NL8005566A - HYDROXYAMINOMETHYL DERIVATIVES OF BENZOYL DIG SUBSTITUTED ALFA-FENOXY-ALKANOYL ESTERS. - Google Patents

Description

* X

J

VO 1016 * i

Hydroxyaminomethyl derivatives of benzoyl disubstituted o-phenoxyalkanoyl esters.

The invention relates to compounds of the general formula 1 of the formula sheet, wherein R is CH-NR-R-, wherein R and R are hydrogen, £ bb 3 alkyl or alkylene of 4-5 carbon atoms, R2 is hydrogen, halogen, haloalkyl, alkyl , alkoxy, alkylthio or CHJ \ IR_R., wherein Δ 3 0 5 R5 and Rg have the meanings given above, Rg hydroxy, alkoxy, branched alkoxy, adamantyloxy, morpholino, amino or amino substituted by alkyl or alkylene with 4-5 carbon atoms , R 2 hydrogen or alkyl and and X 2 hydrogen, alkyl, halogen or when substituted on adjacent carbon atoms of the benzene ring, represent a 1,3-butadienylene bridge, with the proviso that X 2 and X 2 are not simultaneously hydrogen, and the pharmaceutically suitable salts thereof.

These compounds are useful for promoting diuresis in warm-blooded animals.

The compounds of the formula 1 can further be classified as compounds of the formula 2, wherein R 2 is hydrogen, halogen, haloalkyl, alkyl, alkoxy or alkylthio, Rg hydroxyl, alkoxy, branched alkoxy, adamantyloxy, morpholino, amino or by alkyl or alkylene of 4-5 carbon substituted amino, R ^ 20 hydrogen or alkyl, Rg and Rg hydrogen, alkyl or alkylene of 4 or 5 carbon atoms and X ^ and X2 hydrogen, alkyl, halogen or if substituted on neighboring carbon atoms of the benzene ring, a 1,3-butadienylene bridge, wherein X 2 and X 2 do not simultaneously represent hydrogen, and of the formula 3, wherein R 8 is hydroxyl, alkoxy, branched alkoxy, adamantyloxy, morpholino, amino or amino or alkyl substituted with 4 or 5 carbon atoms , R 1 hydrogen or alkyl, Rg and Rg hydrogen, alkyl or alkylene of 4 to 5 carbon atoms, and X 1 and X 2 hydrogen, alkyl, halogen, or when substituted on neighboring carbon atoms of the benzene-8005 566 - 2 - ring represent a 1,3-butadienylene bridge, where X1 and X2 are not simultaneously hydrogen.

The term "alkyl" refers to straight or branched chain alkyl groups of 1-6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, 2-methylhexyl, n-pentyl, 1- methyl butyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.

The term "alkoxy" refers to straight or branched chain alkoxy groups with alkyl groups having 1-6 carbon atoms attached to the oxygen atom.

The term "halogen" refers to chlorine, bromine, fluorine or iodine.

The "pharmaceutically suitable salts" are meant non-toxic acid addition salts of the compounds as described, which salts are usually prepared by reacting the free base with an appropriate organic or mineral acid. Representative salts include the hydrochlorides, hydrobromides, sulfates, bisulfates, acetates, oxalates, valerate, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, phosphates, tosylates, citrates, maleates, fumarates, succinates, tartrates, napsylates and corresponding salts. The invention also includes the metal salts of said compounds, such as the sodium or potassium salts of the acid.

The subject compounds can be administered orally or parenterally to warm-blooded animals. They are usually administered with a pharmaceutical carrier. It is intended to be any carrier suitable for preparing a dosage unit, such as a tablet medium or a pharmaceutically suitable medium or solvent, as commonly used in preparing intravenous or intramuscular solutions.

A pharmaceutical composition containing the present compounds can be administered to warm-blooded animals in the form of parenteral or oral dosage forms. For oral administration, amounts of 0.1-200 mg / kg per day per patient are used, with a total dose of approximately 3 g per day being an appropriate dose for larger animals, such as humans. . The entire dosing range increases total urinary excretion to 2- to 10-fold in most animals. These figures show that the new diuretic compounds are particularly effective in increasing urinary excretion in most animals.

For all dosage forms, the present compounds can be applied in capsules, processed into pills, wafers or tablets in a conventional manner, together with the known and conventional pharmaceutical carriers. Tablets can be made for immediate release of the active agent or they can be coated to release the active slowly into the intestinal tract over several hours *.

To illustrate the manner in which the present compounds can be prepared and to demonstrate their properties, the following examples have been provided, which, however, are not intended to limit the invention in any way.

The following is a general method for preparing mono- and bis-dialkylaminomethyl derivatives of 2,3-dichloro-4-C4'-hydroxybenzoyl] phenoxyacetic acid.

2,3-dichloro-4-C4'-hydroxybenzoylphenoxyacetic acid, prepared as described in US Patent 4,058,559, is slurried in ethanol (1 dm per mole of acid}. 2 moles of a secondary amine are added to this slurry at once. The reaction mixture is then stirred until a solution is formed, to which a mixture of 1 mole formaldehyde and 2 moles secondary amine is added if a monoproduct is desired.2.5 moles formaldehyde and 3 moles secondary amine are added if a bis- The reaction mixture is then boiled IS - 24 hours and then cooled, after which the product is formed.If this product does not precipitate, the reaction solution is concentrated in vaeuo to a glass.This glass is taken up in water, to about pH Acidified to give a solid upon standing This crude solid is recrystallized from an appropriate solvent to yield the desired product.

8005566 - 4 -

Example I

2.3-dichloro-4- (4'-hydroxybenzoylf enoxyacetic acid ethyl ester.

85.33 g CO, 25 mol] 2,3-dichloro-4- (4-hydroxybenzoyl) -phenoxy-3 acetic acid, 34.5 g CO, 75 mol] ethanol and 100 cm ethylene dichloride 3 5 with addition of 3, 5 mixed as sulfuric acid as a Catalyst and boiled overnight with stirring according to the procedure of JACS 7Ό, 3135 C194Θ]. The acid gradually dissolved. The reaction layer was cooled, separated and the organic layer washed successively with water, twice with a KHCOg solution and finally again with water. After drying, the ethylene dichloride extract was evaporated to dryness to yield an oil which solidified to 86 g of crude ester on pentane trituration and filtration; mp 127-129 ° C Cop yield 93%]. This material was used in the following experiments without further purification.

Example II

2.3-dichloro-4 - / (3'-chloro-4'-hydroxy] benzoyl] 7-phenoxyacetic acid ethyl ester.

3

A mixture of 50 cm ethylene dichloride and 9.2 g (0.025 mol) of 2,3-dichloro-4- (4-hydroxybenzoyl] phenoxyethyl ester was treated with 2.5 g (0 * 03 mol) of 30 ^ 012- This mixture was boiled on a steam bath for 6 hours The solvent was driven off and a white solid was obtained This was collected with ether to 8.5 g of solid with a melting point of 135 DEG-140 DEG C. Recrystallization from toluene with activated carbon gave 4. 5 g of product with a melting point of 152 - 155 ° C.

Analysis: Calculated for C H 2 dgOg = 403.65; C 50.59, H 3.24, Cl 26.35%; found: C 50.55, H 3.12, Cl 25.80%.

Example III

2,3-dichloro-4- (3'-chloro-4'-hydroxy] benzoyl-phenoxyacetic acid.

A solution of 10.09 g (0.025 mol) of 2,3-dichloro-4- (3'-3-chloro-4'-hydroxy) benzoyl-7phenaxyacetic acid ethyl ester in 37.5 cm 3 2 N sodium hydroxide solution (3 g in 37.5 cm H Stirred and heated for 5 quarters of an hour at 90 - 98 ° C. The solution was then cooled to ca.

35 50 ° C and acidified with 6 N hydrochloric acid. A white precipitate 8005566 c * * - 5 - precipitated, which was filtered off, washed with water and dried to give 9.0 g of product, mp 104-111 ° C (Conti.). Recrystallization from hot acetic acid and addition of water to the cloud point after cooling yielded a product, melting point 190 DEG-191 DEG C., 8.69 g, 92.5%.

Example IV

2,3-dichloro-4- (4'-methoxybenzoyl) phenaxyoc-methylacetic acetic acid ethyl ester.

A solution of 9.96 g (0.055 mole) of 2-bromopropionic acid ethyl 3 ester in 12 cm of acetone was added over 2 hours to a stirred and boiling mixture of 14.85 g (0.05 mole) of 2,3-dichloro-4- (4'-methoxy-benzoyl) phenol and 7.60 g (0.055 mol) powdered anhydrous potassium carbonate in 200 cm acetone. After the addition, the mixture was boiled for an additional 20 hours and the hot mixture filtered. The filtrate was evaporated to dryness in vacuo and the residue taken up in 250 cm of chloroform.

This chloroform solution was washed with 10% aqueous potassium carbonate, with water, dried over anhydrous sodium carbonate and evaporated in vacuo to the desired product.

Example V

2.3-dichloro-4- (4'-hydroxybenzoyl) phenoxy-C-methyl acetic acid.

A mixture of 19.34 g of 2,3-dichloar-4-C4-methoxybenzoyl-3-phenoxy-methyl-acetic acid ethyl ester and 330 cm of 48% hydrogen bromide was stirred quickly and boiled for 21.5 hours. This mixture was then cooled in an ice bath and diluted with 415 cm of water with stirring. The product formed was filtered off and washed with ice water; Mp. Mp 208-212 ° C.

