DK141439B - Analogous process for the preparation of 3-phenoxyphenylalkylamine compounds or acid addition salts thereof. - Google Patents

Description

00 PUBLICATION 141439 DENMARK (61) Intel.3 c 07 c 93 / u «(21) Application No. 2405/77 (22) Filed on 1 Jun. I977 (23) Race day 14 Aug. 1969 (44) The note presented and made available to the public on 17 · mST · 1 980

DIRECTORATE OF

PATENT AND TRADE MARKET (30) Priority requested from it

Aug 15 1968, 7528ΟΟ US

Aug 15 1968, 752801, US

May 28, 1969, 828756, US

(71) ELI LILLY AND COMPANY, 307 East McCarty Street, Indianapolis, Ιπρ diana, US.

(72) Inventor: Winston Stanley Marshall, 1937 East 'Lilac Drive, Indianapolis, Indiana, US.

(74) Plenipotentiary in the proceedings:

Hofman-Bang & Boutard Engineering Company.

(64) Analogous process for the preparation of 3-phenoxyphenyl 1 alkylamine compounds or acid addition salts thereof.

The present invention relates to an analogous process for the preparation of novel 3-phenoxyphenylalkylamine compounds of the general formula or pharmaceutically acceptable acid addition salts thereof as set forth in the preamble, which compounds have antiinflammatory and mild acetylsalicylic acid-like analgesic and antipyretic action.

Many people and animals are known to suffer from various rheumatic conditions that cause inflammation, swelling, tenderness, reduced mo-; mobility, pain and fever. There are a number of available anti-inflammatory agents that have been shown to be effective in the symptomatic treatment of disorders such as rheumatoid arthritis.

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tis, rheumatoid, spondylitis and osteoarthritis of the hip, but these agents have a number of unwanted side effects.

The object of the present invention is to provide novel compounds useful in drugs for the treatment of inflammation, pain and fever in humans and animals. This is achieved by the method according to the invention, which is characterized by the characterizing part of the claim.

By "acid addition salts" is meant salts prepared by reaction of the free amine with an organic or inorganic acid, for example hydrochloride, hydrobromide, sulfate, bisulfate, acetate, valerate, oleate, laurate, borate, benzoate, lactate, phosphate, tosylate , citrate, maleate, fumarate, succinate, tartrate and napsylate (salt of 2-naphthalenesulfonic acid).

"alkyl of 1-5 carbon atoms" and "alkenyl of 2-6 carbon atoms" may be both straight and branched groups.

All of the compounds of the present invention are useful for the treatment of inflammatory diseases in mammals. In addition to their anti-inflammatory activity, the compounds exert a mild analgesic and antipyretic activity. They can be used in therapeutic mixtures containing as active ingredient one or more of the compounds together with a pharmaceutically acceptable diluent or carrier. The compounds are usually administered to mammals at doses of 0.2-5.0 mg / kg body weight daily, either in single or divided doses over 24 hours. It is to be understood that the preparation of both the d- and 1-isomers of the α-alkyl compounds is encompassed by the invention. Thus, e.g. The α-alkyl acids are cleaved into their d and 1 isomers by well known methods and the two isomers have been found to have essentially identical effect. Thus, both the racemic mixture and the d- and 1-isomer can be used in the treatment of inflammation, pain and fever in mammals.

Surprisingly, some of the compounds prepared by the process of the invention have been found to increase the analgesic effect of a number of analgesic agents. The increase in the analgesic effect occurs when ca. 1 part by weight of the compound prepared by the method of the invention is administered substantially simultaneously with or from 1 hour before to 1 hour after the administration of 0.005-20 parts by weight of the analgesic agent. In general, it can be said that to obtain a greater analgesic effect, 0.5-50 mg / kg of a compound prepared by the method according to the invention must be administered together with the usual therapeutic dose of the analgesic agent.

