DE1941625C3 - Substituted phenyl alkanoic acids - Google Patents

Description

N-

-N

- C

e) —N

wherein Rs and R _{6 represent} methyl groups or Rs represent a hydrogen atom and R _{6 represent} a hydrogen atom, a methyl group, a cyclopropylmethyl group or a cyclopropyl group or Rs represent a methyl group and R _{6 represent} a cyclopropyl group or a cyclopropylmethyl group,

mean.

2, therapeutic preparation, characterized by a content of a compound according to Claim 1 in addition to a pharmaceutically acceptable carrier.

The invention relates to substituted Phenylrlkansäui " ren the general formula

R ₁

and the pharmaceutically acceptable acid addition salts of the basic compounds thereof Group in which

Yi is a hydrogen atom, a halogen atom, a

Methyl group or a methoxy group;
Ri is a hydrogen atom, a methyl group or

an ethyl group;
π the numbers 0 or 1 and
Z the group

a) -COOR ₂ , in which R2 represents a hydrogen atom, a methyl group, an ethyl group or an alkali-alkaline earth or ammonium cation;

CH- (CHJ _n -Z

and the pharmaceutically acceptable acid addition salts of the basic compounds of this group, wherein

Yi represents a hydrogen atom, a halogen atom, a methyl group or a methoxy group;
_r _ Ri is a hydrogen atom or a methyl or

Ethyl group;
η the number 0 or 1 and
Z the group

a) —COOR2, in which R2 is a hydrogen atom, a Represents methyl or ethyl group or an alkali, alkaline earth or ammonium cation;

JO

N
H

or also in the case that η stands for the number 1

wherein R and R _{3 represent} methyl groups or R a hydrogen atom and R3 a hydrogen atom, a hydroxyl group, a methyl group, a cyclopropylmethyl group or a group of the formula -CH ₂ COOH; c) - OR «, in which R4 is a hydrogen atom, an acetyl group, a propionyl group or an N-methylcarbamyl group, where π denotes the number 1;

b) —CON

45 wherein R and R _{3 are} methyl groups, or R is hydrogen and R _{3 is} a hydrogen atom, a hydroxy or a methyl group, a cyclopropylmethyl group; or represent a group of the formula -CH ₂ COOH;

c) - OR * in which R _{4 is} a hydrogen atom, an acetyl group, propionyl group or N-methylcarbamyl group, where η denotes the number 1;

d) N N

N
H

or in the event that η stands for the number 1, also e) the group

R ₅

- N
\

R ₆

where Rs and R _{6 represent} methyl groups or Rs represent a hydrogen atom and R _{6 represent} a hydrogen atom, a methyl, cyclopropylmethyl or a cyclopropyl group or R _{5 represent} a methyl group and R _{6 represent} a cyclopropyl group or a cyclopropylmethyl group,

mean.

Under alkali or alkaline earth cations, sodium, potassium, lithium, calcium, magnesium or Understood barium cations. The term acid addition salts refers to salts that are produced by reaction of the free amine with an organic or inorganic acid. To such salts include, for example, the hydrochlorides, hydrobromides, sulfates, bisulfates, acetates, valerates, oleates, Laurates, Borates, Benzoates, Lactates, Phosphates, Tosylates, Citrates, Mdeates, Fumarates, Succinates, Taitrates and Napsylates (salts of 2-naphthalenesulfonic acid).

The compounds of formula I are medicaments. In particular, they are excellent anti-inflammatory properties Agents, many of which have an ED50 of 0.2 to 1.0 mg / kg in the erythema inhibition test. All of the compounds according to the invention are suitable for treating inflammation in mammals The acids and amines are preferred for this. In addition to their anti-inflammatory activity, they show Compounds mild analgesic and antipyretic effects. The subject matter of the invention also includes therapeutic preparations containing a compound of the formula ί as an active ingredient in conjunction with a pharmaceutically acceptable diluents or carriers. The connections are on Mammals generally in doses of 0.2 to 50.0 mg / kg body weight daily in either one Administered as a single dose or in multiple doses over a period of 24 hours.

Both the d and the I isomers of formula I. are covered by the definition according to the invention. For example, the alpha-alkyl acids can after known methods can be broken down into their d- and I-isomers. The d- and the I-isomers are useful here equally effective. For the treatment of inflammation, pain and fever in mammals one can therefore use either the racemate or the d- and l-isomers.

The compounds of the formula I can be prepared by processes known per se. A row the preferred reaction sequences are described below. In the following explanation, the respective substituents as defined in formula I and Ar denotes the radical

A. Acids

I. Ar-CHj
NaCN

NBS

-> Ar-CH ₂ -Br

Ar-CH ₂ -CN -> Ar-CH ₂ -COOH

The methyl group of a suitable methyl diaryl ether or diaryl thioether is activated by action of N-bromosuccinimide, N-chlorosuccionimide, sulfuryl chloride or similar halogenating agents in the presence of a catalyst, for example benzoyl peroxide, or azobisisobutyronitrile, in an inert Solvents, for example carbon tetrachloride or another halogenated hydrocarbon, halo- -t; The halomethyldiaryl ether or thioether obtained is used with sodium or potassium cyp.nid for Brought implementation, advantageously in dimethyl sulfoxide solution. The nitrile thus obtained is through Action of acidic or basic reagents according to known methods to the corresponding carboxylic acid hydrolyzed

B. σ-alkyl acids _a . Ar-CH ₂ -CN _Af _ _CH _ _CN _ ^ Ρ__ _{> Af} _ _CH _ _COOH

RiX ₂

Hb. Ar-CH ₂ -COOH Ar-CH-COOH

R ₁

R ₁ X ₂

R ₁

lic. Ar-CH ₂ C

NHR ₃

NaNH ₂ ZNH ₃
R ^

Ar-CH - COOH
R ₁

_Ud . Ar-CH ₂ -COOC ₂ H,

Na Ar-CH (CO () C, H0,

Ar-CH-COOII

R ₁

H ₂ O Ar-C (COOH) ₂

Κι

'(X) C-I

lic Ar-CIN-CN

^; > Ar-CH

N a CN

Ar— R. ι ( OOC Il NaOC-Ih
~~ r7x "7 ' I.
C. \ C. N Ar— C. OOII H ₂ O I. C.
I. Ar— I.
R. 1 \
C. ¹ OOII C. H - COOII R. 1

III Ar C Ih CN

HCOOCj

νΤΓΓΓ

Ih / Pd

Ar-C-CN

CHOH

Ar-CH-CN CH-. H, O

-> Ar-C-CN

CHOC -0

I! ο

-> Ar-CM-COOH

CH,

IV. Ar-C-Cl

NaBH ₁

NaCN

OH i Ar-CH-CHj

Ar-CH-CN

i CH ₃ PBr,

H ₃ O

Br
Ar-CH-CH.,

Ar-CH-COOH CH,

V. Ar-C-CH,

NaOCl

CjH ₁ -N ₂

Ar-COOH SOCl ₂

Ar — C —CHN,

1.0CH ₂ OH
Ag.

2. H ₂ O

il

Ar-C-Cl

Ar-CH-COOH

Vl. Ar-C (CH ₂ ) X ^- H ₁

S ΗΝ

/ ■

Ar-Cn ₂ -ICH ₂ KC

N O

ILO

Ar-CH; - (CII ₂ ) "C () () H

(C MLOHOCILiOOC -IL IL / ΙΊ

N. III. Ar-C = O > Ar C-CH COOC-IL> \ r CII CIL COOC-IL

Zero! :

K,

H-O

K,
• Ar-CII CIL COOII

I).

