DE2450042A1 - NEW BENZOXAZOLE DERIVATIVES AND THE PROCESS FOR THEIR PRODUCTION - Google Patents

Description

Applicant: LILLY INDUSTRIES LIMITED ■ Henrietta House, Henrietta Place, London, W. ^Λ , ., England

0? 49 642

New benzoxazole derivatives and processes for their

Manufacturing

The invention relates to certain new benzoxazole derivatives, which have a valuable pharmacological activity or as intermediates for the preparation of such active compounds are suitable, as well as a process for the preparation of these compounds; The invention also relates to pharmaceutical preparations which these pharmacologically active compounds in an effective dose and which can be administered to animals and humans. The invention also relates to new intermediates, from which the new benzoxazole derivatives can be produced.

The invention relates to new benzoxazole derivatives of the general formula

S09817 / 1221 -2-

Λ Ο 7.

worm the group -CR RH ^ is in the 5- or 6-position of the benzoxazole nucleus, R is hydrogen, C ₁ , - alkyl or halogen, R is hydrogen, C ^ g-alkyl, halogen,

Hydroxy, C _1-6 -AIkOXy, Cg ^ -acyloxy or NR ¹¹ R ¹² , where R is hydrogen or C., - alkyl and R ^{12 is} hydrogen,

I-O -z

or C ₂ O-AcJl, R ^ is a nitrile group, a carboxy group or a salt- ^ an ester, amide or hydroxamic acid derivative thereof or a group of the formula

, 13

N-N

-N

or

Yes

Ib

14th

13 14
where R ^y and R independently of one another are hydrogen, C ^ j__g-alkyl or G ^ ^ -hydroxyalkyl, R is phenyl, optionally in an available position by one or more of the radicals C _y ._g-alkylsulfonyl, O ^ -g-alkyl , C _1-6 -AIkOXy, C _1-6 -HaI ο ge nalkyl, C ^ r ₇ -ACyI, nitro, amino, hydroxy or halogen or is optionally substituted in two adjacent positions by methylene or ethylenedioxy, and A-CH ₂ -, -CO-, -CHOR- or -KR-, where R is hydrogen, C ^^ - alkyl or C ₂ ^ i -, - acyl.

As used herein, "C _1-6 -Al-CyI" is a straight-chain (unbranched) or branched-chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, isopropyl, η-butyl, s-butyl, t-butyl, n -Amyl, s-amyl, n-hexyl, 2-lfhylbutyl and 4-methylamyl. In a corresponding manner, the terms "C _1-6 -AlkOXy", "C _1-6 -Alkylsulfonyl",

509817/1221

“C ₂ , -, - acyl” and “C ₂ n-acyloxy” are to be understood as meaning those groups in which the C, c groups defined above are each bonded via an oxygen atom or an -SO ₂ -, -CO- or -COO group are. The terms "C 1-6 hydroxyalkyl" and "C 1-6 haloalkyl" used here are to be understood as meaning groups in which the C 1-6 alkyl groups defined above are substituted by one or more hydroxyl groups or by one or more halogen atoms such as in2-chloroethyl, 2-hydroxyethyl, trifluoromethyl, chloromethyl, 3-hydroxypropyl, 3-bromopropyl, 2- (2-chloroethyl) -3-chloropropyl, pentafluoroethyl, 2-hydroxybutyl, 4-bromobutyl and 6-chlorohexyl.

Within the above group of compounds of the formula I, a subgroup is preferred because of the easy accessibility of the starting materials required for their production, the compounds

1 2 3, in which the group -CR R R ^ in the 5- or 6-

Il

Position of the benzoxazole nucleus, R is phenyl, which is in an .available position by one or two groups selected from C ^^ - alkyl, C ^^ - alkoxy, Co ^ 'acyl, C ^^ - alkylsulfonyl, C ^^ - Monohaloalkyl, trifluoromethyl, halogen, nitro, amino, hydroxy, or is optionally substituted in two adjacent positions by methylenedioxy, 'A -CH ₂ -, -CO-, -CHOR- or -HR- where R is hydrogen, methyl, ethyl or acetyl is, R is hydrogen, methyl, chlorine or bromine, R is hydrogen, methyl, ethyl, chlorine, bromine, hydroxy, 0 _Λ ^ -

11 12 11 oxy, C ₂ ^ -ACyIoXy or IR, where R is hydrogen,

Is methyl or ethyl and R ^{12 is} hydrogen, methyl, ethyl or acetyl; and R ^

(i) the group -COOR ^, in which R ^ is C ^^ - alkyl, or (ii) the group -COR ⁶ , in which R ^{6 is} -NHOH or -NR ^ R ⁸ ,

509817/1221

450042

O Q

where R and R are independently hydrogen or C ^ _ ^ - alkyl, or (iii) the group -GOOH or an alkali metal- or

Alkaline earth metal, aluminum or ammonium salt

of it or
(iv) a nitrile group or

(ν) a group of the formula Ia or Ib, where R and

14-

R, independently of one another, represent hydrogen, methyl, ethyl or hydroxyethyl.

A particularly valuable group of inventive Compounds are those of the general formula

II

R ²

wherein the group -CH-R ^ is in the 5- or 6-position of the benzoxazole _{nucleus, A -CH 2} -, -CO-, OH OCH ₃ OCOCH ₃ .

-CH-, -CH-, -CH-, -NH- or -NCH ₃ -, R ^{4 is} a phenyl group, which is optionally replaced by one or two groups,

selected from halogen, trifluoromethyl, methyl, meth-

oxy, acetyl or methylsulfonyl, R is hydrogen or preferably methyl and R is as defined above under (i) or (iii).

Examples of compounds of the present invention are as follows :

509817/1221

(i) 2- [2-Benzyl-5-benzoxazolyl> acetic acid
2- [2-Benzyl-5-benzoxazolyl] propionic acid

2- [2- (4-methylsulphonylbenzyl) -5-benzoxazolyl] propionic acid 2- [2- (3,4-Dimethylbenzyl) -6-benzoxazolyl / propionic acid 2- [2- (4-methoxybenzyl) -6-benzoxazolyl / propionic acid 2- [2- (4-p-chloro-ethylbenzyl) -5-benzoxazolyl] acetic acid 2- [2- (4-trifluoro-diethylbenzyl) -5-benzoxazolyl] acetic acid 2- [2- (4-.Apetylbenzyl) -6-benzoxazolyl / propionic acid 2- [2- (3j4-Dinitrobenzyl) -5-benzoxazolyl] butyric acid 2- [2- (3-aminobenzyl) -5-benzoxazolyl] propionic acid 2- [2- (4-Hydroxybenzyl) -6-benzoxazolyl] propionic acid 2- [2- (2,4-dichloro-benzyl) -6-benzoxazolyl] propionic acid 2- [2- (4-chloro-benzyl) -5-benzoxazolyl] acetic acid 2- [2- (4-chlorobenzyl) -5-benzoxazolyl] propionic acid. 2- [2- (4-brorft-benzyl) -5-benzoxazolyl] propionic acid 2- [2- (3,4-iethylene-dioxybenzyl) -5-benzoxazolyl] propionic acid 2- [2- (4-chloro-benzyl) -6-benzoxazolyl] -2-methylpropionic acid 2- [2-Benzyl-5-benzoxazolyl] -2-ethyl acetic acid

2- [2- (4-Itifluoro-raethylbenzyl) -5-benzoxazolyl] -2-bromopropionic acid 2- £ 2- (3,4-dichlorobenzyl) -5-benzoxazolyl] -2-methoxybutyric acid 2- [2- ( 4-ChloE-benzyl) -6-benzoxazolyl] -2-aminopropionic acid. 2- [2- (4-Kethylbenzyl) -5-benzoxazolyl] -2- (N-methylamino) propionic acid 2- [2- (4-frethoxybenzyl) -5-benzoxazolyl] -2- (N-acetylamino) acetic acid 2- Benzyi-5- [1- (5-tetrazolyl) ethyl] benzoxazole 2- (4-chloro-benzyl) -5- [1- (5-tetrazolyl) ethyl] benzoxazole _or 2- (4-chloro-benzyl) -5 -tetrazolylmethylbenzbxazol ^ 3 2- <4-oilor-benzyl) -5-1- (4,4-dimethyl-2-oxazolinyl) ethyl] benzoxazole.

