DE2221866A1 - Substituted anilinobenzoxazole for prophylactic use against Marek's disease - Google Patents

Description

Eli Lilly and Company, Indianapolis, Indiana, V.St.A.

Substituted anilinobenzoxazole for prophylactic use against Marek's disease

The invention relates to immunosuppressive agents and anti-fertility agents which use anilinobenzoxazoles as active ingredients contain, on new anilinobenzoxazole and on the production of the new compounds.

The invention relates to immunosuppressive agents which, as an active ingredient, contain a compound of the formula

C-N-

Formula I.

209850/1253

ORIGINAL INSPECTED

contain, in which

X is a hydrogen atom, a C -C.-alkyl radical, a Cj-C - ^ - alkoxy group, a carboxy group,
a carboxy-C. -C, -alkyl radical, an amino-C.-C ₃ -alkyl radical, a mono-C-CU-alkylamino-C., - Chalky lrest, a di-C -Cj-alkylamino-C.-Cg-alkyl radical, a C -C_-alkylanilino-C, -C ^ -alkyl radical or a C -Cj -alkoxy-C ^ -Cg-alkyl radical,

R, R ", R ₃ and R. Hydrogen atoms, bromine atoms, chlorine atoms, fluorine atoms, trifluoromethyl _{radicals, carboxy groups, carboxy-C 1} -C ₃ -alkyl radicals, C ₁ -C ₃ -A ^ y radicals, C ₁ -C ₃ -alkoxy groups or amino groups with the proviso that one of the substituents R, and R ₄ in the same molecule must be a hydrogen atom and only two of the substituents R, R ₃ , R ₃ and R are radicals other than hydrogen atoms,

R _c , R ,, R_ and R ₀ alone are hydrogen atoms,

JO / O

Bromine atoms, chlorine atoms, fluorine atoms, trifluoromethyl groups, carboxy groups, C ₁ -C ₃ -alkyl radicals, C. -C ₃ -alkoxy groups, C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl radicals, phenyl radicals or nitro groups with the proviso that only one of the substituents R _g , R _β , R_ and Rg is a nitro group and only one is a phenyl radical is, and only two of the substituents R ₅ , Rg,

R_ and R _{0 are} radicals other than hydrogen atoms, or / ο

R ₁ - and _{R 1, R c} and R-, or R_ and R ₀ together
bob / / ο

the moiety that forms a fused aryl ring is required in the 2,3- or 3,4-position, mean.

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The invention also relates to anti-fertility agents, which as active ingredient is a compound of the formula,

contain, where X is a hydrogen atom,

Formula I.

R, R ₂ , R ₃ and R _{4 are} hydrogen atoms, bromine atoms, chlorine atoms, fluorine atoms, methyl radicals, trifluoromethyl radicals or methoxy groups, with the proviso that one of the substituents R ₁ and R ₄ in the same molecule must be a hydrogen atom and only two of the substituents

tuenten R,, atoms are,

R ₃ and R ₄ radicals other than hydrogen

Rr

, and R _Q by itself is hydrogen

D O

atoms, bromine atoms, chlorine atoms, fluorine atoms, methyl radicals, Trifluoromethyl radicals, methoxy groups or nitro groups with the proviso that only one of the substituents R, - * Rg and Rg is a nitro group and only two of the substituents

and

are radicals other than hydrogen atoms,

R _{7 is} a hydrogen atom, a bromine atom, a chlorine atom, a fluorine atom, a methyl radical, a trifluoromethyl radical, a methoxy group, a nitro group or a phenyl radical, with the proviso that R_ is only a nitro group when R ₅ , R _g and R _{8 are} others Radicals as a nitro group, and R _{7 is} only a hydrogen atom if two of the substituents R ₁ -, R, - and R ₀

whether ο

Resto other than hydrogen atoms are, mean with the

Ü09850 / 1253

BR - ^ -

Provided that there are no more than two substituents on the phenyl ring of the anilino group which are not hydrogen atoms.

The invention also relates to new compounds of the formula

Formula I 1 _Λ " ⁵ \ / ⁶

^R 3

C-N-

^R 2

X is a hydrogen atom, a C.-C.-alkyl radical, a C.-C, -alkoxy group, a carboxy group, a carboxy-C.-C ^ -alkyl radical, an amino-C.-Cj-alkyl radical, a mono-C .-C ^ -alkylamino-C.-C ^ -alkyl radical, a di-C.-G_-alkylamino-C ₁ -C ₃ -alkyl radical, a CC -alkylanilino-Cj-C ^ -alkyl radical or a Cj-Cj -Alkoxy-C.-C ^ alkyl radical,

R., R ", R- and R _{4 are} hydrogen atoms, bromine atoms, chlorine atoms, fluorine atoms, trifluoromethyl _{radicals, carboxy groups, carboxy-C.-C 3} -alkyl radicals, Cj-Cj-alkyl radicals, C.-C_-alkoxy groups or amino groups with the proviso that one of the substituents R. and R. in the same molecule must be a hydrogen atom and that only two of the substituents R., R., and R. are radicals other than hydrogen atoms,

R _c , R,., R_ and R ₀ alone are hydrogen atoms, bromine atoms, chlorine atoms, fluorine atoms, trifluoromethyl radicals, carboxy green, C.-C, -alkyl radicals, C _; , -C ₃ alkoxy groups, C ₁ -C ₃ alkOXV-C. -Cj-alkyl radicals, phenyl radicals or nitro groups with the proviso that only one of the substituents R ₅ , R _g , R ₇ and R _{g is} a nitroarunoe and only one is a phenyl radical and that only two of the substituents

R _c , R,., R_ and R _{0 are} radicals other than hydrogen atoms, or -> b / ο

R _c and R _c , R ₄ . and R_ or R .. and R _{Q taken} together the

DDD / / O

Grouping which is necessary for the formation of a fused Arvlring in the 2,3- or 3,4-position, mean

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BR - 5 -

with the proviso that X, R ₅ , R _g , R ₇ or R _g denotes an a tuent as a hydrogen atom, and

with the further proviso that when X, R, R ", R ₃ , R ₄ , R ₅ , R _fi , R ₇ or Rq is an alkyl radical, one of the substituents X, R., R _n , R ,, R., R _c , R _c , R_ or R ₀ denotes a substituent other than a hydrogen atom or an alkyl radical.

The invention also relates to a method for production of the new compounds of the formula I, which is characterized in that a 2-chlorobenzoxazole of the formula

Formula II

with a substituted aniline of the formula

Formula III

where R. to R ₀ and X in formulas II and III are as defined above

Io

are, is reacted in an inert solvent and at elevated temperature.

The new compounds are in all cases in the phenyl ring of the aniline residue monosubstituted or doubly substituted so that they can be substituted as 2-anilinobenzoxazoles with 2-, 3-, 4-, 2,3-, 2,4-, 3,4-, 2,5- or 3,5-substituted Aniline residue can be described. The following compounds are preferred:

2- (2-chloroanilino) benzoxazole 2- (3-chloroanilino) benzoxazole 2- (4-chloroanilino) benzoxazole 2- (4-fluoroanilino) benzoxazole 2- (3-fluoro-4-nitroanilino) benzoxazole 2- (4-Bromo-3-methylanilino) benzoxazole 2- (3-methylanilino) benzoxazole 2- (2-Bromo-4-methylanilino) benzoxazole 2- (3-Carboxyanilino) benzoxazole 2- (3-Bromo-5-methylanilino) benzoxazole 2- (4-Carboxyanilino) benzoxazole 2- / 3- (methylthio) anilino / benzoxazole

2-Ti (methylsulfonyl) anilino / benzoxazole

2-72- (trifluoromethyl) anilino / benzoxazole 2- / 3- (trifluoromethyl) anilino / benzoxazole 2- (3-nitroanilino) benzoxazole