VIIb. Ar-C = O
R,

10.1 '- (CII ₂ ) -CN] Mr.
KOi-IHi

Ar C CII (CH ₂ ) ,. , -CN - ^ -. Ar-C II - (CIL) ,, - CN

ILO

Ar-CH- (ClLL-COOH

I.
κ,

The nitrile prepared according to the above scheme can be alkylated with an aliphatic halide or tosylate (RiX ₂ ) in liquid ammonia in the presence of sodium amide to give a Λ-aliphatically substituted nitrile. The alkylated nitrile is hydrolyzed to the corresponding carboxylic acid as above (reaction sequence Ha). In a similar way, an arylacetic acid or an arylacetamide can be alkylated in the \ -position to the carboxyl group, as shown in the reaction sequence Hb to lic. In the case of the arylacetamide, the Λ-alkyl derivative obtained can, if desired, be hydrolyzed to the corresponding carboxylic acid.

According to another method, which is through reaction sequences Hd and He is explained, one can use an aryl acetate ester. z. B. the ethyl ester, or an arylacetonitrile by the action of metallic sodium and diethyl carbonate in the corresponding malonic ester or transfer cyanoacetate. Any of these derivatives can then be alkylated. To carry out such an alkylation is usually the malonic ester or cyanoacetic ester with a strongly basic one Reagent, for example sodium ethoxide. Sodium methoxide, potassium tert-butoxide or sodium hydride, converted, whereby a carbanion is formed on the carbon atom. Subsequent treatment of the intermediate carbanions with an alkylating agent, for example an alkyl halide or tosylate (R1X2), the corresponding Λ-alkylmalonic ester or -cyanacetic ester derivative obtained. Both can the corresponding »-alkylarylmalonic acid hydrolyzed which is then decarboxylated by known methods and so the x-alkylarylacetic acid supplies

A nitrile prepared according to reaction sequence I can optionally be carried out according to the following procedure (reaction sequence III) to be methylated: The nitrile is with ethyl formate under basic conditions, for example in the presence of sodium hydride or sodium methoxide, in an inert hydrocarbon solvent, for example benzene, condensed. The hydroxymethylene derivative obtained is by the action of Benzoic anhydride or benzoylated from benzoyl chloride and pyridine. The benzoic acid ester is then in Hydrogenated in the presence of a noble metal catalyst to give the ic-methylarylacetonitrile which is then hydrolyzed as above.

The Ti-methylarylacetonitrile can optionally a .f the following reaction path (reaction sequence IV): The aryloxyacetophenone (by a Ullman ether synthesis is produced either with hydrogen in the presence of a noble metal catalyst or with a metal hydride, for example lithium aluminum hydride or lithium or sodium borohydride, reduced to the corresponding alcohol. The conversion of this alcohol into the corresponding one Bromide can be obtained by treating the alcohol with phosphorus tribromide. preferably in an inert Solvents such as chloroform. Benzene or carbon tetrachloride. The thus obtained Bromide is then combined with sodium cyanide. advantageously in dimethyl sulfoxide solution. converted to a nitrile, which is hydrolyzed to the carboxylic acid as above.

Another method for the production of α-A! Kylphenoxyphenylessigsäuren makes use of the Arndt-Eistert reaction, as reaction sequence V shows Use of a phenoxybenzoic acid as a starting material.

The ac-alkyl acids thus obtained can after known methods can be broken down into their d- and I-isomers.

The phenoxyphenylalkanoic acids can also be prepared with the help of the Wilgerodt reaction (reaction sequence VI) getting produced. For this purpose, a phenoxyphenyl alkyl ketone, for example with morpholine and sulfur

heated and the thioamide obtained / u the alkanoic acid derivative hydrolyzed by treatment with two equivalents of sodium amide in liquid ammonia and subsequent addition of the alkyl halide or tosylate (R | X>) alkylated according to the reaction sequence Mb can be.

The acids according to the invention, in which η denotes the /.ahI 1, can be prepared using known methods

IO

the well-known Wittig reaction can be produced, such as the reaction sequences Vila and VIIb / Eigen. The intermediate ^ (saturated esters (as in Vila) or Nitriles (as in VIIb) can in the presence of a noble metal catalyst. / for example platinum, hydrogenated will. The saturated oxides and nitriles obtained can be hydrolyzed to the carboxylic acids as above will.

Vllki. Ar CM - (

R,
VIIIh. Ar-C

(C 11.0., CC) OM

C. lister C. H (C. Il 0, .CC) OR, Κ, ΟΙΙ / ΙΚΊ • A r R. C. M. - (C H 0..COCI SOCI: • Ar- U ; -C M. - (C Il 0, .CC) OR., R, C) II “A r R. 1

The carboxylic acids produced by the methods shown in the reaction sequences given above are obtained by known methods, for example by heating the acid with a Alcohol in the presence of a mineral acid (Villa) or

by converting the acid into the corresponding acid chloride and subsequent conversion of the acid chloride with an alcohol, preferably in the presence of a hydrogen chloride acceptor (VIIIb). in the corresponding ester converted.

IX. Ar- CM- (CH-I, -C
K.

Cl

RR ₁ NM

D. amides

Ar - CM - (CH,) - C

R-,

The inventive pri amides are converted by reaction or carbon tetrachloride, in the presence of an acid

tion of the above acid chlorides with an amine acceptor. for example pyridine or H2CO3, or in

obtain. This reaction is usually written in a j "> a tertiary amine solvent, for example

inert solvents, for example chloroform, benzene, collidine, lutidine or triethylamine, carried out.

X. Ar-CM-COOR ₂
R,

LiAlH,

E. Alcohols
Ar-CH-CH ₂ OH

The esters, the preparation of which has been explained above, can by known methods with a metal hydride, for example lithium aluminum hydride, can be reduced to the corresponding alcohols.

F. Ester

XIb. Ar-CH-CH ₂ -OH

Ac ₂ O

Ar-CH-CH ₂ OC-CH ₃

The alcohols obtained by reaction sequence X 65 tertiary amine such as pyridine or triethylamine in

can be converted by known methods, for example by ester derivatives. By using

Treatment of the alcohol with an acid chloride or acetic anhydride for such a reaction will

Acid anhydride, preferably obtained in the presence of, for example, the acetic acid ester.

Il

(i.

Mc. Ar-CII -CH, -Oil --.-- 'J -.-—-— ⁰ -, Ar-C !! - - C II, O - C - N IK II.

R ι R i

N.N-dimethylcarbamoyl chloride from the alcohols obtained according to reaction sequence X. These reactioners are

carbamate derivatives can also be produced. preferably in a tertiary amine. for example

either by reacting the alcohol with an n> Pyridine or triethylamine, as a solvent

Isocyanate or by reacting the alcohol with leads.

XIIa. Ar-CH ■ - C

I. wet nurse

(K.), NH
^: »Ar C

R,

Cl

ONLY,,

I.i.MH,

Ar CII Cll · - N

R, Rs

MIb. Ar C Il CN

Ar-CH CH-NIL

XlIc. Ar-C =

K,

CHiNO.

r-C = CH-NO, - Ar-CH-CH--

R,

The amine derivatives according to the invention can be prepared by known methods, for example -m by reducing an amide with a metal hydride reagent such as lithium aluminum hydride (reaction sequence XlIa). If primary amines are desired, these can be easily obtained by hydrogenating the corresponding Nitriles in the presence of ammonia and an active 4-, Catalyst, for example Raney nickel, produced (reaction sequence XIIb).

If appropriate, a suitably substituted aryl alkyl ketone can be condensed with nitromethane. The resulting nitrostyrene derivative can then be either catalytic or with a metal hydride reagent how lithium aluminum hydride can be reduced to the amine (reaction sequence XIIc).

XIV. Ar - CH- (CH,), - COOR ₂
R,

I. hydroxamic acids

Η, ΝΟΗ Ar-CH- (CH ₂ ), -C

R,

NH-OH

The esters obtainable according to the R <* aktionsfblgen Villa and VIHb can be converted in a known manner be converted into hydroxamic acids with hydroxylamine.

K. Tetrazole N-

XV. Ar - CH (CH ₂ ), - CN

NaN, Ar-CH- (CH ₂₎ - C
R,

-N

I!

