Method of producing derivatives of benzoxazole

The invention relates to a process for the preparation of novel benzoxazole derivatives which have been found to have valuable pharmacological activity or are useful as intermediates for the preparation of such active compounds.

The novel benzoxazole derivatives produced by the process of the invention have the general formula I

3 12 wherein the -GR RR group is in the 5 or 6 position of the benzoxazole nucleus, R and R are each independently hydrogen or C 1 -C 4 alkyl, R is nitrile, carboxy or an alkali metal or alkaline earth metal salt thereof or an aluminum or ammonium salt, or an alkyl ester and R 1 is cyclohexyl or furyl; thienyl, pyridyl or phenyl optionally substituted at any available position by one or two substituents selected from the group consisting of halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, or amino, optionally substituted at two adjacent positions with methylenedioxy.

The term alkyl of 1 to 4 carbon atoms, as used herein, means a straight or branched chain alkyl group containing from 1 to 4 carbon atoms such as methyl, ethyl, isopropyl, n-butyl, sec-butyl and tert-butyl , butyl. Similarly, the term C 1 -C 4 alkoxy means the above C 1 -C 4 alkyl groups bonded via an oxygen atom. The term C 1 -C 4 haloalkyl also means the above C 1 -C 4 alkyl groups substituted with at least one halogen atom, such as chloromethyl, bromomethyl, trifluoromethyl, 2-chloroethyl, pentafluoroethyl, 3-bromopropyl, 2-chlorobutyl and 4-bromobutyl.

The compounds produced by the method of the invention were tested for pharmacological activity and toxicity using a standard animal testing procedure.

Examples of compounds produced by the process of the present invention include:

2- (2-methyl-6-benzoxazolyl) butyric acid, 2- (2-tert-butyl-5-benzoxazolyl) propionic acid ethyl ester,

2- (2-Isopropyl-5-benzoxazolyl) propionamide

2- (5-benzoxazolyl) propyl alcohol,

2- (2-n-butyl-6-benzoxazolyl) propionic acid,

2-cyclohexyl-5-benzoxazolylacetic acid,

2-cyclohexyl-5-benzoxazolylacetonitrile,

2-cyclohexyl-6-benzoxazolylacetic acid, 2- (2-cyclohexyl-5-benzoxazolyl) propionic acid methyl ester, 2-cyclohexyl-5-benzoxazolylacetic acid dimethylaminoethyl ester, 2- (2-cyclohexyl-5-benzoxazolyl) butyric acid potassium salt, 2-C2- (fur-2-yl) -5-benzoxazolyl-2-methylpropionic acid,

2- [2- (fur-2-yl) -6-benzoxazoles] -propionic acid, 2- (fur-2-yl) -5-benzoxazolylacetic acid tert-butyl ester,

2- [2- (fur-3-yl) -5-benzoxazoles] ethyl alcohol,

2- [2- (fur-2-yl) -5-benzoxazolyl] propionitrile,

2- [2- (Thien-2-yl) -5-benzoxazolyl] propyl alcohol,

2- [2- (thien-2-yl) -6-benzoxazolyl] -1-ethylpropionic acid, 2- (thien-3-yl) -5-benzoxazolylacetic acid ethyl ester,

2- (thien-3-yl) -5-benzoxazolylacethydroxamic acid,

2- (pyrid-4-yl) -5-benzoxazolylacetic acid,

2- (pyrid-2-yl) -6-benzoxazolylacetonitrile,

2- [2- (pyrid-2-yl) -5-benzoxazolyl] propionic acid, 2- [2- (pyrid-2-yl) -6-benzoxazolyl isopropyl ester | propionic acids,

2- [2- (pyrid-2-yl) -6-benzoxazolyl] propyl alcohol,

2- (pyrazin-2-yl) -6-benzoxazolylacetic acid,

2- (pyrazin-2-yl) -6-benzoxazolylethyl alcohol,

2- [2- (pyrazin-2-yl) -5-benzoxazolyl] propionic acid, 2- [2- (pyrazin-2-yl) -5-benzoxazolyl] propionic acid ethyl ester,

2- [2- (4-chlorophenyl-5- and 6-benzoxazolyl) propionitrile,

2- (4-nitrophenyl) -5-benzoxazolylacetic acid,

2- (4-aminophenyl) -6-benzoxazolylacetic acid, 2- [2- (3,4-methylenedioxyphenyl) -5-benzoxazolyl] -propionic acid ethyl ester

2- | -? - (4-3-chloroethylphenyl) -6-benzoxazolyl propionic acid,

2- [2- (3,4-diethylphenyl) -5-benzoxazolyl] propionic acid,

2- (3-ethoxyphenyl) -5-benzoxazolylacethydroxamic acid, 2- (4-dimethylaminophenyl) -5-benzoxazolylacetic acid ethyl ester,

2- [2- (4-tert-butoxyphenyl) -6-benzoxazolylbutyric acid],

2- [2- (4-chlorophenyl) -5-benzoxazolyl] butyronitrile, 2- (2-methoxyphenyl) -5-benzoxazolylacetic acid thylaminoethyl ester,

2- [2- (2,4-dinitrophenyl) -5-benzoxazolyl] propyl alcohol,

2- [2- (4-aminophenyl) -6-benzoxazolyl] propionylhydroxamic acid, 2- (4-n-butylphenyl) -5-benzoxazolylacetic acid sodium salt.

Examples of preferred compounds of the invention are

А) 2-phenyl-5- and 6-benzoxazolylacetic acid

2- (4-chlorophenyl) -5- and 6-benzoxazolylacetic acid

2- (4-methylphenyl) -5- and 6-benzoxazolylacetic acid,

2- (4-trifluoromethylphenyl) -5- and 6-benzoxazolylacetic acid,

2- (4-methoxyphenyl) -5- and 6-benzoxazolylacetic acid,

2- (4-bromophenyl) -5- and 6-benzoxazolylacetic acid, *

2- (4-fluorophenyl) -5- and 6-berzoxazolylacetic acid,

2- (3-chlorophenyl) -5- and 6-benzoxazolylacetic acid, and 6-benzoxazolylacetic acid,

2- (3-trifluoromethylphenyl) -5- and 6-benzoxazolylacetic acid, 2- (3,4-dichlorophenyl) -5- and 6-benzoxazolylacetic acid, 2- (2'-methylphenyl) -5- and 6-benzoxazzoylacetic acid, 2- (2-chlorophenyl) -5- and 6-benzoxazolylacetic acid, 2- (2-methoxylinyl) -5- and 6-benzoxazzoylacetic acid, 2- (3,4-dimethylphenyl) -5- and 6-benzoxazolylacetic acid,

A (II) sodium, potassium, aluminum and ammonium salts of the acids A1) listed above,

A (III) alkyl, aminoalkyl, dimethylaminooacyl and diethylaminoolyl esters of the acids A1) mentioned above, each of which is C 1 -C 4 alkyl,

B 2-phenyl-5- and 6-beosoxazolylacetamide,

2-Phenyl-5- and 6-benzylxazllylation-hydroxylamic acid,

2- (4-chlorophenyl) -5- and 6-benzoxazolyl-acetylaminoacetic acid, 2- (4-chlorophenyl) -5- and 6-benzoxazolylacetamide, 2- (4-bromoennyl) -5- and 6-benzoxazolylacetamide, 2- 2- (4-Methoxyphenyl) -5- and 6-benzoxazolylacetamide, 2- (4-methophenyl) -5- and 6-benzoxazzoylacetemide, 2- (4-chlorophenyl) -5- and 6-benzoxazolylacetamide; (5S) -5- and 6-benzoxazooylacetamide, 2- (2-methoxyphenyl) -5- and 6-benzoxazolylacetamide, 2- (2-chlorophenyl) -5- and 6-benzoxazooylacetamide, 2- (3,4) -dichlorophthyl) -5- and 6-benzoxazolylacetamide, 2- (3-chlorophenyl) -5- and 6-beosoxazolylacetamide, 2- (3-Methylphenyl) -5- and 6-benzoxoxysolylacetamide;