- * · 2- [2- (4-Chloro-benzoyl) -5-benzoxazolyl] acetic acid ^ _x 2- [2- (4-Brcm-benzcyl) -5-benzoxazolyl] propionic acid 2- [2- (3,4 -Methylenedioxybenzoyl) ° 5-benzoxa2olyl! Propionic acid ι

- '- ■■ -; ■■,' ■■ .- ■■■ ...- ■ - - 6 -

2- [2-Benzoyl-5-benzoxazolyl] -2-ethylacetic acid 2450042

2- [2- (4-chloro-benzoyl) -6-bp; n _Z ov _{? Z} olyj] -2-hydroxy-acetic acid

2- [2- (4-Methoxybenz! Oyl) -5-benzoxazolyl] -2- (N-met hy I acetyl aminol acetic acid 2- [2-Benzoyl-5-benzoxazolyl] acetic acid

2- [2-Benzoyl-5-benzoxazolyl] propionic acid 2- [2- (4-methylsulphonylbenzoyl) -6-benzoxazolyl] propionic acid 2 [2- (3,4-bimethylbenzoyl) -5-benzoxazolyl] propionic acid 2- [ 2- (4-ß-Öilor-ethylbenzoyl) -6-benzoxazolyl] acetic acid 2- [2- (4-trifluoromethylbenzoyl) -5-benzoxazolyl] propionic acid 2- [2- (3-nitro-4-chloro- benzoyl) -5-benzoxazolyl / propionic acid 2- [2- (4-aniinobenzoyl) -6-benzoxazolyl] propionic acid 2- [2- (4-hydroxybenzoyl) -5-benzoxazolyl] propionic acid 2- [2- (2 _f 4-dichloro -benzoyl) -5-benzoxazolyl] acetic acid 2- [2- (a-flydroxybenzyl) -5-benzoxazolyl] acetic acid 2- [2- (aI ^ rdroxybenzyl) -5-benzoxazolyl] propionic acid 2- [2- (a -Hydroxy-4-chloro-benzyl) -5-benzoxazolyl] propionic acid 2- [2- (a-hydroxy-3 _f 4-diethylbenzyl) -6-benzoxazolyl] acetic acid 2- [2- (a-hydroxy-4 -raethoxybenzyl) -6-benzoxazolyl] propionic acid 2- [2- (a-hydroxy-4-trifluoro-methylbenzyl) -5-benzoxazolyl] propionic acid 2- [2- (a-flydroxy-4-acetylbenzyl) -5- benzoxazolyl] propionic acid 2- [2- (a, 4-dihydroxybenzyl) -6-benzoxazolyl] acetic acid 2- [2, -ahydroxy-2,4-dichloro-be nzyl) -5-benzoxazolyl] propionic acid 2- [2- (r-flydroxy-4-bromo'-benzyl) -5-benzoxazolyl] propionic acid 2- [2- (a-hydroxy-4-chlorobenzyl) - 5-benzoxazolyl] -2-hydroxypropionic acid 2- [2- (α-hydroxy-4-methylbenzyl) -6-benzoxazolyl] -2,2-dibromoacetic acid 2- [2- (α-hydroxybenzyl) -5-benzoxazolyl] -2-methoxypropionic acid Q- 2- (α-Hydroxy-4-chloro-benzyl) -5- [1- (5-tetrazolyl) ethyl] benzoxazole 1- [2- (α-methoxybenzyl) -5-benzoxazolyl] acetic acid

v. '■

- »2- [2- (c £ -ethox) 'benzyl) -5-benzoxazolyl] propionic acid ^ 2- [2- (a-acetoxybenzyl) -5-benzoxazolyl]' butyric acid 2- [2- (a-methoxy- 4-methylsulphonylbenzyl) »5-benzoxazoyl] propionic acid 2- [2- (a-Jithoxy-3,4-dimethylbenzyl) -6-benzoxaKoljrl] propionic acid 2- [2- (ce _f 4-methoxybenzyl) -6-benzoxazolyl] propionic acid - 7 ~

2- [2- (a-Acetoxy-A-ß-chloro-ethylbenzyl) -5-benzoxazolyl3esaip: acid 2- [2- (a-acetoxy-4-trifluoro-methylbc: nzyl .'- 5-bcn ^ o >'a2olyl] acetic acid 2- [2- (oi-ethoxy-4-acetylbenzyl) -6-benzoxazolyl] propionic acid 2- [2- (cc-methoxy-3,4-dinitrobenzyl) -5-benzoxazolyl}) uteric acid 2- [2- (cf-lfethoxy-3-aminobenzyl) -5-benzoxazolyl] propionic acid "2- [2- (ci-acetoxy-2,4-dichlorobenzyl) -6-benzoxazolyl] propionic acid 2- [2- (oi-Acetoxy-4-chlorobenzyl) -5-benzoxazolyl] acetic acid 2- [2- (aj \ ü.ethoxy-4-chlorobenzyl) -5-benzoxazoIyIJpropionic acid 2- [2- (a "ethoxy- 4-bromo-iDenzyl) -5-benzoxazolyl] propionic acid 2- [2- (a-acetoxy-3 _f 4-methylen-dioxybenzyl) -5-benzoxazolyl] propionic acid 2- [2- (oc ~ methoxy-4-chloro -benzyl) -6-benzoxazolyl] 2-propionic acid 2- [2- (a-methoxybenzyl) -5-benzoxazolyl] -2-ethylpropionic acid 2- [2- (a-acetoxy-4-trifluoro-methylbenzyl) -5 -benzoxazolyl] -2-acetoxyacetic-

acid 2- [2- (a-l-ethoxy-3,4-dichlorobenzyl) -6-benzoxazolyl] -2-methoxyessic acid 2- [2 - («- Ethoxy-4-chloro-benzyl) -5-benzoxazolyl] -2-ethoxypropionic acid 2- [2- (a, 4-Hraethoxybenzyl) -5-benzoxazolylj-2-chloropropionic acid 2- (oi-methoxybenz) 'l) -5- [l- (5-tetrazolyl) ethylbenzoxazole 2- (ppiIifethoxy-4-chlorobenzyl) -6- (5-tetrazolylmethyl) benzoxazole

2- (α-ICethoxy-4-chlorobenzyl) -5- [1- (2-oxazolinyl) ethyl] benzoxazole 2- [2-anilino-5-benzoxazolyl] propionic acid

2- [2- (N-i «iethylanilino) -5-benzoxazolyl] propionic acid 2- [2- (N-acetylanilino) -5-benzoxazolyl] essip; acid 2- [2- (4-chloro-anilino) -6-benzoxazolyl] butyric acid 2- [2- (4-i, / [ethylsulphonylanilino) -6-benzoxazolyl] acetic acid 2- [2- (N, 3,4-C trimethylanilino) -5-benzoxazolyl] propionic acid 2- [2- (4-methoxyanilino) -5-benzoxazolyl] propionic acid 2- [2- (4-ß-cJiloK-ethylanilino) -6-benzoxazolyl] propionic acid

Q 2- [2- (4-Trifluoro-methylanilino) -6-benzoxazolyl] acetic acid

co _r

co 2-L2- (Ni4-diacetylanilino) -5-benzoxazolyl-acetic acid - * 2- [2- (N-1, i2thyl-3,4-dinitroanilino) -5-benzoxazoyl] propionic acids ^ 2- [2- (4-hydroxyanilino) -6-benzoxazolyl] propionic acid

2 [(2 anilino) -6-benzoxazolyl] propionic acid

2- [2 -. (Ν · 5, ί ethyl-4-broraoanilino) -5-benzoxazolyl] essii?: säi] rff

2- [2-A-nilino-6-benzoxazolyl] acetic acid 2- [2- (4 € .chloro-anilino) -5-benzoxazolyl] propionic acid 2- (4-chloro-anilino) -5- [1- (5-tetrazolyl) ethyl] benzoxazole 2- (A.nilino) -5- [1- (4,4-di-β-hydroxyethyl-2-oxazolinyl) ethyl] bon20xazole 2- (4-chloro-anilino) -5- [1- (4,4-dimethyl-2-oxazolinyl) ethyl] benzoxazole 2- [2- (3,4-Ethylene-dioxyanilino) -5-benzoxazolyl] acetic acid 2- [2- (4-Chlpr-anilino) -6-benzoxazolyl] -2-triethylpropionic acid 2- [2- (4-trifluoro-methylanilino) -5-benzoxazolyl] -2-aminopropionic acid 2- [2- (4-Bromo-anilino) -5-benzoxazolyl] -2,2-dibromoacetic acid 2- [2- (N, 4-diraethylanilino) -6-benzoxazolyl] -2- (N-methylamino) propionic acid 2- [2- (4-methoxyanilino) -5-benzoxazolylj-2-methoxypropionic acid 2- [2-Anilino-6-benzoxazolyl] propionic acid

(ii) The sodium, potassium, calcium, aluminum and Ammonium salts of those given under (i) above Acids;

(iii) the C ^^ - alkyl esters, especially the methyl and ethyl esters of the acids given under (i) above;

(iv) the acetonitriles, propionitriles and butyronitriles corresponding to the acids given under (i) above;

(v) The acetamides, propionamides and butyranides corresponding to the acids given under (i) above and their N-methyl or N-ethyl derivatives and

(vi) the Acethydroxaidsäuren corresponding to the above under (i) carboxylic acids, propionyl

509817/1221 '- 9 -

hydroxamic acids and butyryl hydroxamic acids

The invention also relates to a process for the preparation of the compounds indicated above of the formula I, which is characterized in that a compound of the general formula

III

■ z v.

wherein Z is the group R ^ or one convertible to R Group means using a cyclizing agent which has the required group R -A- or a

Ii.

provide other group convertible to group R -A can, cyclized and then, if necessary, the compound obtained in the usual manner into the desired Compound of formula I converted.

