FI68609C - FRAMEWORK FOR THERAPEUTIC ACTIVATION OF THERAPEUTIC ACTIVATION - Google Patents

Description

ΓΒΊ ηη ANNOUNCEMENT / Cl ίΓ) Q

B '' UTLÄGG NINGSSKRIFT OOO U..7 • C (45) rat-3r.lli ayonnotty 10 10 1935 ^ eddolat (51.) Kv.lk. * / Lnt.CI.4 C 07 C 49/82, ^ 9 / 76 (21) Patent application - Patentansökning 760999 (22) Filing date - Ansöknlngsdag 13 * 04.76 (Fl) (23) Starting date - Giltighetsdag 13 * 04.76 (41) Becoming external - Blivit offentllg 1 8.1 0.76

National Board of Patents and Registration (44) Date of publication and hearing. - 28.06.85

Patent and registration authorities in the United States of America (32) (33) (31) Privilege claimed — Begärd priority 17 * 04.75 England-England (GB) 15805/75 (71) Lilly Industries Limited, Henrietta House, Henrietta Place, London W.1, England i-England (GB) (72) John Christopher Saunders, Maidenhead, Berkshire, William Robert Nigel Williamson, Slough, Buckinghamshire, England-England (GB) (74) Oy Kolster Ab (54) Method The present invention relates to a process for the preparation of new benzophenone derivatives. The present invention relates to a process for the preparation of new benzophenone derivatives. The compounds according to the invention are therapeutically useful and are particularly suitable for the treatment of allergic conditions.

There is a wealth of literature on benzophenones, their preparation and their use. However, it has not previously been considered that o-hydroxybenzophenones and their derivatives can be used to treat allergic conditions.

The present invention relates to a process for the preparation of new therapeutically active benzophenone derivatives of the general formula 2 68609 R1 2 ^ - \ / - ^ (X'n '-fl- <σΓ / \ O (I)

RJ OH

12 3 wherein R, R and R represent hydrogen or ethyl, at least one of which is ethyl, (X) n represents 1 or 2 substituents, namely chlorine, fluorine or methyl, provided that 13 2 (i) when R and R are hydrogen and R is ethyl, then (X) n does not mean chlorine or fluorine alone; and 1 2 3 (ii) when R is ethyl and R and R are hydrogen, then (X) n is not 4-chloro, 2,4- or 3,4-dichloro, 2- or 3-chloro, 4-fluoro or 3-methyl.

FI patent publication 48 462 discloses benzophenoximes close to the compounds of the formula I, which, however, are not reported to have medicinal use. Compounds closely resembling compounds of formula I are also disclosed in SE patent publication 424 325. They are also not reported to have medicinal use.

The process according to the invention is characterized in that the compound of the general formula

R3 OH

12 3 wherein R, R and R are as defined above are reacted under Friedel-Crafts acylation conditions with a carboxylic acid of the general formula ° -? - <cr ”« «o wherein (X) n is as defined above and Q is OH or halogen.

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When Q in the compound of formula (III) is halogen, the reaction may be carried out using a Lewis acid such as e.g. aluminum halide (e.g. chloride) as a catalyst in a suitable inert solvent such as 1,1,2,2-tetrachloroethane or carbon disulphide.

When Q is hydroxyl, boron trifluoride or (CF 2 CO 2 O) are the preferred catalysts, and the reaction is carried out in a suitable solvent or without a solvent.

The amount of undesired isomer or undesired isomers can be reduced by selecting appropriate reaction conditions in which temperature control is particularly important. A suitable reaction temperature is between 20 ° C and the boiling point, and preferably between 80 ° C and the boiling point.

As indicated above, the preparation of acyl derivatives of o-hydroxy groups can be carried out by various methods, for example by treatment with o-hydroxybenzophenone or an acid anhydride or halogen (mainly chloride) in an alkaline solution (e.g. pyridine or aqueous alkali metal hydroxide such as sodium or potassium hydroxide) and in the presence of a catalyst (e.g. 70% perchloric acid) or by refluxing with an acylating acid of o-hydroxybenzophenone.

The o-hydroxybenzophenones of this invention and their derivatives have been shown to be active in one or more of the four assays commonly used to detect antiallergic activity. Two of these experiments are in vivo experiments - guinea pig and human lung section experiments - and involve the direct determination of mediators, histamine and anaphylaxis slow-acting substance (SRS-A), which have been shown to be released in the lung of asthmatic humans. A compound of this invention is considered active if the release of SRS-A can be inhibited in a guinea pig lung section test at a dose of at least 30% at a dose of 10 μg / ml or less. Depending on the absorption, distribution and metabolism of the drug used in the experiments, this level of activity in the lung section experiment means that the in vivo oral dose is about 0.5 to 100 mg / kg.