20985Q / 12S3

ORIGINAL IMSPECTED

BR _ - 6 -

2- (2-Methyl-5-nitroanili.no) benzoxazole 2- (4-nitroanilino) benzoxazole 2- (3,4-dichloroanilino) benzoxazole 2- (2,5-dichloroanilino) benzoxazole 2- (2,3-dichloroanilino) benzoxazole 2- (2,5-difluoroanilino) benzoxazole 2- / 2-Bromo-5- (trifluoromethyl) anilino / benzoxazole 2- / 4-Bromo-2- (trifluoromethyl) anilino / benzoxazole 2- / 4-chloro-2- (trifluoromethyl) anilino / benzoxazole 2- / 4-fluoro-2- (trifluoromethyl) anilino / benzoxazole 2- / N-benzyl-3- (trifluoromethyl) anilino / benzoxazole 2- / 3- (trifluoromethyl) -N-methylanilino / benzoxazole 2- / N- (n-butyl) -3- (trifluoromethyl) anilino / benzoxazole

2- / 4-chloro-3- (trifluoromethyl) -N-methylanilino / benzoxazole 2- / N-Benzyl-4-chloro-3- (trifluoromethyl) anilino / benzoxazole

2- / 4- (trifluoromethyl) -2-nitroanilino / benzoxazole 2- / 4-Bromo-3- (trifluoromethyl) anilino / benzoxazole 2- / 5- (trifluoromethyl) -2-methylanilino / benzoxazole

The compounds are particularly preferred:

2- (2,4-dichloroanilino) benzoxazole 2- / 4-bromo-3- (trifluoromethyl) anilino / benzoxazole 2- / 4-chloro-3- (trifluoromethyl) anilino / benzoxazole 2- / 4-fluoro-3- (trifluoromethyl) anilino / benzoxazole

2- / N- (η-butyl) -4-chloro-3- (trifluoromethyl) anilino / benzoxazole 2- / N-carboxymethyl-4-chloro-3- (trifluoromethyl) anilino / -

benzoxazole

2- (2,4-difluoroanilino) benzoxazole 2- / 4- (trifluoromethyl) anilino / benzoxazole 2- / 3,5-di (trifluoromethyl) anilino / benzoxazole 2- (4-phenylanilino) benzoxazole 2- / 2- (trifluoromethyl) -5-nitroanilino / benzoxazole 2- (N-Benzylanilino) benzoxazole 2- (1-Naphthylamino) benzoxazole 2- (3-carbethoxyanilino) benzoxazole 2- / 2-fluoro-5- (trifluoromethyl) anilino / benzoxazole 2- / 4-chloro-3- (trifluoromethyl) -N- (3-dimethylamino-n-propyl) -anilinobenzoxazole

2- / N-carbanilino-4-chloro-3- (trifluoromethyl) anilino / benzoxazole

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ORIGINAL INSPECTED

- "7 ■ · -

Compounds in which the substituents designated above in the formula R ₁ , R ₃ , _{R 1, R 4} and X are hydrogen atoms can be prepared by a one-step synthesis using 2-chlorobenzoxazole as the starting material. For this purpose, the 2-chlorobenzoxazole is reacted with a substituted aniline in which the substituents desired in the end product are present on the phenyl ring of the aniline. To carry out the reaction, the desired substituted aniline in a suitable solvent is added dropwise to the 2-chlorobenzoxazole in a suitable solvent. After the addition has ended, the reaction mixture is refluxed on a steam bath for 16 hours or until a solid precipitate has formed. Water is then added to the reaction mixture and the solvent is removed by distillation. The remaining aqueous suspension is filtered and the filter cake is recrystallized from a suitable solvent to give the desired 2-anilinobenzoxazole with a substituted aniline residue.

It has been found that for the synthesis of the foregoing Tetrahydrofuran compounds described in section are a very advantageous solvent for carrying out the reaction is. Other suitable solvents used for this are, for example, acetone, dioxane, benzene, diethyl ether and ethyl acetate. It is appropriate when both reactants are soluble in the solvent used to carry out the reaction are. For carrying out the implementation described herein, it is also advantageous if in the used Solvent the reaction product generated is insoluble.

After the crude reaction product from the aqueous medium is filtered off, it is dried by conventional measures in a vacuum and then in a suitable solvent, for example benzene. More suitable

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Solvents that can be used for recrystallization are, for example, acetone, methanol and the like. The solvent used to dissolve the crude reaction product is heated to complete Keep the amount required as low as possible, and the solution is made with hexane, water or another precipitant is added in an amount sufficient to crystallize the desired 2-anilinobenzoxazole with substituted aniline residue is sufficient. The crystallization is brought about with an amount of precipitant that can be determined by determining the turbidity, which forms in the solution can be determined. The precipitate is filtered off.

The 2-chlorobenzoxazole used to synthesize the described substituted anilinobenzoxazole is used, is available as a commercial product. Lots of the substituted Anilines that can be used in the implementation are also offered as commercial products. Substituted Anilines, which are required for the synthesis of the compounds described herein and not as commercial products can be synthesized by known methods.

The preparation of the compounds in which the substituents R ₁ , R ₂ , R ₃ , R ₄ and X are hydrogen atoms is illustrated by the following Examples 1 and 2.

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example 1

Production of 2- / 4-bromo-3- (trifluoromethyl) -anilino / -

benzoxazole

A solution of 15.4 g (0.1 mol) of 2-chlorobenzoxazole in 250 ml of tetrahydrofuran is added dropwise with vigorous stirring with a solution of 24.0 g (0.1 mol) of 4-bromo-3- (trifluoromethyl) aniline in 100 ml of tetrahydrofuran are added. After the addition, the reaction mixture is heated on a steam bath for 16 hours to boiling under reflux, then cooled to about 25 ⁰ C and treated with about 500 ml of water. The tetrahydrofuran used as the solvent is separated from the reaction mixture by vacuum distillation. The reaction mixture is then cooled ^{to about 25 ° C.} The precipitate is filtered off and the filter residue is dried and taken up in warm acetone. The acetone solution is allowed to cool to room temperature and about 300 ml of water are added, causing crystallization of the reaction product which is dried. This gives 28.0 g of 2- / 4-bromo-3- (trifluoromethyl) anilino / benzoxazole having a melting point of 211-212 ⁰ C.

Analysis: C ₁₄ HgN ₂ OBrP ₃ ; Mol.wt .: 357:

Calculated: C 47.08; H 2.25; N 7.87; Found: C, 47.33; H 2.52; N 7.81.

Following the general procedure of Example 1, using the appropriate reactants made the following connections:

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2- / 4-chloro-3- (trifluoromethyl) aniline q / benzoxazole by reacting 2-chlorobenzoxazole with 4-chloro-3- (trifluoromethyl) aniline. Melting point: 199 - 200 ⁰ C.

Analysis: C ₁₄ HgClF ₃ N ₂ O; Mol Wt: 312.5

Calculated: C 53.77; H 2.57; N 8.96; Found: C, 53.60; H 2.51; N 8.73.

2- (2-fluoro-5-trifluoromethylanilino) benzoxazole by reaction of 2-chlorobenzoxazole with 2-fluoro-5- (trifluoromethyl) -aniline. Melting point: 164-165 ° C.

Analysis: C ₁₄ HgF ₄ N ₂ O; Mol Wt: 296.22

Calculated: C 56.76; H 2.72; N 9.40; Found: C, 56.64; H 2.81; N 9.16.

2- / 4-Fluoro-3- (trifluoromethyl) -anilino / benzoxazole by reacting 2-chlorobenzoxazole with 4-fluoro-3- (trifluoromethyl) -aniline. Melting point: 190 - 191 ⁰ C.

Analysis: C ₁₄ HgN ₃ OF ₄ ; Mol Wt: 296

Calculated: C 56.76; H 2.72; N 9.56; Found: C, 56.78; H 2.89; N 9.35.

2- (2,4-dichloroanilino) benzoxazole by reacting 2-chloro benzoxazole with 2,4-dichloroaniline. Melting point: 98 - 99 ⁰ C.

Analysis: C ₁₃ HgClN ₂ O; Mol Wt: 279

Calcd .: C 55.93; H 2.88; N 10.03; Found: C, 55.92; H 3.03; N 9.99.

2- (2,4-Difluoroanilino) benzoxazole by reacting 2-chlorobenzoxazole with 2,4-difluoroaniline. Melting point: 115 - 117 ⁰ C.

Analysis: C ₁₃ H ₃ F ₂ N ₂ O; Mol Wt: 246

Calculated: C 63.41; H 3.27; N 11.38; Found: C, 63.29; II 3.32; N 11.40.

