DK141724B - Benzoxazole derivatives for use as intermediates in the preparation of therapeutically active benzoxazole derivatives. - Google Patents

Description

(11) PRESENTATION 141724

DENMARK (M> lntcl · 3 t ° b77 S

§ (21) Application No. 3 ^ 74/77 (22) Submitted on 3 · SUg · 1977 (23) unsubscribed on 17 May 1973 (44) The application presented and 1 oRf) the application document published on * - · JU * X * ' DIRECTORATE FOR # βΛ4 _ ^ ___ PATENT AND TRADEMARKET (30) Priontet requested from the

May 18, 1972, 25409/72, GB

(7i) LILLY INDUSTRIES LIMITED, Henrietta House, Henrietta Place, London ¥ .1., GB.

(72) Inventor: Delme Evans, "Pinfold", Hedgerow, Chaifont St. Peter, Buc = kinghamshire, GETT David William Dunwell, 27 Alexandra Avenue, Cam® berley, Surrey, GB: Terence AlanTIickB, 1 Rydal Close, Cove, Farne borough, Hampshire, GB.

(74) Clerk of the case:

Th. Ostenfeld Patentbureau A / s.

(64) Benzoxazole derivatives for use as intermediates in the preparation of therapeutically active benzoxazole derivatives.

The present invention relates to novel benzoxazole derivatives which have been found to be useful as intermediates in the preparation of certain novel benzoxazole derivatives having valuable pharmacological activity, and more particularly to novel benzoxazole derivatives for use as intermediates in the preparation of therapeutically active benzoxazole derivatives (the general form). Ice

JpO ~ "w m R4 wherein R1, R2 and R4 have the meaning set forth below and R

1 7 X

the group -CH2 OH or -C00H, wherein the group -CR R R is in the 5 or 6 position of the benzoxazole nucleus, which derivatives are peculiar to having the general formula (II):

U172 U

2 N-rf ^ i i 2 I - \ - CRVa (II)

Λο ^ / V

Wherein the -CR R A group is in the 5 or 6 position of the benzoxazole nucleus, R and R independently represent hydrogen or alkyl, R 4 represents cyclohexyl, furyl, thienyl, pyridyl or a phenyl group optionally substituted by one or two groups selected from halogen, alkoxy and alkyl or optionally substituted in two adjacent positions with methylenedioxy, and A represents a nitrile, carboxylic acid C 1-6 alkyl ester, carboxyamide, Ν, Ν diethylcarboxyamide or hydroxamic acid group.

The intermediates listed above can be converted by the analogous process to the corresponding pharmacologically active acids (R = -COOH · Danish Patent Application No. 2746/73) by alkaline or acidic hydrolysis, or when A represents a carboxylic acid C alkyl ester is further readily reduced, e.g. with diborane or complex metal hydride, 3 to the pharmacologically active alcohols (R = -Ci 2 OH).

According to the invention, the intermediates are particularly preferred where

The 12 1 -CR R A group is in the 5-position of the benzoxazole nucleus, and R

represents hydrogen, R 2 represents methyl, and R 2 represents p-chlorophenyl, since these intermediates can be converted to the particularly active corresponding acid disclosed in Danish Patent Application No. 2746/73.

Various arylacetic acid derivatives are known which, like the benzoxazole derivatives of formula (I), have anti-inflammatory activity. Eg. For example, Swedish disclosures 313,569, 349,809 and 367,203 disclose a number of oxazole acetic acid derivatives having said effect, but none of these derivatives has, to our knowledge, led to commercial products. Among the anti-inflammatory active arylacetic acid derivatives, "Indomethacin" is the most widely used heretofore, and the novel benzoxazole derivatives prepared from the subject intermediates are distinguished in this respect by substantially less toxicity, as is apparent from the later cited trial report.

The present intermediates of formula (II) can be prepared in the manner described in the description of the original Danish patent application No. 2746/73, e.g. by cyclizing a compound of formula (III): y%! 2 4-crarza (iii) in 2 wherein R, R and A are as defined above and X is either hydrogen or the group R4CO- and Y represents H2N- or X represents hydrogen and Y represents the group R4CO-NH- or R4CHeN-, in which formulas R4 has the previously defined meaning, the ring formation in the case where X represents hydrogen and Y H2N- is carried out in the presence of an ring-forming agent capable of delivering the 4 necessary group R.

The ring formation of a compound of formula (III) wherein X represents hydrogen and Y is R 4 CO-NH- or wherein X represents R 4 CO- and Y H 2 N may be carried out under the influence of heat and / or acidic conditions, e.g. in the presence of hydrochloric or polyphosphoric acid.