N
H

Nitriles, which by the methods of reaction sequences I, Ha, III or IV or by other known methods are obtainable can be converted into the corresponding tetrazoles, for example by reaction with sodium azide using dimethylformamide as a reaction solvent (according to the procedure

by Finnigan, W. G, Henry, R. A., and Lofquist, R-, J. Am. Chem. Soc, 80, 3908 [1958]).

The starting materials for the reactions described above can easily be prepared by a Uilman diaryl ether synthesis as described by Bacon and Steward, J. Am. Chem. See, 87, 4953 (1965) and is shown in the following equation:

Ar'-OH + Ar "X

Ar'-O -Ar "

where Ar 'is an unsubstituted phenyl radical and Ar "is the substituted phenyl radical

Analysis:

for C ₁₅ H ₁₄ O ₄ : C, 69.75; H 5.46; Found: C, 69.47; H 530.

2- (2-methoxy-5-phenoxyphenyl) acetic acid, mp 90 to 94 ° C; pK'a = 7.4,
from 2-

from the general formula 1 means

The invention is further illustrated by the following examples

example 1
Production of 2- (3-phenoxyphenyl) acetic acid

26 ml of morpholine are mixed with 42.4 g of m-phenoxyacetophenone and 9.6 g of sulfur are added. The reaction mixture is stirred for 20 hours at the reflux temperature held. 700 ml of 15% strength aqueous potassium hydroxide solution are then added to the reaction mixture and a small amount of ethyl alcohol added. The reaction mixture is stirred for a further 20 Maintained at reflux temperature for hours. About 20OmI of the solvent are distilled off. the The remaining reaction mixture is filtered hot, partially cooled with ice and with concentrated hydrochloric acid acidified, as a result of which an oily precipitate forms and then the crystalline crystallizes Precipitate is filtered off, washed several times with water and dried, giving 455 g of crude product be obtained as a yellow-orange solid. The crude product is suspended in boiling hexane and ethyl acetate is added until the product goes into solution. The solution is treated with charcoal, filtered and cooled down. There are 22.7 g of white flakes of 2- (3-phenoxyphenyl) acetic acid with a melting point of 84 Maintained up to 86 ° C. pK'a = 6.9.

Analysis:

for CuH ₁₂ O ₃ : C, 73.66; H 530;
Found: C, 73.85; H 535.

Examples 2-5

Following the procedure of Example 1, the following compounds were prepared from the corresponding compounds Phenoxyacetophenones made using appropriate amounts of sulfur and morpholine.

2- (4-methyl-3-phenoxyphenyl) acetic acid,
F.49 to 51 ^o C; pK'a = 7.0,
from 4-MethyU3 = phenoxyacetophenone.

Analysis:

for Ci ₅ HhO): C 7436; H 5.83;
Found: C 74.45: H 5.88.

2- (4-methoxy-3-phenoxyphenyl) acetic acid,
M.p. 85 to 87.5'C;pK'a = 6.9.
from 4-methoxy-3-phenoxyacetophenone.

Analysis:

for C ₁₅ H ₁₄ O ₄ : C, 69.75; H 5.46; Found: C 6938; H 5.6 !.

2- (2-methyl-5-phenoxyphenyl) acetic acid, boiling point 153 to 163 ° C / 0.16 mm; pK'a = 6.9, from 2-methyl-5-phenoxyacetophenone.

Analysis:

for C ₁₅ H ₁₄ O ₃ : C 7436; H 5.83; Found: C 72.08; H 5.82.

Example 6 2- (4-chloro-3-phenoxyphenyl) acetic acid

1200 ml of carbon tetrachloride are mixed with 232.7 g of 3-phenoxy-4-chlorotoluene, 196 g of N-bromosuccinimide and 1.0 g of benzoyl peroxide were added. The reaction mixture is stirred for 24 hours at the reflux temperature held and then filtered. The solids are washed with carbon tetrachloride. That The filtrate is evaporated to an oil. By distillation, fractions A, B and C become crude 4-chloro-3-phenoxybenzyl bromide was obtained.

fraction

Sdp. (mm)

Weight (g)

A 140 to 150 (0.08) 118.5 g 1.5960

B 145 to 153 (0.07) 190.6 g 1.6152

C 145 to 160 (0.07) 79.4 g 1.6250

Fractions B and C are combined and analyzed.

Analysis:

for C ₁₃ H ₁₀ BrClO: C, 52.46; H 338; Found: C, 52.25; H 3.44.

The combined fractions B and C are distilled again in a Vigreux column, creating fractions A, B, C, D and E can be obtained.

NMR studies show that the fractions C and D contain 91 or 92% 4-chloro-3-phenoxyphenyl bromide.

In about 400 ml of dimethyl sulfoxide 22.2 gh) 95 ° / oiges sodium cyanide are dissolved, and the reaction mixture is heated to about 5O ⁰ C. 125 g of the crude 4-chloro-3-phenoxybenzyl bromide are then added dropwise with stirring. The temperature will

fraction Sdp. 145 (0.09) Weight / ή ' (mm) 155 (0.09) (G) A. 105 to 136 (0.07) 24.2 , 5951 B. 145 to 135 (0.07) 29.6 , 6114 C. 130 to 149 (0.06) 79.4 , 6228 D. 128 to 52.9 , 6218 E. 136 to 29.8 , 6274

maintained during the bromide addition between 50 and 60 ⁰ C. Immediately after adding the bromide, a red color appears. After complete addition of the bromide the reaction mixture is heated to 60 ⁰ C and stirred for 3 hours. The mixture is then cooled to room temperature and stirred overnight, then poured onto ice and extracted with ethyl ether and then with hexane. The extracts are washed with water and dried over sodium sulfate. The solvents are evaporated to give a reddish brown viscous oil. Distillation of the oil gives fractions A, B and C of 2- (4-chloro-3-phenoxyphenyl) acetonitrile.

Fraction Sdp. Weight / ι '

(mm) ig)

A 0.4 (170) to 0.15 (170) 51.6 1.5916

B 163 to 174 (0.08) 16.3 1.5917

C 174 to 190 (0, i0) 2.2 1.5917

Analysis:

Ber. for CmHioCINO: C 6839; H 4.13; N 5.74;
Found: C, 68.72; H 4.20; N 5.50.

Acid hydrolysis of the nitrile produces the corresponding 2- (4-chloro-3-phenoxyphenyl) acetic acid was obtained. For this purpose, 500 ml of concentrated hydrochloric acid are added 303 g of the nitrile are added. The reaction mixture is heated to 85 ° C. for 24 hours with stirring. The reaction mixture is distilled with 500 ml Water is added, whereupon the mixture is heated to 105 ° C. for 4 hours with stirring (gentle reflux). Then the Pour reaction mixture into a large volume of ice and water. This is followed by twice Ethyl ether extracted. The ether phases are combined, washed with water and diluted with Sodium carbonate solution extracted. Then the extract is washed with ethyl ether and poured through dropwise Addition of 6 η-hydrochloric acid acidified with stirring. The voluminous white thus obtained Precipitate is filtered off, washed with water and dried in vacuo. There are 34.2 g of white crystalline 2- (4-chloro-3-phenoxyphenyl) acetic acid with a melting point of 77 to 80 ° C.

Examples 7 and 8

The following compounds were prepared from the corresponding ones by the method of Example 6 Toluo derivatives using appropriate amounts of N-bromosuccinimide. Benzoyl peroxide and sodium cyanide manufactured:

2- (2-chloro-5-phenoxyphenyl) acetic acid.
M.p. 88 to 90 ° C; pK'a = 6.8;

Analysis:

ber, for CmHmCIO ₁ ; C 64.00; H 4.22;
Found: C 63.73; H 4.32.