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2- / 3- (trifluoromethyl) anilino / benzoxazole by reacting 2-chlorobenzoxazole with m-aminobenzotrifluoride. Melting point: 193 - 194 ⁰ C.

Analysis: C ₁₄ H ₉ F ₃ N ₂ O; Mol Wt: 278

Calculated: C, 60.43; H 3.25; 10.07; Found: C, 60.30; H 3.23; 9.86.

2- / 4- (trifluoromethyl) anilino / benzoxazole by reacting 2-chlorobenzoxazole with p-aminobenzotrifluoride. Melting point: 180 - 182 ⁰ C.

Analysis: C ₁₄ H ₃ F ₃ N ₂ O; Mol Wt: 278

Calculated: C, 60.43; H 3.26; 10.07; found: C 60.33? H 3.26; 10.27.

2- / 3,5-Di- (trifluoromethyl) -anilino / benzoxazole by reacting 2-chlorobenzoxazole with 3,5-di- (trifluoromethyl) aniline. Melting point: 178-180 ⁰ C.

Analysis: C ₁₅ HgFgN ₂ O; Mol Wt: 376

Calculated: C 52.03; H 2.33; N 8.09 Found: C, 51.82; H 2.31; N 8.23.

2- / 2- (trifluoromethyl) -5-nitroanilino / benzoxazole by reacting 2-chlorobenzoxazole with 2-amino-5-nitrobenzotrifluoride. Melting point 150 - 152 ⁰ C.

Analysis: C ₁₄ H ₃ F ₃ N ₃ O ₃ ; Mol Wt: 323

Calculated: C 52.01; H 2.49; N 12.99; Found:, C 51.90; H 2.68; N 12.97 ..

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Example 2
Production of 2- (3-carbethoxyanilino) benzoxazole

A solution of 15.4 g (0.1 mol) of 2-chlorobenzoxazole in about 200 ml of tetrahydrofuran is added dropwise to a solution of 16.5 g (0.1 mol) of ethyl m-aminobenzoate in about 100 ml of tetrahydrofuran. After this addition, the reaction mixture is refluxed on a steam bath for 16 hours. The reaction mixture is then ^{cooled to about 25 °} C. and about 500 ml of water are added. The tetrahydrofuran used as solvent is distilled off in vacuo. The deposited precipitate is filtered off, washed with a saturated aqueous sodium bicarbonate solution and dried. The dry solid is dissolved in as little ethyl acetate as possible, and about 200 ml of hexane are added to the solution. The crystalline product is separated by filtration and there is obtained 17.6 g of 2- (3-Carbäthoxyanilino) benzoxazole having a melting point of 168-170 ⁰ C.

Analysis: ^c ₁ 6 ^H i4 ^N 2 ° ^{3; Mol} ~ ^{wt : 282}

calc .: C 68.07? H 5.00; N 9.92; Found: C, 68.03; H 5.19; N 10.01.

Following the general procedure of Example 2 using the appropriate reactants, the following are made Connections made:

2- (4-Phenylanilino) benzoxazole by reacting 2-chlorobenzoxazole with p-aminodiphenyl. Melting point 213-214 ⁰ C.

Analysis: ^c ig ^H 14 ^N 2 ^O; Mol Wt 286:

Calculated: C 79.70; H 4.93; N 9.78; Found: C 79.87; H 4.93; N 9.80.

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2221868

2- (1-Naphthylamino) benzoxazole by reacting 2-chlorobenzoxazole with 1-naphthylamine. Melting point 163 - 164 C.

Analysis: C ₁₇ H ₁₂ N ₃ O; Mol Wt: 260

Calculated: C 78.44; H 4.65; N 10.76; Found: C 78.68; H 4.85; N 10.52.

New compounds with one or two substituents other than hydrogen on the phenyl ring of the benzoxazole portion will be obtained by prior to the nitration stage that is the manufacture of the substituted ortho-aminophenol precedes, introduces the particular desired substituents into the phenyl ring. The measures suitable for this purpose are known to the person skilled in the art. It is of course important to ensure that in the case of two substituents on the phenol, these "must not be introduced in the 2,6-position.

The mono- or disubstituted phenol is nitrated in a manner known per se, the nitro group in the ortho position is introduced to the hydroxyl group. As can be seen without further ado, if the simple or double substitutions of the phenol give unsymmetrical configurations, the nitro isomers before hydrogenation the nitro group can be separated to the amino group. This separation can be carried out by fractional crystallization, as required or distillation.

The hydrogenation of the nitro group can be carried out by reacting with Hydrogen using a palladium catalyst or the like, or using tin, hydrochloric acid and heat in a suitable solvent. Both types of hydrogenation are well known, and the im The method used in individual cases depends on the nature of the substituents on the phenyl ring.

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In a preferred method for converting the substituted Aminophenol in a 2-chloro-substituted benzoxazole becomes the corresponding aminophenol with thiophosgene to the corresponding benzoxazolthione (Seidel, J. Prakt. Chem., (2) 42, 456, 1890) reacted, which is then substituted with chlorine in dry chloroform into the desired 2-chloro Benzoxazole can be converted (McCoy, Am. Chem. J., 21, 117, 1899).

The chlorine-substituted benzoxazole is then substituted with the correspondingly substituted aniline according to the above or below described procedure implemented.

The new compounds, in whose formula X is a substituent other than hydrogen, can be according to two different Working methods are produced:

The first working method is suitable for such substituents those in the presence or absence of substituents other than hydrogen on the phenyl ring of the aniline on the nitrogen the aniline compound can be bound without the reactivity of the remaining hydrogen on Affecting aniline nitrogen atom. Such connections can with unsubstituted, monosubstituted or disubstituted 2-chlorobenzoxazoles in the phenyl ring according to the im the following general working method described below.

A solution of the N-substituted (unsubstituted, mono- or disubstituted) aniline in a suitable one Solvent is added dropwise to a solution of 2-chlorobenzoxazole (unsubstituted or mono- or disubstituted in the phenyl ring) in a suitable solvent. Dioxane is a particularly suitable solvent for both reactants. Other solvents that can be used are tetrahydrofuran, acetone, diethyl ether, ethyl acetate and

209850/1253

like that. The reaction mixture is then about 16 hours or until a reaction product has formed, heated to reflux on a steam bath. To If water is added, the reaction mixture is freed from the solvent by distillation in vacuo. The raw product the aqueous slurry thus obtained is washed with a saturated aqueous sodium bicarbonate solution, extracted with a suitable solvent such as diethyl ether, distilled and recrystallized or by customary chromatographic procedure isolated. As a solvent for the extraction of the reaction product from the raw mixture chloroform, ethyl acetate, benzene, methylene chloride and the like are suitable.

Examples 3 and 4 illustrate the preparation of some anilinobenzoxazoles according to that described above first way of working.

Be. ispiel 3 Preparation of 2- (N-Benzylanilino) benzoxazole

A solution of 18.3 g (0.1 mol) of N-benzylaniline approximately 100 ml of dioxane is added dropwise to a solution of 15.4 g (0.1 mol) of 2-chlorobenzoxazole in about 200 ml of dioxane. The reaction mixture is then refluxed on a steam bath for about 16 hours. That as a solvent The dioxane used is removed from the reaction mixture by distillation in vacuo. The crude product obtained is washed with a saturated sodium bicarbonate solution and then extracted with diethyl ether. By distilling the ethereal solution in vacuo gives 23 g of crude reaction product. The crude product is sent to a slurry of

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" ¹⁶ " 222186G

Chromatographed silica gel (Grace-Davidson) column prepared in benzene and eluted with a solvent system of benzene, chloroform and ethanol in a ratio of 25: 24: 1. the Chromatographic separation yields 17.5 g of 2- (N-benzylanilino) -benzoxazole with a melting point of 60-62 C.

Analysis: C ₂₀ H ₁₆ N ₃ O; Mol Wt: 300

, calc .: C 79.98; H 5.37; N 9.33; Found: C 79.74; H 5.55; N 9.40.

The one for the adsorption of substituted 2-anilinobenzoxazoles preferred chromatographic material is silica gel.