In the case where X represents hydrogen and Y R 4 CH = N-, ring formation is easily achieved by treatment with an oxidizing agent such as lead tetraacetate or nickel peroxide.

When a compound of formula (III) is used, wherein X represents hydrogen and Y H 2 N-, ring formation is usually achieved by mixing the ring-sealing agent with the compound of formula (III) usually in a suitable solvent, which may be water or an organic solvent. such as pyridine, at or below room temperature and then heated to complete the reaction. Suitable ring-forming agents which can be used are compounds of the formula R4C00H, (R4C0) 20, R4C0C1, R4CONH2, R4CONHNH2, R4CN, R4C (OR ') = NH and R4CC1' NR \ where R * represents C1-4 alkyl.

A particularly useful intermediate is the nitrile, which can be prepared in good yield and easily converted to the corresponding acid. The nitrile or amide intermediates of the invention can be hydrolyzed with strong base or an acid, such as concentrated hydrochloric acid, to the corresponding acid (R 3 = COOH).

An ester intermediate of the invention may be hydrolyzed to the corresponding acid or alcohol of formula (I) by treatment with a suitable hydrolyzing agent such as an inorganic base or acid.

The compounds of the above formula C1) are useful in that they are pharmacologically active. In particular, these compounds have been found to have low toxicity and to possess analgesic, antipyretic and / or anti-inflammatory activity.

The above biological effects have been demonstrated by tests performed on animals normally at doses of 0.1 to 250 mg / kg. For human treatment, the dose administered may e.g. may be between 0.1 and 25 mg / kg, but of course doses outside this range may be used at the discretion of the treating physician.

The present invention is further illustrated in the following by Examples, Examples 1-12 illustrating the preparation of the subject intermediates, and Examples 13-20 illustrating the use of the intermediates for the preparation of the novel valuable end products.

Example 1 2-C2-phenyl-5-benzoxazolyl) propionitrile (a) 2- (4-hydroxyphenyl) propionitrile

Finely ground 2- (4-aminophenyl) propionitrile (73 g, 0.5 mole) was suspended in concentrated hydrochloric acid (125 ml). With stirring, the suspension was diazotized at 0-5 ° C by dropwise addition of a sodium nitrite solution (36.23 g, 0.525 mol) in 60 ml of water over 1-2 hours. The nearly clear solution was stirred for a further 20 minutes at 5-10 ° C, then poured with stirring into a boiling solution of concentrated sulfuric acid (250 ml) in water (2.5 liters). After 6 minutes, it was cooled in an ice bath and then extracted with ether (4 times). The combined ether extracts were extracted with 2N sodium hydroxide solution (6x). The combined alkaline extracts were cooled in an ice bath, acidified with concentrated hydrochloric acid and extracted with ether (3 times). The combined ether extracts were washed with saturated sodium chloride solution (3x), dried (sodium sulfate) and evaporated to leave a dark brown oil (66.7g) which provided by distillation 2- (4-hydroxyphenyl) propionitrile (59, 58 g), boiling point 112-122 ° C / 0.125 mm, melting point 41-46 ° C.

Analysis: Calculated C: 73.44, H: 6.16, N: 9.51 Found: C: 73.19, H: 5.91, N: 9.31.

(B) 2- (3-Nitro-5-hydroxyphenyl) propionitrile

A solution of 2- (4-hydroxyphenyl) propionitrile (7.79 g, 0.053 mol) in glacial acetic acid (10 ml) was added at 7-10 ° C with stirring to 12N nitric acid (8 ml) over 45 minutes. An additional volume (10 ral) of glacial acetic acid was added during this time. The resulting yellow suspension was stirred for a further 30 minutes at 7-10 ° C and then for 30 minutes at -10 ° C to -15 ° C. The suspension was diluted with water (ca.

90 ml). Filtration provided 2- (3-nitro-4-hydroxyphenyl) propionitrile as a yellow solid (8.43 g), mp 78-81 ° C.

Analysis: Calculated: C: 56.24, H: 4.19, N: 14.57 Found: C: 56.29, H: 4.24, N: 14.47.

