted with ether; two further extractions with ether are carried out and the combined ether phases are extracted with a saturated sodium bicarbonate solution; the new aqueous phase obtained is again acidified in the presence of ether and extracted twice with ether, and the combined ether phases are dried and decolorised with animal charcoal; after evaporating the solvent in vacuo, the acid obtained crystallises gradually.
Melting point = 74"C. Weight = 26 g. Yield = 81%.
Preparation I bis.
Alternative synthesis of 2-[3- (4-chlorobenzyloxy) -phenoxy] -2-methylpropionic acid a) Preparation of isopropyl 2-(3-hydroxyphenoxy) -2-methyl-propionate A mixture of 19 g of the monopotassium salt of resorcinol, 21 g of isopropyl a-bromoisobutyrate and 20 ml of isopropyl alcohol is heated for 3 hours under reflux in a 100 ml flask; the mixture is allowed to cool and is hydrolysed and extracted with ether; the ether phase is dried, decolorised and concentrated in vacuo; the residual oil is distilled.
Boiling point/0.3mm Hg = 137"C. Weight = 23.8 g. b) Preparation of 2-[3- (4-chlorobenzyloxy) -phenoxy] -2-methylpropionic acid 23.8 g of the preceding product, 5.6 g of potassium hydroxide and 100 ml of isopropanol are heated at 40"C in a 500 cm3 flask; a solution of 19.3 g of para-chlorobenzyl chloride is then added dropwise and when this addition is complete, the mixture is heated for 5 hours under reflux; it is allowed to cool and is hydrolysed and extracted with ether; the ether phases are washed with a solution of 20 g/l of sodium hydroxide and then with water, and are dried, decolorised and concentrated in vacuo. Isopropyl 2-[3-(4-chlorobenzyloxy)phenoxy] -2-methylpropionate is obtained in the form of an oil which is saponified, as obtained, in alcoholic potassium hydroxide solution; after acidification and recrystallisation from a 1:1 v/v mixture of diisopropyl ether and hexane, the expected acid is obtained.
Melting point = 74"C. Weight = 15 g.
Preparation II Synthesis of 2-[3- (4-chlorophenoxymethyl) -phenoxy] -2-methylpropionic acid (product of Example 1).
Code No. 666 23.5 g of 3-(4-chlorophenoxymethyl)-phenol (obtained by condensing the sodium salt of para-chlorophenol with the a-bromo derivative of meta-cresol), 120 cm of isopropanol, 32 g of isopropyl a-bromoisobutyrate and 21 g of anhydrous potassium carbonate are placed in a 250 cm3 flask. The whole is heated for 12 hours under reflux. After cooling, the reaction mixture is filtered and the precipitate is washed on the filter with ether. The filtrate is concentrated in vacuo and take up in a mixture of 500 cm3 of ether and 100 cm3 of water; the aqueous phase is rendered alkaline with 2 N sodium hydroxide solution and is extracted twice with ether; the combined ether phases are washed with water until neutral, dried and decolorised with animal charcoal; after evaporating the solvent in vacuo, an oil is obtained, which is saponified directly in an alcoholic potassium hydroxide solution. After acidification, the acid precipitates; it is recrystallised from a 4:1 v/v mixture of alcohol and water.
Melting point = 139"C. Weight = 25 g.
Preparation II bis Alternative synthesis of 2-[3- (4-chlorophenoxymethyl) -phenoxy] -2-methylpropionic acid a) Preparation of isopropyl 2-(3-methylphenoxy) -2-methyl-propionate 54 g of meta-cresol, 120 g of sodium hydroxide and 500 ml of acetone are placed in a 1,000 cm3 flask. The mixture is heated under reflux for half an hour and a solution of 180 g of chloroform and 100 cm3 of acetone is then added, with the heating stopped; the mixture is then heated for 3 hours under reflux and is cooled, and the sodium chloride is filtered off; the acetone is evaporated and the residue is taken up in water, acidified and extracted with ether.
The ether phase is then extracted with a saturated bicarbonate solution, the aqueous phase is acidified and extracted with ether and the combined ether phases are dried, decolorised with animal charcoal and concentrated in vacuo; the acid obtained is an oil (40 g) which is esterified, in 250 ml of benzene, with 38 g of isopropanol and 4 g of p-toluenesulphonic acid; the mixture is heated under reflux for 16 hours (whilst removing the water by azeotropic distillation); it is hydrolysed and extracted with ether, the solvent is concentrated in vacuo and the oily residue is distilled to give the expected ester.