2- (2-fluoro-5-phenoxy phenylacetic acid,
M.p. 80 to 82 C; pK'a = 6.65:

Analysis:

for CmH, FO ₁ : C 68.28; 114.50;
Found: C, 68.08; 114.43.

Example 9

Production of 2- (3-phenoxyphenyl) propionic acid
A) 3-phenoxyacetophenone

A mixture of 908 g (6.68 mol) m-hydroxyacetophenone, 4500 g (28.6 mol) bromobenzene, 996 g (7.2 mol) anhydrous potassium carbonate and 300 g copper bronze is heated to reflux temperature with stirring using a Dean-Stark trap, until the development of water has ended. Then the mixture is stirred for 24 hours Maintained reflux temperature. After cooling to room temperature, the reaction mixture is with a the same volume of CHCl3 diluted and filtered

The filtrate is washed with 5% HCl, then with 5% NaOH and with water, _{dried over Na 2} SO ₃ and evaporated in vacuo. The oily residue is distilled on a 15 cm Vigrey column, giving 918 g of 3-phenoxyacetophenone, boiling point 120 to 121 ° C. (0.09 mm), π? = 1.5868.

Analysis:

for CuH ₁₂ O ₂ : C, 79.22; H 5.70;
Found: C 7939: H 5.79.

B) «-Methyl-3-phenuxybenzyl alcohol

A solution of 700 g of m-phenoxyacetophenone in 3000 ml of anhydrous methanol is stirred into

«) Cooled to 0 ° C in an ice-acetone bath. This solution is added in small portions with 136 g (3.6 mol) of sodium borohydride at such a rate that the The temperature never rises above 10 ° C. After the addition of the borohydride has ended, the reaction mixture increases Allowed to warm to room temperature and stirred for 18 hours. Then it is stirred for 8 hours heated to reflux temperature. About 400 ml of methanol are distilled off, and the remaining Solution is reduced to about 1/3 of its original in a vacuum Evaporated in volume and poured into ice water. This mixture is extracted twice with ether, with 6 n-HCl acidified and extracted again with ether. The ether extracts are combined with saturated NaCl solution washed, dried over anhydrous sodium sulfate and evaporated in vacuo. The remaining oil is distilled on a 15 cm Vigreux column, whereby 666 g of «-methyl-3-phenoxybenzyl alcohol with a boiling point of 132 to 134 ° C (035 mm) are obtained become, n "= 1.5809.

. .

Analysis:

for CuH ₁₄ O ₂ : C 78.48; H 6.59:
Found: C 78.75; H 6.31.

C) «-Methyl-3-phenoxybenzyl bromide

A solution of 1357 g of a-methyl-3-phenoxybenzyl alcohol in 5000 ml of anhydrous CCU (previously dried over a molecular sieve) with stirring Chilled to 0 ° C. 1760 g of Pbrj are then added, with

w) is stirred and cooled so that the temperature remains at 0 to 5 ° C during the addition. The reaction mixture will then warm to room temperature left and stirred overnight (about 12 hours) at room temperature. Thereupon the reaction

h'i mixture poured into ice water and the organic Phase separated. The aqueous phase is extracted with CCh and the extracts are combined, three times washed with water, over anhydrous sodium sulfate

fat dried and evaporated to dryness in vacuo, giving 1702 g * -Methyl-3-phenoxybenzyl bromide can be obtained as a heavy viscous oil, π? = 1.5993.

Analysis:

for C ₁₄ H ₁₃ BrO: C, 60.44; H 4.71; Br 28.73;
Found: C, 60.62; H 4.89; Br 28.47.

D) 2- (3-phenoxyphenyl) propionitrile

A suspension of 316 g of 98 ° / pc alcohol sodium cyanide in 5000 ml of anhydrous dimethyl sulfoxide (previously over a molecular sieve-dried) is heated and with good stirring to 50 to 60 ³ C slowly g at this temperature as 1702 * -methyl-3-phenoxybenzylbromid added After When the addition of the bromide is complete, the temperature is increased to 75 ° C. and the mixture is stirred at this temperature for 1.5 hours. The mixture is then cooled to room temperature, stirred overnight at room temperature and then poured into ice water. The aqueous suspension obtained is extracted twice with ethyl acetate and then with ether. The organic extracts are washed twice with a sodium chloride solution and once with water and dried over anhydrous sodium sulfate. Vigreux column is distilled. 1136 g of 2- (3-phenoxyphenyl) propionitrile with a boiling point of 141 to 148 ° C. (0.1 mm) are obtained, ni ^! = 1.5678.

Analysis:

for C ₁₅ H ₁₃ NO: C 80.69; H 5.87; N 6.27;
Found: Cfco, 89; K 6.10; N 6.14.

E) 2- (3-phenoxyphenyl) p. opionic acid

A mixture of 223 g of 2- (3-phenoxyphenyl) propionitrile and 400 g of sodium hydroxide in 1600 ml of 50% ethanol is kept at reflux temperature with stirring for 72 hours. After cooling to room temperature, the reaction mixture is poured into ice water. The resulting solution is washed with ether, acidified with concentrated HCl and extracted with ether. The ether extract is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. By distillation of the remaining oil 203.5 g (84%) of 2- (3-phenoxyphenyl) propionic acid as a viscous oil of boiling point 168 to 171 of ⁰ C (0.11 mm) obtained ni '= 1.5742, pK'a = 7.3.

Analysis:

for C ₁₅ H ₁₄ O ₃ : C 74.36; H 5.83;
Found: C 74.48; H 6.05.

Example 10

2- (3-Phenoxyphenyl) propionic acid sodium salt dihydrate

6460 g of 2- (3-phenoxyphenyl) propionic acid are converted into the sodium eel in proportions of 26.7 Mo! 2 N sodium hydroxide solution was added with stirring and cooling. Then the aqueous solution is in vacuo concentrated almost to dryness. The semi-dry residue is then stirred with ethyl acetate and evaporated again in vacuo. The white solid residue is in the smallest possible amount dissolved in boiling ethyl acetate, in a large container

filtered (about 18 liters of solution) and left to stand at 7 ^° C. overnight.

The crystalline mass obtained is filtered off and im Vacuum dried at room temperature 6954 g of pure sodium 2- (3-phenoxyphenyl) propionate dihydrate are obtained obtained from melting point 76 to 78 ° C.

Analysis:

for C ₁₅ H ₁₇ O ₅ Na: C 59.99; H 5.70;
Found: C, 59.93; H 5.97.

Example 1
5- (4-chloro-3-phenoxybenzyl) -1H-tetrazole

i "A mixture of 17, Og 4-chloro-3-phenoxyphenylacetonitrile, 5.0 g sodium azide, 4.15 g ammonium chloride and a trace amount of lithium chloride in 80 ml Dimethylformamide (dried over a molecular sieve) is heated to 125 ° C. for 12 hours while stirring The reaction mixture is filtered and the solvents are evaporated until a brown oil is obtained will. The oil is suspended in about 400 ml of water After the mixture has been stirred, the pH of the suspension is raised by the dropwise addition of 3N HCl pH 2 adjusted. After cooling, the precipitate obtained is filtered off, washed with ice water and dried in vacuo. Then the precipitate is taken up in boiling 1,2-dichloroethane and poured over Allowed to crystallize slowly overnight. You get

jo 14.5 g of 5- (4-chloro-3-phenoxybenzyl) -lH-tetrazo! in fine white needles with a melting point of 157 to 158 ° C, pK'a = 5.7.

Analysis:

for C ₁₄ H ₁₁ CINO ₄ : C 58.64; H 3.86; N 19.54;
^ Found: C 58.66; H 4.07; N 19.84.