(c) (i) 2- (3-Amino-4-hydroxyphenyl) propionitrile 2- (3-nitro-4-hydroxyphenyl) propionitrile (123.8 g, 0.64 mol) was suspended in absolute ethanol (950 ml ) and added over 20 minutes with cooling to a solution of stannous chloride dihydrate (437 µg, 1.94 mole) in concentrated hydrochloric acid (591 mL, 7 mole). The addition was carried out at such a rate that the temperature of the reaction mixture did not exceed 20 ° C. Stirring of the mixture was continued for another 19 hours at room temperature. The resulting solution was added with ice (1.75 kg) over 1 hour to a cooled solution of sodium hydroxide (650 g) in water (600 ml). The temperature of the reaction mixture was maintained at 15-20 ° C during the addition. The mixture was stirred for an additional 1 hour and the pH was then adjusted to 6 by the addition of concentrated hydrochloric acid. The resulting suspension was filtered and the filtrate was saturated with sodium chloride, then extracted with ether (6 times). The combined ether extracts were dried (sodium sulfate) and evaporated to leave a solid (69.15 g) which was suspended in chloroform and extracted with 2N hydrochloric acid (6 times). The combined acidic extracts were neutralized to pH 7-8 by the addition of sodium hydrogen carbonate. The resulting suspension was extracted with ether (4 times).

The combined ether extracts were washed twice with water, dried (sodium sulfate) and evaporated to give 2- (3-amino-4-hydroxy-phenyl) -propionitrile) as a light brown solid (62.85 g), mp 110-112 ° C.

Analysis: Calculated: C: 66.64, H: 6.21, N: 17.27 Found: C: 66.45, H: 6.09, N: 16.99.

(C) (ii) 2- (5-Amino-4-hydroxyphenyl) propionitrile was also prepared by the following procedure: 2- (3-nitro-4-hydroxyphenyl) propionitrile (38.4 g, 0.2 mol) was suspended in absolute ethanol (250 ml) and hydrogenated at 4 atmospheric pressure and room temperature over carbon prepared with 10¾ palladium. Hydrogenation was completed in 3.8 hours. The catalyst was removed by filtration. Evaporation of the filtrate provided 2- (3-amino-4-hydroxyphenyl) propionitrile (17 g), m.p. 110 ° C.

(d) 2- (3-Benzamido-4-hydroxyphenyl) propionitrile Benzoyl chloride (27.09 g, 0.19 mol) was added under cooling and stirring over 20 minutes to a solution of 2- (3-amino-4). -hydroxy-phenyl) -propionitrile (28.35 g, 0.175 mol) in dry pyridine (200 ml) at 0-3 ° C. After the addition was complete, the mixture was heated at 100 ° C for 1 hour. Then it was evaporated under reduced pressure to give crude 2- (3-benzamido-4-hydroxyphenyl) propionitrile as an oil.

(e) 2-C2-phenyl-5-benzoxazolyl) -propionitrile

The oil from (d) above was boiled for 30 minutes, during which time the temperature of the steam and oil rose to 130 ° C. Upon cooling, the residue stiffened. The solid recrystallization from methanol provided 2- (2-phenyl-5-benzoxazolyl) propionitrile (27.65 g), mp 118-120 ° C.

Analysis: Calculated: C: 77.39, H: 4.87, N: 11.28

Found: C: 77.33, H: 5.11, N: 11.34.

Example 2

In a process similar to that of Example 1, the following compound was prepared · 2- (2-p-chlorophenyl-5-benzoxazolyl) propionitrile, mp 150-153 ° C.

Analysis: Calculated: C: 67.96, H: 3.92, N: 9.90

Found: C: 67.57, H: 3.96, N: 9.25.

7 U1724

Example 3

Ethyl 2- (2-phenyl-5-benzoxazolyl) propionate 2- (2-phenyl-5-benzoxazolyl) propionic acid (10 g, 0.037 mol) and p - toluenesulfonic acid (0.5 g) were dissolved in a mixture of benzene (60 ml) and absolute ethanol (25 ml). The solution was refluxed for 12 hours. After cooling the solution, it was washed twice with 2N sodium hydroxide solution and then several times with water. After drying (sodium sulfate), it was evaporated under reduced pressure to leave ethyl 2- (2-phenyl-5-benzoxazolyl) propionate (8 g) as an oil which solidified on cooling. Melting point 45-46 ° C.

Analysis: Calculated: C: 73.20; H: 5.80; N: 4.74

Found: C: 72.95, H: 5.51, N: 4.79.

Similarly, the following compound was prepared:

Ethyl 2- (2-p-chlorophenyl-5-benzoxazolyl) propionate, m.p. 59-62 ° C. !

Analysis: Calculated: C: 65.54, H: 4.89, N: 4.24

Found: C: 65.46, H: 4.85, N: 4.11.

Example 4 2-phenyl-6-benzoxazolyl-acetonitrile (a) 6-methyl-2-phenylbenzoxazole

Benzoyl chloride (79 ml) was slowly added with stirring to a suspension of 6-amino-m-cresol (83 g) in pyridine (600 ml). The temperature was kept below 5 ° C. The solution was heated under reflux for 2 hours, then evaporated to dryness to give an oil. This oil was extracted with aqueous 2N sodium hydroxide solution. The aqueous layer was acidified with concentrated hydrochloric acid. The solid, N- (2'-hydroxy-4'-methylbenzanilide), mp 170 ° C, was filtered off. This product was heated until no more water was developed. The resulting liquid was allowed to cool and the solid thus produced was pulverized and taken up in petroleum ether. The solution was treated with carbon and the filtrate was evaporated to dryness to give 6-methyl-2-phenyl-benzoxazole, m.p. 93 ° C.

