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WO2005023790A1 - (s)-(+)-2-ethoxy-4-{[3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid sodium salt - Google Patents

(s)-(+)-2-ethoxy-4-{[3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid sodium salt Download PDF

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WO2005023790A1
WO2005023790A1 PCT/IN2003/000304 IN0300304W WO2005023790A1 WO 2005023790 A1 WO2005023790 A1 WO 2005023790A1 IN 0300304 W IN0300304 W IN 0300304W WO 2005023790 A1 WO2005023790 A1 WO 2005023790A1
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methyl
butylcarbamoyl
ethoxy
phenyl
compound
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French (fr)
Inventor
Joy Mathew
Tom Thomas Puthiaparampil
Sambasivam Ganesh
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Biocon Ltd
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Biocon Ltd
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    • 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 novel 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
  • 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- phenyl)-butylcarbamoyl]-methyl ⁇ -benzoic acid, namely sodium salt of 2-ethoxy-4- ⁇ [3-methyl-l-(2-piperidin-l-yl-phenyl butylcarbamoyl]-methyl ⁇ -benzoic acid or sodium salt of (S)-(+)-2- Ethoxy-4- ⁇ [3-methyl-l-(2-piperidin-l-yl-phenyl)-butylcarbamoyl]- methyl ⁇ -benzoic acid (FORMULA I), which is useful in the , treatment of Type II diabetes.
  • This compound shows good stability in solid form. Also this compound is significantly soluble in water or aqueous media whereas the free acid, namely (S)-(+)-2-ethoxy-4- ⁇ [3-methyl-l-(2-piperidin-l-yl-phenyl)-butylcarbamoyl]-methyl ⁇ - benzoic acid, is practically insoluble in water.
  • the present invention relates to a novel compound of formula I, which is sodium salt of 2-ethoxy-4- ⁇ [3-methyl-l-(2-piperidin-l-yl- phenyl)-butylcarbamoyl]-methyl ⁇ -benzoic acid or sodium salt of (S)-(+)-2-ethoxy-4- ⁇ [3-methyl-l-(2-piperidin-l-yl-phenyl)- butylcarbamoyl]-methyl ⁇ -benzoic acid (FORMULA I), to a novel process for preparing this compound, to a pharmaceutical composition containing this compound and to the prophylactic and/or therapeutic use of the compound and composition.
  • formula I is sodium salt of 2-ethoxy-4- ⁇ [3-methyl-l-(2-piperidin-l-yl- phenyl)-butylcarbamoyl]-methyl ⁇ -benzoic acid or sodium salt of (S)-(+)-2-ethoxy-4- ⁇ [3-methyl-l-
  • the present invention provides a compound of formula I, for use in the treatment of and/or prophylaxis of hyperglycemia.
  • the stability and water solubility of this compound provides for significant advantages in formulation, bioavailability 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 sodium salt of 2-ethoxy-4- ⁇ [3- methyl-l-(2-piperidin-l-yl-phenyl)-butylcarbamoyl]-methyl ⁇ - benzoic acid or sodium salt of (S)-(+)-2-ethoxy-4- ⁇ [3-methyl-l-(2- piperidin-l-yl-phenyl)-butylcarbamoyl]-methyl ⁇ -benzoic acid.
  • 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 freely soluble in water. This has significant pharmacokinetic advantage and enhances bioavailability. As stated the compound of the invention is significantly soluble in water and aqueous media.
  • 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.
  • the compound of formula I show good stability in aqueous conditions.
  • 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 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.
  • 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 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 compound of formula I is obtained by the reaction between (S)-(+)-2-ethoxy-4- ⁇ [3-methyl-l-(2-piperidin-l-yl-phenyl)- butylcarbamoyl]-methyl ⁇ -benzoic acid and a source of sodium counter-ion.
  • the reaction is generally carried out under conventional salt forming conditions, for example by admixing (S)- (+)-2-ethoxy-4- ⁇ [3-methyl-l-(2-piperidin-l-yl-phenyl)- butylcarbamoyl]-methyl ⁇ -benzoic acid and the suitable source of counter-ion, e.g.
  • a suitable solvent generally a Cl-4 alkanolic solvent such as methanol, ethanol, other aprotic solvents like acetonitrile or water immiscible organic solvent like ethyl acetate or isobutyl acetate, at a temperature which provides a suitable rate of formation of the required product, generally at an elevated temperature and thereafter isolating the product.
  • a Cl-4 alkanolic solvent such as methanol, ethanol, other aprotic solvents like acetonitrile or water immiscible organic solvent like ethyl acetate or isobutyl acetate
  • Example 4 To a solution of 2-ethoxy-4- ⁇ [3-methyl-l-(2-piperidin-l-yl- phenyl)-butylcarbamoyl]-methyl ⁇ -benzoic acid (5 g, 0.011 mol) in ethyl acetate (50 ml), sodium carbonate (1.2 g, 0.011 mol) was added. After stirring for 3 hours, the reaction mixture was filtered to afford title compound.
  • Example 5 To a solution of 2-ethoxy-4- ⁇ [3-methyl-l-(2-piperidin-l-yl- phenyl)-butylcarbamoyl]-methyl ⁇ -benzoic acid (5 g, 0.011 mol) in methanol (50 ml), a solution of sodium hydroxide (0.44 g, 0.011 mol) in methanol (10 ml) was added. After stirring for 1 hour, the reaction mixture was concentrated and ethyl acetate (25 ml) was added under stirring. The mixture was filtered to afford 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)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Sodium 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

