CA1144178A - Salts of 2,3-dichloro-4-(hydroxybenzoyl) phenoxyacetic acid - Google Patents
Salts of 2,3-dichloro-4-(hydroxybenzoyl) phenoxyacetic acidInfo
- Publication number
- CA1144178A CA1144178A CA000333648A CA333648A CA1144178A CA 1144178 A CA1144178 A CA 1144178A CA 000333648 A CA000333648 A CA 000333648A CA 333648 A CA333648 A CA 333648A CA 1144178 A CA1144178 A CA 1144178A
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- Prior art keywords
- dichloro
- compound
- phenoxyacetic acid
- salt
- sodium
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/76—Unsaturated compounds containing keto groups
- C07C59/90—Unsaturated compounds containing keto groups containing singly bound oxygen-containing groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
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- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
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- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Health & Medical Sciences (AREA)
- Diabetes (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
SALTS OF 2,3-DICHLORO-4-(4-HYDROXYBENZOYL) PHENOXYACETIC ACID
Abstract of the Disclosure This invention provides 2,3-dichloro-4-(4-hydroxy-benzoyl) phenoxyacetic acid salts of the formula
Abstract of the Disclosure This invention provides 2,3-dichloro-4-(4-hydroxy-benzoyl) phenoxyacetic acid salts of the formula
Description
114~178 ~rou11d oF tho InvoDtio11 4-aroyl-substituted phenoxy acetic acids as described in U.S. }~ate1-t 4,05~3,559 issued November 15, 1977 have been found to possess dluretic, saluretic and uricosuric activities. ~1owever, 2,3-dichloro-4-(4-hydroxybenzoyl)phenoxyacetic acid of the formula Cl Cl }10--~ C ~ O-CH _IC_OH (1) one of the compounds doscrihed and an effective antihypertensive ageT1t, is only spclrillgly soluble in water. It is desirable that such compounds have advantagcous dissolution properties in order to provide good in VlVO bioavailability.
Summary of the Invention This invention relates to compounds selected from the class consisting of 2,3-dichloro-4-~4-hydroxybenzoyl)phenoxyacetic acids salts of the formula Cl Cl E10 ~ C - ~ o-CH,-3-oR
wherein R is sodium, potassium, calcium or ammonium and to a process for their produc1:ion. l`he salts are prepared by reacting the acld oE Formula I, with a sodium, potassium, calcium or ammonium basic compound.
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 advantageous dissolution properties increase the achievable circulating levels of compound I in plasma.
Drawing rrhe invention will be better understood upon consiùeration of the following description and drawing in which:
Figure l is a chart plotting mean plasma level time following admi11istration of the drug indicated.
Detailed~ ription of the Invention The compounds of the present invention are prepared using compound I, 2,3-dichloro-4-~4-hydroxybenzoyl)phenoxyacetic aciù, prepared according to the method described in U.S. patent 4,05~,559, as the starting materi.al. The following examples are exemplclry oE the preparation of eompounds encompassed by the present invention.
dm:~' - 2 -' '' ` 11~17~
~-3-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 ammoniu~
hydroxide to obtain a solution. The solution was allowed to stand overnight and then treated with a basic charcoai (Morite)~
and filteredO The filtrate was concentrated to yield a glas~
which was soluble in methanol but was insoluble in acetone.
The gIass 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 milliliters (ml) of water or approximately a 10+% solution was achieved. The PH was 6.2.
Example 2 Potassium Salt - 0.2027 grams (g) (0.0006 molar (m) of the acid tcompound 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 over-night. The solution was treated with a basic charcoal ~Norite)~
and filtered. The filtrate was concentrated to a glassy resi-due 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.
This 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 bicar-bonate 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 ~ Trade marlc was added and finally the mixture was warmed on a stea~-bath. 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 approximately 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.
lO 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 approxi-15 mately 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 20 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 25 the dis~olution properties of the salts of Compound I (the acid) by comparing the achievable circulating plasma levels of Compound I, in monkeys, following single oral administra-tion 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.
~ ~rade Mark 1~4~
Each of the animals in the other qroup was treated in the same manner, receiving one 334 mg capsule of Compound II with 30 ~ 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 had 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.~7, 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 4C and the resulting plasma specimens transferred to clean tubes. The plasma samples were stored at -10C until analyzed.
The plasma samples were assayed for their concen-trations of Compound I using a high-pressure liquid chromato-graphic procedure. The method had 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 1 is a 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 II, the potassium salt of 2,3-dichloro-4-(4-hydroxy-benzoyl) phenoxyacetic acid (compound I), 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.
