DK143553B - METHOD OF ANALOGY FOR THE PREPARATION OF 1-OXO-5-INDANYLOXYDIC ACETIC ACIDS OR SALTS THEREOF WITH BASES - Google Patents

Description

| J | (12) PUBLICATION OF 143553 B

(19) DENMARK

DIRECTORATE OF

THE PATENT AND TRADEMARKET SYSTEM

(21) Application No. 5066/74 (51) | nt.CI * C 07 C 59/90 (22) Filing date 26 Sep. 1974 C 07 C 79/36 (24) Race day 26 Sep. 1974 C 07 C 101/00 (41) Aim. available Apr 12 1975 (44) Posted 7 Sep 1981 (86) International application no.

(86) International Filing Day ~ (85) Continuation Day - (62) Application No. -

(30) Priority Oct 11 1975 * 4057 ^ 6, US JO. Christmas. 1974, 492651, US

Jul 50 1974, 492652, us 50 Jul. 1974, 492655 * US

(71) Applicant MERCK & CO. INC., Rahway, US.

(72) Inventor Edward Jethro Cragoe Jr., US: Otto William Wolters «dorf jr., US: Warren Kenneth Ruse Jr., US: m.

(74) Associate Engineer Hofman-Bang & Bout ard.

(54) Analogous process for the preparation of 1-oxo-5-indanyloxyacetic acids or salts thereof with rabbits.

The present invention relates to an analogous process for the preparation of novel 1-oxo-5-indanyloxyacetic acids or salts thereof with bases which are disubstituted at the 2-position. These compounds exhibit valuable pharmaceutical properties, exhibiting diuretic, saluretic, and uricosuric activity.

QQ

Fra D From US Patent No. 3,668,241 which corresponds to German Publication No. 1,958,918 other 1-oxo-5-indanoyloxyacetic acids known as monosubstituted at the 2-position and which have been shown said to have a less diuretic and saluretic effect than the compounds of the process of the invention.

and 2 143553

The compounds of the process according to the invention have the general formula set out in the preamble to the claim. The compounds have been found to be effective diuretic and saluted agents which can be used to treat diseases that are accompanied by electrolyte and fluid retention. The compounds are also suitable for the treatment of hypertension. Moreover, these compounds are capable of maintaining the uric acid concentration in the body at a predetermined level or even causing a decrease in the uric acid concentration when administered at therapeutic doses in the usual carrier media.

Many of the diuretic and saluretic agents available so far have a tendency to cause hyperuricemia when administered, thereby excreting uric acid or sodium urate or both in the body, which can cause cases of mild to severe arthritis. The compounds prepared by the method of the invention are effective in treating such patients requiring diuretic and saluretic treatment without any risk of developing gout. When the compounds of this invention are used at appropriate doses, they also act as uricosuric agents.

The method according to the invention is characterized by the characterizing part of the claim.

Particularly preferred compounds are 1-oxo-5-indanyloxy-acetic acids and their pharmacologically acceptable salts having the structure ° y * 6 s ΧνγΗι <ί HOCCH 2 O-US 2 J - * 1a where R is alkyl of 1 to 3 carbon atoms such as methyl, ethyl , n-propyl or isopropyl, X is methyl or chloro; and X is hydrogen, chlorine or fluorine, and pharmaceutically acceptable salts thereof.

3 143553

The group of substances defined above exhibits optimal diuretic and sal-uretic activity, while not altering or reducing the uric acid concentration.

The invention relates to a number of alternative processes. According to such an embodiment, a 2-alkylation of a 1-oxo-5-indanoyloxy-acetic acid or an ester thereof of formula III is carried out with an alkylating agent of formula R Z wherein Z is halogen. This reaction is carried out e.g. by first treating the 1-oxo-5-indanyloxy-acetic acid or ester thereof with a base, e.g. an alkali metal hydride, such as sodium hydride, or an alkali metal alkoxide, e.g. potassium tert.-butoxide or sodium methoxide, or alkali metal amides such as sodium amide, lithium amide or the like. The carbanion formed is then treated with the alkylating agent R Z. Any solvent that is inert or substantially inert to the reagents used can be used. Examples of suitable solvents are 1,2-dimethoxyethane, tertiary butanol, benzene or dimethylformamide. The reaction can be carried out at a temperature between 0 ° C and 150 ° C. The reaction is generally carried out at a temperature of 0-50 ° C. The following equation illustrates this process: 4 t43553, Cl o, vW "

Rr 00CCH 2 O - base 111 2 \ R ^ Z \ vA 'R 3 00 CCH 2 O -WJJ- * if R 3 = alkyl, hydrolysis, or, y if R 3 = t-butyl, pyrolysis H00 CCH 2 0-1 112 λ where X, R and R are as defined in the claim and R is hydrogen or alkyl.

Another method of preparing the subject l-oxo-5-indanyl-oxy-acetic acids consists in the reaction of a haloacetic acid or an ester thereof having the formula: r3ooc-ch2-z having a corresponding compound 17: 5 for 956 $

VRV. x

HO- \ + R3OOC-CH2-Z

IV base \

1? 1 O

XVVVR

R500C-CH2O - * if R3 = alkyl, hydrolysis, or, if R · 3 = ψΐ-butyl, pyrolysis * HOOC-CHOO- ^ J- 2 ^ R · in which formula X, R, R, R ^ and Z has the meaning specified in the claim.

Generally, the reaction may be carried out in the presence of a base such as an alkali metal carbonate, hydroxide or alkoxide such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide or sodium methoxide. Any solvent which is inert or substantially inert to the reagents may be used and wherein reagents have an appropriate solubility. Acetone, ethanol and dimethylformamide are examples of particularly suitable solvents. The reaction can be carried out at a temperature of between 25 ° C and the boiling point of the reaction mixture. If the haloacetic acid ester is used, the formed ester is hydrolyzed to the free acid in a manner known per se. If R 1 is tert-butyl, the ester formed can be catalytically catalyzed, such as by heating in the presence of a strong acid, e.g. in the presence of p-toluenesulfonic acid, sulfuric acid or gaseous hydrogen chloride. Usually, the pyrolysis takes place by heating to a temperature of 70-140 ° C, preferably 80-100 ° C. The pyrolysis can be carried out without a solvent or in the presence of a suitable non-aqueous medium wherein the reagents have an appropriate solubility, e.g. in the presence of benzene, toluene or xylene.