2- (4-Trifluoromethylphthol) -5- and 6-benzoxazolylacetemide; 2- (4-Trifluoromethylphthol) -5- and 6-benzylxazolylcelllyduxaam. 2- (4-bromo-phthyl) -5- and 6-benzoxazolylacetyduoic acid, 2- (4-bromophenyl) -5- and 6-benzoxazolylacetyduoic acid, 2- (3,4-dimethylphthyl) -5- and 6-benzoxazllylacethydloalkylamino acid acid, 2- (4-methoxylphenyl) -5 'and 6-benzoxazolylacetyroaminoic acid, 2- (4-methophenyl) -5- and 6-benzoxazolyl acetlydloamylic acid, 2- (3-chlorophthyl) -5- and 6-benzylxazolylcellol-duxamic acid 2- [2- (3-Chloro-phthyl) -5- and 6-benzoxazolyl-propionylhydroxy acid, 2-Q2 (44_Chiiof_ennl) -5- and 6-beosoxazolyl-propionylhydroxy acid, 2- [2- (2-chlorophenyl) -5- and 6-benzoxazolyl-propionyl-4-hydroxamic acid, 2- [2- (3,4-dihydro-4-morpholyl) - and 6-benzoxazolyl] (i) propionylhydroxamic acid, 2- [(4-trifluoromethylphenyl) -5- and 6-benzoxazole]; prupionylhydoxamic acid, 2- [4- (4-methyl-4-methylphenol) -5- and 6-benzoxazoline] prionylhydroxybutyric acid, 2- [2-44-methoxylylinnyl] -5- and 6-benzoxazolyl-propionylhydroxamic acid 2- [- (3-methoxyl) -5- and 6-beosoxazolyl propionamide, 2- [- (4-methoxyl) -5- and 6-benzoxazolyl propionamide,

2- [22 (44 (τ · ifllormethhlf^enУl) -5- and 6-benzoxazolespropionamide, 2 - [- (4-methoxylphenyl) -5- and 6-benzoxazolespropionamide,

2- [-4-chlorophenyl] -5- and 6-benzoxazolyl propionamide,

2 - [- (4-chloro-5-yl) -5- and 6-benzoxazoles] propionamide,

2- (4-methyl-6-benzoxazolyl) propionamide,

C (I) 2-phthyl-5- and 6-benzolaeo-oylethylalcolol,

2- (4-chlorophenyl) -5- and 6-benzoyloxyethyl ethyl alcohol,

2- (4-Methoxyphenyl) -5- and 6-benzooxoethyl ethyl alcohol,

- (4-Trifluoromethylphenyl) -5- and 6-benzooxazoyl-thienyl, 2- (4-methoxyphenyl) -5- and 6-benzoxxazoylethyl alcohol, 2- (4-bromophenyl) -5- and 6- be.nzolxazOyletlylaУkohol,

2- (3-chlorophenyl) -5- and 6-benzolazoylethyl alcohol, 2- (3-chlorophenyl) -5- and 6-benzol xyl ethyl alcohol, 2- (3-menol-4-yl) -5- and 6 · (Benzol-oxo-ethyl-ethyl) - (3,4-dichlorophenyl) -5- and 6-benzol-oxo-ethyl-alcohol, 2- (2-methyl-phenyl) -5- and 6-benzo-oxo-ethyl-ethyl-alcohol,

2OÓ455

2- (2-methoxyphenyl) -5- and 6-benzoxazolylethyl alcohol,

2- (2-chlorophenyl) -5- and 6-benzooazolylethyl alcohol,

2- (2- (2-chlorophenyl) -5- and б-пепооааооУуЗ propyl alcohol,

2- S- (3-chlorophenyl) -5- and 6-benzoxazolespropyl alcohol,

2- [2- (4-chlorophenyl-5- and 6-benzoyloxy)] propyl alcohol,

2- (2- (3,4-dichlorophenyl) -5- and 6-benzoazoles) propyl alcohol, 2 - [- (3,4-dimethylphenyl) -5- and 6-benzoazolespropyl alcohol, 2- [2 (3-methoxyhenyl)] -5- and 6-benzoylpropyl alcohol, 2- [2- (4-trifluoromethylphenyl) --- and .beta.-benzoazooyl] propyl alcohol; - [4- (4-methylhexyl) phenyl] -5-. and 6-benzoyl-yl] -pyridine, 2- [2- (4-bromophenyl) -5- and 6-benzoyl-ol-propyl alcohol, 2 - [[- (4-fluorophenyl) --- and 6- 2-{'- (4-methylphenyl) -5- and 6-benzoylol-2-yl] propanol, 2- [2- (2-methylphenyl) -5- and 6-benzyl] propanol, - [2 (2-methylhexyl) -5- and 6-benzoazooyl propyl alcohol,

C (II) alkyl; the alcohols mentioned above under C (I) when the alkyl has 1 to 4 carbon atoms,

Examples of the most varied compounds are:

D (1) 2- [2 (nyl-5- and 6-benzylamino)] propionic acid, [eta] & lt; 2 & gt ;-( 3-dimethoxyleenl) -5- and 6-benzoazolespropionic acid,

2- | 2- (3,4-methylenedioxyphenene-5- and 6-benzoazoles) propionic acid,

2- [2- (2-chlorophenyl) -5- and 4-benzoic acid and propionic acid,

2- [2- (2-Fluorophenyl) -5- and 6-benolaalylyl] propionic acid,

2- .j - (- Methylphenyl) --- and 6-benzoazolyl propionic acid,

2 - [- (3,4-Dichlorophenyl) -5- and 6-benzoyl -oolyl] propionic acid,

2- [2-3-phenyl] -2- (5-fluoro-5- (6-benzoyl) -propionic acid),

2- [2 (2,4- (Dichloro-phenyl) -5- and 6-mono-aooloyl] -propionic acid;

2- [2-3-0h2.о ^ пиу!) --- and 6-benzoylolylyl] propionic acid,

2- [2- (3-Trifluoromethylphenyl) -5- and 6-benzoyl -oolyl] propionic acid,

2- [2- (3-fluoro-phenyl) -5- and 6-benzoxazoloyl-propionic acid, [22 (3-methyl-phenyl) -5- and 6-benzoyl-oxyl] -propionic acid ,

2- [2-4-iodinyl) --- and 6-benzoyl} propionic acid,

2- [4- (4-chloro-2-yl) -2- and 6-benzoyl] -2-propionic acid.

2- and 6-benoazazolyl propionic acid,

2- [2- (4-nitroethyl) --- and 6-benzyl-propionic acid,

2- [2-4-phenylethoxy] and 6-benooyl-1-yl] propionic acid,

2 - [- (3-nitro-4-fluorophenyl) -5- and 6-benzylamino] propionic acid,

2- [2 - (- methylphenyl) -5- and 6-benooyaoolyl] propionic acid,

2 - [- (- zetetyiennyl) --- and 6-benzenoic acid propionic acid,

2- [2 - ((4-Trifluoromethylenyl) --- and 6-benooazazolyl) propionic acid,

2- [2- (4-Methylphenyl) --- and 6-benzoyl] propionic acid,

2- [2 (4-Methylphenyl) phenyl] --- and 6 (benooaazo propionic acid), ²- [2 - ^^ 611 ^^^ (^ 1.) --- and 6-^beno1aaoo^ylí0 for^pion^and kyseMnz,

D (II) sodium, potassium, aluminum and ammonium salts of cyseyin mentioned above.

D (III) alkyl-, amino-amino, dimethylamino-alkyl-, and diethyl-amino-amino acids. higher than D (D, where in each case it is an alkyl of 1 to 4 carbon atoms).

The essence of the production of the bnooazzoZ derivatives mentioned above1 of the outbound free-flowing I-like subclass of the outbound free-flowing I-type by the action of the other is in that the cyclic cyclic compound of the outbound free-flowing Illb

H <X>

2 3 '4' 'in which R., ^R and ^R It has the aforementioned effluent and Y else a group substantially free of R ^WHATNH- nnb^OR⁴CH = N- in which ^r4 has an indefinite yield, oa dn] yydrztzδníc^y conditionally

The cyclic compound of the freelancer may be effected by treatment and / or under acidic conditions, for example in the presence of hydrochloric acid or polyphosphoric acid.

If У is R⁴CH = N-^, the cyclization can be readily accomplished by treatment with an oxidizing agent such as lead acetate or nickel peroxide.

^Jand^kbalready mentioned, can^ofE ^být ^pmany different types with^toat^pin on funtoe R³ in the desired compounds produced by the process of the invention. The compound obtained from the cycle. start the reaction can be reacted in many ways,. thus converting it to another compound of formula I. For example, nitrile may not be reacted with a suitable alcohol to^kyselýc^h ^^ ίη ^! ^tand^kže se z^andwith^ká a compound of the formula IV ^kterem R³ Yippee ^toaralkyl group. Hydrolysis of the nitrile with a strong base or acid, for example hydrochloric acid, results in a compound of formula I in which RR is a carboxyl group. The product of formula (I), wherein R @ 1 is (II)³ is a carboxyl group, it can be converted to a hydroxamic acid derivative by treatment with hydroxylamine.