Useful eluting solvents include benzene, ethyl acetate, methanol, chloroform, and mixtures thereof Solvent with ethanol.

Example 4

Production of 2- _/ / N- (n-butyl) -4-chloro-3 ~ (trifluoromethyl) -

anilino / benzoxazole

A solution of 26.3 g (0.1046 mol) of N- (n-butyl) ~ 4-chloro-3- (trifluoromethyl) aniline in about 100 ml of dioxane is added dropwise to a solution of 16.0 g (0, 1046 mol) of 2-chlorobenzoxazole in about 200 ml of dioxane. The resulting reaction mixture is refluxed on a steam bath for about 16 hours. After cooling to about 25 ^° C., about 500 ml of water are added to the reaction mixture. The dioxane used as a solvent is obtained by vacuum distillation

209850/12 5 3

removed from the reaction mixture. The crude product is washed with a saturated aqueous sodium bicarbonate solution and extracted with diethyl ether. The ether solution is distilled, obtaining 25.4 g of 2- / N- (n-Butyl) -4-chloro-3- (trifluoromethyl) anilino / benzoxazole, bp 0.3 mm = 166-168 ⁰ C.

Analysis: C ₁₈ H ₁₆ ClF ₃ N ₃ O; Mol Weight: 368.5

Calculated: C 58.62; H 4.37; N 7.60; Found: C 58.90; H 4.48; N 7.79.

The N- (n-butyl) -4-chloro-3- (trifluoromethyl) aniline used in Example 4 above was made as follows:

140.5 g (1.0 mol) of benzoyl chloride was added dropwise with stirring to a solution of 181.5 g (1.0 mol) of p-chloro-m- (trifluoromethyl) aniline and 79 g (1.0 mole) of pyridine in 2 liters of dry benzene. The reaction was through Heating initiated, but then the heat generated on addition of benzoyl chloride was sufficient to maintain reflux conditions maintain. The reaction mixture was stirred at room temperature overnight and then for 2 hours heated to boiling under reflux. After cooling to about 25 C, the reaction product was successively treated with 6 η hydrochloric acid and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and filtered. The filtrate was evaporated to dryness by vacuum distillation and the residue became from a benzene-hexane Mixture recrystallized. 2 g of 4'-chloro-3 '- (trifluoromethyl) benzanilide were obtained with a melting point of 130 to 131 ° C.

209850/1253

59.9 g (0.2 mol) of this benzanilide in about 300 ml of dioxane were added dropwise with stirring to a solution of 10.1 g (0.22 mol) of sodium hydride (50 percent in oil) in about 250 ml of dioxane in a given with the flame-dried apparatus under a nitrogen atmosphere. The reaction mixture was refluxed for 2 hours and, after cooling to room temperature, a solution of 37.05 g (0.22 mol) of benzyl bromide in about 250 ml of dioxane was added dropwise. The reaction mixture obtained in this way was heated to boiling under reflux for 165 hours and then freed from the dioxane used as solvent by distillation in vacuo. The crude product was dissolved in diethyl ether, and the ethereal solution was washed successively with water and 3N hydrochloric acid, dried over magnesium sulfate and filtered. The filtrate was distilled on a Vigreux column, and 37.6 g of N- (n-butyl) - were obtained 4 '-chloro-S-itrifluormethyl) .- benzanilide, bp 1.4 mm = 177-180 ⁰ C.

33 g (0.093 mol) of this N- (η-butyl) benzanilide were used for Hydrolysis was added to a solution of 10.8 g (0.372 mol) of sodium hydroxide in 200 ml of water and 100 ml of ethanol. the The resulting solution was refluxed for 20 hours. The ethanol was removed by distillation in vacuo. The remaining basic solution was extracted with diethyl ether, and the ethereal extract was over mag- · dried nesium sulfate and filtered. The filtrate was evaporated to dryness in vacuo. That was used for cleaning The crude product obtained was initially mixed with 6N hydrochloric acid. After separation of the water-insoluble salts formed was the acidic solution was made alkaline by adding a 10 percent aqueous sodium hydroxide solution and the product was again extracted with ether as described above and dried. 16.9 g of N- (η-butyl) -4-chloro-3- (trifluoromethyl) aniline were obtained.

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Other N-substituted anilines can be prepared in the same way will. Processes for the preparation of anilines substituted in the phenyl ring are generally known to the person skilled in the art.

The second mode of operation. Which can be used for the preparation of substituted 2-anilinobenzoxazoles, which on the aniline nitrogen carry a substituent other than hydrogen, proceeds as follows:

The anilinobenzoxazole compounds, which already have all the substituents desired on the two phenyl rings, but still do not carry any substituents on the aniline nitrogen, are prepared according to one of the procedures described above. if the group to be attached to the nitrogen of the aniline group is part of a molecule that is reactive Contains substituents that react directly with the hydrogen bonded to the nitrogen, the desired compound can by a single addition displacement reaction in a suitable solvent, for example one those described above. By refluxing the reaction mixture for 2 to 16 hours, the addition completes. The solvent is removed by distillation in vacuo and the reaction product becomes recrystallized from a solvent mixture, for example acetone / hexane or one of those described above.

Example 5 illustrates the preparation of a compound after the second working method.

Example 5

Production of 2- / N- (Carbanilino) -4-chloro-3- (trifluoromethyl) -

anilino / benzoxazole

Mine is a solution of 4.8 g (0.04 mol) of phenyl isocyanate in 20 ml Tetrahydrofuran is added dropwise to a with stirring

209850/1253

Mixture of 12.5 g (0.04 mol) 2- (4-chloro-3-trifluoromethylanilino) benzoxazole and added 100 ml of tetrahydrofuran. The mixture obtained is refluxed for 2 hours heated.

The tetrahydrofuran used as solvent is then removed by distillation in vacuo. The solid residue is recrystallized from a solvent mixture of acetone and hexane provides 14.0 g of 2- / N- (Carbanilino) -4-chloro-3- (trifluoromethyl) anilino / benzoxazol that at 142 - 144 ⁰ C melts.

Analysis: C ₂₁ H ₁₃ ClF ₃ N ₃ O ₃ ; Mol Wt: 431.5

Calcd .: C 58.40; H 3.03; N 9.73; Found: C, 58.54; H 3.14; N 9.42.

The production of an N-substituted anilinobenzoxazole, wherein the substituent to be introduced is not readily available in the form of a group as above described can be reacted directly with the hydrogen bonded to nitrogen, can be done by that you add the corresponding anilinobenzoxazole to a solution of sodium hydride in a dry solvent such as dioxane or one of the solvents described above, the reaction mixture is boiled for about 2 hours Heated to reflux and, after cooling, dropwise with a halogenated derivative of the desired substituent Group added in a dry solvent, whereupon the reaction mixture to complete the reaction refluxed for about 5 hours. The solvent is then removed by distillation in vacuo. The residue contains the crude end product or a derivative thereof, for example an ester, which after an

209850/1253

known methods can be converted into the crude product. The crude product is chromatographed on a suitable adsorbent such as silica gel or purified from a suitable solvent such as benzene or one of the recrystallized as described above.

The general method described in the previous paragraph is illustrated by Examples 6 and 7.

Example6

Production of 2- / N-carboxymethyl-4 ~ chloro-3- (trifluoromethyl) -

anilino / benzoxazole

A solution of 2.0 g (0.4 mol) of sodium hydride (50 percent in Ql) in 50 ml of dioxane is added under a nitrogen atmosphere placed in an apparatus dried with a flame. This solution is added dropwise with stirring with a solution of 12.5 g (0.04 moles) of 2- ^ 4-chloro-3- (trifluoromethyl) anilino / benzoxazole (compare Example 7) added to 200 ml of dioxane. The reaction mixture formed is boiled for 2 hours heated under reflux, cooled and treated dropwise with a solution of 7.4 g (0.044 mol) of ethyl bromoacetate in 25 ml of dioxane offset. The resulting solution is refluxed for 5 hours. Then that is used as a solvent The dioxane used is removed by distillation in vacuo, and it becomes the ethyl ester of the N-carboxymethyl derivative obtained as a crude product.

