WO2005023789A1 - Phosphoric acid salt of (s)-(+)-2-ethoxy-4-{[3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid - Google Patents
Phosphoric acid salt of (s)-(+)-2-ethoxy-4-{[3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid Download PDFInfo
- Publication number
- WO2005023789A1 WO2005023789A1 PCT/IN2003/000303 IN0300303W WO2005023789A1 WO 2005023789 A1 WO2005023789 A1 WO 2005023789A1 IN 0300303 W IN0300303 W IN 0300303W WO 2005023789 A1 WO2005023789 A1 WO 2005023789A1
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- WIPO (PCT)
- Prior art keywords
- methyl
- piperidin
- ethoxy
- phenyl
- compound
- Prior art date
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- FAEKWTJYAYMJKF-UHFFFAOYSA-N CCOc1cc(CC(NC(CC(C)C)c(cccc2)c2N2CCCCC2)=O)ccc1C(O)=O Chemical compound CCOc1cc(CC(NC(CC(C)C)c(cccc2)c2N2CCCCC2)=O)ccc1C(O)=O FAEKWTJYAYMJKF-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Definitions
- the present invention relates to a novel compound and to a process for preparing the novel compound, to a pharmaceutical composition containing the novel compound and to the prophylactic and/or therapeutic use of the compound and composition.
- the present invention discloses a novel salt of 2-ethoxy-4- ⁇ [3-methyl-l-(2-piperidin-l-yl-phenyl)-butylcarbamoyl]-methyl ⁇ - benzoic acid or (S)-(+)-2-ethoxy-4- ⁇ [3-methyl-l-(2-piperidin-l-yl- ph.enyl)-butylcarbamoyl]-methyl ⁇ -benzoic acid namely phosphoric acid salt of 2-ethoxy-4- ⁇ [3-methyl-l-(2-piperidin-l-yl-phenyl)- butylcarbamoyl]-methyl ⁇ -benzoic add or phosphoric acid salt of (S)-(+)-2-ethoxy-4- ⁇ [3-methyl-l-(2-piperidin-l-yl-phenyl)- butylcarbamoyl]-methyl ⁇ -benzoic acid (FORMULA I) which is useful in treatment of Type II diabetes
- This compound shows good stability in solid form. Also this compound is significantly more soluble in water or aqueous media than (S)-(+)-2-ethoxy-4- ⁇ [3- methyl-l-(2-piperidin-l-yl-phenyl)-but ⁇ lcarbamoyl]-methyl ⁇ - benzoic acid.
- the present invention relates to a novel compound of formula I, which is phosphoric acid salt of 2-ethoxy-4- ⁇ [3-methyi- ⁇ - (2-piperidin-l-yl-phenyl)-butylcarbamoyl]-methyl ⁇ -benzoic acid or phosphoric a id salt of (S)-(+)-2-ethoxy-4- ⁇ [3-methyl-l-(2- piperidin-l-yl-phenyl)-butylcarbamoyl]-methyl ⁇ -benzoic acid
- the present invention provides a compound of formula I, for use in the treatment of and/or prophylaxis of hyperglycemia.
- the stability and solubility of this compound in water/aqueous media provides for significant advantages in formulation, bioavailabilit ⁇ and bulk handling.
- DETAILED DESCRIPTION OF THE INVENTION Accordingly, the present invention provides a novel compound of formula I.
- the compound of formula I is a phosphoric acid salt of 2- ethoxy-4- ⁇ [3-methyl-l-(2-piperidin-l-yl-phenyl)-butylcarbamoyl]- methyl ⁇ -benzoic acid or phosphoric acid salt of (S)-(+)-2-ethoxy-4- ⁇ [3-methyl-l-(2-piperidin-l-yl-phenyl)-butylcarbamoyl]-methyl>- benzoic acid.
- the compound of the invention is significantly more soluble in water/aqueous media than the corresponding free base.
- a convenient method for determining the stability of the compounds of the invention in aqueous solution involves determining the degree of precipitation of the parent free base from an aqueous solution of the test compound at known conditions of temperature and over known periods of time. We have found that the compound of formula I show good stability in aqueous conditions.
- the currently marketed (S)-(+)-2-ethoxy-4- ⁇ [3-methyl-l-(2- piperidin-l-yl-phenyl)-butylcarbamoyl]-methyl ⁇ -benzoic acid is insoluble in water (The Merck Index Online, 2003).