The present compounds and their starting materials can be prepared by well known reactions. The preparation of the starting compounds is specifically described in Danish Patent Application No. 4361/69. Various routes may be used in the preparation of the compounds of this invention, but a number of the preferred reaction types are described below. In the following, R, R and R ^ have the same meaning as in the preamble of claim, and "Ar" denotes the group specified in the general formula: / Λ- //......Λ / “1

Ar-CILj NBSj Ar-CHg-Br NaCffj Ar-CH2-Cii HgO Ar-CH2-CCOH

The methyl group in a suitable m-methyl diaryl ether is halogenated by reaction with N-bromosuccinimide. (NBS), N-chloro-succinimide, sulfuryl chloride or a similar halogenating agent, using a suitable catalyst such as benzoyl peroxide or azo-bis-isobutyronitrile in an inert solvent such as carbon tetrachloride or another halogenated hydrocarbon. The resulting halomethyl diaryl ether is reacted with sodium or potassium cyanide, preferably in a dimethyl sulfoxide solution. The nitrile thus obtained is hydrogenated. catalytic to the primary amine or hydrolyzed to the corresponding carboxylic acid by treatment with either acidic or basic reagents in known manner and the acid is converted to an amide which is reduced to the corresponding amine.

141439 4

lla. Ar-CHp-CN NaNH2 / NH3 Ar-CH-CN% O Ar-CH-COOH

RlX2 'R1 * H1

IIb. Ar-CHp-COOH NaNH2 / NH3 Ar-CH-COOH

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The nitrile prepared according to the above Scheme I can be alkylated with an aliphatic halide or tosylate (R-xX) in liquid ammonia in the presence of sodium amide to form an α-aliphatic substituted nitrile. The alkylated nitrile is catalytically hydrolyzed to the primary amine or hydrolyzed to give the corresponding carboxylic acid (Scheme IIa). Similarly, one can alkylate an arylic acetic acid at the α position relative to the carboxyl group as shown in Scheme IIb.

A nitrile prepared according to Scheme I can, if desired, be methylated as follows (Scheme III): The nitrile is condensed with ethyl formate in a basic environment, e.g. in the presence of sodium hydride or sodium methoxide in an inert hydrocarbon solvent such as benzene. The resulting hydroxymethylene derivative is benzoylated by the action of either benzoic anhydride or benzoyl chloride and pyridine; and the benzoic acid ester is then hydrogenated in the presence of a noble metal catalyst to give the desired o-methylarylacetonitrile, which is then hydrogenated or hydrolyzed as above.

Optionally, the desired o-methylarylacetonitrile may be prepared by the following reactions (Scheme IV): carbinol. Conversion of this carbinol to the corresponding bromide can be accomplished by treating the carbinol with phosphorus tribromide, preferably in an inert solvent such as chloroform, benzene and carbon tetrachloride. The bromide thus obtained is reacted with sodium cyanide, preferably in dimethyl sulfoxide solution to form a nitrile, which is then hydrogenated or hydrolyzed as above.

An alternative method for preparing o-alkyl (phenoxyphenyl) acetic acid compounds comprises using the Arndt-Eistert reaction as shown in Scheme V, using an appropriate m-phenoxybenzoic acid as starting material.

The α-alkyl acids thus obtained can be separated into their d- and 1-iso-

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more in known manner. 2 VI. Ar-CH-fCHo XR; >. Ar-CH- (CILj ._- C

h ^ n \ --7 t ^ n \ v · K

λ XC1 R1 XN ^, R - ^ r3 π 2 3 wherein R, R, r and n have the meanings set forth in the preamble of the claim.

The starting materials can be prepared by reacting the above acid chloride with an amine. The reaction is usually carried out in an inert solvent such as chloroform, benzene or carbon tetrachloride in the presence of an acid binding agent such as pyridine, K 2 CO 2 or the like, or in a solvent of a tertiary amine such as eol-lidine, lutidine or triethylamine.

The process according to the invention can be illustrated by the following reaction schemes:

Vila. Ar-CH- (CHP) -Cf * ° / R2 R1 ^ R3

LiAlH ,, 5 * 4 .R2

Ar-CH- (CHp) -CH5-N ^ R1;

VIIb. Ar-CH- (CH2) n-CN Hg / RaNi Ar-CH- (CH2) n-CH2-NH2 R1 * R1 1 2 3 wherein R, R, R and n have the meanings set forth in the preamble of the claim.

The desired 3-phenoxyphenylalkylamine compounds can be prepared by the process of the invention e.g. by reducing an amide with a metal hydride such as lithium aluminum hydride (Vila). In cases where a primary amine is desired to be prepared, this can conveniently be accomplished by hydrogenation of the corresponding nitrile in the presence of ammonia and a catalyst such as Raney Nifckel (Vllb).