If at the 2-position of the compounds of the present invention there is an alkoxy-substituted phenyl group, it can be converted into a hydroxyphenyl group in a known manner. Similarly, a nitrophenyl group at the 2-position of the present compounds can be converted into aminophenyl group in a manner known per se.

The free acids of the above formula I can be converted into non-toxic pharmacologically acceptable salts of alkali metals, alkaline earth metals, other metals and amines such as ammonia, primary and secondary amines, and quaternary ammonium hydroxides. Particularly preferred metal cations are derived from alkali metals, e.g. sodium, potassium or lithium and alkaline earth metals, e.g. calcium or magnesium, and other metals, e.g. aluminum, iron and zinc. These salts are prepared in a manner known per se. Thus, by reaction with alkali metal or alkaline earth metal hydroxides, carbonates, bicarbonates, amines or quaternary ammonium hydroxides, the acid will form the corresponding alkali metal, alkaline earth metal, amine or quaternary ammonium salt.

Pharmaceutically acceptable salts may, as mentioned, be formed from ammonia, primary, secondary or tertiary amines, or quaternary ammonium hydroxides such as methylamine, dimethylamine, trimethylamine, ethylamine, N-methylhexylamine, benzylamine, α-phenethylamine, ethylenediamine, piperidine, 1-methylpiperazine , morpholine, pyrrolidine, 1,4-dimethyl-piperazine, ethanolamine, diethanolamine, triethanolamine, tris (hydroxymethyl) aminome than, N-methylglucamine, N-methylglucosamine, ephedrine, procaine, tetramethylammonium hydroxide, tetraethylammonium hydroxide or benzyl

The above salts are particularly suitable as parenteral solutions as they are highly soluble in pharmaceutical carriers such as water or alcohol.

7 143553

The present compounds contain an asymmetric carbon atom at the 2-position of the indanyl ring, and the optically active antipodes can be separated, e.g. by the methods described below. Thus, the invention encompasses not only the preparation of the racemic 1-oxo-5-indanyloxy acetic acids, but also the preparation of their optically active antipodes.

The separation of the optical isomers of the racemic acids may be accomplished by forming a salt of the racemic mixture with an optically active base such as (+) or (-) amphetimine, (-) - cinchonidine, dehydroabietylamine, (+) or (- ) -α-methylbenzylamine, (+) or (-) - α- (1-naphthyl) ethylamine, brucine or strychnine, in a suitable solvent such as methanol, ethanol, 2-propanol, benzene, acetonitrile, nitromethane or acetone. In this way, two diastereomeric salts are obtained in the solution, one of which is usually more soluble in the solvent than the other. Repeated recrystallizations of the crystalline salt will usually yield the pure diastereomer. The optically pure compound is obtained by acidification of the salt with a mineral acid, extraction in ether, evaporation of the solution and recrystallization of the optically pure antipode.

The second optically pure antipode can generally be obtained by using a second base to form the diastereomeric salt.

It is advantageous to isolate the partially cleaved acid from the filtrate after the separation of one diastereomeric salt and further purify this substance using the other optically active base.

The process according to the invention will be illustrated in the following with the aid of some exemplary embodiments.

EXAMPLE 1

Preparation of (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) -acetic acid ________________________________________________________

Step A; 2,5-dichloro-4-phenylacetylanisol

To a mixture of 2,3-dichloroanisole (62 g, 0.35 mole), phenylacetyl chloride (54 g, 0.35 mole) and carbon disulfide (250 ml) is added portionwise aluminum chloride (47 g, 0.35 mole) under cooling to 0-5 ° C. The reaction mixture is left at 25 ° C for 17 hours, the carbon disulfide removed and the residue treated with ice-water and concentrated hydrochloric acid (50 ml) to give 68.8 g of 2,3-dichloro-4-phenylacetylanisole, which melts at 126-129 ° C after recrystallization from benzene: cyclohexane, 2: 1.

Elemental analysis for C15H12C12 ° 2:

Calculated: C 61.04 - H 4.10.

Found: C, 61.46 - H, 4.11.

Step B: 2.5-Dichloro-4- (2-phenylacryloyl) anisole

Acetic anhydride (100 ml) is added dropwise to a suspension of 2,3-dichloro-4-phenylacetylanisole (29.5 g, 0.01 mol) in bis (dimethylamino) methane (100 ml) under nitrogen and cooling to maintain a The reaction mixture is stirred at 25 ° C for 2 hours and then poured into ice water (1500 ml) to precipitate 7.4 g of 2,3-dichloro-4- (2-phenylacryloyl) anisole, which melts at 87 -89 ° C.

Elemental analysis for C16H12C12 ° 2:

Calculated: C 62.56 - H 3.94

Found: C, 62.67 - H, 4.04.

Step C: 2-Phenyl-5-methoxy-6,7-dichloro-1-indanone 2,3-dichloro-4- (2-phenylacryloyl) anisole (7.4 g, 0.024 mol) is added portionwise to cold concentrated sulfuric acid (150 ml) with stirring; The reaction mixture is stirred in an ice bath for 2 hours and then dripped to ice water to precipitate 3.91 g of 2-phenyl-5-methoxy-6,7-dichloro-1-indanone, which melts at 195 - 195 ° C after recrystallization from benzene: cyclohexane, 1: 2.

9 143553

Elemental Analysis for C16 H12 Cl2202:

Calculated: C 62.56 - H 5> 94.

Found: C 62.84 - H 4.00.

Step D: 2-Phenyl-5-hydroxy-6,7-dichloro-1-indanone

A mixture of 2-phenyl-5-methoxy-6,7-dichloro-1-indanone (3> 91 g> 0.0127 mol) and pyridine hydrochloride (40 g) is heated to 190 ° C for 1 hour and then poured into water (600 ml). The precipitated 2-phenyl-5-hydroxy-6,7-dichloro-1-indanone (2.48 g) melts at 250-252 ° C after recrystallization from ethanol: water, 2: 1.

Elemental analysis for 0-1202202:

Calculated: C 61.46 - H 3> 44

Found: C 60.94 - H 3.66.