209860/1 253

This crude product is refluxed for about 5 hours in a solution of 100 ml of ethanol and 200 ml of a 15 percent strength aqueous potassium hydroxide solution. The ethanol is removed by distillation in vacuo. The potassium hydroxide solution is extracted with diethyl ether, made acidic by adding concentrated hydrochloric acid and then extracted again with ether. This last ether extract is evaporated by distillation in vacuo and gives 2- / H-carboxymethyl-4-chloro-3- (trifluoromethyl) anilino / benzoxazole. This product is dissolved in the smallest possible amount of benzene and crystallized by adding higher aromatic naphtha. The melting point of this product is 141 to 144 ⁰ C.

Analysis: C ₁₆ H ₁₀ ClF ₃ N ₃ O ^{_3; Mo1 wt} * ^{: 386} ' ⁵

Calculated: C 51.83; H 2.71; N 7.55; Found: C 51.96; H 2.76; N 7.44.

Example 7

Preparation of 2- / 4-chloro-3-trifluoromethyl-N- (3-dlmethylamino-n-propyl) anilino / benzoxazole hydrochloride

A solution of 12.5 g (0.04 mol) of 2- / 4-chloro-3- (trifluoromethyl) anilino / benzoxazole in 200 ml of dioxane is added dropwise with stirring to a solution of 2.0 g (0.04 mol ) Sodium hydride (50 percent in oil) in 50 ml of dioxane in a flame-dried apparatus under a nitrogen atmosphere. The reaction mixture is refluxed for 2 hours, cooled and then a solution of 5.4 g (0.044 mol) of dimethylaminopropyl chloride in 25 ml of dioxane is added dropwise. The resulting solution is refluxed for 5 hours. The dioxane used as a solvent is through

209850/1253

Distillation removed in vacuo, with 18 g of crude product, stay behind.

This crude product is purified by chromatography on a silica gel column prepared with ethyl acetate and eluted with a mixture of ethyl acetate and methanol (ratio 1: 1). Further elution with methanol yields 16.2 g of 2- / 4-chloro-3-trifluoromethyl-N- (3-dimethylaminon-propyl) anilino / benzoxazole, which is converted into the hydrochloride salt with a
will.

a melting point of 116 to 118 ⁰ C (9.2 g) converted

Analysis: C ₁₉ H ₂₀ Cl ₃ F ₃ N ₃ O; Mol Wt: 434

Calculated: C 52.54; H 4.64; N 9.68; Found: C, 52.37; H 4.75; N 9.53.

The structure of the compounds synthesized in the above 7 examples was confirmed by nuclear magnetic resonance spectrum confirmed.

The substituted 2-anilinobenzoxazoles act in the way that they suppress the immune response of warm-blooded mammals. The term immunoreaction is generally understood to mean the mechanism that is set in motion by the entry of foreign protein into tissue or cells. The body mobilizes its defense mechanism against the invading foreign matter in order to protect its own tissues or cells from damage protection. An example of this immune response is the rejection of organ transplants, such as kidneys a body other than that of an identical twin or in the case of skin grafts. Heart transplant success depends on effective suppression of the recipient's immune response in addition to the skill of the surgeon.

209850 / 12B3

For the detection of immunosuppressive activity of test compounds certain in vivo tests have been developed. The immunosuppressive activity of substituted anilinobenzoxazoles is achieved by suppressing the development of antibodies against red blood cells in Swiss mice Sheep were detected that were injected intraperitoneally into the mice.

To determine immunosuppressive activity, a modification of the method of Nathan, et al. (Nathan, H. C; Bieber, S .; Elion, G. B .; and Hltchings, G. H .; Proc. Soc. Exptl. Biol. Med., 107, 796, 1961). Groups of five Swiss mice weighing 20 g were injected intraperitoneally with 0.2 ml of 1:80 standardized suspensions of red blood cells from sheep (about 5 × 10 cells / mouse) were administered. 72, 48 and 24 hours before the red blood cell injection, the test compounds were injected by the same route. 8 days After the injections of the blood cell antigens, the blood of the mice was taken by cardia puncture, and the sera of the 5 mice in one group were pooled. The determination of the antibodies of the pooled sera was carried out by a operation based on hemagglutination. The results obtained with treated and untreated animals were compared. The results are given as the minimum amount of drug in mg / kg χ 3 that is necessary is to lower the hemagglutination titer by a factor of at least 4 compared to the control titers.

The test compounds were dissolved or suspended in a surface-active agent (trade name Emulphor), which consists of a polyethoxylated vegetable oil for intraperitoneal injections. The following table shows the immunosuppressive activity of representative substituted 2-anilinobenzoxazoles. The numerical values given are the Amounts in mg test compound / kg body weight administered as described above for each of the 3 injections.

209850/1253

Table I.

Immunosuppressive activity of representative substituted

2-anilinobenz oxaz oils

Amount in mg / kg χ 3, the connection to a minimum of 4 τ

fold lowering of the hemagglutination titer

2- (4-chloroanilino) benzoxazole 50

2- (2,4-dichloroanilino) benzoxazole 12.5

2- (2-chloroanilino) benzoxazole 100

2- (2,5-dichloroanilino) benzoxazole 100

2- / 4-chloro-3- (trifluoromethyl) anilino / benzoxazole 0.8

2- / 2- (trifluoromethyl) anilino / benzoxazole 100 2- / 3- (trifluoromethyl) anilino / benzoxazole 1,6

2- (4-nitroanilino) benzoxazole 100

2- (3-nitroanilino) benzoxazole 100

2- (3-chloroanilino) benzoxazole 100 2- (3,4-Dichlorani1ino) benz oxaz oil 3.1

2- / N-Benzyl-3- (trifluoromethyl) anilino / -benzoxazole p »-25

2- / 4-chloro-3- (trifluoromethyl) -N-

(n-propyl) anilino / benzoxazole 12.5

2- (1-Naphthylamine) benzoxazole 25

2- / 4-chloro-3- (trifluoromethyl) anilino / benzoxazole 100

2- / 4-Bromo-3- (trifluoromethyl) anilino / benzoxazole 0.4

2- / 2-fluoro-5- (trifluoromethyl) -aniline-p / -benzoxazole 12.5

209850/1253

1 - / ^ 4-fluoro-3- (trifluoromethyl) -anilino / -

benzoxazole 12.5

2- / 4-bromo-2- (trifluoromethyl) anilino / -

benzoxazole 100

2- / 4-chloro-3- (trifluoromethyl) --N-

methylanilino / benzoxazole 25

2- (3-ethoxycarbonylanilino) benzoxazole 25

2- (4-ethoxycarbonylanilino) benzoxazole 25

2- (2,4 ~ Difluoroanilino) benzoxazole 50

2- / 4-trifluoromethyl) anilino / benzoxazole 50

2- (3,5-di- (trifluoromethyl) -anilino / -

benzoxazole 12.5

2- / 2- (trifluoromethyl) -5-nitroanilino / -

benzoxazole 25

2- (4-phenylanilino) benzoxazole 25

2- (N-Benzylanilino) benzoxazole 25

2-./4-chlor-3- (trifluoromethyl) -N-benzyl-

anilino / benzoxazole 100

2- / 4-chloro-3- (trifluoromethyl) -N-

(carboxymethyl) anilino / benzoxazole 12.5

2- / 4-chloro-3- (trifluoromethyl-N-

(carbanilino / benzoxazole 25

2- / 3- (methylsulfonyl) -anilino / benzoxazole .100

2- / 3- (methylthio) anilino / benzoxazole 100

209850/1253

222180 ^

The immunoreaction of a mammal is through administration a compound of the formula

suppressed. In this formula:

X hydrogen, C ₁ -C ₄ -AIkYl, C ₁ -C ₃ -AIkOXy, carboxy, carboxy-C. ^ - C ₃ -alkyl, AmInO-C ₁ -C ₃ -alkyl, MOnO-C ₁ -C ₃ - alkylamino-Cj ^ -Cg-alkyl, di-Cj-Cj-alkylamino-Cj-C.jalkyl, Cj-Cg-alkylanilino-Cj-C ^ alkyl or C ₁ -C ₃ -AIk-

R ₁ , R ₂ , R ₃ and R ₄ each individually hydrogen, bromine, chlorine, fluorine, trifluoromethyl, carboxy, carboxy-Cj ^ Cg-alkyl, C -Cj-alkyl, C ₁ -C ₃ -AlkOXy or amino , where one of the radicals R. and R ₄ must be hydrogen and only two of the radicals R ₁ , R ₃ , R ₃ and R _{4 have} a different meaning than hydrogen.

