WO2002100870A1 - New napsylate salts ii - Google Patents

New napsylate salts ii Download PDF

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Publication number
WO2002100870A1
WO2002100870A1 PCT/SE2002/001084 SE0201084W WO02100870A1 WO 2002100870 A1 WO2002100870 A1 WO 2002100870A1 SE 0201084 W SE0201084 W SE 0201084W WO 02100870 A1 WO02100870 A1 WO 02100870A1
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Prior art keywords
napsylate
formula
compound
salt according
salt
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PCT/SE2002/001084
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French (fr)
Inventor
Lynne Taylor
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Astrazeneca Ab
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/33—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of six-membered aromatic rings being part of condensed ring systems
    • C07C309/34—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of six-membered aromatic rings being part of condensed ring systems formed by two rings
    • C07C309/35—Naphthalene sulfonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/30—Phosphinic acids R2P(=O)(OH); Thiophosphinic acids, i.e. R2P(=X)(XH) (X = S, Se)
    • C07F9/301—Acyclic saturated acids which can have further substituents on alkyl

Definitions

  • the present invention is related to novel salt of compounds useful in therapy.
  • the invention is also related to processes for the preparation of the salts, pharmaceutical compositions containing said therapeutically active compounds and the use of said salt compounds in therapy.
  • Gastro-oesophageal reflux disease is the most prevalent upper gastrointestinal tract disease. Current therapy has aimed at reducing gastric acid secretion, or at reducing oesophageal acid exposure by enhancing oesophageal clearance, lower oesophageal sphincter tone and gastric emptying. The major mechanism behind reflux has earlier been considered to depend on a hypotonic lower oesophageal sphincter. However recent research (e.g. Holloway & Dent (1990) Gastroenterol. Clin. N. Amer. 19, pp.
  • TLOSR transient lower oesophageal sphincter relaxations
  • GABAj3-receptor agonists having the property to inhibit TLOSR are disclosed in WO 98/11885, Al. Recently, further GABAB-receptor agonists are shown to have property to inhibit TLOSR (WO 01/41473, Al).
  • GABA (4-aminobutanoic acid) is an endogenous neurotransmitter in the central and peripheral nervous systems.
  • Receptors for GABA have traditionally been divided into GABAA and GABAg receptor subtypes.
  • GABA ⁇ receptors belong to the superfamily of G-protein coupled receptors.
  • GABAg receptor agonists are being described as being of use in the treatment of CNS disorders, such as muscle relaxation in spinal spasticity, cardiovascular disorders, asthma, gut motility disorders such as irritable bowel syndrome (IBS) and as prokinetic and anti-tussive agents.
  • GABAB receptor agonists have also been disclosed as useful in the treatment of emesis (WO 96/11680, A2) and, as mentioned above, in the inhibition of TLOSR (WO 98/11885, Al).
  • EP 0356128, Bl describes the use of the specific compound (3-aminopropyl)- methylphosphinic acid, as a potent GABAB receptor agonist, in therapy.
  • EP 0181833, Bl discloses substituted 3-aminopropylphosphinic acids, which are found to have very high affinities towards GABA B receptor sites.
  • EP 0399949, Bl discloses derivatives of (3- aminopropyl)methylphosphinic acid which are described as potent GABA B receptor agonists. These compounds are stated to be useful as muscle relaxants.
  • GABAB receptor agonists in form of salts are also proposed in EP 0356128, Bl, EP 0181833, Bl, and EP 0399949, Bl.
  • the object of the present invention is to provide novel salt compounds of certain GABAB receptor agonists.
  • the present invention provides a novel napsylate salt of compounds of the formula I, or a solvate of said salt, or the stereoisomers thereof,
  • R l represents hydrogen, hydroxy, C1-C7 alkyl, Ci -C7 alkoxy or halogen
  • R2 represents hydroxy, mercapto, halogen or an oxo group
  • R 3 represents hydrogen or Ci -C7 alkyl (optionally substituted with hydroxy, mercapto, C ⁇ - C7 alkoxy, aryl or C1-C7 thioalkoxy);
  • R4 represents hydrogen, C1-C7 alkyl (optionally substituted with aryl or heteroaryl), aryl or heteroaryl;
  • R5 represents methyl, fmoromethyl, difluoromethyl or trifluoromethyl.
  • the napsylate salts of the invention have improved substances characteristics in relation to hygroscopicity. Further, the salt compounds according to the invention have suitable properties for handling the substances during the preparation of a pharmaceutical dosage form and during storage of the substance or the said dosage form.
  • the napsylate salt may be formed by an acid addition reaction of the parent substance, i.e. the phosphinic acid according to formula I, or a solvate thereof, and naphthalene-2- sulphonic acid, or an intermediate compound formed in the synthesis of the parent . substance, or a solvate thereof, and naphthalene-2-sulphonic acid.
