GB1563871A - Derivatives of 4-(4-(4-chlorophenoxy)phenoxy)phenol - Google Patents

Derivatives of 4-(4-(4-chlorophenoxy)phenoxy)phenol Download PDF

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Publication number
GB1563871A
GB1563871A GB1479277A GB1479277A GB1563871A GB 1563871 A GB1563871 A GB 1563871A GB 1479277 A GB1479277 A GB 1479277A GB 1479277 A GB1479277 A GB 1479277A GB 1563871 A GB1563871 A GB 1563871A
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Prior art keywords
chlorophenoxy
compound
phenoxy
product
reacting
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GB1479277A
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Cephalon France SAS
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Laboratoire L Lafon SA
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Priority to GB1479277A priority Critical patent/GB1563871A/en
Priority to FR7807693A priority patent/FR2387940A1/en
Priority to BE2056845A priority patent/BE865734A/en
Publication of GB1563871A publication Critical patent/GB1563871A/en
Expired legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/16—Preparation of ethers by reaction of esters of mineral or organic acids with hydroxy or O-metal 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
    • C07C59/70—Ethers of hydroxy-acetic acid, e.g. substitutes on the ring

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

(54) DERIVATIVES OF 4- [4- (4-CHLOROPHENOXY) PHENOXY] PHENOL (71) We, LABORATOIRE L. LAFON, a French societe Anonyme, of 1 rue Georges Mederic, 94700 Maisons-Alfort, France, do hereby declare the invention, for which we pray that a patent may be granted to us and the method by which it is to be performed, to be particularly described in and by the following statement :- The present invention relates to derivatives of 4- [4- (4-chlorophenoxy) phenoxy] phenol, their preparation and therapeutic compositions containing them.
The derivatives according to the invention are compounds of the formula:
in which Rs and R, are the same or different and are each hydrogen or methyl and Y is COOH ; COOMI, Z (where M is a metal and x its valency) CHIzOH, COOR (where R is alkyl, aryl, (optionally substituted amino) alkyl e. g. CH2CH2NRIR2), CONR, R2 or CH2NRiR2 in which Ri and R2 are the same or different and each represents hydrogen, alkyl, aryl, hydroxyalkyl (in particular CH, CH, OH) or (optionally substituted amino) alkyl or Rl and R2, together with the nitrogen atom to which they are bound, form a 5 to 7 membered N-heterocyclic group which may be substituted and may contain a second heteroatom such as O and N. The addition salts of the compounds of formula I are within the scope of this invention included. By addition salts we mean (1) addition salts of compounds of formula I in which Y is COOH with organic bases and (2) addition salts of compounds of formula I containing basic groups with mineral and organic acids.
Examples of the NRIR2 groups are dimethylamino, diethylamino, ss-hydroxy- ethylamino, ss-dimethylaminoethylamino, ss-diethylaminoethylarnino, pyrrolidino, morpholino, piperidino, 4-methylpiperidino, 4-phenylpiperidino, 4-methylpiperazino, 4-ss-hydroxyethylpiperazino, 4-phenylpiperazino, 4- (4-chlorophenyl) piperazino and hexamethyleneimino groups.
Y is preferably COOH, COONa, COOK, COOZn, j2, COOCH3, COOCeH5, COO-n-C3H7, COO-i-C3H7, COOCH2CH2N(CH3)2, COOCH2CH2N(C2H5)2, CHZOH, CH2NHCH, CH, OH, CHzNHCH2CH, N (CH3) ,, CH2NHCH, CH2N (C,HH) 2, (, B-piperidinoethyl) oxycarbonyl, pyrrolidinocarbonyl, morpholinocarbonyl or piperidinocarbonyl.