R ₅ , R ₆ , R ₇ and Rq each individually hydrogen, bromine, chlorine, fluorine, trifluprmethyl, carboxy, C ₁ -C ₃ alkYl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkoxy C ₁ -C ₃ -alkyl, phenyl or nitro, where only one of the radicals R ₅ , R _g , R ₇ and Rq is a nitro group and only one is a phenyl group and only two of the radicals R _c , R-,

D O

R ₇ and Rg have a meaning other than hydrogen.

2098 5 0/12 5 3

INSPECTED

R ₅ and Rg, or R _g and R ₇ or R ₇ and Rg taken together are the atoms required to form a fused-on aryl ring in the 2,3- or 3,4-position.

Except for the new substituted 2-anilino described above benzoxazoles also lead to 2-anilinobenzoxazole and C -C -alkyl substituted 2-anilinobenzoxazoles effective suppression of the immunoreaction in warm-blooded mammals. In Table Ia is the effect of the last-mentioned compounds.

Table Ia

Immunosuppressive activity of 2-anilinobenzoxazole and representative C ^ -C ^ -alkyl-substituted 2-ani-

linobenzoxazoles

Compound amount in mg / kg χ 3 that is too

leads to at least a four-fold decrease in the hemagglutination titer

2-anilinobenzoxazole. 100

2- (3-methylanilino) benzoxazole 100

2- (2,3-dimethylanilino) benzoxazole 25

It can thus be seen from Tables I and Ia that

the 2-anilinobenzoxazoles of the general ones given above

Formula are effective immunosuppressors.

The mono- and di-C.-CU-alkyl-substituted 2-anilinobenzoxazoles, and 2-anilinobenzoxazole can according to the general procedures given in Examples 1 to 7 getting produced.

209850/1253

A preferred mode of administration of the immunosuppressive agents is parenteral injection of the Compounds in warm-blooded mammals taken intraperitoneally, intradermally, subcutaneously, or intramuscularly can be done. Parenteral preparations suitable for pharmaceutical purposes can be prepared according to generally known Methods are made.

The compounds according to the invention are able to suppress the immune reaction of Swiss mice even if when given orally. For example, 2- / 4-chloro-3- (trifluoromethyl) anilino / benzoxazole shows the administration to Swiss mice through a gavage in a corn oil suspension in an amount of 100 mg / kg 72, 48 and 24 hours prior to sheep red blood cell infection are effective suppression the immunoreaction.

Preferred pharmaceutical preparations for oral administration to warm-blooded mammals are, for example Capsules and tablets, the manufacture of which is well known.

Some of the new compounds are anti-fertility drugs, These substituted 2-anilinobenzoxazoles have the formula

209850/1253

in which mean

X hydrogen,

R, R ", R_ and R _{4 are} each hydrogen, bromine, chlorine, fluorine, methyl, trifluoromethyl or methoxy, where one of the radicals R and R ₄ must be hydrogen, and only 2 of the radicals R ,, R ~ / R ₃ and R _{4 have} a meaning other than hydrogen,

R ₅ , Rg and Rg are each hydrogen, bromine, chlorine, fluorine, methyl, tri fluorine thy I, methoxy or nitro, where only one of the radicals R ₅ / Rg and R "is a nitro group and only two of the radicals R ₅ , R _ß and R _{g have} a different meaning than hydrogen,

R- is hydrogen, bromine, chlorine, fluorine, methyl, trifluoromethyl, methoxy, nitro or phenyl, where R- is a nitro group only if R ₅ , R _g and R _{g have} a meaning other than nitro and where R _{7 is} only then Is hydrogen when two of the radicals R _c , R ,, and R _{0 are} others

Thu ö

Have meanings as hydrogen,

with the proviso that no more than two of the radicals Rg, Rg, R ^ and Rg have a meaning other than hydrogen.

The anti-fertility effects of the above 2-Anilinobenzoxazole is detected as follows:

The active connection is a group of young sexually mature given to female rats weighing 200 to 300 g for five days before they first started be brought together with sexually mature male rats. The connection is then made during the following 15 days in which the males and females are held together, continued to be administered. One

209850/1253

Control group receives the same feed and is kept in the same way as the test animals.

After 15 days of cohabitation, the administration the effective connection 'ends and the males xverden separated from the individual groups. 7 days later, the females are weighed, sacrificed and examined. Both in the test animals and in the animals of the control group, the number of nidation sites, the resorption sites and the viable fetus are determined.

A measure for the anti-fertility effect results from the ratio of the number of animals with nidation sites to the number of animals in the test group.

A ratio of 0/5 or 1/5 is taken as an indication of effectiveness.

Also of importance are the average number of viable fetuses and the total number of resorption sites, which is why the activity also takes place with the help of a Combination of these parameters can be assessed. A link with estrogenic anti-fertility activity generally indicates a ratio of 0/5 or 1/5 and the lack of viable fetuses or of absorption sites, from which it follows that no pregnancy has occurred, since no conception In contrast, an abortion-causing anti-fertility activity is generally characterized by a high Ratio of 4/5 or 5/5 at 0 or a small average number of viable fetuses and one relatively high number of resorption sites indicated.

2U9850 / 1253

The anti-fertility activity of those described above substituted 2-anilinobenzoxazole was determined by taking the test compounds as solutions or suspensions in corn oil daily in amounts of about 0.1 to 5.0 mg was injected subcutaneously. The administration took place for 20 days, with the male and female rats were held together for at least 15 days. 7 days after the last injection, the female became Animals weighed, killed and examined. The table below shows the anti-fertility activity of five representative substituted 2-anilinobenzoxazoles.

Tabel

Anti-fertility activity of 5 2 representative substituted 2-anilinobenzoxazoles 5 6th 7th 1 administered daily 3 4th avg. avg. Total number Connection enough amount Ratio ^a) Ratio * ¹ * Number of each Number of each d. Resorp (20 days) mg d. pregnant d. pregnant capable capable station opportunities opportunities Foeti / rat Foeti / rat len, Control Test group Control Test group Test group group group - 0.5 12th 3 46 2 «/ 4-chlorine-3- (tri- 1.0 5/5 5/5 12th 3 36 fluoromethyl) -ani- 5.0 5/5 4/5 12th 0 49 lino / benaoxa s oil 0.1 5/5 5/5 13th 8th 18th κ?
O 2- / 3- (Trlfluor- 0.5 4/5 4/5 13th 3 38 <& methyl) ~ aniii.no / - 0.5 4/5 4/5 12th 0 0 foenzoacaz oil i »o 4/5 0/5 12th 0 33 | w cn 2.0 4/5 3/5 12th 4th 34 l> 5.0 5/5 5/5 12th 3 13th «Ft 0.5 4/5 3/5 12th 0 22nd PO
cn 2- / 4-bromo-3 ~ (tri- 1.0 5/5 2/5 10 0 55 fluorm © thyl} -ani- 3.0 5/5 5/5 12th 0 54 lino / bensoxazole, 5.0 4/5 5/5 12th 3 15th 4/5 2/3

2- ^ 4-fluoro-; 0.5 5/5 5/5 12th 0 55 glu © £ pethyl | 1, <8 V / l 5 ^ 2 .18- 8th 5.0 5/5 3/5 10 1 34 I- (tri-

2- C 3 · 4-Dimsthy! Ani

2.0
5.0

4/5
4/5

5/5 3/5

a) relationship

Number of animals with nidation sites Number of animals in the test group

12th

A preferred way of administering the antifertility agents to warm-blooded suckers is parenteral, i.e. intraperitoneal / intradermal, subcutaneous or intramuscular injection of the compound in question in an amount that reduces its replication. Parenterals Preparations which are suitable for such purposes can be produced by generally known methods will.