Example VI

2.3-dichloar-4 - / "(3'-dimethylaminomethyl-4'-hydroxy) benzoyl] phenoxy-acetic acid ethyl ester hydrochloride.

A suspension of 2,3-dichloro-4- (4'-hydroxybenzoyl) phenoxy acetic acid (34 g, 0.1 mol) was dissolved by adding 20 cm of 40% aqueous dimethylamine (0, 2 mol). The resulting solution was endowed dropwise with a mixture of 3 x 20 cm dimethylamine and 10 cm 37% formaldehyde. The reaction solution was boiled overnight. The mixture was then concentrated 8005566-6-.

to a glass. This glass was taken up in DMF without any precipitation. The DMF was distilled off in vacuo and the residue. absorbed in water. A pale white material precipitated from this water solution. Yield of impure solid material 22.5 g, m.p.

5 250-254 ° C Conti.). This crude product was triturated with hot DMF and cooled. The product was then dried in vacuo to 17 g with a melting point of 265-268 ° C Conti.). This material was converted into the ethyl ester by suspending in 300 ml of 3 cm ethanol and adding 20 cm (an excess) of thionyl chloride dropwise. After boiling overnight, the resulting solution was concentrated in vacuo to a solid material which recrystallized from ethanol to 19.0 g of a product, mp 186-188 ° C; yield 41¾ of the theoretical value.

Analysis: Calculated for C-n H 14 ClQNO = 462.761: C 51.92, H 4.79, N 3.02%; Found: C 51.67, H 5.00, N 3.01%.

Example VII

2,3-dichloro-4 - / ((3'-dimethylaminomethyl-4'-hydroxy) benzoyl-7-phenoxy-acetic acid.

20 To a solution of ethyl 2,3-dichloro-4-ZT (3'-dimethylaminomethyl-1-4'-hydroxy) benzoyl phenoxyacetate hydrochloride (13 g, 3 0.028 mol) in 150 cm of 88% formic acid, 6 0.0 g (0.061 mol) of methanesulfonic acid. The resulting solution was heated on a steam bath for 16 hours. This solution was then concentrated to a glass. This glass was taken up in water and treated with a 2% sodium bicarbonate solution until the solution became cloudy. Stand yielded a white solid in a yield of 10.5 g (91%), mp 268-270 ° C (anti.).

Analysis: Calculated for C 1 H H C N NO 3. 398.25: C 54.29, H 4.30, N 3.52%; found: C 54.55, H 4.30, N 3.56%.

Example VIII

Ethyl-2,3-dichloro-4- / T (3'-diethylaminomethyl-4'-hydroxy) -benzoyl-7-phenoxyacetate.

35 A solution of 18.1 g (0.03 mol) of ethyl-2,3-dichloro-4- (4'-8005566-7-hydroxybenzoyl phenoxyacetate and 4.3 g (0.033 mol) of N-ethoxymethyl-diethylamina in 40 to 1.2- dimethoxyethane Cmonoglyme] was boiled for 4 hours.After this the reaction mixture was concentrated and the resulting gum was taken up in ether and filtered.The ether solution was treated with ethereal HCl and after filtration and drying 14 g of a light hygroscopic hydrochloride salt were obtained.

This product was recrystallized from an acetonitrile ether mixture, m.p. 115-120 ° C.

Analysis: calculated for ^ 22¾ 51¾ ^ 5'C 53.84, H 5.34, N 2.85%. Found: C 53.35, H 5.54, N 3.05%.

Example IX

Ethyl-2,3-dichloro-4- [\ C3 "- (1-pyrrolidinylmethyl] -4'-hydroxy} -benzoyl oxyacetate hydrochloric acid.

To a stirred solution of 11.07 g (0.03 mol) 2,3-di-3-chloro-4- (4'-hydroxybenzoyl] phenoxyacetic acid ethyl ester in 50 cm ethanol, cooled in an ice bath, a previously prepared solution was added dropwise ( obtained by slowly adding 2.5 cm (0.033 mole] 37% formaldehyde to a stirred solution of 2.14 g of 3 (0.03 mole) pyrrolidine in 10 cm ethanol, cooled in an ice bath]. the mixture was boiled for 4 hours and evaporated to dryness in vacuo. The residue was extracted with ether. The ether extract was evaporated to dryness in vacuo and the residue purified by chromatography on a Florisil column (100-200 mesh] and eluted with chloroform as well as calibrated. chloroform-ethanol mixtures The product was isolated in the form of the hydrochloride, m.p. 149-152 ° C (from ethanol / ether].

Analysis: Calculated for C-H 10 ClNOc HCl: C 54.06, H 4.95, N 2.87%: 22 23 2 5 30 Found: C 54.18, H 5.31, N 2.84% .

Example X.

Ethyl-2,3-dichloro-4-Z * (3-piperidinomethyl-4'-hydroxy] -benzoyl-7-phenoxyacetate hydrochloride.

3

A 37% formaldehyde solution (2.5 cm, 0.33 mol] was added to a solution of 2.55 g (0.03 mol] piperidine in 40 8005566-8-3 cm ethanol. To this solution 11 .07 g (0.03 mol) of ethyl 1,2-3-3 dichloro-4- (4'-hydroxybenzoyl) phenoxyacetate and 20 cm 3 of ethanol were added The mixture was boiled for 13 hours and evaporated to dryness in vacuo The residue was extracted with ether. ether extract was evaporated to dryness and the residue purified by chromatography on a 100-200 mesh Florisil column and eluted with calibrated chloroform / ethanol mixtures The product was isolated as the hydrochloride mp 109-111 ° C Conti. (from ethanol / ather).

Analysis: Calculated for C 1 H H C 1 NO 2 HCl: C 54.94, H 5.21, N 2.79%; found: C 54.97, H 5.86, N 2.43%.

Example XI

2,3-dichloro-4- (4'1'-hydroxy-31-morpholinomethyl) benzoyl] phenoxy-15 acetic acid.

3

A mixture of 0.1 mole morpholine (9.0 cm) and 0.05 mole or 1.5 g paraformaldehyde was suspended in 100 cm cyclohexane and tertrbutanol (1: 1). This mixture was heated for 2 hours and the water formed was discharged through a Dean-Stark trap. The mixture was then treated with 17 g (0.05 mol) of 2,3-dichloro-4- (4'-3 hydroxybenzoyl phenoxyacetic acid, dissolved in 50 cm DMF. After boiling for 16 hours, the solvents were expelled in vacuo and a solid material was obtained. This precipitate was collected with the aid of ethanol to obtain 7.5 g of a white to tan colored material with a melting point of 263-265 ° C (dec.). A second amount of solid material was obtained by drying the mother liquor. vapors.

The residue was taken up in water and neutralized with 4.5 N hydrochloric acid to 4.5 g of a white material, mp 259-260 ° C (dec.). The two fractions were combined and recrystallized from a minimal amount of DMF (250 cm) and addition of water to the cloud point. The yield of solid material was 9.0 g; melting point 274-276 ° C (dec.). The yield was 41% of the theory.

Analysis: 8005566-9 calculated for * -20 ^ 19C ^ 2N06 = c 54.56, H 4.35, N 3.18%; found CC 54.33, H 4.07, N 3.71%.

Example XII

Ethyl-2,3-dichloro-4- / ((4'-hydroxy-3'-thiomorpholinomethyl) benzoyl] 7'-phenoxyacetate, S.S. dioxide.

11.1 g (0.03 mole) ethyl-2,3-dichloro-4- (4'-hydraxybenzoyl) phenoxyacetate, 4.056 g (0.03 mole) thiomorpholine sulfone, 2.5 g 3 (0.033 mole) 37% formalin and 60 cm 3A alcohol were boiled for 20 hours and then left to cool. A gum which was triturated with ether separated to give 7 g of a colorless solid; this softened at 160 ° C and melted at 173-317 ° C. This solid material was taken up in 100 ml of cracking acetone 3 and filtered, then concentrated to 50 cm and ether added to cloudiness. This gave 6 g of product with a melting point of 184-185 ° C.

Analysis: Calculated for C22 H23 Cl2 NO7 S: C 50.78, H 5.23, N 2.69%; found: C 50.50, H 4.71, N 3.14%.

Example XIII

Ethyl-2,3-dichloro-4-Z "(4'-hydroxy-3'-morpholinomethyl) benzoyl-7-phenoxyacetate hydrochloride.

A suspension of 2,3-dichloro-4- ("C4'-hydroxy-3'-morpholinomethyl) benzoyl-7-phenoxyacetic acid (0.02 mol, 9.0 g) in ethanol was gifted dropwise with 10 ml of thionyl chloride. The resulting solution was Cooked for 2 hours, left overnight to cool and concentrated in vacuo to a glass This glass could not be converted to a solid The glass yield was 9.3 g, the yield was 93% of theory.

Analysis: Calculated for C22H24Cl3NO8 = 504.798: C 52.35, H 4.79, N 2.77%; found: C 52.22, H 4.90, N 2.89%.

Example XIV

2,3-dichloro-4-Z "(4'-hydroxy-3'-sarcosylmethyl) benzoyl-7-phenoxy-acetic acid.

A mixture of 19.6 g (0.22 mol) sarcosine, 3.3 g (0.11 mol) 8005566-10-3 paraformaldehyde and 100 cm cyclohexane / tert-butanol was boiled. To this mixture was then added 17 g (0.05 mol) of 2,3-dichloro-4- (4'-hydroxybenzoyliphenoxyacetic acid, dissolved in 50 cm DMFi. The reaction mixture was boiled for 16 hours and the solvents were expelled in vacuo with a gum This gum was taken up in water and the solution was acidified with 6N hydrochloric acid to precipitate a solid material.This precipitate did not crystallize from any suitable solvent.The yield of precipitate was 3.5 g (16% 3; melting point was 230). - 235 ° C (decomposition 3.) Due to its insolubility, this compound was converted into its diethyl ester hydrochloride salt in the next step.