Boiling point/l mm Hg = 100"C. Weight = 28 g. b) Preparation of isopropyl 2-(3-bromomethylphenoxy) -2-methylpropionate The 28 g of the preceding compound are dissolved in 150 cm of carbon tetrachloride; 22.4 g of N-bromo-succinimide and 2.4 g of benzoyl peroxide are added; the mixture is heated for 8 hours under reflux, the succinimide is then filtered off, the filtrate is evaporated in vacuo and the oily residue is distilled to give the expected a-bromomethyl denvative.
Boiling point/1 mm Hg = 138"C. Weight = 33 g. c) Preparation of 2-[3-(4-chlorophenoxymethyl)-phenoxy] -2-methylpropionic acid A mixture of 17 g of the preceding compound, 120 cm3 of isopropanol, 6.8 g of para-chlorophenol and 2.93 g of potassium hydroxide is heated under reflux for 10 hours; it is allowed to cool, the alcohol is evaporated in vacuo and the residue is taken up with water and with ether; the ether phase is washed with sodium hydroxide solution and then with water; it is then dried and decolorised with animal charcoal and concentrated in vacuo to give an oil which is saponified directly in alcoholic potassium hydroxide solution; after acidification the acid precipitates; it is recrystallised from a 4:1 v/v mixture of alcohol and water.
Melting point = 139"C. Weight = 12 g.
Preparation III Synthesis of 2-[3-(3,4,5-trimethoxy-styryl)-phenoxy] -2-methylpropionic acid (product of Example 37)
This acid is obtained from 3-(3,4,5-trimethoxy-styryl)-phenol (itself prepared by a Wittig condensation of the ylide derivative of 3-(a-bromo-methyl)-phenol with 3, 4, 5trimethoxybenzaldehyde); from 28.6 g of this styryl-puenol, using the method of working described in I for the compound of Example 19, 30 g of the product of Example 37 are obtained.
Melting point = 141"C. Yield = 80%.
Preparation IV Synthesis of ethyl 2-[3- (4-chlorobenzyl-carbonyl) -phenoxy] -2-methylpropionate (product of Example 40)
This ester is obtained by condensing ethyl a-bromo-isobutyrate with the phenol of the formula
The reaction is carried out in the presence of anhydrous K2CO3 in ethyl alcohol in accordance with the method of working described earlier. The expected ester is obtained in a yield of 78% (melting point = 92"C). When saponified in alcoholic potassium hydroxide solution, it gives the corresponding acid (Example 39).
Melting point = 1600C.
Preparation V Synthesis of ethyl 2-[3-(4-chlorophenylthio)-phenoxy] -2-methyl propionate (product of Example 62)
Code No.: 700 23.6 g of 3-(4-chlorophenylthio)-phenol, 5 g of para-toluenesulphonic acid and 15 g of ethyl a-hydroxy-isobutyrate are placed in a 250 cm3 flask; 75 cm3 of anhydrous dimethylformamide are added and the mixture is heated under reflux for 5 hours; after cooling, the reaction mixture is poured into water and is extracted with ether. The ether phases are washed with 2N sodium hydroxide solution, dried, decolorised and concentrated in vacuo; the residual oil is distilled.
Boiling point/0. 1 mm Hg = 180-184"C. Weight = 17 g.
Saponification of this ester in alcoholic potassium hydroxide solution quantitatively gives the acid of Example 61.
Melting point = 77"C.
Preparation VI Synthesis of ethyl 2-[3-(4-chlorophenylsulphinyl)-phenoxy] -2-methylpropionate (product of Example 64)
This ester is easily prepared from the product of Example 62 by oxidation with sodium periodate in an aqueous-alcoholic medium at ambient temperature; the expected ester is an oil, having a refractive index of n = 1.57. Saponification of this ester in alcoholic potassium hydroxide solution gives the corresponding acid, which is the product of Example 62.
Melting point : 81"C.