(b) 6-Bromomethyl-2-phenylbenzoxazole N-bromosuccinimide (25.9 g) was added to a cold solution of 6-methyl-2-phenylbenzoxazole (30 g) in carbon tetrachloride (250 ml). Benzoyl peroxide (500 mg) was added and the mixture was heated under reflux for 3 hours in the presence of U.V. light. The solid 8 U1724 residue was filtered out. The filtrate was slightly evaporated and then treated with carbon and allowed to cool. The crystals which formed were recrystallized from benzene to give 6-bromomethyl-2-phenylbenzoxazole, mp 162 ° C.

(c) 2-phenyl-6-benzoxazolylacetonitrile

A mixture of 6-bromomethyl-2-phenylbenzoxazole (40 g) and sodium cyanide (7.4 g) in dry dimethylformamide (800 ml) was heated on a steam bath for 3 hours. The mixture was filtered and the filtrate evaporated to dryness. The solid was recrystallized to give 2-phenyl-6-benzoxazolyl-acetonitrile as white crystals, mp 144 ° C.

Example 5

Ethyl 2-phenyl-6-benzoxazolylacetat

A solution of 2-phenyl-6-benzoxazolylacetic acid (20 g) in ethanol (200 ml) was heated under reflux for 6 hours, during which time dry hydrogen chloride was bubbled through the solution. The oil residue of the solution obtained by evaporation was extracted with ether and this solution was evaporated to dryness. The solid which formed was recrystallized from toluene / petroleum ether to give white crystals of ethyl 2-phenyl-6-benzoxazolyl acetate, mp 76 ° C.

Analysis found: C: 72.3, H: 5.4, N: 4.8 C17H15NO3 contains: C: 72.6, H: 5.4, N: 5.0.

Example 6

Bthyl-2- (2-phenyl-6-benzoxazolyl) propionate

A solution of ethyl 2-phenyl-6-benzoxazolyl acetate (34 g) in ether (200 ml) was added with stirring to a solution of NaNI 2 (from 3.2 g sodium) in liquid ammonia (500 ml). This red mixture was stirred for 15 minutes, then a solution of methyl iodide (8.5 ml) in ether (10 ml) was quickly added. As the reaction mixture appeared colorless, the reaction was stopped by the addition of ammonium chloride in excess. The mixture was evaporated to dryness and the residue extracted with ether. Ethanol solution was evaporated to dryness to give white crystals of ethyl 2- (2-phenyl-6-benzoxazolyl) propionate, m.p. 46 ° C.

Found: C: 73.0, H: 5.7, N: 5.0 C18H17NO3 contains: C: 73.2, H: 5.8, N: 4.7.

9 141724

Example 7 2- (2-Phenyl-6-benzoxazolyl) propionamide a) A solution of lithium aluminum hydride (about 2 g) in ether (50 ml) was slowly added to a solution of ethyl 2- (2-phenyl-6- benzoxazolyl) propionate (5 g) in ether (40 ml). The mixture was heated under reflux for 1 hour, then slowly added ethyl acetate until the effervescence stopped. 6N aqueous hydrochloric acid was then added and the ether layer was separated and dried. Silica gel chromatography provided pure 2- (2-phenyl-6-benzoxazolyl) -propanol, mp 98 ° C.

Analysis found: C: 76.0, H: 5.8, N: 5.6, 16, 15, 15 contains: C: 75.9, H: 6.0, N: 5.5.

b) A mixture of ethyl 2- (2-phenyl-6-benzoxazolyl) propionate (4.4 g) and ammonia glycerol (40 ml) was heated at 150 ° C in a pressure vessel for 18 hours. Then the mixture was diluted twice with water and the resulting white solid was filtered off and recrystallized from ethyl acetate to give white 2- (2-phenyl-6-benzoxazolyl) propionamide crystals, mp 193 ° C.

Analysis found: C: 72.1, H: 5.4, N: 10.7 ^ 16 ^ 14 ^ 2 ^ 2 contains: C: 72.2, H: 5.3, N: 10.5.

By the same procedure, the following compounds were prepared: (a) 2- (2-phenyl-5-benzoxazolyl) -propionamide, m.p.