Example XV

Ethyl-2,3-dichloro-4 - / "(3'-ethylsarcosylmethyl-4 * -hydroxy 3-benzoyl-7-phenoxyacetate hydrochloride.

A suspension of 3.5 g (0.008 mol 3 of 2,3-dichloro-4-Z "(4'-hydroxy-S'-sarcosylmethyl-benzoyl] phenoxyacetic acid in 100 cm of ethanol 3 was endowed with 10 cm of thionyl chloride. This mixture was Boiled for 16 hours, cooled, concentrated in vacuo to a glass, which yielded a solid on drying in vacuo overnight at 80 ° C. The yield was 3.6 g, the melting point was 198 - 201 ° C (dec. 3. The solid material was recrystallized by dissolving it in ethanol, concentrating to a glass and triturating it with warm ethyl acetate to give 3.0 g of product, m.p. 200 DEG-202 DEG (dec. 3). .

Analysis: calculated for C23H2BC13N07 = 534.825i C 51.65, H 4.90, N 2.62%; found: C 51.76, H 4.93, N 2.66%.

Example XVI

2,3-dichloro-4-T (3'-chloro-5'-dimethylaminomethyl-4'-hydroxy-3-ben-30-yl-phenoxyacetic acid.

3

A mixture of 0.05 mol (1.5 g 3 paraformaldehyde and 20 cm 3 (0.2 mal 3 40% aqueous dimethylamine as well as 50 cm each) of tert-butanol and cyclohexane was boiled and the water formed therewith removed with a Dean Stark trap The resulting solution was treated with 8.0 g (0.02 mole} 2,3-dichloro-4- 'O-chloro-A'-hydro- 8005566 3-11-xy] benzoyl-phenoxyacetic acid in 50 cm DUF This mixture was boiled overnight The solution was concentrated in vacuo to a solid material This material was collected in the form of 3.0 g of product with a melting point of 225-228 ° C Conti.

A second crop was obtained from the ethanol mother liquor; yield 5.0 g with Mp. 75-100 ° C Conti.]. The second crop was dissolved in water and heated to a cloudy solution. Glacial acetic acid was added to this solution. A white solid material precipitated. This material was collected and washed with ethanol and finally with ether to 4.0 g of product, mp 221-223 ° C Conti.]. This solid material was recrystallized by dissolving in a 2% aqueous KHCOg solution and precipitating by adding glacial acetic acid. The precipitate melted at 223 DEG-225 DEG C. Conti.] And was obtained in a yield of 2.7 g.

Analysis: calculated for CiaH16Cl3NO5 = 432.69: C 49.97, H 3.73, N 3.23%; found: C 49.64, H 3.79, N 3.20%.

Example XVII

Ethyl-2,3-dichloro-4-Z "C3'-chloro-5'-dimethylaminomethyl-4'-hydroxy-20-benzoylphenoxyacetate hydrochloride.

To a mixture of 3 g of 2,3-dichloro-4-ZTC3-chloro-5'-dimethylaminomethyl-4'-hydroxy] benzoyl-7phenoxyacetic acid in 50 cm ethanol was added dropwise 6 cm Cover size] thionyl chloride. After this addition was completed, the mixture was heated to a solution on a steam bath. The solvent was then distilled off in vacuo and a white solid was obtained. This was recrystallized from acetone / ether (1: 1] to a product with a melting point of 178 - 179.5 ° C Conti.].

Analysis: calculated for C 1 H H Cl Cl 2 O = 497.206: C 48.31, H 4.26, N 2.82%; found: C 48.63, H 4.38, N 2.92%.

Example XVIII

2,3-dichloro-4-1 C3 * .5'-bis- (dimethylaminomethyl] -4'-hydroxy_ / benzoyliphenoxyacetic acid dihydrochloride.

* 3 A solution of 40 cm CO, 4 mol] 40% aqueous dimethyl- 8005566-12 -3 amine and 20 cm (0.2 mol) 37% formaldehyde solution was treated with 17 g of 2,3-dichloro-4 - (4'-hydroxybenzoyl) phenoxyacetic acid (0.05 mol). The mixture was heated on a steam bath to a light amber solution. This solution was heated on a steam bath overnight. The amber solution was concentrated in vacuo 3 and azeotropically distilled with 50 cm toluene to a gray-brown solid. This crude material was triturated with hot ethanol and collected on a Buchner funnel in the form of a yellow solid. This was air dried to 23.5 g with a melting point of 165-170 ° C (dec.). Recrystallization first from DMF and then from ethanol / water (1: 1) and finally again from DMF gave 13.6 g with a melting point of 215-217 ° C (dec.). Analysis: calculated for ^ 21 ^ 24 ^ 2 ^ 2 ^ 1'S ^^ = 411.457: C 52.29, H 5.64.

N, 5.60%; found: C 52.07, H 5.53, N 5.95%.

2 g of the base thus obtained was converted into the dihydrochloride salt as follows. The base was dissolved in glacial acetic acid and an excess of ethereal hydrochloric acid added. The flask was then heated on a steam bath to drive off the excess HCl and the dihydrochloride salt precipitated on addition of ether. This gave a gum which was taken up in acetonitrile and yielded a white precipitate with a melting point of 221-223 ° C (dec.) On cooling.

The yield was 2.3 g.

Analysis: Calculated for C 4 H 14 Cl 4 µg = 528.263: C 47.75, H 4.96, N 5.30,

Cl 26.85%; found: C 47.89, H 5.09, N 5.19, Cl Cl 27.11%.

Example XIX

Ethyl-2,3-dichloro-4- | 3'5'-bis- (dimethylaminomethyl) -4'-hydro-) xy_7benzoyl, phenoxyacetate dihydrochloride.

J r 2,3-dichloro-4-beta 3'5 / -bis- (dimethylaminomethyl) -4-hydroxy-1 * 35 droxy.Jbenzoyl-phenoxyacetic acid (54 g, 0.13 mol) was added in a 3-3 1 dm round neck flask fitted with a mechanical stirrer, addition funnel, and reflux condenser. 500 ml of absolute ethanol was further introduced into this flask. The stirred suspension was endowed with 50 cm (0.7 mol) of thionylochloride in a slow flow for 15 minutes. The reaction heat caused the mixture to boil, and this boiling was continued for 2 hours by heating with a steam bath. The mixture was then cooled with an ice bath to form a precipitate, which was collected and washed first with ethanol and then with ethyl ether. There were thus obtained white solid platelets which were dried in vacuo XQ to give 59 g (32%) of product with a melting point of 208 DEG-210 DEG C. (dec.). ) yielded a product with a melting point of 222 DEG-224 DEG C. (dec.) The final yield of purified product was 23.5 g (33%).

Analysis: calculated for ^ 23 ^ 8 ^ 2 ^ 2 ^ 5 * 556.32: C 49.66, H 5.44, N 5.05%; found: C 49.74, H 5.58, N 5.08%.

Example XX

Ethyl-2,3-dichloro-4- [3'.5'-bis- (dimorpholinomethyl) -4'-hydroxyJ7 ~

1 L

Benzoyl-phenoxyacetate dihydrochloride.

3

A mixture of 36 cm (0.4 mol) morpholine and 6.6 g (0.22 mol) of paraformaldehyde in a solution of 100 cm cyclohexane and 3 100 cm tert-butanol was boiled on an oil bath. The water formed was removed via a Dean-Stark trap. After the theoretical amount of water was removed (after about 2 hours), the flask was allowed to cool and a solution of 17 g (0.05 mol) of 2,3-dichloro-4-y-4'-hydroxybenzoylphenoxyacetic acid was added. in 50 cm DMF The reaction mixture was boiled overnight The mixture was then cooled with an ice bath to obtain 12.0 g (44%) of product 30, mp 175 DEG-185 DEG (dec.). was recrystallized from absolute ethanol to give 9 g of product with a melting point of 188 DEG-191 [deg.] C. This product was suspended in ethanol and 10 cm (an excess) of thionyl chloride was added dropwise with stirring. boiled, cooled and concentrated in vacuo to a glass This glass could not be done 8005566 - 14 -

Crystallize. The yield of glass was 10 g (93%].

Analysis: Calculated for C 1 H H Cl N N 640.39: C 50.64, H 5.35, N 4.38%; found: C 50.45, H 5.50, N 4.27%.

5 Example XXI

2.3-dichloro-4- [Γ3'.5'-bis- (pyrrolidinylmethyl] -4'-hydroxyJ7-) 1 benzoyl-phenoxyacetic acid.

3 7.5 cm (0.1 mol) of a 37% formaldehyde solution was added dropwise to a stirred solution of 17.05 g of 10 (0.05 mol) of 2,3-dichloro-4- (4'-hydroxybenzoyl] phenoxyacetic acid and 3 14.22 g (0.2 mol] pyrrolidine in 80 cm ethanol. This mixture was stirred for 3 hours and boiled for 6 hours and more (3.75 cm 3) of the 37% formaldehyde solution was added dropwise, after which the mixture was added Boiled for 183 hours After evaporation to dryness in vacuo, the residue was triturated with ether and recrystallized from 2-butanone / ethanol, mp.

233-236 ° C.

Example XXII

Ethyl-2,3-dichloro-4 - [/ * 3'5'-bis- (1-pyrrolidinylmethyl] -4'-hydr-xy] benzoylphenoxyacetate dihydrochloride.

