Nothing Special   »   [go: up one dir, main page]

WO2000063191A1 - Novel polymorphic forms of an antidiabetic agent: process for their preparation and a pharmaceutical composition containing them - Google Patents

Novel polymorphic forms of an antidiabetic agent: process for their preparation and a pharmaceutical composition containing them Download PDF

Info

Publication number
WO2000063191A1
WO2000063191A1 PCT/IB1999/000681 IB9900681W WO0063191A1 WO 2000063191 A1 WO2000063191 A1 WO 2000063191A1 IB 9900681 W IB9900681 W IB 9900681W WO 0063191 A1 WO0063191 A1 WO 0063191A1
Authority
WO
WIPO (PCT)
Prior art keywords
phenoxazin
ethoxy
phenyl
ethoxypropanoic acid
arginine salt
Prior art date
Application number
PCT/IB1999/000681
Other languages
French (fr)
Inventor
Om Reddy Gaddam
Rajender Kumar Potlapally
Raju Sirisilla
Vyas Krishnamurthi
Sreenivasa Rao Dharmaraja
Ramabhadra Sarma Mamillapalli
Original Assignee
Dr. Reddy's Research Foundation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dr. Reddy's Research Foundation filed Critical Dr. Reddy's Research Foundation
Priority to PCT/IB1999/000681 priority Critical patent/WO2000063191A1/en
Priority to AU29536/99A priority patent/AU2953699A/en
Priority to PCT/US2000/010309 priority patent/WO2000063193A1/en
Priority to CN00807705A priority patent/CN1351597A/en
Priority to RU2001130883/04A priority patent/RU2001130883A/en
Priority to PCT/IB2000/000470 priority patent/WO2000063192A1/en
Priority to BR0010683-6A priority patent/BR0010683A/en
Priority to JP2000612284A priority patent/JP2003508348A/en
Priority to PL00351492A priority patent/PL351492A1/en
Priority to EP00917222A priority patent/EP1171430A1/en
Priority to MXPA01010472A priority patent/MXPA01010472A/en
Priority to EEP200100529A priority patent/EE200100529A/en
Priority to AU39578/00A priority patent/AU3957800A/en
Priority to AU44652/00A priority patent/AU4465200A/en
Priority to PCT/DK2000/000188 priority patent/WO2000063189A1/en
Priority to CZ20013711A priority patent/CZ20013711A3/en
Priority to AU38313/00A priority patent/AU3831300A/en
Priority to US09/550,862 priority patent/US6528507B1/en
Priority to IL14595800A priority patent/IL145958A0/en
Priority to CA002370401A priority patent/CA2370401A1/en
Priority to TR2001/03851T priority patent/TR200103851T2/en
Priority to HU0200758A priority patent/HUP0200758A3/en
Publication of WO2000063191A1 publication Critical patent/WO2000063191A1/en
Priority to NO20015016A priority patent/NO20015016L/en
Priority to HR20010748A priority patent/HRP20010748A2/en
Priority to BG106022A priority patent/BG106022A/en
Priority to US10/142,857 priority patent/US20020173647A1/en
Priority to US10/209,567 priority patent/US20030004341A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/38—[b, e]-condensed with two six-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • 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
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups

Definitions

  • This invention relates to novel polymorphic / pseudopolymorphic forms of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I shown below.
  • the invention also relates to a pharmaceutical composition comprising the novel polymorphic form or their mixture and a pharmaceutically acceptable carrier.
  • the polymorphic forms of the present invention are more active, as antidiabetic and hypolipidemic agent, than the novel 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
  • the present invention also relates to a process for the preparation of novel polymo ⁇ hic / pseudopolymorphic Forms of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula (I).
  • polymo ⁇ hic Forms of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]- 2-ethoxypropanoic acid, of formula (I) defined above of the present invention are useful for the treatment and / or prophylaxis of hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, obesity, glucose intolerance, insulin resistance and also diseases or conditions in which insulin resistance is the underlying pathophysiological mechanism. Examples of these diseases and conditions are type II diabetes, impaired glucose tolerance, dyslipidaemia, hypertension, coronary heart disease and other cardiovascular disorders including atherosclerosis.
  • polymo ⁇ hic Forms of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, of formula (I) are also useful for the treatment of insulin resistance associated with obesity and psoriasis.
  • the polymo ⁇ hics Forms of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid, of formula (I) can also be used to treat diabetic complications and can be used for treatment and / or prophylaxis of other diseases and conditions such as polycystic ovarian syndrome (PCOS), certain renal diseases including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal diseases and microalbuminuria as well as certain eating disorders, as aldose reductase inhibitors and for improving cognitive functions in dementia.
  • PCOS polycystic ovarian syndrome
  • certain renal diseases including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal diseases and microalbum
  • Aldose reductase is the enzyme which reduces aldose present in the humans and animals into corresponding polyols which, in turn, are stored or accumulated in the kidneys, peripheral nerves, eye lens of the diabetic patients and manifest themselves in the above mentioned complications.
  • polymo ⁇ hism we mean to include different physical forms, crystal forms, crystalline / liquid crystalline / non-crystalline (amo ⁇ hous) forms. This has especially become very interesting after observing that many antibiotics, antibacterials, tranquilizers etc., exhibit polymo ⁇ hism and some/one of the polymo ⁇ hic forms of given drug exhibit superior bio-availability and consequently show much higher activity compared to other polymo ⁇ hs. Sertraline, Frentizole, Ranitidine, Sulfathiazole, Indomethacine etc.
  • the pharmaceutical salts of the compounds of the general formula (a) includes salts of the organic bases such as guanine, arginine, guanidine, diethylamine, choline, and the like. Particularly the compounds disclosed include 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
  • Form I-[4-[2-(phenoxazin- 10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid exhibits polymo ⁇ hism, which has not been reported till date.
  • the polymo ⁇ hic Forms I, II, III, IN and N are obtained from different solvents like isopropyl alcohol, acetone, 1,4-dioxane, dimethylsulphoxide, and dimethylformarnide respectively.
  • Form NI is obtained by dissolving any form (Form I-
  • Form VII is obtained by dissolving any form (Form I-V) in methanol and quick evaporation of the solvent under reduced pressure at
  • Form VIII is obtained by refluxing Form-I in 1,4-dioxane.
  • Form-IX is obtained by refluxing Form- VIII in isopropyl alcohol.
  • Form X is prepared by heating
  • Form I to 185 °C and cooling it to room temperature.
  • Form XI is prepared by heating
  • DSC of the polymo ⁇ hic Form I shows melting endotherm at 181 °C.
  • Form II displays endotherms at 131 °C, 166 °C, 178 °C, 214 °C and 276 °C and exotherms at 169 °C.
  • Form III exhibits melting endotherm 182 °C in addition to an exotherm at 168 °C.
  • Form IV exhibits endotherms at 149 °C, 164 °C and 185 °C and an exotherm at 171 °C.
  • Form V exhibits endotherms at 119 °C, 164 °C, 172 °C and 185 °C in addition to a melting exotherm at 173 °C.
  • Form VI exhibits exotherm at 157 °C and endotherms at 179 °C and 183 °C.
  • Form VII exhibits exotherm at 132 °C and endotherms at 176 °C and 184 °C.
  • Form VIII there was a similar exotherm of Form VI at 158 °C and the melting endotherm at 178 °C, whereas in Form IX there was only one sha ⁇ melting endotherm at 176 °C.
  • Form X displays an exotherm at 163 °C and melting endotherm at 184 °C.
  • Form XI exhibits a melting endotherm at 184 °C. All these polymo ⁇ hic forms were proved to be identical in solution as evident from Nuclear Magnetic Resonance (NMR), Ultra Violet (UV) & Mass spectral data. On the other hand, solid state techniques like Differential Scanning Calorimetry (DSC), Powder X-Ray Diffractometry (XRD) and Infra Red spectroscopy (IR) revealed the difference among these forms.
  • DSC Differential Scanning Calorimetry
  • XRD Powder X-Ray Diffractometry
  • IR Infra Red spectroscopy
  • X-ray powder diffraction pattern has been obtained on a Rigaku D/Max 2200 model diffractometer equiped with horizontal gonimometer in ⁇ /2 ⁇ geometry.
  • Fig. 1 is a characteristic X-ray powder diffraction pattern of Form I.
  • Fig. 2 is a characteristic X-ray powder diffraction pattern of Form II.
  • Fig. 3 is a characteristic X-ray powder diffraction pattern of Form III.
  • Fig. 4 is a characteristic X-ray powder diffraction pattern of Form IN.
  • Fig. 5 is a characteristic X-ray powder diffraction pattern of Form N.
  • Fig. 6 is a characteristic X-ray powder diffraction pattern of Form VI.
  • Fig. 7 is a characteristic X-ray powder diffraction pattern of Form VII.
  • Fig. 8 is a characteristic X-ray powder diffraction pattern of Form VIII.
  • Fig. 9 is a characteristic X-ray powder diffraction pattern of Form IX.
  • Fig. 10 is a characteristic X-ray powder diffraction pattern of Form X.
  • Fig. 11 is a characteristic X-ray powder diffraction pattern of Form XI.
  • Fig. 12 is a characteristic X-ray powder diffraction pattern of polymo ⁇ hic form mixture.
  • Differential scanning calorimeter was performed on a Shimadzu DSC-50 equipped with a controller. The data was collected on to a Pentium PC using a Shimadzu TA-50 software. The samples weighed in aluminum cells were heated from room temperature to 220 °C at a heating rate of 5 °C /min. The empty aluminum cell was used as a reference. Dry nitrogen gas was purged through DSC cell continuously throughout the analysis at a flow of 30 ml/min.
  • Fig. 13 is a characteristic differential scanning calorimetric thermogram of Form I.
  • Fig. 14 is a characteristic differential scanning calorimetric thermogram of Form II.
  • Fig. 15 is a characteristic differential scanning calorimetric thermogram of Form III.
  • Fig. 16 is a characteristic differential scanning calorimetric thermogram of Form IV.
  • Fig. 17 is a characteristic differential scanning calorimetric thermogram of Form V.