If A in the end product of the formula I is -CH ₂ - or -CHOR, in which R is hydrogen or C ^ _ ^ - alkyl, the compound of the formula I can be prepared directly by reacting a suitable cyclization

H.

by means of, for example, a compound of the formula R -A-COOH, (R ^ -ACO) ₀ O, R ^ -A-COCl, R ⁴ -A-COITH _o , R ^4- -A-COKHNH ₀ or R -A -CN, with the compound of the formula III, the reaction under the influence of heat and / or under acidic conditions, for example in the presence of, hydrochloric acid, phosphorus oxychloride or polyphosphoric acid, or under basic conditions, for example in the presence of pyridine or Tiiäthylamini in Depending on the reactants used in each case. ,,

609817/1221

It is believed that the above cyclization proceeds via an intermediate in which one or more of the hydrogen atoms in the amino or phenol groups has (have) been replaced by a radical from the cyclizing agent. If, for example, the cyclizing agent is a compound of the formula R ^ -A-COOH, R ^ -A-COCl, R ^ -A-CONHp, R ^ -A-CONHNH ₂ or R ^ -A-CHO , the hydrogen atom in the phenolic hydroxyl group can be replaced by an R -A-CO group and one or both of the hydrogen atoms in the amino group can be replaced by R -A-CO- or by the group R -A-CH = ( if the aldehyde is used as a cyclizing agent). If A is -CH ₂ -, the intermediates are stable and, if desired, they can be isolated before the ring closure to give the benzoxazole. If the cyclizing agent is R -A-CHO, the ring closure can be carried out in the presence of an oxidizing agent such as lead tetraacetate or nickel peroxide.

If A in the end product of the formula I is -CO- or -CHOR-, wherein R is -Cp - ^ - acyl, the desired Compound from the corresponding compound prepared as described above, in which A denotes -CHOH-, by oxidation, for example using manganese dioxide or chromium trioxide, or by a conventional one Acylation can be produced.

When A is in the final product of formula I -NH-, the ring closure of the intermediate of formula III are carried out with an isocyanate of formula R can CNO, wherein directly the compound of formula I is obtained. Alternatively, the intermediate of the formula III • can be cyclized to a benzoxazolyl-2-thione, for example using an alkali metal alkyl • 603817/1221 - " ¹¹ "

xanthates, such as potassium ethyl xanthate, as cyclizing agents and the thione can then be converted into the corresponding 2-halogen compound by halogenation, for example with chlorine gas, for example 2-chlorobenzoxazole. To establish the connection of the Formula I, in which A is -NR-, becomes the 2-halogen compound then with the appropriate aniline of the formula

Zl
R, -UHR implemented. Alternatively, the thione can be reacted directly with the aniline.

The benzoxazole-2-thiones and halides in which R ^ denotes a nitrile, carboxylic acid or hydrochloric, amido, ester or hydroxamic acid group, represent new compounds If one considers the thione group in its thiol form writes, these compounds can be represented by the general formula

.CR ¹ R ² R ³

IV

wherein Q is -SH or halogen.

As is readily apparent to those skilled in the art, the intermediates of the formula IV in which Q denotes a halogen atom, e.g. iodine, using, for example, the known Ullmann reaction (cf. e.g. The Merck Index, VIIIth Edition, published 1968, page 1222) also converted into 2-phenyl derivatives will. The reactants and reaction conditions required for this "reaction are known to those skilled in the art. For the sake of explanation, however, the following typical reaction scheme is given:

- 12 S09817 / 1221

- 1

12 3 CR ¹ RR

CR ¹ R ² R ³

wherein X is hydrogen or halogen and Q and X are also halogen.

It should be noted that in carrying out the above reactions, if the group Z in the starting material of Formula III is allowed to react with the cyclizing agent or other reagents employed, the reaction will result in the formation of a mixture of products rather than the formation of the compound of Formula I alone · can Although the undesired products from the reaction mixture separated v can ground /, it is expedient to provide a compound of formula III react to use, in which Z is such a group that does not nit the other reactants. If Z is a group which can be converted into R, Z is preferably hydrogen or halogen and if Z is one of the groups as defined for B? Z is preferably a nitrile group or an esterified carboxy group, a carboxy or carboxyamide group converted into a salt,

As indicated above, if Z is not the group R ^, then the completion of the cycli-

509817/1221 -

transformation of the group Z into the desired one Connect group R ^. It is well known that many different Types of groups converted into the R functions in the desired compounds according to the invention will. According to the invention, however, it is preferred that when Z does not denote the group R ^, denotes hydrogen or halogen. If Z hydrogen means, can be obtained in the cyclization reaction Connection in the usual way, for example using chlorine, sulfuryl chloride, bromine or N-bromosuccinimide, preferably in the presence of a suitable solvent such as carbon tetrachloride, are halogenated to form the corresponding compound in which Z is halogen. This connection or the same compound used in the above cyclization reaction can then be obtained with an alkali metal cyanide in a suitable diluent or solvents, usually under the action of heat, are reacted to form a compound of the formula I, in which R is CN.

The latter compound or the same compound which is obtained directly in the above cyclization reaction can then be treated in various ways in order to convert it into another compound of the formula I. For example, the nitrile can be treated with a suitable alcohol under acidic conditions to form a compound of Formula I in which ~ Br is an esterified carboxy group. Alternatively, the nitrile can be hydrolyzed, for example using sulfuric acid, to form a compound of Formula I in which R ^ is a carboxyamide group. The hydrolysis of the nitrile or the last-mentioned carboxyamide with a strong base or acid, such as concentrated hydrochloric acid, leads to the formation of a compound of the formula I ₉ in the R ^

S09817 / 1221 _

means a carboxy group. The compound of the formula I obtained in this way, in which R ^ is a Vere;, berte Carboxy group means, can be converted into a hydroxamic acid derivative by reaction with hydroxylamine will.

A nitrile of the formula I can also be converted into a compound in which R ^ is a group of the formula Ia by reaction with ammonium azide, in Hegel under the action of heat. In a corresponding manner, the resulting compound of the formula I, in which Ir denotes carboxy, can be converted by reaction with a suitable amino alcohol of the formula

-CH ₀ -OH can be converted into a compound in which R ^ is a group of the formula Ib.

The compound of formula I obtained in which R or

2
R means hydrogen, can be halogenated under

Λ 2 Formation of a compound in which R or R denotes halogen, for example a bromine atom can be introduced by reaction with N-bromosuccinimide and, if desired, the halogen compound obtained can be halogenated again to form a

1 2
Compound in which R and R are halogen. One

2 obtained compound in which R is halogen, can in turn be used to prepare a Number of other compounds of the formula I. In this way, they can by hydrolysis, for example under Use of sodium hydroxide, in the appropriate

2 compound converted v / earth, in richer R denotes hydroxy, and the latter can be acylated under BiI-

2 formation of a compound in which R is acyloxy; by Reaction with an alkali metal alkoxide, such as sodium

2 alkylate, the corresponding compound in which R is alkoxy can be obtained and by reaction

9617/1221 - ¹⁵ *

with ammonia, an N-alkylamine or an N ₁ N-

p dialkylamine, the compound in which R is halogen means into the corresponding compound of formula I.

ρ
be converted, in which R is amino, N-alkylamino or N, N-dialkylamino. In addition, a

2
bond in which R is amino or N-alkylamino, acylated in the usual way to form a

2 Compound of the formula I ₁ .in which R is N-acylamino or N-acyl-N-alkylamino. In addition, a

■ 7.
Bond of the formula I, in which R ^ is a halogen, can be converted into the corresponding acid using the known Grignard reaction (cf., for example, the Merck Index, VIII. Edition, published 1968, page 1172, or another standard reference text) . After the reaction with magnesium and after treatment with CO ₀ , a compound of the formula I is formed in which

'S' yO

Br denotes the group -C ^ q, .. _t -r, in which X is a halogen atom. This group can be converted into a carboxylic acid group simply by hydrolysis.