  • a further aspect of the invention is a napsylate salt of compounds of Formula I selected from anyone of (3-amino-2-fluoropropyl)(methyl)phosphinic acid, and, (2R)-(3-amino-2- fluoropropy ⁇ )(methyl)phosphinic acid, and, (2S)-(3-amino-2- fluoropropyl)(methyl)phosphinic acid, and, (3-amino-2-fluoro-l- methylpropyl)(methyl)phosphinic acid .
  • alkyl group means, inter alia, C1-C4 alkyl, such as methyl, ethyl, n-propyl or n-butyl, also isopropyl, isobutyl, secondary butyl or tertiary butyl, but may also be a C5-C7 alkyl group such as a pentyl, hexyl or heptyl group.
  • alkoxy group means, inter alia, C1-C 4 alkoxy, such as methoxy, ethoxy, n-propoxy or n-butoxy, also isopropoxy, isobutoxy, secondary butoxy or tertiary butoxy, but may also be a C5-C7 alkoxy group, such as a pentoxy, hexoxy or heptoxy group.
  • thioalkoxy group means, inter alia, -C 4 thioalkoxy, such as thiomethoxy, thioethoxy, n-thiopropoxy, n-thiobutoxy, thioisopropoxy, thioisobutoxy, secondary thiobutoxy or tertiary thiobutoxy, but may also be a C5-C7 thioalkoxy group, such as a thiopentoxy, thiohexoxy or thioheptoxy group.
  • Halogen as used herein is anyone of chlorine, fluorine, bromine or iodine.
  • aryl means aromatic rings with 6-14 carbon atoms including both single rings and polycyclic compounds, such as phenyl, naphthyl, optionally substituted with one or more substituents such as C1-C7 alkyl, C1-C7 alkoxy, C1-C7 thioalkoxy, halogen, hydroxy, mercapto, carboxylic acid, carboxylic acid ester, carboxylic acid amide or nitrile.
  • heteroaryl as used herein means aromatic rings with 5-14 atoms including both single rings and polycyclic compounds in which one or several of the ring atoms is either oxygen, nitrogen or sulphur.
  • the heteroaryl is optionally substituted with one or more substituents such as C1-C7 alkyl, C1-C7 alkoxy, C1-C7 thioalkoxy, halogen, hydroxy, mercapto, carboxylic acid, carboxylic acid ester, carboxylic acid amide or nitrile.
  • substituents such as C1-C7 alkyl, C1-C7 alkoxy, C1-C7 thioalkoxy, halogen, hydroxy, mercapto, carboxylic acid, carboxylic acid ester, carboxylic acid amide or nitrile.
  • halogen can be anyone of chlorine, fluorine, bromine or iodine.
  • the compounds according to formula I can be in the form of a stereoisomeric mixture, i.e. a mixture of diastereomers and/or racemates, or in the form of the single stereoisomers, i.e. the single enantiomer and/or diastereomer.
  • the napsylate salt of formula I above, or a solvate, or a stereoisomer thereof, have a surprisingly high chemical and physical stability during handling the substance, as well as formulating into a pharmaceutical dosage form and during storage of the prepared dosage form.
  • the hydrolytic instability due to adsorbed free moisture is improved. If the active compound which deliqueses at a low relative humidity, the handling and processing of the compound is made difficult. Therefore, further object of the invention is an aim to reduce the tendency of the compound of deliquesce.
  • a hygroscopic substance shows an increase in mass which is less than 15 % m/m (mass of water/ mass of drug) and equal to or greater than 2 % m/m during a period of 24 hours at 25 °C and 80 % RH.
  • the increase in mass is equal or greater than 15 % m/m.
  • napsylate salts according to the invention have advantageous properties regarding the processing and handling of the active compound.
  • the hygroscopic properties are improved, the napsylate salt does not deliquesce at as low relative humidity (RH) as the parent compound.
  • the relative humidity, RH, of a gas is defined as % RH being equal to lOOx (p)/(ps) wherein (p) is the partial pressure of the water vapor present in the gas mixture and (ps) is the saturation pressure, or the partial pressure of water vapor above pure water at the temperature of the gas.
  • One aspect of the invention is the process for producing a salt compound according to formula I above.
  • One aspect of the invention is the use of a salt compound according to formula I above, for the manufacture of a medicament for the treatment of anyone of the diseases mentioned above.
  • One aspect of the invention is the pharmaceutical preparation comprising the pharmaceutically acceptable salt compound according to formula I above.
  • One aspect of the invention is the method for treatment of anyone of the diseases mentioned above with a pharmaceutical preparation comprising a salt compound according to formula I above.
  • Preparation of the napsylate salt of compounds of formula I or solvate thereof can be performed from the parent substance, i.e. the phosphinic acid according to formula I.
  • the first step in the formation of the napsylate salt of the parent substances in formula I, or a solvate thereof is the addition of a solvent, such as methanol, to the parent substance, which then is let to reflux.