Step E: (1-oxo-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid 2-phenyl-5-hydroxy-6,7-dichloro-1-indanone (5.86 g, 0.023 mol), iodoacetic acid (4.28 g, 0.023 mol), potassium carbonate (3.04 g, 0.022 mol) and acetone (250 ml) are heated to reflux for 48 hours. The reaction mixture is cooled to 25 ° C, evaporated in vacuo to give a solid which is dissolved in water and acidified with 6N hydrochloric acid to precipitate 6.8 g of a mixture of (1-oxo-2-phenyl-6.7 -dichloro-5-indanyloxyacetic acid and 2-phenyl-5-hydroxy-6,7-dichloro-1-indanone. The 5-hydroxy compound is removed by recrystallization from nitromethane. Evaporation of the filtrate to dryness in vacuo and eluting with toluene gives 470 mg of (1-oxo-2-phenyl-6,7-dichloro-5-indanyl-oxy) acetic acid, melting veo 181-185 ° C.

El ementa ranaly see for C17H12C12 ° 4;

Calculated: C 58.14 - H 3.45 - Cl 20.19

Found: C 58.17 - H 3.54 - Cl 19.94.

Step F: (1-oxo-2-phenyl-2-methyl-6,7-dichloro-5-indanyloxy) - acetic acid

A solution of (1-oxo-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid (0.351 g, 0.001 mol) in dimethylformamide (7 ml) is cooled in an ice bath and then treated with sodium hydride (0.084 g of a 57 % oil dispersion, 0.002 mol) and stirred for 2 hours. Methyl iodide (1 ml) is added and the reaction mixture is stirred at 25 ° C for 2 hours, poured onto ice water and acidified with dilute aqueous hydrochloric acid to give (1-oxo-2-phenyl-2-methyl-6). 7-dichloro-5-indanyloxyacetic acid, melting at 168-169 ° C.

EXAMPLE 2

IlrS ^ I ^ LSSI Xil ^ ^ ^ -phenyl-T-S-dichloro ^ indanyloxyle acid

Step A: 2f, 3'-dichloro-4r-methoxyisobutyrophenone

A mixture of 2,3-dichloroanisole (100 g, 0.565 mol) and isobutyryl chloride (66 g, 0.62 mol) in methylene chloride (400 ml) is cooled to 5 ° C and treated with aluminum chloride (83 g, 0.62 mol) over 1 hour. The reaction mixture is allowed to warm at 25 ° C and poured after 24 hours into 400 ml of ice water and 30 ml of hydrochloric acid. The organic phase is washed with 5% sodium hydroxide solution, water, dried over magnesium sulfate and distilled under reduced pressure to give 68 g of 2 ', 3'-dichloro-41-methoxyisobutyrophenone, distilled at 120-130 ° C / 0.5 mmHg.

Elementary analysis for

Calculated: C, 53.46 - H, 5.89

Found: C 54.25 - H 5.07.

Step B: 2-bromo-2 *, 3 * -dichloro-41-methoxyisobutyrophenone

A solution of 2 ', 3'-dichloro-4'-methoxyisobutyrophenone (45 g, 0.183 mol) in 150 ml acetic acid is treated with bromine (30 g, 0.187 mol) over 1/2 hour. The reaction mixture is stirred for 10 minutes, then poured into 600 ml of ice water containing 2 g of sodium bisulfite.

The separated 2-bromo-2 *, 3'-dichloro-4'-methoxyisobutyrophenone (48g) melts at 72-73 ° C after recrystallization from hexane.

Elemental analysis for 0Ί -, Ηη Ί BrCl? 0 ?:

Calculated: C 40.52 - H 3.40

Found: C, 40.68; H, 3.38.

11 143963

Step C: 2-Methylene-2 *, 3 * -dichloro-4 * -methoxyproolonehenone

A solution of 2-bromo-2 ', 31-dichloro-41-methoxyisobutyrophenone (32 g, 0.1 mol) and anhydrous lithium bromide (17.4 g, 0.2 mol) in dimethylformamide (200 ml) is stirred at 95 ° C in an inert atmosphere for 3 hours and poured into ice water (500 ml). The separated 2-methylene-2r, 3t-dichloro-4'-methoxypropiophenone melts at 59 ° C after recrystallization from petroleum ether.

Elemental Ranalysis for ^ 11 ^ 0 ^^ 2 ^ 3:

Calculated: C, 53.90 - H, 4.11

Found: C, 53.72; H, 4.11.

Step D: 2-methyl-5-methoxy-6,7-dichloro-1-indanone

A solution of 2-methylene-2 *, 3'-dichloro-41-methoxypropiophenone (40 g, 0.163 mol) in concentrated sulfuric acid (75 ml) is left at 25 ° C for 24 hours and then slowly poured under vigorous stirring into ice water ( 500 ml). The separated 2-methyl-5-methoxy-6,7-dichloro-1-indanone (40 g) melts at 129 ° C after recrystallization from methylcyclohexane.

Elemental analysis for C11H10C12 ° 2:

Calculated: C, 53.90 - H, 4.11

Found: C, 53.84; H, 4.00.

Step E: 2-methyl-2-phenyl-5-methoxy-6,7-diohloro-1-indanone

Potassium tert-butoxide (8.42 g, 0.075 mol) is dissolved in tert-butanol (300 ml) and added to a boiling solution of 2-methyl-5-methoxy-6,7-dichloro-1-indanone ( 12.26 g, 0.05 mole), refluxed for 2 hours, then a suspension of diphenyl iodonium chloride (19.0 g, 0.06 mole) in tert-butanol (1 liter) is added, and the reflux is continued for 2 hours. The reaction mixture is cooled to 25 ° C, 300 ml of water is added and the mixture is evaporated to dryness in vacuo to give 4.97 g of 2-methyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone, which melts at 16-16 C after recrystallization from benzene: cyclohexane, 1: 2.

Elemental analysis for ci7Hi4C1202:

Calculated: C 63.57 - H 4.39 Found: C 63.24 - Ή 4.68.

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Step F: 2-methyl-2-phenyl-5-hydroxy-6,7-dichloro-1-indanone

A mixture of 2-methyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone (4.94 g, 0.015 mol) and pyridine hydrochloride (50 g) is heated to 175 ° C for 1 hour and is then poured into water (500 ml). The separated 2-methyl-2-phenyl-5-hydroxy-6,7-dichloro-1-indanone (2.05 g) melts at 194 - 196 ° C after recrystallization from ethanol: water, 2: 1.

Elemental analysis for Cl6H12C12 ° 2i

Calculated: C 62.56 - H 5.94 Found: C 62.60 - H 4.11.