The process according to the invention is further illustrated by the following embodiments, in which Examples 1-3 and 5-7 show the preparation of the starting compounds.

EXAMPLE 1 8 HOURS 39

Preparation of 2- (3-bhenoxyphenyl) propionic acid A. 3-phenoxyacetophenone. A mixture of 908 g (6.68 mole) of m-hydroxy-acetophenone, 4500 g (28.6 mole) of bromobenzene, 996 g (7.2 mole) of anhydrous potassium carbonate and 300 g of copper bronze was heated at reflux until the formation of water was complete, below use of a Dean-Stark water separator. The mixture was stirred and heated under reflux for 24 hours. After cooling to room temperature, the reaction mixture was diluted with an equal volume of chloroform and filtered. The filtrate was washed with 5% hydrochloric acid, then with 5% sodium hydroxide, with water, dried over sodium sulfate and evaporated in vacuo. The oily residue was distilled through a 15 cm Vigreux column to give 918 g of 3-pheno-xyacetophenone, m.p. 120-121 ° C (0.09 mmHg), n | p = 1.5868.

Analysis calculated for C, 79.22; H, 5.70

Found: C, 79.39; H, 5.79.

B. α-methyl-3-phenoxybenzyl alcohol

A stirred solution of 700 g of m-phenoxyacetophenone in 3000 ml of anhydrous methanol was cooled to 0 ° C on an ice-acetone bath. 136 g (3.6 mole) of sodium borohydride was added in small portions to the solution at such a rate that the temperature did not rise above 10 ° C. After the borohydride addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for 18 hours. Then it was heated under reflux and stirring for 8 hours. There were distilled approx. 400 ml of methanol and the remaining solution evaporated to ca. one third of the original volume in vacuo and poured into ice water. This mixture was extracted twice with ether, acidified with 6N hydrochloric acid and extracted again with ether. The ether extracts were mixed, washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The oily residue was distilled through a 15 cm Vigreux column to give 666 g of α-methyl-3-phenoxybenzyl alcohol, b.p. 132-134 ° C. (0.35 mmHg) n + = 1.5809.

9 141439

Analysis calculated for C, 78.48; Η 6.59

The pound; C, 78.75; Η 6.31.

C. oc-methyl-5-phenoxybenzyl bromide

A stirred solution of 1357 g of α-methyl-3-phenoxybenzyl alcohol in 5000 ml of anhydrous CCI (dried over a molecular sieve) was cooled to 0 ° C. To this was added 1760 g of PBr 2 and the stirring and cooling maintained so that the temperature remained at 0-5 ° C during the addition. The reaction mixture was then allowed to warm to room temperature and stirred overnight (about 12 hours). The reaction mixture was then poured into ice water and the organic phase separated. The aqueous phase was extracted with CCl 2 and the combined extracts were washed 3 times with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to give 1702 g of α-methyl-3-phenoxybenzyl bromide as a heavy viscous oil, njp 1.5993;

Analysis calculated for C C HH ^^ BrOO BrO; C, 60.44; H, 4.71; Br, 28.73;

found; C, 60.62; H, 4.89; Br 28.47- D. 2- (3-, phenoxyphenyl) propionyltrl

A vigorously stirred suspension of 316 g of 989 e sodium cyanide in 5000 ml of anhydrous dimethyl sulfoxide (dried over a molecular sieve) was heated to 50-60 ° C and maintained at this temperature while slowly adding 1702 g of α-methyl-3-phenoxybenzyl bromide. After the bromide addition was complete, the temperature was raised to 75 ° C and the mixture was stirred at this temperature for 1.5 hours. The mixture was allowed to cool to room temperature and stirred overnight at room temperature, then poured into ice water. The resulting aqueous suspension was extracted twice with ethyl acetate and then with ether. The organic extract was washed twice with a sodium chloride solution, once with water, and then dried over anhydrous sodium sulfate. Evaporation of the solvent in vacuo left an oily residue which was distilled through a 15 cm Vigreux column to obtain 1136 g of 2- (3-phenoxyphenyl) v propionitrile, b.p. 14-1-148 ° C (0.1 mmHg), njp = 1.5678.