  • a solvent such as methanol
  • a suitable amount of the naphthalene-2-sulphonic acid is added and the acid addition reaction is started.
  • the mixture is cooled and the napsylate is crystallised by addition of an antisolvent, such as n-butyl acetate, which lower the solubility of the napsylate salt and further cooling of the mixture follows. Crystals of the napsylate salt are isolated by filtration and following wash.
  • the crude product is recrystallised by dissolving it in a solvent such as methanol followed by an addition of an antisolvent, such as isopropylalcohol.
  • a solvent such as methanol
  • an antisolvent such as isopropylalcohol.
  • the solution is then cooled and a slurry is formed which is further cooled.
  • the crystalline napsylate salt of formula I is isolated by filtering, washed with a suitable solvent and finally dried.
  • Preparation of the napsylate salt of formula I, or solvate thereof can also be performed from an intermediate compound formed in the synthesis of the parent compound.
  • the formation of the present napsylate salt may start from an ammonium of a compound of formula II, or a solvate or a stereoisomer thereof,
  • Ri represents hydrogen or a Ci -C7 alkyl
  • R 2 represents fluoro
  • R 3 represents hydrogen
  • R5 represents methyl, fluoromethyl, difluoromethyl or trifluoromethyl
  • Z represent a protecting group.
  • the synthesis starts with a neutralisation of the intermediate with sulphuric acid, the corresponding phosphinic acid is obtained.
  • Ammonium salt is formed and is filtered off.
  • Naphthalene-2-sulphonic acid is added and the reaction is held for completion, i.e. the phosphinic acid of formula II is deprotected by reaction with the added naphthalene-2- sulphonic acid which also form the napsylate salt of formula I.
  • the solvent is evaporated off and a crude product is obtained.
  • the crude product is recrystallised with suitable solvent and antisolvent, for example, methanol and isopropyl alcohol, respectively.
  • the intermediate compound of Formula II is substituted with a suitable protecting group such as carbamates or other N-protecting groups, which are deprotected under acidic conditions.
  • a suitable protecting group such as carbamates or other N-protecting groups, which are deprotected under acidic conditions.
  • suitable protecting groups see Protective groups in organic synthesis, Theodora W. Greene, 1999, 3 rd edition, page 218-287 and page 323-334.
  • compositions in another aspect, provides formulated pharmaceutical formulations comprising as active ingredient a therapeutically effective amount of a pharmaceutically acceptable napsylate salt of compounds of formula. I as an enantiomer or a racemate, or a combination of such salts and/or solvates, optionally in association with diluents, excipients or carriers.
  • the compounds of the invention will normally be administered orally, rectally or parenterally, in the form of a pharmaceutically acceptable non-toxic salt or as a solvate of such salt in a pharmaceutically acceptable dosage form.
  • the dosage form may be a solid, semisolid or liquid preparation.
  • the active substance will constitute between 0.1 and 99 % by weight of the preparation, more specifically between 0.5 and 20 % by weight for preparations intended for injection and between 0.2 and 80 % by weight for preparations suitable for oral administration.
  • compositions comprising the compound of the invention are manufactured by pharmaceutical conventional techniques.
  • Suitable daily doses of the compound of the invention in therapeutical treatment of humans are about 0.001 - 100 mg/kg body weight for parenteral administrations and about 0.01 - 100 mg/kg bodyweight for other administration routes.
  • the salts of the compound according to the invention can be used for the inhibition of TLOSR, and thus for the treatment of gastro-oesophageal reflux diseases
  • the said inhibition of TLOSR also implies that the said compounds can be used for the treatment of regurgitation in infants. Effective management of regurgitation in infants would be an important way of managing failure to thrive due to excessive loss of ingested nutrient.
  • the novel compounds can be used for the treatment of GORD-related or non- GORD related asthma, belching, coughing, pain, cocaine addition, hiccups, IBS, dyspepsia, emesis and nociception.
  • novel napsylte salts according to the invention are useful in therapy.
  • a further aspect of the invention is the use of a napsylate salt according to the invention for the manufacturing of any one of the indications mentioned above.
  • a further aspect of the invention is the method for treatment of the indications mentioned above by administering to a subject suffering from said conditions a pharmaceutical preparation comprising the napsylate salt according to the invention.