  • Fig. 18 is a characteristic differential scanning calorimetric thermogram of Form VI.
  • Fig. 19 is a characteristic differential scanning calorimetric thermogram of Form VII.
  • Fig. 20 is a characteristic differential scanning calorimetric thermogram of Form VIII.
  • Fig. 21 is. a characteristic differential scanning calorimetric thermogram of Form IX.
  • Fig. 14 is a characteristic differential scanning calorimetric thermogram of Form II.
  • Fig. 15 is a characteristic differential scanning calorimetric thermogram of Form III.
  • Fig. 16 is a characteristic differential scanning
  • Fig. 22 is a characteristic differential scanning calorimetric thermogram of Form X.
  • Fig. 23 is a characteristic differential scanning calorimetric thermogram of Form XI.
  • Fig. 24 is a characteristic differential scanning calorimetric thermogram of polymo ⁇ hic form mixture.
  • FT-IR Spectrum was recorded in solid state as KBr dispersion using Perkin-Elmer 1650 FT-IR Spectrophotometer.
  • Fig. 25 is a characteristic infrared abso ⁇ tion spectrum of Form I in KBr.
  • Fig. 26 is a characteristic infrared abso ⁇ tion spectrum of Form II in KBr.
  • Fig. 27 is a characteristic infrared abso ⁇ tion spectrum of Form III in KBr.
  • Fig. 28 is a characteristic infrared abso ⁇ tion spectrum of Form IV in KBr.
  • Fig. 29 is a characteristic infrared abso ⁇ tion spectrum of Form V in KBr.
  • Fig. 30 is a characteristic infrared abso ⁇ tion spectrum of Form VI in KBr.
  • FFiigg.. 3311 i iss aa cchhaarraacctteeririssttiicc infrared abso ⁇ tion spectrum of Form VII in KBr.
  • Fig. 32 is a characteristic infrared abso ⁇ tion spectrum of Form VIII in KBr.
  • Fig. 33 is a characteristic infrared abso ⁇ tion spectrum of Form IX in KBr.
  • Fig. 34 is a characteristic infrared abso ⁇ tion spectrum of Form X in KBr.
  • Fig. 35 is a characteristic infrared abso ⁇ tion spectrum of Form XI in KBr.
  • 3366 i iss aa cchhaarraaccttee ⁇ rissttiicc infrared abso ⁇ tion spectrum of polymo ⁇ hic form mixture in KBr.
  • a novel polymo ⁇ hic Form-I of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid having the formula I which is characterized by the following data :
  • a novel polymo ⁇ hic Form-Ill of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid having the formula I which is characterized by the following data : DSC: Endotherm at 182.20 °C (onset at 171 °C) (Fig-15)
  • a novel polymo ⁇ hic Form- VI of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid having the formula I which is characterized by the following data : DSC: Endotherms at 179.11 °C and 183.69 °C (onset at 157.98 °C), (Fig -18)
  • a novel polymo ⁇ hic Form-X of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid having the formula I which is characterized by the following data : DSC: Endotherm at 184.53 °C, (Fig -22)
  • step (ii) adding L-arginine dissolved in water slowly with constant stirring to the solution obtained in step (i), (iii) stirring the reaction mixture at a temperature of 40-80 °C for a period in the range of 18-30 h to obtain a white crystalline precipitate, (iv) filtering the white crystalline precipitate obtained in step (iii) above and (v) drying under vacuum at a temperature of 40-45 °C for a period in the range of 4- 16 h to yield Form-I of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid.
  • step (ii) adding L-arginine dissolved in water slowly with constant stirring to the solution obtained in step (i), (iii) stirring the reaction mixture at room temperature for a period in the range of 90-
  • the temperature employed in the stirring step (iii) may be preferably 40-50 °C.
  • step (iv) filtering the white crystalline precipitate obtained in step (iii) above and (v) drying under vacuum at a temperature of 40-45 °C for a period in the range of 4- 16 h to yield Form-V of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid.
  • step (ii) adding L-arginine dissolved in water slowly with constant stirring to the solution obtained in step (i), (iii) stirring the reaction mixture at a temperature of 40-80 °C for a period in the range of 18-30 h to obtain a white crystalline precipitate, (iv) filtering the white crystalline precipitate obtained in step (iii) above and (v) drying under vacuum at a temperature of 40-45 °C for a period in the range of 4- 16 h to yield Form-I of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid and
  • step (vi) heating the polymo ⁇ hic Form-I obtained in step (v) to 185 °C and cooling it to room temperature to yeild Form-X of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
  • step (vii) heating the polymo ⁇ hic Form-X obtained in step (vi) to 175 °C and cooling it to room temperature to yield Form-XI of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
  • step (iv) filtering the white crystalline powder obtained in step (iii) and (v) drying under vacuum at a temperature of 40-45 °C for a period in the range of 4-
  • the organic solvents are selected from acetonitrile, ethanol, methanol and, isopropanol.
  • the invention also envisages a pharmaceutical composition
  • a pharmaceutical composition comprising a polymo ⁇ hic Forms I and X of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid, of the formula (I) or the mixture of polymo ⁇ hic Form of I and X and a pharmaceutically acceptable carrier .
  • the pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, may contain flavourants, sweeteners etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions.
  • Such compositions typically contain from 1 to 20 %, preferably 1 to 10 % by weight of active compound, the remainder of the composition being pharmaceutically acceptable carriers, diluents or solvents.
  • the compound of the formula (I) as defined above are clinically administered to mammals, including man, via either oral or parenteral routes. Administration by the oral route is preferred, being more convenient and avoiding the possible pain and irritation of injection. However, in circumstances where the patient cannot swallow the medication, or abso ⁇ tion following oral administration is impaired, as by disease or other abnormality, it is essential that the drug be administered parenterally.
  • the dosage is in the range of about 0.01 to about 100 mg / kg body weight of the subject per day or preferably about 0.01 to about 30 mg / kg body weight per day administered singly or as a divided dose.
  • the optimum dosage for the individual subject being treated will be determined by the person responsible for treatment, generally smaller doses being administered initially and thereafter increments made to determine the most suitable dosage.
  • Suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions.
  • the active compound will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above.
  • the compounds can be combined ' with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like.
  • the pharmaceutical compositions may, if desired, contain additional components such as flavourants, sweeteners, excipients and the like.
  • the compounds can be combined with sterile aqueous or organic media to form injectable solutions or suspensions.
  • solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically-acceptable acid addition salts or salts with base of the compounds.
  • the injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans.
  • Examples 1-4 illustrates the process for the preparation of the polymorphicForm-1 of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
  • Example-1
  • Example 6 Process for the preparation of the polymorphic Form-II of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyI]-2-ethoxypropanoic acid,
  • Example 7 Process for the preparation of the polymorphic Form-Ill of arginine salt of 3-[4-[2-(phenoxazin-l 0-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
  • Example 8 Process for the preparation of the polymorphic Form-IN of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyI]-2-ethoxypropanoic acid, To a solution of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (1 g) in 1,4-DMSO (20 ml) was added L-arginine dissolved in water (1.2 ml) slowly with constant stirring. The reaction mixture was stirred at room temperature for 24h.
  • Example 9 Process for the preparation of the polymorphic Form-V of arginine salt of3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
  • Example 10 Process for the preparation of the polymorphic Form- VI of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
  • Example 11 Process for the preparation of the polymorphic Form- VII of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, Polymo ⁇ hic Form-I of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid (1 g), obtained by the process described in Example-3 above was dissolved in methanol (25 ml) and evaporated under vacuum to yield Form- VII of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, as an amo ⁇ hous white powder (0.9 g) which has the characteristics given earlier.
  • Example 12 Process for the preparation of the polymorphic form- VIII of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyI]-2-ethoxypropanoic acid,
  • Example 13 Process for the preparation of the polymorphic Form-IX of arginine salt of 3-[4-[2-(phenoxazin-10-yI)ethoxy]phenyl]-2-ethoxypropanoic acid,
  • Example 14 Process for the preparation of the polymorphic Form-X of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
  • Example 15 Process for the preparation of the polymorphic Form-XI of arginine salt of 3-[4-[2-(phenoxazin-10-yI)ethoxy]phenyI]-2-ethoxypropanoic acid,
  • Example 16 Process for the preparation of mixture of polymorphic Forms I and X of arginine salt of 3-[4-[2-(phenoxazin-10-yI)ethoxy]phenyl]-2-ethoxypropanoic acid,
  • Example 17 Process for the preparation of polymorphic Form I of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Cardiology (AREA)
  • Obesity (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Rheumatology (AREA)
  • Hematology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Endocrinology (AREA)
  • Urology & Nephrology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Dermatology (AREA)
  • Pain & Pain Management (AREA)
  • Ophthalmology & Optometry (AREA)
  • Reproductive Health (AREA)
  • Epidemiology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Vascular Medicine (AREA)
  • Emergency Medicine (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