Analysis: Calculated: C: 72.2, H: 5.3, N: 10.5

Found: C: 72.0, H: 5.1, N: 10.4.

(b) 2- (2-p-chlorophenyl-5-benzoxazolyl) propionamide, mp 245-246 ° C.

Analysis: Calculated: C: 63.89; H. 4.35; N: 9.31 Found:. C: 63.64, H: 4.30, N: 9.22.

Example 8 2- (2-p-chlorophenyl-6-benzoxazolyl) propionate (a) 2- (3-hydroxy-4-aminophenyl) propionic acid hydrochloride A solution of ethyl 2- (2-phenyl-6-benzoxazolyl) ) propionate (10 g) in concentrated hydrochloric acid (150 ml) was heated to 160 ° C for 24 hours.

The resulting mixture was evaporated to dryness and the residue was taken up in water. This solution was washed out with chloroform and then evaporated to dryness to give 2- (3-hydroxy-4-aminophenyl) propionic acid, hydrochloride as a white powder, mp 170 ° C (decomposition).

(B) Ethyl 2- (3-hydroxy-4-aminophenyl) propionate

A solution of 2- (3-hydroxy-4-aminophenyl) propionic acid, hydrochloride (5 g) in ethanol (100 ml) was saturated with hydrogen chloride and the resulting solution was heated under reflux for 6 hours. The solution was evaporated to dryness and the residue was taken up in ethanol, and this solution was neutralized with sodium hydroxide solution. After evaporation, the residue was taken up in chloroform and the solution washed with water. Evaporation of the chloroform solution provided ethyl 2- (3-hydroxy-4-aminophenyl) propionate, mp 114-115 ° C.

Analysis found: C: 63.2, H: 7.2, N: 6.9 C11H15NO3 contains: C: 63.1, H: 7.2, N: 6.7.

(c) Ethyl 2- (2-p-chlorophenyl-6-benzoxazolyl) propionate

A solution of ethyl (3-hydroxy-4-aminophenyl) propionate (2.5 g) in pyridine (15 ml) was treated with p-chlorobenzoyl chloride (1.65 ml) at 5 ° C. After stirring for 2 hours at room temperature, the solution was evaporated to dryness.

The residue was heated to 220 ° C until no more water was developed and allowed to cool. Ethyl 2- (2-p-chlorophenyl-6-benzoxazolyl) propionate was thus obtained.

Similarly, the following compound was prepared;

Ethyl 2 / 2- (3,4-methylenedioxyphenyl) -5-benzoxazolyl7 propionate, m.p. 76-79 ° C.

Analysis: Calculated: C: 67.25, H: 5.0, N: 4.1 Found: C: 67.1, H: 5.05, N: 4.4.

Example 9

Ethyl 2- (2-o-chlorophenyl-6-benzoxazolyl) propionate

A solution of o-chlorobenzaldehyde (4.3 g) and ethyl 2- (3-hydroxy-4-aminophenyl) propionate (6 g) in toluene (100 ml) was heated using a Dean and Stark collection apparatus of the water formed. After 30 minutes, the solution was evaporated to dryness.

The residue was dissolved in acetic acid (100 ml) and 15 g of lead tetraacetate was added and the solution was heated on a steam bath for 1 hour. The solution was poured into ice / water and extracted with ether to give the oil, ethyl 2- (2-o-chlorophenyl-6-benzoxazolyl) propionate, one of which gave a satisfactory microanalysis.

η 14172Λ

Example 10 N, N-Dicthyl-2- (2-phonyl-5-benzoxazolyl) propionamicl 2- (2-phenyl-5-benzoxazolyl) propionic acid (50 g) and thionyl chloride (20 ml) were heated together in a steam bath for 20 minutes. minutes. The excess thionyl chloride was removed by evaporation under reduced pressure. The residue was cooled to 0 ° C and treated gently with excess diethylamine. After 1 hour, the reaction mixture was quenched with water (100 ml) and ether (100 ml). The ether layer was washed three times with water (50 ml), dried (sodium sulfate) and evaporated. The residue was chromatographed on silica gel, then recrystallized from a small volume of ethanol to give the desired diethylamide, mp 108-110 ° C.

Analysis: Calculated: C: 74.5, H: 6.8, N: 8.7 Found: C: 74.6, H: 6.6, N: 8.7.

Example 11 2- (2-Phenyl-5-benzoxazolyl) propionyl hydroxamic acid

A solution of sodium (0.16 g) in absolute ethanol (5 ml) was added to a solution of hydroxylamine hydrochloride (0.46 g) in absolute ethanol (12 ml). The cooled mixture was filtered and a solution of ethyl 2- (2-phenyl-5-benzoxazolyl) propionate (2.0 g) in ethanol (10 ml) was added to the filtrate. 3 days standing at room temperature provided a precipitate which was filtered off. The solid was stirred in aqueous acetic acid and filtered, dried and recrystallized from dimethylformamide ethanol. The resulting white crystals of the desired hydroxamic acid melted at 204-205 ° C.