Abstract

Novel napsylate salts of formula I, or solvates of said salt, and stereoisomers thereof, as well as a process for the preparation thereof, pharmaceutical compositions containing the therapeutically active napsylate salt and the use of said active compounds in therapy.

Description

NEW NAPSYLATE SALTS LT
Field of the invention
The present invention is related to novel salt of compounds useful in therapy. The invention is also related to processes for the preparation of the salts, pharmaceutical compositions containing said therapeutically active compounds and the use of said salt compounds in therapy.
Background of the invention
Gastro-oesophageal reflux disease (GORD) is the most prevalent upper gastrointestinal tract disease. Current therapy has aimed at reducing gastric acid secretion, or at reducing oesophageal acid exposure by enhancing oesophageal clearance, lower oesophageal sphincter tone and gastric emptying. The major mechanism behind reflux has earlier been considered to depend on a hypotonic lower oesophageal sphincter. However recent research (e.g. Holloway & Dent (1990) Gastroenterol. Clin. N. Amer. 19, pp. 517-535) has shown that most reflux episodes occur during transient lower oesophageal sphincter relaxations, hereinafter referred to as TLOSR, i.e. relaxations not triggered by swallows. It has also been shown that gastric acid secretion usually is normal in patients with GORD.
Consequently, there is a need for compounds that reduce the incidence of TLOSR and thereby prevent reflux. GABAj3-receptor agonists having the property to inhibit TLOSR, are disclosed in WO 98/11885, Al. Recently, further GABAB-receptor agonists are shown to have property to inhibit TLOSR (WO 01/41473, Al).
GABA (4-aminobutanoic acid) is an endogenous neurotransmitter in the central and peripheral nervous systems. Receptors for GABA have traditionally been divided into GABAA and GABAg receptor subtypes. GABAβ receptors belong to the superfamily of G-protein coupled receptors. GABAg receptor agonists are being described as being of use in the treatment of CNS disorders, such as muscle relaxation in spinal spasticity, cardiovascular disorders, asthma, gut motility disorders such as irritable bowel syndrome (IBS) and as prokinetic and anti-tussive agents. GABAB receptor agonists have also been disclosed as useful in the treatment of emesis (WO 96/11680, A2) and, as mentioned above, in the inhibition of TLOSR (WO 98/11885, Al).
EP 0356128, Bl, describes the use of the specific compound (3-aminopropyl)- methylphosphinic acid, as a potent GABAB receptor agonist, in therapy. EP 0181833, Bl, discloses substituted 3-aminopropylphosphinic acids, which are found to have very high affinities towards GABAB receptor sites. EP 0399949, Bl, discloses derivatives of (3- aminopropyl)methylphosphinic acid which are described as potent GABAB receptor agonists. These compounds are stated to be useful as muscle relaxants.
Use of GABAB receptor agonists in form of salts are also proposed in EP 0356128, Bl, EP 0181833, Bl, and EP 0399949, Bl.
Some of the substances disclosed in the documents above have a relatively high hygroscopicity, i.e. absorb moisture or water, which has an effect to the chemical and physical stability. Therefore, there exists a need for active substances having a reduced hygroscopicity.
Outline of the invention
The object of the present invention is to provide novel salt compounds of certain GABAB receptor agonists.
More particularly, the present invention provides a novel napsylate salt of compounds of the formula I, or a solvate of said salt, or the stereoisomers thereof,
Figure imgf000004_0001
wherein
Rl represents hydrogen, hydroxy, C1-C7 alkyl, Ci -C7 alkoxy or halogen;
R2 represents hydroxy, mercapto, halogen or an oxo group;
R3 represents hydrogen or Ci -C7 alkyl (optionally substituted with hydroxy, mercapto, Cι- C7 alkoxy, aryl or C1-C7 thioalkoxy);
R4 represents hydrogen, C1-C7 alkyl (optionally substituted with aryl or heteroaryl), aryl or heteroaryl;
R5 represents methyl, fmoromethyl, difluoromethyl or trifluoromethyl.
The napsylate salts of the invention have improved substances characteristics in relation to hygroscopicity. Further, the salt compounds according to the invention have suitable properties for handling the substances during the preparation of a pharmaceutical dosage form and during storage of the substance or the said dosage form.
The napsylate salt may be formed by an acid addition reaction of the parent substance, i.e. the phosphinic acid according to formula I, or a solvate thereof, and naphthalene-2- sulphonic acid, or an intermediate compound formed in the synthesis of the parent . substance, or a solvate thereof, and naphthalene-2-sulphonic acid.