Step G: (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid

A mixture of 2-methyl-2-phenyl-5-hydroxy-6,7-dichloro-1-indanone (2.05 g, 0.0067 mol), potassium carbonate (1.85 g, 0.0134 mol) and ethyl bromoacetate (2.23 g, 0.0134 mol) in dimethylformamide (30 ml) is heated to 55 - 60 ° C for 3 hours and then treated with potassium hydroxide (0.97 g, 0.0147 mol) dissolved in a minimal amount water in 30 ml of methanol and heated on a steam bath for 2.5 hours. The reaction mixture is poured into 500 ml of water, acidified with 6N hydrochloric acid and the precipitate is collected after rubbing off with ether-petroleum ether and dried to give 1.31 g of (1-oxo-2-methyl-2-phenyl-6,7-dichloro). 5-indanyloxyacetic acid, which melts at 168 - 169 ° C after recrystallization of acetic acid: water, 1: 1.

Elemental analysis for C18H14C12 ° 4:

Calculated: C 59.20 - H 3.86 Found: C 58.94 - H 4.20.

Example 3, Preparation of [1-oxo-2- (4-chlorophenyl) -2-methyl-6,7-dichloro-5-indanylbxy] acetic acid hemihydrate

Step A: 2- (4-Chlorophenyl) -2-methyl-5-methoxy-6,7-dichloro-1-indanone

Potassium tert.-butoxide (2.81 g, 0.025 mol) dissolved in tert-butanol (150 ml) is added to a solution of 2-methyl-5-methoxy-6,7-dichloro-1-indanone (4 , 90 g, 0.02 mole) in tert-butanol (100 ml) -benzene (200 ml), keeping the mixture under reflux for 3 hours, then 4,41-dichloro-diphenyliodonium chloride (11.55 g, 03 mol) is added, 13 143 SE 3 and the reflux is continued for 2 hours. The reaction mixture is cooled to 25 ° C, 100 ml of water is added, and the mixture is concentrated to dryness in vacuo to give 4.30 g of 2- (4-chlorophenyl) -2-methyl-5-methoxy-6,7-dichloro-1- indanone, melting at 176 - 178 ° C after recrystallization from cyclohexane: benzene, 5: 1.

Step B; 2- (4-chlorophenyl) -2-methyl-5-hydroxy-6,7-dichloro-l-indanone

A mixture of 2- (4-chlorophenyl) -2-methyl-5-methoxy-6,7-dichloro-1-indanone (4.15 g, 0.012 mol) and pyridine hydrochloride (40 g) is heated to 180 ° C for 1 hour. and then poured into 500 ml of water. The separated 2- (4-chlorophenyl) -2-methyl-5-hydroxy-6,7-dichloro-1-indanone (3.11 g) melts at 211 - 213 ° C after recrystallization from ethanol: water, 1: 1 .

Elemental analysis for C16H11C13 ° 2!

Calculated: C 56.25 - H 3.25 Found: C 55.53 - H 3.23.

Step C: [1-Oxo-2- (4-chlorophenyl) -2-methyl-6,7-dichloro-5-indanyl-oxy] acetic acid hemihydrate

A mixture of 2- (4-chlorophenyl) -2-methyl-5-hydroxy-6,7-dichloro-1-indanone (2.95 g, 0.00863 mol), potassium carbonate (2.26 g, 0.0163 mole) and ethyl bromoacetate (2.72 g, 0.0163 mole) in dimethylformamide (50 ml) are heated to 55 - 60 ° C for 10 hours, then treated with water (50 ml) -ion sodium hydroxide solution (2.5 ml , 0.025 mol) and heated to 80 ° C for 1 hour. The reaction mixture is slowly added to water (500 ml) -12N hydrochloric acid (10 ml) to precipitate 1.37 g of [1-oxo-2- (4-chlorophenyl) -2-methyl-6,7-dichloro-5-indanyloxy] -acetic acid hemihydrate melting at 141 - 142 ° C after recrystallization of acetic acid: water, 1: 1.

Elemental Analysis for Ο- ^ Η- ^ ΟΙ ^ Ο ^ Ί / ^ Ι ^ Ο:

Calculated: C 52.90 - H 3.45 - Cl 26.03

Found: C 52.47 - H 3.45 - Cl 26.11.

EXAMPLE 4

Preparation of [1-oxo-2- (4-methoxyphenyl) -2-methyl-6,7-dichloro-5-indanyloxy] acetic acid ________________________________________

Step A: 2-methyl-5-hydroxy-6,7-dichloro-1-indanone

A mixture of 2-methyl-5-methoxy-6,7-dichloro-1-indanone (30.0 g, 0.123 mol) and pyridine hydrochloride (270 g) is heated to 180 ° C for 1 hour and then poured into water (1500 ml). The separated 2-methyl-5-hydroxy-6,7-dichloro-1-indanone (27.6 g) melts at 224-230 ° C and is used without further purification.

Step B: 2-methyl-5-benzyloxy-6,7-dichloro-1-indanone

A solution of 2-methyl-5-hydroxy-6,7-dichloro-1-indanone (27.6 g, 0.12 mol), potassium carbonate (24.9 g, 0.18 mol) and benzyl bromide (21.4 in dimethylformamide (100 ml) is heated to 55 -60 ° C for 2 hours and then poured into water (1 liter) to precipitate 35.5 g of 2-methyl-5-benzyloxy-6.7 -dichloro-1-indanone, which melts at 153 - 155 ° C after recrystallization from benzene: hexane, 3: 2.

Elemental analysis for cxyHi4C12 ° 2:

Calculated: C 63.57 - H 4.39 Found: C 64.28 - H 4.61.

Step C: 2- (4-Methoxyphenyl) -2-methyl-5-benzyloxy-6,7-dichloro-1-indanone

Potassium tert.-butoxide (8.42 g, 0.075 mol) dissolved in tert-butanol (450 ml) is added to a boiling solution of 2-methyl-5-benzyl-oxy-β, 7-dichloro-1-indanone (16.1 g, 0.05 mol) in tert-butanol (150 ml) -benzene (600 ml), continuing to boil for 2.5 hours, then 4,4-dimethoxydiphenyliodonium chloride (37.66 g, 0 (10 mol) is added and the refluxing is continued for 3 hours. The reaction mixture is cooled to 25 ° C, 500 ml of water is added and the mixture is evaporated in vacuo to give a brown oil which, by ether extraction, drying over anhydrous magnesium sulfate, removing the ether and chromatography of the residue on silica gel with chloroform gives 3.44 g of 2- (4-methoxyphenyl) -2-methyl-5-benzyloxy-6,7-dichloro-1-indanone, which melts at 115 - 119 ° C and further purification is used over time.