Preparation VII Synthesis of ethyl 2-[3-(4-chlorophenylsulphonyl)-phenoxy] -2-methylpropionate (product of Example 66) This ester is also prepared from the ester of Example 62; this time, a more extensive oxidation is carried out, with hydrogen peroxide in acetic acid; the expected ester is obtained in a yield of 87% (melting point = 70"C). By saponification in alcoholic potassium hydroxide solution, this ester gives the acid of Example 65, which has a melting point of 64-100"C; in fact, this acid starts to melt at 640C, then sets solid again, and melts again at 100"C.
Preparation VIII Synthesis of 2-[3-(4-fluoroanilino)-phenoxy] -2-methyl-propionic acid (product of Example 75) This acid is easily obtained from 3-(4-fluoroanilino)-phenol (melting point = 98"C) by application of the "acetone-chloroform" reaction described for the preparation of the acid of Example 19. In this case, the product of Example 75 is obtained in a yield of 73%. Melting point = 105"C.
This acid, on esterification in ethyl alcohol in the presence of sulphuric acid, gives the corresponding ester, which is the product of Example 76.
Melting point = 64"C.
TABLE I
Example R1 Z R Y 1 4-Cl-C6-H4 OCH2 CH3 OH 2 4-Cl-C6H4 OCH2 CH3 OCH(CH3)2 3 4-Cl-C6-H4 OCH2 CH3 OC2H5 4 4-Cl-C6H4 OCH2 CH3 OCH2CH2N(CH3)2,HCl
J N r c I X o o V 6 4-Cl-C6H4 OCH2 CH3 NHCH2CH2N(C2H5)2,HCl 7 4-Cl-C6H4 OCH2 H OH 8 4-Cl-C6H4 OCH2 H OCH3 9 4-CF3-C6H4 OCH2 CH3 OH 10 4-CF3-C6H4 OCH2 CH3 OCH(CH3)2
3 c N V X 4-CF3-C6H4 OCH2 CH3 ,KCL V o VS 12 2,4-(Cl2)-C6H3 OCH2 CH3 OH 13 2,4-(Cl)2-C6H3 OCH2 CH3 OC2H5 14 2,4-(Cl)2-C6H3 OCH2 H OCH(CH3)2 15 2,4-(Cl)2-C6H3 OCH2 H OH 16 4-F-C6H4 OCH2 CH3 OH 17 4-F-C6H4 OCH2 CH3 OCH(CH3)2 18 C6H5 OCH2 CH3 OH 19 4-Cl-C6H4 CH2O CH3 OH 20 4-F-C6H4 CH2O CH3 OH 21 4-F-C6H4 CH2O CH3 OC2H5 22 4-Cl-C6H4 CH2O CH3 OCH(CH3)2 TABLE I (continuation 1) Example R1 Z R Y
r Q N r X o 9 X 24 4-F-C6H4 CH2O CH3 OCH2CH2N(C2H5)2,HCl 25 3-CF3-C6H4 CH2O CH3 OH 26 2,4-(Cl)2-C6H3 CH2O CH3 OH 27 C6H5 CH2O CH3 OH 28 4-Cl-C6H4 CH2CH2 CH3 OH 29 4-Cl-C6H4 CH2CH2 CH3 OC2H5 30 4-F-C6H4 CH2CH2 CH3 OH 31 4-Cl-C6H4 CH=CH CH3 OH 32 4-Cl-C6H4 CH=CH CH3 OCH(CH3)2 33 4-Cl-C6H4 CH=CH CH3 OCH2CH2N(CH3)2,HCl 34 4-Br-C6H4 CH=CH CH3 OH 35 4-Br-C6H4 CH=CH CH3 OC2H5 36 4-CH3O-C6H4 CH=CH CH3 OH 37 3,4,5-(CH3O)3-C6H2 CH=CH CH3 OH 38 3,4,5-(CH3O)-C6H2 CH=CH H OH 39 4-Cl-C6H4 CH2CO CH3 OH 40 4Cl-C6H4 CH2CO CH3 OC2H5 41 4-Cl-C6H4 COCH2 CH3 OH 42 4-Cl-C6H4 COCH2 CH3 OCH(CH3)2 43 4-Cl-C6H4 CHOHCH2 CH3 OH 44 4-Cl-C6H4 CHOHCH2 CH3 OCH(CH3)2 45 4-Cl-C6H4 CH2CHOH CH3 OH 46 4-Cl-C6H4 CH2CHOH CH3 