An acid of the formula I can be obtained by treatment with a suitable base, such as an ammonium, alkylammonium, Aralkylammonium, aluminum, alkali metal or alkaline earth metal hydroxide, be converted into a salt and a salt of the formula I can by treatment with a Acid, such as hydrochloric acid or sulfuric acid, can of course be easily converted into the free acid. An acid of the formula I or a salt thereof can through Treatment with a suitable alcohol or by treatment with a halide of the appropriate ester residue or a salt of this halide, if the ester radical contains a basic nitrogen atom, into an ester being transformed. An ester of the formula I can of course ■ borrowed by treatment with a suitable hydrolysis agent, such as an inorganic base or acid,

509817/1221 - 16 -

450042

hydrolyzed to the corresponding acid of formula I. will. An acid of the formula I or an ester thereof can be obtained by reaction with ammonia or a suitable one primary or secondary amine can also be converted into an amide of formula I.

A compound of the formula I in which R and / or R denotes (denotes) hydrogen »can be alkylated with formation of the corresponding compound of the formula I in which R and / or R is (are) C 1-6 alkyl. The alkylation can be carried out by reacting an alkali metal derivative of the appropriate benzoxazole derivative with a Alkyl halide such as methyl or ethyl iodide will.

As indicated above, the compounds of Formula II are particularly valuable. These compounds can be prepared by a method in which a compound of the formula V given below is hydrolyzed

R ²

.CH-Z

in which Z denotes a nitrile, ester, carboxylate, amido, hydroxamic acid group or a group of the formula ^ in which X is a halogen atom.

The compounds of the formula III given above can be prepared by reducing the corresponding nitro compounds, which in turn can easily be prepared from known or easily prepared chemicals according to the following reaction scheme:

- 17 509817/1221

ORIGINAL INSPECTED

ι t- *

<r

• tr

S θ "§ 8 1 7/1 2 2 1

In the above scheme, step a is carried out by calculating and then treating the resulting diazonium salt with dilute sulfuric acid. Step b is carried out by nitration, for example by adding nitric acid to a solution of the nitrile in glacial acetic acid. Steps c, d and e are the same as above in connection with the conversion of Z = R-? Z = halogen—> Z = CN— »Z = R ^ described.

The compounds of the above formula I, wherein R * is a Nitrile group means, as can be seen from the above description, are suitable as intermediates for the conversion into other compounds of the formula I. The other compounds of the formula I are useful, because they are pharmacologically active. In particular, has have been shown to have low toxicity and an analgesic, antipyretic and / or anti-inflammatory Have activity.

The above activities were demonstrated in tests performed on animals, typically at doses of 0.1 to 250 mg / kg. When treating people The dose administered can be, for example, between 0.1 and 25 mg / kg, depending on the medical treatment of the patient, however, doses outside this range can also be applied. The pharmacologically active Compounds of formula I can be enteral or parenteral V / e are administered and for this purpose they usually become pharmaceutical preparations formulated containing the active ingredient in conjunction with at least one pharmaceutically acceptable Carrier for it included. These preparations are also the subject of the present invention and they exist usually of the active ingredient mixed with a carrier, or diluted with a carrier, or surrounded

509817/1221 ~

or encapsulated in a carrier in the form of a capsule, in the form of a letter, a sachet • or another container. The carrier can be a solid, semi-solid or liquid material, as a diluent, auxiliary agent, coating agent or serves as a medium for the active ingredient. Some examples of carriers that can be used are lactose, Dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, liquid paraffin, cocoa butter, Theobroma oil, alginates, tragacanth; Gelatin, methyl cellulose, Polyoxyethylene, sorbitan monolaurate, methyl or Propyl hydroxybenzoate, ethyl cellulose acetate phthalate, low viscosity acetyl cellulose acetate, paraffin wax, Mineral wax (montan wax), Myrthenv / achs, vegetable gum, Silicone rubbers such as liquid polydimethylsiloxane rubber, plasticized or non-plasticized Polyvinyl chloride, plasticized polyethylene terephthalate, modified collagen, crosslinked hydros phile polyether gel, crosslinked polyvinyl alcohol or cross-linked, partially hydrolyzed polyvinyl acetate.

The preparations according to the invention are expediently produced in a dosage unit form which is 1 to 1000 mg (preferably 25 to 500 mg) of the active ingredient contains. Examples of suitable dosage unit forms are tablets, hard or soft gelatine capsules, microcapsules and suppositories as well as drug delivery systems, containing the active ingredient in a flexible, imperforate polymeric material through which the drug can be slowly released by diffusion. In general is under the term "dosage unit form" as used herein to understand a physically discrete entity that contains the active ingredient, generally in the form a mixture with and / or surrounded by a pharmaceutical

- 20 509817/1221

-QO-

table carrier, in an amount such that for a single therapeutic administration usually one or more units are required.

In addition to the active ingredient of the formula I, the preparations according to the invention can also contain one or more pharmacologically active ingredients such as acetylsalicylic acid and salts thereof, caffeine, codeine phosphate, Phen3 ^T lbutazone, paracetamol, dextropropo: cphen and indomethacin.

The preparations according to the invention can be adapted to the particular mode of administration. So can for oral administration tablets, pills, capsules, solutions or suspensions, for parenteral administration sterile injection solutions or suspensions, for rectal administration and for suppositories Topical administration creams, lotions or ointments can be used, any of the above preparations can of course in a manner known per se to a preparation with delayed or sustained release (dispensing).

The following examples illustrate the preparation of the compounds according to the invention. However, the invention is not limited to these examples.

- 21 -

50981 7/1221
ORIGINAL INSPECTED

example 1

(a) 2.2 ml of phenylacetyl chloride was added to a stirred Solution of 3.15 g of ethyl 2- (3-amino-4-hydroxyphenyl) -

propionate in 50 ml of anhydrous pyridine was added and the solution was heated to 100 ° C. for 2 hours. The excess pyridine was removed by distillation and the residue was heated until the temperature of the distillate was immediately above the reaction mixture 200 ⁰ C. The dark brown resin obtained was dissolved in 75 ml of ether and then washed three times with 50 ml of water. The ethereal solution was extracted with 50 ml of 1N sodium hydroxide, washed twice with 50 ml of water and evaporated to give ethyl 2- (2-benzyl-5-benzoxazolyl) propionate in the form of a light brown mobile resin which was pure like that Thin layer chromatography showed. The following esters were prepared and characterized in a corresponding manner:

(b) ethyl 2- £ 2- (4-chlorobenzyl) -5-benzoxazolyl] acetate

(c) Ethyl 2- £ 2- (4-chlorobenzyl) -6-benzoxazolyl acetate

(d) ethyl 2- £ 2- (4-chlorobenzyl) -6-benzoxazolyl / propionate

(e) Ethyl 2 - ["^ - benzyl-6-benzoxazolyl acetate

(f) ethyl 2-f2- (3,4-dichlorobenzyl) -5-benzoxazolyl] propionate.

(g) 5 »5 g of 4-chlorophenylacetyl chloride became a solution from 5 »5 g of ethyl 2- (3-amino-4-hydroxyphenyl) -

propionate was added dropwise in 20 ml of pyridine. The solution was heated on a steam bath for 2 hours. The excess pyridine was removed by distillation and the residue was heated until the temperature of the distillate was immediately above the reaction mixture 23O ⁰ C. The dark brown resin thereby obtained was dissolved in chloroform. The chloroform solution was washed with 2N sodium hydroxide, water, 2N hydrochloric acid and water. The chloroforin solution

- 22 -

5 0 9 817/1221 _{0 RIGINAL} inspected

was then rait activated charcoal and anhydrous sodium sulfate stirred, filtered and evaporated, leaving ethyl 2- £ 2- (4-chlorobenzyl) -5-benzoxazolylJ propionate in the form of a brown resin.

Example 2

(a) 15 ml of 2N sodium hydroxide was added to 3.1 g of ethyl 2-L2-benzyl-5-benzoxazolyl] propionate in 20 ml of ethanol

admitted. After 2 hours at room temperature, 50 ml of water were added and the volume was reduced by evaporation at 4-O ⁰ C to a quarter. The cooled solution obtained in this way was extracted twice with 25 ml of ether, acidified with concentrated hydrochloric acid and again extracted three times with 50 ml of ether. The ether extracts were washed twice with 25 ml of water, dried over sodium sulfate and evaporated. The residue was crystallized from acetone

and one erhielt- 2- £ 2-benzyl-5-berizoxazolylJ propionic acid, m.p. 136 to 138 ⁰ C.