A further aspect of the invention is a napsylate salt of compounds of Formula I selected from anyone of (3-amino-2-fluoropropyl)(methyl)phosphinic acid, and, (2R)-(3-amino-2- fluoropropyι)(methyl)phosphinic acid, and, (2S)-(3-amino-2- fluoropropyl)(methyl)phosphinic acid, and, (3-amino-2-fluoro-l- methylpropyl)(methyl)phosphinic acid .
In accordance with the invention, it is to be understood that when R2 is an oxo group, the bond between R2 and the carbon is a double bond.
Examples of the herein used term alkyl group means, inter alia, C1-C4 alkyl, such as methyl, ethyl, n-propyl or n-butyl, also isopropyl, isobutyl, secondary butyl or tertiary butyl, but may also be a C5-C7 alkyl group such as a pentyl, hexyl or heptyl group.
Examples of the herein used term alkoxy group means, inter alia, C1-C4 alkoxy, such as methoxy, ethoxy, n-propoxy or n-butoxy, also isopropoxy, isobutoxy, secondary butoxy or tertiary butoxy, but may also be a C5-C7 alkoxy group, such as a pentoxy, hexoxy or heptoxy group.
Examples of the herein used term thioalkoxy group means, inter alia, -C4 thioalkoxy, such as thiomethoxy, thioethoxy, n-thiopropoxy, n-thiobutoxy, thioisopropoxy, thioisobutoxy, secondary thiobutoxy or tertiary thiobutoxy, but may also be a C5-C7 thioalkoxy group, such as a thiopentoxy, thiohexoxy or thioheptoxy group.
Halogen as used herein is anyone of chlorine, fluorine, bromine or iodine.
The herein used term aryl means aromatic rings with 6-14 carbon atoms including both single rings and polycyclic compounds, such as phenyl, naphthyl, optionally substituted with one or more substituents such as C1-C7 alkyl, C1-C7 alkoxy, C1-C7 thioalkoxy, halogen, hydroxy, mercapto, carboxylic acid, carboxylic acid ester, carboxylic acid amide or nitrile. The term heteroaryl as used herein means aromatic rings with 5-14 atoms including both single rings and polycyclic compounds in which one or several of the ring atoms is either oxygen, nitrogen or sulphur. The heteroaryl is optionally substituted with one or more substituents such as C1-C7 alkyl, C1-C7 alkoxy, C1-C7 thioalkoxy, halogen, hydroxy, mercapto, carboxylic acid, carboxylic acid ester, carboxylic acid amide or nitrile. Herein the term halogen can be anyone of chlorine, fluorine, bromine or iodine.
When one or more stereocentre is present in the molecule, the compounds according to formula I can be in the form of a stereoisomeric mixture, i.e. a mixture of diastereomers and/or racemates, or in the form of the single stereoisomers, i.e. the single enantiomer and/or diastereomer.
The napsylate salt of formula I above, or a solvate, or a stereoisomer thereof, have a surprisingly high chemical and physical stability during handling the substance, as well as formulating into a pharmaceutical dosage form and during storage of the prepared dosage form. By preparing the salt-form of the parent substance and incorporating said substance into a suitable dosage form, the hydrolytic instability due to adsorbed free moisture is improved. If the active compound which deliqueses at a low relative humidity, the handling and processing of the compound is made difficult. Therefore, further object of the invention is an aim to reduce the tendency of the compound of deliquesce.
According to the European Pharmacopeia Technical Guide (1999), Appendix II a hygroscopic substance shows an increase in mass which is less than 15 % m/m (mass of water/ mass of drug) and equal to or greater than 2 % m/m during a period of 24 hours at 25 °C and 80 % RH. For a very hygroscopic substance the increase in mass is equal or greater than 15 % m/m.
Surprisingly, napsylate salts according to the invention have advantageous properties regarding the processing and handling of the active compound. The hygroscopic properties are improved, the napsylate salt does not deliquesce at as low relative humidity (RH) as the parent compound.
The relative humidity, RH, of a gas is defined as % RH being equal to lOOx (p)/(ps) wherein (p) is the partial pressure of the water vapor present in the gas mixture and (ps) is the saturation pressure, or the partial pressure of water vapor above pure water at the temperature of the gas.
One aspect of the invention is the process for producing a salt compound according to formula I above.
One aspect of the invention is the use of a salt compound according to formula I above, for the manufacture of a medicament for the treatment of anyone of the diseases mentioned above.
One aspect of the invention is the pharmaceutical preparation comprising the pharmaceutically acceptable salt compound according to formula I above.
One aspect of the invention is the method for treatment of anyone of the diseases mentioned above with a pharmaceutical preparation comprising a salt compound according to formula I above.
Preparation