This invention relates to novel polymorphic/pseudopolymorphic forms of arginine salt of 3-[4-[2-(phenoxazin-10-y1)ethoxy]pheny1]-2-ethoxypropanoic acid, having formula (I). The invention also relates to a pharmaceutical composition comprising the novel polymorphic form or their mixture and a pharmaceutically acceptable carrier. The polymorphic forms of the present invention are more active, as antidiabetic and hypolipidemic agent, than the novel 3-[4-[2-(phenoxazin-10-y1)ethoxy]phenyl]-2-ethoxypropanoic acid.

Description

NOVEL POLYMORPHIC FORMS OF AN ANTIDIABETIC
AGENT : PROCESS FOR THEIR PREPARATION AND A
PHARMACEUTICAL COMPOSITION CONTAINING THEM
Background of the invention
This invention relates to novel polymorphic / pseudopolymorphic forms of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I shown below. The invention also relates to a pharmaceutical composition comprising the novel polymorphic form or their mixture and a pharmaceutically acceptable carrier. The polymorphic forms of the present invention are more active, as antidiabetic and hypolipidemic agent, than the novel 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
Figure imgf000003_0001
(I)
The present invention also relates to a process for the preparation of novel polymoφhic / pseudopolymorphic Forms of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula (I).
The polymoφhic Forms of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]- 2-ethoxypropanoic acid, of formula (I) defined above of the present invention are useful for the treatment and / or prophylaxis of hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, obesity, glucose intolerance, insulin resistance and also diseases or conditions in which insulin resistance is the underlying pathophysiological mechanism. Examples of these diseases and conditions are type II diabetes, impaired glucose tolerance, dyslipidaemia, hypertension, coronary heart disease and other cardiovascular disorders including atherosclerosis. The polymoφhic Forms of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, of formula (I) are also useful for the treatment of insulin resistance associated with obesity and psoriasis. The polymoφhics Forms of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid, of formula (I) can also be used to treat diabetic complications and can be used for treatment and / or prophylaxis of other diseases and conditions such as polycystic ovarian syndrome (PCOS), certain renal diseases including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal diseases and microalbuminuria as well as certain eating disorders, as aldose reductase inhibitors and for improving cognitive functions in dementia.
Previously, the oral diabetic medicines consisting of sulphonyl urea were believed to be effective in bringing down the sugar level in blood (Hypoglycemic) but they lacked efficiency in preventing/reducing diabetes related complications like cataract, nervous break down, retinopathia etc. (which are usually the chronic ailments accompanied by diabetes). Aldose reductase is the enzyme which reduces aldose present in the humans and animals into corresponding polyols which, in turn, are stored or accumulated in the kidneys, peripheral nerves, eye lens of the diabetic patients and manifest themselves in the above mentioned complications.
The latest trend that has, of late, crept into the pharmaceutical industry is the studies on polymoφhism in drugs and the difference in the activity of different polymoφhic forms of a given drug. By the term polymoφhism we mean to include different physical forms, crystal forms, crystalline / liquid crystalline / non-crystalline (amoφhous) forms. This has especially become very interesting after observing that many antibiotics, antibacterials, tranquilizers etc., exhibit polymoφhism and some/one of the polymoφhic forms of given drug exhibit superior bio-availability and consequently show much higher activity compared to other polymoφhs. Sertraline, Frentizole, Ranitidine, Sulfathiazole, Indomethacine etc. are some of the important examples of pharmaceuticals which exhibit polymoφhism. Polymoφhism in drugs is a topic of current interest and is evident from the host of patents being granted. To cite a few, US 5700820 discloses six polymoφhic forms of Troglitazone, US 5248699 discusses about five polymoφhic forms of Sertraline hydrochloride while EP 014590 describes four polymoφhic forms of Frentizole. EP 490648 and EP 022527 also deal with the subject of polymoφhism in drugs.
Summary of the invention
In our copending application number 2416/MAS/97 we have described novel β-aryl α- oxy substituted alkylcarboxylic acids of the general formula (a),
Figure imgf000005_0001
their pharmaceutically salts, their pharmaceutically solvated and their pharmaceutically acceptable compositions containing them. The pharmaceutical salts of the compounds of the general formula (a) includes salts of the organic bases such as guanine, arginine, guanidine, diethylamine, choline, and the like. Particularly the compounds disclosed include 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid. The current interest in the field of polymoφhism in drugs prompted us to take up the investigation as to the possibility of polymoφhism in such compounds particularly the arginine salt of 3- [4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid. Our observations and results form the subject matter of the present invention.
We have, due to our sustained research directed towards finding out effective antidiabetic drugs, observed that arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid, exists in different polymoφhic forms possessing enhanced anti-diabetic activity. Accordingly we have, in the course of research, prepared and studied at least eleven polymoφhic forms of arginine salt of 3-[4- [2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid. These polymoφhs have been designated, by us, as Forms I, II, III, IN, V, VI, VII, VIII, IX, X and the mixture. Detailed Description of the Invention
Our present invention relates to an observation that arginine salt of 3-[4-[2-(phenoxazin- 10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid exhibits polymoφhism, which has not been reported till date. The polymoφhic Forms I, II, III, IN and N are obtained from different solvents like isopropyl alcohol, acetone, 1,4-dioxane, dimethylsulphoxide, and dimethylformarnide respectively. Form NI is obtained by dissolving any form (Form I-
V) in water and freeze drying. Similarly Form VII is obtained by dissolving any form (Form I-V) in methanol and quick evaporation of the solvent under reduced pressure at
40-60 °C. Form VIII is obtained by refluxing Form-I in 1,4-dioxane. Form-IX is obtained by refluxing Form- VIII in isopropyl alcohol. Form X is prepared by heating
Form I to 185 °C and cooling it to room temperature. Form XI is prepared by heating
Form X to 175 °C and cooling it to room temperature.
From powder X-ray diffraction studies Forms I, II, III, IV, N, NIII, IX and XI are found to be crystalline in nature. Forms VI, VII and X did not give any peaks in X- ray diffraction due to amoφhous nature.
DSC of the polymoφhic Form I shows melting endotherm at 181 °C. In the mixture of polymoφhic Forms I and X there is an indication to one of the endotherm at 185 °C and 181 °C. Form II displays endotherms at 131 °C, 166 °C, 178 °C, 214 °C and 276 °C and exotherms at 169 °C. Form III exhibits melting endotherm 182 °C in addition to an exotherm at 168 °C. Form IV exhibits endotherms at 149 °C, 164 °C and 185 °C and an exotherm at 171 °C. Form V exhibits endotherms at 119 °C, 164 °C, 172 °C and 185 °C in addition to a melting exotherm at 173 °C. Form VI exhibits exotherm at 157 °C and endotherms at 179 °C and 183 °C. Form VII exhibits exotherm at 132 °C and endotherms at 176 °C and 184 °C. Form VIII there was a similar exotherm of Form VI at 158 °C and the melting endotherm at 178 °C, whereas in Form IX there was only one shaφ melting endotherm at 176 °C. Form X displays an exotherm at 163 °C and melting endotherm at 184 °C. Form XI exhibits a melting endotherm at 184 °C. All these polymoφhic forms were proved to be identical in solution as evident from Nuclear Magnetic Resonance (NMR), Ultra Violet (UV) & Mass spectral data. On the other hand, solid state techniques like Differential Scanning Calorimetry (DSC), Powder X-Ray Diffractometry (XRD) and Infra Red spectroscopy (IR) revealed the difference among these forms.
Brief Description of the Figures
X-ray powder diffraction pattern has been obtained on a Rigaku D/Max 2200 model diffractometer equiped with horizontal gonimometer in Θ/2 Θ geometry. The copper K α ( λ=1.5418A) radiation was used and the sample was scanned between 3-45 degrees
2Θ.
Fig. 1 is a characteristic X-ray powder diffraction pattern of Form I. Fig. 2 is a characteristic X-ray powder diffraction pattern of Form II.
Fig. 3 is a characteristic X-ray powder diffraction pattern of Form III.
Fig. 4 is a characteristic X-ray powder diffraction pattern of Form IN.
Fig. 5 is a characteristic X-ray powder diffraction pattern of Form N.
Fig. 6 is a characteristic X-ray powder diffraction pattern of Form VI. Fig. 7 is a characteristic X-ray powder diffraction pattern of Form VII.
Fig. 8 is a characteristic X-ray powder diffraction pattern of Form VIII.
Fig. 9 is a characteristic X-ray powder diffraction pattern of Form IX.
Fig. 10 is a characteristic X-ray powder diffraction pattern of Form X.
Fig. 11 is a characteristic X-ray powder diffraction pattern of Form XI. Fig. 12 is a characteristic X-ray powder diffraction pattern of polymoφhic form mixture.
Differential scanning calorimeter was performed on a Shimadzu DSC-50 equipped with a controller. The data was collected on to a Pentium PC using a Shimadzu TA-50 software. The samples weighed in aluminum cells were heated from room temperature to 220 °C at a heating rate of 5 °C /min. The empty aluminum cell was used as a reference. Dry nitrogen gas was purged through DSC cell continuously throughout the analysis at a flow of 30 ml/min.
Fig. 13 is a characteristic differential scanning calorimetric thermogram of Form I. Fig. 14 is a characteristic differential scanning calorimetric thermogram of Form II. Fig. 15 is a characteristic differential scanning calorimetric thermogram of Form III. Fig. 16 is a characteristic differential scanning calorimetric thermogram of Form IV. Fig. 17 is a characteristic differential scanning calorimetric thermogram of Form V. Fig. 18 is a characteristic differential scanning calorimetric thermogram of Form VI. Fig. 19 is a characteristic differential scanning calorimetric thermogram of Form VII. Fig. 20 is a characteristic differential scanning calorimetric thermogram of Form VIII. Fig. 21 is. a characteristic differential scanning calorimetric thermogram of Form IX. Fig. 22 is a characteristic differential scanning calorimetric thermogram of Form X. Fig. 23 is a characteristic differential scanning calorimetric thermogram of Form XI. Fig. 24 is a characteristic differential scanning calorimetric thermogram of polymoφhic form mixture.
FT-IR Spectrum was recorded in solid state as KBr dispersion using Perkin-Elmer 1650 FT-IR Spectrophotometer.
Fig. 25 is a characteristic infrared absoφtion spectrum of Form I in KBr. Fig. 26 is a characteristic infrared absoφtion spectrum of Form II in KBr. Fig. 27 is a characteristic infrared absoφtion spectrum of Form III in KBr. Fig. 28 is a characteristic infrared absoφtion spectrum of Form IV in KBr. Fig. 29 is a characteristic infrared absoφtion spectrum of Form V in KBr.
Fig. 30 is a characteristic infrared absoφtion spectrum of Form VI in KBr. FFiigg.. 3311 i iss aa cchhaarraacctteeririssttiicc infrared absoφtion spectrum of Form VII in KBr. Fig. 32 is a characteristic infrared absoφtion spectrum of Form VIII in KBr. Fig. 33 is a characteristic infrared absoφtion spectrum of Form IX in KBr. Fig. 34 is a characteristic infrared absoφtion spectrum of Form X in KBr. Fig. 35 is a characteristic infrared absoφtion spectrum of Form XI in KBr. F Fiigg.. 3366 i iss aa cchhaarraacctteeπrissttiicc infrared absoφtion spectrum of polymoφhic form mixture in KBr. According to a feature of the present invention, there is provided a novel polymoφhic Form-I of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I which is characterized by the following data :
DSC: Endotherms at 181.21 °C (onset at 177.70 °C) (Fig -13) X-ray powder diffraction (2Θ): 8J8, 12.40, 16.66, 18.80, 19.44, 22.32, 22.84,
23.10, 23.50, 24.72, 29.84, (Fig -1)
Infrared absoφtion bands (cm"1): 3249, 3062, 1709, 1587, 1489, 1374, 1272,
1243, 1112, 1043, 919, 737, 673, 543, (Fig -25)
According to another feature of the present invention, there is provided a novel polymoφhic Form-II of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid, having the formula I which is characterized by the following data :
DSC: Endotherms at 131 °C, 166.24 °C and 178.96 °C (Fig -14) Exotherm at 169.73 °C
X-ray powder diffraction (2Θ): 6.78, 11.5, 12.08, 16.44, 19.34, 22.30, 22.72, 24.40, 26.66 (Fig -2)
Infrared absoφtion bands (cm-1): 3055, 1711, 1589, 1510, 1491, 1376, 1274, 1111, 1039, 810, 730, 543, (Fig -26)
According to yet another feature of the present invention, there is provided a novel polymoφhic Form-Ill of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid, having the formula I which is characterized by the following data : DSC: Endotherm at 182.20 °C (onset at 171 °C) (Fig-15)
Small endotherms at 99.66 °C, 164.38 °C Exotherm at 168.00 °C
X-ray powder diffraction (2Θ): 6.80, 12.10, 15.84, 17.02, 19.40, 22.32, 22.68, 24.38, 26.36, (Fig -3) Infrared absoφtion bands (cm-1): 3061, 1710, 1588, 1510, 1491, 1379, 1273,
1110, 1040, 805, 739, and 543, (Fig -27) According to yet another feature of the present invention, there is provided a novel polymoφhic Form-IV of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid, having the formula I which is characterized by the following data :
DSC: Endotherms at 149.85 °C, 185.60 °C (onset at 147.78 °C) (Fig -16)
Small Endotherm at 164.51 °C
Small Exotherm at 171.80 °C
X-ray powder diffraction (2Θ): 6.78, 12.66, 15.96, 16.54, 1934, 22.78, 24.42, 26.70, 31.70, (Fig -4)
Infrared absoφtion bands (cm"1): 3056, 1711, 1589, 1493, 1381, 1274, 1242,
1101, 1060, 805, 743, and 543.7, (Fig -28)
According to yet another feature of the present invention, there is provided a novel polymoφhic Form-V of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid, having the formula I which is characterized by the following data :
DSC: Endotherm at 185.95 °C, (onset at 178.09 °C) (Fig -17) Small endotherms at 119.81 °C, 164.69 °C, 172.44 °C Small exotherm at 173.82 °C