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The other two trials are in vivo trials - the Herxheimer trial and the rat peritoneal anaphylaxis trial - and are reflected in two different modes of action when administered orally. Guinea pigs exposed in the Herxheimer test are protected by antigen aerosol induction of bronchial decoration, whereas instead of directly measured SRS-A in the peritoneal anaphylaxis test in rats. When testing active compounds in these in vivo experiments, the effect was usually achieved at doses of 300 mg / kg or less.

The compounds of this invention show activity in one or more of the above experiments (the broadest spectrum of activity is in compounds with anti-allergic activity in all four experiments) and are therefore useful in the prophylactic and therapeutic treatment of acute hypersensitivity diseases, including asthma, and in relieving status asthmaticus. In some cases, the compounds have been found to be useful in diseases in which excess prostaglandins are released and as a respiratory stimulant. The toxicity of the compounds is low.

The invention is further illustrated by the following examples:

Example 1 2- [4-Dichloro-3-ethyl-2-hydroxybenzophenone

Aluminum chloride (26.7 g) was added portionwise to a stirred mixture of 2-ethylphenol (12.2 g) and 2,4-dichlorobenzoyl chloride (23.1 g) in 1,1,2,2--tetrachloroethane (100 ml). ), and then the mixture was heated to reflux for 21 hours. The cooled solution was poured into ice-cold concentrated hydrochloric acid (100 ml) (200 g). The organic fraction was separated and combined with the other two portions of chloroform obtained by washing the aqueous fraction, then the organic solution was washed twice with 10% aqueous sodium carbonate solution, dried over magnesium sulphate monohydrate and evaporated to a dark viscous oil (30.0 g). This oil was distilled in vacuo, the first fraction (156-172 ° C / 0.06 mmHg) containing 85% of the desired product. (Treatment with the ferric chloride solution gave a purple solution, indicating the presence of o-hydroxyketone). The ketone product was purified by chromatography on a silica column, n22 = 1.6163.

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Example 2

A method analogous to the process of the invention: 4-chlorobenzoyl chloride (1.35 g, 0.0077 mol) was added dropwise to a solution of 4-ethylphenol (0.86 g, 0.0070 mol) in aqueous 2.5 N sodium hydroxide solution (5, 6 ml). The mixture was shaken vigorously for 15 minutes to give a light brown solid. The mixture was diluted with water (10 mL) and the solid was filtered off, washed with water (3 x 20 mL) and dried. The solid was recrystallized twice from n-hexane to give light brown 4-ethylphenyl-4-chlorobenzoate crystals, m.p. 66.5 to 67 ° C.

The above ester (2.6 g) was heated with aluminum chloride (1.33 g) in tetrachloroethane for 6 hours at 125 ° C. After this time, the sample was added to dilute hydrochloric acid, and the organic matter was extracted with chloroform. Gas chromatographic analysis showed no ester in the solution, and by comparison with an authentic sample, the product was found to be 41-chloro-5-ethyl-2-hydroxybenzophenone.

By this method, the following were also prepared: 5-ethyl-2-hydroxy-4'-methylbenzophenone, m.p. 49-51 ° C and 4'-chloro-3,5-diethyl-2-hydroxybenzophenone, b.p. 188 ° C / 1.4 mmHg.

Claims (1)

A process for the preparation of novel therapeutically active benzophenone derivatives of the general formula R 1, W and R 3 OH 12 3 wherein R, R and R are hydrogen or ethyl, at least one of which is ethyl, (X) n represents 1 or 2 substituents, namely chlorine, fluorine or methyl, provided that 13 2 (i) when R and R are hydrogen and R is ethyl, then 00 n does not mean chlorine or fluorine alone; and 1 2 3 (ii) when R is ethyl and R and R are hydrogen, then (X) is not 4-chloro, 2,4- or 3,4-dichloro, 2- or 3-chloro, 4-fluoro or 3-methyl, characterized in that a compound of the general formula H 2 - (O) 3 / \ R OH 12 3 in which R, R and R have the same meaning as above is reacted under Friedel-Crafts acylation conditions with a carboxylic acid of the general formula is r— <X'n Q jj '\ py 0 v— (III) wherein (X) n is as defined above and Q is OH or halogen.