Analysis: Calculated: C: 68.1; H: 5.0; N: 9.9 Found: C: 68.1; H: 5.0; N: 9.75.

Example 12 2- (2-Phenyl-5-benzoxazolyl) -isobutyronitrile

By treatment of 2- (2-phenyl-5-benzoxazolyl) -propionitrile with methyl iodide in the manner described in Example 6, 2- (2-phenyl-5-benzoxazolyl) -isobutyronitrile is obtained.

Example 13 12 U1724 2- (2-Phenyl-5-benzoxazolyl) propionic acid

A solution of 2- (2-phenyl-5-benzoxazolyl) propionitrile (24 g, 0.096 mol) prepared by the procedure of Example 1 in concentrated hydrochloric acid (220 ml) was refluxed for 1 hour. The mixture was poured into ice / water (1 liter). The precipitated 2- (2-phenyl-5-benzoxazolyl) propionic acid was filtered off and washed well with water. The dry acid weighed 23 g and had a melting point of 177-179 ° C.

Analysis: Calculated: C: 71.89, H: 4.90, N: 5.24 Rnd: C: 72.13, H: 4.95, N: 5.39.

Example 14

By a procedure similar to that of Example 13, the following compounds were prepared: (a) 2- (Z-fluorophenyl-5-benzoxazolyl) -propionic acid, m.p.

Analysis: Calculated: C: 67.36, H: 4.24, N: 4.91

Found: C: 67.58, H: 4.45, N: 5.07.

(b) 2- (2-p-chlorophenyl-5-benzoxazolyl) propionic acid, m.p. 188-191 ° C.

Analysis: Calculated: C: 63.68, H: 4.00, N: 4.64

Found: C: 63.50, H: 4.16, N: 4.72.

(c) 2- (2-m-chlorophenyl-5-benzoxazolyl) propionic acid, mp 173-175 ° C.

Analysis: Calculated: C: 63.68, H: 4.00, N: 4.64

Found: C: 63.50, H: 4.01, N: 4.75.

(d) 2- (2-p-methylphenyl-5-benzoxazolyl) propionic acid, m.p. 166-168 ° C.

Analysis: Calculated: C: 72.58, H: 5.37, N: 4.97

Found: G: 72.36, II: 5.46, N: 5.4.

(e) 2- (2-m-methylphenyl-5-benzoxazolyl) propionic acid, m.p. 155--157 ° C.

Analysis: Calculated: C: 72.58, H: 5.37, N: 4.97

Found: C: 72.39, H: 5.61, N: 5.14.

(F) 2- (2-o-methylphenyl-5-benzoxazolyl) -propionic acid, mp 107--110 ° C.

Analysis: Calculated: C: 72.58, H: 5.37, N: 4.97

Found: C: 72.54, H: 5.59, N: 4.77.

(g) 2- (2-p-methoxyphenyl-5-benzoxazolyl) propionic acid, m.p. 189--191 ° C.

Analysis: Calculated:. C: 68.67, H: 5.08, N: 4.71

Found: C: 68.42, H: 5.36, N: 4.72.

Example 15 2-Phenyl-5-benzoxazolylacetic acid *

A solution of 2-phenyl-5-benzoxazolylacetonitrile (8.9 g) prepared by the procedure described in Example 1 (e) was heated in concentrated hydrochloric acid (80 ml) on a steam bath for 2 hours. hour. The solution was then diluted with ice / water and allowed to stand. The solid which was prepared was crystallized from toluene to give white crystals of 2-phenyl-5-benzoxazolylacetic acid, m.p. 175 ° C.

Analysis: Calculated for C 15 H 11 NO 3: C: 71.1, H: 4.4, N: 5.5 Found: C: 71.0, i $: 4.4, N: 5; 6.

Example 16 2-Phenyl-6-benzoxazolylacetic acid - - - - - prepared by the method 1g. Ex. 4,

A solution of 2-phenyl-6-benzoxazolylacetonitrile K (11 g) in concentrated hydrochloric acid (100 ml) was heated on a steam bath for 1 hour. The solution was then allowed to cool and the resulting solid was filtered off and shaken with aqueous sodium hydrogen carbonate solution and chloroform. The chloroform layer was acidified with hydrochloric acid and extracted with chloroform. The chloroform solution was evaporated to dryness. The residue was recrystallized from toluene to give white crystals of 2-phenyl-6-benzoxazolylacetic acid, mp 170 ° C.

