NO146022B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY EFFECTIVE BENZOFENO DERIVATIVES - Google Patents

Description

The present invention relates to the production of

new therapeutically active benzophenone derivatives with the general formula:

12 3

where R , R and R are hydrogen or ethyl, with at least one being ethyl, (X)n is from 1 to 3 of the substituents chlorine, fluorine,

methyl, or an arbitrarily chosen combination of these, Z is hydrogen or COR 5 , where R 5 is C^_^ alkyl or phenyl, for-

exposed that when R is ethyl, R<2> and R^ are hydrogen and Z has the above meaning, (X)n is not 2,4- or 3,4-

dichloro, 2- or 3-chloro, 4-fluoro or 3-methyl.

The production and use of benzophenones is discussed in the literature. However, it has not yet been mentioned that o-hydroxybenzophenones and derivatives thereof can be used in the treatment of allergic conditions.

The compounds of formula I can be used for treat-

treatment of mammals suffering from allergic conditions and especially for the treatment of immediate hypersensitive patients

judgments such as asthma in animals including humans.

The compounds of formula I are prepared according to the invention by a compound of the general formula:

12 3

where R , R and R have the meaning given above, and Y

is hydrogen or methyl, is reacted with a compound of the general formula:

where CX^") is from 1 to 3 of the substituents chlorine, fluorine, methyl, or an arbitrarily selected combination thereof, and Q is OH or a halogen atom, under Friedel-Crafts acylating conditions, the product being hydrolyzed if necessary to obtain a benzophenone of formula I where Z is hydrogen,

after which a compound of formula I where Z is hydrogen is optionally acylated to obtain a compound of formula (I) where Z is COR 5 and R 5 has the meaning indicated above.

The preferred compound produced according to the invention is 4'-chloro-5-ethyl-2-hydroxybenzophenone by reaction of 4-ethylphenol with 4-chloro-benzoyl chloride.

An example of a Friedel-Crafts' acylation as discussed above is the reaction between a compound with the formula ArCOX and a compound with the formula:

where Z"*" means hydrogen or a protecting group such as methyl.

The reaction can be reproduced with the following reaction scheme:

wherein X means a halogen atom or hydroxyl.

When X is halogen, the reaction can be carried out by using a Lewis acid such as an aluminum halide (e.g. the chloride) as a catalyst in a suitable inert solvent such as 1,1,2,2-tetrachloroethane or carbon disulphide.

When X is hydroxyl, boron trifluoride or (CF 3 CO) 2 O are preferred catalysts used with or without a suitable solvent.

If Z is a protecting group it can be removed in situ or later it should be desirable to form a compound of formula I in which Z^" is hydrogen.

Removal of the unwanted isomer or isomers can be achieved by suitable choice of reaction conditions, the temperature control being particularly important. Preferably, the reaction temperature is from 20°C to reflux temperature and preferably from 80°C up to reflux temperature.

The preparation of the acyl derivatives of the o-hydroxy group can be carried out by various methods, for example by treating the o-hydroxybenzophenone in a basic solution (e.g. pyridine or an aqueous solution of a group IA hydroxide such as sodium or potassium hydroxide) with an acid hydride or halide (preferably chloride) or with a solution of the acylating acid in the presence of the acid anhydride with a trace of catalyst (eg perchloric acid - 70%), or by refluxing o-hydroxybenzophenone with the acylating acid.

o-hydroxybenzophenones and derivatives thereof have shown

to exercise activity in one or more of the four tests used to demonstrate anti-allergic activity. Two of the aforementioned tests are in vitro tests - guinea pig and human chopped lung samples - involving the direct measurement of mediators, histamine and slow-reacting substances in anaphylaxis (SRS-A), shown to be released by asthmatic human lung. For compounds of the type produced according to the invention, a compound is considered to be active if at least 30% inhibition of SRA-A release is achieved in guinea pig minced lung sample at a dose of 10 µg/ml or less. Depending on the absorption, distribution and metabolism of the drug during the test, the activity in the chopped lung sample at this level indicates in vivo doses ranging from 0.5 to 100 mg/kg orally.