OC2H5 47 4-Cl-C6H4 OCH2CO CH3 OC2H5 48 4-Cl-C6H4 COCH2O CH3 OC2H5 49 4-Cl-C6H4 OCH2CHOH CH3 OC2H5 50 4-Cl-C6H4 CHOHCH2O CH3 OC2H5 51 4-Cl-C6H4 O CH3 OH 52 4-Cl-C6H4 O CH3 OCH(CH3)2 53 4-Cl-C6H4 O H OH 54 4-Cl-C6H4 O H OC2H5 55 4-F-C6H4 O CH3 OC2H5 56 4-F-C6H4 O CH3 OH TABLE I (continuation 2) Example R1 Z R Y 57 4-CF3-C6H4 O CH3 OH 58 3-NO2-C6H4 O CH3 OH 59 4-Br-C6H4 O CH3 OH 60 4-Br-C6H4 O CH3 NHCH2CH2OH 61 3,4-(Cl)2-C6H3 O CH3 OH 62 4-Cl-C6H4 S CH3 OH 63 4-Cl-C6H4 S CH3 OC2H5 64 4-Cl-C6H4 SO CH3 OH 65 4-Cl-C6H4 SO CH3 OC2H5 66 4-Cl-C6H4 SO2 CH3 OH 67 4-Cl-C6H4 SO2 CH3 OC2H5 68 C6H5 S CH3 OH 69 C6H5 SO CH3 OH 70 C6H5 SO2 CH3 OH 71 3-CF3-C6H4 S CH3 OH 72 4-NO2-C6H4 S CH3 OH 73 4-CH3-C6H4 S CH3 OH
3 d 0 0 iu 3N X 4-Cl-C6H4 3:m V 4-Cl-C6H4 SO CH3 0Cw2CH2 ,HcL o X V V V V 76 4-F-C6H4 NH CH3 OH 77 4-F-C6H4 NH CH3 OC2H5 78 4-Cl-C6H4 NH CH3 OH 79 4-Cl-C6H4 NH CH3 OC2H5 80 4-Cl-C6H4 NH CH3 OCH2CH2N(C2H5)2,HCl 81 4-Cl-C6H4 NH CH3 OC(CH3)3 82 4-Br-C6H4 NH CH3 OC2H5 83 4-Br-C6H4 NH CH3 OH TABLE II Example Code No. Melting Point LD-50, intra- Variation or n20D peritoneal Cholesterol Lipids administration to mice (dose, mg/kg) (dose, mg/kg) mg/kg oral oral administration % administration % 1 666 M.p. +139 C 450 ( 50) -39.3% ( 50) -20.1% 19 667 M.p. = 74 C 320 ( 50) -39.8% ( 50) -27.4% 20 692 M.p. = 74 C 350 ( 50) -34% ( 50) -28% 21 693 n = 1.523 > 1,600 (100) -29% (100) -30% 31 698 M.p. = 145 C 400 ( 50) -22% ( 50) -29% 39 696 M.p. = 160 C 480 ( 50) -20% ( 50) -19% 40 697 M.p. = 92 C > 1,600 (100) -18% (100) -21% 47 728 M.p. 48 C > 1,600 (100) -18% (100) -20% 48 727 n = 1.550 > 1,600 (100) -19% (100) -18% 51 683 M.p. = 67 C 190 ( 50) -33% ( 50) -30% 53 706 M.p. = 107 C 210 ( 50) -30% ( 50) -25% 54 705 n = 1.557 1,000 (100) -25% (100) -25% 55 717 M.p. = 48 C 1,200 (100) -22% (100) -20% 56 718 M.p. = 74 C 180 ( 50) -26% ( 50) -29% 62 700 M.p. = 77 C 200 ( 50) -18% ( 50) -25% 63 731 n = 1.553 1,300 (100) -20% (100) -21% 64 711 M.p. = 88 C 600 ( 50) -16% ( 50) -11% 2 666A M.p. = 54 C > 1,600 (100) -41% (100) -35% 65 715 n = 1.570 > 1,600 (100) -18% (100) -15% 66 716 (a) 600 ( 50) -28% ( 50) -32% 67 713 M.p. = 70 C > 1,600 (100) -25% (100) -30% 76 720 M.p. = 105 C 370 ( 50) -27% ( 50) -33% 77 719 M.p. = 64 C 1,400 (100) -27% (100) -32% Note (a) : double melting point, M.p. = 64 C and then 100 C TABLE III R E S U L T S Name Sex Age Weight Hyperlipidaemia Before treatment After treatment* Tolerance BLA F 59 55 type IV TL = 10.20 TL = 7.50 excellent TC = 3 TC = 2.25 TG = 2.70 TG = 1.70 DAL M 50 70 type IIa TL = 10.30 TL = 7.50 excellent with TC = 3.50 TC = 2.35 xanthoma TG = 1.50 TG = 1.50 BAR M 69 64 type IIb TL = 8.20 TL = 6.80 excellent TC = 2.75 TC = 2.25 TG = 0.95 TG = 0.90 BER M 63 64 type IIa TL = 12 TL = 11.25 excellent with TC = 4.75 TC = 3.70 xanthoma TG = 1.15 TG = 1.15 HUE M 48 66 type IIa TL = 8.68 TL = 6.92 excellent with TC = 2.95 TC = 2.57 xanthoma TG = 1.27 TG = 1.20 GAL M 28 74 type IIa TL = 8.10 TL = 7.45 excellent TC = 3.13 TC = 2.58 TG = 0.61 TG = 0.60 BOU F 62 67 type IIb TL = 8.79 TL 6.25 excellent TC = 3.26 TC = 2.46 TG = 1.97 TG = 0.94 * (after 3 months' treatment with 300 mg/day, administered orally) TL : total lipids; TC : total cholesterol; TG : triglyceides

Claims (19)

  1. WHAT WE CLAIM IS: 1. A compound having the general formula:
    in which X1, X2 and X3, which may be identical or different, each represent H, F, Cl, Br, NO2, CF3, C1-C4-alkyl or C1-C4-alkoxy, Z represents a -OCH2-, -CH2O-, -CH=CH-, -CH2CH2-, -COCH2-, -CH2CO-, -CH(OH)CH2-, -CH2CH(OH)-, -OCH2CO-, -COCH2O-, -OCH2CH(OH)-, -CH(OH- )CH2O-, -O-, -S-, -SO-, -SOz- or -NH- group, R represents H or C1-C4-alkyl, and Y represents OH, a C1-C12-alkoxy group (whereof the hydrocarbon radical has a linear or branched chain), a C3-C8-cycloalkoxy group, a C1-C4-alkylthio group, a 2,3dihydroxypropoxy group, a 3-pyridylmethyleneoxy group, a 2-methyl-3-hydroxy-4- hydroxymethylpyrid-5-yl-methyleneoxy group, or a NZ1Z2, NH(CH2)mNZ1Z2, O(CH2)mNZ1Z2, or O(CH2)mCONZ1Z2 group (where m = 2, 3 or 4, and Z1 and Z2, which may be identical or different, each represent H, a C1-C4-alkyl group or a CH2CH2OH group, or Z1 and Z2 together with the nitrogen atom to which they are bonded, represent an N-heterocyclic group of 5 to 7 ring members, which can contain a second hetero-atom and can be substituted), with the additional condition that where X1 = X2 = X3 = H, if Z = O and R = H or CH3, Y is different from OH and OC2H5, and if Z = CH2O and R = H, Y is different from OH, OCH3, and OC2H5, and acid addition salts of the compound (I) if Y contains a basic group.
  2. 2. A compound or salt according to claim 1, wherein Z is OCH2 or CH2O, R is H or CH3, and Y is OH, C1-C2 alkoxy, or NZ1Z2, NH(CH2)2NZ1Z2, or
    where m is 2 or 3 and Z1 and Z2 are independently H or C1-C4 alkyl or jointly with the N atom are said heterocyclic group.
  3. 3. A compound or salt according to claim 1 or 2, wherein NZ1Z2 represents an N(CH3)2, N(C2H5)2, NHCH2CH2OH, pyrrolidino, morpholino, piperidino, 4methylpiperazino, 4-(p-chlorophenyl)-piperazino or hexamethyleneimino group.