X-ray powder diffraction (2Θ): 6.76, 12.10, 15.96, 17.00, 18.50, 19.40, 22.38, 22.44, 24.44, 26.30, (Fig -5)
Infrared absoφtion bands (cm'1): 3266, 3055, 1711, 1589, 1510, 1492, 1379, 1274, 1175, 1111, 1040, 918, 819, 730, 676, 544, (Fig -29)
According to yet another feature of the present invention, there is provided a novel polymoφhic Form- VI of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid, having the formula I which is characterized by the following data : DSC: Endotherms at 179.11 °C and 183.69 °C (onset at 157.98 °C), (Fig -18)
Small endotherm at 77.80 °C Exotherm at 157.98 °C,
X-ray powder diffraction (2Θ): No diffraction peaks due to its amoφhous nature, (fιg-6)
Infrared absoφtion bands (cm'1): 3065, 1629, 1490, 1377, 1273, 1244, 1109, 1042, 805, 740, 539, (Fig -30)
According to yet another feature of the present invention, there is provided a novel polymoφhic Form- VII of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid, having the formula I which is characterized by the following data :
DSC: Endotherms at 176.63 °C (onset at 169.06 °C) and 184.09 °C (Fig -19) Exotherm at 132.93 °C,
X-ray powder diffraction (2Θ): No diffraction peaks due to its amoφhous nature, (Fig-7) Infrared absoφtion bands (cm-1): 3065, 1629, 1490, 1377, 1273, 1109, 1042,
740, 541, (Fig -31)
According to yet another feature of the present invention, there is provided a novel polymoφhic Form- VIII of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid, having the formula I which is characterized by the following data :
DSC: Endotherm at 178.12 °C (onset at 167.15 °C), (Fig -20)
Small Endotherm at 152.72 °C
Exotherm at 158.27 °C X-ray powder diffraction (2Θ): 4J6, 11.02, 15.94, 19.50, 20.22, 22.22, 27.38,
(Fig -8)
Infrared absoφtion bands (cm'1): 3151, 1629, 1490, 1378, 1272, 1244, 1104,
1041, 742, 549, (Fig -32) According to yet another feature of the present invention, there is provided a novel polymoφhic Form-IX of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid, having the formula I which is characterized by the following data :
DSC: Endotherm at 176.67 °C (onset at 173.36 °C), (Fig -21)
X-ray powder diffraction (2Θ): 8.20, 12.42, 16.66, 18.80, 19.44, 22.30, 23.08,
27.38, 28.48, 29.84, (Fig -9)
Infrared absoφtion bands (cm"1): 3066, 1588, 1489, 1376, 1273, 1243, 1110,
1043, 919, 805, 737, 543, (Fig -33)
According to still another feature of the present invention, there is provided a novel polymoφhic Form-X of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid, having the formula I which is characterized by the following data : DSC: Endotherm at 184.53 °C, (Fig -22)
Exotherm at, 162.67 °C
X-ray powder diffraction (2Θ): No diffraction peaks due to its amoφhous nature,
(Fig -10)
Infrared absoφtion bands (cm"1): 3413, 1630, 1511, 1491, 1377, 1273, 1244, 1176, 1108, 741, (Fig -34)
According to yet another feature of the present invention, there is provided a novel polymoφhic Form-XI of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid, having the formula I which is characterized by the following data :
DSC: Endotherm at 184.40 °C (onset at 177.67 °C), (Fig -23) X-ray powder diffraction (2Θ): 7.38, 7.56, 11.90, 12.32, 14.80, 16.40, 19.58, 20.48, 22.34, 22.90, 23.54, (Fig -11)
Infrared absoφtion bands (cm'1): 3383, 2925, 1629, 1510, 1490, 1377, 1273, 1243, 1090, 1041, 739, 539, (Fig -35) According to yet another feature of the present invention, there is provided a novel mixture of polymoφhic Forms I and X of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I which is characterized by the following data :
DSC: Endotherms at 181.28 °C, 18531 °C, (onset at 173.54 °C) (Fig -24) X-ray powder diffraction (2Θ): 8J6, 12.40, 16.64, 18.78, 19.42, 2234, 22.80, 23.08, 29.84, (Fig -12)
Infrared absoφtion bands (cm'1): 3247, 3066, 1708, 1587, 1510, 1489, 1375, 1273, 1244, 1178, 1111, 1043, 805, 737, 673, 543, (Fig -36)
According to another feature of the present invention, there is provided a process for the preparation of novel polymoφhic Form-I of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid, of the formula I, having the characteristics described earlier, which comprises :
(i) synthesizing 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, employing known methods and dissolving in an organic solvent,
(ii) adding L-arginine dissolved in water slowly with constant stirring to the solution obtained in step (i), (iii) stirring the reaction mixture at a temperature of 40-80 °C for a period in the range of 18-30 h to obtain a white crystalline precipitate, (iv) filtering the white crystalline precipitate obtained in step (iii) above and (v) drying under vacuum at a temperature of 40-45 °C for a period in the range of 4- 16 h to yield Form-I of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid.
According to another feature of the present invention, there is provided an alternate process for the preparation of novel polymoφhic Form-I of arginine salt of 3-[4-[2- (phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, of the formula I, having the characteristics described earlier, which comprises : (i) synthesizing 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxyρropanoic acid, employing known methods and dissolving in an organic solvent,
(ii) adding L-arginine dissolved in water slowly with constant stirring to the solution obtained in step (i), (iii) stirring the reaction mixture at room temperature for a period in the range of 90-
100 h to obtain a white crystalline precipitate,
(iv) filtering the white crystalline precipitate obtained in step (iii) above and
(v) drying under vacuum at a temperature of 40-45 °C for a period in the range of 4-
16 h to yield Form-I of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid.
The temperature employed in the stirring step (iii) may be preferably 40-50 °C.
According to another feature of the present invention, there is provided a process for the preparation of novel polymoφhic Form-II of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid, of the formula I, having the characteristics described earlier, which comprises :
(i) synthesizing 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, employing known methods and dissolving in acetone,
(ii) adding L-arginine dissolved in water slowly with constant stirring to the solution obtained in step (i),
(iii) stirring the reaction mixture at room temperature for a period in the range of 18-
30 h to obtain a white crystalline precipitate (iv) filtering the white crystalline precipitate obtained in step (iii) above and
(v) drying under vacuum at a temperature of 40-45 °C for a period in the range of 4-
16 h to yield Form-II of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid.
According to yet another feature of the present invention, there is provided a process for the preparation of novel polymoφhic Form-Ill of arginine salt of 3-[4-[2-(phenoxazin- 10-yl)ethoxy]ρhenyl]-2-ethoxyproρanoic acid of the formula I, having the characteristics described earlier, which comprises :
(i) synthesizing 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, employing known methods and dissolving in 1,4-dioxane,
(ii) adding L-arginine dissolved in water slowly with constant stirring to the solution obtained in step (i),
(iii) stirring the reaction mixture at room temperature for a period in the range of 18-
30 h to obtain a white crystalline precipitate (iv) filtering the white crystalline precipitate obtained in step (iii) above and
(v) drying under vacuum at a temperature of 40-45 °C for a period in the range of 4-
16 h to yield Form-Ill of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid.
According to yet another feature of the present invention, there is provided a process for the preparation of novel polymoφhic Form-IV of arginine salt of 3-[4-[2-(phenoxazin- 10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid of the formula I, having the characteristics described earlier, which comprises :
(i) synthesizing 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, employing known methods and dissolving in dimethyl sulfoxide,
(ii) adding L-arginine dissolved in water slowly with constant stirring to the solution obtained in step (i),
(iii) stirring the reaction mixture at room temperature for a period in the range of 18- 30 h to obtain a white crystalline precipitate
(iv) filtering the white crystalline precipitate obtained in step (iii) above and
(v) drying under vacuum at a temperature of 40-45 °C for a period in the range of 4-
16 h to yield Form-IV of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid. According to another feature of the present invention, there is provided a process for the preparation of novel polymoφhic Form-V of arginine salt of 3-[4-[2-(phenoxazin- 10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid of the formula I, having the characteristics described earlier, which comprises :
(i) synthesizing 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, employing known methods and dissolving in dimethyl formamide, (ii) adding L-arginine dissolved in water slowly with constant stirring in the solution obtained in step (i), (iii) stirring the reaction mixture at room temperature for a period in the range of 18- 30 h to obtain a white crystalline precipitate,
(iv) filtering the white crystalline precipitate obtained in step (iii) above and (v) drying under vacuum at a temperature of 40-45 °C for a period in the range of 4- 16 h to yield Form-V of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid.
According to another feature of the present invention, there is provided a process for the preparation of novel polymoφhic Form- VI of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid of the formula I, having the characteristics described earlier, which comprises :
(i) dissolving any of the polymoφhic Forms I-V of arginine salt of 3-[4-[2- (phenoxazϊn-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid in water and (ii) freeze drying the resulting solution to yield an amoφhous white powder of Form- VI of arginine salt of 3-[4-[2-(phenoxazin-10-yi)ethoxy]phenyl]-2- ethoxypropanoic acid.
According to another feature of the present invention, there is provided a process for the preparation of novel polymoφhic Form- VII of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid of the formula I, having the characteristics described earlier, which comprises : (i) dissolving any of the polymoφhic Forms I-V of arginine salt of 3-[4-[2- (phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid in methanol and (ii) evaporating the resulting solution under vacuum to obtain an amoφhous white powder of Form- VII of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid..
According to another feature of the present invention, there is provided a process for the preparation of novel polymoφhic Form- VIII of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid, of the formula I, having the characteristics described earlier, which comprises :
(i) synthesizing 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, employing known methods and dissolving in an organic solvent,
(ii) adding L-arginine dissolved in water slowly with constant stirring in the solution obtained in step (i),
(iii) stirring the reaction mixture at a temperature of 40-80 °C for a period in the range of 18-30 h to obtain a white crystalline precipitate,
(iv) filtering the white crystalline precipitate obtained in step (iii) above and
(v) drying under vacuum at a temperature of 40-45 °C for a period in the range of 4- 16 h to yield Form-I of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid,
(vi) refluxing the Form-I of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid, obtained above in step (v) in 1,4-dioxane for a period in the range of 8-16 h and (vii) filtering and drying under vacuum at a temperature of 40-45 °C for a period in the range of 4-16 h to yield Form-VIII of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
According to another feature of the present invention, there is provided a process for the preparation of novel polymoφhic Form-IX of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid, of the formula I, having the characteristics described earlier, which comprises :
(i) synthesizing 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, employing known methods and dissolving in an organic solvent,
(ii) adding L-arginine dissolved in water slowly with constant stirring in the solution obtained in step (i),
(iii) stirring the reaction mixture at a temperature of 40-80 °C for a period in the range of 18-30 h to obtain a white crystalline precipitate, (iv) filtering the white crystalline precipitate obtained in step (iii) above and
(v) drying under vacuum at a temperature of 40-45 °C for a period in the range of 4-
16 h to yield Form-I of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid,
(vi) refluxing the Form-I of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid, obtained above in step (v) in 1,4-dioxane for a period in the range of 8-16 h,
(vii) filtering and drying under vacuum at a temperature of 40-45 °C for a period in the range of 4-16 h to yield Form- VIII of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid, (viii) refluxing the Form- VIII of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid, obtained in step (vii) above in isopropyl alcohol for a period in the range of 8-16 h and
(ix) filtering and drying under vacuum at a temperature of 40-45 °C for a period in the range of 4-16 h to yield Form-IX of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
According to another feature of the present invention, there is provided a process for the preparation of novel polymoφhic Form-X of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid, of the formula I, having the characteristics described earlier, which comprises : (i) synthesizing 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, employing known methods and dissolving in an organic solvent,
(ii) adding L-arginine dissolved in water slowly with constant stirring to the solution obtained in step (i), (iii) stirring the reaction mixture at a temperature of 40-80 °C for a period in the range of 18-30 h to obtain a white crystalline precipitate, (iv) filtering the white crystalline precipitate obtained in step (iii) above and (v) drying under vacuum at a temperature of 40-45 °C for a period in the range of 4- 16 h to yield Form-I of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid and
(vi) heating the polymoφhic Form-I obtained in step (v) to 185 °C and cooling it to room temperature to yeild Form-X of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
According to another feature of the present invention, there is provided a process for the preparation of novel polymoφhic Form-XI of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid, of the formula I, having the characteristics described earlier, which comprises :
