GB2028320A - Salts of 2,3-dichloro-4-(4- hydroxybenzoyl) phenoxyacetic acid - Google Patents

Abstract

This invention provides 2,3- dichloro-4-(4-hydroxy-benzoyl) phenoxyacetic acid salts of the formula <IMAGE> wherein R is sodium, potassium, calcium or ammonium and which are useful as diuretic or uricosuric agents.

Description

SPECIFICATION Salts of 2,3-dichloro-4-(4-hydroxybenzoyl phenoxyacetic acid This invention relates to salts of 2,3-dichloro-4-(4-hydroxybenzoyl) Phenoxyacetic Acid.

4-aroyl-substituted phenoxy acetic acids as described in U.S. Patent 4,058,559 issued November 15, 1977 have been found to possess diuretic, saluretic and uricosuric activities. However, 2,3-dichloro-4-(4-hydroxybenzoyl)phenoxyacetic acid of the formula

one of the compounds described and an effective antihypertensive agent, is only sparingly soluble in water.

It is desirable that such compounds have advantageous dissolution properties in order to provide good in vivo bioavailability.

This invention relates to compounds selected from the class consisting of 2,3-dichloro-4-(4hydroxybenzoyl)phenoxyacetic acids salts of the formula

wherein R is sodium, potassium, calcium or ammonium.

The compounds of this invention are useful as diuretic and uricosuric agents. They are quite soluble in water and dissolve considerably faster than compound I under the same conditions. These advantages dissolution properties increase the achievable circulating levels of compound I in plasma; The invention will be better understood upon consideration of the following description and the accompanying drawing which is a chart plotting mean plasma level time following administration of the drug indicated.

The compounds of the present invention are prepared using compound I, 2,3-dichloro-4-(4- hydroxybenzoyl) phenoxyacetic acid, prepared according to the method described in U.S. patent 4,058,559, as the starting material. The following examples are exemplary of the preparation of compounds encompassed by the present invention.

Example 1 Ammonium Salt 0.2027 grams (g) (0.006 molar (m) of compound I the acid, was suspended in water and made basic with ammonium hydroxide to obtain a solution. The solution was allowed to stand overnight and then treated with a basic charcoal (norite) and filtered. The filtrate was concentrated to yeild a glass which was soluble in methanol but was insoluble in acetone. The glass was triturated with acetone to yield a solid which was collected on a filter and washed with acetone. The weight was 0.2069 g which was soluble in approximately 2 millilitres (ml) of water or approximately a 10+% solution was achieved. The PH was 6.2.

Example 2 Potassium Salt 0.2027 grams (g) (?.??3/4 MOLAR (m) of the acid (compound I) was suspended in water and treated with 0.0601 g (0.0006 m) of potassium bicarbonate. The mixture was then warmed to yield a solution which was allowed to stand overnight. The solution was treated with a basic charcoal (Norite) and filtered. The filtrate was concentrated to a glassy residue which was slurried with methanol to yield a solid. The solid was collected on a sintered glass funnel and washed with methanol. The weight was 0.1245 g. The solid product was placed in a flask and water slowly added. Approximately 9 ml of water was required before solution was attained. The represented approximately a 1.4% solution.

Example 3 Sodium Salt Compound I in the amount of 23.0957 g (0.0683 m) was added to a solution of 5.7377 g (0.0683 m) sodium bicarbonate in approximately 300 ml of water. The acid went into solution rapidly at the beginning of the addition of the acid to the basic solution and then more slowly. 200 ml of water was added and finally the mixture was warmed on a steambath. The salt appeared to precipitate the longer the solution was allowed to set. The warm mixture was filtered rapidly thru a medium sintered glass filter and divided into two 250 ml portions for freeze-drying overnight. The solid material from both flasks was stirred with approximtely 500 ml of ethyl acetate and then collected on a filter and washed with fresh ethyl acetate and then with petroleum ether. The solid salt was dried in a vacuum oven at 70" overnight. The weight was 24.6 g.

Example 4 Disodium Salt 0.3635 g (0.0011 m) of the sodium salt obtained as described in example 3 was suspended in water and approximately 5.9 ml (0.0011 m) of 0.1868 m) sodium hydroxide added. A pink solution resulted. Allowed to stand overnight. pH is 10.5. The solution was treated with a basic charcoal (Norite) and filtered. The filtrate was concentrated to yield a pale yellow glass which was soluble in methanol and upon reconcentration a glass was again obtained. The glass appeared to be insoluble in isopropyl alcohol.