Preparation of the napsylate salt of compounds of formula I or solvate thereof can be performed from the parent substance, i.e. the phosphinic acid according to formula I. The first step in the formation of the napsylate salt of the parent substances in formula I, or a solvate thereof, is the addition of a solvent, such as methanol, to the parent substance, which then is let to reflux. A suitable amount of the naphthalene-2-sulphonic acid is added and the acid addition reaction is started. After terminated reaction, the mixture is cooled and the napsylate is crystallised by addition of an antisolvent, such as n-butyl acetate, which lower the solubility of the napsylate salt and further cooling of the mixture follows. Crystals of the napsylate salt are isolated by filtration and following wash.
The crude product is recrystallised by dissolving it in a solvent such as methanol followed by an addition of an antisolvent, such as isopropylalcohol. The solution is then cooled and a slurry is formed which is further cooled. The crystalline napsylate salt of formula I is isolated by filtering, washed with a suitable solvent and finally dried.
Preparation of the napsylate salt of formula I, or solvate thereof, can also be performed from an intermediate compound formed in the synthesis of the parent compound. The formation of the present napsylate salt may start from an ammonium of a compound of formula II, or a solvate or a stereoisomer thereof,
Figure imgf000008_0001
wherein Ri represents hydrogen or a Ci -C7 alkyl; R2 represents fluoro; R3 represents hydrogen; R5 represents methyl, fluoromethyl, difluoromethyl or trifluoromethyl; Z represent a protecting group.
The synthesis starts with a neutralisation of the intermediate with sulphuric acid, the corresponding phosphinic acid is obtained. Ammonium salt is formed and is filtered off. Naphthalene-2-sulphonic acid is added and the reaction is held for completion, i.e. the phosphinic acid of formula II is deprotected by reaction with the added naphthalene-2- sulphonic acid which also form the napsylate salt of formula I. The solvent is evaporated off and a crude product is obtained. The crude product is recrystallised with suitable solvent and antisolvent, for example, methanol and isopropyl alcohol, respectively. The intermediate compound of Formula II is substituted with a suitable protecting group such as carbamates or other N-protecting groups, which are deprotected under acidic conditions. For details of further suitable protecting groups see Protective groups in organic synthesis, Theodora W. Greene, 1999, 3rd edition, page 218-287 and page 323-334.
Pharmaceutical formulations In another aspect, the present invention, provides formulated pharmaceutical formulations comprising as active ingredient a therapeutically effective amount of a pharmaceutically acceptable napsylate salt of compounds of formula. I as an enantiomer or a racemate, or a combination of such salts and/or solvates, optionally in association with diluents, excipients or carriers.
According to the present invention the compounds of the invention will normally be administered orally, rectally or parenterally, in the form of a pharmaceutically acceptable non-toxic salt or as a solvate of such salt in a pharmaceutically acceptable dosage form. The dosage form may be a solid, semisolid or liquid preparation. Usually, the active substance will constitute between 0.1 and 99 % by weight of the preparation, more specifically between 0.5 and 20 % by weight for preparations intended for injection and between 0.2 and 80 % by weight for preparations suitable for oral administration.
The pharmaceutical formulations comprising the compound of the invention are manufactured by pharmaceutical conventional techniques.
Suitable daily doses of the compound of the invention in therapeutical treatment of humans are about 0.001 - 100 mg/kg body weight for parenteral administrations and about 0.01 - 100 mg/kg bodyweight for other administration routes. The salts of the compound according to the invention can be used for the inhibition of TLOSR, and thus for the treatment of gastro-oesophageal reflux diseases The said inhibition of TLOSR also implies that the said compounds can be used for the treatment of regurgitation in infants. Effective management of regurgitation in infants would be an important way of managing failure to thrive due to excessive loss of ingested nutrient. Furthermore the novel compounds can be used for the treatment of GORD-related or non- GORD related asthma, belching, coughing, pain, cocaine addition, hiccups, IBS, dyspepsia, emesis and nociception.
Thus, the novel napsylte salts according to the invention are useful in therapy.
A further aspect of the invention is the use of a napsylate salt according to the invention for the manufacturing of any one of the indications mentioned above.
A further aspect of the invention is the method for treatment of the indications mentioned above by administering to a subject suffering from said conditions a pharmaceutical preparation comprising the napsylate salt according to the invention.