(i) synthesizing 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, employing known methods and dissolving in an organic solvent,
(ii) adding L-arginine dissolved in water slowly with constant stirring to the solution obtained in step (i),
(iii) stirring the reaction mixture at a temperature of 40-80 °C for a period in the range of 18-30 h to obtain a white crystalline precipitate,
(iv) filtering the white crystalline precipitate obtained in step (iii) above and
(v) drying under vacuum at a temperature of 40-45 °C for a period in the range of 4-
16 h to yield Form-I of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid, (vi) heating the polymoφhic Form-I obtained in step (v) to 185 °C and cooling it to room temperature to yeild Form-X of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid and
(vii) heating the polymoφhic Form-X obtained in step (vi) to 175 °C and cooling it to room temperature to yield Form-XI of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
According to another feature of the present invention, there is provided a process for the preparation of novel mixture of polymoφhic Form of I and X of arginine salt of 3-[4-[2- (phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, of the formula I, described earlier, which comprises :
(i) synthesizing 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, employing known methods and dissolving in an organic solvent, (ii) adding L-arginine dissolved in water slowly with constant stirring in the solution obtained in step (i),
(iii) stirring the reaction mixture at room temperature for a period in the range of 18-
30 h to separate white crystalline powder,
(iv) filtering the white crystalline powder obtained in step (iii) and (v) drying under vacuum at a temperature of 40-45 °C for a period in the range of 4-
16 h to yield mixture of polymoφhic Form of I and X of arginine salt of 3-[4-[2-
(phenoxazin- 10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
According to another feature of the present invention, there is provided an alternate process for the preparation of novel polymoφhic Form-I of arginine salt of 3-[4-[2- (phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, of the formula I, having the characteristics described earlier, which comprises :
(i) suspending any of the polymoφhic Form II to XI or the mixture of polymoφhic Form I and X of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid in isopropyl alcohol and stirring in dark conditions at room temperature for a period of 35-50 h, (ii) filtering and washing with isopropyl alcohol and
(iii) drying under vacuum at a temperature of 40-45 °C for a period in the range of 4- 16 h to yield polymoφhic Form of I of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
The organic solvents are selected from acetonitrile, ethanol, methanol and, isopropanol.
The invention also envisages a pharmaceutical composition comprising a polymoφhic Forms I and X of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid, of the formula (I) or the mixture of polymoφhic Form of I and X and a pharmaceutically acceptable carrier .
The pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, may contain flavourants, sweeteners etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions. Such compositions typically contain from 1 to 20 %, preferably 1 to 10 % by weight of active compound, the remainder of the composition being pharmaceutically acceptable carriers, diluents or solvents.
The compound of the formula (I) as defined above are clinically administered to mammals, including man, via either oral or parenteral routes. Administration by the oral route is preferred, being more convenient and avoiding the possible pain and irritation of injection. However, in circumstances where the patient cannot swallow the medication, or absoφtion following oral administration is impaired, as by disease or other abnormality, it is essential that the drug be administered parenterally. By either route, the dosage is in the range of about 0.01 to about 100 mg / kg body weight of the subject per day or preferably about 0.01 to about 30 mg / kg body weight per day administered singly or as a divided dose. However, the optimum dosage for the individual subject being treated will be determined by the person responsible for treatment, generally smaller doses being administered initially and thereafter increments made to determine the most suitable dosage.
Suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions. The active compound will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above. Thus, for oral administration, the compounds can be combined ' with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical compositions, may, if desired, contain additional components such as flavourants, sweeteners, excipients and the like. For parenteral administration, the compounds can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. For example, solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically-acceptable acid addition salts or salts with base of the compounds. The injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans.
The present invention is described in detail in the examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
Examples 1-4 illustrates the process for the preparation of the polymorphicForm-1 of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
Example-1 ;
To a solution of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (1 g) in ethanol (25 ml) was added L-arginine dissolved in water (1.2 ml) slowly with constant stirring. The reaction mixture was stirred at 40-50 °C for 24h. The white crystalline precipitate formed was separated and dried under vacuum at 40-45 °C for 4h to yield Form-I of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (1J5 g) which has the characteristics given earlier.
Example- 2 ;
To a solution of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (1 g) in isopropyl alcohol (25 ml) was added L-arginine dissolved in water (1.2 ml) slowly with constant stirring. The reaction mixture was stirred at 40-50 °C for 24h. The white crystalline precipitate formed was separated and dried under vacuum at 40-45 °C for 4h to yield Form-I of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid (1.27 g) which has the characteristics given earlier.
Example -3 ;
To a solution of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (1 g) in acetonitrile (25 ml) was added L-arginine dissolved in water (1.2 ml) slowly with constant stirring. The reaction mixture was stirred at 40-50 °C for 24h. The white crystalline precipitate formed was separated and dried under vacuum at 40-45 °C for 4h to yield Form-I arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid (1.24 g) which has the characteristics given earlier.
Exampie-4 :
To a solution of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (1 g) in methanol (15 ml) was added L-arginine dissolved in water (1.2 ml) slowly with constant stirring. The reaction mixture was strrred at 40-50 °C for 24h. The white crystalline precipitate formed was separated and dried under vacuum at 40-45 °C for 4h to yield Form-I arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid (1.05 g) which has the characteristics given earlier.
ExampIe-5 : To a solution of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (1 g) in isopropyl alcohol (25 ml) was added L-arginine dissolved in water (1.2 ml) slowly with constant stirring. The reaction mixture was stπred at room temperature for 90-100 h. The white crystalline precipitate formed was separated and dried under vacuum at 40- 45 °C for 4h to yield Form-I arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]- 2-ethoxypropanoic acid (1.05 g) which has the characteristics given earlier.
Example 6 : Process for the preparation of the polymorphic Form-II of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyI]-2-ethoxypropanoic acid,
To a solution of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (1 g) in acetone (25 ml) was added L-arginine dissolved in water (1.2 ml) slowly with constant stirring. The reaction mixture was stirred at room temperature for 24h. The white crystalline precipitate formed was separated and dried under vacuum at 40-45 °C for 4h to yield Form-II of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid (1.29 g) which has the characteristics given earlier.
Example 7 : Process for the preparation of the polymorphic Form-Ill of arginine salt of 3-[4-[2-(phenoxazin-l 0-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
To a solution of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (1 g) in 1,4-dioxane (25 ml) was added L-arginine dissolved in water (1.2 ml) slowly with constant stirring. The reaction mixture was stirred at room temperature for 24h. The white crystalline precipitate formed was separated and dried under vacuum at 40-45 °C for 4h to yield Form-Ill of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid (1.25 g) which has the characteristics given earlier.
Example 8 : Process for the preparation of the polymorphic Form-IN of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyI]-2-ethoxypropanoic acid, To a solution of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (1 g) in 1,4-DMSO (20 ml) was added L-arginine dissolved in water (1.2 ml) slowly with constant stirring. The reaction mixture was stirred at room temperature for 24h. The white crystalline precipitate formed was separated and dried under vacuum at 40-45 °C for 4h to yield Form-Ill of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid (1.3 g) which has the characteristics given earlier.
Example 9 : Process for the preparation of the polymorphic Form-V of arginine salt of3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
To a solution of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (1 g) in 1,4-DMF (25 ml) was added L-arginine dissolved in water (1.2 ml) slowly with constant stirring. The reaction mixture was stiπed at room temperature for 24h. The white crystalline precipitate formed was separated and dried under vacuum at 40-45 °C for 4h to yield Form-V of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid (1J7 g) which has the characteristics given earlier.
Example 10 : Process for the preparation of the polymorphic Form- VI of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
Polymoφhic Form-I of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid (1 g), obtained by the process described in Example-2 above was dissolved in water (10 ml) and freeze dried to yield Form- VI of arginine salt of 3-[4-[2- (phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, as an amoφhous white powder (0.95 g) which has the characteristics given earlier.
Example 11 : Process for the preparation of the polymorphic Form- VII of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, Polymoφhic Form-I of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid (1 g), obtained by the process described in Example-3 above was dissolved in methanol (25 ml) and evaporated under vacuum to yield Form- VII of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, as an amoφhous white powder (0.9 g) which has the characteristics given earlier.
Example 12 : Process for the preparation of the polymorphic form- VIII of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyI]-2-ethoxypropanoic acid,
Polymoφhic Form-I of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid (1 g), obtained by the process described in Example-2 above was refluxed in 1,4-dioxane (10 ml), filtered and dried under vacuum to yield Form- VIII of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid which has the characteristics given earlier.
Example 13 : Process for the preparation of the polymorphic Form-IX of arginine salt of 3-[4-[2-(phenoxazin-10-yI)ethoxy]phenyl]-2-ethoxypropanoic acid,
Polymoφhic Form-VIII arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid (1 g), obtained by the process described in Example- 12 was refluxed in isopropanol (10 ml), filtered and dried under vacuum to yield Form-IX of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid which has the characteristics given earlier.
Example 14 : Process for the preparation of the polymorphic Form-X of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
Polymoφhic Form-I of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid obtained by any of the process described in Examples- 1-5 was heated to 185 °C and cooled it to room temperature to yield Form-X of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid which has the characteristics given earlier.
Example 15 : Process for the preparation of the polymorphic Form-XI of arginine salt of 3-[4-[2-(phenoxazin-10-yI)ethoxy]phenyI]-2-ethoxypropanoic acid,
Polymoφhic Form-X of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid obtained by the process described in Example 14 was heated to 175 °C and cooled it to room temperature to yield Form-XI of arginine salt of 3-[4-[2- (phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid which has the characteristics given earlier.
Example 16 : Process for the preparation of mixture of polymorphic Forms I and X of arginine salt of 3-[4-[2-(phenoxazin-10-yI)ethoxy]phenyl]-2-ethoxypropanoic acid,
To a solution of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (1 g) in isopropyl alcohol (25 ml) was added L-arginine dissolved in water (1.2 ml) slowly with constant stirring. The reaction mixture was stirred at room temperature for 24h. The white crystalline powder formed was separated and dried under vacuum at 40-45 °C for 4h to yield a mixture of polymoφhic Forms I and X of arginine salt of 3-[4-[2- (phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (1.05 g).
Example 17 : Process for the preparation of polymorphic Form I of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
A mixture of polymoφhic Forms I and X of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid (1.0 g) is suspended in isopropyl alcohol (10 ml) the reaction flask was covered with carbon paper and stirred at room temperature for a period of 35-50 h. The reaction mixture was filtered, washed with little isopropyl alcohol and dried under vacuum at 40-45 °C for 4h to yield polymoφhic Form I of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (0.97 g).
ADVANTAGES OF THE INVENTION :
• The 'polymoφhic Forms of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid, are more active / bio-available and are therefore very useful for the treatment or prophylaxis.
• Ease in formulation containing these forms resulting in higher activity / bioavailability, in terms of lowering plasma blood sugar and plasma triglycerides.