The compounds of formula I may be prepared by conventional methods. The preferred process according to the invention comprises the following : (a) reacting p-chlorophenol with p-bromoanisole in an alkaline medium (preferably KOH or NaOH) to obtain p- (p-chlorophenoxy) anisole ; (b) reacting the product of step (a) with a demethylating agent (preferably HBr acid) to obtain p- (p-chlorophenoxy)-phenol ; (c) reacting the product of step (b) with p-bromoanisole in an alkaline medium (preferably KOH or NaOH) to obtain p-[p-(p-chlorophenoxy) phenoxy]-anisole ; (d) reacting the product of step (c) with a demethylating agent (preferably HBr acid) to obtain p-[p-(p-chlorophenoxy)-phenoxy] phenol; and (e) reacting the product of step (d) with a compound of the formula A-CR,, R,-COOH in which A is hydroxy or halogen, preferably Br or Cl, and Rs and R, are as defined above. This process yields an acid of formula I (Y is COOH). The acid may be converted into an ester by esterification, into an amide by amidification, or into the corresponding alcohol (Y is CHzOH) by reduction. If desired, the alcohol may then be converted into an amino derivative of formula I (Y is CH2NR, R2).
In stage (e), the acid reactant of formula II may be replaced by any equivalent reactant. Thus, the acid may be replaced by a corresponding ester, in particular a Cl~, alkyl ester. Moreover, when it is desired to prepare an acid of formula I in which Ri and R, are both methyl, the acid of formula II may be replaced by a mixture of acetone and chloroform.
The starting materials used in steps (b) to (e) may, if desired, be obtained by means other than those described above and thus one or more of steps (a) to (d) may be omitted if the starting material for step (e) is obtained in an alternative manner. The compounds of formula I where Y is COOH may be converted in conventional manner to those in which Y is COOMi/ and the reverse conversion may also be effected by conventional means. Likewise, the compounds where there is a basic group or Y is COOH can be converted in conventional manner to the addition salts and these may be converted in conventional manner to the free compounds.
The derivatives according to the invention are hypolipidaemiant, hypocholesterol aemiant and anti-agglomerant agents for blood platelets; by reason of their properties, they are particularly useful in the treatment and prevention of cardiovascular diseases.
The treatment or prevention of such diseases may be effected by administering an effective amount, optionally in the form of a composition, of one or more of the derivatives to a human or other subject.
According to the invention, a therapeutic composition comprises a compound of formula I, in which any salt is pharmaceutically acceptable, in association with physiologically acceptable excipient. The excipient may be conventional. Suitable proportions of the compounds in the compositions, and suitable dosage rates, may be deter mined with regard to the efficacy of the particular compound and the nature and con dition of the subject. The following Examples illustrate the invention EXAMPLE 1.
4- (4- (4-chlorophenoxy) phenoxy] phenoxyacetic acid (Code CRL 40493) a) p- (p-chlorophenoxy) anisole A mixture of 94.5 g (0.710 mol) of p-chlorophenol and 40 g (0.710 mol) of potash in the form of pellets is heated for 1 hour at about 130 C under a pressure of 8 mm Hg. When the mass has cooled, 160 g (0. 855 mol) of p-bromoaniscole and 1.4 g of copper in powder form are added and the mixture is then heated for 5 hours at about 220-230 C. The reaction medium is taken up in diethyl ether, the insoluble material is eliminated by filtration and the filtrate is washed with 2N soda and water.
After drying over dry sodium sulphate and evaporation of the solvent, 181 g of a red-brown oil, which crystallises, are obtained. This product is purified by distillation under reduced pressure to give 100 g of a crystallised white mass.
M. p., n, (Kofler) G 50 C B. p. 5 mm Hg=165-170 C Yield=60%. b) p- (p-chl orophenoxy) phenol A suspension of 100 g (0.425 mol) of the above product and 380 ml of 47% hydrobromic acid in 900 ml of acetic acid is heated for 3 hours under reflux. The reaction medium is brought to dryness under reduced pressure and the residue is taken up in diethyl ether. The organic phase is washed with water and a solution of potassium bicarbonate, then dried over dry sodium sulphate and the solvent is evaporated to give 100 g of an orange mass. After purification of this product by crystallization in cyclohexane, 84.6 g of the desired product are obtained, the product being in the form of a slightly pink powder.