(S)-(+)-2-ETHOXY-4-{[3-METHYL-l-(2-PIPERIDIN-l-YL-
PHENYL)-BUTYLCARBAMOYL]-METHYL}-BENZOIC ACID
SODIUM SALT
FIELD OF THE INVENTION The present invention relates to a novel compound and to a novel 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- phenyl)-butylcarbamoyl]-methyl}-benzoic acid, namely sodium salt of 2-ethoxy-4-{[3-methyl-l-(2-piperidin-l-yl-phenyl butylcarbamoyl]-methyl}-benzoic acid or sodium salt of (S)-(+)-2- Ethoxy-4-{[3-methyl-l-(2-piperidin-l-yl-phenyl)-butylcarbamoyl]- methyl}-benzoic acid (FORMULA I), which is useful in the , treatment of Type II diabetes. This compound shows good stability in solid form. Also this compound is significantly soluble in water or aqueous media whereas the free acid, namely (S)-(+)-2-ethoxy-4- {[3-methyl-l-(2-piperidin-l-yl-phenyl)-butylcarbamoyl]-methyl}- benzoic acid, is practically insoluble in water.
SUMMARY OF THE INVENTION
The present invention relates to a novel compound of formula I, which is sodium salt of 2-ethoxy-4-{[3-methyl-l-(2-piperidin-l-yl- phenyl)-butylcarbamoyl]-methyl}-benzoic acid or sodium salt of (S)-(+)-2-ethoxy-4-{[3-methyl-l-(2-piperidin-l-yl-phenyl)- butylcarbamoyl]-methyl}-benzoic acid (FORMULA I), to a novel process for preparing this compound, to a pharmaceutical composition containing this compound and to the prophylactic and/or therapeutic use of the compound and composition.
Figure imgf000003_0001
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 water solubility of this compound provides for significant advantages in formulation, bioavailability and bulk handling. DETAILED DESCRIPTION OF THE INVENTION Accordingly, the present invention provides a novel compound of formula I.
Figure imgf000004_0001
FORMULA I The compound of formula I is sodium salt of 2-ethoxy-4-{[3- methyl-l-(2-piperidin-l-yl-phenyl)-butylcarbamoyl]-methyl}- benzoic acid or sodium salt of (S)-(+)-2-ethoxy-4-{[3-methyl-l-(2- piperidin-l-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid. 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 freely soluble in water. This has significant pharmacokinetic advantage and enhances bioavailability. As stated the compound of the invention is significantly soluble in water and aqueous media. 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 quantitative analysis of the test may be carried out using conventional methods e.g. HPLC. As mentioned above 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. Thus the present invention provides a compound of formula I, for use in the treatment of and/or prophylaxis of hyperglycemia. 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 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 compound of formula I is obtained by the reaction between (S)-(+)-2-ethoxy-4-{[3-methyl-l-(2-piperidin-l-yl-phenyl)- butylcarbamoyl]-methyl}-benzoic acid and a source of sodium counter-ion. The reaction is generally carried out under conventional salt forming conditions, for example by admixing (S)- (+)-2-ethoxy-4-{[3-methyl-l-(2-piperidin-l-yl-phenyl)- butylcarbamoyl]-methyl}-benzoic acid and the suitable source of counter-ion, e.g. sodium methoxide, sodium hydroxide, sodium carbonate, sodium bicarbonate, in approximately equimolar amounts but preferably using an excess of the source of counter- ion, in a suitable solvent, generally a Cl-4 alkanolic solvent such as methanol, ethanol, other aprotic solvents like acetonitrile or water immiscible organic solvent like ethyl acetate or isobutyl acetate, at a 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-piperidιn- l-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid (5 g, 0.011 mol) in ethyl acetate (50 ml), sodium methoxide (0.6 g, 0.011 mol) was added. After stirring for 3 hours, the reaction mixture was filtered to afford title compound. Example 2 To a solution of (SH+)-2-ethoxy-4-{[3-methyl-l-(2-piperidin- l-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid (100 g, 0.22 mol) in acetonitrile (500 ml), sodium methoxide (12 g, 0.22 mol) was added. After stirring for 2 hours, the reaction mixture was filtered to afford title compound. Example 3 To a solution of (S)-(+)-2-ethoxy-4-{[3-methyl-l-(2-piperidin- l-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid (100 g, 0.22 mol) in isobutyl acetate (500 ml), sodium methoxide. (12 g, 0.22 mol) was added. After stirring for3 hours, the reaction mixture was filtered to afford title compound. Example 4 To a solution of 2-ethoxy-4-{[3-methyl-l-(2-piperidin-l-yl- phenyl)-butylcarbamoyl]-methyl}-benzoic acid (5 g, 0.011 mol) in ethyl acetate (50 ml), sodium carbonate (1.2 g, 0.011 mol) was added. After stirring for 3 hours, the reaction mixture was filtered to afford title compound. Example 5 To a solution of 2-ethoxy-4-{[3-methyl-l-(2-piperidin-l-yl- phenyl)-butylcarbamoyl]-methyl}-benzoic acid (5 g, 0.011 mol) in methanol (50 ml), a solution of sodium hydroxide (0.44 g, 0.011 mol) in methanol (10 ml) was added. After stirring for 1 hour, the reaction mixture was concentrated and ethyl acetate (25 ml) was added under stirring. The mixture was filtered to afford title compound.