143553

Step D: 2- (4-Methoxyphenyl) -2-methyl-5-hydroxy-6,7-dichloro-1-indanone 2- (4-methoxyphenyl) -2-methyl-5-benzyloxy-6.7 dichloro-1-indanone (3.44 g, 0.008 mol) is hydrogenated in absolute ethanol (500 ml) over 5% palladium on carbon (500 mg) in a Parr apparatus at 25 ° C for 4 hours. The reaction mixture is filtered and evaporated in vacuo to give 2.6 g of 2- (4-methoxyphenyl) -2-methyl-5-hydroxy-6,7-dichloro-1-indanone, which melts at 149 - 156 ° C and used without further purification.

Step E: [1-oxo-2- (4-methoxyphenyl) -2-methyl-6,7-dichloro-5-indanyl] acetic acid

A mixture of 2- (4-methoxyphenyl) -2-methyl-5-hydroxy-6,7-dichloro-1-indanone (2.6 g, 0.0077 mol), potassium carbonate (2.14 g, 0.0154 mole) and ethyl bromoacetate (2.58 g, 0.0154 mole) in dimethylformamide (60 ml) are heated to 55 - 60 ° C for 2.5 hours and then treated with water (60 ml) -10 N sodium hydroxide solution (5 ml, 0.05 mol) and heated to 100 ° C for 1 hour. The reaction mixture is slowly added to crushed ice and water (600 ml) -12 N hydrochloric acid (20 ini) to precipitate 1.69 g of [1-oxo-2- (4-methoxyphenyl) -2-methyl-6,7-dichloro-2 5-indanoyloxy] acetic acid, which melts at 173 - 175 ° C after recrystallization from nitromethane.

Element Ran Analysis for C19H16C12 ° 5:

Calculated: C 57> 74 - H 4.08 Found: C 57.35 - H 4.31.

EXAMPLE 5

Preparation of [1-oxo-2- (4-hydroxyphenyl) -2-methyl-6,7-dichloro-5-indanyloxy] acetic acid ___________________________________________

A mixture of [1-oxo-2- (4-methoxyphenyl) -2-methyl-6,7-dichloro-5-indanyloxy] acetic acid (1.80 g, 0.0046 mol), prepared as described in Example 4, Step E, 48% hydrobromic acid (50 ml) and acetic acid (50 ml are heated under reflux for 1 hour and then poured onto crushed ice-water (800 ml) to precipitate 900 mg of [1-oxo-2- (4-hydroxy) phenyl) -2-methyl-6,7-dichloro-5-indanyloxyacetic acid, which melts at 220-222 ° C after recrystallization of acetic acid: water, 1: 1, and nitromethane.

Elemental analysis for C18H14C12 ° 5'1 / 3CH3NO2:

Calculated: C 54.84 - H 5.77 - N 1.16

Found: C 54.58 - H 5.93 - N 0.94.

EXAMPLE 6

Preparation of [1-oxo-2- (4-fluorophenyl) -2-methyl-6,7-dichloro-5-indanyloxy] acetic acid __________________________________________

Step A: 2- (4-Fluorophenyl) -2-methyl-5-methoxy-6,7-dichloro-1-indanone

Potassium tert-butoxide (3> 38 g, 0.03 mol) dissolved in tert-butanol (150 ml) is added to a boiling solution of 2-methyl-5-methoxy-6,7-dichloro-1-indanone (4.90 g, 0.02 mol) in tert-butanol (50 ml) -benzene (200 ml), refluxed for 3 hours, then 4,4'-difluorodiphenyliodonium chloride (10.58 g, 0 (03 mol) is added and the reflux is continued for 2.5 hours. The reaction mixture is cooled to 25 ° C, 100 ml of water is added and the mixture is evaporated to dryness in vacuo to give 1.24 g of 2- (4-fluorophenyl) -2-methyl-5-methoxy-6,7-dichloro-1 indanone which melts at 163 - 170 ° C after treatment with ether-hexane and is used without further purification.

Step B; 2- (4-fluorophenyl) -2-methyl-5-hydroxy-6,7-dichloro-l-indanone

A mixture of 2- (4-fluorophenyl) -2-methyl-5-methoxy-6,7-dichloro-1-indanone (1.2 g, 0.00354 mol) and pyridine hydrochloride (12 g) is heated to 180 ° C. for 1 hour and then pour into water (500 ml).

The resulting 2- (4-fluorophenyl) -2-methyl-5-hydroxy-6,7-dichloro-1-indanone melts at 193 - 200 ° C and is used without further purification.

Step C; [L-oxo-2- (4-fluorophenyl) -2-methyl-6,7-dichloro-5-indanyl-oxy] eddikesyre_

A mixture of 2- (4-fluorophenyl) -2-methyl-5-hydroxy-6,7-dichloro-1-indanone (1.04 g, 0.0032 mol), potassium carbonate (0.885 g, 0.0064 mol) and ethyl bromoacetate (1.07 g, 0.0064 mol) in dimethylformamide (30 ml) are heated to 55 - 60 ° C for 3 hours and then treated with water (30 ml) -10N sodium hydroxide solution (1 mol, 0.01 mol) and heated to 80 ° C for 1 hour. The reaction mixture is slowly added to water (500 ml) -12N hydrochloric acid (10 ml) to precipitate 450 mg of [1-oxo-2- (4-fluorophenyl) -2-methyl-6,7-dichloro-5-indanyloxy] vinegar acid which melts at 150 - 156 ° C after recrystallization from ethyl acetate: hexane, 1: 3.

Elementary analysis for (^ 18 ^ 13 ^ 2 ^ 41

Calculated: C 56.42 - H 3.42 - Cl 18.50

Found: C 56.30 - H 3.65 - Cl 18.57.

EXAMPLE 7

Preparation of (1-oxo-2-ethyl-2-phenyl-6,7-dichloro-5-indanyloxy) -acetic acid

Step A: 2-Ethyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone

Sodium methoxide (1.24 g, 0.023 mol) is added portionwise with stirring to a mixture of 2-phenyl-5-methoxy-6,7-dichloro-1-indanone (4.61 g, 0.015 mol), iodoethane (15.5 ml, 0.15 mol), benzene (60 ml) and dimethylformamide (60 ml) under nitrogen in an ice-water bath. The reaction mixture is allowed to stand at room temperature for 1 hour and then poured into a liter of water, the benzene layer is separated, dried over anhydrous magnesium sulfate and evaporated in vacuo to give 3.23 g of 2-ethyl-2-phenyl-5-methoxy-6,7-dichloro. -1-indanone, melting at 139-141 ° C after recrystallization from benzene: hexane, 1: 1.