Claims

Claims
1. A napsylate-salt of a compound according to' formula I, or solvate of said salt,
Figure imgf000011_0001
wherein
Ri represents hydrogen or a Ci -C7 alkyl;
R2 represents fluoro;
R3 represents hydrogen;
R4 represents hydrogen;
R5 represents methyl, fluoromethyl, difluoromethyl or trifluoromethyl;
and the stereoisomers thereof.
2. A napsylate-salt according to claim 1 in which the compound of formula I is (3-
amino-2-fluόropropyl)(methyl)phosphinic acid or a stereoisomer thereof.
3. A napsylate-salt according to claim 1 in which the compound of formula I is (3-amino-
2-fluoropropyl)(methyl)phosphinic acid in form of the racemate.
4. A napsylate-salt according to claim 1 in which the compound of formula I is (2R)-(3-
amino-2-fiuoropropyl)(methyl)phosphinic acid.
5. A napsylate-salt according to claim 1 in which the compound of formula I is (2S)-(3-
amino-2-fluoroproρyl)(methyl)phosphinic acid.
6. A napsylate-salt according to claim 1 in which the compound of formula I is (3-amino-
2-fluoro-l-methylpropyl) (methyl) phosphinic acid.
7. A napsylate salt according to any one of claims 1-6, for use in therapy.
8 .Use of a napsylate salt according to any one of claims 1-6 for the manufacture of a
medicament for the inhibition of transient lower oesophageal sphincter relaxations.
9. Use of a napsylate salt according to any of claims 1-6 for the manufacture of a medicament for the treatment of gastro-oesophageal reflux disease.
10. Use of a napsylate salt according to any of claims 1-6 for the manufacture of a
medicament for the treatment of regurgitation in infants.
11. Use of a napsylate salt according to any one of claims 1 -6 for the manufacture of a
medicament for the treatment of GORD-related or non-GORD related asthma, belching
coughing, pain, cocaine addition, hiccups, IBS, dyspepsia, emesis or nociception.
12. A method for the inhibition of transient lower oesophageal sphincter relaxations which
method comprises administering to a subject suffering from said condition a
pharmaceutical preparation comprising a napsylate salt according to any one of claims 1-6.
13. A method for the treatment of gastro-oesophageal reflux disease which method
comprises administering to a subject suffering from said condition a pharmaceutical
preparation comprising a napsylate salt according to any one of claims 1-6.
14. A method for the treatment of regurgitation in infants which method comprises administering to a subject suffering from said condition a pharmaceutical
preparation comprising a napsylate salt according to any one of claims 1-6.
15. A method for the treatment of GORD-related or non-GORD related asthma, belching,
coughin, pain, cocaine addition, hiccups, IBS, dyspepsia,emesis or nociception which
method comprises administering to a subject suffering from said condition a
pharmaceutical preparation comprising a napsylate salt according to any one of claims 1-6.