Claims

We claim
1. A compound of formula I
Figure imgf000008_0001
FORMULA I
2. A 'compound according to claim 1, which is sodium salt of 2- ethoxy-4-{[3-methyl-l-(2-piperidin-l-yl-phenyl)- butylcarbamoyl]-methyl}-benzoic acid.
3. A compound according to claim 1, which is sodium salt of (S)-(+)-2-ethoxy-4-{[3-methyl-l-(2-piperidin-l-yl-phenyl)- butylcarbamoyl]-methyl}-benzoic acid .
4. A process for the preparation of compound of formula I, of claim 1, comprising contacting 2-ethoxy-4-{[3-methyI-l-(2- piperidin-l-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid or (S)-(+)-2-ethoxy-4-{[3-methyl-l-(2-piperidin-l-yl-phenyl)τ butylcarbamoyl]-methyl}-benzoic acid, with a source of sodium ion.
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.
6. A process as in claim 5, 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 5, wherein the solvent is water immiscible.
10. A process as claim 9, wherein the solvent is selected from ethyl acetate or isobutyl acetate.
11. A process as in claim 4, wherein the reaction is carried out at a temperature between 25-100°C.
12. A pharmaceutical composition comprising a prophylactically and/or therapeutically effective amount of the compound of claim 1.
13. A method of prevention and/or treatment of hyperglycemia comprising administering effective amount of compound of claim 1.
14. Use of compound of claim 1 as ingredient in the manufacture of medicament for use in the prevention and/or treatment of hyperglycemia.
PCT/IN2003/000304 2003-09-10 2003-09-10 (s)-(+)-2-ethoxy-4-{[3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid sodium salt Ceased WO2005023790A1 (en)

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AU2003269481A AU2003269481A1 (en) 2003-09-10 2003-09-10 (s)-(+)-2-ethoxy-4-{(3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl)-methyl}-benzoic acid sodium salt
PCT/IN2003/000304 WO2005023790A1 (en) 2003-09-10 2003-09-10 (s)-(+)-2-ethoxy-4-{[3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid sodium salt

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4735959A (en) * 1981-01-10 1988-04-05 Dr. Karl Thomae Gmbh Carboxylic acid amides and pharmaceutical compositions containing them
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

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4735959A (en) * 1981-01-10 1988-04-05 Dr. Karl Thomae Gmbh Carboxylic acid amides and pharmaceutical compositions containing them
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

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