2 ä 5

Claims (1)

Claims 1. Inununosuppressive agent, characterized in that that it is a compound of the formula as active ingredient Formula I. contains where X is a hydrogen atom, a C.-C.-alkyl radical, a C.-C-j-alkoxy group, a carboxy group, a carboxy-Cj-C-j-alkyl radical, an amino-Cj-Cj-alkyl radical, a Μοηο-ΰ, -σ, -β ^ γ ^ ΐηΙηο-ΰ.-σ, -α ^ γίΓββ ^ a Di-C ^ -C, - Xj X O ί 3 alkylamino-C ₁ -C ₃ -alkyl radical, a Cj-C ^ alkylanilino-Cj ^ -Cg-alkyl radical or a Cj-C ^ alkoxy-Cj-Cg-alkyl radical, R ₁ , R ₀ , R and R hydrogen atoms, α bromine atoms, chlorine atoms, fluorine atoms, trifluoromethyl _{radicals, carboxyl groups, carboxy-C 1} -C ₃ -alkyl radicals, C - C ₃ -alkyl radicals, Cj-Cj -alkoxy groups or amino groups with the Provided that one of the substituents R ₁ and R ^ in the same molecule must be a hydrogen atom and that only two the substituents R., 1 are hydrogen atoms, R ₃ and R ₄ radicals other than ^R 5 ' ^R 6' R- and Rg for themselves hydrogen atoms, Bromine atoms, chlorine atoms, fluorine atoms ₀ trifluoromethyl radicals, carboxy groups, C ₁ -C ₃ -AIkYIrOStO ^ C ₁ -C ₃ -alkoxy groups, 209850/1263 BR - 36 - e.-C ^ -alkoxy-C.-Cj-alkyl radicals, phenyl radicals or nitro groups with the proviso that only one of the substituents R ^, R _g , R ₇ and R _{ß is} a nitro group and only one is a phenyl radical and that only two the substituents R ₁ -, R _c , R- and R _{0 are} radicals other than hydrogen atoms, or R ₅ and Rg, Rg and R ₇ or R- and Rg taken together are the grouping required to form a fused aryl ring in the 2,3 or 3,4 position, mean. 2 ₅ agent according to claim 1, characterized in that the compound 2- / 4-BrOm-S- (trifluoromethyl) anilino / benzoxa- ZOj. Is. 3ο means according to claim 1 _f, characterized in that (as a compound 2- / 4-chloro-3- (trifluoromethyl) aniiino / benzoxajsol Ast » 4. Medium according to claim 1, characterized in that Öia compound is 2- / 3- (trifluoromethyl) anilino / benzoxazole, 5 «means according to claim 1, characterized in that the compound 2- £ 4-chloro-3- (trifluoromethyl) «N-n-propylanilino / bensoxa ^ ol is". 6. Mittel naöh Ans.pxwsk I, characterized in that the compound 2 "/ 4" ChIOr-S-Ctriflucrmethyl) -N-carboxy- is. 2Q98S0. 1253 7. Antifertilitatsraittel, characterized in that it is a compound of the formula as active ingredient Formula I. C-N- // i W contains,
wherein X is a hydrogen atom, R, R ₂ , R_ and R. Hydrogen atoms, bromine atoms, chlorine atoms, fluorine atoms, methyl radicals, trifluoromethyl radicals or methoxy groups with the proviso that one of the substituents R. and R. in the same molecule must be a hydrogen atom and that only two of the substituents R ., R ₂ # R ₃ and R, are radicals other than hydrogen atoms, R ₅ , R ₆ and Rg hydrogen atoms, bromine atoms, chlorine atoms, fluorine atoms, methyl radicals, trifluoromethyl radicals, methoxy groups or nitro groups with the proviso that only one of the substituents R ₅ , Rg and Rg is a nitro group and only two of the nt
atoms are Substituents R _g , R _g , R _g and R "radicals other than hydrogen R _{7 represents} a hydrogen atom, a bromine atom, a chlorine atom, a fluorine atom, a methyl radical, a trifluoromethyl radical, a methoxy group, a nitro group or a phenyl radical 209850/1283 BR - 38 - 12218ίβ with the proviso that R- is only a nitro group if R ₅ , R ₆ and Rg mean a substituent other than a nitro group, and R- is only a hydrogen atom if two of the substituents R ₅ , R _g and R " are radicals other than hydrogen atoms, mean, with the proviso that on the phenyl ring of the anilino radical there are no more than two substituents other than hydrogen atoms. 8. Composition according to claim 7, characterized in that the compound is 2- / 3- (trifluoromethyl) anilino / benzoxazole. 9. Composition according to claim 7, characterized in that the compound 2- / 4-chloro-3- (trifluoromethyl) anilino / -benzoxazole is. 10. Composition according to claim 7, characterized in that the compound is 2- (3,4-dimethylanilino) benzoxazole. 11. Means according to claim 7, characterized in that the compound 2- / 3- (trifluoromethyl) anilino / 5,6-dichlorobenzoxazole is. 12. Composition according to claim 7, characterized in that the compound 2- / 4-bromo-3- (trifluoromethyl) anilino / -4-methy! Benzoxazole is. 209850/1253 13th Compounds characterized by the formula Formula I. R, Rr wherein X is a hydrogen atom, a C - C «alkyl _t a C.-C ₃ alkoxy group, a carboxy group, a carboxy-C.-C, alkyl group, a Amlno-C.-Cj-alkyl group, a mono-C -C ₃ -alkylamino-C _{1 -C 3} -alkyl radical, a di-C ₁ -C ₃ -alkylamino-C ₁ -C ₃ -alkyl radical, a C.-C ^ alkylanilino-Cj ^ -Cj-alkyl radical or a C ₁ -C ₃ -alkoxy-C ₁ -C ₃ ~ alkyl radical, R, R_, R ₃ and R are hydrogen atoms, bromine atoms, chlorine atoms, fluorine atoms, trifluoromethyl _g · Carboscy- groups, carboxy-C _t -C ~ alkyl groups, C _{1 -C-}} -Älkylres3te _(> Cj-C ₃ alkoxy or amino groups; with the proviso that one of the substituents R. and R ₄ in the same molecule must be a hydrogen atom and that only two the substituents R ₁ , 1 are hydrogen atoms, R, and R, residues other than R _1. , R _c , R_ and R _Q alone are hydrogen atoms, eromatic atoms, chlorine atoms, fluorine atoms, trifluoromethyl radicals, carboxy groups, C.-C ^ alkyl radicals, Cj-C, -alk © siy groups, C.-C ₃ -alkoxy -C ₁ -C ₃ -alkyl radicals, phenyl radicals or nitro groups with the proviso that only one of the substituents Around a nitro group and nua: one one 2098S0 / 12S3 BR - 40 - ZW866 Phenyl radical and that only two of the substituents R ₅ , Rg, R- and Rg are radicals other than hydrogen atoms, or R ₅ and R _{g /} R g and R ₇ or R- and R "taken together represent the grouping which is required for the formation of a fused aryl ring in the 2,3- or 3,4-position, mean with the proviso that either X, R ₅ , R _g , R- or R "is a substituent other than a hydrogen atom, and with the further proviso that when X, R ₁ , R ₂ / R ₃ , R., R ₅ , Rg, R- or Rg is an alkyl radical, one of the substituents X, R ₁ , R ₂ ' ^R 3 » ^R 4 ^{'κ ς' R} g ^'R 7 ^{or R} a ^ei ~ nen radical other than a hydrogen atom or an alkyl radical. 14. A compound according to claim 13, namely 2- / 4-bromo-3- (trifluoromethyl) anilino / benzoxazole. 15. A compound according to claim 13, namely 2- / 4-chloro-3- (trifluoromethyl) anilino / benzoxazole. 16. A compound according to claim 13, namely 2- / 3- (trifluoromethyl) anilino / benzoxazole. 17. A compound according to claim 13, namely 2- / 4-chloro-3- (trifluoromethyl) -N-n-propylanilino / benzoxazole. 209850/1263 18. Compound according to claim 13, namely 2- / 4-chloro-3- (trifluoromethyl) -N-carboxymethylanilinoZ-S-methylbenzoxa zol. / IiK method of connecting the formula N - Formula I. wherein X represents a hydrogen atom, a Cj-C.-alkyl radical, a C ₁ -C ₃ -alkoxy group, a carboxy group, a carboxy-C.-C ₃ -alkyl radical, an amino-C.-CU-alkyl radical, a mono-Cj- Cj-alkylamino-Cj-Cg-alkyl radical, a di-C ₁ -C ₃ -alkylamino-Cj-Cj-alkyl radical, a C.-C ₃ -alkylanilino-C ₁ -C ₃ -alkyl radical or a Cj-Cg R f R_, R ₃ and R. Hydrogen atoms, bromine atoms, chlorine atoms, fluorine atoms, trifluoromethyl radicals, carboxy groups, carboxy-C.