M. p., n, (Kofler) =82 C Yield=90.5% c) p-[p-(p-chlorophenoxy) phenoxy] anisole 40 g (0.181 mol) of the above product and 10.1 g (0.181 mol) of potash in the form of pellets are dissolved in 75 ml of methanol. The major portion of the solvent is distilled azeotropically and the residue is then heated for 30 minutes at about 130 C under a pressure of 10 mm Hg. When the mass has cooled, 41 g (0.218 mol) of p-bromoanisole and 0.4 g of copper in powder form are added and the mixture is then heated for 1 hours at about 220-230 C. The reaction medium is taken up in chloroform, the insoluble material is eliminated by filtration and the filtrate is washed with 2N soda and water. After drying over dry sodium sulphate, treatment with CXA black and evaporation of the solvent under reduced pressure, 56 g of an orange powder are obtained. The desired product is purified by crystallization in cyclohexane to give 38 g of a beige powder.
M. p., o, t (Kofler) =106 C Yield=64.5%. d) p- [p- (p-chlorophenoxy) phenoxy] phenol A suspension of 36 g (0.11 mol) of the above product and 100 ml of 47% bromohydric acid in 250 ml of acetic acid is heated under reflux for 6 hours. The reaction medium is brought to dryness under reduced pressure and the residue is taken up in water. 33.5 g of a faintly violet powder are isolated by filtration. The desired product is purified by crystallization and treatment with CXA black in a mixture of cyclohexane and isopropanol (9: 1) v/v to give 22 g of a slightly pink powder.
M. p. (K6aer) =104 C Yield =66% e) CRL 40493 A suspension of 20 g (0.064 mol) of the above product, 7.3 g (0.077 mol) of chloroacetic acid and 3.6 g (0.064 mol) of potash in the form of pellets in 100 ml of water is heated under reflux for 2 hours. The reaction medium is then acidified with Congo red with concentrated hydrochloric acid and the precipitate is extracted with tepid ethyl acetate. The organic phase is dried over dry sodium sulphate, the solvent is evaporated under reduced pressure and the residue is washed in diisopropyl ether to obtain 16.7 g of a slightly pink powder. After purification of 15. 5 g of this product by two succesive crystallizations in benzene, 14 g of a white powder insoluble in water are obtained.
M. p.,,. t (K6fler) =1420 C Yield of stage e) =63. 5% Total yield= 14. 7%.
EXAMPLE 2.
4- [4- (4-chlorophenoxy) phenoxy] phenoxyethanol (Code CRL 40494) A solution of 11.5 g (0.031 mol) of 4- [4- (4-chlorophenoxy)-phenoxy] phenoxyacetic acid (CRL 40493) in 50 ml of tetrahydrofuran is passed in li hours into a suspension under reflux of 2.65 g (0.070 mol) of AlLiH, in 25 ml of tetrahydrofuran and the mixture is then heated for 1 hour more under reflux. The excess of hydride is neutralized with ethyl acetate and the complex is then hydrolyzed with dilute hydrochloric acid. The organic phase is decanted, diluted with hot ethyl acetate, washed with water and a 2N soda solution and dried over dry sodium sulphate and the solvent is evaporated under reduced pressure. The residue is purified by crystallization in benzene to give 8.5 g of the desired product, which is in the form of a white powder insoluble in water.
M. p.,.., (Kbfler) =116- C Yield=77. 3%.
EXAMPLE 3.
N- (B-hydroxyethyl)-4- [4- (4-chlorophenoxy) phenoxy] phenoxy-ethylamine hydrochloride (Code CRL 40495) a) -4- [4- (4-chlorophenoxy) phenoxy] phenoxyethyl mesylate 2.3 g (0.02 mol) of methanesulphonyl chloride is passed in 15 minutes into a solution of 7.1 g (0.02 mol) of 4- [4- (4-chlorophenoxy) phenoxy] phenoxyethanol (CRL 40494) in 15 ml of pyridine, which is held at about 50 C, and the mixture is agitated for 1 hour at room temperature. The reaction medium is poured over ice and is acidified with Congo red with concentrated hydrochloric acid. The precipitate is filtered, washed and then dried to give 8.4 g of a white powder.