The salts of the formula I can be prepared by treating them with the appropriate bases such as ammonium hydroxide, alkylammonium, arylalkylmonia, aluminum, alkali metals or alkali metal, and of course the salts of the formula I can be immediately converted to the free acids by acid treatment. such as hydrochloric acid or sulfuric acid. The acid of formula (I) or a salt thereof may be converted to an ester by treatment with an appropriate alcohol or by treatment with a halide of the respective ester moiety or salt thereof if the ester moiety contains a basic nitrogen atom. However, the ester of formula I may be hydrolyzed to the corresponding acid or alcohol of formula I by treatment with a suitable hydrolyzing agent such as an organic base or acid.

The product of formula I wherein R and / or R is hydrogen may be coupled to form the corresponding compound of formula I wherein R 1 and / or R² is alkyl having 1 and 4 carbon atoms. The alkylation may be carried out by the action of an alkali metal derivative of the corresponding benzoxazole derivative and an alkyl halide, for example methyl or ethyl iodide.

Compounds of formula IIIb are novel compounds. The following reaction scheme shows the preparation of these nitro intermediates from known or readily known chemistry.

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<img file="CS200455B2_D0002.tif" />

<img file="CS200455B2_D0003.tif" />

<img file="CS200455B2_D0004.tif" />

<img file="CS200455B2_D0005.tif" />

In the scheme, step (a) is performed by diazotization followed by reaction of the resulting diazonium compound with dilute sulfuric acid. Step (b) is carried out by nitration, for example by treatment of nitric acid. solution of nitrile in glacial acetic acid. Steps (c), (d), and (e) are described above in connection with day R³. -&gt; R³= haoogen -&gt; R³cCN) Suupen. (f) is carried out by conventional acetylation using a suitable acylating agent such as an acyl halide or acid anhydride.

As is apparent from the foregoing, the compounds of formula I are those in which R @ 1³ is a nitride group.^-, used as meei^pro^dat^{kty p}ro ^exexchange on other merge^Cenin^y These other compounds, i.e. those in which) is a carboxyl or a salt thereof, are important because they are pharmacologically active. In particular, these compounds have been shown to have low toxicity and analgesic, antipyretic and / or anti-inflammatory activity. In certain cases, they also have the ability to inhibit the synthesis or release of prostaglandin.

The foregoing efficacy has been demonstrated in a test carried out on animals generally at distances of 0.1 to 250 mg / kg. For example, in the treatment of humans, drugs in the range of 0.1 and 25 mg / kg may also be administered, but doses outside this range may also be used on prescription by the physician treating the patient. The pharmacologically active compounds of the formula I can be administered by the enteral or parenteral route and are therefore usually formulated as pharmaceutical preparations containing the active ingredient in association with at least one pharmaceutically acceptable carrier. Such formulations will normally consist of the active ingredient mixed with the carrier or enclosed or surrounded by the carrier in the form of a capsule, sachet, capsule or other capsule. The carrier can be a solid, semi-solid, or liquid material that serves as a transporter, exotion, a cover, or an environment for the active ingredient. Some examples of carriers that can be used are: Lactose, dextrose, sucrose, sorbitol, maniol, starch, pecking, calcium phosphate, liquid paraffin, cocoa liquor and oil, β, γ, gelatin, meethylceulosa, polyoxyythylensobithium monnolurate, methyl or propyl ayioxyienozoate, ethylcellulose acetate phthalate, low-viscosity acetylcellulose acetate, paraffin wax, mineral waxes, essential wax, vegetable gum, silicone rubbers such as liquid polydimers, non-plasticized rubber mixtures, softened pooyyjháУeeleeietatet_^ monolithic collagen, crosslinked hydrophilic polyether gels, crosslinked polyvilyl alcohol or crosslinked partially hydrolyzed polyvinyl acetate.

The formulations are preferably prepared in the form of dosage units containing from 1 to 5

000 mg (preferably 25 to 500 mg) of the active ingredient. Examples of suitable dosage unit forms are tablets, hard or soft gelatin capsules, microcapsules and suppositories as well as drug dispersing systems comprising the active ingredient contained in a flexible, reformed polymeric material through which the drugs can slowly release diffusion. As used herein, a dosage unit form is a physically discrete unit containing an active ingredient, generally in admixture with and / or surrounded by a pharmaceutical carrier, wherein the amount of active ingredient is such that, for monoactive therapeutic administration, a single dose is normally used. or more units.

In addition to the active ingredient of formula (I), the compositions may also contain one or more pharmaceutically active ingredients, for example, non-estlicylic acid and its salts, caffeine, codeine phosphate, phthalic acid, placet amol, di-propoxy and indomeehacin.

Of course, the formulations may be adapted to the mode of administration. Thus, for oral administration, tablets, pills, capsules, solutions or suspensions may be used; for administration parenterally, a sterile injectable solution or suspension may be used; suppositories may be used for rectal administration; creams, solutions or maati may be used for topical administration. However, any of the foregoing preparations may be formulated in a delayed or sustained release form in a manner well known to those skilled in the art.

The following examples further illustrate the preparation of novel intermediates and novel end products of Formula I.

Example

2- (2-Phelyl-5-benzoxazolyl) propionic acid (a) 2- (4- · HycldooχУielУ) ppooPonltril

The finely ground 2- (4-amino-10-yl) -piperidine (73 g, 0.5 mol) was suspended in concentrated hydrochloric acid (125 mL). The stirred suspension was dinzotolane at 0 to 5 ° C with a solution of sodium nitrite (36.23 g, 0.525 mol) in water (60 ml), which was added dropwise over * 2 hours. The almost clear solution was stirred for an additional 10 minutes at 5-10 ° C, then poured into a stirred, boiling solution of concentrated sulfuric acid (250 mL) in water (2.5 mL).

After 6 minutes, it was cooled in an ice bath and then extracted with ether (4x). The combined ether extracts were extracted with 2N sodium hydroxide solution (6x). The combined extracts were cooled in an ice bath, acidified with concentrated hydrochloric acid and ex. needed with ether (3x). The combined ether extracts were washed with brine (3x), dried (Na 2 SO 4) and dried to give a dark brown oil (66.7 kg), which afforded 2- (4-hydroxyphenyl) in the rain. propionitrii (59.58 g), tv

to 46 ° C. '

112 to 122 ° C / 16.6 Pa, mp

Analysis:

calculated: 73.44% C, 6.16% H, 9.51% N;

Found:% C, 73.19;% H, 5.91;% N, 9.31.

(b) 2- (3-Nitro-4-lyydopxyphenyl) propionitil

A solution of 2- (4-hydroxy-phenyl) -propionitrile (7.79 g, 0.053 mol) in acetic acid (10 µL) was added over 40 minutes at 7-10 ° C with stirring to 12 N nitric acid (8 mL). During this time, an additional volume of glacial acetic acid (10 mL) was added. The resulting yellow suspension was stirred for an additional 30 minutes at 7 to 10 ° C, then an additional 30 minutes at -10 to -15 ° C. The suspension was diluted with water (approximately 90 mL). Filtration afforded 2- (3-nitro-4- (4-methylsulfonyl) -cyclohexyl) -

<td>^ ^ Cr pnítU</td><td colspan="2">as a yellow solid</td><td>(8.43 g), m.p.</td><td colspan="2">78-81</td>

<td>AinlVza:</td><td>calculated:</td><td>56.24%% C,</td><td>4.19% H,</td><td> 14,57</td><td>% N;</td>

<td></td><td>found:</td><td>56.29% C,</td><td>4.24% H,</td><td> 14,47</td><td>% N.</td>

c) (1) 2- (3-Amino-4-hydroxy-phenyl) -propipitate

2- (3-Nitro-4-hydrooietteitolpiooiooittil (123.8 g, 0.64 mol) was suspended in absolute ethanol (950 ml) and added over 20 minutes to a solution of stannous chloride dihydrate (437.8 g, 1, 94 mol) in concentrated hydrochloric acid (591 ml, 7 mo) The addition was carried out so quickly that the temperature of the reaction mixture did not exceed 20 DEG C. The mixture was stirred for an additional 19 hours at room temperature. The resulting solution mixed with ice (1.75 kg) was added 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 hour and the pH was then adjusted to 6 by addition of concentrated hydrochloric acid. The resulting suspension was filtered, the filtrate was saturated with sodium chloride and then extracted with ether (6x). The combined ether extracts after drying (Na 2 SO 4) and evaporation gave a solid (69.15 g), which was suspended in chloroform and extracted with 2 N hydrochloric acid (6x). The combined acid extracts were neutralized to pH 7-8 by the addition of sodium bicarbonate. The resulting suspension was extracted with ether (4x). The combined ether extracts were washed twice with water dried (Na 2 SO 4) and evaporated to give 2- (3-amino-4-hydroxyphenyl) ploplioitrile as a light brown solid (62.85 g), m.p. mp 110-112 ° C.