Example 5 Metabolism study The study was conducted to assess the effect of the dissolution properties of the salts of Compound I (the acid) by comparing the achievable circulating plasma levels of Compound I, in monkeys, following single oral administration of Compound I or the potassium salt (Compound II). The study was conducted as follows.

Six male and six female rhesus monkeys were used. Upon initiation of the study, each animal was randomly assigned to one of two groups, each containing 3 males and 3 females. In the first treatment, each of the monkeys in one group received one 300 mg capsule of Compound I with 30 ml of water. Each of the animals in the other group was treated in the same manner, receiving one 334 mg capsule of Compound II with 30 ml of water. After being allowed a 14 day wash-out, the monkeys received their second drug treatment in which the groups were crossed over. Thus, at the end of the study each animal has been given each of the two drugs once. The animals were faster for at least 15 hours prior to drug administration but were allowed free access to water throughout the study.. They were provided food at 10 hours post dosing.

At 0.33, 0.67, 1, 1.5,2,3,4,6, 8, 10, 12,24,28,32 and 48 hours post dosing, two milliliters of blood were withdrawn from a femoral vein into a heparinized syringe and transferred to a test tube. The blood samples were immediately centrifuged at 4"C and the resulting plasma specimens transferred to clean tubes. The plasma samples were stored at-100C until analyzed.

The plasma samples were assayed for their concentrations of Compound I using a high-pressure liquid chromatographic procedure. The method has a lower sensitivity limit of approximately 0.01 mg/ml when 1 ml plasma samples were used. The treatment data are summarized in Table 1.

Table lisa tabulation of plasma concentrations of Compound I found in monkeys following oral administration of Compound I or compound II. The zero values at 0 hour after administration represent theoretical values, and the remaining zero values in the table indicate plasma samples with compound II levels below the sensitivity of the assay procedure (less than about 0.01 mcg per ml).

As is apparent from the data tabulated in Table 1, or as summarized and illustrated graphically in Figure 1, compound 11, the potassium salt of 2,3-dichloro-4-(4-hydroxybenzoyl) phenoxyacetic acid (compound 1), provides increased peak plasma levels and a greater area under the curve. As can readily be seen, the mean plasma levels resulting from treatment with compound II were initially substantially higher than those from treatment with equimolar doses of compound I. Likewise, the mean area under the curve was 18% greater than that obtained from compound I.