In a similar manner, the following acids were prepared, the structures of which were confirmed by microanalysis became:

(b) 2- f2- (4 ~ Clilorbenzyl) -5-benzoxazolyl3 acetic acid

(c) 2- £ 2- (4-chlorobenzyl) -6-benzoxazolyl-acetic acid

(d) 2 - /] 2- (4-chlorobenzyl) -6-benzoxazolyl] j propionic acid

(e) 2- £ 2-benzyl-6-benzoxazolyl acetic acid

(f) 2-Γ2- (3 »4- dichlorobenzyl) -5-benzoxazolyl / propionic acid

(g) 30 ml of a 2N sodium hydroxide solution became 5-8 g of the ester prepared in Example 1 (g) in 40 ml

Ethanol added. After stirring for two hours at room temperature, the volume was reduced by evaporation at A-O C and the solution was diluted with 120 ml of water. Then it was extracted twice with ether, with

509817/1221 - 23 -

ORlQlNAL SisISPECTED

concentrated hydrochloric acid and then extracted three times with chloroform. The combined chloroform extracts were washed with water, dried over anhydrous sodium sulfate and evaporated to give an oil. This oil was purified using preparative TLC plates, the 2- £ 2- (4-chlorobenzyl) -5-benzoxazolyl / propionic acid, mp 135-137 ° C., obtained by IR, UV and NMR- Was characterized by spectroscopy and microanalysis, which gave the following values: calculated for C ₁₇ H ₁₄ ClNo ₃ : C 64.66 H 4-, 44 N 4.44% found: 64.41 4.71 4.57 %

(h.) A mixture of 4 g of ethyl 3-amino-4-hydroxy-

phenyl propionate, 3 g of 4-fluorophenylacetic acid, 0.1 g of p-toluenesulfonic acid and 50 ml of xylene were refluxed for 20 hours and the water formed was removed using a Dean-Stark apparatus. The solution was evaporated to dryness and the residue was dissolved in ether. The solution was washed twice with a 2N sodium hydroxide solution and with water, then stirred with activated charcoal and anhydrous sodium sulfate, filtered and evaporated to dryness. The remaining oil (3.7 g, N _D ²² ^ ₌ 1.54.69) was. Dissolved in 30 ml of ethanol and while stirring, 30 ml of a 2N sodium hydroxide solution were added over a period of 15 minutes. The reaction mixture was stirred for 2 1/2 hours, during which time 250 ml of water was slowly added. The solution was extracted twice with ether, acidified with concentrated hydrochloric acid, and then extracted three times with ether. These essential extracts were washed with water, dried over anhydrous sodium sulfate and evaporated to give an oil. This oil was purified using preparative TLC plates, yielding the 2- £ 2- (4-fluorobenzyl) -5-benzoxazolyrjpropionic acid as a white solid,

509817/1 221

- 24 -

24500 ^ 2

M.p. 91 to 93 ° C, which was characterized by IR, UV and NMR spectroscopy and by microanalysis, which gave the following values: calculated for C ₁₇ H ₁₄ PNO ₅ : C 68.2 $ H 4, 68 N 4.68% found: 68.40 3.86 4.64%

(i) 15.1 g of 2,6-dichlorophenylacetic acid were added in portions added to 30 ml of thionyl chloride with heating. The solution was left on a steam bath for 1/2 hour heated, then left to stand at room temperature for 2 1/2 hours. The excess thionyl chloride was removed by distillation under reduced pressure and the residue was distilled to obtain the Acid chloride obtained in the form of a colorless oil, boiling point 149 to 150 ° C / 15 mm.

14.8 g of this oil were added in small portions to a solution of 13 g of ethyl 3-amino-4-hydroxyphenylpropionate in 30 ml of lyridine. The resulting solution was heated on a steam bath for 2 hours. The excess pyridine was removed by distillation and the residue was heated until the temperature of the distillate was immediately above the reaction mixture 210 ⁰ C. After 5 minutes the reaction mixture was allowed to cool and then dissolved in ether. The ethereal solution was washed twice with a 2N sodium hydroxide solution and with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was triturated with a small amount of ether to give 1.6 g of a white solid which was removed by filtration (the IR spectrum of the solid indicated it was a non-cyclic material). The ethereal solution was evaporated to give a ^ l.

11 g of this oil were dissolved in 40 ml of ethanol and within 15 minutes 40 ml of a 2N sodium

509817/1221 -25-

^ 450042

hydroxide solution added in portions. The reaction mixture was stirred at room temperature for 2 hours and then diluted with 400 ml of water. The solution was extracted twice with ether, acidified with concentrated hydrochloric acid, and then extracted three times with ether. The last three essential extracts were washed with water, dried over anhydrous sodium sulfate and evaporated to give an oil. This oil was purified using preparative TLC plates to give the 2- £ 2- (2,6-dichlorobenzyl) -5-benzoxazolyl] propionic acid in the form of a white solid, mp 122-124 ° C, which was characterized by IR, UV and NMR spectroscopy and by microanalysis, which gave the following values: calculated for C ₁₇ B ₁₃ Cl ₂ NO ₅ : C 58.29 H 3.71 N 4.00% found: 58, 58 3.78 3.90%

(j) In a manner analogous to that used in Example 2 (h) *, compound 2- / ~ 2- (2-chlorobenzyl) -5-benzoxazolyl] propionic acid was prepared. The product was isolated in the form of a white powder, F. 92 to 9+ ⁰ C.

Example 3

(a) A mixture of 4.86 g of 2- (3-amino-4-hydroxyphenyl) -

Propionitrile, 5 »3 g of potassium ethylxanthate, 30 ml of ethanol and 5.0 ml of water were refluxed for 4 hours. The mixture was filtered, diluted with 15 ml of water, acidified with acetic acid, and then diluted with more water. The brown precipitate thus obtained was filtered and recrystallized from aqueous ethanol to give 2- (2-thioxo-2,3-d.ihydrobenzoxazol-5-yl) propionitrile, m.p. 173 to 176 ⁰ C, obtained. In a suspension of 8.0 g of the thione in 200 ml of freshly dried and distilled chloroform was dry

509817/1221

^ 450042

Chlorine initiated. After 20 hours the groute Part of the solid dissolved and the mixture was filtered. The filtrate was with 100 ml of water, 50 ml 1N sodium hydroxide and washed three times 100 ml of water. The organic solution, dried over NapSO ^, was evaporated and 2- £ 2-chloro-5-benzoxazolyl] propionitrile was obtained in the form of a brown oil which thin layer chromatography showed to be a single one Connection acted. The oil distilled at 128-134 ° C / 0.3 mm Hg.

A mixture of 6.15 g of 2-chloro compound and 10.0 g of p-chloroaniline was heated for 3 1/2 hours at 100 G ^0. The residue was partitioned between 100 ml of chloroform and 100 ml of 2N hydrochloric acid. The chloroform layer was washed with 2 times 100 ml of water, 100 ml of 1N sodium hydroxide and 3 times 100 ml of water. After evaporation of the _{solution, which had been dried over Na 2} SO 4, 2- £ 2- (4-chloroanilino) -5-benzoxazolyl] propionitrile was obtained in the form of a creamy solid which was characterized by NMR spectroscopy. The following nitriles were prepared and characterized in a corresponding manner:

(b) 2- ^ 2-anilino-5-benzoxazolyl] propionitrile

(c) 2-C2- (N-methylanilino) -5-benzoxazolyl / propionitrile

(d) 2- £ 2- (N, 4- dimethylanilino) -6-benzoxazolyl-acetonitrile

(e) 2- £ "2- (4- chloroanilino) -6-benzoxazolyl] acetonitrile

(f) 2- £ 2- (4-chloroanilino) -5-benzoxazoly ^ acetonitrile

(g) 2- [2- (N-methyl-3, ^ - dichloroanilino) -5-benzoxazolylI-propionitrile

(h) 2- £ 2- (N-acetyl-4-chloroanilino) -5-benzoxazolyl} -

propionitrile
(i) 2- £ 2- (4-Siethoxyanilino) -6-benzoxazolylpropionitrile.

(j) A stirred mixture of 8.4 g of ethyl 2- (3-amino-4-hydroxyphenyl) propionate, 6.33 g potassium ethyl xanthate,

509817/122 1 - ²⁷ ~

ORIGINAL INSPECTED

38 ml of ethanol and 6.5 ml of water was under for 4 hours Heated reflux. The solution was evaporated to half its volume and diluted with 65 ml v / water. The mixture was acidified with 2N hydrochloric acid and extracted several times with ether. The ethereal solution was washed with water, then with anhydrous Dried sodium sulfate and evaporated, leaving ethyl 2- (2-thioxo-2,3-dihydrobenzoxazol-5-yl) propionate in the form of an oil. received. In a solution of 9 g of thione in 150 ml of freshly dried and distilled Chloroform was passed in dry chlorine with stirring for 4 hours. The solution was then using Water, an n-sodium hydroxide solution and then washed with water (three times). The dried over Na ^ SCL organic solution was evaporated and the ethyl 2- (2-chloro-5-benzoxazolyl) propionate was obtained in the form of a brown oil, which thin layer chromatography showed to be a single compound.