AAnaysis:

calculated: 66%, 64% C, 6.21% H, found: 66.45% C, 6.09% H,

N, 17.27;

16.99% N.

(c) (III) 2- (3-Amino-4-hydroxyXteeitprl) pionitrile was also prepared by the following method: 2- (3-Nitro-4-hydroxyl-4-hydroxyethyl) -polooloitil (38.4 g, 0.2 mol) was suspended in absolute ethanol (250 mL) and hydrogenated at 10 atmospheric pressure to 10% palladium on carbon at room temperature The hydrogenation was complete in 3.8 hours The catalyst was filtered off, evaporation of the filtrate gave 2- (3-aminip-4-ltr). Phenylphenylprooionitrile (17 g), mp, 110 ° C.

(d) 2- (3-Beelzaaiddp4-htroxyphthyl-ypropioate)

Beeioyl chloride (27.09 g, 0.19 mol) was added over 20 minutes while cooling to 0 to 3 ° C to a stirred solution of 2- (3-amino-4-hydroxy-phenyl) ppooionitrile (28.35 g, 0.175 mol). ) in dry pyridine (200 mL). When the addition was complete, the reaction mixture was heated at 100 ° C for 1 hour. Evaporation under reduced pressure gave crude 2- (3-. Enzaidido-4-lydroxyethyl) ploplipitrile as an oil.

(e) 2- (2-Phenyl-5-benzoyl-azyl) -polyolonitrile

The oil mentioned under (d) was boiled for 30 minutes so that the vapor temperature over the oil was raised to 130 ° C during this time. After cooling, the solution solidified. Reconstitution of the solids from methanol affords 2- (2-ethyl-5-benzoazlyl) -polylitrile (27.65 g), mp 118-120 ° C.

calculated: 77.39% C, 4.87% H, 11.28% N; Found: C 77.33, H 5.11, N. 11.34.

(f) 2- (2-Phenyl-5-benzoxazolyl) propionic acid

A solution of 2- (2-phenyl-5-benzoxazolyl) propionitrile (24 g, 0.096 mol) in concentrated hydrochloric acid (220 mL) was refluxed for 2.5 hours. The mixture was poured onto ice with 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 mp of 177-179^OC.

<td>Analysis:</td><td>H, 4.90; N, 5.24. Found:% C, 72.13;% H, 4.95;% N, 5.39.</td>

Example 2

In a similar manner to Example 1, the following compounds were synthesized:

(a) 2- (2-p-Fluorophenyl-5-benzoxazolyl) propionic acid, mp 162-164 ° C.

<td>Analysis: calculated: found:</td><td>67.36% C, 67.58% C,</td><td>4.24% H, 4.45% H,</td><td>4.91% N; 5.07% N.</td>

<td>(b) 2- (2-p-Chlorophenyl-5-)</td><td colspan="3">benzoxazolyl) propionic acid, mp 188-191 ° C.</td>

<td>Analysis: calculated:</td><td>63.68% C,</td><td>4.00% H,</td><td>4.64% N;</td>

<td>found:</td><td>63.50% C,</td><td>4.16% H,</td><td>4.72% N.</td>

<td colspan="4">(c) 2- (2-m-Chlorophenyl-5-benzoxazolyl) propionic acid, mp 173-175 ° C.</td>

<td>Analysis: calculated:</td><td>63.68% C,</td><td>4.00% H</td><td>4.64% N;</td>

<td>found:</td><td>63,50 «C,</td><td>4.01% H,</td><td>4.75% N.</td>

<td>(cl) 2- (2-p-Methylphenyl-5)</td><td colspan="2">(benzoxazolyl) propionic</td><td>acid, mp 166-168 ° C.</td>

<td>Analysis: calculated:</td><td>72.58% C,</td><td>5.37% H,</td><td>4.97% N;</td>

<td>found:</td><td>72.36% C,</td><td>5.46% H,</td><td>5.4% N.</td>

<td>(e) 2- (2-m-Methylphenyl-5)</td><td colspan="2">(benzoxazolyl) propionic</td><td>acid, mp 155-157 ° C.</td>

<td>Analysis: calculated:</td><td>72.58% C,</td><td>5.37% H,</td><td>4.97% N;</td>

<td>found:</td><td>72.39% C,</td><td>5.61% H,</td><td>5.14% N.</td>

<td>(f) 2- (2-o-Methylphenyl-5)</td><td colspan="2">(benzoxazolyl) propionic</td><td>acid, mp 107-110 ° C.</td>

<td>Analysis: calculated:</td><td>72.58% C,</td><td>5.37 «H,</td><td>4.97% N;</td>

<td>found:</td><td>72.54% C,</td><td>5.59% H,</td><td>4.77% N.</td>

<td>(g) 2- (2-p-Methoxyphenyl-</td><td colspan="2">5-benzoxalazolyl) propionic acid</td><td>acid, mp 180-191 ° C</td>

<td>Analysis: calculated:</td><td>68.67% C,</td><td>5.08% H,</td><td>4.71% N;</td>

<td>found:</td><td>68.42% C,</td><td>5.36% H,</td><td>4.72% N.</td>

<td colspan="3">(h) 2- (2-p-chlorophenyl-5-benzoxazclyl) propionitrile</td><td>mp 150-153 ° C.</td>

<td>Analysis: calculated:</td><td>67.96% C,</td><td>3.92% H,</td><td>N, 9.90;</td>

<td>found:</td><td>67.57% C,</td><td>3.96% H,</td><td>9.25% N.</td>

(i) 2- (2-p-Acetylphenyl-5-benzoxazolyl) propionic acid, mp 207-209 ° C.

if

Analysis: Calculated: C 69.90, H 4.85, N 4.53.

Found:% C, 69.72;% H, 4.75;% N, 4.50.

Example 3 (a) 2- (2-p-Bromophenyl-5-benzoxazolyl) propionic acid from one third hydrochloride. This compound was prepared using the procedure described in Example 1.

The product, mp 195-197 ° C, contained one third of the hydrogen chloride molecule.

Analysis: Calculated: C 53.60, H 3.46, N 3.90.

Found: C, 53.25; H, 3.37; N, 3.88.

(b) 2- (2-p-Bromophenyl-5-benzoxazolyl) propionic acid sodium salt 2- (2-p-Bromophenyl-5-benzoxazolyl) propionic acid, one-third hydrochloride (4.3 g, 0.012 mol) was ground in 1 N sodium hydroxide (20 mL). An equal volume of chloroform was added to the suspension. The suspension was stirred, then filtered. Recrystallization of the solid residue from aqueous ethanol gave 2- (2-p-bromophenyl-5-benzoxazolyl) -propionic acid sodium salt, mp &amp; gt; 316 ° C.

H, 3.01; N, 3.8%.

Found:% C, 51.99;% H, 3.17;% N, 4.07.

Example 4

2-Phenyl-5-benzoxazolylacetic acid

A solution of 2-phenyl-5-benzoxazolylacetonitrile (8.9 g) prepared according to the method described in Example 1 (e) - in concentrated hydrochloric acid (80 ml) was heated on a steam bath for 2.5 hours. The solution was then diluted with ice-water and allowed to stand. The solid product was crystallized from toluene to give white crystals of 2-phenyl-5-benzoxazolylacetic acid, mp 175 ° C.

For C15H11NO3: calculated: 71.1% C, 4.4% H, 5.5% N; found: 7), 0% C, 4.4% H, 5.6% N.

Example 1

2-Phenyl-6-benzoxazolylacetic acid (a) 6-Methyl-2-phenylbenzoxazole

Benzoyl chloride (79 mL) was added slowly to a stirred suspension of 6-amino-m-cresol (83 g) in pyridine (600 mL). The temperature was kept under reflux for 2 hours, then evaporated to dryness to give an oil. This oil was extracted with aqueous 2 N 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 as water was released. The resulting liquid was cooled, the solid product was pulverized and poured into petroleum ether. The solution was mixed with activated carbon and the filtrate evaporated to dryness to give 6-methyl-2-phenyl-benzoxazole, mp 93 ° C.