5.71 g (0.048 mol] thionyl chloride was added dropwise to a stirred suspension of 4.85 g (0.0096 mol) 2,3-dichloro-4-3'5'-bis- (1-pyrrolidinylmethyl]] -4'-Hydroxy-7benzoyl-3-phenoxyacetic acid in 100 cm ethanol, and cooled in an ice bath After addition was complete, the mixture was boiled for 3 hours and then evaporated to dryness in vacuo The residue was triturated with ether and recrystallized from ethanol Mp product 171-173 ° C (anti.].

Analysis: Calculated for C 7 H 14 ClN-O 2 C 2 HCl: C 53.30, H 5.63, N 4.61%; Found 27 32 225: C 52.70, H 5.75, N 4.48%.

Example XXIII

2,3-dichloro-4- ^ 3 ^ 51-bis-piperidinomethyl] -4'-hydroxy-7-benzoyl-phenoxyacetic acid.

3 7.5 cm (0.1 mol) of a 37% formaldehyde solution was added dropwise to a stirred solution of 17.05 g of 35 (0.05 mol] of 2,3-dichloro-4- (4'-hydroxybenzoyl] phenoxyacetic acid and 8005566 -15-.

3 17.03 g (0.2 mol] piperidine in 80 cm ethanol. The mixture was heated at 95 DEG-100 DEG C. for 2 hours and then an additional 3.75 ml of the 37% formaldehyde solution was added and the mixture was added for 15 hours. kept at 96 ° C. After evaporation to dryness in vacuo, the resulting residue was triturated with ether and recrystallized from dimethylformamide, mp 201-205 ° C.

Example XXIV

Ethyl-2,3-dichloro-4-3'5'-bis (piperidinomethyl) -4'-hydroxy-benzoylphenoxyacetate dihydrochloride.

9.64 g (0.061 mol) of thionyl chloride was added dropwise to a stirred suspension of 3.70 g (0.0162 mol) of 2,3-di-chloro-4-Lf 3'5'-bis (piperidinomethyl) - 4'-Hydroxy-7-benzoyl phenoxy-1/3 'acetic acid in 150 cm ethanol while cooling with an ice bath. The mixture was then boiled for 3½ hours and evaporated to dryness in vacuo.

The residue was triturated with ether and recrystallized from ethanol, Mp. 165-188 ° C Conti.).

Analysis: Calculated for C 2 H 3 Cl 2 N 2 O 5 · 2HCl: C 54.72, H 6.02, N 4.40%; found: C 53.99, H 6.06, N 4.35%.

20 Example XXV

Ethy1-2.3-dichloro-4-Lf * 3'.5 * -bis (thiomorpholinomethyl) -4'-hydroxy_7-

i L

benzoyl phenoxyacetate-S.S.S'.S'-tetraoxide.

A mixture of 8.1 g (0.06 mole) of thiomorpholine sulfone and 1.8 g (0.06 mole) of formalin (5 g of a 37% solution) was mixed under cooling to form an intermediate methylol product . To this mixture, 5.55 g (0.15 mol) of Z-2,3-dichloro-4- (4'-hydroxybenzoyl) -phenoxy-7-acetic acid ethyl ester in 30 cm 3A alcohol was added. This mixture was boiled for 23 hours. The reaction mixture was filtered hot and the resulting solid material washed well with a 50/50 mixture of alcohol and ether and finally with ether. Thus 8.5 g with a melting point of 228-230 ° C were obtained (yield 81%). This basic mannich product was recrystallized from 2-btitanone; Mp. Mp 228-230 ° C.

Analysis: calculated for ^ 27 ^ 32 ^ 2 ^ 2 ^ 9 ^ 25 ^ H 4.86, N 4.22%; found: C 48.74, H 5.02, N 4.05%.

8005566 - 16 -

Example XXVI

Esters of 2,3-dichloro-4- | z "3'5'-bis (dimethylaminamethyl) -4'-hydroxy-7-benzoyl, phenoxyacetic acid.

* 3

These esters were prepared as follows: 0.63 cm of thionyl chlorine-5de was added to a suspension of 2,3-dichloro-4- / '3,5'-bis- (dimethylaminomethyl) -4'-hydraxybenzoylJ7-phenoxyacetic acid, 2 g , in 3 15 cm anhydrous dimethylformamide, with stirring and under a nitrogen atmosphere. The solid material went into solution. After 5 minutes, the alcohol (specified below) was added. The solution was cooled thereon and concentrated in vacuo to a white solid. This material was dissolved in a methanol / dichloromethane / concentrated ammonia solution in the proportions 20/80/1. A white precipitate of ammonium chloride formed thereby. The solution was filtered through 10 g of 80-15 230 mesh silica gel using the same solvent ratio as eluate. The solvent was then expelled in vacuo to leave a gum. This gum was dissolved in methylene chloride and treated with anhydrous hydrogen chloride gas with cooling.

The white solid obtained was filtered off. This material was dried in vacuo to yield the pure ester dihydrochloride salt.

Alcohol Used Yield Melting point amount of octanol 2.77 cm3 1.151 g / 40.9% 205-206 ° C dec.

O

Benzyl alcohol 1.83 cm 0.928 g / 33.9% 202-204 ° C dec.

N-pentanol 1.90 cm 0.950 g / 36% 210-212 ° C dec.

2,2-dimethylpropano1 1.547 g 0.910 g / 34.6% 226-228 ° C dec.

q cyclohexylmethanol 2.16 cm 2.250 g / 81.9% 230-231 ° C dec.

benzhydrol 3.2353 g 0.897 g / 29.4% 206-207 ° C dec.

Elemental analysis: Octyl ester calculated for C 4 H 14 Cl 4 Og: C 54.38, H 6.61, 4.37, Cl 22.14%; found: C 54.62, H 6.81, N 4.37, Cl 22.50%.

Elemental analysis: Benzyl ester calculated for C28H32C * 4N2 ° 5! C 54'38, H 5'22 'N 4 »53» 22.93%; Found: C 54.00, H 5.35, N 4.44, Cl 24.30%.

8005566 r - 17 -

Elemental analysis: n-pentyl ester calculated for a, eHeeCl.N_Ol C 52.19, H 6.06, N 4.68, Cl 23.70%; found: C 52.37, H 6.28, N 4.76, Cl 23.92%;

Elemental analysis: 2,2-dimethylpropyl ester 5 calculated for C26H36C14N2 ° 5! C 52.19, H 6.06, N 4.68, Cl 23.70%; found: C 52.07, H 6.31, N 4.82, Cl 23.53%.

Elemental analysis: cyclohexylmethyl ester calculated for C 1 HggCl N 0 .s. O: C 53.09, H 6.21, N 4.42, Cl 22.39% found: C 52.73, H 6.12, N 4. 43, Cl 21.77% Elemental analysis: Benzhydryl ester calculated for C 1 H H Cl Cl 2 O: C 58.80, H 5.23, N 4.03, Cl 20.42%; found: C 58.84, H 5.34, N 3.96, Cl 22.02%.

Example XXVII

Phthylethyl-2,3-dichloro-4-3,5'-bis-dimethylaminomethyl-4'-hydroxy-7) phenoxy-acetate dihydrochloride.

2.6 ml of thionyl chloride was added dropwise to a stirred suspension of 8 g of 2,3-dichloro-4- [if 3'-5'-bis (dime-) 1 3 thylaminomethyl] -4'-hydroxy'-benzoyl-phenoxyacetic acid in 1 cm wa-

3 J

free of dimethylformamide and 60 cm of methanol under a nitrogen atmosphere. The mixture was boiled for 6 hours and the resulting solution cooled, then the solvent was expelled in vacuo and a white solid was obtained. This material was recrystallized from methanol to 2.75 g ¢ 28.9%] of the pure methyl ester dihydrochloride with m.p. 214-215 ° C.

Analysis: Calculated for C 10 H 6 ClN 6 O C: C 48.73, H 5.20, N 5.17, Cl 26.15%; found: C 48.83, H 5.39, N 5.24, Cl 26.36%.

Example XXVIII

Ethyl-2,3-dichloro-4-, C3,5-bis (dimethylaminomethyl) -4'-hydroxyJ7-) benzoyl .. phenoxyacetate dihydrochloride.

50 ml of thionyl chloride was added over 15 minutes to a stirred suspension of 2,3-dichloro-4 - [/ "3'5'-bis-C-dimethylaminomethyl] -4'-hydroxy-7-benzoyl-phenoxy acetic acid f54 g ] 3 l in 500 ml of absolute ethanol This addition brought the solution to the boil 35. The boiling was continued by heating for an additional hour from outside 8005566-18 The mixture was then cooled in an ice bath and filtered. Precipitated precipitate was washed with cold ethanol and diethyl ether The crude precipitate was recrystallized twice from 1 dm 3 ethanol containing 10 cm thionyl chloride to 5 23.5 g (33%) of the pure ethyl ester dihydrochloride with Mp.

222-224 ° C.

Analysis: calculated for ^ 23 ^ 28 ^ 4 ^ 21½: C 49.66, H 5.44, N 5.05%, found: C 49.74, Η 5.6Η, N 5.08%.

10 Example XXIX

Isopropyl-2,3-dichloro-4- [ZT3'5'-bis (dimethylaminomethyl) -4'-hy-); 1 hydroxy / benzoyl-phenoxyacetate dihydrochloride.