(k) A mixture of 12.5 g of the 2-chloro compound des

Example 3 (u) and 25 g of p-chloroaniline were heated on a steam bath for 1 hour. The reaction mixture was dissolved in chloroform and the solution was washed twice with 2N hydrochloric acid, water, twice with a 2N sodium hydroxide solution and three times with water. The chloroform solution was stirred with activated charcoal and anhydrous sodium sulfate, then filtered and evaporated. The residue was purified using preparative TLC plates, using ethyl 2-r2- (4-chloroanilino) -5-benzoxazolyl] propionate, F. 135 to 137 ⁰ C, which was then characterized by IR, UV and NMR spectroscopy and microanalysis, which gave the following values:

Calcd for C ₁₈ H ₁ "Cl, O ₂ : C 62.70 H 4.93 N 8.13 % found: 62.45 5.11 7.97 %.

- 28 509817/1221

- ²⁸ - -'150042

Example 4

(a) 2.75 g of 2- £ 2- (4-chloroanilino) -5-b3nzoxazolyl / propionitrile and 20 ml of concentrated hydrogen chloride

acid were refluxed together for 2 1/2 hours. The cooled mixture was neutralized to pH 5 with 5N sodium hydroxide and the solid obtained was filtered off, washed with a little ice / water and dried. The solid was partitioned between 0.1N sodium hydroxide and chloroform. The aqueous layer was washed with chloroform for several years, adjusted to pH 3, and the product was extracted with chloroform. The chloroform extract was then washed with water, dried over sodium sulphate and evaporated, and 2 - / "2- (4-chloroanilino) -5-benzoxazolyl / propionic acid was obtained, which, as thin-layer chromatography showed, was pure (mp 206 to 208 ⁰ C).

The following acids were prepared in a corresponding manner :

(b) 2-f2-Ani1ino-5-benzoxazoyl / propionic acid

(c) 2-f2- (N-methylanilino) -5-benzoxazolyl] propionic acid

(d) 2-f2 - (^, 4-dimethylanilino) -6-benzoxazolyl-acetic acid

(e) 2-f2- (4-chloroanilino) -6-benzoxazolyl acetic acid

(f) 2 - / "2- (4-chloroanilino) -5-benzoxazolyl-acetic acid

(s) 2-f "2- (i'i-methyl-5, 4-dichloroanilino) -5-benzoxazolyl / propionic acid

(h) 2-r2- (fi-acetyl-4-chloroanilino) -5-benzoxazolylpropionic acid

(i) 2- £ 2- (4-methoxyanilino) -6-benzoxazolyl] propionic acid. The production of the acids was confirmed by thin layer chromatography.

(J) A stirred mixture of 2.9 g of ethyl 2- / ~ 2- (4-

chloranilino) -5-benzoxazolyl propionate, 10 g dry Lithium iodide, 0.4 g sodium cyanide and 35 ml methyl

509817/1221 _o0 _

_ 2 'ORIGINAL INSPECTED

■ L'450042

ethyl ketone was refluxed for 18 hours. The solution was diluted with tasser and made alkaline with sodium bicarbonate. The solution was washed several times with chloroform, filtered through a "3upercel" pad, and acidified with concentrated hydrochloric acid. The solid obtained was filtered off, ater V "washed, and recrystallized from aqueous methanol to give the 2- £ 2- (4-chloroanilino) -5-benzoxazolyl] propionic acid, in the form of a buff-colored powder, m.p. 206 to 208 ⁰ C. which was characterized by IR, UV and NMR spectroscopy and by microanalysis, which gave the following values: Calculated for C ₁₆ H ₁₃ ClN ₂ O ₅ : C 60.66 H 4.11 N 8.85% found : 60.45 4.31 8.75 #.

Example 5

(a) A mixture of 1.2 g of ethyl 2- (3-aoiino-4-hydroxy-. phenyl) propionate, 1 g mandelic acid and 50 ml xylene

was heated using a Dean-Stark apparatus. After 24 hours the solution was evaporated to dryness and the residue was taken up in chloroform. This solution was washed first with a sodium hydroxide solution, then with hydrochloric acid and finally dried over sodium carbonate. The solution was evaporated to dryness and the ethyl 2- £ 2 - (& -hydroxybenzyl) -5-benzoxazolyl] propionate, its Structure was confirmed by NMR spectroscopy.

The following esters were prepared and characterized in a corresponding manner:

(b) S.thyl-2 - /. 2- (oL-methoxybenzyl) -5-benzoxazolyl / propionate

(c) ethyl 2- [2- (tf- -hydroxy-3,4-dichlorobenzyl) -6-benzoxazolyl acetate .

509817/1221

ORIGINAL INSPECTED

(d) Ethyl-2-r2- (oL-hydroxy-4-cilorbenzyl) -6-benzoxazolylJ propionate

(e) ethyl 2-f2- (dL-hydroxybenzyl) -5-benzoxazolyl] acetate

(f) A mixture of 10 g of ethyl-J-amino - ^ - hydroxyphenylpropionate, 9.33 g of 4-chloromandelic acid and 150

ml of xylene was refluxed for 22 hours and the water which formed was removed using a Dean-Stark device. The solution was evaporated to dryness and the residue was dissolved in ither. The solution was washed with NaOH, HCl and water, then stirred with activated charcoal and anhydrous sodium sulfate, filtered and evaporated to dryness. The remaining oil (15 g) was dissolved in a small amount of chloroform and placed on a silica gel column Use of chloroform as a solvent chromatographed; included the first fractions a carbonyl compound that has been discarded. The obtained crude product was prepared using preparative Cleaned TLC silica plates and obtained the Ethyl 2- / 2- (oi.-hydroxy-4-chlorobenzyl) -5-benzoxazoly 11-

21 4 propionate in the form of a resin, N ~ * = 1.5681. the Structure was determined by IR, UV and IMR spectroscopy and confirmed by microanalysis, which gave the following values:

for C ₁₉ H ₁₈ ClNO ₄ : C 63.4 H 5.01 N 3.89 % found: 62.54 5.20 3.79 %.

Example 6

(a) A mixture of 10 g of 3-amino-4-hydroxyhydroproprio-

nitrile, 14 g of mandelic acid and 300 ml of xylene was refluxed for 24 hours using a Dean-Stark apparatus. The solution was filtered, evaporated to dryness and the residue was dissolved in chloroform. The solution was made with an acid and a base

509817/1221 - 31 -

ORlGfNAL INSPECTED

- 31 - 9 ^ 50042

washed, dried over sodium carbonate and eluted from a silica gel column with ether to give 2- [2- (cL -. Hydroxybenzyl) -? - benzoxazolyl] propionitrile, the structure of which was confirmed by NMR spectroscopy.

The following nitriles were prepared and characterized in a corresponding manner:

(b) 2- ^ 2- (oL-methoxybenzyl) -5-benzoxazolyl] propionitrile

(c) 2- [2- (d. -hydroxy-4-chlorobenzyl) -5-benzoxazolyl] propionitrile

(d) 2- [2- (ηµ -Hyaroxy-J ^ -dichlorobenzyD-e -benzoxazolylI-acetonitrile

(e) 2- [2- (oil-hydroxy-4-chlorobenzyl) -6-benzoxazolyl / propionitrile

(f) 2- [2 - (<$ - -hydroxybenzyl) -5-benzoxazolyl / acetonitrile.

Example 7

By hydrolyzing the ^ ster of Example 5 by the method of Example 2 or by hydrolysing the nitriles of Example 6 by the method of Example 4, the following acids were prepared: (a) 2- [2- (ol -hydroxybenzyl ") -5 -benzoxazolyl / propionic acid

(b) 2-f2- (α-methoxybenzyl) -5-benzoxazolyIJ propionic acid

(c) 2-f2- (oL-hydroxy-3,4-dichlorobenzyl) -6-benzoxazolyl] acetic acid

(d) 2-f2- (oL-hydroxy-4-chlorobenzyl) -5-benzoxazolyl-propionic acid

(e) 2 - ["2- (ol -hydroxy- ^z + - chlorobenzyl) -6-benzoxazolyl / propionic acid

(f) 2- [2- (cL-hydroxybenzyl) -5-benzoxazolylj -acetic acid

microanalysis performed with the above acids was completely in line with the expected structures.

- 32 50981 7/122 1

Example 8

(a) A solution of 5 g of ethyl-2 ~ r2- (oL-hydroxy-4-chlorobenzyl-5-benzoxazolyl] propionate in 25 ml glacial acetic acid

was slowly added to a stirred solution of 1.4 g of chromium trioxide in 75 ml of glacial acetic acid. The temperature of the reaction mixture was slowly increased to 115 ° C. and held there for 30 minutes. The solution was evaporated to small volume and the residue was diluted with water and extracted with chloroform. The chloroform solution was dried over anhydrous sodium sulfate and evaporated to give an oil which was partially purified using preparative TLC plates. The oil thus obtained was triturated with petroleum ether (b.p. 40 to 60 ⁰ C), wherein i'ithyl-2- [2- (4-chlorobenzoyl) -5-benzoxazolylJpropionat as a white solid, mp bo to 67 ° C, was obtained. The structure was confirmed by IR, UV and NMR spectroscopy and by microanalysis, which gave the following values:

for C ₁₉ H ₁₆ ClNO ₄ : C 63.78 H 4.48 N 3.92 % found: 64.01 4.64 4.11%.