M. p., , t (Kofler) =105 C Yield=96. 5%. b) CRL 40495 A mixture of 8.2 g (0.0188 mol) of the above product and 11.5 g (0.1880 mol) of 2-aminoethanol is heated to 170 C. The reaction medium is taken up in water and 7.6 g of a beige powder (free base of CRL 40495) are isolated by filtration.
M. p., (K6aer) =123 C This product is treated in a hot state in ethyl acetate with ethyl chloride and the precipitate obtained is purified by crystallization and treatment with CXA black in ethanol to give 5. 4 g of CRL 40495, which is in the form of a white powder soluble in hot water.
M. p. X, (K9er) = 176 C Yield of stage b) =66% Total yield=63. 7%.
The results of the pharmacological tests are summarised hereinafter as regards the hypolipidaemiant and hypocholesterolaemiant properties, on the one hand, and the anti-agglomerant properties, on the other hand.
1. Hypolipidaemiant and Hypocholesterolaemiant properties.
These were studied in rats (batch of six animals per product and per dose) subjected to a normal diet and receiving CRL 40493, CRL 40494 and CRL 40495 orally in daily doses of 10 mg/kg and 20 mg/kg (CRL 40495 having moreover been tested at SO mg/kg) for the duration of the test (3 or 5 days), three types of measurement being carried out, with respect to the controls, which received only the normal diet, so as to determine the percentages of activity: -the Burstein test (determination of degrees Verne), -the concentration of cholesterol (in g/1) in the blood, and -the concentration of total lipids (in g/1) in the blood.
The results are recorded in the following four Tables. Tables I and II, which relate to CRL 40493, show that this product has a hypocholesterlaemiant and hypolipidaemiant activity of the order of about 20% with a dose of 20 mg/kg. Table III, which relates to SRL 40494, shows that this product has no activity in a dose of 10 mg/kg, but that in a dose of 20 mg/kg the hypocholesterolaemiant and hypolipidaemiant activity is about 20%. Table IV, which relates to CRL 40495, shows that this product is active in the three doses used ; the hypocholesterolaemiant and hypolipidaemiant activity is about 15% with a dose of 10 mg/kg and about 30% with doses of 20 mg/kg and SO mg/kg.
TABLE I
DURATION OF TEST 3 days Burstein test Cholesterol Total lipids Product Daily dose Verne % activity Conc. g/l % activity Conc. g/l % activity Controls - 22.5 0.6 3.04 CRL 40493 10 mg/kg 20 9 0.54 10 2.8 8 CRL 40493 20 mg/kg 15 33 0.483 19.5 2.18 28 TABLE II
DURATION OF TEST 5 days Burstein test Cholesterol Total lipids Product Daily dose Verne % activity Conc. g/l % activity Conc. g/l % activity Controls - 18 0.5 2.5 CRL 40493 10 mg/kg 19 0 0.507 0 2.46 0 CRL 40493 20 mg/kg 15 17 0.393 21 2.04 18 TABLE III
DURATION OF TEXT : 5 days Burstein test Cholesterol Total lipids Product Daily dose Verne % activity Conc. g/l % activity Conc. g/l % activity Controls - 21.5 0.499 2.69 CRL 40494 10 mg/kg 20 7 0.537 0 2.67 1 CRL 40494 20 mg/kg 22 0 0.387 22 2.26 16 TABLE IV
DURATION OF TEST . 5 days Burstein test Cholesterol Total lipids Product Daily dose Verne % activity Conc. g/l % activity Conc. g/l % activity Controls - 21.5 0.499 2.69 CRL 40495 10 mg/kg 17.5 19 0.437 12 2.38 11 CRL 40495 20 mg/kg 16 26 0.350 30 1.98 26 CRL 40495 50 mg/kg 15 30 0.332 33 2.00 25 2. Anti-agglomerant properties.
These were studied in rats (batch of six animals per dose) with respect to two agglomerating agents: collagen (diluted to 1/10) and ADP (1 M). The results are recorded in Table V below.
TABLE V
Variation in agglomeration Collagen ADP Daily Inhibition on Inhibition on dose Duration of Time of transmission transmission Product mg/kg treatment latency Speed % % CRL 40494 100 4 days 0 -14 -7 -10 CRL 40495 100 4 day +71 -27 -7 -32.5