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The solubility of compound I in water was found to be 0.104 mg/ml at 37C 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 ln vivo data.
The compounds of this inventi`on can be formulated into various pharmaceutically acceptable dosage forms such as tablets, capsules, pills, and the like, for im~ediate or sustained release by combining the active compound with suit-able pharmaceutically acceptable carriers or diluents accordingto methods well known in the art. Such dosage forms may in-clude 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.
Summary of the Invention This invention relates to compounds selected from the class consisting of 2,3-dichloro-4-~4-hydroxybenzoyl)phenoxyacetic acids salts of the formula Cl Cl E10 ~ C - ~ o-CH,-3-oR
wherein R is sodium, potassium, calcium or ammonium and to a process for their produc1:ion. l`he salts are prepared by reacting the acld oE Formula I, with a sodium, potassium, calcium or ammonium basic compound.
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 advantageous dissolution properties increase the achievable circulating levels of compound I in plasma.
Drawing rrhe invention will be better understood upon consiùeration of the following description and drawing in which:
Figure l is a chart plotting mean plasma level time following admi11istration of the drug indicated.
Detailed~ ription of the Invention The compounds of the present invention are prepared using compound I, 2,3-dichloro-4-~4-hydroxybenzoyl)phenoxyacetic aciù, prepared according to the method described in U.S. patent 4,05~,559, as the starting materi.al. The following examples are exemplclry oE the preparation of eompounds encompassed by the present invention.
dm:~' - 2 -' '' ` 11~17~
~-3-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 ammoniu~
hydroxide to obtain a solution. The solution was allowed to stand overnight and then treated with a basic charcoai (Morite)~
and filteredO The filtrate was concentrated to yield a glas~
which was soluble in methanol but was insoluble in acetone.
The gIass 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 milliliters (ml) of water or approximately a 10+% solution was achieved. The PH was 6.2.
Example 2 Potassium Salt - 0.2027 grams (g) (0.0006 molar (m) of the acid tcompound 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 over-night. The solution was treated with a basic charcoal ~Norite)~
and filtered. The filtrate was concentrated to a glassy resi-due 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.
This 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 bicar-bonate 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 ~ Trade marlc was added and finally the mixture was warmed on a stea~-bath. 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 approximately 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.
lO 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 approxi-15 mately 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 20 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 25 the dis~olution properties of the salts of Compound I (the acid) by comparing the achievable circulating plasma levels of Compound I, in monkeys, following single oral administra-tion 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.
~ ~rade Mark 1~4~
Each of the animals in the other qroup was treated in the same manner, receiving one 334 mg capsule of Compound II with 30 ~ 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 had 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.~7, 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 4C and the resulting plasma specimens transferred to clean tubes. The plasma samples were stored at -10C until analyzed.
The plasma samples were assayed for their concen-trations of Compound I using a high-pressure liquid chromato-graphic procedure. The method had 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 1 is a 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 II, the potassium salt of 2,3-dichloro-4-(4-hydroxy-benzoyl) phenoxyacetic acid (compound I), 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.
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The solubility of compound I in water was found to be 0.104 mg/ml at 37C 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 ln vivo data.
The compounds of this inventi`on can be formulated into various pharmaceutically acceptable dosage forms such as tablets, capsules, pills, and the like, for im~ediate or sustained release by combining the active compound with suit-able pharmaceutically acceptable carriers or diluents accordingto methods well known in the art. Such dosage forms may in-clude 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 (10)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound of the formula wherein R is sodium, potassium, calcium or ammonium, which comprises reacting an acid of the formula with a sodium, potassium, calcium or ammonium basic compound.
2. The process of claim 1 wherein the basis compound is ammonium hydroxide and the product obtained is the ammonium salt of 2,3-dichloro-4-(4-hydroxybenzoyl)-phenoxyacetic acid.
3. The process of claim 1 wherein the basic compound is potassium bicarbonate and the product obtained is the potassium salt of 2,3-dichloro-4-(4-hydroxybenzoyl)-phenoxyacetic acid.
4. The process of claim 1 wherein the basic compound is sodium bicarbonate and the product obtained is the sodium salt of 2,3-dichloro-4-(4-hydroxybenzoyl)-phenoxyacetic acid.