3 '10 cm thionyl chloride was added to a mixture of 3.8 g of 2,3-dichloro-4- | z'3'-5'-bis (dimethylaminomethyl) -4'-hydroxy-phenyl-benzoylphenoxyacetic acid and 200 cm of isopropanol . This mixture was boiled for 2 hours and 20 ml of methyl formamide added. After boiling overnight, the solution was cooled with an ice bath and filtered to yield 3.8 g of solid material. This material was recrystallized by dissolving the crystals in 50 cm warm dimethylformamide on 3 3 20, adding 50 cm isopropanol, cooling and adding 50 cm diethyl ether. Filtration of the cold mixture gave 2.5 g (52.5%) of the pure isopropyl ester hydrochloride with Mp.

Mp 212-213 ° C.

Analysis: Calculated for C 1 H H C N N: C 50.54, H 5.66, N 4.91%; found: C 50.49, H 5.88, N 4.95%.

Example XXX

Adamantyl-2,3-dichloro-4-3'5'-bis (dimethylaminomethyl) -4'-hy-] L

droxyJ7benzoyl-phenoxyacetate dihydrochloride.

0.95 ml of thionyl chloride was added dropwise to a suspension of 3 g of 2,3-dichloro-4-z'3'-5'-bis (dimethylamino-methyl) -4'-hydroxy-7-benzoyl, phenoxyacetic acid and 4.013 g of 1-adamantane. 3

nol in 23 cm of dimethylformamide with stirring and under nitrogen atmosphere. The slurry was heated to 70¾ to dissolve the solids. The mixture was then heated at 70 ± 3 ° C for an additional 6 hours

8005566-19 - heated, cooled to room temperature and concentrated in vacuo to a white solid. This material was taken up in water and extracted with diethyl ether. The water layer was made basic to pH 10 with concentrated ammonia. The basic solution was then extracted with dichloromethane. The dichloromethane extracts were dried over magnesium sulfate, filtered and concentrated to a gum in 3 vacuo. This gum was dissolved in 25 cm dichloromethane. The solution was then cooled in an ice bath and treated with dry hydrogen chloride gas. A white solid material was thereby formed, which then went into solution. This solution was concentrated to dryness to provide 0.928 g of the adamantyl ester dihydrochloride as a white powder with Mp. 243-244 ° C Conti. J.

Analysis: 15 calculated for ^ 32 ^ 40 ^ 4 ^ 2 ^ 5 '^ 55.45, H 6.15, N 4.17, Cl 21.12% found: C 55.43, H 6.09, N 4 .06, Cl 21.67%.

The aminomethyl derivatives of 4- (hydroxybenzoyl) -phenoxyacetic acid were prepared as follows:

These compounds are obtained by reaction of 4-20 ChydroxybenzoyPhenoxyacetic acid with 2-chloro-N- (hydroxymethyl) acetamide or other amidoalkylating agent in the presence of acetic acid and sulfuric acid, or methanesulfonic acid to form an amidoalkyl product followed by hydrolysis of the amido group to form the esters.

Example XXXI

Ethyl-2,3-dichloar-4-C 3'-aminamethyl-4'-hydroxy) -benzoyl-phenoxy-acetate hydrochloride.

2.72 g of 2-chloro-N- (hydroxymethyl) acetamide [0.022 mol) was added in small amounts to a stirred solution of 6.82 g (0.02 mol) of 2,3-dichloro-4- (4'-hydroxybenzoylphenoxyacetic acid) in 135 cm 3 of acetic acid and 15 cm 3 of concentrated sulfuric acid at 57 ° C.

The mixture was heated at 57 ° C for half an hour, then cooled to room temperature, held for 3 hours and then poured into ice water. A rubbery solid was separated in this process, which was boiled with 50 cm ethanol and 10 cm concentrated hydrogen chloride 8005565 for 20-6 hours. After evaporation to dryness in vaouo, the residue was recrystallized from ethanol and ether. After overnight cooling, a crystalline material separated which could be filtered off. More ether was added to the filtrate and the mixture was left in a cold room for several days. The solid material was collected thereon and recrystallized from ethanol and ether. Mp. 200-210 ° C. Analysis: Calculated for C 12 H 14 C 12 NOc HCl: C 49.73, H 4.17, N 3.22%; found: C 49.50, H 4.31, N 3.18%.

Example XXXII

Ethyl-2,3-dichloro-4-3'5'-bis (aminomethyl) -4'-hydroxy-benzoyl-phenoxyacetate dihydrochloride.

5.44 g of 2-chloro-N- (hydroxymethyl-acetamide (0.044 mol) was added in small amounts to a stirred solution of 6.82 g (0.02 mol) of 2,3-dichloar-4- (4-hydroxybenzoyl) phenoxyacetic acid 3 3 o in 135 cm acetic acid and 15 cm concentrated sulfuric acid of 57 C.

After stirring for half an hour at 57 ° C and 3 hours at room temperature, the mixture was poured into ice water. The gum solid 33 was separated and boiled with 100 cm ethanol and 20 cm concentrated hydrochloric acid for 10 hours. After evaporation to dryness in vacuo, the residue was recrystallized twice from ethanol and ether.

Mp. Mp 225-230 ° C (dec.).

Analysis: Calculated for cigH20 Cl2 N2 O5.2HCl: C 45.62, H 4.43, N 5.60%; Found: C 45.92, H 4.48, N 5.58%.

Example XXXIII

Ethyl-2,3-dichloro-4 ~ Z ”(3'-aminomethyl-4'-hydroxy-5'-chloro) benzoyl 7 phenoxyacetate hydrochloride.

2.59 g of 2-chloro-N- (hydroxymethyl) acetamide (0.021 mol) was added in small amounts to a stirred solution of 7.51 g (0.02 mol) of 2,3-dichloro-4- (3'-chlorine -4'-hydroxybenzoyl) pheno-xyacetic acid in 35 ml of methanesulfonic acid at 40-50 ° C. After all was added, the mixture was stirred and heated in a 95 ° C oil bath for 3.75 hours. On cooling, the mixture was poured into water, after which the solid material obtained was filtered off and with 8005566 t -21-.

water washed. This crude product was stirred and boiled with 75 ml of ethanol and 15 cm of concentrated hydrochloric acid for 5 hours. The resulting solid material was filtered off and recrystallized twice from ethanol; Mp. Mp 224-226 ° C.

Analysis: Calculated for C.Ci.cCl_NDc.HCl: C 46.08, H 3.65, N 2.99%; Found: C 45.90, H 3.69, N 2.99%.

Example XXXIV

2,3-dichloar-4- [z "3" - (2-chloaracetamido) methyl 1-4'-hydroxy J7-benzo-10-yl-phenoxyacetic acid.

5.44 g of 2-chloro-N- (hydroxymethyl) acetamide (0.044 mol) was added in small amounts to a stirred solution of 13.64 g (0.04 mol) of 2,3-dichloro-4- (4'-hydroxybenzophenoxyacetic acid in 120 cm 3 of concentrated sulfuric acid and cooled in an ice bath. The mixture was stirred overnight at room temperature and poured into 3 l of dm ice water. The impure product thereby obtained was filtered off, washed with ice water and used in the next experiment.

Example XXXV

Ethyl-2,3-dichloro-4-Z * (3'-aminomethyl-4, -hydroxy-5'-iodine) benzoyl-7-phenoxyacetate hydrochloride.

A solution of 3.57 g (0.022 mol) of iodine monochloride in 3 10 cm of acetic acid was added dropwise to a stirred solution of 8.92 g (0.02 mol) of crude 2.3-dichloro-4 - [/ ^ 3 ^ (2- Chloroacetamido) methyl 4'-hydroxy-7-benzoyl-phenoxyacetic acid in 100%

crn acetic acid from 75 - 80aC. This mixture was kept at 75 DEG-80 DEG for 20 hours

stirred and evaporated in vacuo. The residue was stirred with trituration with water and boiled with 100 cm ethanol and 20 cm concentrated hydrochloric acid for 7 hours. After cooling, the resulting product was filtered off and recrystallized from ethanol; Mp. Mp 215-218 ° C (dec.).

Analysis: Calculated for C.QHieClnIN0e.HCl: C 38.56, H 3.06, N 2.50%; 10 lb 2 b found: C 38.33, H 3.03, N 2.54%.

Example XXXVI

Ethyl-2,3-dichloro-4- (3 '-aminomethyl-4'-hydroxy) -benzoyl-phenoxy-methyl-acetate.

8 η nrka β - 22 - 11, 2-chloro-N- (hydroxymethyl) acestamide (0.09 mol) was added in small amounts to a stirred solution of 15.89 g (0.045 mol) 2.3-dichloro-4- (4'-Hydroxybenzoyl] -phenoxy-0d-3 3 methyl acetic acid in 270 cm acetic acid and 30 cm concentrated sulfuric acid at 45-50 ° C. This mixture was stirred at 45 ° C for half an hour and at room temperature for 2 hours. and poured into 1 dm ice water The gum solid formed was separated and boiled with 200 cm ethanol and 40 cm concentrated hydrochloric acid for 18 hours After evaporation to dryness in vacuo, the residue was recrystallized from ethanol and ether overnight After cooling, the solid material was filtered off. A little more ether was added to the filtrate and the solution was kept cold. This solution was decanted and evaporated to dryness in vacuo. The residue was neutralized with a potassium bicarbonate solution and extracted with methylene chloride. extracts were washed with water ss, dried with sodium sulfate and evaporated to dryness. The residue was recrystallized from ethanol} Mp. 122-124 ° C.

Analysis: calculated for C ^ gH ^ gCl ^ NOg! C 55.35, H 4.85, N 3.40%; Found: C 55.57, H 4.58, N 3.53%.