Example 12
2- (3-phenoxyphenyl) prcoionamide

A solution of 0.5 mol of 2- (3-phenoxyphenyl) propionyl chloride in 300 ml of dry ethyl ether is added dropwise with stirring to 2 l of liquid ammonia given. After the addition has ended, the reaction mixture is stirred for 1 hour and then with 500 ml Diethyl ether added. The reaction mixture is stirred overnight, whereby the excess Ammonia is evaporated. Dilute hydrochloric acid is then added to the reaction mixture. the The ether layer is separated off, washed with sodium hydroxide and water and dried over sodium sulfate. After evaporation of the ether in vacuo, a gummy residue remains, which after trituration crystallized with cold hexane. Recrystallization from ethyl acetate and hexane gives 76.2 g of 2- (3-phenoxyphenyl) propionamide obtained from melting point 67 to 69 ° C.

Analysis:

Calcd. for C ₁₅ H ₁₅ NO _2: C 74.66; H 6.27; N 5.81;
Found: C 74.01; H 6.30; N 6.15.

Example 13
N, N-dimethyl-2- (3-phenoxyphenyl) propionamide

400 ml of dry chloroform are mixed with 72.6 g of 2- (3-phenoxyphenyl) propionic acid and 36.9 g of thionyl chloride offset. The reaction mixture is under

Stirring held for about 3 hours at reflux temperature. The chloroform is then evaporated and the residue is twice azeotroped with benzene. The residue is dissolved in ethyl ether and added, with stirring and cooling, to a solution of 45 g of diethylamine in ethyl ether. The temperature is maintained at about 0 ^° C. or below during the addition. The reaction mixture is allowed to warm to room temperature, 1.5 Held at gentle reflux for hours, poured into ice and water and acidified. The ethyl ether layer is separated off. The aqueous layer is extracted with ethyl ether. The ether extracts are combined, washed with water, dried over sodium sulfate and evaporated to a white solid ι "> is dissolved in boiling hexane, and the solution is allowed to cool slowly to room temperature, whereby 67.6 g of N, N-dimethyl-2- (3-phenoxyphenyl) propionamide with a melting point of 73.5 to 76 ° C are obtained. ·? »

Analysis:

for C ₁₇ H ₁₉ NO ₂ : C 75.80; H7, ii; N 5.20;
Found: C 7553; H 6.90; N 5.27. ·

Example 14

N, N-Dimethyl-2- (3-phenoxyphenyl) propylamine hydrochloride

A flame-dried flask is filled with 6.08 g of lithium aluminum hydride and under nitrogen 500 ml of ethyl ether charged. The mixture is stirred for about 30 minutes at room temperature and then dropwise with a solution of 673 g of N, N-dimethyl-2- (3-phenoxyphenyI) propionamide (Prepared according to the method of Example 13) in 800 ml of ethyl ether offset. The reaction mixture is kept at reflux temperature overnight with stirring. then 4.65 ml of water, 3.5 ml of 20% sodium hydroxide solution and 16.5 ml of water were added. The reactive mixture is then poured onto ice, with more Sodium hydroxide solution is added and the mixture is extracted with ethyl ether. The ether layer is washed with water and extracted with dilute hydrochloric acid. The acidic extract is washed with ethyl ether with Made sodium hydroxide alkaline and extracted twice with ethyl ether. The ether extracts are with Washed water, dried over sodium sulfate and evaporated to an oil. By distilling the oil 39.2 g of N, N-dimethyl-2- (3-phenoxyphenyl) propylamine with a boiling point of 114 to 120 ° C / 0.1 mm received, M.G. 255.

Analysis:

for C ₇ H ₂₁ NO: C 79.96; H 8.29; N 5.49;
Found: C 79.76; H 8.06; N 538. "

34 g of this amine are dissolved in about 800 ml of dry ethyl ether. Hydrogen chloride gas is introduced into the solution initiated until saturated. The white solid precipitate obtained is filtered off with ethyl ether washed, partially dried and from boiling ethyl alcohol to give 34.3 g of N, N-dimethyl-2- (3-phenoxyphenyl) propylamine hydrochloride recrystallized from melting point 215 to 217 ° C

Analysis:

for C ₁₇ H ₂₁ NO
found:

60

h>

Example 15

N-Cyclopropylmethyl-2- (3-pherioxypheny!) Propionamide

350 ml of chloroform are mixed with 60.5 g of 2- (3-phenoxyphenyl) propionic acid and 30.4 g of thionyl chloride. The reaction mixture is kept at reflux temperature overnight with stirring and evaporated. The residue is azeotroped three times with benzene. The oily acid chloride obtained is taken up in chloroform. 40 g of aminomethylcyclopropane hydrochloride are dissolved in a small amount of water, made alkaline with 5N sodium hydroxide solution and extracted with chloroform. The aqueous layer is saturated with sodium chloride and extracted again with chloroform. The chloroform extracts are combined and dried over sodium carbonate and sodium sulfate. The extracts are filtered and 50 ml of triethylamine are added. The mixture is cooled in an ice-acetone bath. Then v ^{:. r} d the chloroform solution of the acid chloride was added dropwise. During the addition, cool and grind

The reaction mixture is allowed to warm to room temperature, stirred for 30 minutes until Heated to reflux temperature, allowed to cool to room temperature and stirred overnight. Then it will be the solution partially evaporated and poured into an ice-water mixture. The chloroform layer becomes washed with dilute hydrochloric acid, dried over sodium sulfate and given an oily residue evaporated. The residue is covered with a layer of hexane and scraped off, resulting in a crystalline Solid forms. The crystalline solid is taken up in boiling ethyl acetate and up to Hexane added to turbidity. After the solution has cooled, 50.6 g of crystalline N-cyclopropylmethyl-2- (3-phenoxyphenyl) propionamide are obtained obtained from melting point 94.5 to 90 ° C.

Analysis:

for Ci ₉ H ₂ | NO ₂ :
found:

C 77.26; H 7.17; N 4.74;
C 77.14; H 7.17; N 4.71.

Examples 16 and 17

The following compounds were prepared according to the method of Example 13 from appropriate starting materials manufactured

N-methyl-2- (3-phenoxyphenyl) butyramide,

F. 84 to 86 ° C.

Analysis:

for C ₁₇ Hi ₉ NO ₂ : C 75.81; H 7.11; N 5.20;

Found: C 75.60; H 7.11; N 5.00.

N-methyl-2- (3-phtnoxyphenyl) propionaniid,

F. 57 to 58 ⁰ C.

Analysis:

for C ₆ Hi ₇ NO ₂ : C 75.27; H 6.71; N 5.49;

Found: C 75.51; H 6.86; N 5.61.

HCl: C, 69.96; H 7.60;
C 69.68; H 7.40;

N 4.80;
N 4.90.

Examples 18-20

The following compounds were prepared by the method of Example! 4 from the corresponding Amides produced using suitable starting materials.

· HCl: C 69.17: H 7.25; N 5.04; C 69.21; H 7.02; N 5.30.

N-Methyl-2- (3-phenoxyphenyl) butylamine hydrochloride, m.p. 124 to 126 "C.
Analysis:

for C, -H ,, NO · HCl: C 69.96: H 7.60; N 4.80;

Found: C: 69.83; H 7.80: N 4.87.

N-methyl-2- (3phenoxyphenyl) propylamine hydrochloride. F. 160 to 162 ⁰ C.

Analysis:

ber. for CcH ^

found:

N-Cyclopropylamine-2- (3-phen (ixyphenyl) -pmpylamine hydrochloride. F. 11 5 to 117 C.

Analysis:

for C , W-, NO · HCI: C 71.79: H7.6I; N 4.40;

Found: C 7.96: H 7.46; N 4.39.

Example 21

Separation of \ -dl-2- (3-phenoxy phenyl) propionic acid

20 g of dl-2- (3-phenoxyphenyl) propionic acid (prepared according to Example 9) are dissolved in 3000 ml of hot ethyl acetate solved. The solution is mixed with 100 g of d- (+) -iX-methyl benzylamine added. After cooling, a crystalline mass separates out. which after filtering off 229 g d! -2- (3-Phenoxyphenyl) propionic acid-d- (+) - ^ - methylbenzylamine salt with a melting point of 15 to 126 "C. Recrystallizing five times from hot ethyl acetate gives 63.5 g of d - (+) -2- (3-phenoxyphenyl) propionic acid-d- ( -t -) - vmethylbenzylaniinsal /. from the

Melting point 142 to 144 "C obtained, [λ] + 14.5 (C = I ⁰ O. CHCli). [\] + 3.74 (C = 1%. CHiOI-I).