Analysis calculated for C ^ cH- ^NO; C, 80.69; H, 5.87; N, 6.27

found; C, 80.89; H, 6.10; N, 6.14.

EXAMPLE 2 2- (3-Uhenoxyphenyl) propionamide

A solution of 0.5 M 2- (3-phenoxyphenyl) propionyl chloride in 300 ml of dry ethyl ether was added dropwise to 2 liters of liquid ammonia with stirring. After the addition was complete, the reaction mixture was stirred for 1 hour and 500 ml of diethyl ether was added. The reaction mixture was stirred overnight, thereby evaporating excess ammonia. Dilute hydrochloric acid was added to the reaction mixture, the ether layer was separated, washed with sodium hydroxide and water and dried over sodium sulfate. Evaporation of the ether in vacuo left a gummy residue which crystallized after tearing off with cold hexane ·. Recrystallization from ethyl acetate and hexane gave 76.2 g of 2- (3-phenoxyphenyl) propionamide, m.p. 67-69 ° C.

Analysis calculated for C- HH- ^NO: C, 74.66; H, 6.27; N, 5.81;

Found: C, 74.01; H, 6.30; N, 6.15.

Example N, N, N-dimethyl-2- (3-phenoxyphenyl) pronionamide

To 400 ml of dry chloroform were added 72.6 g of 2- (3-phenoxyphenyl) propionic acid and 36.9 g of thionyl chloride. The reaction mixture was heated under reflux and stirring for ca. 3 hours. The chloroform was then evaporated and the residue Tooth was cast twice an azeotropic distillation with benzene. The residue was dissolved in ethyl ether and added with stirring and cooling to a solution of 45 g of dimethylamine in ethyl ether. The temperature was kept at approx. 0 ° C or lower during the addition. The reaction mixture was allowed to warm to room temperature and was gently refluxed for 1.5 hours in ice water and acidified, and the ethyl ether layer was separated. The aqueous layer was extracted with ethyl ether. The ether extracts were combined, washed with water, dried over sodium sulfate and evaporated to a white solid. The solid was dissolved in boiling hexane and allowed to cool to room temperature to give 67.6 g of N, N-dimethyl-2- (3-phenoxyphenyl) propionamide, m.p. 73.5 to 76 ° C.

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Analysis calculated for c 75.80; H, 7.11; N, 5.20;

Pound: C, 75.93; H, 6.90; N, 5.27.

EXAMPLE 4 N, N-Dimethyl-2- (3-phenoxyphenyl) proplonamine hydrochloride

To a flame-dried flask was added under nitrogen atmosphere 6.08 g of lithium aluminum hydride and 500 ml of ethyl ether. The mixture was stirred at room temperature for approx. 30 min. To this mixture was slowly added 67.3 g of N, N-dimethyl-2- (3-phenoxyphenyl) propionamide (prepared according to the procedure of Example 3) dissolved in 800 ml of ethyl ether. The reaction mixture was heated under reflux and stirring overnight. To the reaction mixture was then added 4.65 ml of water, 3.5 ml of 20% sodium hydroxide and 16.5 ml of water. The reaction mixture was then poured over ice, additional sodium hydroxide was added and the reaction mixture was extracted with ethyl ether. The ether layer was washed with water and extracted with dilute hydrochloric acid. The acid extract was washed with ethyl ether, made basic with sodium hydroxide and extracted twice with ethyl ether. The ether extracts were washed with water, dried over sodium sulfate and evaporated to an oil. The oil was distilled to give 39.2 g of N, N-dime thyl-2- (3-phenoxyphenyl) propylamine, m.p. 114-120 ° C, 0.1 mmHg, molecular weight 255.

Analysis calculated for ΟΟ γΕΕ, χΝΟ: C 79.96; H, 8.29; N, 5.49

Pound: C 79.76; H, 8.06; N, 5.38.

34 g of the above amine was dissolved in ca. 800 ml of dry ethyl ether and gaseous hydrogen chloride were passed through the solution until saturated. The resulting white solid precipitate was filtered off, washed with ethyl ether, partially dried and recrystallized from ethyl alcohol to give 34.3 g of N, N-dimethyl-2- (3-phenoxyphenyl) propylamine hydrochloride, m.p. 215-217 ° C.