The other two tests are in vivo tests - Herxheimer and rat peritoneal anaphylaxis - and reflect oral activity in two different species. In the Herxheimer test, sensitive guinea pigs are protected against bronchospasm induced by an aerosol of antigen, while in the rat peritoneal anaphylaxis test, SRS-A released by signal is measured directly. When an active compound is tested in these in vivo tests, activities are normally obtained at doses of 300 mg/kg or less.

The compound produced according to the invention exerts activity in one or more of the above-mentioned samples (compounds with a broad spectrum are those that exert anti-allergic activity in all four samples) and are therefore useful in the prophylactic and therapeutic treatment of immediate hyper-sensitive diseases including asthma and in the relief of status asthmaticus. In certain cases, the compounds have been found to be useful in diseases in which excess amount of prostaglandin is released and as a respiratory stimulant. The compounds have low toxicity.

The compounds (I) or preparations containing them can be administered in different ways and can for this purpose be formulated in different forms. Thus, the compounds or preparations can be administered orally or rectally, topically, parenterally, e.g. by injection or by continuous or discontinuous intra-arterial infusion, in the form of, for example, tablets, dragees, sub-lingual tablets, inhalation cloths, capsules, elixirs, suspensions, aerosols, wraps, for example containing 1-10% by weight of the active compound in a suitable base, soft and hard gelatin capsules, suppositories, injection solutions and suspensions in physiologically tolerable media and sterile packaging powders adsorbed on a carrier material for the preparation of injection solutions. Advantageously for this purpose, the preparations can be provided

in dosage unit form, preferably each dose containing 5-

500 mg, (5.0-50 mg in the case of parenteral administration, 5.0-50 mg in the case of inhalation and 25-500 mg in the case of oral or rectal administration) of a compound of formula I.

As indicated by the samples referred to above, doses of 0.5-300 mg/kg/day may be administered, preferably

0.5-20 mg/kg of the active substance.

The following examples illustrate the invention.

Example 1

4'-chloro-5-ethyl-2-hydroxybenzophenone

Aluminum chloride (267 g) was added portionwise over 30 minutes to a stirred solution of 4-ethylphenol (122.1 g) and 4-chlorobenzoyl chloride (140 mL) in dry 1,1,2,2-tetrachloroethane (800 mL ). The mixture was heated at 105°C

for 22 hours while stirring and upon cooling, a mixture of ice (600 g) and concentrated hydrochloric acid was slowly added. A strong reaction occurred and some material was lost. The remaining material was separated, the aqueous fraction extracted twice with chloroform (200 mL) and the combined organic layers evaporated to a dark oil which was distilled in vacuo to give two major fractions: B (17.4 g) 15-160° C,

0.3 mmHg; C (110.8 g) 160-168°C, 0.3 mm Hg.

The desired compound indicated above was crystallized by cooling to -20°C and recrystallized from n-hexane at 0°C to give yellow solid crystals of melting point 35-38°C.

Microanalysis: C15H13C102 calcd 69.1% C, 5.0% H, 13.6% Cl;

found 69.0% C, 5.0% H, 13.9% Cl. Example 2

4- ethyl- 4'- fluoro- 2- hydroxybenzophenone

3-Ethylphenol (24.4 g) and 4-fluorobenzoyl chloride (34.9 g) were reacted as indicated in Example 1 to give three fractions: B (11.4 g) 126-129°C, 0.07 ram Hg; C (7.9 g), 129-132°C,

0.06 mmHg; D (5.9 g), 132-150°C, 0.06 mm Hg, all containing about 80% of the required isomer. B (4.0 g) was separated by preparative thin layer chromatography to give the title compound (2.6 g), mp 44-48°C.

Example 3

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 under reflux for 21 hours. On cooling, the solution was poured into concentrated hydrochloric acid (100 ml) and cooled with ice (200 g). The organic fraction was separated and combined with two additional chloroform washes of the common fraction and then these were washed twice with 10% aqueous sodium carbonate solution, dried over magnesium sulfate monohydrate and evaporated to a dark viscous oil (30.0 g). The oil was distilled in vacuo, first fraction (156-172°C at 0.06 mm Hg) containing 85% of the desired product. (With ferric chloride solution, a pink color was obtained indicating the presence of o-hydroxyketone). The ketone product was purified by chromatography on a silica column nD<22> 1.6163.