In a corresponding manner, the other benzoyl compounds given below were prepared by oxidation of the cL-hydroxybenzyl compounds of Example 7:

(b) 2- £ 2-benzoyl-5-benzoxazolyl / propionic acid

(c) 2- £ 2- (3,4-dichlorobenzoyl) -6-benzoxazolyl-acetic acid (ά) 2-f2- (4-chlorobenzoyl) -5-benzoxazolyl / propionic acid

(e) 2-f2- (4-chlorobenzoyl) -6-benzoxazolyl] propionic acid

(f) 2-f2-Benzoyl-5-benzoxazolyl} acetic acid.

(g) The benzoyl compounds of Examples 8 (b) to (f) were also derived from the δ * -hydroxybenzyl compounds of

Example 7 using manganese dioxide as an oxidizing agent manufactured. The compounds of Examples (b) to (g) were determined by thin layer chromatography

509817/1221 - 33 -

ORIGINAL INSPECTED

- 33 characterized. ^ 450042

Example 9

Acylation of the rc -hydroxybenzyl compounds des Example 7 using acetyl chloride in the presence of sodium bicarbonate and in toluene as a solvent the following qL-acetoxybenzyl compounds were produced:

(a) 2-F2- (ct -acetoxybenzyl) -5-benzoxazolyl] propionic acid

(b) 2- [2- (oL-acetoxy-3,4-dichlorobenzyl) -6-benzoxazolyl / acetic acid r

(c) 2- £ 2- (ql-acetoxy-4-chlorobenzyl) -5-benzoxazolyl] propionic acid

(d) 2- / T2- (dv -acetoxy-4-chlorobenzyl) -6-benzoxazolyl] propionic acid

(e) 2- [2- (cL · -Acetoxybenzyl) -5-benzoxazolyl / acetic acid.

The microanalysis of the above compounds was consistent with the expected structures.

Example 10

(a) 28.0 g of phenylacetyl chloride was added over a period of 20 minutes to a cooled, stirred solution of 29.0 g of 2- (3-amino-4-hydroxyphenyl) propionitrile in 200 ml of anhydrous pyridine at 0 to 3 ° C, oeach completion of the addition the mixture was heated for 1 hour at 100 ⁰ C. After evaporation under reduced pressure, the 2- (3-phenylacetamido-4- hydroxyphenyl) propionitrile was isolated as an oil.

This oil was isolated and then boiled for 30 minutes, during this time the temperature of the

509817/1221 " ⁵⁴ "

The vapor above the oil rose to 20O ⁰ C. When paying off, the residue solidified. After recrystallization of the solid from methanol, 2- (2-benzyl-5-benzoxazolyl) propionitrile was obtained, which was pure, as thin-layer chromatography showed.

The following nitriles were prepared in a corresponding manner and characterizes:

(b) 2- £ 2- (4-chlorobenzyl) -5-benzoxazolyl] propionitrile (α) 2-f2- (4-chlorobenzyl) -5-benzoxazolyl / acetonitrile

(d) 2- [2- (4- chlorobenzyl) -6-benzoxazolyl] acetonitrile

(e) 2-r2- (4-chlorobenzyl) -6-benzoxazolyl] propionitrile (f *) 2-f2-Benzyl-6-benzoxazolyl] acetonitrile

(g) 2-Γ2- (3> 4— dichlorobenzyl) -5-benzoxazolyIJpropio-

nitrile
(h) 2- [2- (4-fluorobenzyl) -5-benzoxazolyl / propionitrile.

Example 11

Example 1 (a) was repeated, but this time instead of phenylacetyl chloride, the following compounds were used as the cyclizing agent:

(a) phenylacetic acid,

(b) phenylacetic anhydride,

(c) phenylacetamide and

(d) benzyl hydrazone.

In any case, ethyl-2- (2-benzyl-5-benzoxazolyl) propionate _t formed as thin layer chromatography indicated.

Example 12

(a) 5 »1 g of 4-chlorophenyl isocyanate was slowly stirred Solution of 3 »3 g 2- (3-Amino-4 - hydroxyphenyl) -

- 35 -5098T7 / 1221

"* ³⁵ '"' 450042

propionitrile in 35 ml of xylene was added at room temperature. After the addition was complete, 25 ^U mg of p-toluenesulfonic acid was added and the solution was heated using a Dean-Stark apparatus. After cooling, the solution was washed with an aqueous sodium bicarbonate solution and evaporated to dryness. The residue was recrystallized and 2-1 [2 - (^ - chloroanilino) -5-benzoxazolyl] propionitrile was obtained in the form of a creamy solid, which was characterized by NMR spectroscopy.

(b) In a similar manner, 2- / ~ 2-anilino-5-benzoxazolyl] propionitrile produced.

In the following examples of pharmaceuticals according to the invention Preparations, the term "active ingredient" as used here stands for the compound 2- (2-benzyl-5-benzoxazolyl) propionic acid. This compound can of course also be replaced by any other active compound of the formula I can be replaced and the amount of the active ingredient can be increased depending on the level of activity of the active ingredient used or be reduced.

Example 15

Tablets were made, each containing 100 mg des Active ingredient contained:

Active ingredient 100 mg

Potato starch 38 mg

Lactose 25 mg

Ethyl cellulose (in the form of a 20% solution in technical Alcohol) 2 mg

Alginic acid 7 mg

Magnesium stearate 1 mg

Talc 2 mg

total 175 mg 5098 17/122 1 - 3 &"

ORIGINAL INSPECTED

The active ingredient, starch and lactose were passed through a No. 44 BSS sieve and mixed together thoroughly. The Äthylcelluloselösung was "mixed with the resultant powders which were then passed through a BSS sieve no. 12, the granules formed were dried at 50 to 60 ⁰ C and then passed through a No. B33-3ieb. 1 * 6. The alginic acid, magnesium stearate and talc previously passed through a BSS No. 60 sieve were added to the granules, mixed therewith and compressed in a tabletting machine to form tablets weighing 175 each

example

Capsules were made, each containing 200 mg des

Active ingredient contained:

Active ingredient 200 mg

Lactose. 48 mg

Magnesium stearate 2 mg

The active ingredient, the lactose and the magnesium stearate were made passed through a No. 44 BSS sieve and filled into hard gelatin capsules in quantities of 250 mg.

Example 15

Injection solutions were prepared, which per 5 ml Solution each contained 100 mg of the active ingredient: Active ingredient 100 mg

Sodium hydroxide (in the form

a 10 # solution) in sufficient

lot

Water for injection ad 5 ml The active ingredient was suspended in the water and the

509817/1221 - 37 -

ORiGlNAL INSPECTED

-37- / 450042

Sodium hydroxide solution was added dropwise with stirring until until the active ingredient was dissolved. The pH of the solution was adjusted to a value between 8.0 and 8.5, the solution was sterilized by filtering through a bacteria-proof filter and sterilized in advance Filled with glass ampoules, which were then hermetically sealed under aseptic conditions.

Example 16

Suppositories were made, each 250 mg of the active ingredient contained:

Active ingredient 250 mg

Theobroma oil ad 2000 mg

The active ingredient used was passed through a No. 60 BSS sieve and previously using the required minimal heat suspended theobroma oil. The mixture was then put into a suppository mold Poured at a nominal capacity of 2 g and allowed to cool.