Found: C: 71.0, H: 4.4, N: 5.5% C 15 H 11 NO 3 contains: C: 71.1, H: 4.4, N: 5.4%

Example 17 2- (2-Phenyl-6-benzoxazolyl) propionic acid

A solution of ethyl 2- (2-phenyl-6-benzoxazolyl) propionate (15 g) prepared by the procedure of Example 6 in concentrated hydrochloric acid (150 ml) was heated on a steam bath for 6 hours. The solution was cooled and the crystals formed formed were filtered off. These were recrystallized from ethanol / water to give 2- (2-phenyl-6-benzoxazolyl) -propionic acid, mp 132 ° C.

141724 14

Found: C: 71.7, Η: 5.0, N: 5.3, 16H13N®3 contains: C: 71.9, H: 4.9, N: 5.2¾.

Example 18 2- (2-p-chlorophenyl-6-benzoxazolyl) -pxopionic acid

A solution of ethyl 2- (2-p-chlorophenyl-6-benzoxazolyl) propionate (4 g) prepared by the procedure of Example 8 in aqueous sodium hydroxide (30 ml) was heated on a steam bath for half an hour. After cooling, the black solution was washed with chloroform. After acidification of the black solution with hydrochloric acid, the mixture was extracted with chloroform. This solution gave, after evaporation, 2- (2- (2'-chlorophenyl-6-benzoxazolyl) propionic acid, mp 196 ° C.

Found: C: 63.9, H: 4.2, N: 4.8, Cl: 12.0 ° C16% 2 6, Cl: 11.8.

Similarly, the following compounds were prepared: 2- [2- (3,4-methylenedioxyphenyl) -5-benzoxazolyl] -propionic acid, m.p. 185-188 ° C.

Analysis: Calculated: C: 65.5, H: 4.2, N: 4.5

Found: C: 65.4, H: 3.9, N: 4.7.

2- [2- (3,4-Dichlorophenyl) -5-benzoxazolyl7-propionic acid, m.p. 169-173 ° C.

Analysis: Calculated: C: 57.1, H: 3.3, N: 4.2

Found: C: 56.9, H: 3.4, N: 4.1.

2- / 2- (2,4-dichlorophenyl) -5-benzoxazolyl7-propionic acid, mp 151-153 ° C.

Analysis: Calculated: C: 57.1, H: 3.3, N: 4.2

Found: C: 57.1, H: 3.3, N: 4.4.

2- / 2- (2-furyl) -5-benzoxazolyl-7-propionic acid, mp 160-162 ° C. Analysis: Calculated: C: 65.4, H: 4.3, H: 5.4

Found: C: 65.3, H: 4.4, N: 5.4.

2- (2-cyclohexyl-5-benzoxazolyl) propionic acid, m.p. 115-117 ° C. Analysis: Calculated: C: 70.30, H: 7.00, N: 5.12

Found: C: 70.58, II: 6.86, N: 5.35.

2- / 2- (2-thienyl) -5-benzoxazolyl-7-propionic acid, m.p. 161-163 ° C Analysis: Calculated: C: 61.52, H: 4.05, N: 5.12 Found: C : 61.72, H: 4.19, N: 5.07.

2- (2-o-chlorophenyl-5-benzoxazolyl) propionic acid, mp 101-103 ° C.

Analysis: Calculated: C: 63.68, H: 4.01, N: 4.64

Found: C: 63.80, H: 4.22, N: 4.82.

2- (2-p-iodo-phenyl-5-benzoxazolyl) -propionic acid, m.p. 205-208 ° C. Analysis: Calculated: C: 48.87, H: 3.07, I: 32.27, N: 3.56

Found: C: 48.91, H: 2.93, I: 32.51, N: 3.26.

2- (2-m-fluorophenyl-5-benzoxazolyl) -propionic acid, mp 135-141 ° C.

Analysis: Calculated: C: 67.36, H: 4.24, N: 4.91

Found: C: 67.46, H: 4.37, N: 5.11.

2- / 2- (3,5-dichlorophenyl) -5-benzoxazolyl7-propionic acid, m.p. 161-165 ° C.

Analysis: Calculated: C: 57.16, H: 3.29, N: 4.16

Found: C: 57.13, H: 3.51, N: 4.22.

2- (2-o-fluorophenyl-5-benzoxazolyl) propionic acid, m.p. 180-183 ° C.

Analysis: Calculated: C: 67.36, H: 4.24, N: 4.91

Found: C: 67.16, H: 4.50, N: 4.91.