Elemental analysis for ciqhi6c12 ° 2:

Calculated: C 64.49 - H 4.81 Found: C 64.73 - H 4.99 ·

Step B: 2-Ethyl-2-phenyl-5-hydroxy-6,7-dichloro-1-indanone

A mixture of 2-ethyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone (3.01 g, 0.009 mol) and pyridine hydrochloride (35 g) is heated to 175 ° C for 1/2 hour and then poured into water (350 ml). The separated 2-ethyl-2-phenyl-5-hydroxy-6,7-dichloro-1-indanone (2.64 g) melts at 177 - 179 ° C.

Elemental analysis for C17 H14 Cl2 ° 2:

Calculated: C 63.57 - H 4.39 Found: C 63.73 - H 4.81.

18 143553

Step C: (1-oxo-2-ethyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid

A mixture of 2-ethyl-2-phenyl-5-hydroxy-6,7-dichloro-1-indanone (2.6 g, 0.008 mole), potassium carbonate (2.24 g, 0.016 mole) and ethyl bromoacetate (2 (71 g, 0.016 mol) in dimethylformamide (40 ml) is heated to 55 - 60 ° C for 2.5 hours and then treated with water (40 ml) -10 N sodium hydroxide solution (3 ml, 0.03 mol) and heated to 100 ° C for 1 hour. The reaction mixture is slowly added to water (600 ml) -12 N hydrochloric acid (10 ml) to form a gummy remnant which after drying and evaporation in vacuo gives 2.16 g (1-oxo-2-ethyl-2-phenyl-6 , 7-cichloro-5-indanyloxyacetic acid, melting at 187-189 ° C.

Elemental analysis for C19H16Cl2 ° 4:

Calculated: C 60.18 - H 4.25 Found: C 59.76 - H 4.24.

EXAMPLE 8

Preparation of 1-oxo-2-methyl-2- (4-nitrophenyl) -6,7-dichloro-5-acetic acid

Step A; 2-methyl-2- (4-nitrophenyl) -5-methoxy-6,7-dichloro-l-indane

Amyl nitrate (40 ml) is added in 10 ml portions at two hour intervals to 2-methyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone (9.36 g, 0.03 mol) in polyphosphoric acid ( 150 g) at 50 - 60 ° C with stirring. The total heating period is 8 hours. The reaction mixture is treated with crushed ice and water to precipitate 4.82 g of 2-methyl-2- (4-nitrophenyl) -5-methoxy-6,7-dichloro-1-indanone, which melts at 179 - 180 ° C after recrystallization of butyl chloride.

19 143553

Elemental Ran Analysis for C

Calculated: C 55.76 - H 5.58 - N 3.82

Found; C, 55.83; H, 3.66; N, 3.85.

Step B: 2-methyl-2- (4-nitrophenyl) -5-hydroxy-6,7-dichloro-1-indanone

A mixture of 2-methyl-2- (4-nitrophenyl) -5-methoxy-6,7-dichloro-1-indanone (4.82 g, 0.013 mol) and pyridine hydrochloride (50 g) is heated to 175 ° C for 1 hour. / 2 hours and then poured into crushed ice and water (1 liter) The separated 2-methyl-2- (4-nitrophenyl) -5-hydroxy-6,7-dichloro-1-indanone (4.42 g) melts at 268-270 ° C after recrystallization from ethanol.

Elemental Analysis for C16H11G12I®4:

Calculated: C 54.57 - H 3.15 - N 3.98

Found: C, 54.18; H, 3.27; N, 4.66.

Step C: [1-Oxo-2-methyl-2- (4-nitrophenyl) -6,7-dichloro-5-indanyl-oxide]

A mixture of 2-methyl-2- (4-nitrophenyl) -5-hydroxy-6,7-dichloro-1-indanone (4.4 g, 0.0126 mol), potassium carbonate (3.49 g, 0.0252 mole) and ethyl bromoacetate (4.21 g, 0.0252 mole) in dimethylformamide (150 mL) are heated to 55 - 60 ° C for 3 hours and treated with water (150 mL) -10N sodium hydroxide solution (7.5 mL, 0.075 mole ) and heated to 100 ° C for 1.5 hours. The reaction mixture is slowly added to 1 liter of water and 15 ml of 12N hydrochloric acid to precipitate 2.44 g of [1-oxo-2-methyl-2- (4-nitrophenyl) -6 7-Dichloro-5-indanyloxy] acetic acid, which melts at 202-205 ° C after recrystallization from nitromethane.

Elemental analysis for C- QHH ^C CNOg;

Calculated: C 52.70 - H 3.19 - N 3.41

Found: C 52.72 - H 3.16 - N 3.30.

EXAMPLE 9

Preparation of [1-oxo-2- (4-aminophenyl) ~ 2-methyl-6,7-dichloro-5- [1-oxo-2-methyl-2- (4-nitrophenyl) -6,7-dichloro] -5-indanyloxyacetic acid (6.11 g, 0.015 mol) in absolute ethanol (250 ml) -36N sulfuric acid (2 ml) is hydrogenated over 5% palladium-on-carbon (500 mg) in a Parr. apparatus. After 1 hour, the reaction mixture is filtered, which is then concentrated in vacuo to a volume of 50 ml. 200 ml of water are added to precipitate the ethyl ester, which is hydrolyzed by refluxing in 200 ml of ethanol, 1N sodium hydroxide solution (4.5 ml), 0.045 mol) and 100 ml of water for 1.5 hours. The reaction mixture is cooled, evaporated to a third volume, filtered, then neutralized with 6N hydrochloric acid to precipitate 1.09 g of [1-oxo-2- (4-aminophenyl) -2-methyl-6,7-dichloro-5-indanyloxy] acetic acid, melting at 235 - 236 ° C, dec.

Elemental analysis for C- gHH CC ^NO::

Calculated: C 56.86 - H 3.98 - N 3.68

Found: C 56.46 - H 4.04 - N 3.62.

