GB1579839A - Chlorophenoxybenzene derivatives - Google Patents

Chlorophenoxybenzene derivatives Download PDF

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Publication number
GB1579839A
GB1579839A GB1590777A GB1590777A GB1579839A GB 1579839 A GB1579839 A GB 1579839A GB 1590777 A GB1590777 A GB 1590777A GB 1590777 A GB1590777 A GB 1590777A GB 1579839 A GB1579839 A GB 1579839A
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Prior art keywords
chlorophenoxy
crl
acid
mol
formula
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
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GB1590777A
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Cephalon France SAS
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Laboratoire L Lafon SA
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Publication date
Application filed by Laboratoire L Lafon SA filed Critical Laboratoire L Lafon SA
Priority to GB1590777A priority Critical patent/GB1579839A/en
Priority to FR7809931A priority patent/FR2396738A1/en
Priority to BE2056875A priority patent/BE865975A/en
Priority to FR7903500A priority patent/FR2422615A1/en
Publication of GB1579839A publication Critical patent/GB1579839A/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
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/257—Ethers having an ether-oxygen atom bound to carbon atoms both belonging to six-membered aromatic rings
    • C07C43/29—Ethers having an ether-oxygen atom bound to carbon atoms both belonging to six-membered aromatic rings containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/257—Ethers having an ether-oxygen atom bound to carbon atoms both belonging to six-membered aromatic rings
    • C07C43/295—Ethers having an ether-oxygen atom bound to carbon atoms both belonging to six-membered aromatic rings containing 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
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
    • C07C65/24—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic

Description

(54) CHLOROPHENOXYBENZENE DERIVATIVES (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:- This invention relates to new derivatives of chlorophenoxybenzene, to the preparation of these derivatives and to their application in therapy.
The new derivatives according to this invention are a) derivatives having the formula:
in which A is a single bond or an oxygen atom and X is COOH, CH2COOH, CH(CH3)COOH, C(CH,)2COOH, CH2OH, CH2CH20H, CH(CH,)CH2OH, C(CH3)2CH2OH, CH2NHCH2CH2OH, CH2CH2NHCH2CH2OH, CH(CH.a) CH2NHCH2CH.2OH or C(CH3)2CH2NHCH2CH2OH; and b) salts of the derivatives of formula I.
The term "salts" is used here to mean salts derived from an acid of formula I (e.g. in which X is COOH), e.g. by reaction with a base, and acid addition salts of compounds of formula I in which X contains a basic moiety with a mineral or organic acid, e.g. formed by reaction of the free base with such an acid.
The derivatives of formula I and their salts are hypolipidaemiant agents, hypocholesterolaemiants and anti-aggregants or anti-coagu- lants for blood platelets. They are particularly useful in therapy in the treatment and prevention of cardiovascular disorders.
According to the invention, a therapeutic composition contains, in association with a physiologically acceptable excipient, a compound of formula I or a non-toxic salt thereof.
The compounds of formula I may be prepared by applying conventional reaction mechanisms. A convenient starting material for the compounds of formula I in which A is an oxygen atom is o-(p-chlorophenoxy)phenol which may be prepared by hydrolysis of o-(p-chlorophenoxy)anisole which itself may be prepared from p-chlorophenol and obromoanisole by conventiontl procedures. By way of example, compounds of formula I in which A is an oxygen atom may be formed by reacting o-(p-chlorophenoxy)phenol with a halide of the formula XHal in which the halogen may be, for example, chlorine.
When it is desired that A should be a valence bond, then the compound of formula I in which X is COOH may be prepared by reacting together p-chlorophenol o-chlorobenzoic acid, potassium carbonate, copper iodide and copper, followed by acidification.
Modification of the carboxylic acid group to the other X groups may then be carried out by conventional means.
One preferred group of compounds of the invention comprises those compounds of formula I in which A is an oxygen atom and X is CH2COOH, C(CH3)2COOH or C(CHJ),CH,OH.
Another preferred group is that in which A is a valence bond and X is COOH or CH2OH.
The following Examples illustrate how the compounds of formula I may be prepared.
Melting points are determined using Köfler apparatus.
Example 1. o- (p-Chlorophenoxy) phenoxyacetic acid (Code No. = CRL 40 444). a) o-(p-Chlorophenoxy) anisole.
A mixture of 57 g (0.443 mol) of p-chlorophenol and of 24.8 g (0.443 mol) of potassium in pellet form is heated to 1500C under 10 mm Hg pressure for 1 hour and then cooled. 100 g (0.534 mol) of o-bromoanisole and 1 g of copper in powder form are added to the mass which is obtained, and then heating is carried out for 5 hours at 220-2300C. The reaction medium is taken up in diethyl ether, the insolubles are removed by filtration and the filtrate obtained is washed with water.
After drying on anhydrous sodium sulphate, carbon black treatment and evaporation of the solvent from the organic phase, 111.3 g of a brown oil is obtained (b.p. 153-1550C (4 mm Hg), yield 56.5%). b) o-(p-Chlorophenoxy)phenol.
A suspension of 57 g (0.242 mol) of the preceding product and of 220 ml of 47% hydrogen bromide in 525 ml of acetic acid are heated at reflux for 2 hours. The reaction medium is brought to dryness under reduced pressure and the residue is dissolved in diethyl ether which is washed with water. After drying on dry sodium sulphate and evaporation of the solvent from the organic phase, 57 g of a pale yellow oil is obtained, which crystallises.
This product is purified by crystallisation in cyclohexane to give 41 g of a white powder (m.p. 82 C, yield 76.7%). c) CRL 40 444.
Into a suspension of 37 g (0.168 mol) of the above product and 15.6 g (0.165 mol) of chloroacetic acid in 125 ml of water, there is poured in 30 minutes a solution of 14 g (0.350 mol) cf soda in pellet form in 50 ml of water, then reflux heating is carried out for 4 hours. The thus obtained solution is acidified to Congo red and the insoluble is extracted by ethyl acetate. The organic phase in its turn is extracted by a solution of potassium bicarbonate. After acidification of this aqueous phase by concentrated hydrochloric acid, 35.5 g of an orange oil is isolated by extraction with ethyl acetate, and this product crystallises.
This product s purified by crystallisation in cyclohexane, to give 28.7 g of a light beige powder, insoluble in water (m.p. 1200C, total yield w.r.t. p-chlorophenol 26.5%).
Example 2.
2- [o-(p-Chlorophenoxy)phenoxy] -2- methylpropionic acid.
(Formula I: A=O, X=C(CH3)2COOH) Code No. CRL 40474.
A suspension of 50 g of o-p-chlorophenoxy)phenol (0.226 mol) and 54.3 g (1.358 mol) of soda in pellet form in 345 ml (4,700 mols) of acetone is heated to reflux. Heating is then stopped, and 23.8 ml (0.294 mol) of chloroform are poured in over 40 minutes and reflux heating is continued for a further 5 hours.
The reaction medium is brought to dryness under reduced pressure and the residue is taken up with water. Acidification is carried out to Congo red with concentrated hydrochloric acid and the insoluble is extracted by diethyl ether. The organic phase in its turn is extracted by a solution of potassium bicarbonate which, after acidification, liberates 65 g of an orange red oil which crystallises. The thus obtained product is purified by washing in ligroin, then by crystallisation and carbon black treatment in cyclohexane, to give 43 g of a yellow powder, insoluble in water (m.p.
84 C, yield 62.3%).
Example 3.
2- [o- (p--Chlorophenoxy) phenol -2 methyl-1-propanol.
(Formula I: A=O, X=C(CH,)2CH2OH) Code No. CRL 40479.