2- (2-p-fluorophenyl-6-benzoxazolyl) propionic acid, m.p. 147 ° C. Analysis: Calculated: C: 67.4, H: 4.2, N: 4.9, F: 6.7

Found: C: 67.2, H: 4.4, N: 4.9, F: 6.8.

2- (2-p-chlorophenyl-5-benzoxazolyl) propionic acid, m.p. 188-191 ° C.

Analysis: Calculated: C: 63.68, H: 4.00, N: 4.64

Found: C: 63.50, II: 4.16, N: 4.72.

Example 19 2- (2-phenyl-5-benzoxazolyl) -isobutyric acid 2- (2-phenyl-5-benzoxazolyl) -isobutyronitrile prepared by the procedure of Example 12 was treated with concentrated hydrochloric acid as described in Example 13 to give: 2- (2-phenyl-5-benzoxazolylisobutyric acid, mp 92 - 95 ° C.

Analysis: Calculated: C: 77 * 9, H: 5.3, N: 10.7

Found: C: 77.6, H: 5.3, N: 10.45.

Example 20 2- (2-Phenyl-6-benzoxazolyl) propanol

A solution of lithium aluminum hydride (about 2 g) in ether (50 ml) was slowly added to a solution of ethyl 2- (2-phenyl-6-benzoxazolyl) propionate (5 g) in ether (40 ml). The mixture was heated under reflux for 1 hour, then slowly added ethyl acetate until the effervescence stopped. 6N aqueous hydrochloric acid was then added and the ether layer was separated and dried. Silica gel chromatography provided pure 2- (2-phenyl-6-benzoxazolyl) propanol, m.p. 98 ° C.

Analysis found: C: 76.0, H: 5.8, N: 5.6 C 16 H 15 NO 2 contains: C: 75.9, H: 6.0, N: 5.5.

Study report

To demonstrate the low toxicity of the compounds of formula (I) prepared from the subject intermediates, LD 50 values in mice were determined for a wide variety of these compounds as well as the commercially available anti-inflammatory active arylacetic acid derivative "Indomethacin".

The results set forth in the table below clearly show the substantially lower toxicity of the compounds prepared from the intermediates in question.

141724 17

Table j-, Π-crVr3 r4 ^ 0A ^ R1 R2 R3 R4 -CR1R2R3 Approximate LDS0 mg / kg Η H C02H Ph 5- 1200 Η H C02H 4-Cl Ph S-1600

Me H C02H Ph 5- 800 Η H C02H Ph 6- 1200 Η H CH2OH Ph 6- 1600 H Me CH2OH Ph 5- 800

Me H C02Na 4-Br Ph 5- 1200

Me H C02H 2-C1 Ph 5- 1200 H Me CO? H 3-Cl Ph 5- 1200 H Me C02H 4-Cl Ph 5- 800

Me H CH 2 OH Ph 6- 800 H Me Me CO 2 H Ph 6- 600

Me H C02H 2-Cl Ph 6- 1200 H Me C02Na 4-C1 Ph 5- 1200 H Me COzH 2,4-di Cl Ph 5- 800

Me H CO 2 H 2,5-di Cl Ph 5- 1606

Me H CO 2 H 3,4-di Cl Ph 5- 600 H Me CO 2 H 2.5-di Cl Ph 5- 600

Me H C02H 2 - FPh 5- 1600 H Me CQ2H 3 - FPh 5- 800 H Me COzH 4 - FPh 5- 1200 H Me C02H 4 - Cl Ph 6- 1200

Me H C02H 4 - FPh 6- 1200 H Me C02H 4 - Me Ph 6- 1200

Me H C02H 4 - IPh 5- 1200 H Me C02H 2 - Me Ph 5- 600 H Me COzH 3 - Me Ph 5- 1200

Me H C02H 4 - OMe Ph 5- 1600

Me H CO 2 H 3,4-OCH 2OPh 5- 800 H Me CO 2 H 4-t Bu Ph 5- 1200

Claims (2)

Table (continued) R1 R2 R3 R4 -CR1R2R3 Approximate LD50 mg / kg Me H CO 2 H 2-Fury1 5- 600 H Me CO 2 H Cyclohexyl S-1200 Me H CO 2 H 2-Thienyl 5- 400 H Me. CO 2 H 3-Pyridyl 5- 600 IMXMETHACIN 10 1. Benzoxazole derivatives for use as intermediates in the preparation of therapeutically active benzoxazole derivatives of the general formula (I): T, N 107 --CRiRzR'5 (I) R4 wherein R1, R2 and R4 have the meaning set forth below and R3 represents the group -CH2OH or -C00H wherein the -CR RR group is in the 5 or 6 position of the benzoxazole nucleus, characterized in that they have the general formula (II): Ni 2 I --CR-Va (II) R4