Example XXXVII

2,3-dichloro-4- / "(3'-aminomethyl-4'-hydroxy] benzoyl-7phenoxyacetic acid hydrochloride.

5.44 g of 2-chloro-N- (hydroxymethyl] acetamide (0.044 mol] was added in small amounts to a stirred solution of 13.64 g (0.04 mol) of 2,3-dichloro-4- (4'-hydroxybenzoyl ] phenoxyacetic acid 3 in 60 cm methanesulfonic acid and cooled in an ice bath.

The mixture was stirred at room temperature for 24 hours and then poured out into ice water. The resulting precipitate was filtered off, washed well with water and hydrolysed by heating with 125 cm @ 10% hydrochloric acid for 10 hours. After cooling, the crude product was collected and recrystallized from 2 N hydrochloric acid: mp. 237-240 ° C (dec. 3.

Analysis: Calculated for C 11 H 14 Cl-NQ-HCl: C 47.25, H 3.47, N 3.44%; io lo L3 found: C 47.49, H 3.51, N 3.35%.

8005566 - 23 -

Example XXXVIII

Ethyl-2,3-dimethyl-4 - / "(3'-aminomethyl-4'-hydroxy) benzoyl-phenoxyacetate hydrochloride, 1.23 g of 2-chloro-N- (hydroxymethyl) acetamide CO, 0.01 mol) was added 5 portions to a stirred solution of 3.0 g of CO, 01 mol) 2,3-dimethyl-4- (4-hydroxybenzoyl) phenoxyacetic acid in 3.3 cm concentrated sulfuric acid, under cooling with an ice bath. The mixture was stirred at ice bath temperature for 2 hours, then at room temperature for 25 hours and finally poured into ice water. The precipitate formed was filtered off, washed with water and re-

Crystallized from 1: 1 water / acetic acid. 1.24 g of the amido-3 alkylated product was cooked with 15 cm ethanol and 3 cm concentrated hydrochloric acid for 17 hours. The mixture was then evaporated to dryness in vacuo and the residue recrystallized twice from ethanol and ether to pure product, mp 204-207 ° C (Conti.).

Analysis: Calculated for? GH? NOg.HCl: C 60.99, H 6.14, N 3.56%; found: C 60.29, H 6.19, N 3.54%.

Example XXXVIII

2,3-dichloro-4-C3'-aminomethyl-4-hydroxy-5'-methyl) -benzoyl-7-phenoxyacetate hydrochloride.

1.48 g of 2-Chloro-N-Chydroxymethyl) acetamide (0.012 mol) was added in small amounts to 2,3-dichloro-4 - / ((4'-hydroxy-25 3'-methyl) benzoyl-phenoxyacetic acid in 25 cm concentrated sulfuric acid under cooling with an ice bath. The mixture was stirred at room temperature for another 17 hours and poured into ice water. The precipitate formed was filtered off, washed with water and hydrolysed by heating with 30 cm 10% hydrochloric acid for 21 hours. After cooling at room temperature, the product was collected yield 3.54 g.

The ethyl ester was obtained by passing hydrogen chloride through a stirred suspension of this acid (3.54 g) under 3 hours of cooling.

After cooling, the ethyl ester hydrochloride was filtered off and recrystallized from ethanol. Mp. 231 DEG-233 DEG C. Conti.).

Analysis: 8005566 - 24 - Calculated for C 25 g H gCl N 2 NO.HCl: C 50.85, H 4.49, N 3.12% Found: C 50.72, H 4.51, N 3, 11%.

The diuretic activity of the present compounds 5 was determined in normotensive rats. Male normotensive rats CSprague-Dawley] weighing 275 - 375 g were used in this test. Groups of eight rats were used for each dose level.

The test compound or control (suspension hiculum) was administered orally to each animal via a probe and immediately each animal was loaded with 0.9% saline (Sal) solution to 5% of body weight via an oral catheter. of the animal. The animals were then housed in separate stainless steel cages. No further food or water was administered to the 15 rats during the test. Urine volume was measured and recorded, while samples were taken at 2 hour and 6 hour intervals after administration. When dose studies were performed, the urine volume was read and recorded 1, 2, 3, 4, 5, 6 and 24 hours after administration.

Each test compound, control or dose of the test compound was tested in eight animals. As a control, the suspension medium was given (0.5% methyl cellulose] in a volume of 3.2 cm per kg body weight.

The drugs were dissolved or suspended in 0.5% methyl cellulose such that the appropriate dose is present in 2 cm per kg body weight. For routine screen tests, a dose of 100 mg per kg peroral was used.

For convenience, the compounds tested are in Table A.

identified with the volume of urine obtained at each dose level of the compound used in Table B.

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Compound Dose Route Load Time Volume thing mg / Kg hours 1 30 PO SAL 5% 0-2 4.47 / 0-6 3.23 / 0-24 1.58 / 2 100 PO SAL 5% 0-2 4, 42 / 0.00x 0-6 3.29 / 0, OOx 0-24 2.15 / 0, OOx 2-5 2.00 / 0.00x 6-24 1.05 / 0.61 30 PO SAL 5% 0-2 5.05 / 0.00x 0-6 3.47 / 0, OOx 0-24 2.15 / 0, OOx 2-6 1.66 Ό, ΟΙχ 6-24 0.88 / 0.04x 10 PO SAL 5¾ 0-2 4.81 / 0.00x 0-6 3.25 / 0.0Qx 0-24 1.93 / Ο, ΟΟχ 2-6 l, 46 / 0.03x 6-24 0.65 / 0.0Ox 3 PO SAL 5% 0-2 4.68 / 0, Ox 0-6 3.22 / 0, OOx 0-24 1.86 / 0, OOx 2-6 l, 53 / 0.02x 6- 24 0.54 / 0, OOx 1 PO SAL 5% 0-2 4.11 / 0, OOx 0-6 2.78 / 0, OOx 0-24 1.57 / 0, OOx 2-6 1.27 / 0.22 6-24 · 0.39 / 0.0x x statistically significant p-values (0.05 or less] 8005566 - 30 -

Table B (continued) 0.30 PO SAL 5% 0-2 2.41 / O, 0x 0-6 2.06 / 0.00x 0-24 1.27 / 0.01x 2-6 0.51 / 0 .00x 6-24 0.51 / 0.00x 0.10 PO SAL 5% 0-2 1.11 / 0.58 3 100 PO SAL 5% 0-2 7.20 / 0.00x 0-6 3, 34/0, OOx '2-6 1.12 / 0.46 100 PO SAL 5% 0-2 5.51 / 0, OOx'; 0-6 3.40 / 0, OOx 0-24 L, 79 / 0, Q2x 2-6 ...... O, ΑΙ / Q, OOx 30 PO SAL 5% 0-2 4.64 / 0, OOx 0-6 2.92 / 0, OOx 0-24 1.57 / 0, OOx 2-6 l, 43/0, Q3x 6-24 O, 41/0, OOx 10 PO SAL 5¾ 0-2 3.23 / 0, OOx 0-6 2.31 / 0, OOx 0- 24 1.28 / 0, OOx 2-6 1.52 / 0.06 6-24 O, 40/0, OOx 3 PO SAL 5% 0-2 l, 84 / 0.03x 0-6 1.57 / 0.0x 0-24 1.10 / 0.18 2-6 1.33 / 0.08 6-24 0.171/0.0X 1 PO SAL 5% 0-2 0.60 / 0.11 0- 6 '0.89 / 0.34 0-24 0.96 / 0.58 2-6 1.14 / 0.41 6-24 1.03 / 0.81 8005566 - 31 -

Table B [continued] 4 100 IV SAL 5% 0-2 6.16 / Ο, ΟΟχ 0-6 3.79 / 0.00x 2-6 2.15 / Ο, ΟΟχ 100 PO SAL 5% 0-2 1 .17 / 0.60 0-6 0.99 / 0.96 2-6 0.83 / 0.39 5 100 PO SAL 5% 0-2 1.64 / 0.13 0-6 1.29 / 0 .07 2-6 1.16 / 0.33 S 100 PO SAL 5% 0-2 4.05 / 0.00x 0-6 3.03 / 0.00x 2-6 1.89 / Ο .30 PO SAL 5% 0-2 '5.02 / 0.00x 0-6 2.75 / Ο, ΟΟχ 0-24 l, 52 / 0.00x 2-6 1.08 / 0.60 6-24 0.32 / 0.0Οχ 10 PO SAL 5% 0-2 3.22 / Ο, ΟΟχ 0-6 1.83 / Ο, ΟΟχ 0-24 1.13 / 0.04χ 2-6 0.80 / 0.11 6 -24 0.46 / 0.00χ 3 PO SAL 5% 0-2 1.78 / 0.01χ 0-6 1.41 / Ο, ΟΙχ 0-24 1.03 / 0.62 2-6 1.14 / 0.32 6-24 0.67 / 0.01χ 1 PO SAL 5% 0-2 0.77 / 0.30 0-6 0.99 / 0.92 7 1 PO SAL 5% 0-24 '0 .98 / 0.74 2-6 1.15 / 0.37 100 PO SAL 5% 0-2 1.33 / 0.53 0-6 1.52 / 0.02x 2-6 1.61 / Ο, 100 8 100 PO SAL 5% 0-2 1.48 / 0.20 8 0 0 5 5 6 6 0-6 l, 45 / 0.03x - 32 -