(b) 6-Bromomethyl-2-phenylbenzoxazole

N-Bromosuccinimide (25.9 g) was added to a cooled solution of 6-methyl-2-phenylbenzoxazole (30 g) in carbon tetrachloride (250 mL). After addition of benzoyl peroxide (500 mg), the mixture was refluxed for 3 hours in the presence of ultraviolet light. Solid residue. was filtered. The filtrate was evaporated somewhat, decolourised with charcoal and cooled. The crystals 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 dimethyl200455 formamide (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-benzoxazolylacetonitrile as white crystals, mp 144 ° C.

(d) 2-Phenyl-6-benzoxazolylacetic acid

A solution of 2-phenyl-6-benzoxazolylacetonitrile (11 g) in concentrated hydrochloric acid (100 mL) was heated on a steam bath for 1 hour. The solution was then cooled. The solid obtained was filtered and partitioned between aqueous sodium bicarbonate and chloroform. The aqueous layer was acidified with hydrochloric acid and extracted with chloroform. The chloroform extract was evaporated to dryness. Recrystallization from toluene gave a residue

<td colspan="3">white crystals of 2-phenyl-6-benzoxazolylacetic acid</td><td colspan="2">acids, e.g.</td><td>mp 170 ° C</td>

<td>Analysis: for C ^ HH ^NO ^</td><td></td><td></td><td></td><td></td><td></td>

<td>calculated:</td><td>71.1% C,</td><td> 4,4</td><td>% H,</td><td> 5,4 %</td><td>N;</td>

<td>found:</td><td>71.0% C,</td><td> 4,4</td><td>% H,</td><td> 5,5 %</td><td>N.</td>

He attaches

2-Phenyl-6-benzoxazolylacetic acid ethyl ester

A solution of 2-phenyl-6-benzoxazolylacetic acid (20 g) in ethanol (200 mL) was refluxed for 6 hours during which hydrogen chloride gas was bubbled into the solution. The oil obtained after evaporation of the solution was extracted with ether and this solution was evaporated to dryness. The solid formed by recrystallization from toluene / petroleum ether gave white crystals of 2-phenyl-6-benzoxazolylacetic acid ethyl ester, mp 76 ° C.

Analysis: for C ^ HH ^NO ^ requires: C, 72.6; H, 5.4; N, 5.0; Found: C 72.3%, H 5.4%, N 4.8%.

Example 7

2- (2-Phenyl-6-benzoxazolyl) propionic acid ethyl ester,

A solution of 2-phenyl-6-benzoxazolylacetic acid ethyl ester (34 g) in ether (200 mL) was added to a stirred solution of NaN? (From 3.2 g sodium) in liquid ammonia (500 mL). The red mixture was stirred for 15 minutes, then a solution of methyl iodide (8.5 mL) in ether (10 mL) was quickly added. When the reaction mixture was decolorized, the reaction was quenched by addition of excess ammonium chloride. The mixture was evaporated to dryness and the residue was extracted with ether. The ether solution was evaporated to dryness to give white crystals of 2- (2-phenyl-6-benzoxazolyl) propionic acid ethyl ester, mp 46 ° C.

Analysis: for ^C18^H17^N° C calculated: 73.2% C, 5.8% H, 4.7% N; Found:% C, 73.0;% H, 5.7;% N, 5.0.

Example 8

2- (2-Phenyl-6-benzoxazolyl) propyl alcohol

A solution of lithium aluminum hydride (about 2 g) in ether (50 ml) was slowly added to a solution of 2- (2-phenyl-6-benzoxazolyl) propionic acid ethyl ester (5 g) in ether (40 ml). The mixture was refluxed for 1 hour, then ethyl acetate was added slowly until gas escape stopped. Then 6 N hydrochloric acid was added and the ether layer was separated and dried. Silica gel chromatography gave pure 2- (2-phenyl-6-benzoxazolyl) propyl alcohol, mp 98 ° C.

<td>Analysis: for calculated:</td><td>75.9% C,</td><td>6.0% H,</td><td colspan="2">5.5% N;</td>

<td>found:</td><td>76.0% C,</td><td>5.8% H,</td><td> 5,5</td><td>«N.</td>

Example 9

2- (2-Phenyl-6-benzoxazolyl) propionamide

A mixture of 2- (2-phenyl-6-benzoxazolyl) propionic acid ethyl ester (4.4 g) and ammoniacal glycerol (40 mL) was heated to 150 ° C in an autoclave for 18 hours. The mixture was diluted to twice with water, the resulting white solid was filtered off and recrystallized from ethyl acetate to give white crystals of 2- (2-phenyl-6-benzoxazolyl) propionamide, mp 193 ° C.

Analysis: for C

<td></td><td>calculated: found:</td><td>72.2% C, 72.1% C,</td><td>5.3% H, 5.4% H,</td><td>10.5% N; 10.7% N.</td>

<td colspan="2">They were the same method</td><td colspan="2">prepared the following</td><td>compounds:</td>

<td colspan="4">(a) 2- (2-phenyl-5-benzoxazolyl) propionamide, m.p.</td><td>Mp 202-204 ° C</td>

<td>Analysis:</td><td>calculated:</td><td>72.2% C,</td><td>5.3% H,</td><td>10.5% N;</td>

<td></td><td>found:</td><td>72.0% C,</td><td>5.1% H,</td><td>10.4% N.</td>

<td>(b) 2-</td><td colspan="3">-p-Chlorophenyl-5-benzoxazolyl) propionamide</td><td>, mp 245 to</td>

<td>Analysis:</td><td>calculated:</td><td>63.89% C,</td><td>4.35% H,</td><td>N 9.31;</td>

<td></td><td>calculated:</td><td>63.64% C,</td><td>4.30 «H,</td><td>, 9.22% N.</td>

246 Noc: 2 ° C

Example 10

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

A solution of 2- (2-phenyl-6-benzoxazolyl) propionic acid ethyl ester (15 g) in concentrated hydrochloric acid (150 mL) was heated on a steam bath for 6 hours. The solution was cooled and the crystals formed were filtered off. These, after crystallization, ethanol-water mixtures gave 2- (2-phenyl-6-benzoxazolyl) propionic acid, mp 132 ° C.

Analysis: for ^H13^NO3 calculated: 71.9% C, 4.9% H, 5.2% N; Found: C 71.7, H 5.0, N 5.3%.

Example 11

2- (2-p-Chlorophenyl-6-benzoxazolyl) propionic acid (a) 2- (3-hydroxy-4-aminophenyl) propionic acid hydrochloride

A solution of 2- (2-phenyl-6-benzoxazolyl) propionic acid ethyl ester (10 g) in concentrated hydrochloric acid (150 mL) was heated at 160 ° C for 24 hours. The resulting mixture was evaporated to dryness and the residue was dissolved in water. This solution was washed with chloroform then evaporated to dryness to give 2- (3-hydroxy-4-aminophenyl) propionic acid hydrochloride as a white powder, mp 170 ° C (dec.).

(b) 2- (3-Hydroxy-4-aminophenyl) propionic acid ethyl ester

A solution of 2- (3-hydroxy-4-aminophenyl) propionic acid (5 g) in ethanol (100 mL) was saturated with hydrogen chloride and the resulting solution was refluxed for 6 hours. The solution was evaporated to dryness, the residue was dissolved in ethanol and this solution neutralized with sodium hydroxide solution. The evaporation residue was dissolved in chloroform and the solution was washed with water. Evaporation of the chloroform solution gave 2- (3-hydroxy-4-amino) ethyl ester

<td>PhenyDpropionic acids</td><td>tt 114</td><td>to 115 ° C.</td>

<td>Analysis: for C ^ HH ^NO ^</td><td></td><td></td>

<td>vypččteno:</td><td>63.1 56 C,</td><td>7.2, 56 H, 6.7 * N;</td>

<td>nelezeno:</td><td>63.2 56 C,</td><td>7.2 56 H, 6.9 56 N.</td>

(c) 2- (2-p-Chloro-phenyl-6-benzoxazolyl) -propionic acid ethyl ester

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

The residue was heated to 220 ° C until water was released, then cooled. This gave 2- (2-p-chlorophenyl-6-benzoxazolyl) propionic acid ethyl ester.