Analysis calculated for C- yHH NONO.HCl: C, 69.96; H, 7.60; N, 4.80

Found: C, 69.68; H, 7.40; N, 4.90.

EXAMPLE 5 N-cyclopropylmethyl-2- (3-phenoxyphenyl) propionamide

To 350 ml of chloroform were added 60.5 g of 2- (3-phenoxyphenyl) propionic acid and 30.4 g of thionyl chloride. The reaction mixture was heated under reflux overnight, evaporated and the residue was subjected to azeotropic distillation with benzene three times. The resulting oily acid chloride was treated with chloroform. 40 g of aminomethylcyclopropane hydrochloride was dissolved in a small amount of water, basified with 5N sodium hydroxide and extracted with chloroform.

The aqueous layer was saturated with sodium chloride and extracted again with chloroform. The chloroform extracts were combined and dried over sodium carbonate and sodium sulfate. The extracts were filtered and 50 ml of triethylamine were added. The mixture was cooled on an ice-acetone bath. To this was added dropwise the solution of acid chloride in chloroform. It was cooled and stirred throughout the addition. The reaction mixture was allowed to warm to room temperature, stirred for 30 minutes, heated to reflux temperature, then allowed to cool to room temperature, and stirred overnight. The solution was partially evaporated and poured into an ice-water mixture. The chloroform layer was washed with dilute hydrochloric acid, dried over sodium sulfate and evaporated to an oily residue. The residue was covered with hexane and scraped into it to give a solid crystalline substance. The crystalline substance was treated with boiling ethyl acetate and hexane was added until the mixture became cloudy. The solution was allowed to cool to give 50.6 g of crystalline N-cyclopropylmethyl-2- (3-phenoxyphenyl) propionamide, m.p. 94.5 to 96 ° C.

Analysis calculated for C C CH ^N NCC: C 77.26; H, 7.17; N, 4.74;

found; C, 77.14; H, 7.17; N, 4.71.

EXAMPLES 6-7

The following compounds were prepared according to the procedure of Example 3 using the appropriate starting materials; N-methyl-2- (3-phenoxyphenyl) butyramide., M.p. 84-86 ° C.

13 UU39

Analysis calculated for C ^ yHH gNOgt C 75.81; H, 7.11; N, 5.20;

Pound: C, 75.60; H, 7.11; N, 5.00.

N-methyl-2- (3-phenoxyphenyl) propionamide, m.p. 57-58 ° C.

Analysis for C ^ gHH yNOg: C, 75.27; H, 6.71; N, 5.49;

Found: C, 75.51; H, 6.86; N, 5.61.

EKSEMPEL_8r10

The following compounds were prepared according to the procedure of Example 4 from the corresponding amide using the appropriate starting materials: N-methyl-2- (3-phenoxyphenyl) butyl amine hydrochloride, m.p. 124-126 ° C.

Analysis calculated for C C CHH-NO.HCl: C, 69.96; H, 7.60; N, 4.80;

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

N-methyl-2- (3-phenoxyphenyl) propylamine hydrochloride, m.p. 160-162 ° C.

Analysis calculated for C- gHH ^NO.HCl: C 69.17; H, 7.25; N, 5.04;

Found: C, 69.21; H, 7.02; N, 5.30.

N-cyclopropylmethyl-2- (3-phenoxyphenyl) propylamine hydrochloride, m.p. 115-117 ° C.

Analysis calculated for C C HH NONO.HCl: C 71.79; H, 7.61; N, 4.40;

Found: C, 71.96; H, 7.46; N, 4.39.

EXAMPLE_11 A ♦ 2- (3-Bhenoxyphenyl) propylamine 100 g of 2- (3-phenoxyphenyl) propionitrile, prepared as in Example 2D, 10 g of Raney nickel, 250 ml of ethyl alcohol and 150 g of ammonia were combined in a pressure vessel under a hydrogen atom. initial pressure of 14 141439 70 kp / em. The reaction mixture was kept under pressure and heated to 70-80 ° C with shaking for 4 hours, resulting in a 91% hydrogen uptake. After cooling and filtering off the catalyst, the reaction mixture was poured into ice water, acidified with hydrochloric acid, washed with ethyl ether, basified with 10% sodium hydroxide solution and extracted with ethyl ether. The ethyl ether layer was washed with water, dried over sodium sulfate and evaporated to an oily residue, distilled to give 78.9 g of 2- (3-phenoxyphenyl) propylamine, b.p. 158-166 ° C / 0.08 mmHg njp = 1.5752.