  4. 4. A compound or salt according to claim 1 or 2, wherein Y represents OH, OCH3, OC2H5, OCH(CH3)2, OC(CH3)3, piperidino, morpholino, ss-dimethylaminoethylamino, ss-diethylaminoethylamino, ss-hexamethyleneiminoethoxy, ss-morpholinoethoxy, ssdimethylaminoethoxy or ss-diethylaminoethoxy.
  5. 5. A compound according to claim 1, wherein X1 = 4-Cl, X2 = X3 = H,Z = OCH2, R = CH3 and Y = OH.
  6. 6. A compound according to claim 1, wherein X1 = 4-Cl or 4-F, X2 = X3 = H,Z = CH2O, R = CH3 and Y = OH or OC2H5.
  7. 7. A compound according to claim 1, wherein X1 = 4-Cl,X2 = X3 = H,Z is CH = CH, R = CH3 and Y = OH.
  8. 8. A compound according to claim 1, wherein X1 =4-Cl, X2 = X3 = H,Z = CH2CO,R = CH3 and Y is OH or OC2H5.
  9. 9. A compound according to claim 1, wherein X1 = 4-Cl, X2 = X3 = H, Z = OCH2CO or COCH2O, R = CH3 and Y is OC2H5.
  10. 10. A compound according to claim 1, wherein X1 = 4-Cl or 4-F, X2 = X3 = H, Z = 0, R = H or CH3 and Y = OH or OC2H5.
  11. 11. A compound according to claim 1, wherein X1 = 4-Cl, X2 = X3 = H,Z = S,SO or SO2, R = CH3 and Y = OH or OC2H5.
  12. 12. A compound according to claim 1, wherein X1 = 4-F, X2 = X3 = H,Z = NH,R = CH3, and Y = OH or OQH5.
  13. 13. Any one of the exemplary compounds or salts 1 to 83 hereinbefore listed, except those according to claims 5 to 12.
  14. 14. A process for preparing a compound or salt of the general formula (I) according to any of claims 1 to 13, wherein an m-phenol of the formula:
    in which X1, X2 and X3 are as defined in claim 1 and Z0 represents an -OCH2-, -CH2O-, -CH=CH-, -CH2CH2-, -COCH2-, -CH2CO-, -OCH2CO-, -COCH2O-, -O-, -S-, -SO-, -SO2-, or -NH- group, is reacted with HOC(CH3)2COY,
    (where R and Y are as defined in claim 1), or a mixture of acetone and chloroform; a product compound of formula (I) where R = CH3 and Y = OH obtained by reaction with a mixture of acetone and chloroform is converted, where appropriate, to a compound (I) where Y is different from OH by esterification or amidification; and a product compound of the formula (I) where Z is -COCH2-, -CH2CO-, -OCH2CO-, or -COCH2O- is subjected, if desired, to a reduction reaction to give a compound of the formula (I) where Z is -CH(OH)CH2-, -CH2CH(OH)-, -OCH2CH(OH)-, or -CH(OH)CH2O-.
  15. 15. A process according to claim 14, wherein a compound of the formula (I), where Z represents Z0 and Y represents an OCH3 or OC2H5 group, is prepared, and the said group Y is converted to an acid, ester or amide group by hydrolysis, trans-esterification, or amidification, respectively, after reduction where appropriate of the carbonyl group of Z0 to the corresponding secondary alcohol group.
  16. 16. A process according to claim 14 substantially as described in any one of the foregoing Preparations I to VIII.
  17. 17. A compound or salt according to claim 1 when prepared by the process claimed in any of claims 14 to 16.
  18. 18. A therapeutic composition, which contains at least one compound according to any of claims 1 to 13 and 17 or one of its addition salts (if appropriate) with non-toxic acids, in association with a physiologically acceptable excipient or diluent.
  19. 19. A herbicidal composition which contains at least one compound according to any of claims 1 to 13 and 17 or one of its addition salts (if appropriate) with acids, in association with a suitable carrier or diluent, as a herbicide which is selective towards graminaceae.
