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WO2009053754A2 - Nouvelles formes cristallines - Google Patents

Nouvelles formes cristallines Download PDF

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Publication number
WO2009053754A2
WO2009053754A2 PCT/GB2008/050992 GB2008050992W WO2009053754A2 WO 2009053754 A2 WO2009053754 A2 WO 2009053754A2 GB 2008050992 W GB2008050992 W GB 2008050992W WO 2009053754 A2 WO2009053754 A2 WO 2009053754A2
Authority
WO
WIPO (PCT)
Prior art keywords
tegaserod
citrate
process according
crystalline form
designated
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/GB2008/050992
Other languages
English (en)
Other versions
WO2009053754A3 (fr
Inventor
Abhay Gaitonde
Bindu Manojkumar
Rahul Bhalerao
Sinderpal Tank
Vikas Padalkar
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Generics UK Ltd
Mylan Pharmaceuticals Pvt Ltd
Original Assignee
Generics UK Ltd
Mylan Development Centre Pvt Ltd
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 Generics UK Ltd, Mylan Development Centre Pvt Ltd filed Critical Generics UK Ltd
Publication of WO2009053754A2 publication Critical patent/WO2009053754A2/fr
Publication of WO2009053754A3 publication Critical patent/WO2009053754A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • 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

Definitions

  • Tegaserod chemically named 2-[(5-methoxy-li ⁇ -indol-3-yl)methylene]-IV-pentylhydrazine- carboximidamide, is a selective serotonin 4 (5-HT 4 ) receptor agonist, which can be used to treat gastrointestinal disorders such as heartburn, bloating, postoperative ileus, abdominal pain and discomfort, epigastric pain, nausea, vomiting, regurgitation, intestinal pseudoobstruction, irritable bowel syndrome and gastro-oesophageal reflux.
  • Tegaserod as the maleate salt is marketed for the short-term treatment of irritable bowel syndrome in women whose primary bowel symptom is constipation.
  • WO 2006/116953 describes crystalline forms of the hydrobromide, fumarate and oxalate salts of tegaserod. Also claimed is a process for preparing the hydrochloride, hydrobromide, fumarate, tartrate, citrate, lactate, mesylate, oxalate, succinate, glutarate, adipate, salicylate, sulphate, mandelate, camphor sulphonate and hydrogen sulphate salts of tegaserod from a specific crystalline form of tegaserod base.
  • Another process described is a method of preparing the fumarate, maleate, tartrate, citrate, mesylate, lactate, succinate, oxalate, hydrochloride, salicylate, glutarate, adipate, hydrobromide, sulphate and hydrogen sulphate from a hydrogen halide salt of tegaserod.
  • a novel crystalline form of tegaserod citrate designated form 1, with a characteristic XRD spectrum having two or more peaks (preferably three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, thirteen or more, or all fourteen peaks) with 2 ⁇ values at 4.6, 5.6, 9.4, 11.3, 14.1, 17.1, 17.6, 18.3, 19.2, 21.2, 22.2, 23.0, 25.0, 26.0 ⁇ 0.2 °2 ⁇ .
  • tegaserod citrate is dissolved in step (a).
  • the solvent used in step (a) is a C 1 -C 6 alcohol, preferably a C 1 -C 3 alcohol, preferably a primary alcohol, preferably ethanol.
  • ethanol is heated to between about 70-90 0 C, preferably about 78°C.
  • the tegaserod citrate form 1 is caused to precipitate by cooling the solution or suspension obtained in step (a) to between about 0-5 0 C.
  • the tegaserod citrate form 1 is isolated by filtration and most preferably is dried, particularly preferred is drying under vacuum, preferably until a constant weight is achieved.
  • the novel crystalline form 2 of tegaserod citrate has a characteristic XRD spectrum having two or more peaks (preferably three or more, four or more, five or more, six or more, seven or more, eight or more, or all nine peaks) with 2 ⁇ values at 4.94, 5.27, 5.64, 10.03, 15.42, 18.82, 20.30, 25.82 and 26.48 ⁇ 0.2 °2 ⁇ .
  • a novel crystalline form of tegaserod citrate designated form 2, having an XRPD trace substantially as shown in figure 3.
  • tegaserod citrate is dissolved in step (a).
  • the solvent used in step (a) is acetone.
  • the acetone is heated to between about 50-60 0 C, preferably about 56°C.
  • the tegaserod citrate form 2 is caused to precipitate by cooling the solution or suspension obtained in step (a), preferably to about 0- 5°C.
  • the tegaserod citrate form 2 is isolated by filtration, most preferably the tegaserod citrate form 2 is dried under vacuum, preferably until a constant weight is achieved. Preferably the drying occurs at between about 20-40 0 C, preferably at about 30 0 C.
  • the novel crystalline form 3 of tegaserod citrate has a characteristic XRD spectrum having two or more peaks (preferably three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, fifteen or more, twenty or more, or all twenty-five peaks) with 2 ⁇ values at 5.01, 7.2, 7.65, 9.23, 11.04, 11.78, 13.08, 14.60, 16.48, 17.17, 17.62, 18.32, 19.35, 19.70, 20.46, 22.12, 22.60, 22.85, 23.13, 23.70, 24.03, 24.72, 25.17, 25.89, 29.23 ⁇ 0.2 °2 ⁇ .
  • a novel crystalline form of tegaserod citrate designated form 3, characterized by a DSC with endothermic peaks at about 70 0 C and about 111°C, preferably at about 69.98°C and about 111.21°C, all ⁇ 2°C.
  • a fourteenth aspect according to the invention there is provided a novel crystalline form of tegaserod citrate, designated form 3, having a DSC trace substantially as shown in figure 6.
  • tegaserod citrate is dissolved in step (a).
  • the solvent used in step (a) is ethylene glycol.
  • the ethylene glycol is heated to between about 70-90 0 C, preferably about 80 0 C.
  • a further solvent is added to the mixture before step (b) to complete the dissolution and form a solution of the tegaserod citrate, most preferably the further solvent is ethylene glycol, preferably about 5 volumes are added.
  • this solution is heated to between about 100-120 0 C, most preferably about 107 0 C.
  • the tegaserod citrate form 3 is caused to precipitate by cooling the solution or suspension, preferably to about 0-5 0 C.
  • the tegaserod citrate form 3 is isolated by filtration, most preferably the tegaserod citrate form 3 is dried under vacuum, preferably until a constant weight is achieved. Preferably the drying occurs at a temperature of between about 20- 40 0 C, preferably about 30 0 C.
  • a novel crystalline form of tegaserod citrate designated form 4, having an XRPD trace substantially as shown in figure 7.
  • a method for the treatment of a 5- HT 4 receptor mediated disorder in a subject in need thereof comprising administering to the subject a composition comprising a therapeutically effective amount of a novel polymorph of tegaserod citrate according to the invention.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne de nouvelles formes cristallines d'un sel de citrate de tégasérod ainsi que des procédés de préparation de ces nouvelles formes cristallines. L'invention concerne également des compositions pharmaceutiques contenant ces nouveaux polymorphes ainsi que les utilisations desdites compositions dans des méthodes de traitement de patients souffrant de troubles gastro-intestinaux.
PCT/GB2008/050992 2007-10-24 2008-10-24 Nouvelles formes cristallines Ceased WO2009053754A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2109/MUM/2007 2007-10-24
IN2109MU2007 2007-10-24