5. The process of claim 4, including the step of treating the sodium salt thus obtained with sodium hydroxide to provide the disodium salt of 2,3-dichloro-4-(4-hydroxy-benzoyl)phenoxyacetic acid.
6. A compound of the formula wherein R is sodium, potassium, calcium or ammonium, whenever prepared by the process of claim 1 or by the obvious chemical equivalent.
7. The ammonium salt of 2,3-dichloro-4-(4-hydroxy-benzoyl)phenoxyacetic acid, whenever prepared by the process of claim 2 or by the obvious chemical equivalent.
8. The potassium salt of 2,3-dichloro-4-(4-hydroxy-benzoyl)phenoxyacetic acid, whenever prepared by the process of claim 3 or by the obvious chemical equivalent.
9. The sodium salt of 2,3-dichloro-4-(4-hydroxy-benzoyl)phenoxyacetic acid, whenever prepared by the process of claim 4 or by the obvious chemical equivalent.
10. The disodium salt of 2,3-dichloro-4-(4-hydroxy-benzoyl)phenoxyacetic acid, whenever prepared by the process of claim 5 or by the obvious chemical equivalent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US93329578A | 1978-08-14 | 1978-08-14 | |
| US933,295 | 1978-08-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1144178A true CA1144178A (en) | 1983-04-05 |
Family
ID=25463701
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000333648A Expired CA1144178A (en) | 1978-08-14 | 1979-08-13 | Salts of 2,3-dichloro-4-(hydroxybenzoyl) phenoxyacetic acid |
Country Status (12)
| Country | Link |
|---|---|
| JP (1) | JPS5527187A (en) |
| AU (1) | AU4949179A (en) |
| BE (1) | BE878211A (en) |
| CA (1) | CA1144178A (en) |
| DE (1) | DE2932802A1 (en) |
| FR (1) | FR2433339A1 (en) |
| GB (1) | GB2028320B (en) |
| GR (1) | GR69707B (en) |
| NL (1) | NL7906197A (en) |
| PH (1) | PH14655A (en) |
| SE (1) | SE7906717L (en) |
| ZA (1) | ZA793907B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0683787U (en) * | 1991-02-14 | 1994-11-29 | 徳島県フックドラッグ自動化事業協同組合 | Hook gun for planting fibers on base cloth |
| JPH0661992U (en) * | 1993-02-05 | 1994-09-02 | 日本省力機械株式会社 | Air hook gun |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1563195A (en) * | 1975-08-20 | 1980-03-19 | Sori Soc Rech Ind | Derivating of phenoxy-alkylcarboxylic acids |
| US4058559A (en) * | 1975-09-24 | 1977-11-15 | Abbott Laboratories | 4-Aroyl-substituted phenoxy acetic acids |
-
1979
- 1979-07-31 ZA ZA00793907A patent/ZA793907B/en unknown
- 1979-08-01 GB GB7926749A patent/GB2028320B/en not_active Expired
- 1979-08-02 AU AU49491/79A patent/AU4949179A/en not_active Abandoned
- 1979-08-03 PH PH22846A patent/PH14655A/en unknown
- 1979-08-07 JP JP9994179A patent/JPS5527187A/en active Pending
- 1979-08-10 SE SE7906717A patent/SE7906717L/en not_active Application Discontinuation
- 1979-08-13 GR GR59826A patent/GR69707B/el unknown
- 1979-08-13 CA CA000333648A patent/CA1144178A/en not_active Expired
- 1979-08-13 DE DE19792932802 patent/DE2932802A1/en not_active Withdrawn
- 1979-08-13 FR FR7920608A patent/FR2433339A1/en active Granted
- 1979-08-13 BE BE2/58015A patent/BE878211A/en not_active IP Right Cessation
- 1979-08-14 NL NL7906197A patent/NL7906197A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| NL7906197A (en) | 1980-02-18 |
| FR2433339A1 (en) | 1980-03-14 |
| BE878211A (en) | 1980-02-13 |
| GB2028320B (en) | 1983-01-19 |
| AU4949179A (en) | 1980-02-21 |
| SE7906717L (en) | 1980-02-15 |
| ZA793907B (en) | 1980-11-26 |
| PH14655A (en) | 1981-10-14 |
| GB2028320A (en) | 1980-03-05 |
| JPS5527187A (en) | 1980-02-27 |
| GR69707B (en) | 1982-07-09 |
| FR2433339B1 (en) | 1982-04-09 |
| DE2932802A1 (en) | 1980-02-28 |
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| MKEX | Expiry |