Claims (11)

  1. WHAT WE CLAIM IS :- 1. A compound of the formula
    in which R3 and R, are the same or different and are each hydrogen or methyl and Y is COOH; COOM, wherein M is a metal and x its valency ; CHzOH ; COOR wherein R is alkyl, aryl or (optionally substituted amino) alkyl ; CONTR, R, or CH2NR1R2 wherein either Ri and R2 are the same or different and are each hydrogen, alkyl, aryl, hydroyalkyl or (optionally substituted amino) alkyl or NRiR : Is a 5 to 7 membered N-heterocyclic group which may be substituted and which may contain a second heteroatom; or an addition salt thereof.
  2. 2. A compound as claimed in claim 1 in which Y is CH, NR, R wherein Ri and R, are as defined in claim 1.
  3. 3. A compound as claimed in claim 2 wherein NR1R2 is dimethylamino, diethylamino, ss-hydroxyethylamino, ss-dimethylaminoethylamino, ss-diethylaminoethylamino, pyrrolidino, morpholino, piperidino, 4-methylpiperidino, 4-phenylpiperidino, 4methylpiperazino, 4-, B-hydroxyethylpiperazino, 4-phenylpiperazino, 4- (4-chloro phenyl)-piperazino or hexameth leneimino
  4. 4. A compound's daimedin daim 1 in which Y is COOH, COONa, COOK, COOZn1/2, COOCH3, COOC2H5, COO-n-C3H7, COO-i-C3H7, COOCH, CH3N (CH,) 2, COOCH2CH2N (CsHs) 2, CHZOH, CH, NHCH2CHZOH, CH2NHCH2CH2N(CH3)2, CH2NHCH2CH2N(C2H5)2, (ss-piperidinoethyl) - oxy carbonyl, pyrrolidinocarbonyl, morpholinocarbonyl or piperidinocarbonyl.
  5. 5. 4- [4- (4-chlorophenoxy) phenoxy] phenoxyacetic acid or an addition salt thereof.
  6. 6.4- [4- (4-chlorophenoxy) phenoxy] phenoxyethanol.
  7. 7. N- (ss-hydroxyethyl)-4- [4- (4-chlorophenoxy) phenoy] phenoxyethylamine or an addition salt thereof.
  8. 8. A process for preparing a compound as claimed in claim 1 when Y is COOH which comprises (a) reacting p-chlorophenol with p-bromoanisole in an alkaline medium to obtain p- (p-chlorophenoxy) anisole; (b) reacting the product of step (a) with a demethylating agent to obtain p- (p- chlorophenoxy) phenol; (c) reacting the product of step (b) with p-bromoanisole in an alkaline medium to obtain p- [p- (p-chlorophenoxy) phenoxy]-anisole ; (d) reacting the product of step (c) with a demethylating agent to obtain p [p-(p-chlorophenoxy) phenoxy] phenol ; and (e) reacting the product of step (d) with a compound of the formula A-CR3R,-COOH in which A is hydroxy or halogen and R, and R ; are as defined in claim 1.
  9. 9. A process for preparing a compound as claimed in claim 1 substantially as described in any of the Examples.
  10. 10. A compound as claimed in claim 1 when prepared by a process according to claim 8 or claim 9.
  11. 11. A pharmaceutical composition comprising a compound as claimed in any of claims 1 to 7 and 10, in which any salt is pharmaceutically acceptable, in association with a physiologically acceptable excipient.
GB1479277A 1977-04-07 1977-04-07 Derivatives of 4-(4-(4-chlorophenoxy)phenoxy)phenol Expired GB1563871A (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
GB1479277A GB1563871A (en) 1977-04-07 1977-04-07 Derivatives of 4-(4-(4-chlorophenoxy)phenoxy)phenol
FR7807693A FR2387940A1 (en) 1977-04-07 1978-03-16 DERIVATIVES OF 4- (4- (4-CHLOROPHENOXY) -PHENOXY) -PHENOL, USEFUL PARTICULARLY IN THERAPEUTICS, AND THEIR PROCESS FOR PREPARATION
BE2056845A BE865734A (en) 1977-04-07 1978-04-06 DERIVATIVES OF 4- (4- (4-CHLOROPHENOXY) -PHENOXY) -PHENOL, USEFUL ESPECIALLY IN THERAPEUTICS, AND THEIR PREPARATION PROCESS

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GB1479277A GB1563871A (en) 1977-04-07 1977-04-07 Derivatives of 4-(4-(4-chlorophenoxy)phenoxy)phenol

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007508382A (en) * 2003-10-14 2007-04-05 イーライ リリー アンド カンパニー Phenoxyether derivatives as PPAR modulators

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1519147A (en) * 1974-09-30 1978-07-26 Lafon Labor Sulphur and oxygen-containing diaryl compounds

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007508382A (en) * 2003-10-14 2007-04-05 イーライ リリー アンド カンパニー Phenoxyether derivatives as PPAR modulators
US7608639B2 (en) * 2003-10-14 2009-10-27 Eli Lilly And Company Phenoxyether derivatives as PPAR modulators

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FR2387940B1 (en) 1983-03-04
FR2387940A1 (en) 1978-11-17
BE865734A (en) 1978-10-06

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