EXAMPLE 10

Preparation of [1-oxo-2- (4-bromophenyl) -2-methyl-6,7-dichloro-5-indanyloxy] acetic acid __ __ ______

Step A: 2,3-Dichloro-4- (4-bromophenyl) acetylanisole

To a mixture of 2,3-dichloroanisole (73.5 g, 0.414 mole), 4-bromo-phenylacetyl chloride (105 g, 0.456 mole) and carbon disulfide (300 ml) is added portionwise aluminum chloride (60.9 g, 0.456 mole) under cool to 0 - 5 ° C. The reaction mixture is left at 25 ° C for 17 hours, then rinsed with nitrogen, and the solid residue is treated with crushed ice and 80 ml of 12N hydrochloric acid to give 147.7 g of 2,3-dichloro-4 - (4-bromophenyl) acetylanisole, which melts at 163 - 164.5 ° C after recrystallization from benzene rhexane, 1: 1.

Elemental Analysis for C

Calculated: C 48.16 - H 2.96 Found: C 48.38 - H 3.10.

Step B: 2 *, 3R-Dichloro-4'-methoxy-2- (4-bromophenyl) acrylophenone

To a suspension of 2,3-dichloro-4- (4-bromophenyl) acetylanisole (142.5 g, 0.38 mol) in bis-dimethylaminomethane (325 ml) under nitrogen is added dropwise 325 ml of acetic anhydride under cooling to maintain the reaction mixture. temperature below 40 ° C.

21 143563

The reaction mixture is stirred at 25 ° C for one hour, then poured into 4 liters of ice water to precipitate 143 g of 2 ', 3'-dichloro-41-methoxy-2- (4-bromophenyl) acrylophenone, which melts at 110 - 116 ° C after recrystallization from benzene: hexane, 1: 5.

Elemental analysis for:

Calculated: C 49.78 - H 2.87 Found: C 49.73 - H 2.88.

Step C: 2- (4-bromophenyl) -5-methoxy-6,7-dichloro-1-indanone 2 *, 3'-dichloro-4 * -methoxy-2- (4-bromophenyl) acrylophenone (143g, O , 37 mol) dissolved in 2 liters of dichloromethane is showered in a mixture of 1 liter of cold 36N sulfuric acid and 1 liter of dichloromethane in an ice bath over 4 hours. After stirring for an additional half hour, the reaction mixture is slowly added to crushed ice, the dichloromethane layer is separated, washed with saturated brine and evaporated in vacuo to give 134.8 g of 2- (4-bromophenyl) -5-methoxy-6,7-dichloro. 1-indanone, melting at 202 - 203 ° C after tearing off with water, followed by recrystallization from benzene: hexane, 1: 1.

Elemental analysis for C 2 H 6 Br 2

Calculated: C 49.78 - H 2.87 Found: C 50.46 - H 3.07.

Step D: 2- (4-Bromophenyl) -2-methyl-5-methoxy-6,7-dichloro-1-indanone

Sodium methoxide (28.4 g, 0.522 mol) is added with stirring to a mixture of 2- (4-bromophenyl) -5-methoxy-6,7-dichloro-1-indanone (134.6 g, 0.348 mol), iodomethane ( 217 ml, 3.48 mol), dry benzene (1700 ml) and dry dimethylformamide (1700 ml) under nitrogen on an ice-water bath. The reaction mixture is allowed to warm to room temperature over 2 hours and then poured into 8 liters of water to precipitate 92.2 g of 2- (4-bromophenyl) -2-methyl-5-methoxy-6,7-dichloro-1-indanone , m.p. 200-203 ° C, which is not soluble in benzene.

Elemental Analysis for Ζ- ^ Ά - ^, να ^ 2 '

Calculated: C 51.03 - H 3.28 Found: C 50.71 - H 3.24.

143553 22

Step E: 2- (4-Bromophenyl) -2-methyl-5-hydroxy-6,7-dichloro-1-indarione

A mixture of 2- (4-bromophenyl) -2-methyl-5-methoxy-6,7-dichloro-1-indanone (5.0 g, 0.0125 mol) and pyridine hydrochloride (50 g) is heated to 185 ° C for 1 hour and poured on crushed ice and water (500 ml).

The separated 2- (4-bromophenyl) -2-methyl-5-hydroxy-6,7-dichloro-1-indanone (4.68 g) melts at 221 - 223 ° C after recrystallization from ethanol.

Elemental Ran Analysis for O ^ gH- ^ BrCl ^ O ^:

Calculated: C 49.78 - H 2.87 Pound: C 49.18 - H 2.87

Step F: [1-Oxo-2- (4-bromophenyl) -2-methyl-6,7-dichloro-5-indanyl-oxy) acetic acid

A mixture of 2- (4-bromophenyl) -2-methyl-5-hydroxy-6,7-dichloro-1-indanone (4.48 g, 0.0116 mol), potassium carbonate (3.88 g, 0.0232 mole) and ethyl bromoacetate (3.21 g, 0.0232 mole) in dimethylformamide (100 mL) are heated to 55 - 60 ° C for 3 hours, then treated with a mixture of 100 mL water and 5 mL (0.05 mole) of an ION sodium hydroxide solution and heated to 100 ° C for 2 hours. The reaction mixture is slowly added to a mixture of crushed ice and water (1500 ml) containing 50 ml of 12N hydrochloric acid to precipitate 3.24 g of [1-oxo-2,4- (4-bromophenyl) -2-methyl-6,7-dichloro -5-indanyloxy] acetic acid, which melts at 171 - 172 ° C after recrystallization of nitromethane followed by acetic acid: water, 3: 2.

Elemental analysis for C ^ gH ^ BrCl₂O ^:

Calculated: C 48.68 - H 2.95 Found: C 48.64 - H 2.93 · 143553 EXAMPLE_11

Separation of (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) -acetic acid _______________________________________________________

Step A: Tert.-Butyl (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetate

A mixture of 2-methyl-2-phenyl-5-hydroxy-6,7-dichloro-1-indanone (9.2 g, 0.03 mol), potassium carbonate (8.29 g, 0.06 mol) and tert Butyl bromoacetate (6.44 g, 0.033 mol) in dimethylformamide (30 ml) is stirred at 25 ° C for 2 hours. The reaction mixture is poured into cold water (150 ml) and the separated tert-butyl (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetate is filtered off, rinsed with water and dried.

Step B: (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid

A solution of tert.-butyl (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetate (1.0 g, 0.00237 mol) in benzene (25 ml) is treated with methanesulfonic acid (2 drops) and reflux for 0.5 hour. The reaction mixture is treated with cyclohexane (20 ml) and cooled to give (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid, which is filtered off and dried. The product melts at 168-169 ° C after recrystallization of acetic acid: water 1: 1.