Analysis:

calcd for C _{; i} H:; NO .: C 76.00: H 6.93: N 3.85: get '.: C 75.72: H 6.80; N 3.63.

In the same way 1 ■ (-) -2- (3-Pheno \ .yphenyl) propionic acid-1 · (-) -vmethylbenzylamine salt of melting point 141 to 142 "C prepared, [λ] -3.63 (C = 1%. CHiOH).

52 g of d- (-) -2- (3-phenoxyphenyl) propionic acid-d- (+) -1-methylbenzylamine salt are dissolved in a mixture of 1.5 1 H: O and 0.5 1 Et _; Suspended O and acidified by adding 6N HCl. The ether layer is washed with water, dried over sodium sulfate and evaporated in vacuo to give d- (-) -2- (3-phenoxyphenyl) propionic acid. [. \] -46.0 (C = 1%. CHCI.) -

In the same way becomes l - (-) - 2- (3-phenoxyphene; l) propionic acid. [\] -45.7 (C = I ¹ vol. CHCh) prepared from 1- (-) -2- (3-Phv.-noxyphenyl) propionic acid-1- (-) - IL-methyibenzylamine acid.

Example 22

A) 2- (3-phenoxyphenyl) propylene amine

100 g of 2- (3-phenoxyphenyl) propionitrile (prepared according to Example 9D). 10 g Raney nickel. 250 ml of ethyl alcohol and 50 g of ammonia are placed in a pressure vessel under an initial hydrogen pressure of 70 kg / cm ^; united. The reaction mixture is kept under pressure and heated to 70 to 80 ° C. for 4 hours with shaking, which results in a hydrogen uptake of 91%. After cooling and filtering off the catalyst, the reaction mixture is poured into ice water, acidified with hydrochloric acid, with Washed ethyl ether, made alkaline with 10% sodium hydroxide solution and extracted with ethyl ether. The ethyl ether layer is washed with water, dried over sodium sulfate and evaporated to an oil, the distillation of which is 78.9 g of 2- (3-phenoxyphenyl) propylamine with a boiling point of 158 up to 16rC / 0.08mm ran η '= 1.5752.

Analysis:

for ChHi ₇ NO: C 79.26: H 7.54: N 6.16; Found: C 79.18; H 7.29: N 6.07.

B) 2- (3-phenoxy phenyl) propylene with n-hydrochloride

20 g of the 2- (3-phenoxyphenyl) propyl amines obtained above are dissolved in ethyl ether and the solution wire saturated with hydrogen chloride gas, forming a solid precipitate. The precipitate is collected triert, washed with ethyl ether and dissolved in hot ethyl alcohol. After adding ethyl ether bi to cloudiness, the reaction mixture is cooled and crossed, whereby 18.3 g of 2- (J-P! "ic-i" mXypiiorivί) ί> ί "ι> pylamine hydrochloride with a melting point of 147 to 147.5 ° C.

Analysis:

ber. for CiILrNO
found:

HCI: C 68.30: 116.88; N 5.31; C 68.11: H 6.58; N 5.32.

Example 23

2- (3-Phenoxyphenyl) buticric acid A) 2- (3-Phenoxy phenylbut ν ronitrile

To 4 l of liquid ammonia in a 5 L flask. de contains a catalytic amount of femchloride, 23g of sodium are given. The reaction mixture was stirred for about 30 minutes. Then 209; 2- (3-phenoxyphenyl) acetonitrile (prepared according to reaction sequence I) was added. The reaction mixture is stirred for 30 minutes and then mixed with 187.2 g of ethyl iodide while stirring eggs. The mixture is then stirred overnight so that ammonia can evaporate. Anhydrous ethyl ether is added to the residue and the mixture is acidified with 6N hydrochloric acid and stirred for about 1 hour. It is then extracted with ethyl ether. The ether layer is washed with water and sodium thiosulphate solution and evaporated. 155.2 g of 2- (3-phenoxyphenyl) -butyronitrile with a boiling point of 138 to 140 ^; C / ~ 0.14 mn won.

B) 145 g of the 2- (3-phenoxyphenyl) butyro nitrile obtained are hydrolyzed to the corresponding acid by the method of Example 9E. It will! 95.9 <2- (3-phenoxyphenyl) obtained buitersäure ^C to 77 C from the melting point 7.

Analysis:

calcd for C; f, H ₁₆ O .: C 74.98: H 6.29: found: C 74.70; H 6.33.

Example 24 Ethyl 2- (3-phenoxyphenyl) propionate

200 g 2- (3-phenoxyphenyi) propionic acid (according to Bei game 9) are produced in 1500 m! Dissolved ethanol. L. the ethanol solution is introduced with hydrogen chloride gas until it is saturated. The reaction mixture is then stirred overnight at reflux temperature held. A large part of the ethanol is then evaporated in vacuo and the remaining reaction mixture

Schung poured into ice water. The reaction mixture is made alkaline with 10% sodium hydroxide solution and extracted twice with ethyl ether. The ether extracts are combined and washed twice with water and dried over sodium sulfate. After the ethyl ether has evaporated, crude ethyl 2- (3-phenoxyphenyl) propionate remains as an oily residue. This procedure is repeated with a further 20C <j 2- (3-phenoxyphenyl) propionic acid. The crude products are combined and distilled in a 15 cm Vigreux column, whereby 339.9 g of ethyl 2 (3-phenoxyphenyl) propionate with a boiling point of 128 to 1 34C70.1 5 mm are obtained, η - 1.54 58.

Analysis:

here. for OrII ₁ "Ο,: C 75.53: 116.71:
found: C 75.75: Il 6.70.

2- (3-phenoxyphenyl) prop; inol

27.4 g of lithium aluminum nitride hydride. which are in a flame-dried flask flushed with nitrogen are mixed with about II ethyl ether. The mixture is stirred vigorously for 45 minutes. Then the Lithiumaliiminiumhydridsuspension is added dropwise with a solution of 300 g of ethyl 2- (3-phenoxyphenyl) proptonate (prepared according to Example 41), in 500 ml of ethyl ether at such a rate that a constant gentle reflux he -seht. After the addition of the ether has ended, the reaction mixture is stirred overnight and kept under gentle reflux. After the reaction mixture has cooled to room temperature, 44.5 ml of water are carefully added dropwise. 33.3 ml of 20% sodium hydroxide solution and 155 ml of water are decomposed. Then a larger amount of water is added, whereby an emulsion is formed. The emulsion becomes clear on acidification. The reaction mixture is then extracted with ethyl ether. The ether layer is separated and the aqueous layer is extracted again with ethyl ether. The ether extracts are combined, washed with water and dried over sodium sulfate and a little sodium carbonate. The dried ether solution is then evaporated to an oily residue. By distilling this residue, 241.6 g of 2- (3-phenoxyphenyl) propanol with a boiling point of 128 to 131C / 0.1 mm are obtained, π '= 1.5771.

Analysis:

for C; H _; , O: C 78.92: H 7.06:
cef .: C 78.65: H 7.17.

Example 26

2- (3-phenoxyphenyl) propyi-N-melhvicarbamate
A solution of 2.51 g of methyl isocyanate in 75 ml of dry benzene is added dropwise with stirring at room temperature with a solution of 10 g of 2- (3-phenoxyphenyOpropano! (Prepared according to Example 25) in 25 ml of benzene. The resulting reaction mixture is stirred for 5 hours The reaction mixture is then evaporated to an oil, the distillation of which gives 8.7 g of 2 (3-phenoxypheiiyi) propy! -N-methy! carbarn3t with a boiling point of 170 to 180 ⁼ C / 0.1 mm, π = 1 J6i5.