- the compound of present invention is significantly soluble in water. This has important pharmacokinetic advantage and enhances bioavailabitity.
- the quantitative analysis of the test may be carried out using conventional methods e.g. HPLC.
- the compound of the invention is indicated as having useful therapeutic properties.
- the present invention accordingly provides a compound- of formula I, for use as an active therapeutic substance.
- the present invention provides a compound of formula I, for use in the treatment of and/or prophylaxis of hyperglycemia.
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier therefor.
- the pharmaceutical compositions of the present invention will be adapted for oral administration, although compositions for administration by other routes, such as by injection and percutaneous absorption are also envisaged.
- Particularly suitable compositions for oral administration are unit dosage forms such as tablets and capsules.
- Other fixed unit dosage forms, such as powders presented in sachets, may also be i: used.
- the present invention further provides a method for the treatment and/or prophylaxis of hyperglycemia in a human or non- human mammal, which comprises administering an effective, non- toxic, amount of a compound of formula I, , to a hyperglycemic human or non-human mammal in need thereof.
- the reaction between (S)-(+)-2-ethoxy-4- ⁇ [3-methyl-l-(2- piperidin-l-yl-phenyl)-butylcarbamoyl]-methyl ⁇ -benzoic acid and the source of phosphoric acid counter-ion is generally carried out under conventional salt forming conditions, for example by admixing 2-ethoxy-4- ⁇ [3-methyl-l-(2-piperidin-l-yl-phenyl)- butylcarbamoyl]-methyl ⁇ -benzoic acid and the source of counter- ion, phosphoric acid, in approximately equimolar amounts but preferably using an excess of the source of counter-ion, phosphoric acid, in a solvent, generally a Cl-4 alkanolic solvent such as methanol, ethanol, or other aprotic solvents like acetonitrile, at any temperature which provides a suitable rate of formation of the required product, generally at an elevated temperature and thereafter isolating the product.
- Example 1 To a solution of (S)-(+)-2-ethoxy-4- ⁇ [3-methyl-l-(2-piperidin- l-yl-phenyl)-butylcarbamoyl]-methyl ⁇ -benzoic acid (5 g, 0.009 mol) in methanol (50 ml), phosphoric acid (85%, 0.7 g) was added. 5 After stirring for 30 minutes, the reaction mixture was concentrated to about 10 ml and chilled. Filtration of the mixture afforded title compound.
- Example 2 To a solution of 2-ethoxy-4- ⁇ [3-methyl-l ⁇ (2-piperidin-l-yl- ⁇ o phenyl)-butylcarbamoyl]-methyl ⁇ -benzoic acid (100 g, 0.18 mol) in acetonitrile (500 ml), phosphoric acid (85%, 14 g) was added. After stirring for 30 minutes, the reaction mixture was concentrated to about 250 ml and chilled. Filtration of the mixture afforded title compound.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Diabetes (AREA)
- General Chemical & Material Sciences (AREA)
- Emergency Medicine (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Endocrinology (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Phosphoric acid salt of (S)-(+)-2-ethoxy-4-{[3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid is novel and exhibits, blood sugar-lowering activity in mammals and is of value as a prophylactic and/or therapeutic agent for prevention and/or treatment of diabetes.