Table B [continued] 2-6 1.44 / Q, 03x 3 100 PO SAL 5% 0-2 4.76 / 0, OOx 0-6 3.11 / 0, OOx 2-6 1.90 / 0, OOx 300 PO SAL 5% 0-2 6.59 / 0, OOx 0-6 4.07 / 0, OOx 0-24 2.38 / 0, OOx 2-6 2.74 / 0, OOx 6-24 1 , 11 / 0.20 100 PO SAL 5% 0-2 7.57 / 0, OOx 0-6 4.22 / 0, OOx 0-24 2.17 / 0, OOx 2-6 2.45 / 0, OOx 6-24 O, 64/0, OOx 30 PO SAL 5¾ 0-2 6.71 / 0, OOx 0-6 3.60 / 0, OOx 0-24 1.81 / 0, OOx 2-6 1, 96/0, OOx 6-24 0.48 / 0, OOx 10 PO SAL 5% 0-2 4.62 / 0, OOx 0-6 2.54 / 0, OOx 0-24 1.36 / 0, OOx 2-6 l, 43 / 0.05x 6-24 O, 49/0, OOx 3 PO SAL 5% 0-2 3.56 / 0, OOx 0-6 1.92 / 0, OOx 0-24 1, ll / 0.04x 2-6 1.05 / 0.74 6-24 O, 50/0, OOx 10 100 PO SAL 5% 0-2 '0.71 / 0.07 0-6 0.67 / 0 .02x 2-6 0.65 / 0.05x 11 100 PO SAL 5% 0-2 0.62 / 0.03x Λ Λ Λ 0-6 0.63 / 0 .Ox 8 Ο Ο Y 5 6 6 2- 6 0.64 / 0.03χ - 33 -

Table B Continued) 12 100 PO SAL 5% 0-2 1.19 / 0.36 0-6 1.23 / 0.06 2-6 1.26 / 0.09 13 100 PO SAL 5% 0-2 0 .91 / 0.66 0-6 0.85 / 0.20 2-6 0.81 / 0.35 14 100 PO SAL 5¾ 0-2 1.09 / 0.73 0-6 1.16 / 0, 41 2-6 1.19 / 0.42 15 100 PO SAL 5% 0-2 1.38 / 0.41 '' 0-6 1.23 / 0.17 2-6 1.15 / 0.48 16 100 PO SAL 5% 0-2 5.71 / 0.00x 0-6 3.43 / 0.00x 2-6 L, 86 / 0.00x 300 PO SAL 5% 0-2 5.59 / Ο, ΟΟχ 0-6 3.36 / Ο, ΟΟχ 0-24 1.89 / Ο, ΟΟχ 2-6 1.74 / Ο, ΟΟχ 6-24 1.74 / 0.01χ 100 PO SAL 5% 0-2 5, 58 / Ο, ΟΟχ 0-5 3.11 / Ο, ΟΟχ 0-24 1.71 / Ο, ΟΟχ 2-6 1.33 / 0.05χ 6-24 0.47 / 0.00χ 30 PO SAL 5% 0-2 3.30 / 0.00χ 0-6 2.22 / Ο, ΟΟχ 0-24 1.26 / Ο, ΟΟχ 2-S 1.43 / 0.03χ 6-24 '0.42 / 0, 00χ 10 PO SAL 5% 0-2 1.34 / 0.45 0-6 1.48 / 0.01χ 0-24 1.11 / 0.13 8 0 0 5 5 6 6 2-6 6-24 0 , 77 / 0.09 - 34 -

Table B (continued) 3 PO SAL 5% 0-2 1.00 / 0.99 0-6 1.04 / 0.76 0-24 1.06 / 0.36 2-6 1.07 / 0.66 6-24 1.08 / 0.53 17 100 PO SAL 5% 0-2 4.33 / 0.00x 0-6 3.06 / 0.0x 2-6 L. 96 / 0.00x 18. 100 PO SAL 5% 0-2 0.63 / 0.35 0-6 1.00 / 0.99: '2-6 1.08 / 0.69 19 100 PO SAL 5% 0-2 0.72 / 0.13 0-6 0.76 / 0.13 2-6 0.84 / 0.36 20 100 PO SAL 5% 0-2 5.26 / 0.00x 0-6 3.39 / 0.00x 2 -6 1.99 / Ο, ΟΟχ 21 100 PO SAL 5% 0-2 0.96 / 0.82 0-6 1.35 / Q, 02x 2-6 l, 64 / 0.01x 22 100 PO SAL 5 % 0-2 0.90 / 0.56 0-6 l, 31 / 0.00x 2-6 l, 61 / Q, Q0x 23 100 PO SAL 5% 0-2 0.97 / 0.83 0-6 l, 23 / 0.02x 2-6 l, 43 / 0.04x 24 100 PO SAL 5% 0-2 0.81 / 0.23 0-6 0.98 / 0.88 2-6 1.13 / 0.62 25 100 PO SAL 5% 0-2 '0.50 / 0.00x 0-6 0.80 / 0.12 2-6 1.06 / 0.75 26 100 PO SAL 5% 0-2 5 , 07 / 0.00x ~ Λ Λ r- - «„ 0-6 3.68 / 0, OOx 8 0 0 5 5 6 6 2-5 2.23 / 0, OOx - 35 - '

Table B Continued] 27 100 PO SAL 5% 0-2 4.94 / 0, OOx 0-6 3.63 / 0, OOx 2-6 2.26 / 0, OOx 28 100 PO SAL 5% 0-2 3 .49 / 0, OOx 0-6 2.10 / 0, OOx 2-6 0.92 / 0.63 30 PO SAL 5% 0-2 l, 59 / 0.02x 0-6 l, 45/0, 01x 2-6 1.35 / 0.10 29 100 PO SAL 5% 0-2 6.19 / 0.00x '' 0-6 3.28 / 0.0x 2-6 L 53 / 0.01x 300 PO SAL 5% 0-2 5.09 / 0, OOx 0-6 3.57 / 0, OOx 0-24 2.12 / 0, OOx 2-6 2.22 / 0, OOx 6-24 0.89 / 0.47 100 PO SAL 5% 0-2 5.72 / 0, OOx 0-6 3.53 / 0, OOx 0-24 1.78 / 0, OOx 2-6 1.55 / 0.06 6 -24 O, 31/0, OOx 30 PO SAL 5% 0-2 4.07 / 0, OOx 0-6 2.71 / 0, OOx 0-24 1.42 / 0, OOx 2-6 1.49 / 0.09 6-24 O, 32/0, OOx 10 PO SAL 5% 0-2 2.22 / Q, 01x 0-6 2.04 / 0, OOx 0-24 'l, 21 / 0.04x 2-6 1.87 / 0.02x 6-24 0.51 / 0.0Xx 3 PO SAL 5% 0-2 1.06 / 0.86 0-6 l 42 / 0.05x 8 0 0 5 5 6 6 0-24 1.05 / 0.57 - 36 -

Table B (continued) 2-6 l, 74 / 0.02x 6-24 0.74 / 0.0lx 30 100 PO SAL 5% 0-2 8.21 / Ο, -6 0-6 4.57 / 0, 00x 2-6 2.23 / 0.00x 30 PO SAL 5% 0-2 5.19 / Ο, -6 0-6 3.12 / Ο, ΟΟχ 0-24 1.39 / Ο, ΟΟχ 2-6 1 , 48 / 0.07 6-24 0.30 / 0.00χ 10 ΡΟ SAL 5% 0-2 3.04 / 0.00χ 0-6 2.26 / 0.00χ 0-24 1.10 / 0 , 16 2-6 1.64 / Ο, ΟΟχ 6-24 0.38 / 0.00χ 3 PO SAL 5% 0-2 1.46 / 0.13 0-6 1.37 / 0.02χ 0-24 0.94 / 0.39 2-6 1.29 / 0.12 6-24 0.67 / 0.00χ 1 PO SAL 5% 0-2 1.27 / 0.50 0-6 1.25 / 0 .30 0-24 1.02 / 0.80 2-6 1.24 / 0.25 6-24 0.88 / 0.22 31 100 PO SAL 5% 0-2 8.75 / Ο, ΟΟχ 0- 6 4.28 / Ο, ΟΟχ 2-6 1.87 / 0.01χ 30 PO SAL 5% 0-2 5.34 / Ο, ΟΟχ Q-6 '3.28 / Ο, ΟΟχ 0-24 1.42 / Ο, ΟΟχ 2-6 1.88 / 0.04χ 6-24 0.31 / 0.00χ 10 PO SAL 5% 0-2 3.52 / Ο, ΟΟχ 8005566 - 37 -

Table B (continued) 0-6 2.11 / 0, ΟΟχ 0-24 1.17 / 0.01χ 2-6 1.16 / 0.35 6-24 0.60 / 0, Q0x 3 PO SAL 5% 0-2 1.77 / Ο, ΟΙχ 0-6 1.66 / Ο, ΟΟχ 0-24 1.20 / 0, ΟΟχ 2-6 1.59 / Ο, ΟΙχ 6-24 0.92 / 0.29 1 PO SAL 5% 0-2 1.43 / 0.25 0-6 1.56 / 0.02χ .0-24 1.12 / 0.04χ 2-6 1.65 / Ο, ΟΟχ 6-24 0 .86 / 0.15 100 PO SAL 5% 0-2 8.31 / 0.00χ 0-6 4.22 / 0, ΟΟχ 2-6 2.01 / 0, ΟΟχ 32 30 PO SAL 5% 0-2 7.15 / 0, ΟΟχ 0-6 3.48 / 0, ΟΟχ 0-24 1.49 / 0, ΟΟχ 2-6 1.00 / 0.99 6-24 Ο, 30/0, ΟΟχ 10 PO SAL 5% 0-2 4.53 / 0, -6 0-6 2.25 / 0, ΟΟχ 0-24 1.13 / 0.04χ 2-6 Ο, 70/0, Ο1χ 6-24 Ο, 46/0 , ΟΟχ 3 PO SAL 5% 0-2 1.68 / 0.04χ 0-6 1.51 / 0.01χ 0-24 '1.12 / 0.14 2-6 1.38 / 0, Ο3χ 6- 24 0.89 / 0.37 1 PO SAL 5% 0-2 1.08 / 0.75 0-6 1.23 / 0.16 8 Ο ϋ 5 5 6 6 - 38 -