(d) 2- (p-Chlorophenyl-6-benzoxazolyl) propionic acid

A solution of 2- (2-p-chlorophenyl-6-benzoxazolyl) -propionic acid ethyl ester (4 g) in aqueous sodium hydroxide (30 mL) was heated on a steam bath for 1/2 hour. After cooling, the black solution was washed with chloroform. After acidifying the black solution with hydrochloric acid

The mixture was extracted with chloroform. This solution after evaporation gave 2- (2-p-chlorophenyl-6-benzoxazolyl) propionic acid, mp 196 ° C.

For C ^ HH ^CINO 11: calculated: 63.7% C, 4.0% H, 4.6% N, 11.8% Cl; Found: C 63.9%, H 4.2%, N 4.8%, Cl 12.0.

The following compounds were prepared in a similar manner:

(a) 2- (E - (3,4-methylenedioxyphenyl) -5-benzoxazolylpropionic acid ethyl ester, mp 76-79 ° C).

Anal. Calcd: 67.25 56.0, 5.0 56 H, 4.1 56 N;

found: 67.156C, 5.0556H, 4.4% N.

(b) 2- ¢ 2- (3,4-Methylenedioxyphenyl) -5-benzoxazolyl} propionic acid, mp 185-188 ° C.

H, 4.2; H, 4.5; 96 N;

found: 65.4 56 0, 3.9 56 Η, 4.7 56 N.

(c) 2- [2- (3,4-Dichlorophenyl) -5-benzoxazolyl] propionic acid, mp 169-173 ° C.

Anal. Calc &amp; apos; d: 57.156C, 3.356H, 4.256N;

Found: 56.9 56 C, 3.4 56 H, 4.1 56N.

(d) 2- [2- (3,4-Dichlorophenyl) -5-benzoxazolyl] propionic acid, mp, 151-153 ° C.

Anal. Calc &amp; apos; d: 57.156C, 3.356H, 4.256N;

₄ Found: 57.156C, 3.356H, 4.456N.

(e) 2- (2-p-Methylsulfonylphenyl-5-benzoxazolyl) propionic acid ethyl ester, m.p.

141 to 142 ° C.

<td>Analysis:</td><td>calculated:</td><td>61, 1 56 C,</td><td>5.1% H,</td><td>3.75 56 N;</td><td> *</td>

<td></td><td>found:</td><td>61, 2 56 C,</td><td>5.1% H,</td><td>3,6 56 N.</td><td></td>

(f) 2- U- (2-Furyl) -5-benzoxazolyl-propionic acid, mp 160-162 ° C.

Analysis:

calculated: 65.4% C, 4.3 56 H, 5.4 56 N; Found: 65.3% C, 4.4 56 H, 5.4 56 N.

(g) 2- (2-Cyclohexyl-5-benzoxazolyl) propionic acid, mp 115-117 ° C.

H, 7.00; N, 5.12.

Found:% C, 70.58;% H, 6.86;% N, 5.35.

(h) 2- (2-m-Trifluoromethylphenyl-5-benzoxazolyl) propionic acid, mp 144-147 ° C.

Found: C, 60.89; H, 3.60; N, 4.17.

Found:% C, 61.05;% H, 3.87;% N, 4.41.

(i) 2- / 2- (2H-thienyl) -5,5-benzoxezolyl propionic acid, mp 161-163 ° C.

Analysis: calculated: 61.5% C, 4.05% H, 5.12%. N;

Found:% C, 61.72;% H, 4.19;% N, 5.07.

(j) 2- (2-O-ChloophenylT5Tb)_enof_OXB7Oiy) propionic acid, mp 101-103 ° C. .

% H, 4.01;% N, 4.64.

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

(K) 2- (2-p-Trifluoromethylphenyl-5-benzoxazolyl) propionic acid, mp 165-168 ° C.

AAelysis: calculated: 60.89% C, 3.60% H, 4.17% N;

Found: C 60.76, H 3.88, N 4.34.

(1) 2T (2-p-iodophenylT5Tbenzoxazolyl) propionic acid, mp 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.

(m) 2- (2-m-Fluorophenyl-5-benzoxazolyl) propionic acid, mp 135-141 ⁰C.

<td>Analysis:</td><td>calculated: 67-36% C, 4.24% H, 4.91% N; found: C, 67.46; H, 4.37; N, 5.11.</td>

(n) 2- [3- (3,5-Dichlorophenyl) -5-benzoxazolyl] propionic acid, mp 161-165 ° C.

<td>Aialysis:</td><td>H, 3.29; N, 4.16. Found: C 57.13, H 3.51, N 4.22.</td>

(o) 2T (2-o-Floorphenyl-5-benzoxazolyl) propionic acid, mp 180-183 ° C.

AAnysis:

calculated: 67.36% C, 4.24% H, 4.91% N;

Found:% C, 67.16;% H, 4.50;

(p) 2- (2-fluoro-phenyl (-6-benzoxisolyl) -propionic acid, mp 147 ° C).

<td></td><td>Analysis:</td><td>calculated:</td><td>67-, 4% C,</td><td>4.2% H, 4.9% N,</td><td>6.7% F;</td>

<td></td><td></td><td>found:</td><td>67.2% C,</td><td>H, 4.4; N, 4.9;</td><td>6.8% Ί.</td>

<td></td><td> (^q) 2-(2-</td><td>p-Chlor^Fen^yl-⁵“</td><td colspan="2">be ^ r ^ zoxaz ^^^yl)^ f ^] ^^ P^and^ c ^ n ^ ov^and V, U</td><td>188 to</td>

<td> * </td><td>Ainlýza:</td><td>calculated:</td><td>63.68% C,</td><td>H, 4.00; N, 4.64.</td><td></td>

<td></td><td></td><td>found:</td><td>6 ^ 3 5 ^ 0 ° C.</td><td>4-116% H. 4&gt; 72% N.</td><td></td>

Example 12

2- (2-o-Chloro-phenyl-6-benzoxazolyl) -propionic acid (a) 2- (2-o-Chloro-phenyl-6-eenzoxazoles) -dopopionic acid ethyl ester

A solution of o-chlorobenzaldehyde (4.3 g) and 2- (3-hydroxy-4-aminophenyl) propionic acid ethyl ester (6 g) was heated in toluene (100 mL), while the water formed during the galling was collected from use of Deen-Stark apparatus. After 30 minutes the solution was evaporated to dryness. .

The residue was dissolved in acetic acid (100 mL), lead acetate (15 g) 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 an oil, 2- (2-o-chlorophenyl-eenzoxazolyl) -popionic acid ethyl ester, a sample of which passed a successful microanalysis.

(b) 2- (2-t-Chloro-phenyl-6-benzyl) -propioic acid

The 2- (2-i-chlorophenyl-6-benzoxazolyl) -popionic acid ethyl ester prepared according to (a) was stirred with sodium hydroxide solution (50 m). After 1 1/2 hour the solution was evaporated to dryness. Recrystallization from ether yielded 2- (2-i-chloro-1-yelix-6-azixazziyl) -propioic acid, mp 108-110 ° C. .

Analysis: for C ^ HH ClClNOj: C, 63.7; H, 4.0; N, 4.6; Cl, ​​11.8;

found: 63.5% C. 4J% H. 4.8% N · 12.0% Cl.

Example 13

2- β- (3-Nitri-4-chloro-phenyl) -bentoxazin-5-yl-propionic acid

A solution of 3-nitro-4-trienzaldehyde (0.925 g) and 2- (3-amino-4-hydroxyreeyl) ​​propionic acid (0.900 g) in ethanol (25 m) was refluxed for 3.5 hours. Ro of the after-flow gave a solid Schirr base which was dissolved in hot acetic acid (50 mL). After addition of lead vinegar (2.8 g), the reaction mixture was allowed to stand at room temperature. The next morning, water (200 mL) was added causing a sticky solid to precipitate from the reaction mixture. This was dried and triturated with a small amount of chloroform, resulting in ^whosestou ^benzoxazole acid ⁽0^,5 ^G) · ^t. t.²¹⁰ and^of 213 ° C.

Analysis: Calculated: C 55.4%, H 3.2%, N 8.1%;

Found:% C, 55.2;% H, 3.2%;

In a similar manner, the following compound was prepared: 2- (2-p-Nitrophenyl-5-benzylxazilyl) propionic acid, mp 211-217 ° C.

H, 3.87; N, 8.97.

Found: C 61.29, H 3.75, N 8.68.