Description
PHOSPHORIC ACID SALT OF (S)-(+)-2-ETHOXY-4-{[3- METHYL-l-(2-PIPERIDIN-l-YL-PHENYL BUTYLCARBAMOYL]-METHYL}-BENZOIC ACID FIELD OF THE INVENTION The present invention relates to a novel compound and to a process for preparing the novel compound, to a pharmaceutical composition containing the novel compound and to the prophylactic and/or therapeutic use of the compound and composition. BACKGROUND OF THE INVENTION US 5,216,167 discloses 2-ethoxy-4-{[3-methyl-l-(2-piperidin- l-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid. The compound exhibits blood-glucose lowering action with lower toxicity and may be safely administered, orally or parenterally, as it is or advantageously as a pharmaceutical composition comprising an effective amount of the compound or its pharmacologically acceptable salt and a pharmacologically acceptable carrier, excipient or diluent therefor, in the form of powder, granule, tablet, hard capsule, soft capsule, dry syrup, suppository, injection or the like. US 6,143,769 discloses (S)-(+)-2-ethoxy-4-{[3-methyl-l-(2- piperidin-l-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid which is currently marketed for treatment of Type II diabetes. The present invention discloses a novel salt of 2-ethoxy-4- {[3-methyl-l-(2-piperidin-l-yl-phenyl)-butylcarbamoyl]-methyl}- benzoic acid or (S)-(+)-2-ethoxy-4-{[3-methyl-l-(2-piperidin-l-yl-
ph.enyl)-butylcarbamoyl]-methyl}-benzoic acid namely phosphoric acid salt of 2-ethoxy-4-{[3-methyl-l-(2-piperidin-l-yl-phenyl)- butylcarbamoyl]-methyl}-benzoic add or phosphoric acid salt of (S)-(+)-2-ethoxy-4-{[3-methyl-l-(2-piperidin-l-yl-phenyl)- butylcarbamoyl]-methyl}-benzoic acid (FORMULA I) which is useful in treatment of Type II diabetes. This compound shows good stability in solid form. Also this compound is significantly more soluble in water or aqueous media than (S)-(+)-2-ethoxy-4-{[3- methyl-l-(2-piperidin-l-yl-phenyl)-butγlcarbamoyl]-methyl}- benzoic acid. SUMMARY OF THE INVENTION The present invention relates to a novel compound of formula I, which is phosphoric acid salt of 2-ethoxy-4-{[3-methyi-ϊ- (2-piperidin-l-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid or phosphoric a id salt of (S)-(+)-2-ethoxy-4-{[3-methyl-l-(2- piperidin-l-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid
(FORMULA I), to a process for preparing this novel compound, to a pharmaceutical composition containing this compound and to the prophylactic and/or therapeutic use of the compound and composition.
FORMULA I
The present invention provides a compound of formula I, for use in the treatment of and/or prophylaxis of hyperglycemia. The stability and solubility of this compound in water/aqueous media provides for significant advantages in formulation, bioavailabilitγ and bulk handling. DETAILED DESCRIPTION OF THE INVENTION Accordingly, the present invention provides a novel compound of formula I.
Accordingly, the present invention also provides a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier therefor. Usually the pharmaceutical compositions of the present invention will be adapted for oral administration, although compositions for administration by other routes, such as by injection and percutaneous absorption are also envisaged. Particularly suitable compositions for oral administration are unit dosage forms such as tablets and capsules. Other fixed unit
dosage forms, such as powders presented in sachets, may also be i: used. The present invention further provides a method for the treatment and/or prophylaxis of hyperglycemia in a human or non- human mammal, which comprises administering an effective, non- toxic, amount of a compound of formula I, , to a hyperglycemic human or non-human mammal in need thereof. The reaction between (S)-(+)-2-ethoxy-4-{[3-methyl-l-(2- piperidin-l-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid and the source of phosphoric acid counter-ion is generally carried out under conventional salt forming conditions, for example by admixing 2-ethoxy-4-{[3-methyl-l-(2-piperidin-l-yl-phenyl)- butylcarbamoyl]-methyl}-benzoic acid and the source of counter- ion, phosphoric acid, in approximately equimolar amounts but preferably using an excess of the source of counter-ion, phosphoric acid, in a solvent, generally a Cl-4 alkanolic solvent such as methanol, ethanol, or other aprotic solvents like acetonitrile, at any temperature which provides a suitable rate of formation of the required product, generally at an elevated temperature and thereafter isolating the product. The following Example illustrates the invention but does not limit it in any way. EXAMPLES Example 1 To a solution of (S)-(+)-2-ethoxy-4-{[3-methyl-l-(2-piperidin- l-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid (5 g, 0.009 mol) in methanol (50 ml), phosphoric acid (85%, 0.7 g) was added.