Analysis calculated for C- HH ^ NONO: C 79.26; H, 7.54; N, 6.16

Pound: C 79.18; H, 7.29; N, 6.07.

B. 2- (5-Phenoxyphenyl) propylamine hydrochloride 20 g of the above 2- (3-phenoxyphenyl) propylamine were dissolved in ethyl ether and the resulting solution saturated with hydrogen chloride gas to give a solid precipitate. The precipitate was filtered off, washed with ethyl ether and dissolved in hot ethyl alcohol. Ethyl ether was added until the mixture became cloudy and the reaction mixture was cooled, then scraped into it to give 18.9 g of 2- (3-phenoxyphenyl) propylamine hydrochloride, m.p. 147 to 147.5 ° C.

Analysis calculated for C C CH-jNO.HCl: C, 68.30; H, 6.88; N, 5.31;

Found: C, 68.11; H, 6.58; N, 5.32.

EXAMPLES 12-21

The following compounds were also prepared according to the procedure of Example 4 using the appropriate starting materials: N-cyclopropyl-2- (3-phenoxyphenyl) propylamine hydrochloride, mp, 129-131 ° C, pK'a 7.9.

Analysis calculated for C C CE ^NO.HCl: C, 71.15; H, 7.30; N, 4.61

Found: C, 71.23; H, 7.48; N, 4.61.

N-methyl-2- (3-phenoxyphenyl) ethylamine hydrochloride, mp, 139-141 ° C, pK'a 9.7.

141439 15

Analysis calculated for C C CH NONO.HCl: C, 68.30; H, 6.88; N, 5.31.

Found: C, 68.21; H, 6.75; N, 5.13.

N, N-dimethyl-2- (3-phenoxyphenyl) ethylamine hydrochloride, m.p., 163-165 ° C, pK'a 8.5.

Analysis calculated for Cl 6 H 19 NO.HCl: C 69.18; H, 7.26; N, 5.04; 0. 5.76.

Found: C, 69.38; H, 7.45; N, 5.07; 0 5.59.

N-methyl-N-cyclopropyl-2- (3-phenoxyphenyl) propylamine hydrochloride, m.p., 129-130 ° C, pk'a 6.9.

Analysis calculated for C ^ IH NO NOHCl: C 71.80; H, 7.61; N, 4.41.

Found: C, 71.53; H, 7.84; N, 4.58.

N-methyl-N-cyclopropylmethyl-2- (3-phenoxyphenyl) propylamine hydrochloride, m.p., 90-92 ° C, pK * a 8.3.

Analysis calculated for C 20 H 25 NO, HCl: C 72.38; H, 7.90; N, 4.22; 0 4.82.

Found: C, 72.33; H, 7.90; N, 4.41; 0 5.09.

N-methyl-N- (2-phenylethyl) -2- (3-phenoxyphenyl) per opylamine hydr and chloride, m.p. 137-138 ° C, pK'a 7.7.

Analysis calculated for C C CHgyNO.HCl: C 75.46; H, 7.39; N, 3.67.

Found: C, 75.23; H, 7.58; N, 3.56.

N-ally 1-2- (3-phenoxyphenyl) propylamine hydrochloride, m.p. 118-120 ° C, pK'a 8.5 ·

Analysis calculated for C ^ gNg ^NO: C, 71.16; H, 7.30; N, 4.61.

Found: C, 71.13; H, 7.50; N, 4.54.

N- (2-phenylethyl) -2- (3-phenoxyphenyl) per opylamine hydrochloride, m.p., 120-124 ° C.

Analysis calculated for C₂ ^H₂ ^NO.HCl: C 75.08; H, 7.12; N, 3.81.

Found: C, 75.11; H, 7.30; N, 3.64.

N-methyl-3- (3-phenoxyphenyl) butylamine hydrochloride, m.p. 124-126 ° C, pK'a 10.0.

Analysis calculated for HCl: C, 69.96; H, 7.60; N, 4.80.