Into a refluxing suspension of 3 g (0.0792 mol) of lithium aluminium hydride in 30 ml of diethyl ether, a solution of 10.8 g (0.0352 mol) of 2 [o - (p - chlorophenoxy)phenoxyJ- 2 - methyl - propionic acid (CRL 40474) in 60 ml of diethyl ether is poured over one hour.
Reflux is continued for 90 minutes, the excess hydride is neutralised with ethyl acetate and the complex is decomposed by dilute hydrochloric acid. The organic phase is decanted and washed with water and then with 1N soda.
The solution is dried over anhydrous sodium sulphate and the solvent is evaporated under reduced pressure to give 10.3 g of an orange oil, insoluble in water (yield 100%).
Example 4. o- (p-Chlorophenoxy)benzoic acid.
(Formula 1: A=bond, X=COOH) Code No. CRL 40485.
A suspension of 28 g (0.22 mol) of pchlorophenol, 31.3 g (0.20 mol) of o-chlorobenzoic acid, 35 g (0.25 mol) of anhydrous potassium carbonate, 0.2 g of copper iodide and 0.2 g of copper in powder form in 200 ml of nitrobenzene is heated for 6 hours to 155-160 C. The solvent is removed by steam entrainment, the residue is taken up with water and acidification to Congo red is carried out with concentrated hydrochloric acid. The precipitate is extracted with diethyl ether and the resultant organic phase is extracted with a solution of potassium bicarbonate; the extract liberates, after acidification, 34.4 g of a crystallised beige mass. The product is purified by two successive crystallisations in cyclohexane and one crystallisation in ligroin-isopropanol (6:1 v/v) to give 22 g of a white powder, insoluble in water.
M.p. = 117"C inst Yield = 45% Example 5. o-(p-Chlorophenoxy)benzyl alcohol.
(Formula I; A=bond, X=CH2OH) Code No. 40486. a) Methyl o-(p-Chlorophenoxy) benzoate.
A solution of 19 g (0.0765 mol) of o-(pchlorophenoxy)benzoic acid (CRL 40485), 9.3 ml (0.23 mol) of methanol and 0.25 ml of concentrated sulphuric acid in 25 ml of 1,2dichloroethane is heated at reflux for 15 hours.
The reaction medium is washed with water and the organic phase is dried over anhydrous sodium sulphate. After evaporation of the solvent under reduced pressure, 20 g of a clear yellow oil is obtained (yield ~ 100%). b) CRL 40486.
Into a suspension of 4.4 g (0.1150 mol) of LiAIH4 in 50 ml of diethyl ether, a solution of 20 g (0.0765 mol) of the above product is poured over 90 minutes, and heating at reflux is continued for 2 hours. The excess hydride is neutralised by ethyl acetate and the complex is decomposed at about 100C by dilute hydrochloric acid. The organic phase is decanted, washed with water and then with dilute soda, dried on anhydrous sodium sulphate and brought to dryness, to give 18 g of a clear yellow oil (yield 100%).
The results of tests undertaken with CRL 40444 are summarised below.
1) Toxicity.
In a male rat, the LD-50 per os of CRL 40444 is 775 mg/kg.
2) Gastric Tolerance.
In rats, CRL 40444 was administered orally for five days at a dose of 300 mg/kg/d, at a concentration of 1 ml/100 g. The animals were autopsied on the fifth day and the digestive tract examined. Two animals out of six died after three and four administrations.
They exhibited haematuria from the first administration for one animal and after the third for the other.
Death occurred during the night, and no autopsy was carried out. All the animals lost weight after the second administration. The four surviving animals exhibited gastric ulcerations, the attack being weak in two of them while, in the other two, ulceration in the non-glandular pre-stomach area was considerable. At a dose less than 300 mg/kg/d, no gastric intolerance was observed.
3) Intestinal Tolerance.
In rats( an intestinal loop of approximately 5 cm was ligatured at both ends. CRL 40444 was injected through the wall at a dose of 10 or 20 mg/kg. The intestinal loops were examined after 1, 2 and 3 hours. No particular modification could be observed.
4) Cardiovascular Properties.
The anti-aggregant properties for blood platelets were studied in rats with respect to two aggregant agents, collagen (diluted to 1/10) and ADP (1 ism), over 4 days. The hypocholesterolaemiant and hypolipidaemiant properties were also studied in normal rats by comparison with controls, by measuring the percentage of variation of the rate of cholesterol and total lipids in the blood. The results are summarised in the following Table.
VARIATION OF AGGREGATION VARIATION Collagen ADP CRL 40 444 Cholesterol Total Lipids Dose % of inhibition %of inhibition (%) (%) (mg/kg) Reaction Time Velocity (on transmission) (on transmission) 25 + 25 - 83 - 71 - 40 5 6 50 + 25 - 83 - 66 - 66 12 11 100 + 12.5 - 83 - 64 - 97 7 3 In this series of experments, CRL 40444 exhibits very good anti-aggregant activity with collagen and ADP. Even at 25 mg/kg, this product exhibits considerable activity.
A second series of experiments which was undertaken, at progressively higher doses, can be summarised as follwos: at 10 mg/kg, CRL 40444 exhibits weak anti-aggregant and normolipaemiant properties; at 25 mg/kg, the activuity percentages relating to aggregation have increased, while those relating to lipids remain stable; at 50 mg/kg, the activity on aggregation is still higher; at 100 mg/kg, there is strong anti-aggregant activity and very weak lipid activity.
CRL 40444 is therefore a good antiaggregant agent.
In addition, it has been observed that CRL 40474 and CRL 40485 (products of Examples 2 and 4) possess anti-aggregant, hypolipidasmiant and hypochloesterolaemiant properties.
CRL 40474 exhibits, at a dose of 100 mg/kg, an anti-aggregant activity principally on ADP and the velocity (one of the parameters of the study of the aggregation induced by coolagen).
However, CRL 40474 has normolipidaemiant activity; it reduces the cholesterol rate by 29% and the total lipids rate in the blood by 22%.
CRL 40485, at a dose of 100 mg/kg, exhibits an anti-aggregant activity with respect of the platelet aggregation induced by ADP.
In addition, CRL 40485 decreases he cholesterol rate by 25% and the total lipids rate in the blood by 22%.
In human clinical trials, good results were obtained in the treatment of hypolopidaemia by the daily oral administration of 3 capsules each containing 75 mg of CRL 40474.