Analysis:
ber. for
found:

C 71.56: H 6.71; N 4.91;
C 71.64; Il 6.90; N 4.77.

Example 27
2 (3-phenoxy pheny / propyl acetate

11.4 g 2 (3-phenoxyphenylpropanol (according to Example 25 manufactured). 7 ml of acetic anhydride and about 100 ml of pyridine are combined and stirred for 18 hours Maintained reflux temperature. Most of the pyridine is evaporated in vacuo and the residue is dissolved in chloroform, washed with dilute hydrochloric acid and water, and over anhydrous sodium sulfate dried. After evaporation of the chloroform in vacuo and distillation of the oily obtained Residue will be 10.6g 2- (3-phenoxyphene> l) propy! - aceta! from boiling point 138 to 145 "CVO. 1 mm gained./) 1.5478.

Anaivse:

for CrH ₁ -O ₁ : C 75.53; 116.71;
Found: C 75.40; H 6.59.

Example 28
2- (3-Phenoxy pheny I jp ropy Ipropionat

In the same way as in Example 27, 2- (3-phenoxyphenvi) propyl propionate is obtained from suitable starting materials from boiling point 142 to 149 C70.1 mm manufactured./)■ '= 1.5420.

Ap ilyse:

for CmHvO,: C 76.03: H 7.09:
found: C 75.7 3: H 7.32. ·

Example 29
2 (3-phenoxy pheny I) propionohydroxy acid

By adding 5 g of sodium metal to 150 ml Methanol is made from sodium methoxide. The cooled sodium methoxide solution is mixed with a solution of 7 g of hydroxylamine hydrochloride in l00i.il Methanol is added and the precipitated sodium chloride is filtered off. Then the filtrate is stirred 25.6 g of methyl 2- (3-phenoxyphenyl) propionate (prepared by the method of Example 24) were added. the Reaction hybrid becomes' /: hour at room temperature stirred and then kept at reflux temperature with stirring for 1 ½ hours. Thereupon the reaction mixture cooled and acidified by adding 6 η hydrochloric acid dropwise. After removal part of the solvent in vacuo forms a yellow oil. which then crystallizes. By Recrystallization from a small amount of ethyl acetate and methylcyclohexane yields 12.2 g of 2- (3-phenoxyphenyl) propionohydroxamic acid obtained from melting point 121 to 122 = C

Analysis:

for CnHi ₅ NOj: C 70.02; H 5.88: N 5.44:
Found: C 69.95: H 5.96: N 5.41.

Example 30

3- (3-phenoxyphenyl) butyric acid
A) Ethyl 3- (3-phenoxyphenyl) croionate

224 g of Triäthyiphosphop.oacetat are slowly with stirring to a suspension of 48 s of a 50%

Sodium hydride dispersion is added to 300 ml of ethylcnglycol monomethyl ether. A solution of 212 g of m-phenoxyacetophenone in 1500 ml of ethylene glycol monomethyl ether is then added dropwise to the reaction mixture and the mixture is stirred for 1 hour. The reaction mixture is then kept overnight at flow temperature, cooled to room temperature and decomposed by adding water. After evaporation of the solvent in vacuo, the crude product is dissolved in ethyl acetate, washed twice with water and dried over sodium sulfate. After evaporation of the ethyl acetate ties an oily residue is left behind which was distilled 52.6 g of ethyl-3- (phen oxyphenyl) crotonai boiling point of ¹ 163 to 170 mm provides CY 0.2, π '= 1.5770.

B) ethyl 3- (3-phenoxyphenyl) butyrate

A solution of 197 g of the ethyl 3- (phenoxyphenyl) crotonais thus obtained in 400 ml of ethanol is hydrogenated in the presence of 5 g of piatine oxide. After evaporation of the ethanol an oily residue remains, the distillation of which gives 160 g of ethyl 3- (3-phenoxyphenyl) hutyrate with a boiling point of 137 to 139C70.06mm. η = 1.5401.

C) 3- (3-Phenox \ phenyl) bisperic acid

106 g of the ethyl 3- (3-phenoxyphenyl) butyrate thus obtained are obtained by the method of Example 9F. hydrolyzed. 117.2 g of 3 (3-phenoxyphenyl) butyric acid with a boiling point of 193 to 195C70.2J mm are obtained, η : - '= 1.5687, pK'a = 7.2.

Analysis:

for CrUO: C 74.98; H 6.29:
Found: C 75.18: H 6.41.

Within the scope of the invention are pharmaceutical agents which, as an active ingredient, are one of the substances according to the invention Compounds contained in association with a pharmaceutical carrier or diluent. The invention Compounds are effective both orally and parenterally and can be used as dosage forms be prepared for oral, parenteral, rectal or topical administration.

Solid dosage forms for oral administration are, for example, capsules. Tablets. Pills. Powder and granules. In such solid preparation forms the active compound is with at least one inert diluent, e.g. B. sucrose, lactose or starch mixed. Such dosage forms can, as usual, contain, in addition to inert diluents, other weather substances, e.g. B. lubricants such as magnesium stearate. In the case of capsules, tablets and pills , the dosage forms can also contain buffering agents. In addition, tablets and pills can be provided with enteral layers.

Liquid preparations for oral administration include pharmaceutically acceptable emulsions, Solutions, suspensions, syrups and elixirs, the inert diluents, as they are usual for this purpose, included, e.g. B. water. In addition to inert diluents, such preparations can also contain auxiliaries, e.g. B. Contain wetting agents, emulsifiers and suspending agents and sweeteners, flavorings and fragrances.

The preparations according to the invention for parenteral administration include sterile aqueous or non- aqueous solutions, suspensions or emulsions. Examples of non-aqueous solvents or carriers are propylene glycol, polyethylene glycol and vegetable oils.

/. Π. Olive oil, and mjicatable organic esters. /. 13th Ethyl oleate. Other forms of representation can also be used Contain auxiliary materials. e.g. preservatives. Wetting agents, emulsifiers and dispersants. she can, for example, by filtration through a bacteria-retaining filter, by adding sterilizing agents on the preparations, by irradiating the preparations or by heating of the preparations are sterilized. They can also be produced in the form of sterile solid preparations be placed in sterile water or in another sterile injectable immediately before use Medium can be dissolved.

Preparations for rectal administration are suppositories. which, in addition to the active ingredient, can contain carriers such as cocoa butter or a suppository wax.

The dosage of the active ingredient in the inventive pemiißen Means can fluctuate, but it is necessary.

tlitii CItTI active ingredient iü 5GtCnCr MCngC CrithriltCn i ^ i. c! n'3 a suitable dosage form is achieved. The dosage chosen depends on the desired therapeutic effect, the route of administration and the duration of treatment. In general, dosages between 0.2 and 50 mg / kg body weight per day are administered to mammals to provide effective relief from inflammation. Cause pain and fever.

The pharmaceutical compositions according to the invention are further illustrated by the following examples.

Example 31

Tablets are made with a weight of 500 mg and with the following composition:

2- (3-phenoxyphenyl) propionic acid

sodium salt dihydrate 250 mg

Strength 190 mg

Colloidal silica 50 mg

Magnesium stearate 10 mg

Example 32

Tablets are made with a weight of 200 mg and with the following composition:

2- (3-Phenoxyphenyl) acetic acid 50 mg

Strength 120 mg

Colloidal silica 27 mg

Magnesium stearate 3 mg

Example 33

Tablets are made with a weight of 500 mg and with the following composition:

2- (3,5-dichloro-4-phenoxypheny I) -

acetic acid sodium salt 250 mg

Strength 190 mg

Colloidal silica 50 mg

Magnesium stearate 10 mg

Example 34

Tablets are mg with a weight of 200 and manufactured with the following composition:

2- (3-methyl-4-phenoxyphenyl) -

propionic acid 50 mg

Strength 120 mg

Colloidal silica 27 mg Magnesium stearate 3 mg

2 «

Ζίγ Manufacture of tablets analogous to those in the Examples 32 to 35 are described, the abovementioned active ingredients can be replaced by the same amount by weight of another compound according to the invention be replaced. Such tablets can be made with decal coating and also contain buffer media.