Table B [continued] 0-24 1.11 / 0.08 2-6 1.34 / 0.06 6-24 1.04 / 0.62 33 100 PO SAL 5% 0-2 10.40 / 0, 00x 0-6 4.13 / 0.00x 2-6 0.84 / 0.35 30 PO SAL 5% 0-2 5.62 / Ο, -6 0-6 3.12 / 0.00x 0-24 1 .35 / 0.00x 2-6 1.14 / 0.45 6-24 0.23/0, OOx 10 PO SAL 5% 0-2 3.45/0, OOx __0-6 1.35 / 0, OOx 0-24 1.02 / 0.82 2-6 0.76 / 0.17 6-24 O, 43/0, OOx 3 PO SAL 5% 0-2 '1.92 / 0, OOx 0-6 1.71 / 0.0x 0-24 1.09 / 0.21 2-6 l, 54 / 0.01x 6-24 0.70 / 0.0x 1 PO SAL 5% 0-2 1.15 / 0 50 0-6 1.16 / 0.29 0-24 0.99 / 0.91 2-6 1.16 / 0.46 6-24 0.89 / 0.14 34 100 PO SAL 5% 0- 2 6.11 / 0, OOx 0-6 3.65 / 0, OOx 2-6 1.52 / 0.04x 35 100 PO SAL 5% 0-2 9.06 / 0, OOx 0-6 3.08 / 0, OOx 2-6 Q, 80 / 0.02x 3B 100 PO SAL 5% 0-2 5.16 / 0, OOx 0-6 3.07 / 0, OOx 8 0 0 5 5 6 6 2's i · 1 "0 · 43 - 39 --Table B [continued] 300 P0 SAL 5¾ 0-2 3.98 / 0, ΟΟχ 0-6 2.83 / 0, ΟΟχ 0-24 1.73 / 0, ΟΟχ 2- 6 1.83 / Ο, ΟΟχ 6-24 0.80 / 0.03χ 100 PO SAL 5% 0-2 4.51 / 0, ΟΟχ 0-6 2.61 / 0.00χ 0-24 1.36 / Ο, ΟΟχ 2-6 0.96 / 0.59 6-24 0.31 / 0.00χ 30 PQ 'SAL 5% 0-2 3.03 / 0.00χ 0-6 1.81 / 0.01χ 0 -24 1.00 / 0.99 2-6 0.75 / 0.13 6-24 0.32 / 0.00χ 10 PO SAL 5% 0-2 1.10 / 0.60 0- 6 1.25 / 0.05χ 0-24 1.04 / 0.33 2-6 1.38 / 0.01χ 6-24 0.86 / 0.05χ 3 PO SAL 5% 0-2 0.81 / 0.29 0-6 0.98 / 0.79 0-24 1.00 / 0.99 2-6 1.13 / 0.08 6-24 1.02 / 0.82 37 30 PO SAL 5¾ 0- 2 4.49 / Ο, ΟΟχ 0-6 2.63 / 0, ΟΟχ 2-6 1.46 / 0, ΟΟχ 30 PO SAL 5% 0-2 5.67 / 0, ΟΟχ 0-6 '3.32 / 0, ΟΟχ 0-24 1.65 / Ο, ΟΙχ 2-6 1.95 / 0, ΟΟχ 6-24 0.35 / 0.01χ 10 PO SAL 5% 0-2 2.96 / 0, ΟΟχ 8 0 0 5 5 6 6 0-6 2 · 30/0 · 00 40 - 40 -

Table B (continued) 0-24 1.38 / 0.09 2-6 1.92 / 0.0x 6-24 0.65 / 0.15 3 PO SAL 5% 0-2 L. 87 / 0.01x 0-6 1.98 / 0, OOx 0-24 1.20 / 0.34 2-6 2.04 / 0, OOx 6-24 0.60 / 0.09 1 PO SAL 5% 0-2 2, 13 / 0.01x 0-6 1.75 / 0, Olx; 0-24 1.30 / 0.17 2-6 1.52 / 0.08 6-24 0.95 / 0.82 8005566

Claims (19)

1. Compounds of formula I of the formula sheet, wherein R, CHnNR-R ', wherein Rc and Re are hydrogen, alkyl or an alkylene group 1 zbobo of 4 or 5 carbon atoms, R2 hydrogen, halogen, haloalkyl, alkyl, alkoxy, alkylthio or CH2NR5Rg, wherein Rg and Rg have the meanings shown above, Rg hydroxy, alkoxy, branched alkoxy, adamantyloxy, morpholino, amino or amino, R 4 hydrogen or alkyl substituted by alkyl or alkylene with 4 or 5 carbon atoms and and X 2 hydrogen, alkyl , halogen or when substituted on neighboring carbon atoms of the benzene ring also represent a 1,3-butadienylene bridge 10, with the proviso that X 1 and X 2 do not simultaneously represent hydrogen, and salts thereof. 2. Compounds of the formula wherein Rg is hydroxyl, alkoxy, branched alkoxy, adamantyloxy, morpholino, amino or amino, R4 hydrogen or alkyl substituted by alkyl or alkylene with 4 or 5 carbon atoms, Rg and Rg hydrogen, alkyl or alkylene of 4 or 5 carbon atoms and X 2 and X 2 hydrogen, alkyl, halogen or when substituted on neighboring carbon atoms of the benzene ring, represent a 1,3-butadienylene bridge, with the proviso that X 2 and X 2 are not both hydrogen, and the salts thereof. A compound according to claim 2, wherein Rg is ethoxy or isopropoxy, R4 is hydrogen, Rg and Rg are both methyl and X2 and X2 are each chlorine. 4. A compound according to claim 2, characterized in that Rg represents ethoxy, Rg hydrogen, Rg Rg both hydrogen and Xg and X2 both represent chlorine. 5 Rg each represent hydrogen and X ^ and Xg both represent chlorine. A compound of the formula II of the formula sheet, wherein R 2 is hydrogen, halogen, haloalkyl, alkyl, alkoxy or alkylthio, Rg hydroxy, alkoxy, branched alkoxy, adamantyloxy, morpholino, amino, or with alkyl or alkylene of 4 or 5 carbon atoms substituted amino, R 1 hydrogen or alkyl, Rg and Rg hydrogen, alkyl or alkylene of 4 or 5 carbon atoms and X 1 and X 2 hydrogen, alkyl, halogen or when substituted on neighboring carbon atoms of the 8005566 - 42 benzene ring, represent a butadienylene bridge, with the proviso that and Xg are not both hydrogen. A compound according to claim 5, characterized in that R 2 is hydrogen, R 3 ethoxy, isopropoxy or hydroxy, R 1 is hydrogen, R 8 and Compound according to claim 5, characterized in that Rg represents hydrogen, R3 ethoxy, R4 hydrogen, Rg and Rg each represent hydrogen and X ^ and Xg each represent methyl. " 8. A compound according to claim 5, characterized in that Rg methyl, R3 ethoxy, R1 hydrogen, Rg and Rg each represent hydrogen and X1 and Xg chlorine. A compound according to claim 4, characterized in that Rg hydrogen, Rg ethoxy, hydrogen, Rg and Rg each represent methyl and X 1 and Xg each represent chlorine. —- 10. A compound according to claim 5, characterized in that R 2 represents chlorine, R 3 ethoxy, R 1 hydrogen, Rg and Rg each hydrogen and X 1 and X 2 each chlorine. 11. A compound according to claim 5, characterized in that R2 iodine, Rg ethoxy, Rl hydrogen, Rg and Rg each represent hydrogen and Xl and X2 each represent chlorine. 12. A compound according to claim 5, characterized in that R 2 represents hydrogen, R 8 ethoxy, R 8 hydrogen, R 9 and R 9 each represent hydrogen and X 1 and X 2 each represent chlorine. 13. A compound according to claim 5, characterized in that R 2 hydrogen, R 1 hydroxy, R 1 hydrogen, Rg and Rg each represent hydrogen and X 1 and X 2 each represent chlorine. Compound according to claim 5, characterized in that Rg represents hydrogen, Rg ethoxy, Rg hydrogen, Rg and Rg each represent ethyl and Xl and Xg each represent chlorine. Compound according to claim 5, characterized in that Rg chlorine, Rg ethoxy, Rg hydrogen, Rg and Rg each represent methyl and Xl and X2 each represent chlorine. 16. A compound according to claim 2, characterized in that Rg represents methoxy, Rg hydrogen, Rg and Rg each methyl and Xl and Xg each chlorine. Compound according to claim 2, characterized in that Rg represents oc-8005566-43 - tyloxy, hydrogen, Rg and Rg elK methyl and and X2 elR chlorine. 18. A compound according to claim 2, characterized in that Rg represents pentoxy, Rg hydrogen, Rg and Rg each represent methyl and Xl and X2 sik chlorine. Compound according to claim 2, characterized in that Rg represents iso-butoxy, Rg hydrogen, Rg and Rg each methyl and Xj and Xj each chlorine. 8005566