Claims (10)

  1. WHAT WE CLAIM IS:1. Acompound of the formula
    in which A is a single bond or an oxygen atom and X is COOH) CH2COOH, CH(CH3 ) COOH, C(CH3)2COOH, CH2OH, CH2CH2OH, CH(CH,)CH2OH, C(CH3)2CH2OH, CH2NHCH2CH2OH, CH,CH2NHCH2CH2OH, CH(CH3)CH2NHCH2CH2OH or C(CH3)2NHCH2CH2OH; or a salt thereof.
  2. 2. A compound as claimed in claim 1 in which A is an oxygen atom and X is CH2COOH, C(CH3)2COOH or (CH3) 2CH2OH.
  3. 3. A compound as claimed in claim 1 in which A is a valence bond and X is COOH or CH2OH.
  4. 4. o-(p-Chlorophenoxy)phenoxyacetic acid or a salt thereof.
  5. 5. 2 - [o - (p - Chlorophenoxy)phenoxy]2 - methoxypropionic acid or a salt thereof.
  6. 6. 2 - [o - (p - Chlorophenoxy) phenoxy]2 - methyl - 1 - propanol.
  7. 7. o - (p - Chlorophenoxy)benzoic acid or a salt thereof.
  8. 8. o - (p - Chlorophenoxy)benzyl alcohol.
  9. 9. A compound as claimed in claim 1 substantially as described in any of the Examples.
  10. 10. A pharmaceutical composition comprising a compound as claimed in any preceding claim, or a non-toxic salt thereof, in association with a phvsiologically acceptable excipient.
GB1590777A 1977-04-16 1977-04-16 Chlorophenoxybenzene derivatives Expired GB1579839A (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
GB1590777A GB1579839A (en) 1977-04-16 1977-04-16 Chlorophenoxybenzene derivatives
FR7809931A FR2396738A1 (en) 1977-04-16 1978-04-04 NEW CHLOROPHENOXY-BENZENE DERIVATIVES USEFUL PARTICULARLY IN THERAPEUTICS
BE2056875A BE865975A (en) 1977-04-16 1978-04-14 NEW CHLOROPHENOXY-BENZENE DERIVATIVES USEFUL PARTICULARLY IN THERAPEUTICS
FR7903500A FR2422615A1 (en) 1977-04-16 1979-02-12 NEW CHLOROPHENOXY-BENZENE DERIVATIVES USEFUL PARTICULARLY IN THERAPEUTICS

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB1590777A GB1579839A (en) 1977-04-16 1977-04-16 Chlorophenoxybenzene derivatives

Publications (1)

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GB1579839A true GB1579839A (en) 1980-11-26

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FR (2) FR2396738A1 (en)
GB (1) GB1579839A (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0068222A1 (en) * 1981-06-18 1983-01-05 Technobiotic Ltd. Process for the preparation of 2-(2,4-dichlorophenoxy)phenylacetic acid
EP0128648A1 (en) * 1983-04-25 1984-12-19 Sumitomo Chemical Company, Limited Nitrogen-containing heterocyclic compounds, and their production and use
AP28A (en) * 1985-09-23 1988-12-20 Ici Plc Insecticidal alkenes.

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0068222A1 (en) * 1981-06-18 1983-01-05 Technobiotic Ltd. Process for the preparation of 2-(2,4-dichlorophenoxy)phenylacetic acid
EP0128648A1 (en) * 1983-04-25 1984-12-19 Sumitomo Chemical Company, Limited Nitrogen-containing heterocyclic compounds, and their production and use
AP28A (en) * 1985-09-23 1988-12-20 Ici Plc Insecticidal alkenes.

Also Published As

Publication number Publication date
FR2396738B1 (en) 1984-05-04
FR2422615B1 (en) 1983-11-04
FR2396738A1 (en) 1979-02-02
FR2422615A1 (en) 1979-11-09
BE865975A (en) 1978-10-16

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PS Patent sealed
746 Register noted 'licences of right' (sect. 46/1977)
PCNP Patent ceased through non-payment of renewal fee