-Co-alkyl radicals, C.-C ^ -alkyl radicals, C.-C4 -alkoxy groups or amino groups with the proviso that one of the substituents R ₁ and R in the same molecule must be a hydrogen atom and that only two of the substituents R ₁ , R _{1, R 3} and R are radicals other than hydrogen atoms; 20S8S0 / 1253 BR - 42 - R ₅ "Rg, R_ and Rg for themselves hydrogen atoms, bromine atoms, chlorine atoms, fluorine atoms, trifluoromethyl _{radicals, carboxy groups, C.-C 3} - * alkyl radicals, C.-C ₃ -alkoxy groups, C.-C ₃ -alkoxy-C ₁ -C ₃ -alkyl radicals, phenyl radicals or nitro groups with the proviso that only one of the substituents R ₅ , Rg, R_ and Rg is a nitro group and only one is a phenyl radical, and that only two of the substituents R ₅ , Rg, R_ and Rg are other Radicals as hydrogen atoms are, or R ₅ and Rg, Rg and R ₇ or R_ and R _{fl taken} together represent the grouping required to form a fused aryl ring in the 2,3 or 3,4 position, mean, with the proviso that either X, R ₅ , R _g , R- or R "denotes a substituent other than a hydrogen atom, and with the further proviso that when either X, R., R ₂ , R-, R., Rp, Rg, R_ or Rg is an alkyl radical, one of the substituents X, R., R ₃ , R ₃ , R ₄ , R ₅ , Rg, R ₇ or R ₃ denotes a radical other than a hydrogen atom or an alkyl radical, characterized in that a 2-chlorobenzoxazole of the formula Formula II with a substituted aniline of the formula Formula III where R. to R _n and X in formulas II and III as above χ ο are defined, is reacted in an inert solvent and at elevated temperature * 20. The method according to claim 19, characterized in that in a further stage with a compound of the formula I in which X is a hydrogen atom, an addition-displacement reaction to replace this hydrogen on the anilino radical by a group X as defined in claim 19 is carried out with a meaning other than hydrogen. 21. The method according to claim 19, characterized in that; that in further stages an anilinobenzoxazole of the formula I, wherein X is hydrogen, reacted with sodium hydride in a dry solvent and the so obtained Product a halogenated derivative of the residue X with others Meaning as hydrogen in the formula I is added. 22. The method according to claim 19, characterized in that that dioxane is used as the solvent. 209850/1253 BR - 44 - 23. The method according to claim 19, characterized in that 2-chlorobenzoxazole with 4-bromo-3- (trifluoromethyl) aniline in tetrahydrofuran to give 2- / 4-bromo-3- (trifluoromethyl) anilino / benzoxazole is implemented. 24. The method according to claim 19, characterized in that 2-chlorobenzoxazole with 4-chloro-3- (trifluoromethyl) aniline in tetrahydrofuran to give 2- / 4-chloro-3- (trifluoromethyl) anilino / benzoxazole is implemented. 25. The method according to claim 19, characterized in that 2-chlorobenzoxazole with 2-fluoro-5- (trifluoromethyl) aniline is converted in tetrahydrofuran to 2- (2-fluoro-5-trifluoromethylanilino) -benzoxazole. 26. The method according to claim 19, characterized in that 2-chlorobenzoxazole with 4 ~ fluoro-3 ~ (trifluoromethyl) aniline converted to 2 ~ / 4-Plii.or-3- (trifluoromethyl) anilino / benzoxazole will. 27. The method according to claim 19, characterized in that 2-chlorobenzoxazole with 2,4-dichloroaniline in tetrahydrofuran is converted to 2- (2,4-dichloroanilino) benzoxazole. Process according to Claim 19, characterized in that 2-chlorobenzoxazole is ^{reacted with 2,4-difluoroaniline in tetrahydrofuran to give 2- (2e4 ra} di £ luoranillno) benzoxazole. 209850/1253 29. The method according to claim 19, characterized in that that 2-chlorobenzoxazole with m-trifluoromethylaniline in tetrahydrofuran is converted to 2- / 3- (trifluoromethyl) aniline / benzoxazole. 30. The method according to claim 19, characterized in that that 2-chlorobenzoxazole with p-trifluoromethylaniline in tetrahydrofuran is converted to 2- / 4- (trifluoromethyl) anilino / benzoxazole. 31. The method according to claim 19, characterized in that 2-chlorobenzoxazole with 3,5-di (trifluoromethyl) aniline in Tetrahydrofuran to 2- / 3,5-D (trifluoromethyl) anilino / benz ™ oxazole is implemented. 32. The method according to claim 19, characterized in that 2-chlorobenzoxazole with 2-trifluoromethyl-5-nitroaniline in tetrahydrofuran to give 2- / 2- (trifluoromethyl) -5-nitroanilino / benzoxazole is implemented. 33. The method according to claim 19, characterized in that 2-chlorobenzoxazole with ethyl m-aminobenzoate in tetrahydrofuran is converted to 2- (3-carbethoxyanilino) benzoxazole. 34. The method of claim 13 _t characterized in that 2-chlorobenzoxazole with p-Arainodiphenyl benzoxazol is reacted in tetrahydrofuran to give 2- (4-phenylanilino). 20SSSO / 12i3 35. The method according to claim 19, characterized in that that 2-chlorobenzoxazole with 1-naphthylamine in tetrahydrofuran is converted to 2- (1-naphthy! amino) benzoxazole. 36. The method according to claim 19, characterized in that 2-chlorobenzoxazole with N-benzylaniline in dioxane 2- (N-Benzylanilino) benzoxazole is implemented. 37. The method according to claim 19, characterized in that 2-chlorobenzoxazole with N- (η-butyl) -4-chloro-3- (trifluoromethyl) aniline in dioxane is converted to 2- / N- (n-butyl) -4-chloro-3- (triff luoromethyl) anilino / benzoxazole. 38. The method according to claim 20, characterized in that 2- (4-chloro-3-trifluoromethylanilino) with benzoxazole Phenyl isocyanate in tetrahydrofuran to form 2- / N- (carbanilino) -4-chloro-3 ™ (trifluoromethyl) anilino / benzoxazole is implemented. 39. The method according to claim 21, characterized in that by reacting 2- / 4-chloro-3- (trifluoromethyl) anilino / benzoxazole with sodium hydride in dioxane, treatment of the product thus obtained with a solution of ethyl bromoacetate in dioxane and removal of the ethyl residue from the N-ester group 2- / N-carboxymethyl-4-chloro-3- (trifluoromethyl) anilino / benzoxazole is produced. 40. The method according to claim 21, characterized in that the reaction of 2- / 4-chloro-3- (trifluoromethyl) -anlllnü / benaoxazoi with sodium hydride in dioxane and reaction of the product thus obtained with dimethylaminopropyl chloride in Dioscan 2- / 4-chloro-3 = trifluoromethyl-N- (3-dimethylamino- n-propvD & nilino / benzoxazole is produced. - 20S8EÖ / 1253 41. Immunosuppressive agent, characterized in that that it is a compound of the formula as active ingredient Formula I. C-N- contains, wherein the substituents R ₁ to Rg and X are defined in claim 13. 42. Agent according to claim 41, characterized in that it is a compound according to one of the claims as the active ingredient 14 to 18 contains. 43. Anti-fertility drugs, characterized by » that it is a compound of the formula as active ingredient Formula I. contains, wherein the substituents R 1 to R _n and X as I ö in claim 13, are defined. 209850/1253 BR - 48 - 44. Agent according to claim 43 , characterized in that it contains a compound according to one of claims 14 to 18 as active ingredient. 09850/125