Elemental analysis for C18H14C12 ° 4:

Calculated: C 59.20 - H 3.86 Pound: C 58.94 - H 4.20 EXAMPLE_12

Resolution of the optical isomers of (1-oxo-2-methyl-2-phenyl-6,7-dichloro-1-indanyloxy2) acetic acid __________________________________

Step A; (+) - isomer

A mixture of racemic (1-oxo-2-methyl-2-phenyl-1-6,7-dichloro-5-indanyloxy) acetic acid (26 g, 0.071 mol) and L - (-) - α-methylbenzyl -amine (8.6 g, 0.071 mol) is dissolved in 250 ml of hot acetonitrile and the solution is left at 25 ° C for 18 hours.

The acetonitrile is decanted off from the formed salt (13.2 g), which is recrystallized three times by a minimal volume of 2-propanol to give 1.9 g of salt of the pure (+) enantiomer which is converted to the acid by treatment of the salt with dilute hydrochloric acid and ether. The ether phase is washed with water, dried over magnesium sulfate and the ether is distilled at reduced pressure. The (+) - isomer melts at 163 ° C after recrystallization from toluene.

[oc] + p = + 88 °. (C, 2, acetone).

Step B; (-) - isomer

Analogous to the procedure described in step A, partially digested (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid (15.5 g, 0.042 mol) is used as reagent; (recovered from the acetonitrile mother liquor from step A) and D - (+) - α-methylbenzylamine (5> 15 g> 0.042 mol) in acetonitrile (150 ml) and after recrystallization three times of the minimal salt formed of a minimum volume 2-propanol, 2.2 g of the salt is obtained from the pure (-) enantiomer.

The (-) isomer is obtained in a similar manner to the (+) - isomer obtained in step A and melts at 164 ° C after recrystallization from toluene.

[α] D = -88 ° (C, 2, acetone).

143553 25

Some typical compounds prepared by the method of the invention were tested for diuretic and uricosuric activity by the following procedure:

Male chimpanzees weighing 21-77 kg were immobilized with phencyclidine (which was found to have no effect on the results) (1.0 - 1.5 mg / kg im plus 2.5 mg / kg iv if needed) and prepared for catheterization for standard renal depletion examination by the usual clinical aseptic procedure. Pyrogen-free inulin (iv) was used to measure glomerular filtration rate (GFR). Depletion of inulin, urate and excretion rate of Na +, K + and Cl "was determined by standard auto-analysis (chimpanzee inulin and urate are freely filterable). Average control depletion was calculated from three consecutive 20-min periods. Response was determined as an average of eight 15 - 20 min depletion periods following oral administration of an aqueous solution of the compound through a nasal catheter, all data were determined as difference between (mean) treatment and control values obtained from single experiments.

The diuretic (D) and uricosuric (U) data for chimpanzees are indicated by a point system as follows:

Chimpanzee diuretic test data were initially calculated as C * c * a Δyu equiv / lin, and urate data were measured as A urate / inulin. The points values obtained are as follows:

Diuretic activity Uricosuric activity

Points 4 / h eq / min Points Aβ urate / "inulin 0 0 - 49 0 0 - 0.05 - 50 - 99 - 0.05 - 0.09 1 100 - 199 1 0.1 - 0.19 2 200 - 299 2 0.2 - 0.29 5 300 - 399 3 0.3 - 0.39 4 4oo - 499 4 0.4 - 0.49 5 500 - 599 5 0.5 - 0.59> 5> 600 26 ί * 3 $$ 3

All doses were 5 mg / kg po (oral).

Furosemide = 4-Cl-N-furfuryl-5-sulfamoyl-anthranilic acid.

The results obtained are shown in the following table: HOgCCHgO ^ S ^

X1 R1 R2 Chimpanzees 5 PO

_YOU

Cl. C6H5 Me 5 3

Cl CgH ^ Me (+ isomer) * 1 PO 1

Cl CgH ^ Me isomer)> 5 1 PO 2

Me CgH ^ Me> 5 4

Cl CgH5 Et 3 1

ci c6h5 c-c5h9- t O

ci c6h5 c6h5 0 0

Cl p-F-CgH ^ Me 3 4

Cl p-Cl-C6H4 Me 3 2

Cl p-Br-CgH ^ Me O 0

Cl p-MeO- Me 4 0 C6h4

Cl P-02N- Me 10 C6H4

Cl p-H2N- Me 2 + C6H4

Cl p-HO-CgH ^ Me 10

Furosemide y5 0

Hydrochlorothiazide 1 0 27 143553

Comparison test.

Comparative experiments have been made to compare some typical compounds prepared by the process of the invention and a compound known from US Patent No. 3,668,241. The experiments were performed by examining various compounds for diuretic and saluretic activity in female rats by measuring excreted salt in the urine for a period of 24 hours after administration. The effect of the compound prepared by the process of the invention (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid was added to 1.0 and the other compounds judged accordingly. The results obtained are shown in the following Table 28 143553 -p 0

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Claims (1)

Patent Claims: Analogous Process for Preparation of 1-Oxo-5-Indanyloxy-Acetic Acids of the General Formula: C10 xi_p X (j substituted with amino, nitro, hydroxyl, alkoxy of 1-6 carbon atoms or halogen, and R is alkyl of 1-6 carbon atoms or pharmaceutically acceptable salts thereof with bases, characterized in: a) a compound of the formula: - HO Wherein X, R and R have the above meaning, are reacted with a compound of the formula R is hydrogen or alkyl and Z is halogen, after which the reaction product if R 1 is alkyl is hydrolyzed or, if R 1 is t-butyl, pyrolysed or b) a compound of the formula: C Wherein X and R are as defined above and R is hydrogen or an alkyl group is reacted with an alkylating agent to introduce an alkyl group of 1-6 carbon atoms, whereby the reaction product, if R 1 is an alkyl group, is hydrolyzed or, if R 1 is t-butyl, pyrolyzed, or c) a compound of the formula: C 10 x 11 11 R 2 H 6 CCH 2 O 5 wherein X 1 and R 2 have the above meaning and R 1 is an alkyl group of 1-6 carbon atoms, treated with ether cleavage agent to form the corresponding indenone compound with a p-hydroxyphenyl substituent at the 2-position »or d) a compound of the formula: