WO1997003983A1 - 4-[3-(trans-3-dimethylaminocyclobutyl)-1h-indol-5-ylmethyl]-4(s)oxazolidin-2-one monobenzoate and sulphate salt - Google Patents

4-[3-(trans-3-dimethylaminocyclobutyl)-1h-indol-5-ylmethyl]-4(s)oxazolidin-2-one monobenzoate and sulphate salt Download PDF

Info

Publication number
WO1997003983A1
WO1997003983A1 PCT/EP1996/003188 EP9603188W WO9703983A1 WO 1997003983 A1 WO1997003983 A1 WO 1997003983A1 EP 9603188 W EP9603188 W EP 9603188W WO 9703983 A1 WO9703983 A1 WO 9703983A1
Authority
WO
WIPO (PCT)
Prior art keywords
salt
trans
indol
ylmethyl
oxazolidin
Prior art date
Application number
PCT/EP1996/003188
Other languages
French (fr)
Inventor
David Lawrence Selwood
Michael Alan BROCKWELL
Original Assignee
Glaxo Group Limited
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 Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to EP96926370A priority Critical patent/EP0842173A1/en
Priority to AU66581/96A priority patent/AU6658196A/en
Priority to JP9506303A priority patent/JPH11509537A/en
Publication of WO1997003983A1 publication Critical patent/WO1997003983A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents

Definitions

  • the present invention is concerned with novel salts of 4-[3-(trans-3- dimethylaminocyclobutyl)- lH-indol-5-ylmethyl]-4(S)oxazolidin-2-one, their preparation, pharmaceutical formulations containing such salts, and their use in medicine, particularly as "5HT ⁇ -like" receptor agonists for prophylaxis and treatment of migraine.
  • 5-hydroxytryptamine 5-hydroxytryptamine
  • 5-HT 5-hydroxytryptamine
  • European Patent Specification 0313397 describes a class of 5-HT agonists which act selectively at a particular subtype of 5-HT j receptor and are effective therapeutic agents for the treatment of clinical conditions in which a selective agonist for this type of receptor is indicated.
  • the receptor in question mediates selective cranial arterial vasoconstriction and inhibition of plasma protein extravasation into the dura mater evoked by activation ofthe Vth (trigeminal) nerve.
  • the compounds described in the European specification are therefore beneficial in the treatment or prophylaxis of conditions wherein these actions are indicated, for example, migraine, a condition associated with excessive dilation of the carotid vasculature and/or neurogenically-evoked inflammation dilation ofthe cranial vasculature.
  • the target tissue may be any tissue wherein action is mediated by 5-HTj receptors of the type referred to above.
  • EP-A-0486666 discloses a class of compounds having exceptional activity at the 5-HT] receptor mentioned above and excellent absorption following oral dosing. These properties render the compounds particularly useful for certain medical applications, notably the prophylaxis and treatment of migraine, cluster headache and headache associated with vascular disorders, hereinafter referred to collectively as "migraine”.
  • WO95/20588 discloses a class of compounds which not only demonstrate improved metabolic stability and the necessary 5HT " ⁇ receptor agonism, but also display a potentially selective inhibition of neurogenic inflammation and the nerve pathways responsible for the transmission of head pain.
  • the compounds also display partial agonism at the 5HT ⁇ receptor and thus may have reduced side effects compared to previously known 5HT ⁇ receptor agonists.
  • a particularly preferred compound described in this International Patent Application is 4-[3-(trans-3- dimethylaminocyclobutyl)-lH-indol-5-ylmethyl]-(4S)oxazolidin-2-one.
  • salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent, i.e. basic, compound. They also display su ⁇ risingly improved stability in comparison to other salts of the parent compound and unlike such other salts, they are not hygroscopic.
  • the present invention provides the monobenzoate and sulphate salts of 4-[3-(trans-3-dimethylaminocyclobutyl)-lH-indol-5-ylmethyl]-4-(S)oxazoIidin-2-one.
  • the monobenzoate salt is preferred.
  • the salts are suitably provided in a solid form and more specifically in a crystalline form. These salts are anhydrous and not hygroscopic.
  • a monobenzoate or sulphate salt of 4-[3-(trans-3-dimethylaminocyclobutyl)-lH- indol-5-ylmethyl]-4(S)oxazolidin-2-one is at least 70%, more preferably at least 90% and most preferably greater than 95% pure.
  • the monobenzoate or sulphate salt of 4-[3-(trans-3-dimethylaminocyclobutyl)-lH-indol-5-ylmethyl]- 4(S)oxazolidin-2-one for use as a therapeutic agent, specifically as a "5-HT -like" receptor agonist, for example, as a carotid vasoconstrictor or as an inhibitor of neurogenic inflammation in the prophylaxis and treatment of migraine.
  • target organs for the present compounds other than the carotid vasculature are within the scope ofthe present invention.
  • a typical daily dose for the treatment of migraine may be expected to lie in the range O.Ol ⁇ g to 5mg per kilogram body weight and is suitably in the range O.Ol ⁇ g to lOO ⁇ g/kg.
  • the daily dose is in the range 0.01 to 2 ⁇ g/kg.
  • Unit doses may contain from l ⁇ g to lOOmg of a salt of the invention.
  • a suitable unit dose contains I ⁇ g to lmg of a salt ofthe invention.
  • a salt ofthe invention is contained in a unit dose in an amount of l ⁇ g to lOO ⁇ g.
  • compositions comprising, as active ingredient, at least one salt ofthe invention together with at least one pharmaceutical carrier or excipient.
  • pharmaceutical compositions may be used in the prophylaxis or treatment of clinical conditions for which a "5-HT -like" receptor agonist is indicated, for example, migraine.
  • the carrier must be pharmaceutically acceptable to the recipient and must be compatible, with, i.e. not have a deleterious effect upon, the other ingredients in the composition.
  • the carrier may be a solid or liquid and is preferably formulated with at least one salt ofthe invention as a unit dose formulation, for example, a tablet which may contain from 0.05 to 95% by weight of the active ingredient. If desired, other physiologically active ingredients may also be inco ⁇ orated in the pharmaceutical compositions ofthe invention.
  • Possible formulations include those suitable for oral, buccal, parenteral (for example, subcutaneous, intramuscular, or intravenous), rectal, topical and intranasal administration.
  • parenteral for example, subcutaneous, intramuscular, or intravenous
  • rectal topical and intranasal administration.
  • topical and intranasal administration are particularly suitable.
  • Formulations suitable for oral administration may be provided as discrete units, such as tablets, capsules, cachets, or lozenges, each containing a predetermined amount of the active compound; as powders or granules; as solutions or suspensions in aqueous or non ⁇ aqueous liquids; or as oil-in-water or water-in-oil emulsions.
  • Formulations suitable for sublingual or buccal administration include lozenges comprising the active compound and, typically, a flavoured base, such as sugar and acacia or tragacanth, and pastilles comprising the active compound in an inert base, such as gelatin and glycerin or sucrose and acacia.
  • a flavoured base such as sugar and acacia or tragacanth
  • an inert base such as gelatin and glycerin or sucrose and acacia.
  • Formulations suitable for parenteral administration typically comprise sterile aqueous solutions containing a predetermined concentration ofthe active compound; the solution is preferably isotonic with the blood of the intended recipient. Although such solutions are preferably administered intravenously, they may also be administered by subcutaneous or intramuscular injection.
  • Formulations suitable for rectal administration are preferably provided as unit-dose suppositories comprising the active ingredient and one or more solid carriers forming the suppository base, for example, cocoa butter.
  • Formulations suitable for topical or intranasal application include ointments, creams, lotions, pastes, gels, sprays, aerosols and oils.
  • Suitable carriers for such formulations include petroleum jelly, lanolin, polyethylene glycols, alcohols, and combinations thereof.
  • the active ingredient is typically present in such formulations at a concentration of from 0.1 to 15% w/w.
  • the formulations of the invention may be prepared by any suitable method, typically by uniformly and intimately admixing the active compound(s) with liquids or finely divided solid carriers, or both, in the required proportions and then, if necessary, shaping the resulting mixture into the desired shape.
  • a tablet may be prepared by compressing an intimate mixture comprising a powder or granules ofthe active ingredient and one or more optional ingredients, such as a binder, lubricant, inert diluent, or surface active dispersing agent, or by moulding an intimate mixture of powdered active ingredient and inert liquid diluent.
  • one or more optional ingredients such as a binder, lubricant, inert diluent, or surface active dispersing agent, or by moulding an intimate mixture of powdered active ingredient and inert liquid diluent.
  • Aqueous solutions for parenteral administration are typically prepared by dissolving the active compound in sufficient water to give the desired concentration and then rendering the resulting solution sterile and isotonic.
  • a salt ofthe invention in the preparation of a medicament for the prophylaxis or treatment of a clinical condition for which a "5-HT ⁇ -like" receptor agonist is indicated, for example, migraine.
  • a method for combattting a clinical condition in a mammal for example, a human, for which a "5-HT -like" receptor agonist is indicated, for example, migraine, which comprises the administration to said mammal of a therapeutically effective amount of a salt ofthe invention.
  • the invention provides a process for the preparation of a salt ofthe invention which comprises reacting 4-[3-(trans-3-dimethylaminocyclobutyl)-lH-indol-5- ylmethyl]-4(S)oxazolidin-2-one in the free base form with benzoic acid, when it is desired to prepare the monobenzoate salt, or with sulphuric acid, when it is desired to prepare the sulphate salt, and crystallising out the salt.
  • the reaction is typically carried out by heating the free base to a non-extreme elevated temperature, suitably in the range 40 to 80°C and preferably in the range 40-60°C, and then adding the acid before allowing to cool to, for example, room temperature.
  • the reaction mixture is then set aside to allow crystals to form.
  • This reaction is suitably carried out in the presence of an organic solvent such as ethyl acetate.
  • the crystals are preferably washed, for example with ethyl acetate and then dried in air.
  • the reaction may be carried out by mixing the free base with the acid and then heating to a non-extreme elevated temperature, suitably in the range 30 to 100°C and preferably at about 50°C and then allowing to cool followed by evaporation to dryness.
  • a non-extreme elevated temperature suitably in the range 30 to 100°C and preferably at about 50°C and then allowing to cool followed by evaporation to dryness.
  • the reaction is suitably carried out in the presence of an organic solvent such as isopropanol or ethylacetate.
  • the final product is crystallised from a solvent, e.g. ethyl acetate, to give the salt in crystalline form.
  • the free base of 4-f 3-(trans-3-dimethylaminocyclobutvl)- 1 H-indol-5-ylmethyll- 4(S)oxazolidin-2-one may be prepared by the methods described in Published International Application WO95/20588, inco ⁇ orated herein by reference. One particularly suitable method is described in Example 1 hereinafter.
  • Benzoic and sulphuric acids are commercially available. Alternatively they can be prepared from known starting materials using standard methods which are well known to those skilled in the art.
  • the present invention further provides a process for producing the monobenzoate and sulphate salts of 4-[3-(trans-3-dimethylaminocyclobutyl)-lH-indol-5-ylmethyl]- 4(S)oxazolidin-2-one, which process comprises a first step of reacting a salt other than the monobenzoate with benzoic acid, when it is desired to prepare the monobenzoate, or reacting a salt other than the sulphate with sulphuric acid when it is desired to prepare the sulphate, and a second step of removing the original salt forming ion. The final product is then crystallised.
  • the invention will now be described by way of example only.
  • the second product eluted (r.f. ⁇ 0.1) was a mixture of as and trans straight chain aldehydes.
  • Microanalysis for C14H17NO3 Calculated C 68.02, H 6.88, N 5.67; Found C 67.92, H 6.90, N 5.63.
  • step (c) 4-f3-(trans-3-dimethylaminocyclobuty ⁇ -lH-indol-5-ylmethyll-4(S)oxazolidin-2-one
  • Formaldehyde (0.18 ml, 2.22 mmol) in methanol (5 ml) was added to the product of step (b) (250 mg, 0.88 mmol), acetic acid (0.26ml, 4.55 mmol) and sodium cyanoborohydride (70mg, 1.17 mmol) in methanol (15ml) and stirred at room temperature under a nitrogen atmosphere overnight.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

4-[3-(trans-3-dimethylaminocyclobutyl)-1H-indol-5-ylmethyl]-(4S)oxazolidin-2-one displays potentially selective inhibition of neurogenic inflammation and the nerve pathways responsible for transmission of head pain. The present invention provides the monobenzoate and sulphate salts of 4-[3-(trans-3-dimethylaminocyclobutyl)-1H-indol-5-ylmethyl]-(4S)oxazolidinone. These salts have particularly good properties and may be obtained in substantially pure form. They are useful in therapy, particularly in the treatment and prophylaxis of migraine. The invention also provides a process for the preparation of these salts and pharmaceutical compositions containing at least one such salt as active ingredient.

Description

4-[3-(TRANS-3-DIMETHY MIN0CYCL0BUTYL)-lH-IND0L-5-YLMETHYL]-4(S)0XAZ0LIDIN-2- ONE MONOBENZOATE AND SULPHATE SALT
The present invention is concerned with novel salts of 4-[3-(trans-3- dimethylaminocyclobutyl)- lH-indol-5-ylmethyl]-4(S)oxazolidin-2-one, their preparation, pharmaceutical formulations containing such salts, and their use in medicine, particularly as "5HTι-like" receptor agonists for prophylaxis and treatment of migraine.
Receptors which mediate the actions of 5-hydroxytryptamine (5-HT) have been identified in mammals in both the periphery and the brain. Currently, as many as seven 5-HT receptor classes are proposed (Hoyer et al., Pharmacol. Rev., 46, 157-203, 1994), although only the classes nominated 5-HT], 5-HT2, 5-HT3, and 5-HT4 have established physiological roles. European Patent Specification 0313397 describes a class of 5-HT agonists which act selectively at a particular subtype of 5-HTj receptor and are effective therapeutic agents for the treatment of clinical conditions in which a selective agonist for this type of receptor is indicated. For example, the receptor in question mediates selective cranial arterial vasoconstriction and inhibition of plasma protein extravasation into the dura mater evoked by activation ofthe Vth (trigeminal) nerve. The compounds described in the European specification are therefore beneficial in the treatment or prophylaxis of conditions wherein these actions are indicated, for example, migraine, a condition associated with excessive dilation of the carotid vasculature and/or neurogenically-evoked inflammation dilation ofthe cranial vasculature. However, it is within the scope ofthe earlier application that the target tissue may be any tissue wherein action is mediated by 5-HTj receptors of the type referred to above.
EP-A-0486666 discloses a class of compounds having exceptional activity at the 5-HT] receptor mentioned above and excellent absorption following oral dosing. These properties render the compounds particularly useful for certain medical applications, notably the prophylaxis and treatment of migraine, cluster headache and headache associated with vascular disorders, hereinafter referred to collectively as "migraine".
Published International Application no. WO95/20588 discloses a class of compounds which not only demonstrate improved metabolic stability and the necessary 5HT"ι receptor agonism, but also display a potentially selective inhibition of neurogenic inflammation and the nerve pathways responsible for the transmission of head pain. The compounds also display partial agonism at the 5HTι receptor and thus may have reduced side effects compared to previously known 5HTι receptor agonists. A particularly preferred compound described in this International Patent Application is 4-[3-(trans-3- dimethylaminocyclobutyl)-lH-indol-5-ylmethyl]-(4S)oxazolidin-2-one.
It has now been found that the monobenzoate and sulphate salts of 4-[3-(trans-3- dimethylaminocyclobutyl)- lH-indol-5-ylmethyl]-4(S)oxazolidin-2-one have particularly good properties and may be obtained in substantially pure form.
These salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent, i.e. basic, compound. They also display suφrisingly improved stability in comparison to other salts of the parent compound and unlike such other salts, they are not hygroscopic.
Thus, in a first aspect the present invention provides the monobenzoate and sulphate salts of 4-[3-(trans-3-dimethylaminocyclobutyl)-lH-indol-5-ylmethyl]-4-(S)oxazoIidin-2-one. The monobenzoate salt is preferred. The salts are suitably provided in a solid form and more specifically in a crystalline form. These salts are anhydrous and not hygroscopic. Preferably a monobenzoate or sulphate salt of 4-[3-(trans-3-dimethylaminocyclobutyl)-lH- indol-5-ylmethyl]-4(S)oxazolidin-2-one is at least 70%, more preferably at least 90% and most preferably greater than 95% pure.
According to a second aspect ofthe present invention, there is provided the monobenzoate or sulphate salt of 4-[3-(trans-3-dimethylaminocyclobutyl)-lH-indol-5-ylmethyl]- 4(S)oxazolidin-2-one for use as a therapeutic agent, specifically as a "5-HT -like" receptor agonist, for example, as a carotid vasoconstrictor or as an inhibitor of neurogenic inflammation in the prophylaxis and treatment of migraine. As indicated, however, target organs for the present compounds other than the carotid vasculature are within the scope ofthe present invention.
The monobenzoate and sulphate salts of 4-[3-(trans-3-dimethylaminocyclobutyl)-lH-indol- 5-ylmethyl]-4(S)oxazolidin-2-one are hereinafter referred to as "salts ofthe invention".
The amount of a salt of the invention which is required to achieve the desired biological effect will depend on a number of factors such as the specific salt, the use for which it is intended, the means of administration, and the recipient. A typical daily dose for the treatment of migraine may be expected to lie in the range O.Olμg to 5mg per kilogram body weight and is suitably in the range O.Olμg to lOOμg/kg. Preferably, the daily dose is in the range 0.01 to 2μg/kg. Unit doses may contain from lμg to lOOmg of a salt of the invention. A suitable unit dose contains Iμg to lmg of a salt ofthe invention. Preferably a salt ofthe invention is contained in a unit dose in an amount of lμg to lOOμg.
Whilst it may be possible for a salt ofthe invention to be administered as the raw chemical it is preferable to present it as a pharmaceutical formulation. According to a third aspect of the present invention, therefore, there are provided pharmaceutical compositions comprising, as active ingredient, at least one salt ofthe invention together with at least one pharmaceutical carrier or excipient. These pharmaceutical compositions may be used in the prophylaxis or treatment of clinical conditions for which a "5-HT -like" receptor agonist is indicated, for example, migraine. The carrier must be pharmaceutically acceptable to the recipient and must be compatible, with, i.e. not have a deleterious effect upon, the other ingredients in the composition. The carrier may be a solid or liquid and is preferably formulated with at least one salt ofthe invention as a unit dose formulation, for example, a tablet which may contain from 0.05 to 95% by weight of the active ingredient. If desired, other physiologically active ingredients may also be incoφorated in the pharmaceutical compositions ofthe invention.
Possible formulations include those suitable for oral, buccal, parenteral (for example, subcutaneous, intramuscular, or intravenous), rectal, topical and intranasal administration. The most suitable means of administration for a particular patient will depend on the nature and severity of the condition being treated and on the nature ofthe active compound, but, where possible, oral administration is preferred.
Formulations suitable for oral administration may be provided as discrete units, such as tablets, capsules, cachets, or lozenges, each containing a predetermined amount of the active compound; as powders or granules; as solutions or suspensions in aqueous or non¬ aqueous liquids; or as oil-in-water or water-in-oil emulsions.
Formulations suitable for sublingual or buccal administration include lozenges comprising the active compound and, typically, a flavoured base, such as sugar and acacia or tragacanth, and pastilles comprising the active compound in an inert base, such as gelatin and glycerin or sucrose and acacia.
Formulations suitable for parenteral administration typically comprise sterile aqueous solutions containing a predetermined concentration ofthe active compound; the solution is preferably isotonic with the blood of the intended recipient. Although such solutions are preferably administered intravenously, they may also be administered by subcutaneous or intramuscular injection.
Formulations suitable for rectal administration are preferably provided as unit-dose suppositories comprising the active ingredient and one or more solid carriers forming the suppository base, for example, cocoa butter.
Formulations suitable for topical or intranasal application include ointments, creams, lotions, pastes, gels, sprays, aerosols and oils. Suitable carriers for such formulations include petroleum jelly, lanolin, polyethylene glycols, alcohols, and combinations thereof. The active ingredient is typically present in such formulations at a concentration of from 0.1 to 15% w/w.
The formulations of the invention may be prepared by any suitable method, typically by uniformly and intimately admixing the active compound(s) with liquids or finely divided solid carriers, or both, in the required proportions and then, if necessary, shaping the resulting mixture into the desired shape.
For example, a tablet may be prepared by compressing an intimate mixture comprising a powder or granules ofthe active ingredient and one or more optional ingredients, such as a binder, lubricant, inert diluent, or surface active dispersing agent, or by moulding an intimate mixture of powdered active ingredient and inert liquid diluent.
Aqueous solutions for parenteral administration are typically prepared by dissolving the active compound in sufficient water to give the desired concentration and then rendering the resulting solution sterile and isotonic.
Thus, according to a fourth aspect of the present invention, there is provided the use of a salt ofthe invention in the preparation of a medicament for the prophylaxis or treatment of a clinical condition for which a "5-HTι-like" receptor agonist is indicated, for example, migraine.
According to a fifth aspect, there is provided a method for combattting a clinical condition in a mammal, for example, a human, for which a "5-HT -like" receptor agonist is indicated, for example, migraine, which comprises the administration to said mammal of a therapeutically effective amount of a salt ofthe invention. In a further aspect the invention provides a process for the preparation of a salt ofthe invention which comprises reacting 4-[3-(trans-3-dimethylaminocyclobutyl)-lH-indol-5- ylmethyl]-4(S)oxazolidin-2-one in the free base form with benzoic acid, when it is desired to prepare the monobenzoate salt, or with sulphuric acid, when it is desired to prepare the sulphate salt, and crystallising out the salt.
The reaction is typically carried out by heating the free base to a non-extreme elevated temperature, suitably in the range 40 to 80°C and preferably in the range 40-60°C, and then adding the acid before allowing to cool to, for example, room temperature. The reaction mixture is then set aside to allow crystals to form. This reaction is suitably carried out in the presence of an organic solvent such as ethyl acetate. The crystals are preferably washed, for example with ethyl acetate and then dried in air.
Alternatively, the reaction may be carried out by mixing the free base with the acid and then heating to a non-extreme elevated temperature, suitably in the range 30 to 100°C and preferably at about 50°C and then allowing to cool followed by evaporation to dryness. The reaction is suitably carried out in the presence of an organic solvent such as isopropanol or ethylacetate. The final product is crystallised from a solvent, e.g. ethyl acetate, to give the salt in crystalline form.
The free base of 4-f 3-(trans-3-dimethylaminocyclobutvl)- 1 H-indol-5-ylmethyll- 4(S)oxazolidin-2-one may be prepared by the methods described in Published International Application WO95/20588, incoφorated herein by reference. One particularly suitable method is described in Example 1 hereinafter.
Benzoic and sulphuric acids are commercially available. Alternatively they can be prepared from known starting materials using standard methods which are well known to those skilled in the art.
The present invention further provides a process for producing the monobenzoate and sulphate salts of 4-[3-(trans-3-dimethylaminocyclobutyl)-lH-indol-5-ylmethyl]- 4(S)oxazolidin-2-one, which process comprises a first step of reacting a salt other than the monobenzoate with benzoic acid, when it is desired to prepare the monobenzoate, or reacting a salt other than the sulphate with sulphuric acid when it is desired to prepare the sulphate, and a second step of removing the original salt forming ion. The final product is then crystallised. The invention will now be described by way of example only.
Example 1 : 4-[3-ftrans-3-dimethylaminocyclobutylVlH-indol-5-ylmethyl]- 4(S oxazolidin-2-one
(a) Trans-N-(benzyloxy carbonyl)-cyclobutanamine-3 -acetaldehyde
Trans-N-(benzyloxycarbonyl)-3-methylenecyclobutanamine (18g, 83 mmol) (prepared as described in EP-A-0366059) and tris(triphenylphosphine)rhodium chloride (400 mg 0.43 mmol) were heated to 70°C in toluene (250ml) under 100 atmospheres of CO:F-2 (1:1 mixture) for 18 hrs. The solvent was evaporated under reduced pressure and the residue chromatographed on silica eluting with 25% ethylacetate in cydohexane. The first product eluted (r.f.~0.25) was a mixture of cis and trans branched chain aldehydes. The second product eluted (r.f.~0.1) was a mixture of as and trans straight chain aldehydes. The trans isomer was crystallised from ether as white needles (mpt = 66-67°C). Microanalysis for C14H17NO3: Calculated C 68.02, H 6.88, N 5.67; Found C 67.92, H 6.90, N 5.63.
(b) 4-f3-(trans-3-aminocyclobutyπ-lH-indol-5-ylmethyl-(4S)-oxazolidin-2-one
The appropriate hydrazine, 4-hydrazinophenyl-(4S)-oxazolidin-2-one, (6.3g, 30mmol) and trans-N-(benzyloxycarbonyl)cyclobutanamine-3-acetaldehyde (6.3g, 25.5mmol) were heated to 80°C for 7 hours in 1% sulphuric acid (aq) (100ml) and ethanol (150ml). The reaction mixture was evaporated in vacuo and brine added. Extraction with ethyl acetate gave the crude product (10.5g, 83%) MS (FAB) 420 (M+l)+.
The product from the above was refluxed in 10% formic acid-methanol with palladium hydroxide on carbon (lg) for 7 hours. The solvent was removed in vacuo and brine added. The solution was then washed with ethyl acetate and then made basic (pH 10-12) with dil. ammonium hydroxide solution. Extraction with THF gave the crude product which was purified by flash chromatography (2:14:84 NH3, EtOH) (2g, 28%) MS (FAB) 286 (M+l)+.
(c) 4-f3-(trans-3-dimethylaminocyclobutyπ-lH-indol-5-ylmethyll-4(S)oxazolidin-2-one Formaldehyde (0.18 ml, 2.22 mmol) in methanol (5 ml) was added to the product of step (b) (250 mg, 0.88 mmol), acetic acid (0.26ml, 4.55 mmol) and sodium cyanoborohydride (70mg, 1.17 mmol) in methanol (15ml) and stirred at room temperature under a nitrogen atmosphere overnight.
Water was added and the mixture washed with ethylacetate. The aqueous phase was then adjusted to pH 10 with potassium carbonate and saturated with sodium chloride. Extraction with ethylacetate gave a sticky gum which was chromatographed on silica eluting with 1% 0.88 NH3 solution in methanol (r.f. -0.4) to give an off white powder. Elemental analysis for C]g H23 N3 O2 0.35 CHCI3: Calculated C 62.05, H 6.63, N 1 1.83; Found C 62.21, H 6.76, N 11.55. mpt = Becomes gummy at 77-78°C.
This solvated compound can be dried in vacuo at 80°C to provide an anhydrous compound which has mpt = 159-160°.
Example 2: Monobenzoate salt of4-[3-(trans-3-dimethylaminocyclobutylVlH-indol-5- ylmethyl]-4fS oxazolidin-2-one
A mixture ofthe free base product ofExample 1 (lOOmg) and benzoic acid (39mg) in isopropanol (2mL) was warmed together. The cooled suspension was evaporated in vacuo. The resulting residual gum was treated with dichloromethane and evaporated to dryness. This treatment procedure was repeated twice more to give a foam which was then crystallised from ethyl acetate to give the title product in crystalline form, mp 155-157°C.
Example 3: Monobenzoate salt of 4-[3-(trans-3-dimethylaminocyclobutylVlH-indol-5- ylmethyl]-4(S oxazolidin-2-one (alternative preparation)
A hot solution of the free base product of Example 1 (0.66g) in ethyl acetate (15 mL) was treated with a solution of benzoic acid (0.257g) in ethyl acetate (3 mL). The solution was set aside at room temperature to give crystals. The crystals were collected, washed with a little ethyl acetate and dried in air to give 0.84g of pale yellow crystals, mp 155-157°C.
Analysis - Calculated C68.97, H6.72.N9.66 Found C68.78,H6.79,N9.48 Example 4: Sulphate salt of 4-[3-(trans-3-dimethylaminocvclobutyl)- 1 H-indol-5- ylmethyl]-4(S oxazolidin-2-one
A solution of the free base product of Example 1 (lOOmg) in isopropanol was treated with a solution of concentrated sulphuric acid in isopropanol (1 mL). The mixture was warmed, cooled to room temperature and evaporated to dryness. The residue was treated with dichloromethane and evaporated and this procedure was repeated 3 times. The solid was crystallised from ethyl acetate, mp. 170°C dec.
Analysis - Calculated 0.9 H2SO4 C53.84,H6.23,N10.47 Found C54.06,H6.55,N10.08
Example 5: Comparative Stability Tests of salts of 4-|"3-(trans-3- dimethylaminocyclobutyl)-lH-indol-5-ylmethyll-4(S)oxazolidin-2-one
Six salts of the free base compound of Example 1 were synthesised and their stability measured by testing hygroscopicity. The results are shown in Table 1 below.
TABLE 1
Salt Description Solvent Melting Point (°C) Stability
Hydrochloride Colourless powder ether Very hygroscopic
Sulphate Solid EtOAc 175-180 Stable
Succinate Yellow powder ether 50-55 effer. Hygroscopic
Hemisuccinate White powder ether 09.60 effer. Hygroscopic
After standing 24hr ether 78-80 effer. Hygroscopic in air, more crystalline
Monobenzoate Pale yellow crystals EtOAc 155-157 Stable Mesylate Oil EtOAc Darkens at room temperature
These results show that only the monobenzoate and sulphate salts are stable and non-hygroscopic.

Claims

1. A salt selected from 4-[3-(trans-3-dimethylaminocyclobutyl)-lH-indol-5-ylmethyl]- 4(S)oxazolidin-2-one monobenzoate or 4-[3-(trans-3-dimethylaminocyclobutyl)-lH- indol-5-ylmethyl]-4(S)oxazolidin-2-one sulphate.
2. A salt according to Claim 1 in a solid form.
3. A salt according to Claim 2 in crystalline form.
4. A salt according to any of Claims 1 to 3 which is 4-[3-(trans-3- dimethylaminocyclobutyl)-lH-indol-5-ylmethyl]-4(S)oxazolidin-2-one monobenzoate.
5. A salt according to any of Claims 1 to 5 which is at least 95% pure.
6. A process for preparing a salt according to any of Claims 1 to 5 which comprises reacting 4-[3-(trans-3-dimethylaminocyclobutyl)-lH-indol-5-ylmethyl]- 4(S)oxazolidin-2-one
a) with benzoic acid, when it is desired to prepare the monobenzoate salt; or
b) with sulphuric acid, when it is desired to prepare the sulphate salt.
7. A process for preparing a salt according to any of Claims 1 to 5 which comprises reacting a salt of 4-[3-(trans-3-dimethylaminocyclobutyl)-lH-indol-5-ylmethyl]- 4(S)oxazolidin-2-one
a) with benzoic acid wherein the salt is other than the monobenzoate, when it is desired to prepare the monobenzoate salt; or
b) with sulphuric acid wherein the salt is other than the sulphate, when it is desired to prepare the sulphate salt
followed by removing the original salt forming ion.
8. A process according to Claim 6 or Claim 7 for the preparation ofthe monobenzoate salt of 4-[3-(trans-3-dimethylaminocyclobutyl)-lH-indol-5-ylmethyl]-4(S)oxazolidin- 2-one.
9. A pharmaceutical formulation comprising a salt according to any of Claims 1 to 5 together with one or more pharmaceutically acceptable carriers therefor and optionally one or more other therapeutic agents.
10. A salt according to any of Claims 1 to 5 for use in therapy.
11. A salt according to any of Claims 1 to 5 for use in the prophylaxis and/or treatment of a clinical condition for which a 5HTι-like receptor agonist is indicated.
12. A salt according to any of Claims 1 to 5 for use in the prophylaxis and/or treatment of migraine.
13. The use of a salt according to any of Claims 1 to 5 in the manufacture of a medicament for the prophylaxis or treatment of a clinical condition for which a "SHTj-like" receptor agonist is indicated.
14. , The use according to Claim 13 wherein the clinical condition is migraine.
15. A method for combatting a clinical condition in a mammal, for example, a human, for which a "5HT]-like" receptor agonist is indicated which comprises administering a salt according to any of Claims 1 to 4 in an effective amount.
16. A method according to Claim 14 wherein the clinical condition is migraine.
PCT/EP1996/003188 1995-07-22 1996-07-19 4-[3-(trans-3-dimethylaminocyclobutyl)-1h-indol-5-ylmethyl]-4(s)oxazolidin-2-one monobenzoate and sulphate salt WO1997003983A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP96926370A EP0842173A1 (en) 1995-07-22 1996-07-19 4-[3-(trans-3-dimethylaminocyclobutyl)-1h-indol-5-ylmethyl]-4(s)oxazolidin-2-one monobenzoate and sulphate salt
AU66581/96A AU6658196A (en) 1995-07-22 1996-07-19 4-{3-(trans-3-dimethylaminocyclobutyl)-1h-indol-5-ylmethyl}- 4(s)oxazolidin-2-one monobenzoate and sulphate salt
JP9506303A JPH11509537A (en) 1995-07-22 1996-07-19 4- [3- (trans-3-dimethylaminocyclobutyl) -1H-indol-5-ylmethyl] -4 (S) oxazolidin-2-one monobenzoate and sulfate