GB15777/76A 1976-04-15 1976-04-15 M-substituted phenoxypropionic acid dervatives Expired GB1565972A (en)

Priority Applications (11)

Application Number Priority Date Filing Date Title
GB15777/76A GB1565972A (en) 1976-04-15 1976-04-15 M-substituted phenoxypropionic acid dervatives
FR7710456A FR2348182A1 (en) 1976-04-15 1977-04-06 NEW DERIVATIVES OF M-PHENYL-PHENOXY-PROPIONIC ACIDS
DE19772716189 DE2716189A1 (en) 1976-04-15 1977-04-12 PHENOXYPROPIONIC ACID DERIVATIVES, METHOD FOR THEIR PRODUCTION AND USE AS OR IN THERAPEUTIC AND HERBICIDAL AGENTS
AU24216/77A AU2421677A (en) 1976-04-15 1977-04-13 New m-substituted phenoxy-propionic acid derivatives
BE2055831A BE853574A (en) 1976-04-15 1977-04-14 NEW DERIVATIVES OF M-PHENYL-PHENOXY-PROPIONIC ACIDS
DD7700198400A DD129777A5 (en) 1976-04-15 1977-04-14 PROCESS FOR THE PREPARATION OF PHENOXYPROPIONSAEUREDERIVATES
SE7704303A SE7704303L (en) 1976-04-15 1977-04-14 WAY TO PRODUCE PHENOXY ASSOCIATIONS
JP4402077A JPS52136138A (en) 1976-04-15 1977-04-15 Metaasubstituted phenoxyy propionic acid derivative
NL7704174A NL7704174A (en) 1976-04-15 1977-04-15 NEW M-PHENYLPHENOXYPROPION ACID DERIVATIVES AND THEIR PREPARATION.
ZA00772310A ZA772310B (en) 1976-04-15 1977-04-15 New-m-substituted phenoxy-propionic acid derivatives
ES77457882A ES457882A1 (en) 1976-04-15 1977-04-15 M-substituted phenoxypropionic acid dervatives

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DE2709032A1 (en) * 1977-03-02 1978-09-07 Hoechst Ag HERBICIDAL AGENTS
CH626318A5 (en) * 1977-03-08 1981-11-13 Ciba Geigy Ag
DE2860339D1 (en) * 1977-06-30 1981-02-12 Ciba Geigy Ag Substituted 3-(2'-nitro phenoxy)-alpha-phenoxy alcanoic acids and their derivatives, their preparation and their use as herbicides
DE2961372D1 (en) * 1978-01-20 1982-01-28 Ciba Geigy Ag Phenoxy-phenoxy-alkylcarboxylic acid derivatives with herbicidal activity, their preparation, compositions containing them and their use
DE2805982A1 (en) * 1978-02-13 1979-08-16 Bayer Ag PHENOXY ACETIC ACID DERIVATIVES, PROCESS FOR THEIR PRODUCTION AND USE AS HERBICIDES
DE2805981A1 (en) * 1978-02-13 1979-08-16 Bayer Ag PHENOXYPROPIONIC ACID DERIVATIVES, PROCESS FOR THEIR PRODUCTION AND USE AS HERBICIDES
FR2420522A1 (en) * 1978-03-20 1979-10-19 Unicler ACID (M-BENZOYL-PHENOXY) -2 PROPIONIC DERIVATIVES AND THEIR APPLICATIONS AS MEDICINAL PRODUCTS
US4259105A (en) * 1978-05-10 1981-03-31 Nippon Soda Company, Ltd. Diphenylamine derivatives
NZ192353A (en) * 1978-12-22 1982-03-16 Ici Australia Ltd Diphenylamine derivatives herbicidal compositions
NZ194883A (en) * 1979-10-02 1983-05-31 Ici Australia Ltd -(quinoxalin-2-ylaminophen (oxy or ylthio) alkanoic acid derivatives
ZA814144B (en) * 1980-07-01 1982-07-28 Ici Australia Ltd Compounds and compositions
DE3125059A1 (en) * 1981-06-26 1983-01-05 Bayer Ag, 5090 Leverkusen DIOXYBENZOLETHER DERIVATIVES, THESE MEDICINAL PRODUCTS, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE
DE4133674A1 (en) * 1991-10-11 1993-04-15 Bayer Ag FLUORINATED PHENOXYPHENOXYCARBONIC ACID DERIVATIVES
FR2704224B1 (en) * 1993-04-20 1995-08-25 Adir New acids and substituted isobutyric phenoxy esters.

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DD129777A5 (en) 1978-02-08
ZA772310B (en) 1978-03-29
AU2421677A (en) 1978-10-19
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SE7704303L (en) 1977-10-16

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