5 After stirring for 30 minutes, the reaction mixture was concentrated to about 10 ml and chilled. Filtration of the mixture afforded title compound. Example 2 To a solution of 2-ethoxy-4-{[3-methyl-l~(2-piperidin-l-yl- ιo phenyl)-butylcarbamoyl]-methyl}-benzoic acid (100 g, 0.18 mol) in acetonitrile (500 ml), phosphoric acid (85%, 14 g) was added. After stirring for 30 minutes, the reaction mixture was concentrated to about 250 ml and chilled. Filtration of the mixture afforded title compound. i5 Example 3 To a solution of (S)-(+)-2-ethoxy-4-{[3-methyl-l-(2-piperidin- l-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid (100 g, 0.18 mol) in isopropyl alcohol (500 ml), phosphoric acid (85%, 14 g) was added. After stirring for 30 minutes, the reaction mixture waso concentrated to about 250 ml and chilled. Filtration of the mixture afforded title compound.
Claims
5 We claim 1. A compound of formula I
3. A compound according to claim 1, which is phosphoric acid salt of (S)-(+)-2-ethoxy-4-{[3-methyl-l-(2-piperidin-l-yl- i5 phenyl)-butγlcarbamoyl]-methyl}-benzoic acid.
4. A process for the preparation of compound of formula I, of claim 1, comprising contacting the 2-ethoxy-4-{[3-methyl-l- (2-piperidin-l-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid or (S)-(+)-2-ethoxy-4-{[3~methyl-l-(2-piperidin-l-yl- o phenyl)-butylcarbamoyl]-methyl}-benzoic acid, with phosphoric acid. 5. A process as in claim 4, wherein the reaction is carried out in ' a solvent selected from water miscible solvent or water immiscible solvent.
5
6. A process as in claim 4, wherein the solvent is water miscible.
7. A process as in claim 6, wherein the solvent is a linear or branched alkanol or acetonitrile.
8. A process as in claim 7, wherein the alkanol is selected from methanol, ethanol or isopropyl alcohol.
9. A process as in claim 4, wherein the reaction is carried out at a temperature between 25-100°C.
10. A pharmaceutical composition comprising a prophylactically and/or therapeutically effective amount of the compound of claim 1.
11. A method of prevention and/or treatment of hyperglycemia comprising administering effective amount of compound of claim 1.
12. Use of compound of claim 1 as ingredient in the manufacture of medicament for use in the prevention and/or treatment of hyperglycemia.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IN2003/000303 WO2005023789A1 (en) | 2003-09-10 | 2003-09-10 | Phosphoric acid salt of (s)-(+)-2-ethoxy-4-{[3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid |
| AU2003269480A AU2003269480A1 (en) | 2003-09-10 | 2003-09-10 | Phosphoric acid salt of (s)-(+)-2-ethoxy-4-{(3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl)-methyl}-benzoic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IN2003/000303 WO2005023789A1 (en) | 2003-09-10 | 2003-09-10 | Phosphoric acid salt of (s)-(+)-2-ethoxy-4-{[3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2005023789A1 true WO2005023789A1 (en) | 2005-03-17 |
Family
ID=34259918
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2003/000303 WO2005023789A1 (en) | 2003-09-10 | 2003-09-10 | Phosphoric acid salt of (s)-(+)-2-ethoxy-4-{[3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid |
Country Status (2)
| Country | Link |
|---|---|
| AU (1) | AU2003269480A1 (en) |
| WO (1) | WO2005023789A1 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4863724A (en) * | 1983-06-08 | 1989-09-05 | Dr. Karl Thomae Gmbh | Anti-diabetic pharmaceutical compositions and the preparation thereof |
| US5216167A (en) * | 1983-12-30 | 1993-06-01 | Dr. Karl Thomae Gmbh | Phenylacetic acid benzylamides |
| US6143769A (en) * | 1983-12-30 | 2000-11-07 | Karl Thomae Gmbh | Phenylacetic acid benzylamides |
-
2003
- 2003-09-10 WO PCT/IN2003/000303 patent/WO2005023789A1/en active Application Filing
- 2003-09-10 AU AU2003269480A patent/AU2003269480A1/en not_active Abandoned
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4863724A (en) * | 1983-06-08 | 1989-09-05 | Dr. Karl Thomae Gmbh | Anti-diabetic pharmaceutical compositions and the preparation thereof |
| US5216167A (en) * | 1983-12-30 | 1993-06-01 | Dr. Karl Thomae Gmbh | Phenylacetic acid benzylamides |
| US6143769A (en) * | 1983-12-30 | 2000-11-07 | Karl Thomae Gmbh | Phenylacetic acid benzylamides |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2003269480A1 (en) | 2005-03-29 |
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