In the following examples of pharmaceutical compositions of the present invention, the term medicament is used to refer to 2- (2-p-chlorrenyl-5-beezxaztlyl) propioic acid. This compound can, of course, be replaced by any other active compound of formula I and multiply. The medicament may be increased or decreased according to the degree of efficacy of the medicament.

Example 1 14

Tablets, each containing 100 mg of medicament, are prepared as follows.

medicament potato starch lactone

100 ALIGN! mg mg mg ethylcellulose (as a 20½ solution in crude alcohol) 2 mg alginic acid · 7 mg magnesium stearate · 1 mg talc · · · 2 mg. total. 175 mg

The medicament, starch and lactose are sieved through a sieve. 44 mesh BSS and blended together.

It is mixed with the recovered dust. ethylcellulose solution and sieving through a sieve 12 mesh BSS The obtained granules are dried at 50-60 ° C and then. -prosety síeem 16.mesh BS.S. Alginic acid, magnesium stearate and talc, which are first sieved through No. 60 mesh BSS are added to the granules, mixed and blended with a 175 mg hmoonoot tablet.

The capsules, each containing 200 mg of medicament, are prepared as follows. medicament 200mg lactose 443mg stdarao magnesium 2mg

Medicines, lactose and magnesium stearate are sieved through a sieve. 44 mesh BSS and filled to 250 mg in hard gelatin capsules.

Example 16 Injectable solutions each containing 100 mg of medicamene in 5 ml of solution are prepared as follows:

medicament 100 mg sodium hydroxide (1 (9? solution) qs

water for injection up to 5 ml

Sodium hydroxide solution is added dropwise with stirring to the drug suspended in water until the medicament is in solution. The pH of the solution is adjusted to 8.0-8.5, the solution is sterilized by bacterial filter filtration and filled into pre-sterilized glass ampoules, which are then hermetically sealed under aseptic conditions.

Example 17

Suppositories, each containing 250 mg of medicament, are prepared as follows. as follows:

250 mg cocoa powder up to 2000 mg

МесИк ^ ет !, after screening No. 60 mesh BSS, is suspended in cocoa butter previously thawed using as little as possible. heat. The mixture is then poured into a suppository mold having a capsule of 2 g and allowed to cool.

Example 18

The assay used to determine prziiianli activity was modified from the rat foot edema test by Wiiner, Risley et al., Proc. Soc. exp. Bizl. Copper. 11, 544 (196;?).

Groups of 4 rats of 140-170 g weight were orally dosed for 3 hours at 0.5 hours prior to injection of 0.1 ml of a 1% suspension of camaradol (Gelozzod ST-1) in 0.9% saline to plantation surface of the right hind leg of each rat. The total dose of each compound administered did not exceed approximately one quarter of the oral LD50 predetermined by the graphic method, up to a maximum of 200 mg / kg, two at half an hour. volumes (right) were measured by mercury positive-pressure plethysmogref after caragdeolin injection. feet injected with korageenin and volumes of (left) feet injected with carageenin. Rooddl was considered as the degree of inflammation induced. The average volume increase for each group was calculated and the results were expressed as a percentage of swelling prevention as compared to the control group of ten rats dosed with saline and tested in parallel.

The toxicity of the subject compounds was investigated in mice using assays designed to determine a level at which no clear fumacological effects were observed in untreated animals and approximate LD 50. Groups of mice of about 20 g were administered orally or italy at the same time^,conclusively at levels increasing steadily by double. The oral doses of finely divided drugs in an inert suspension medium were 1,600, 800, 400, 200 and 100 mg / kg, and the intraperitoneal doses were 800, 400, 200, 100 and 50 mg / kg. A series of tests were performed to detect changes in the autonomous console, reflexes, and -coordination, many times within the first 4 hours after administration, · again the next day and possibly 2 days or days thereafter.

The results are summarized in the following table:

CHU ^ K³

<td rowspan="2">Example #</td><td rowspan="2">Position CHR²R³</td><td rowspan="2">R²</td><td rowspan="2">R³</td><td rowspan="2">R⁴</td><td rowspan="2">T. t. Noc: 2 ° C</td><td colspan="2" rowspan="2">Approximate^LD5_tomg / kg</td><td colspan="2">Anti-inflammatory activity! vzhlddmrn to karagee_nand_nu</td>

<td>Dose, nm / ik? x2 ·</td><td>Inhibition of edema %</td>

<td> 1</td><td> 5-</td><td>Me</td><td>CO2H</td><td>Ph</td><td> 177-179</td><td></td><td> 800</td><td> 50</td><td> 55</td>

<td>2 (a)</td><td> 5-</td><td>Me</td><td>what₂H</td><td>pF.Ph</td><td> 162-164</td><td> 1</td><td> 200</td><td> 100</td><td> 41</td>

<td>2 (b)</td><td> 5-</td><td>Me</td><td>what₂H</td><td>p-Cl.ph</td><td> 189-190</td><td></td><td> 800</td><td> 50</td><td> 78</td>

<td>2 (c)</td><td> 5-</td><td>Me</td><td>what₂H</td><td>md.Ph</td><td> 173-175</td><td> 1</td><td> 200</td><td> 100</td><td> 40</td>

<td>2 (d)</td><td> 5-</td><td>Me</td><td>WHAT₂H</td><td>p-Me Ph</td><td> 166-168</td><td> 1</td><td> 600</td><td> 100</td><td> 69</td>

<td>2 (e)</td><td> 5-</td><td>Me</td><td>COgH</td><td>m-Me, Ph</td><td> 155-157</td><td> 1</td><td> 200</td><td> 100</td><td> 40</td>

<td>2 (f)</td><td> 5-</td><td>Me</td><td>CO2H</td><td>o-Me, Ph</td><td> 107-110</td><td></td><td> 600</td><td> 100</td><td> 70</td>

<td>2 (g)</td><td> 5-</td><td>Me</td><td>CO.H.</td><td>p-OME, Ph</td><td> 189-191</td><td> &gt;1</td><td> 600</td><td> 100</td><td> 40</td>

<td>2 (h)</td><td> 5-</td><td>Me</td><td>CN</td><td>p-Cl.Ph</td><td> 150-153</td><td></td><td colspan="2">Intermediate</td><td></td>

<td> 2(1)</td><td> 5-</td><td>Me</td><td>CO2H</td><td>p-Ac.Ph</td><td> 207-209</td><td> 1</td><td> 600</td><td>NT</td><td></td>

<td>3 (b)</td><td> 5-</td><td>Me</td><td>WHAT₂On</td><td>p-Br.Ph</td><td> &gt;316</td><td> 1</td><td> 200</td><td> 100</td><td> 58</td>

<td> 4(</td><td> 5-</td><td>Me</td><td>WHAT₂Et</td><td>Ph</td><td> 45-46</td><td> &gt;1</td><td> 600</td><td> 100</td><td> 29</td>

<td> (</td><td> 5-</td><td>Me</td><td>HOgEt</td><td>p-Cl.Ph</td><td> 59-62</td><td> 1</td><td> 600</td><td> 100</td><td> 51</td>

<td> 5</td><td> 5-</td><td>Me</td><td>CH2OH</td><td>Ph</td><td> 99-103</td><td></td><td> 800</td><td> 100</td><td> 44</td>

<td> 6</td><td> 5-</td><td>H</td><td>COgH</td><td>Ph</td><td> 175</td><td> 1</td><td> 200</td><td> 100</td><td> 68</td>

<td> 7</td><td> 6-</td><td>H</td><td>CO2H</td><td>Ph.</td><td> 170</td><td> 1</td><td> 200</td><td> 100</td><td> 61</td>

<td> 8</td><td> 6-</td><td>H</td><td>WHAT₂Et</td><td>Ph</td><td> 76</td><td> 1</td><td> 200</td><td> 100</td><td> 61</td>

<td> 9</td><td> 6-</td><td>H</td><td>WHAT₂Et</td><td>Ph</td><td> 46</td><td></td><td>NT</td><td>NT</td><td></td>

<td> 10</td><td> 6-</td><td>Me</td><td>CHgOH</td><td>Ph</td><td> 98</td><td></td><td> 800</td><td> 100</td><td> 61</td>

<td> 1 1</td><td> 6-</td><td>Me</td><td>CONH₂</td><td>Ph</td><td> 193</td><td></td><td>NT</td><td>NT</td><td></td>

<td>(and)</td><td> 5-</td><td>Me</td><td>CONH₂</td><td>Ph</td><td> 202-204</td><td> &gt;1</td><td> 600</td><td> 100</td><td> 50</td>