Claims

We claim
1. A polymoφhic Form-I of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I,
Figure imgf000029_0001
which is characterized by the data described hereunder :
DSC: Endotherms at 181.21 °C (onset at 177.70 °C)
X-ray powder diffraction (2Θ): 8J8, 12.40, 16.66, 18.80, 19.44, 22.32, 22.84,
23.10, 23.50, 24.72, 29.84,
Infrared absoφtion bands (cm'1): 3249, 3062, 1709, 1587, 1489, 1374, 1272, 1243, 1112, 1043, 919, 737, 673, 543.
2. A polymoφhic Form-II of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I,
Figure imgf000029_0002
which is characterized by the data described hereunder :
DSC: Endotherms at 131 °C, 166.24 °C and 178.96 °C
Exotherm at 169.73 °C
X-ray powder diffraction (2Θ): 6.78, 11.5, 12.08, 16.44, 19.34, 2230, 22.72,
24.40, 26.66 Infrared absoφtion bands (cm'1): 3055, 1711, 1589, 1510, 1491, 1376, 1274,
1111, 1039, 810, 730, 543.
3. A polymoφhic Form-Ill of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I,
Figure imgf000030_0001
which is characterized by the data described hereunder :
DSC: Exotherm at 168.00 °C
Endotherm at 182.20 °C (onset at 171 °C),
Small endotherms at 99.66 °C, 164.38 °C
X-ray powder diffraction (2Θ): 6.80, 12.10, 15.84, 17.02, 19.40, 22.32, 22.68,
24.38, 2636,
Infrared absoφtion bands (cm'1): 3061, 1710, 1588, 1510, 1491, 1379, 1273,
1110, 1040, 805, 739, and 543.
4. A polymoφhic Form-IN of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl] -2 -ethoxypropanoic acid, having the formula I,
Figure imgf000030_0002
which is characterized by the data described hereunder : DSC: Small Exotherm at 171.80 °C
Endotherms at 149.85 °C, 185.60 °C (onset at 147.78 °C) Small Endotherm at 164.51 °C
X-ray powder diffraction (2Θ): 6.78, 12.66, 15.96, 16.54, 19.34, 22.78, 24.42, 26.70, 31.70, Infrared absoφtion bands (cm'1): 3056, 1711, 1589, 1493, 1381, 1274, 1242,
1101, 1060, 805, 743, and 543.7.
5. A polymoφhic Form-V of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I,
Figure imgf000031_0001
which is characterized by the data described hereunder : DSC: Small exotherm at 173.82 °C Endotherm at 185.95 °C, (onset at 178.09 °C) Small endotherms at 119.81 °C, 164.69 °C, 172.44 °C
X-ray powder diffraction (2Θ): 6.76, 12.10, 15.96, 17.00, 18.50, 19.40, 22.38, 22.44, 24.44, 26.30,
Infrared absoφtion bands (cm'1): 3266, 3055, 1711, 1589, 1510, 1492, 1379, 1274, 1175, 1111, 1040, 918, 819, 730, 676, 544.
6. A polymoφhic Form- VI of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I,
Figure imgf000031_0002
which is characterized by the data described hereunder : DSC: Exotherm at 157.98 °C,
Endotherms at 179.11 °C and 183.69 °C (onset at 157.98 °C), Small endotherm at 77.80 °C
X-ray powder diffraction (2Θ): No diffraction peaks due to its amoφhous nature, Infrared absoφtion bands (cm'1): 3065, 1629, 1490, 1377, 1273, 1244, 1109, 1042, 805, 740, 539.
7. A polymoφhic Form- VII of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I,
Figure imgf000032_0001
which is characterized by the data described hereunder : DSC: Exotherm at 132.93 °C,
Endotherms at 176.63 °C (onset at 169.06 °C) and 184.09 °C X-ray powder diffraction (2Θ): No diffraction peaks due to its amoφhous nature, Infrared absoφtion bands (cm'1): 3065, 1629, 1490, 1377, 1273, 1109, 1042, 740, 541.
A polymoφhic Form- VIII of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I,
Figure imgf000032_0002
which is characterized by the data described hereunder : DSC: Exotherm at 158.27 °C Endotherm at 178.12 °C (onset at 167.15 °C), Small Endotherm at 152.72 °C
X-ray powder diffraction (2Θ): 4.16, 11.02, 15.94, 19.50, 20.22, 22.22, 27.38, Infrared absoφtion bands (cm'1): 3151, 1629, 1490, 1378, 1272, 1244, 1104, 1041, 742, 549.
A polymoφhic Form-IX of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I,
Figure imgf000032_0003
which is characterized by the data described hereunder :
DSC: Endotherm at 176.67 °C (onset at 173.36 °C), (Fig -21) X-ray powder diffraction (20):
8.20, 12.42, 16.66, 18.80, 19.44, 22.30, 23.08, 27:38, 28.48, 29.84,
(Fig -9) Infrared absoφtion bands (cm"1): 3066, 1588, 1489, 1376, 1273, 1243, 1110,
1043, 919, 805, 737, 543, (Fig -33)
10. A polymoφhic Form-X of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I,
Figure imgf000033_0001
which is characterized by the data described hereunder :
DSC: Endotherm at 184.53 °C,)
Exotherm at, 162.67 °C
X-ray powder diffraction (2Θ): No diffraction peaks due to its amoφhous nature, Infrared absoφtion bands (cm'1): 3413, 1630, 1511, 1491, 1377, 1273, 1244,
1176, 1108, 741.
11. A polymoφhic Form-XI of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I,
Figure imgf000033_0002
which is characterized by the data described hereunder :
DSC: Endotherm at 184.40 °C (onset at 177.67 °C),
X-ray powder diffraction (2Θ): 7.38, 7.56, 11.90, 12.32, 14.80, 16.40, 19.58,
20.48, 22.34, 22.90, 23.54, Infrared absoφtion bands (cm"1): 3383, 2925, 1629, 1510, 1490, 1377, 1273, 1243, 1090, 1041, 739, 539.
12. A mixture of polymoφhic Form I and X of arginine salt of 3-[4-[2-(phenoxazin- 10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I,
Figure imgf000034_0001
which is characterized by the following data :
DSC: Endotherms at 181.28 °C, 185.31 °C, (onset at 173.54 °C) X-ray powder diffraction (2Θ): 8J6, 12.40, 16.64, 18.78, 19.42, 22.34, 22.80,
23.08, 29.84,
Infrared absoφtion bands (cm"1): 3247, 3066, 1708, 1587, 1510, 1489, 1375, 1273, 1244, 1178, 1111, 1043, 805, 737, 673, 543.
13. A pharmaceutical composition comprising a polymoφhic Form selected from Form I to XI or a mixture of polymoφhic Form I and X of arginine salt of 3-[4- [2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I
Figure imgf000034_0002
and a pharmaceutically acceptable carrier.
14. A process for the preparation of the polymoφhic Form-I of arginine salt of 3-[4- [2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the characteristics defined in claim 1 , which comprises : (i) synthesizing 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, employing known methods and dissolving in an organic solvent, (ii) adding L-arginine dissolved in water slowly with constant stirring to the solution obtained in step (i), (iii) stirring the reaction mixture at a temperature of 40-80 °C for a period in the range of 18-30 h to obtain a white crystalline precipitate, (iv) filtering the white crystalline precipitate obtained in step (iii) above and (v) drying under vacuum at a temperature of 40-45 °C for a period in the range of 4-
16 h to yield Form-I of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
15. A process for the preparation of the polymoφhic Form-I of arginine salt of 3-[4- [2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the characteristics defined in claim 1, which comprises :
(i) synthesizing 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, employing known methods and dissolving in an organic solvent, (ii) adding L-arginine dissolved in water slowly with constant stirring to the solution obtained in step (i), (iii) stirring the reaction mixture at room temperature for a period in the range of 90- 100 h to obtain a white crystalline precipitate, (iv) filtering the white crystalline precipitate obtained in step (iii) above and (v) drying under vacuum at a temperature of 40-45 °C for a period in the range of 4- 16 h to yield Form-I of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
16. A process for the preparation of the polymoφhic Form-II of arginine salt of 3-[4- [2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the characteristics defined in claim 2, which comprises : (i) synthesizing 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, employing known methods and dissolving in acetone, (ii) adding L-arginine dissolved in water slowly with constant stirring to the solution obtained in step (i), (iii) stirring the reaction mixture at room temperature for a period in the range of 18-
30 h to obtain a white crystalline precipitate (iv) filtering the white crystalline precipitate obtained in step (iii) above and (v) drying under vacuum at a temperature of 40-45 °C for a period in the range of 4-
16 h to yield Form-II of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
17. A process for the preparation of the polymoφhic Form-Ill of arginine salt of 3- [4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the characteristics defined in claim 3, which comprises :
(i) synthesizing 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, employing known methods and dissolving in 1,4-dioxane, (ii) adding L-arginine dissolved in water slowly with constant stirring to the solution obtained in step (i), (iii) stirring the reaction mixture at room temperature for a period in the range of 18- 30 h to obtain a white crystalline precipitate (iv) filtering the white crystalline precipitate obtained in step (iii) above and (v) drying under vacuum at a temperature of 40-45 °C for a period in the range of 4- 16 h to yield Form-Ill of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
18. A process for the preparation of the polymoφhic Form-IV of arginine salt of 3- [4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the characteristics defined in claim 4, which comprises : (i) synthesizing 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, employing known methods and dissolving in dimethyl sulfoxide, (ii) adding L-arginine dissolved in water slowly with constant stirring to the solution obtained in step (i), (iii) stirring the reaction mixture at room temperature for a period in the range of 18-
30 h to obtain a white crystalline precipitate (iv) filtering the white crystalline precipitate obtained in step (iii) above and (v) drying under vacuum at a temperature of 40-45 °C for a period in the range of 4-
16 h to yield Form-IV of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
19. A process for the preparation of the polymoφhic Form-V of arginine salt of 3-[4- [2-'(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the characteristics defined in claim 5, which comprises :
(i) synthesizing 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, employing known methods and dissolving in dimethyl formamide, (ii) adding L-arginine dissolved in water slowly with constant stirring in the solution obtained in step (i), (iii) stirring the reaction mixture at room temperature for a period in the range of 18- 30 h to obtain a white crystalline precipitate, (iv) filtering the white crystalline precipitate obtained in step (iii) above and (vi) drying under vacuum at a temperature of 40-45 °C for a period in the range of 4- 16 h to yield Form-V of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
20. A process for the preparation of the polymoφhic Form- VI of arginine salt of 3- [4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the characteristics defined in claim 6, which comprises : (i) dissolving any of the polymoφhic Forms I-V of arginine salt of 3-[4-[2- (phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, in water and
(ii) freeze drying the resulting solution to yield an amoφhous white powder of Form- VI of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid.
21. A process for the preparation of the polymoφhic Form- VII of arginine salt of 3- [4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the characteristics defined in claim 7, which comprises :
(i) dissolving any of the polymoφhic Forms I-V of arginine salt of 3-[4-[2- (phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, in methanol and
(ii) evaporating the resulting solution under vacuum to obtain an amoφhous white powder of Form-VII of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
22. A process for the preparation of the polymoφhic Form- VIII of arginine salt of 3- [4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the characteristics defined in claim 8, which comprises :
(i) synthesizing 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, employing known methods and dissolving in an organic solvent, (ii) adding L-arginine dissolved in water slowly with constant stirring in the solution obtained in step (i), (iii) stirring the reaction mixture at a temperature of 40-80 °C for a period in the range of 18-30 h to obtain a white crystalline precipitate, (iv) filtering the white crystalline precipitate obtained in step (iii) above and (v) drying under vacuum at a temperature of 40-45 °C for a period in the range of 4- 16 h to yield Form-I of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid, (vi) refluxing the Form-I of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid, obtained above in step (v) in 1,4- dioxane for a period in the range of 8-16 h and
(vii) filtering and drying under vacuum at a temperature of 40-45 °C for a period in the range of 4-16 h to yield Form- VIII of arginine salt of 3-[4-[2-(phenoxazin-
10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
23. A process for the preparation of the polymoφhic Form-IX of arginine salt of 3- [4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the characteristics defined in claim 9, which comprises :
(i) synthesizing 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, employing known methods and dissolving in an organic solvent, (ii) adding L-arginine dissolved in water slowly with constant stirring in the solution obtained in step (i),
(iii) stirring the reaction mixture at a temperature of 40-80 °C for a period in the range of 18-30 h to obtain a white crystalline precipitate, (iv) filtering the white crystalline precipitate obtained in step (iii) above and (v) drying under vacuum at a temperature of 40-45 °C for a period in the range of 4- 16 h to yield Form-I of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid, (vi) refluxing the Form-I of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid, obtained above in step (v) in 1,4- dioxane for a period in the range of 8-16 h, (vii) filtering and drying under vacuum at a temperature of 40-45 °C for a period in the range of 4-16 h to yield Form- VIII of arginine salt of 3-[4-[2-(phenoxazin- 10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, (viii) refluxing the Form- VIII of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid, obtained in step (vii) above in isopropyl alcohol for a period in the range of 8- 16 h and (viii) filtering and drying under vacuum at a temperature of 40-45 °C for a period in the range of 4-16 h to yield Form-IX of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
24. A process for the preparation of the polymoφhic Form-X of arginine salt of 3-[4- [2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the characteristics defined in claim 10, which comprises :
(i) synthesizing 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, employing known methods and dissolving in an organic solvent,
(ii) adding L-arginine dissolved in water slowly with constant stirring to the solution obtained in step (i), (iii) stirring the reaction mixture at a temperature of 40-80 °C for a period in the range of 18-30 h to obtain a white crystalline precipitate, (iv) filtering the white crystalline precipitate obtained in step (iii) above and
(v) drying under vacuum at a temperature of 40-45 °C for a period in the range of 4-
16 h to yield Form-I of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid and
(vi) heating the polymoφhic Form-I obtained in step (v) at 185 °C and cooling it to room temperature to yeild Form-X of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
25. A process for the preparation of the polymoφhic Form-XI of arginine salt of 3- [4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the characteristics defined in claim 11 , which comprises :
(i) synthesizing 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, employing known methods and dissolving in an organic solvent, (ii) adding L-arginine dissolved in water slowly with constant stirring to the solution obtained in step (i), (iii) stirring the reaction mixture at a temperature of 40-80 °C for a period in the range of 18-30 h to obtain a white crystalline precipitate, (iv) filtering the white crystalline precipitate obtained in step (iii) above and (v) drying under vacuum at a temperature of 40-45 °C for a period in the range of 4- 16 h to yield Form-I of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid, (vi) heating the polymoφhic Form-I obtained in step (v) to 185 °C and cooling it to room temperature to yeild Form-X of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid and (vii) heating the polymoφhic Form-X obtained in step (vi) to 175 °C and cooling it to room temperature to yield Form-XI of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
26. A process for the preparation of the mixture of polymoφhic Form I and X of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the characteristics defined in claim 11, which comprises :
(i) synthesizing 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, employing known methods and dissolving in an organic solvent
(ii) adding L-arginine dissolved in water slowly with constant stirring in the solution obtained in step (i),
(iii) stirring the reaction mixture at room temperature for a period in the range of 18- 30 h to separate white crystalline powder, (iv) filtering the white crystalline powder obtained in step (iii) and
(v) drying under vacuum at a temperature of 40-45 °C for a period in the range of 4- 16 h to yield mixture of polymoφhic Form I and X of arginine salt of 3-[4-[2- (phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
27. A process for the preparation of polymoφhic Form I of arginine salt of 3-[4-[2- (phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the characteristics defined in claim 1 , which comprises :
(i) suspending any of the polymoφhic Form II to XI or the mixture of polymoφhic Form I and X of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid in isopropyl alcohol and stirring in dark conditions at room temperature for a period of 35-50 h, (ii) filtering and washing with isopoφyl alcohol and (iii) drying under vacuum at a temperature of 40-45 °C for a period in the range of 4- 16 h to yield polymoφhic Form of I of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
28. A process as claimed in claim 13, wherein the temperature used in step (iii) is in the range of 40-80 °C.
29. A process as claimed in claims 14 and 22 to 26, wherein the organic solvents are selected from acetonitrile, ethanol, methanol, 1 ,4-dioxane, and isopropanol.
PCT/IB1999/000681 1999-04-16 1999-04-16 Novel polymorphic forms of an antidiabetic agent: process for their preparation and a pharmaceutical composition containing them WO2000063191A1 (en)

Priority Applications (27)

Application Number Priority Date Filing Date Title
PCT/IB1999/000681 WO2000063191A1 (en) 1999-04-16 1999-04-16 Novel polymorphic forms of an antidiabetic agent: process for their preparation and a pharmaceutical composition containing them
AU29536/99A AU2953699A (en) 1999-04-16 1999-04-16 Novel polymorphic forms of an antidiabetic agent: process for their preparation and a pharmaceutical composition containing them
AU44652/00A AU4465200A (en) 1999-04-16 2000-04-17 Novel polymorphic forms of an antidiabetic agent: process for their preparation and a pharmaceutical composition containing them
CZ20013711A CZ20013711A3 (en) 1999-04-16 2000-04-17 Novel polymorphous forms of antidiabetic agents, process of their preparation and pharmaceutical preparations in which they are comprised
RU2001130883/04A RU2001130883A (en) 1999-04-16 2000-04-17 NEW POLYMORPHIC FORMS OF ANTI-DIABETIC AGENT, METHOD FOR PRODUCING THERE AND THEIR PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
PCT/IB2000/000470 WO2000063192A1 (en) 1999-04-16 2000-04-17 Novel polymorphic forms of an antidiabetic agent: process for their preparation and pharmaceutical compositions containing them
BR0010683-6A BR0010683A (en) 1999-04-16 2000-04-17 Polymorphic forms of an antidiabetic agent: process for its preparation and pharmaceutical compositions containing the same
JP2000612284A JP2003508348A (en) 1999-04-16 2000-04-17 Novel polymorphic forms of antidiabetic agents: methods for their preparation and pharmaceutical compositions containing them
PL00351492A PL351492A1 (en) 1999-04-16 2000-04-17 Novel polymorphic forms of an antidiabetic agent: process for their preparation and pharmaceutical compositions containing them
EP00917222A EP1171430A1 (en) 1999-04-16 2000-04-17 Novel polymorphic forms of an antidiabetic agent: process for their preparation and pharmaceutical compositions containing them
MXPA01010472A MXPA01010472A (en) 1999-04-16 2000-04-17 Novel polymorphic forms of an antidiabetic agent: process for their preparation and pharmaceutical compositions containing them.
EEP200100529A EE200100529A (en) 1999-04-16 2000-04-17 Novel Polymorphic Forms of the Antidiabetic Agent: Method of Preparation and Pharmaceutical Compositions Containing Them
AU39578/00A AU3957800A (en) 1999-04-16 2000-04-17 Crystalline r- guanidines, arginine or (l) -arginine (2(s)) -2- ethoxy -3-(4- (2-(10(h) -phenoxazin -10-yl)ethoxy}phenyl)propanoate
PCT/US2000/010309 WO2000063193A1 (en) 1999-04-16 2000-04-17 Novel polymorphic forms of an antidiabetic agent: process for their preparation and a pharmaceutical composition containing them
PCT/DK2000/000188 WO2000063189A1 (en) 1999-04-16 2000-04-17 Crystalline r- guanidines, arginine or (l) -arginine (2s) -2- ethoxy -3-{4- [2-(10h -phenoxazin -10-yl)ethoxy]phenyl}propanoate
CN00807705A CN1351597A (en) 1999-04-16 2000-04-17 Novel polymorphic forms of an antidiabetic agent, for their preparation and pharmaceutical compositions containing them
AU38313/00A AU3831300A (en) 1999-04-16 2000-04-17 Novel polymorphic forms of an antidiabetic agent: process for their preparation and pharmaceutical compositions containing them
US09/550,862 US6528507B1 (en) 1999-04-16 2000-04-17 Polymorphic forms of an antidiabetic agent: process for their preparation and a pharmaceutical composition containing them
IL14595800A IL145958A0 (en) 1999-04-16 2000-04-17 Polymorphic form of arginine salt of (2s)-3-[4-[2-phenoxazin-10-yl)ethoxy] phenyl]2-ethoxypropanoic acid, processes for the preparation thereof and pharmaceutical compositions containing the same
CA002370401A CA2370401A1 (en) 1999-04-16 2000-04-17 Novel polymorphic forms of an antidiabetic agent: process for their preparation and pharmaceutical compositions containing them
TR2001/03851T TR200103851T2 (en) 1999-04-16 2000-04-17 New polymorphic forms of an antidiabetic agent, the process for their preparation, and pharmaceutical compositions thereof
HU0200758A HUP0200758A3 (en) 1999-04-16 2000-04-17 Novel polymorphic forms of an antidiabetic agent: process for their preparation and pharmaceutical compositions containing them
NO20015016A NO20015016L (en) 1999-04-16 2001-10-15 New polymorphic forms of an antidiabetic agent; process for their preparation and pharmaceutical compositions containing them
HR20010748A HRP20010748A2 (en) 1999-04-16 2001-10-15 Novel polymorphic forms of an antidiabetic agent: process for their preparation and pharmaceutical compositions containing them
BG106022A BG106022A (en) 1999-04-16 2001-10-16 Novel polymorphic forms of an antidiabetic agent, process for their preparation and pharmaceutical compositions containing them
US10/142,857 US20020173647A1 (en) 1999-04-16 2002-05-09 Novel polymorphic forms of an antidiabetic agent: process for their preparation and a pharmaceutical composition containing them
US10/209,567 US20030004341A1 (en) 1999-04-16 2002-07-30 Crystalline R-guanidines, arginine or (L)-arginine (2S)-2-ethoxy-3-{4-[2-(10H-phenoxazin-10-yl)ethoxy]phenyl}propanoate

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IB1999/000681 WO2000063191A1 (en) 1999-04-16 1999-04-16 Novel polymorphic forms of an antidiabetic agent: process for their preparation and a pharmaceutical composition containing them

Publications (1)

Publication Number Publication Date
WO2000063191A1 true WO2000063191A1 (en) 2000-10-26

Family

ID=11004846

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB1999/000681 WO2000063191A1 (en) 1999-04-16 1999-04-16 Novel polymorphic forms of an antidiabetic agent: process for their preparation and a pharmaceutical composition containing them

Country Status (3)

Country Link
JP (1) JP2003508348A (en)
AU (1) AU2953699A (en)
WO (1) WO2000063191A1 (en)

Cited By (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002062772A1 (en) * 2001-02-05 2002-08-15 Dr. Reddy's Research Foundation Salts of 3-4(4-(2-phenoxazin- or phenothiazin-10-yl)alkoxy)phenyl)-2-alkoxypropanoic acid derivatives with ppar activity for the treatment of hyperlipimedia and type ii diabetes
WO2003031432A1 (en) 2001-10-12 2003-04-17 Novo Nordisk A/S Substituted piperidines and their use for the treatment of diseases related to the histamine h3 receptor
WO2003055482A1 (en) 2001-12-21 2003-07-10 Novo Nordisk A/S Amide derivatives as gk activators
WO2004002481A1 (en) 2002-06-27 2004-01-08 Novo Nordisk A/S Aryl carbonyl derivatives as therapeutic agents
WO2004101505A1 (en) 2003-05-14 2004-11-25 Novo Nordisk A/S Novel compounds for treatment of obesity
WO2005030797A2 (en) 2003-09-30 2005-04-07 Novo Nordisk A/S Melanocortin receptor agonists
WO2005105785A2 (en) 2004-05-04 2005-11-10 Novo Nordisk A/S Indole derivatives for treatment of obesity
EP1634605A2 (en) 2000-03-08 2006-03-15 Novo Nordisk A/S Treatment of dyslipidemia in a patient having type 2 diabetes
WO2006053906A1 (en) 2004-11-22 2006-05-26 Novo Nordisk A/S Soluble, stable insulin-containing formulations with a protamine salt
WO2006058923A1 (en) 2004-12-03 2006-06-08 Novo Nordisk A/S Heteroaromatic glucokinase activators
WO2007006814A1 (en) 2005-07-14 2007-01-18 Novo Nordisk A/S Urea glucokinase activators
WO2007015805A1 (en) 2005-07-20 2007-02-08 Eli Lilly And Company 1-amino linked compounds
WO2007110364A1 (en) 2006-03-28 2007-10-04 High Point Pharmaceuticals, Llc Benzothiazoles having histamine h3 receptor activity
WO2007123581A1 (en) 2005-11-17 2007-11-01 Eli Lilly And Company Glucagon receptor antagonists, preparation and therapeutic uses
WO2007137968A1 (en) 2006-05-29 2007-12-06 High Point Pharmaceuticals, Llc 3- (1, 3-benz0di0x0l-5-yl) -6- (4-cyclopropylpiperazin-1-yl) -pyridazine, its salts and solvates and its use as histamine h3 receptor antagonist
WO2008059025A1 (en) 2006-11-15 2008-05-22 High Point Pharmaceuticals, Llc Novel 2-(2-hydroxyphenyl) benzothiadiazines useful for treating obesity and diabetes
WO2008059026A1 (en) 2006-11-15 2008-05-22 High Point Pharmaceuticals, Llc Novel 2-(2-hydroxyphenyl)benzimidazoles useful for treating obesity and diabetes
WO2008084044A1 (en) 2007-01-11 2008-07-17 Novo Nordisk A/S Urea glucokinase activators
EP2233470A1 (en) 2005-07-04 2010-09-29 High Point Pharmaceuticals, LLC Histamine H3 receptor antagonists
EP2298337A2 (en) 2003-12-09 2011-03-23 Novo Nordisk A/S Regulation of food preference using GLP-1 agonists
EP2316446A1 (en) 2004-06-11 2011-05-04 Novo Nordisk A/S Counteracting drug-induced obesity using GLP-1 agonists
WO2011104379A1 (en) 2010-02-26 2011-09-01 Novo Nordisk A/S Peptides for treatment of obesity
WO2011104378A1 (en) 2010-02-26 2011-09-01 Novo Nordisk A/S Peptides for treatment of obesity
WO2011117415A1 (en) 2010-03-26 2011-09-29 Novo Nordisk A/S Novel glucagon analogues
EP2444397A1 (en) 2004-01-06 2012-04-25 Novo Nordisk A/S Heteroaryl-ureas and their use as glucokinase activators
WO2012130866A1 (en) 2011-03-28 2012-10-04 Novo Nordisk A/S Novel glucagon analogues
WO2013082106A1 (en) 2011-12-02 2013-06-06 The General Hospital Corporation Differentiation into brown adipocytes
US8541368B2 (en) 2011-09-23 2013-09-24 Novo Nordisk A/S Glucagon analogues
US9474790B2 (en) 2013-04-18 2016-10-25 Novo Nordisk A/S Stable, protracted GLP-1/glucagon receptor co-agonists for medical use
WO2018167194A1 (en) 2017-03-15 2018-09-20 Novo Nordisk A/S Bicyclic compounds capable of binding to melanocortin 4 receptor
US10130684B2 (en) 2011-02-03 2018-11-20 Pharmedica Ltd. Oral dissolving films for insulin administration, for treating diabetes
WO2019219714A1 (en) 2018-05-15 2019-11-21 Novo Nordisk A/S Compounds capable of binding to melanocortin 4 receptor
US10570184B2 (en) 2014-06-04 2020-02-25 Novo Nordisk A/S GLP-1/glucagon receptor co-agonists for medical use
WO2020053414A1 (en) 2018-09-14 2020-03-19 Novo Nordisk A/S Bicyclic compounds capable of acting as melanocortin 4 receptor agonists

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5248699A (en) * 1992-08-13 1993-09-28 Pfizer Inc. Sertraline polymorph
WO1997027191A1 (en) * 1996-06-19 1997-07-31 Dr. Reddy's Research Foundation Novel polymorphic forms of troglitazone having enhanced anti-diabetic activity and a process for their preparation
WO1997033878A1 (en) * 1996-03-13 1997-09-18 Rhodia Chimie Improved method for preparing 3-(10-phenothiazyl)propanoic or 3-(10-phenoxazyl)propanoic acid derivatives
US5700820A (en) * 1996-02-20 1997-12-23 Dr. Reddy's Research Foundation Polymorphic forms of troglitazone having enhanced anti-diabetic activity and a process for their preparation
WO1999019313A1 (en) * 1997-10-27 1999-04-22 Dr. Reddy's Research Foundation Novel tricyclic compounds and their use in medicine; process for their preparation and pharmaceutical compositions containing them
WO1999038850A1 (en) * 1998-01-29 1999-08-05 Dr. Reddy's Research Foundation Novel alkanoic acids and their use in medicine, process for their preparation and pharmaceutical compositions containing them