Tabel 1 Monkey Plasma Levels of Compound 1 Following Oral Administration of Compound I or Compound II 300 mg of Compound I Concentration in Micrograms per ml Hours after Dosing Area under Monkey 0.48 hr curve Number 0 0.33 0.67 1 1.5 2 3 4 6 8 10 12 24 28 32 48 (hr mcg per ml) 1 0.00 0.18 1.24 1.55 1.63 1.34 1.81 1.74 1.75 1.63 1.85 1.12 0.52 0.33 0.20 0.10 34.01 2 0.00 0.00 0.20 2.92 4.01 2.78 3.00 3.52 4.78 3.46 3.27 6.30 0.58 0.26 0.15 0.00 87.95 3 0.00 0.29 1.10 2.65 6.28 3.90 5.82 2.48 3.35 3.16 3.21 2.73 0.29 0.10 0.06 0.00 59.04 4 0.00 1.48 2.04 1.83 2.96 4.64 3.26 2.05 2.80 2.36 1.20 1.83 0.08 0.05 0.00 0.00 39.60 5 0.00 0.51 2.72 4.98 6.26 6.07 3.07 3.19 2.69 1.90 1.84 2.15 0.11 0.03 0.00 0.00 47.60 6 0.00 0.36 1.39 2.91 4.44 6.90 2.87 2.63 1.84 1.62 1.05 2.97 0.51 0.16 0.41 0.09 55.35 7 0.00 0.00 1.28 1.98 2.26 2.54 2.83 4.84 3.03 2.65 2.91 5.41 0.43 0.16 0.00 0.00 73.51 8 0.00 1.14 2.69 2.63 4.15 1.82 1.17 1.07 0.88 1.20 1.36 3.03 0.00 0.00 0.00 0.00 36.68 9 0.00 0.33 0.48 1.71 8.77 5.64 3.93 2.21 1.25 1.25 1.47 2.77 0.33 0.00 0.00 0.00 46.81 10 0.00 0.27 2.07 1.83 1.43 1.04 2.07 2.63 1.64 2.28 3.76 4.96 0.35 0.05 0.00 0.08 62.77 Mean 0.00 0.46 1.52 2.50 4.22 3.67 2.98 2.64 2.40 2.15 2.19 3.33 0.32 0.11 0.08 0.03 54.33 SD 0.00 0.48 0.85 1.01 2.34 2.08 1.27 1.04 1.16 0.77 1.00 1.67 0.20 0.11 0.14 0.04 17.11 Sem 0.00 0.15 0.27 0.32 0.74 0.66 0.40 0.33 0.37 0.24 0.32 0.53 0.06 0.03 0.04 0.01 5.41 SD: Standard Deviation SEM:Standard Error of the Mean 334 mg of Compound II Concentration in Micrograms per ml Hours after Dosing Area Under Monkey 0-48 hr curve Number 0 0.33 0.67 1 1.5 2 3 4 6 8 10 12 24 28 32 48 (hr mcg per ml) 1 0.00 4.37 3.91 6.03 10.07 5.68 8.73 2.28 1.82 1.54 1.31 2.15 0.15 0.00 0.00 0.00 52.31 2 0.00 4.70 3.90 4.17 8.66 12.84 9.95 7.81 3.05 1.87 1.47 2.72 0.57 0.36 0.27 0.06 81.24 3 0.00 5.19 4.06 4.54 5.56 5.56 5.19 3.79 1.17 0.94 0.79 1.71 0.26 0.15 0.08 0.00 44.06 4 0.00 4.91 5.16 7.83 7.70 4.49 2.12 1.87 2.12 1.68 1.43 2.99 0.00 0.00 0.20 0.28 54.40 5 0.00 2.44 5.64 7.45 8.25 4.08 2.66 2.16 1.86 1.98 1.86 3.55 0.11 0.00 0.00 0.00 56.01 6 0.00 3.00 3.68 3.84 5.10 5.70 3.87 2.67 2.22 3.54 3.06 5.45 0.31 0.09 0.01 0.00 77.26 7 0.00 10.97 3.47 7.02 6.98 7.30 6.55 4.78 5.88 5.76 5.72 7.02 0.18 0.10 0.07 0.00 116.84 8 0.00 13.21 12.51 12.51 5.27 3.94 3.49 4.07 2.47 1.55 0.80 0.53 0.05 0.02 0.00 0.00 42.82 9 0.00 10.10 7.09 7.46 10.84 6.65 3.48 2.12 1.70 1.68 1.50 3.43 0.24 0.12 0.00 0.00 62.09 10 0.00 1.75 4.19 6.74 4.51 4.72 4.16 2.28 1.73 1.77 1.60 2.81 0.35 0.09 0.05 0.00 51.69 Mean 0.00 6.06 5.36 6.76 7.29 6.10 5.02 3.38 2.40 2.23 1.95 3.24 0.22 0.09 0.07 0.03 63.87 SD 0.00 3.94 2.75 2.49 2.19 2.60 2.61 1.84 1.32 1.41 1.47 1.85 0.17 0.11 0.09 0.09 22.51 SEM 0.00 1.25 0.87 0.79 0.69 0.82 0.83 0.58 0.42 0.45 0.46 0.59 0.05 0.03 0.03 0.03 7.12 SD: Standard Deviation SEM: Standard Error of the Mean The solubility of compound I in water was found to be 0.104 mg/ml at 37"C while the potassium salt (compound II) was found to have a solubility of 10.5 mg/ml, an approximately 100 fold increase. The increase solubility is substantiated by the in vivo data.

The compounds of this invention can be formulated into various pharmaceutically acceptable dosage forms such as tablets, capsules, pills and the like, for immediate or sustained release by combining the active compound with suitable pharmaceutically acceptable carriers or diluents according to methods well known in the art. Such dosage forms may include excipients, binders, fillers, flavoring and sweetening agents, and other therapeutically inert ingredients necessary in the formulation of the desired preparation. Preparations for parenteral administration generally include sterile aqueous or nonaqueous solutions, suspensions or emulsions.

Claims (6)

1. Acompound oftheformula

wherein R is sodium, potassium, calcium or ammonium.

2. The compound of Claim 1 wherein R is sodium.

3. The compound of Claim 1 wherein R is potassium.

4. The compound of Claim 1 wherein R is calcium.

5. The compound of Claim 1 wherein R is ammonium.

6. The compound according to any one of the example herein.