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9515060.3 1995-07-22
GBGB9515060.3A GB9515060D0 (en) 1995-07-22 1995-07-22 Therapeutic heterocyclic compounds

Publications (1)

Publication Number Publication Date
WO1997003983A1 true WO1997003983A1 (en) 1997-02-06

Family

ID=10778112

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1996/003188 WO1997003983A1 (en) 1995-07-22 1996-07-19 4-[3-(trans-3-dimethylaminocyclobutyl)-1h-indol-5-ylmethyl]-4(s)oxazolidin-2-one monobenzoate and sulphate salt

Country Status (5)

Country Link
EP (1) EP0842173A1 (en)
JP (1) JPH11509537A (en)
AU (1) AU6658196A (en)
GB (1) GB9515060D0 (en)
WO (1) WO1997003983A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11103478B2 (en) * 2017-06-14 2021-08-31 Anavex Life Sciences Corp. Anavex2-73 for the treatment of alzheimer's disease

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991018897A1 (en) * 1990-06-07 1991-12-12 The Wellcome Foundation Limited Therapeutic heterocyclic compounds
WO1995020588A1 (en) * 1994-01-26 1995-08-03 The Wellcome Foundation Limited Indole derivatives as 5-ht1 agonists

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991018897A1 (en) * 1990-06-07 1991-12-12 The Wellcome Foundation Limited Therapeutic heterocyclic compounds
WO1995020588A1 (en) * 1994-01-26 1995-08-03 The Wellcome Foundation Limited Indole derivatives as 5-ht1 agonists

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11103478B2 (en) * 2017-06-14 2021-08-31 Anavex Life Sciences Corp. Anavex2-73 for the treatment of alzheimer's disease

Also Published As

Publication number Publication date
GB9515060D0 (en) 1995-09-20
AU6658196A (en) 1997-02-18
JPH11509537A (en) 1999-08-24
EP0842173A1 (en) 1998-05-20

Similar Documents

Publication Publication Date Title
EP1499589B1 (en) Derivatives of n-phenyl(piperidin-2-yl)methyl benzamide, the preparation method thereof and application of same in therapeutics
US20090156671A1 (en) Deuterium-enriched oxybutynin
US20090082366A1 (en) Deuterium-enriched telaprevir
US20130245067A1 (en) Deuterium-enriched lenalidomide
US20090076121A1 (en) Deuterium-enriched sumatriptan
LU81284A1 (en) NOVEL 4-AMINO-2-PIPERIDINO-QUINAZOLINE DERIVATIVES, THEIR PRODUCTION PROCESS AND MEDICAMENTS CONTAINING THEM
US20090082432A1 (en) Deuterium-enriched ramelteon
US20120035261A1 (en) Deuterium-enriched saxagliptin
US20090076097A1 (en) Deuterium-enriched atazanavir
US20090076162A1 (en) Deuterium-enriched desvenlafaxine
WO1997003983A1 (en) 4-[3-(trans-3-dimethylaminocyclobutyl)-1h-indol-5-ylmethyl]-4(s)oxazolidin-2-one monobenzoate and sulphate salt
US20090062374A1 (en) Deuterium-enriched lasofoxifene
US20090082364A1 (en) Deuterium-enriched levocedtirizine
WO2008157565A1 (en) Deuterium-enriched ezetimibe
US20090082383A1 (en) Deuterium-enriched buprenorphine
US20090082380A1 (en) Deuterium-enriched rosuvastatin
US20080319064A1 (en) Deuterium-enriched oseltamivir
WO2008157657A1 (en) Deuterium-enriched tenofovir
WO1997005133A1 (en) Prodrugs of 4-[3-(trans-3-dimethylaminocyclobutyl)-1h-indol-5-yl-methyl]-4(s)oxazolidin-2-one, their preparation and their use as 5ht1-like receptor agonists
US20090076157A1 (en) Deuterium-enriched senicapoc
US20090076069A1 (en) Deuterium-enriched apixaban
US20090076135A1 (en) Deuterium-enriched hydromorphone
US20090076008A1 (en) Deuterium-enriched fosaprepitant
US20090076117A1 (en) Deuterium-enriched laropiprant
US20090076165A1 (en) Deuterium-enriched memantine

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

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

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): KE LS MW SD SZ UG AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 1996926370

Country of ref document: EP

ENP Entry into the national phase

Ref country code: JP

Ref document number: 1997 506303

Kind code of ref document: A

Format of ref document f/p: F

WWP Wipo information: published in national office

Ref document number: 1996926370

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

NENP Non-entry into the national phase

Ref country code: CA

WWW Wipo information: withdrawn in national office

Ref document number: 1996926370

Country of ref document: EP