Example 4

4- ethyl~ 3'- fluoro- 2- hydroxybenzophenone

This compound was prepared from 3-ethylphenol (12.2 g), 3-fluorobenzoyl chloride (17.5 g) and aluminum chloride (26.7 g) in 1,1,2,2-tetrachloroethane (75 ml), using same conditions as in example 1, but heating during reflux, not at 105°C. The product was purified by chromatography on a silica column, melting point between 0 and 20°C.

n<22> 1.5962.

o

Example 5

4'-chloro-5-ethyl-2-hydroxybenzophenone

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 2.5 N aqueous sodium hydroxide (5.6 mL). The mixture was shaken vigorously for 15 minutes when a faint brown solid precipitated. The mixture was diluted with water (10 mL) and the solid filtered off, washed with water (3 x 20 mL) and dried. The solid was recrystallized twice from n-hexane to give slightly brown crystals of 4-ethylphenyl-4-chlorobenzoate, mp 66.5-67°C.

The above ester (2.6 g) was heated with aluminum chloride (1.33 g) in tetrachloroethane for 6 hours at 125°C. A sample taken at the end of this time was added to dilute hydrochloric acid and the organic material was extracted into chloroform. Gas chromatographic analysis of this solution showed no residual ester and comparison with an authentic sample showed that the product was 4<1->chloro-4-ethyl-2-hydroxybenzophenone, m.p. 35-38°C.

The following were prepared in a similar manner: 5-ethyl-2-hydroxy-4'-methylbenzophenone, melting point 49-51°C and 4<1->chloro-3,5-diethyl-2-hydroxybenzophenone, boiling point 188°C at 1 .4 mm Hg.

Example 6

2- benzoyloxy- 5- ethyl- 4'- chlorobenzophenone

2-Hydroxy-5-ethyl-4<1->chlorobenzophenone (5 g, 0.019 mol) was stirred vigorously in a solution of NaOH (7.5 g, 0.187 mol)

in water (75 ml) and benzoyl chloride was added dropwise over 5 minutes. The temperature rose to around 50°C. The mixture was stirred for 1.5 h at room temperature and was then extracted with ether, the ether washed with saturated NaCl solution, dried (Na^SO^), filtered and evaporated to give the product, which was recrystallized from n-hexane to give give white crystals of the desired product, mp 79-81°C.

Example 7

2- acetoxy- 4'- chloro- 5- ethylbenzophenone

2-hydroxy-5-ethyl-4'-chlorobenzophenone (3 g), in acetic anhydride (10 ml) and acetic acid (1 ml) was refluxed for 3.5 hours and cooled. The mixture was poured onto dilute NaOH solution and extracted with chloroform. The chloroform was washed with 10% NaHCO 3 solution (50 mL), dried (MgSO 4

and evaporated to give an oil which was distilled, bp 160-165°C at 3.5 mm Hg (2.3 g) to give the desired product.

Claims (2)

1. Analogous method for the preparation of therapeutically active benzophenone derivatives with the general formula: 12 3 where R , R and R are hydrogen or ethyl, with at least one being ethyl, (X)R is from 1 to 3 of the substituents chlorine, fluorine, methyl, or an arbitrarily chosen combination of these, Z is hydrogen R el1 leer r CeOtyRl^, , hR v2 oor g RR ^ 3 er er Ch,y_d. roaglken yl and ellZ ehr ar fendyen l, ovfoenrufotr saatnt gaitt tenår meaning, (X)n is not 2,4- or 3,4-dichloro, 2- or 3-chloro, 4-fluoro or 3-methyl, characterized in that a compound with the general formula: 12 3 where R , R and R have the meaning given above, and Y is hydrogen or methyl, is reacted with a compound of the general formula: where (X1) is from 1 to 3 of the substituents chlorine, fluorine, methyl, or an arbitrarily chosen combination thereof, and Q is OH or a halogen atom, under Friedel-Crafts acylating conditions, the product being hydrolyzed if necessary to obtain a benzophenone of formula (I) where Z is hydrogen, after which a compound of formula (I) where Z is hydrogen is optionally acylated to obtain a compound of formula (I) 5 5 where Z is COR and R has the above meaning. 2. Analogous process according to claim 1, for the production of 4'-chloro-5-ethyl-2-hydroxybenzophenone, characterized in that 4-ethylphenol is reacted with 4-chloro-benzoyl chloride.