<td>(b)</td><td> 5-</td><td>Me</td><td>C0NH₂</td><td>pH.Ph</td><td> 245-246</td><td> &gt;1</td><td> 600</td><td> 50</td><td> 46</td>

<td> 12</td><td> 6-</td><td>Me</td><td>CO2H</td><td>Ph</td><td> 132</td><td></td><td> 600</td><td> 50</td><td> 60</td>

<td> 13</td><td> 6-</td><td>Me</td><td>CO2H</td><td>p-Cl.Ph</td><td> 196</td><td> 1</td><td> 200</td><td> 50</td><td> 28</td>

<td>(and)</td><td> 5-</td><td>Me</td><td>WHAT₂Et</td><td>3,4-OMeO.</td><td> 76-79</td><td></td><td>NT</td><td>. NT</td><td></td>

<td></td><td></td><td></td><td></td><td>.Ph</td><td></td><td></td><td></td><td></td><td></td>

<td>(b)</td><td> 5-</td><td>Me</td><td>CO2H</td><td>3,4-OMeO.</td><td> 185-188</td><td></td><td> 800</td><td> 100</td><td> 48</td>

<td></td><td></td><td></td><td></td><td>.Ph</td><td></td><td></td><td></td><td></td><td></td>

<td>(C)</td><td> 5-</td><td>Me</td><td>CO2H</td><td>3,4-diCl.</td><td> 169-173</td><td></td><td> 600</td><td> 50</td><td> 37</td>

<td></td><td></td><td></td><td></td><td>.Ph</td><td></td><td></td><td></td><td></td><td></td>

<td> (4).</td><td> 5-</td><td>Me</td><td>CO2H</td><td>2,4-diCl.</td><td> 151-153</td><td></td><td> 800</td><td> 100</td><td> 74</td>

<td></td><td></td><td></td><td></td><td>.Ph</td><td></td><td></td><td></td><td></td><td></td>

<td>(E)</td><td> 5-</td><td>· Me</td><td>COzgEt</td><td>p-MeSO-.</td><td> 141-142</td><td></td><td>NT</td><td>NT</td><td></td>

<td></td><td></td><td></td><td></td><td>.Ph</td><td></td><td></td><td></td><td></td><td></td>

<td rowspan="3">Example #</td><td colspan="2" rowspan="3">Position chr²r³</td><td rowspan="3">R²</td><td rowspan="3">R³</td><td rowspan="3">R⁴</td><td rowspan="3">T. t. Noc: 2 ° C</td><td colspan="3">Approximate Anti-inflammatory</td>

<td rowspan="2">^LD50 mg / kg</td><td colspan="2">activity relative to carageenin</td>

<td>Dose, mg / kg x2</td><td>Inhibition of edema %</td>

<td>I3 (f)</td><td> 5-</td><td></td><td>Me</td><td>what₂h</td><td>2-furyl</td><td> 160-162</td><td> 600</td><td> 50</td><td>²³</td>

<td>(G)</td><td> 5-</td><td></td><td>Me</td><td>what₂h</td><td>cyclohexyl</td><td> 115-117</td><td> 1 200</td><td>NT</td><td></td>

<td>(h)</td><td> 5-</td><td></td><td>Me</td><td>WHAT₂H</td><td>m-CF-pPh</td><td> 144-147</td><td> 1 200</td><td> 100</td><td> 0</td>

<td>(and)</td><td> 5-</td><td></td><td>Me</td><td>WHAT₂H</td><td>2-thienyl</td><td> 161-163</td><td> 400</td><td> 50</td><td> 24</td>

<td> (3)</td><td> 5-</td><td></td><td>Me</td><td>C0₂H</td><td>o-Cl.Ph</td><td> 101-103</td><td> 1 200</td><td> 100</td><td> 52</td>

<td>(to)</td><td> 5-</td><td></td><td>Me</td><td>C0₂H</td><td>p-CFyPh</td><td> 165-168</td><td> 300</td><td> 100</td><td> 27</td>

<td> (1)</td><td> 5-</td><td></td><td>Me</td><td>C0₂H</td><td>pI.Ph</td><td> 205-208</td><td> 1 200</td><td> 100</td><td> 40</td>

<td>(m)</td><td> 5-</td><td></td><td>Me</td><td>WHAT₂H</td><td>mF. Ph</td><td>135-U2</td><td> 800</td><td> 100</td><td> 41</td>

<td>(n)</td><td> 5-</td><td></td><td>Me</td><td>C0₂H</td><td>3,5-diCl. .Ph</td><td> 161-165</td><td> 600</td><td> 50</td><td> 56</td>

<td>(O)</td><td> 5-</td><td></td><td>Me</td><td>^C02^H</td><td>oFPh</td><td> 180-183</td><td> 1 600</td><td> 100</td><td> 50</td>

<td>(p)</td><td> 6-</td><td></td><td>Me</td><td>C0₂H</td><td>pF.Ph</td><td> 147</td><td> 1 200</td><td> 50</td><td> 48</td>

<td>(Q)</td><td> 5-</td><td></td><td>Me</td><td>WHAT₂H</td><td>p-Cl.Ph</td><td> 188-191</td><td> 800</td><td> 50</td><td> 78</td>

<td> 14</td><td> 6-</td><td></td><td>Me</td><td>WHAT₂H</td><td>o-Cl.Ph</td><td> 108-110</td><td> 1 200</td><td> 50</td><td> 60</td>

<td> 15</td><td> 5-</td><td></td><td>Me</td><td>WHAT₂H</td><td>3-pyridyl</td><td> 197-200</td><td> 600</td><td> 50</td><td> 37</td>

<td>. (and)</td><td> 5-</td><td></td><td>Me</td><td>C0₂H</td><td>4-pyridyl</td><td> 247-250</td><td> 600</td><td> 50</td><td> 15</td>

<td>(b)</td><td> 5-</td><td></td><td>Me</td><td>WHAT₂H</td><td>2-pyriayl</td><td> ’ 177-179</td><td> 600</td><td> 50</td><td> 36</td>

<td>(C)</td><td> 5-</td><td></td><td>Me</td><td>WHAT₂H</td><td>p-Cl.Ph</td><td> 188</td><td> 800</td><td> 50</td><td> 78</td>

<td> 16</td><td> 5-</td><td></td><td>Me</td><td>CONEt</td><td>Ph</td><td> 108-110</td><td> &gt;1 600</td><td> 100</td><td> 0</td>

<td> 17</td><td> 5-</td><td></td><td>Me</td><td>CONHOH</td><td>Ph</td><td> 204-205</td><td>NT</td><td>NT</td><td></td>

<td> 18</td><td> 5-</td><td></td><td>H</td><td>WHAT₂H</td><td>p-Cl.Ph</td><td> 241-242</td><td> &gt;1 600</td><td> 50</td><td> 31</td>

<td> 19</td><td> 5-</td><td></td><td>Me</td><td>WHAT₂On</td><td>p-Cl.Ph</td><td> 312-314</td><td> 1 200</td><td> 50</td><td> 52</td>

<td>20 b</td><td> 5-</td><td></td><td>Me</td><td>^C02^Et</td><td>Me</td><td></td><td>NT</td><td></td><td></td>

<td>(C)</td><td> 5-</td><td></td><td>Me</td><td>what₂h</td><td>Me</td><td>15-П7</td><td> 1 600</td><td> 100</td><td> 4</td>

<td> 21*</td><td> 5-</td><td></td><td>Me₂</td><td>what₂h</td><td>Ph</td><td> 92-95</td><td>NT</td><td>NT</td><td></td>

<td> 22</td><td> 5-</td><td></td><td>Me</td><td>what₂h</td><td>3-no₂. .4-Cl.Ph</td><td> 210-213</td><td>NT</td><td>NT</td><td></td>

<td> 23</td><td> 6-</td><td></td><td>H</td><td>CH₂0H</td><td>Ph</td><td> 69</td><td> &gt;1 600</td><td> 100</td><td> 47</td>

<td colspan="2">Explanatory notes:</td><td>Me =</td><td>methyl</td><td></td><td>Ph = phenyl</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>Et =</td><td>ethyl</td><td></td><td>Ас = асеtyl</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>NT =</td><td colspan="2">netestováno</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td colspan="2">* acid</td><td>isomáselná</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td colspan="2">From the above</td><td colspan="2">• the table shows</td><td>that derivatives</td><td>benzoxazole</td><td>produced</td><td>way</td><td>according to</td>

of the invention have excellent anti-inflammatory activity and low toxicity.