Example 35

A number of compounds according to the invention were tested for their anti-inflammatory effectiveness tested. The experimental set-up is described below.

To determine the anti-inflammatory effectiveness ('he compounds was a modification animal Method of Winder. C. V .. Wax.)., Burr, V. and Posiere. C. E .: "Study of Pharmacological Influences on Ultraviolet Eruhema in Guinea Pigs «. Arch. Int. Pharmacoihn., Lib. 261. 1958. applied. Male

W eight of 225 - iOO g were shaved on the back and 18 to 20 itunden. depilated with a chemical agent before exposure to ultraviolet light. The animals were left without food overnight. Immediately after the guinea pigs were treated with a test compound, gummed notebook paper backings were placed on their backs and exposed to high intensity ultraviolet light for 7 seconds. A Lamp ° served as the ultraviolet light source. which has been brought into contact with the skin of the back of the guinea pigs. Then the reinforcements were removed and the backs of the animals were cleaned with a water-soaked gauze sponge. The unexposed GeO 'He under the reinforcements served as comparison areas for evaluating the erythema. The animals were placed in containers made of transparent plastic with the dimensions 10 × 20 × 15 cm. One hour after the irradiation and then at half-hour intervals for a further 1.5 hours, the extent of the erythema was determined with H ¹ IIe of a rating system based on the strength of the reddening and the contrast to the unirradiated area. Anti-inflammatory agents delay the development of erythema, so they show their greatest effect in the first reviews. For this reason, the evaluations were given an additional weight by a factor of 4.3, 2 and 1 for the determination after 1.0, 1.5, 2.0 and 2.5 hours. The erythema grades were rated as follows:

Ery them rating system
valuation

0 keit.e redness and no contrast

1 slight reddening with an indistinct borderline to the unirradiated area

2 weak to moderate reddening with a clear borderline

3 pronounced reddening with sharp delimitation

The overall scores for each treatment group of 5 or 6 guinea pigs were compared with those of the control animals and the percentage Inhibition was calculated as follows:

11) 11

Control animals - treat animals

Control IiMiibierunu

The test compounds were in a suspension of 1% methyl cellulose in water in amounts of 1.0 ml / kg administered orally to guinea pigs. The control animals received 1.0 ml / kg of the 1 percent Methyl cellulose suspension alone. The dose at which a 50 percent inhibition of the erythema reaction is achieved was calculated (ED5n). The received EDyi values in mg / kg are in the table below compiled.

-O

I: ryth em blocking * example
exam, oral. ED.- ,, No.

(ms / kei

CH - CH, NH _: HCl CH,

CH-CH ₃ NHCH ₃ - HCl CH ₃
CH-CH ₁ N (CH ₃ ), -HCl

CH ₃

22nd

19th

14th

29
Formula / app CH, CH-CH, NHCH, CH
\ O
Η O
π 0
H CH-C 11, NH-CH Hj 19 41 625
30th At-
No. R. Il
CH-CH ₂ OC-CH 1 -CH ₃ Il
CH-CH ₂ OC-NHCH, Il
CH-C-NH ₂ tirylheni-BliKkicr-
prul'ung. orally. IiD> ,,
(mg / kg ι \
CH; CH, CH ₃ CH ₃ CH, \
: il · c 20th CH-CH ₂ OH CH- COONa HCI 20 CH, CH, 25th CH-COOCa / 2 2 CH, CH-COOCH, 28 CH, ! 0 ZH-COOC ₂ H ₅ 26th CH-CONHCH ₂ COOh 40 CH, CH ₂ CH ₂ -NHCH, HCl 12th .H, -CH, N (CH, h ■ HCI 3 CII, in 0.9 1.0 1.0 2 ' 1.5 5 10 7th HCI 9

3ί

Korlsei / iing

CH ₃ CH-CH ₂ N CH ₂ HCl

CH ₃ CH

CH ₂

CH,

CH - CH ₂

CH ₃

CH ₂

CH ₂ -CH \

CH ₂

Il

CH - CH ₂ - O - CCH ₃

CH ₃

N N

CH-C N

CH ₃ N

HO

Il

CH-C-NHCH ₃ CH ₃

O CH ₃

Il /

CH-C-N CH ₃

CH ₃

CH-C -NHOH CH ₃

Acetylsalicylic acid phenylbutazone

HCI

Erythema Blocking Sample Exam, Oral, ED ₅₀ No.

(mg / kg)

27

17th

13th

29

Example 36

The inhibition of acetic acid indu / icrtcn tr> of compounds according to the invention

Seizure syndrome in mice is used / to provide evidence of a method used by Koster. R .. et al ..

relative analgesic effects of "Acetic Acid for Analgesic Screening" to be examined Fed. Proa. 18:

Links. For the detection of the analgesic we- 412 (1959). is comparable.

method

Male albino mice weighing 16 up to 18 g, the compounds to be tested were either subcutaneously or through a gastric tube administered. At various times after the administration were given by intraperitoneal administration 60 mg / kg acetic acid (0.6 percent) induced convulsions. Each test group consisted of 6 mice. the

The total number of convulsions in a test group was recorded during an observation period of 10 minutes, starting 5 minutes after the administration of acetic acid, counted. The total numbers of test groups were used with those of control groups to calculate percent inhibition:

% Inhibition = 100 -

Total number of test groups

Total number of control group

100

The table below shows the doses in mg of compound / kg of body weight which lead to a 50 percent inhibition of the frequency of cramps (ED ₅₀ ).

2- (3-Phenoxyphenyl) -R Meaning of R

ED ₅₀

mg / kg

(subcutaneous)

example

No.

CHCH ₂ NH ₂ CH ₃

HCI

CH-CH ₂ NHCH _{3 -HCl}

20th

20th

22nd

19th

CH ₃

- CH ₂ N (CH ₃ ) ₂ HCI

10

14th

CH ₃

Acetylsalicylic acid

20th

In the drawing, the results of this greater inhibition of the spasms are substantial

Investigation with the calcium salt of the 2- (3-phenoxy- lower dosages than the comparative

phenyl) propionic acid. It can be seen * o substances phenylbutazone and acetylsalicylic acid.
that the substance of the invention is an essential

Example 37

Some of the compounds of the invention have "percent inhibition of erythema are in the."

The following table is compiled in the following table, described in Example 36. The ones from the

subject to examination. The compounds tested, the results are calculated values for the ED ₅₀

the dose administered, the number of test animals and the number also stated.

link

dose Number of animals in; (mg / kg) % 0.25 5 9 0.75 5 41 2.25 5 74 0.33 6th 25th 1.00 6th 72 3.00 CTv 87 10 S. 37 20th 5 52 40 5 90 10 6th 49 20th 6th 64 40 6th 88

Example no.

2- (3-phenoxyphenyl) propionic acid

2- (3-Phenoxyphcnyl) -ess (acid

0.8

13.9

risci / iinu

rhinUung [Jiisis /.jihl of the animals Inhihieruni; li | ii _M H ^

3-phenoxyphenyl) butyric acid 0.33 5 24-23

47 70 87 22 44 68 79 i, 2

The other compounds falling under the general formula show a comparable effect.

IJiisis 5 (mg / kg) 5 0.33 5 1.00 5 3.00 5 9.00 5 0.33 5 1.00 5 3.00 9.00

For this purpose I sheet drawings

Claims (1)

Patent claims: 1. Substituted phenylalkanoic acids of the general Formula I. R. (I) b) —CON