Found: 069.83; H, 7.80; N, 4.87.

3- (3-phenoxyphenyl) butylamine hydrochloride, m.p. 133-135 ° C, pK'a 10.0.

Analysis calculated for C C CH ^ NONO.HCl: C, 69.17; H, 7.26; N, 5.04.

Found: C, 69.36; H, 7.47; N, 5.06.

EXAMPLE 22 N-methyl-N- (3-methylbut-2-enyl) -2- (3-phenoxyphenyl) propylamine hydrochloride

A mixture of 23.9 g of N-methyl-2- (3-phenoxyphenyl) propylamine and 13.8 g of potassium carbonate in benzene was treated with 20.8 g of 1-chloro-3-methyl-2-butene. The reaction mixture was heated under reflux with mechanical stirring for 60 hours. After cooling to room temperature, the reaction mixture was washed with water and extracted with dilute hydrochloric acid. The acidic extract was made basic with sodium hydroxide solution and extracted with ether. The ether extract was washed twice with water and dried over sodium sulfate. Dry hydrogen chloride gas was then introduced into the ether solution and the precipitated hydrochloride salt was filtered off and recrystallized from an alcohol / ether mixture to give 11.5 g of the above product, m.p. 120-122 ° C, pK * a 8.5 ·

Analysis calculated for Cg -H NNQ.HCl: C 72.92; H 8.16; N, 4.05.

Found: C, 72.87; H, 8.34; N, 4.04.

EXAMPLE 25 N-Methyl-N-allyl-2- (3-phenoxyphenyl) propylamine hydrochloride, m.p. 135-136 ° C, pK'a 7.6, was prepared by the procedure of Example 4.

Analysis calculated for C C CH NONO.HCl: C 71.79; H, 7.61; N, 4.41.

Found: C, 71.63; H, 7.80; N, 4.21.

17 UU 39

A number of the compounds of this invention have been tested for anti-inflammatory action in an erythema-blocking test as follows:

A method is used which is a modification of that of C.V. Winner et al. described method (C.V. Winner, V. Burr and C.E. Posierej "A Study of Pharmacological Influences on Ultraviolet Erythrea in Guinea Pigs", Arch. Int. Fharmacodyn., 116, 261, 1958). This method uses guinea pigs (albinos) of both sexes weighing 225-30Q g. The guinea pigs are shaved on their backs and chemically distilled (NAIR, Lotion Hair Remover, Carter Products, N.Y., N.Y.). After 18 to 20 hours, the animals are exposed to ultraviolet radiation after fasting overnight. Immediately after treatment with one of the compounds in question, a protective piece of self-adhesive paper is placed on the backs of the animals, after which they are exposed to high intensity ultraviolet radiation for 7 seconds. The ultraviolet light source is placed in contact with the skin on the back of the animals. The protective paper is then removed and the guinea pigs' backs are cleaned with a gauze tampon dipped in water. The piece of skin that has been protected by the paper acts as a contrasting area when assessing the erythema formed. The animals are placed in transparent plastic holders. After 60, 90, 120, and 150 minutes, the degree of the resulting erythema is judged by an arbitrary scoring system based on the degree of contrast and redness formed.

Anti-inflammatory agents delay the development of erythema and therefore have the greatest effect in the initial assessments. Therefore, the judgments are weighed by a factor of 4, 3, 2 and 1 when judged after 60, 90, 120 and 150 minutes respectively. The erythema formed is evaluated as follows:

Erythema Assessment System Appearance of treated area

Rating 0 No blush and no contrast 1 Light blush with slight outline of the protective paper 2 Light to moderate blush with clear outline 3 Distinct blush with clear circular outline

The total assessment from each group of treated animals (5 or 6 guinea pigs in each group) is compared to a control group and the percentage inhibition is calculated by the following formula: 18 1.41438

Control - Treated 100 x control = percent inhibition

The test compounds are prepared in a suspension of 1% methylcellulose in water and administered orally. Guinea pigs are treated orally with 1 ml suspension per day. kg body weight. Control animals are treated with 1 ml per day. kg body weight of a 1% suspension of methyl cellulose. The dosage in mg per kg, which causes a 50% inhibition of the erythematous response (ED ^ q) is listed in the following Table I for a number of the compounds concerned: Table I:

CH

q / Erythema Blocking Test \ = J Oral ED ^ q _ R_ (mg compound / kg body weight) CH2CH2NH2 * HC1 75 CH2CH2NHCH3-HC1 lo CH2CH2N (CH3) 2 * HC1 7 (j3H-CH2NH2 * HCl 1 0 3 CH-CH2NHCH3 HCl 1 CH2 pH-CH2N (.CH3) 2-HCl8CH, CH-CH9NH-CH <f I * .HC1 9 k CH2 3 / 9H2 (j; h-ch2nhch2chQ | -hci 20 CH, CH2 3 / CH , GH-CH9-N <. ^^ CH ^ -HCl 3 L ^ CH <f] 2

CH5 \ 6h2 CH-CH ~ N <^ ΛΗ0 3 L · * ^ 0¾ - CH <\ 2 * HC1 CH3 2 \ CH2 CH-CH2imCH2CH = CH2 · HC1 10 CH, 3 14U39 19

Erythema blocking test

_R_ Oral ED ^ Q

qjj (mg / compound / kg body weight) CHCH-N ^ 3 / CH, 15

Yes ^ CHOCH = C <"5.HC1 CH3 2 ^ CH3

CfiC ^ NHCHgC ^ E-HCl 5 CH, 5. CH, CHCH9NCT d -HC1 2 crH ^^ ch2ch2ø

CjH-CH₂CH2CH2NHCH3 * HCl 5 η Comparative Compounds: ch-ch2oc-nhch3 L 40 5 / CH-C-NHq I 3 ch3 O CH-C-NHCH, T 3 CH, 3 O CH, // 3 CH-CH2 I \ 25 l CH, CH3 3 Ϊ (jH-C-NHOH 2 ch3 CH-C-NHCH2C00H 5 ch3 acetylsalicylic acid 50

The inhibition of acetic acid-induced twisting in mice is used to demonstrate the relative analgesic effect of the compounds of the invention. To demonstrate the analgesic effect of the compounds, a method similar to that described by R. Koster et al., "Acetic Acid for Analgesic Screening" Fed. Proc., 18; 412 (1959). Here's how:

Male albino mice weighing 16 - 18g are used. The mice receive treatment by subcutaneous route or through the abdomen. At various times after treatment, twisting is induced by intraperitoneal administration of 0.6% acetic acid. Each group consists of 6 mice.

The total number of twists in a group of 6 mice is determined over a period of 5 - 15 minutes after the acetic acid treatment.

The percent inhibition in treatment with the compounds of the invention is determined by comparison with untreated control mice according to the following formula:

f Total number of turns (processing) x 100 J

Percent Inhibition = 100 - —----. . ......... I

\ Total number of turns (control) /

The ED ^ values listed in Table II indicate the dosages in milligrams per milligram. pounds of body weight which induces a 50% inhibition of the frequency of the twists.

TABLE II:

Test compound Analgesic torsion test 2- (3-phenoxyphenyl) -R Subcutaneous ED ^ q where R is_mg / kg ___ CH2CH2NH2. -CH2NHCH3 * HC1 ch3 CH-CH2K (CH3) 2-HCl, 10

Jh3 CH-CH2NHCH3 * HCl CH2CH3 CHa CH-CH2-II-CH2-CH ^ | · HC1 <$ 0 ot K ^

Acetylsalicylic acid 20

Claims (2)

Patent Claims: Analogous Process for the Preparation of 3-Phenoxyphenylalkylamine Compounds of the General Formula R1 - ((\ -CH- (CH9) -CH9-N ^ \ 3 ΓΧ- * 'wherein n is 0, 1 or 2, R " * · Means hydrogen or alkyl of 1-5 2 K carbon atoms and R and R being the same or different means hydrogen, alkyl of 1 to 5 carbon atoms, alkenyl of 2-6 carbon atoms, cyclopropyl, cyclopropylmethyl or phenethyl, or pharmaceutically acceptable acid addition salts thereof, characterized in that a) an amide of the formula> - ^ R1 o R2 jT \ i li / V 7-CH- (CH2) nCN ^ 12 3 wherein n, R, R and R have the above meaning are chemically reduced, or b) a nitrile with the formula