Publications (2)

Publication Number Publication Date
WO2009053754A2 true WO2009053754A2 (fr) 2009-04-30
WO2009053754A3 WO2009053754A3 (fr) 2009-09-03

Family

ID=40289317

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2008/050992 Ceased WO2009053754A2 (fr) 2007-10-24 2008-10-24 Nouvelles formes cristallines

Country Status (1)

Country Link
WO (1) WO2009053754A2 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0297651A1 (fr) 1987-06-29 1989-01-04 Duphar International Research B.V Dérivés d'indole annulaires
US5510353A (en) 1991-03-22 1996-04-23 Sandoz Ltd. Certain aminoguanidine compounds, pharmaceutical compositions containing them and their use in treating gastrointestinal motility disorders and disorders associated with cephalic pain
WO1999017755A2 (fr) 1997-10-07 1999-04-15 Glaxo Group Limited Medicaments
WO2006116953A1 (fr) 2005-05-02 2006-11-09 Zentiva, A.S. Procede de preparation de tegaserod et de sels sélectionnés dérivés de ce composé

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1939176A1 (fr) * 2006-12-22 2008-07-02 Novartis AG Sels de Tegaserod

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0297651A1 (fr) 1987-06-29 1989-01-04 Duphar International Research B.V Dérivés d'indole annulaires
US5510353A (en) 1991-03-22 1996-04-23 Sandoz Ltd. Certain aminoguanidine compounds, pharmaceutical compositions containing them and their use in treating gastrointestinal motility disorders and disorders associated with cephalic pain
WO1999017755A2 (fr) 1997-10-07 1999-04-15 Glaxo Group Limited Medicaments
WO2006116953A1 (fr) 2005-05-02 2006-11-09 Zentiva, A.S. Procede de preparation de tegaserod et de sels sélectionnés dérivés de ce composé

Also Published As

Publication number Publication date
WO2009053754A3 (fr) 2009-09-03

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