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5248699A (en) * 1992-08-13 1993-09-28 Pfizer Inc. Sertraline polymorph
US5700820A (en) * 1996-02-20 1997-12-23 Dr. Reddy's Research Foundation Polymorphic forms of troglitazone having enhanced anti-diabetic activity and a process for their preparation
WO1997033878A1 (en) * 1996-03-13 1997-09-18 Rhodia Chimie Improved method for preparing 3-(10-phenothiazyl)propanoic or 3-(10-phenoxazyl)propanoic acid derivatives
WO1997027191A1 (en) * 1996-06-19 1997-07-31 Dr. Reddy's Research Foundation Novel polymorphic forms of troglitazone having enhanced anti-diabetic activity and a process for their preparation
WO1999019313A1 (en) * 1997-10-27 1999-04-22 Dr. Reddy's Research Foundation Novel tricyclic compounds and their use in medicine; process for their preparation and pharmaceutical compositions containing them
WO1999038850A1 (en) * 1998-01-29 1999-08-05 Dr. Reddy's Research Foundation Novel alkanoic acids and their use in medicine, process for their preparation and pharmaceutical compositions containing them

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GIRON ET AL: "Thermal analysis and calorimetric methods in the characterisation of polymorphs and solvates", THERMOCHIMICA ACTA,NL,ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, vol. 248, no. 248, pages 1-59-59, XP002101808, ISSN: 0040-6031 *
THRELFALL ET AL: "Analysis of Organic Polymorphs", ANALYST,GB,LONDON, vol. 120, no. 120, pages 2435-2460-2460, XP002101807 *

Cited By (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1634605A2 (en) 2000-03-08 2006-03-15 Novo Nordisk A/S Treatment of dyslipidemia in a patient having type 2 diabetes
WO2002062772A1 (en) * 2001-02-05 2002-08-15 Dr. Reddy's Research Foundation Salts of 3-4(4-(2-phenoxazin- or phenothiazin-10-yl)alkoxy)phenyl)-2-alkoxypropanoic acid derivatives with ppar activity for the treatment of hyperlipimedia and type ii diabetes
EP2243776A1 (en) 2001-10-12 2010-10-27 High Point Pharmaceuticals, LLC Substituted piperidines and their use for the treatment of diseases related to the histamine H3 receptor
WO2003031432A1 (en) 2001-10-12 2003-04-17 Novo Nordisk A/S Substituted piperidines and their use for the treatment of diseases related to the histamine h3 receptor
WO2003055482A1 (en) 2001-12-21 2003-07-10 Novo Nordisk A/S Amide derivatives as gk activators
EP2305648A1 (en) 2001-12-21 2011-04-06 Novo Nordisk A/S Amide derivatives useful as glucokinase activators
WO2004002481A1 (en) 2002-06-27 2004-01-08 Novo Nordisk A/S Aryl carbonyl derivatives as therapeutic agents
EP2471533A1 (en) 2002-06-27 2012-07-04 Novo Nordisk A/S Aryl carbonyl derivatives as therapeutic agents
WO2004101505A1 (en) 2003-05-14 2004-11-25 Novo Nordisk A/S Novel compounds for treatment of obesity
WO2005030797A2 (en) 2003-09-30 2005-04-07 Novo Nordisk A/S Melanocortin receptor agonists
EP2298337A2 (en) 2003-12-09 2011-03-23 Novo Nordisk A/S Regulation of food preference using GLP-1 agonists
EP2444397A1 (en) 2004-01-06 2012-04-25 Novo Nordisk A/S Heteroaryl-ureas and their use as glucokinase activators
WO2005105785A2 (en) 2004-05-04 2005-11-10 Novo Nordisk A/S Indole derivatives for treatment of obesity
EP2316446A1 (en) 2004-06-11 2011-05-04 Novo Nordisk A/S Counteracting drug-induced obesity using GLP-1 agonists
WO2006053906A1 (en) 2004-11-22 2006-05-26 Novo Nordisk A/S Soluble, stable insulin-containing formulations with a protamine salt
WO2006058923A1 (en) 2004-12-03 2006-06-08 Novo Nordisk A/S Heteroaromatic glucokinase activators
EP2233470A1 (en) 2005-07-04 2010-09-29 High Point Pharmaceuticals, LLC Histamine H3 receptor antagonists
EP2386554A1 (en) 2005-07-04 2011-11-16 High Point Pharmaceuticals, LLC Compounds active at the histamine H3 receptor
WO2007006814A1 (en) 2005-07-14 2007-01-18 Novo Nordisk A/S Urea glucokinase activators
EP2377856A1 (en) 2005-07-14 2011-10-19 Novo Nordisk A/S Urea glucokinase activators
WO2007015805A1 (en) 2005-07-20 2007-02-08 Eli Lilly And Company 1-amino linked compounds
WO2007123581A1 (en) 2005-11-17 2007-11-01 Eli Lilly And Company Glucagon receptor antagonists, preparation and therapeutic uses
WO2007110364A1 (en) 2006-03-28 2007-10-04 High Point Pharmaceuticals, Llc Benzothiazoles having histamine h3 receptor activity
EP2402324A1 (en) 2006-05-29 2012-01-04 High Point Pharmaceuticals, LLC Benzodioxolylcyclopropylpiperazinylpyridazines
WO2007137968A1 (en) 2006-05-29 2007-12-06 High Point Pharmaceuticals, Llc 3- (1, 3-benz0di0x0l-5-yl) -6- (4-cyclopropylpiperazin-1-yl) -pyridazine, its salts and solvates and its use as histamine h3 receptor antagonist
WO2008059026A1 (en) 2006-11-15 2008-05-22 High Point Pharmaceuticals, Llc Novel 2-(2-hydroxyphenyl)benzimidazoles useful for treating obesity and diabetes
WO2008059025A1 (en) 2006-11-15 2008-05-22 High Point Pharmaceuticals, Llc Novel 2-(2-hydroxyphenyl) benzothiadiazines useful for treating obesity and diabetes
WO2008084044A1 (en) 2007-01-11 2008-07-17 Novo Nordisk A/S Urea glucokinase activators
WO2011104378A1 (en) 2010-02-26 2011-09-01 Novo Nordisk A/S Peptides for treatment of obesity
WO2011104379A1 (en) 2010-02-26 2011-09-01 Novo Nordisk A/S Peptides for treatment of obesity
WO2011117416A1 (en) 2010-03-26 2011-09-29 Novo Nordisk A/S Novel glucagon analogues
WO2011117415A1 (en) 2010-03-26 2011-09-29 Novo Nordisk A/S Novel glucagon analogues
US10130684B2 (en) 2011-02-03 2018-11-20 Pharmedica Ltd. Oral dissolving films for insulin administration, for treating diabetes
WO2012130866A1 (en) 2011-03-28 2012-10-04 Novo Nordisk A/S Novel glucagon analogues
US8541368B2 (en) 2011-09-23 2013-09-24 Novo Nordisk A/S Glucagon analogues
US9486505B2 (en) 2011-09-23 2016-11-08 Novo Nordisk A/S Glucagon analogues
WO2013082106A1 (en) 2011-12-02 2013-06-06 The General Hospital Corporation Differentiation into brown adipocytes
US9474790B2 (en) 2013-04-18 2016-10-25 Novo Nordisk A/S Stable, protracted GLP-1/glucagon receptor co-agonists for medical use
US9751927B2 (en) 2013-04-18 2017-09-05 Novo Nordisk A/S Stable, protracted GLP-1/glucagon receptor co-agonists for medical use
US10570184B2 (en) 2014-06-04 2020-02-25 Novo Nordisk A/S GLP-1/glucagon receptor co-agonists for medical use
WO2018167194A1 (en) 2017-03-15 2018-09-20 Novo Nordisk A/S Bicyclic compounds capable of binding to melanocortin 4 receptor
WO2019219714A1 (en) 2018-05-15 2019-11-21 Novo Nordisk A/S Compounds capable of binding to melanocortin 4 receptor
WO2020053414A1 (en) 2018-09-14 2020-03-19 Novo Nordisk A/S Bicyclic compounds capable of acting as melanocortin 4 receptor agonists

Also Published As

Publication number Publication date
AU2953699A (en) 2000-11-02
JP2003508348A (en) 2003-03-04

Similar Documents

Publication Publication Date Title
WO2000063191A1 (en) Novel polymorphic forms of an antidiabetic agent: process for their preparation and a pharmaceutical composition containing them
EP1171430A1 (en) Novel polymorphic forms of an antidiabetic agent: process for their preparation and pharmaceutical compositions containing them
WO2000063193A1 (en) Novel polymorphic forms of an antidiabetic agent: process for their preparation and a pharmaceutical composition containing them
US20070203146A1 (en) Specific salt, anhydrous and crystalline form of a dihydropteridione derivative
EP1322647A1 (en) Novel polymorphic forms of 5-[4-[2-[n-methyl-n-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleic acid salt and process for their preparation
US7241895B2 (en) Polymorphic forms of 5-[4-[2-[n-methyl-n-(2-pyridyl)amino[ethoxy]benzyl] thiazolidine-2,4-dione maleate and process for their preparation
TWI333856B (en) Crystals of taxane and process for their production
WO2002028857A1 (en) Polymorphs of pioglitazone hydrochloride and their use as antidiabetics
US8377950B2 (en) Crystalline form of 5-[4-[[3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy]benzyl]thiazolidine-2,4-dione potassium salt
US6528507B1 (en) Polymorphic forms of an antidiabetic agent: process for their preparation and a pharmaceutical composition containing them
AU2001291232B2 (en) Novel polymorphic forms of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl] thiazolidine-2,4-dione maleate and process for their preparation
CN112851640B (en) Sulfate of pyrimidine benzamide compound and application thereof
CN114685512B (en) Ibutotinib-nicotinic acid eutectic crystal and preparation method thereof
AU2001291232A1 (en) Novel polymorphic forms of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl] thiazolidine-2,4-dione maleate and process for their preparation
WO2003066612A1 (en) Novel polymorphic forms of bicyclic antidiabetic agents: process for their preparation and pharmaceutical compositions containing them
KR20220142383A (en) Crystalline form of sphingosine-1-phosphate receptor agonist
EP2471783A1 (en) Novel polymorphic form of efavirenz
KR20070116188A (en) Novel polymorphic forms of 5-[4-[2-[n-methyl-n-(2-pyridyl)amino]ethoxy]benzyl] thiazolidine-2,4-dione maleate and process for their preparation
KR20070113328A (en) Novel polymorphic forms of 5-[4-[2-[n-methyl-n-(2-pyridyl)amino]ethoxy]benzyl] thiazolidine-2,4-dione maleate and process for their preparation
KR20070116189A (en) Novel polymorphic forms of 5-[4-[2-[n-methyl-n-(2-pyridyl)amino]ethoxy]benzyl] thiazolidine-2,4-dione maleate and process for their preparation

Legal Events

Date Code Title Description
ENP Entry into the national phase

Ref country code: US

Ref document number: 2000 550843

Date of ref document: 20000417

Kind code of ref document: A

Format of ref document f/p: F

WWE Wipo information: entry into national phase

Ref document number: 09550858

Country of ref document: US

Ref document number: 09550862

Country of ref document: US

Ref document number: 09551507

Country of ref document: US

Ref document number: 09551228

Country of ref document: US

AK Designated states

Kind code of ref document: A1

Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SL SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
WWE Wipo information: entry into national phase

Ref document number: 10142857

Country of ref document: US

ENP Entry into the national phase

Ref country code: US

Ref document number: 2002 217593

Date of ref document: 20020730

Kind code of ref document: A

Format of ref document f/p: F

Ref country code: US

Ref document number: 2002 209567

Date of ref document: 20020730

Kind code of ref document: A

Format of ref document f/p: F