509817/1221

ORIGINAL INSPECTED

Claims (18)

T 49 642 PATENT CLAIMS ^ I · Benzoxazole derivative, characterized by the general formula R-A 1 ? 3 CR R "R (D 1 2 'p
where the group -CR RR is in the 5- or 6-position of the benzoxazole nucleus, R V. 'hydrogen, C _x , ^ - ^ I --Ό Alkyl or halogen, R hydrogen, C, - alkyl, halogen, 11 12 Hydroxy, C ₁ , - alkoxy, C ₀ "-acylox ;. ' or ITR R, where R is hydrogen or C _{1 c} -alkyl and R is hydrogen, Gy, _C -alkyl or C ₀ "-acyl, R is a nitrile group) iDe, a Car. oxy group or a salt ^ an ester, amide or hy acid derivative thereof or a group of the formula or Ib where R ^ and R independently of one another are hydrogen, C ^ C-alkyl or C ^^^ - hydroxyalkyl, R is phenyl which is optionally substituted in any available position by one or more of the radicals C ^ _ ~ ₆ alkylsulfonyl, Cj__ ₆ -alkyl, C _1-6 -alkoxy, C ^ ^ -Haloalkyl, C ₂ -7 * " acyl, nitro, 'amino, hydroxy or halogen or is optionally substituted in two adjacent positions by methylene or ethylenedioxy , and A - -CO-, -CHOR- or -NR-, where R Hydrogen, 509817/1221 ORIGINAL INSPECTED or Cp is o-acyl. 2. A compound according to claim 1, characterized in that R is phenyl, which is in any available position by one or two groups selected from ο ,,, .- alkyl, C ^. -Alkoxy, C ₀ , acyl, 0 _Λ , .- I — if »I — Η- £ 1— H-. I - H- Alkylsulfonyl, C ^ _ ^ - monohalpgenealkyl, trifluoromethyl, halogen, nitro, amino, hydroxy, or optionally substituted in two adjacent positions by methylenedioxy, A -CH ₂ -, -CO-, -CHOR- or -NR-, where R is hydrogen, methyl, ethyl or acetyl, 1 'P R hydrogen, methyl, chlorine or bromine, R hydrogen, Methyl, ethyl, chlorine, bromine, hydroxy, C ^, .- alkoxy, 11 1P 11 C ₀ , .- acyloxy or HB R, where R is hydrogen, · ■ 12 Is methyl or ethyl and R is hydrogen, methyl, ethyl or acetyl, and R ^ (i) the group -COOR- ⁷ , in which R ^ is -Cj ^ -alkyl, or (ii) the group -COR, in which R ⁶ -MEOH or -NR ⁷ R ⁸ , where R ⁷ and R ^{8 are} independently hydrogen or C ^ _ ^ - alkyl, or (iii) the group -COOH or an alkali metal or alkaline earth metal, aluminum or ammonium salt thereof or (iv) a nitrile group or (v) a Group of the formula Ia or / 13 given in claim 1 Ib, where R ^J and R are independently hydrogen, methyl, ethyl or hydroxyethyl. 3. A compound according to claim 1 and / or 2, characterized by the general formula CH-R " (H) 50981 7/1221 -tr- 2450CH2 E ² wherein the group -CH-R ^ is in the 5- or 6-position of the benzoxazole nucleus, A -CHp-, OH OCH ₃ OCOCH ₃ -CO-, -CH-, -CH-, -CH-, -M- or -NCH _x -, E phenyl, the optionally -.l by one or ζ v / ei groups, selected bxxs halogen, trifluoromethyl, Methyl, methoxy, 'acetyl or methylsulfonyl, R is hydrogen or preferably methyl and R ^ is the group COOR- ⁷ or the group COOH or an alkali metal or alkaline earth metal, aluminum or ammonium salt thereof. 4. A compound according to at least one of claims 1 to 3, characterized in that A is -CHo-, 5. 2- [2-Benzyl-5-benzoxazolyl] propionic acid. 6. 2- [2-Benzyl-5-benzoxazolyl] acetic acid. 7. 2- [2- ( ^z (-chlorobenzyl) -5-benzoxazolyl] propionic acid, 8. Benzoxazole derivative, characterized by the general formula (IV) 12-5
in which the group -CR RR ^- ^ is in the 5- or 6- 1 position of the benzoxazole nucleus, R and R are as defined in claims 1 to 3, R ^ a nitrile group, a carboxylic acid group or a Salt-; an ester, amide or hydroxamic acid derivative thereof 509817/122 1 ORIGINAL INSPECTED 245001.2 and Q is -SH or a halogen atom. 9. Connection according to claim 8. 1 2 draws that R is Y / hydrogen and R is methyl. 10. A compound according to claim 8 and / or 9 «thereby 1 2 characterized in that R is hydrogen, R is methyl, R is a nitrile, carboxylic acid or salt group, an amide or ester group and Q is halogen 12 5
and wherein the group -CR RR ^ is attached in the 5-position of the benzoxazole nucleus. 11. A compound according to at least one of claims 1 to 5j, characterized in that in the formula I Ή? denotes a nitrile group or a group of the formula -COGMgX, in which X is a halogen atom. 12. Pharmaceutical preparation, characterized in that it contains at least one benzoxazole derivative as the active ingredient according to at least one of claims 1 to 11, optionally together with a pharmaceutical compatible carrier. 13. A method for producing a benzoxazole derivative the general formula (I) - 5 -5098 17/122 1 ORIGINAL INSPECTED / 450042 in which the group CR R Ir in the 5 or 6 position: of the benzoxazole nucleus, R is hydrogen, C., - alkyl or halogen, R hydrogen, C., .- alkyl, halogen, 11 ΊΡ hydroxy, C ₁ , - alkoxy, G ₀ "-acyloxy or NR R, where 11 '1? R is hydrogen or O ^ _g-alkyl and R is hydrogen, _{| -o} . or C ₂ -C 7 acyl, R 1 is a tri! group, a caroxy group or a salt; an ester, amide or hydroxamic acid derivative thereof or a group of the formula N N ^ N_N or Yes Ib 13th
where R ^ and R independently of one another \ 7hydrogen, or C ^^^ - hydroxyalkyl, R phenyl, which is optionally in an available position by one or more of the radicals C ^ _ ^ - alkylsulfonyl, CL g-alkoxy, C ^^ g-haloalkyl, G ₂ ^ r ₇ -ACyI, nitro, amino, hydroxy or halogen or optionally substituted in two adjacent positions by methylene or ethylenedioxy, and AC ^ -, -CO-, -CHOR- or -NR-, where R is hydrogen, C ^^ or C _2- O-ACyI, mean characterized in that a compound of the general formula CR ¹ R ² -Z (HD 509817/1221 ORfGiNAL INSPECTED 7, 7. wherein Z is the group R or a group convertible to Ir, using a cyclization G- i ± means that the required group R -A- or a / j.
can provide other group convertible into the group R -A-, cyclized and then, if necessary, the compound obtained is converted into the desired compound of the formula I in a customary manner. 14. The method according to claim I3 _f, characterized in that R is phenyl in any available position by one or two groups selected from C ,, ^ - alkyl, C _1-4 -AIkOXy, C ₂ _ ₄ -acyl, C ^ ^ -Alkylsulfonyl, G ^ _ ^ - monohaloalkyl, trifluoromethyl, halogen, nitro, amino, hydroxy, or is optionally substituted in two adjacent positions by methylenedioxy, A ₂ -J-CO-, -CHOR- or -KE-, where R is hydrogen, methyl, ethyl or acetyl, RV / water st off, methyl, Chlorine or bromine, R ² hydrogen, methyl, ethyl, chlorine, 11 1P bromine, hydroxy, C ^, -alkoxy, G _0. -Acyloxy or NR R, 11 ·· '1? where R 7 is hydrogen, methyl or ethyl and R is hydrogen, methyl, ethyl or acetyl, and R ^ (i) the group -COOR ^, where R ^ is C ₁ , .- alkyl, or (ii) the group -COR wherein R ^ü -ITHOH or -NR'R ^o, wherein R ^ and R are independently hydrogen or C ^^ - alkyl, oier (iii), the group -COOH or an alkali metal or alkaline earth metal, aluminum or an arionium salt thereof or (iv) a nitrile group or (v) a group of the claims 15 14 · 1 given formula Ia or Ib, wherein R and R are each independently hydrogen, methyl, ethyl or hydroxyethyl, mean « 50981 7/122 1 15. The method according to claim 13 and / or 14 thereby characterized in that the compound of formula I has the structure R-A CH-R * (II) wherein the group -CH-Ir is in the 5- or 6-position of the benzoxazole nucleus, A -CH ^ -, -CO-, OH OCH, OCOCH ₅ -CH-, -CH-, -GH-, -NH- or -NCH ₅ -, R ⁴ phenyl, which is optionally substituted by one or two groups selected from halogen, trifluoromethyl, methyl, methoxy, acetyl or methylsulfonyl or preferably methyl and Ir the group -COOR ^ or -COOH or an alkali metal or alkaline earth metal, aluminum or ammonium salt thereof. 16. The method according to at least one of claims to 15f, characterized in that the cyclization Zj. A compound of the formula R -A-COOH, (R ^ -A-CO) ₀ O, R ⁴ -A-COC1, R ⁴ -A-CONH ~, 1 ^ -A R -A-CN or a xanthate of the formula c. OR SM 15th / 1 C where R? an alkyl group having 1 to 4 carbon atoms and M represent an alkali metal atom, is used, 509817/1221 ORIGINAL INSPECTED 17. The method according to at least one of claims 13 to 16, characterized in that A denotes the group j-. 18. The method according to claim 3, characterized in that 2- [2-benzyl-5-benzoxazolyl] propionic acid or 2- [2- (4- chlorobenzyl) -5-benzoxazolyl] propionic acid is prepared. 19 * The method according to claim 15, characterized in that that one is a compound of the general formula wherein Z is a nitrile, ester, carboxylate, amido, Is hydroxamic acid group or a group of the formula wherein X is a halogen atom, hydrolyzed. 509817/1221