16. A pharmaceutical formulation comprising as active ingredient a therapeutically
acceptable amount of a napsylate salt defined in any one of claims 1-6, optionally in
association with diluents, excipients or inert carriers.
17. A process for the preparation of napsylate salt of a compound of formula I or a solvate,
or a stereoisomer of said salt according to claim 1 , whereby an acid' addition reaction of the
compound of formula I, optionally as an individual stereoisomer,
Figure imgf000015_0001
wherein
Ri represents hydrogen or a Ci -C7 alkyl;
R2 represents fluoro;
R3 represents hydrogen;
R4 represents hydrogen;
R5 represents methyl, fluoromethyl, difluoromethyl or trifluoromethyl;
and naphthalene-2-sulphonic acid is performed.
18. A process for the preparation of napsylate salt of a compound of formula I or a solvate,
or a stereoisomer of said salt according to claim 1 , whereby an acid addition reaction of the
compound of formula TJ, optionally as an individual stereoisomer,
Figure imgf000015_0002
wherein
Ri represents hydrogen or a C1-C7 alkyl;
5 R2 represents fluoro;
R3 represents hydrogen;
R5 represents methyl, fluoromethyl, difluoromethyl or trifluoromethyl; 10
Z represents a protecting group;
and naphthalene-2-sulphonic acid is performed.
15.
19. A process for the preparation of a napsylate salt of a compound of formula I or a
solvate, or a stereoisomer thereof, according to claim 18 wherein Z represents a carbamate.
0
20. A process for the preparation of a napsylate salt of a compound of formula I or a
solvate, or a stereoisomer thereof, according to claim 19 wherein Z represents tert-
25 butoxycarbonyl.
0
PCT/SE2002/001084 2001-06-08 2002-06-04 New napsylate salts ii WO2002100870A1 (en)

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SE0102058-5 2001-06-08

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Cited By (7)

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WO2006050472A2 (en) * 2004-11-03 2006-05-11 Xenoport, Inc. Acyloxyalkyl carbamate prodrugs of 3-aminopropylphosphonous and -phosphinic acids
WO2006071185A1 (en) * 2004-12-27 2006-07-06 Astrazeneca Ab New use of gabab receptor agonists
WO2006071186A1 (en) * 2004-12-27 2006-07-06 Astrazeneca Ab Use of gabab receptor agonists
US7566738B2 (en) 2004-11-03 2009-07-28 Xenoport, Inc. Acyloxyalkyl carbamate prodrugs of sulfinic acids, methods of synthesis, and use
US7585996B2 (en) 2006-09-15 2009-09-08 Xenoport, Inc. Acyloxyalkyl carbamate prodrugs, methods of synthesis and use
WO2012009646A1 (en) 2010-07-15 2012-01-19 Xenoport, Inc. Methods of treating fragile x syndrome, down's syndrome, autism and related disorders
US11905286B2 (en) 2018-08-09 2024-02-20 Antabio Sas Diazabicyclooctanones as inhibitors of serine beta-lactamases

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Publication number Priority date Publication date Assignee Title
WO1998011885A1 (en) * 1996-09-18 1998-03-26 Astra Aktiebolag Reflux inhibitors

Patent Citations (1)

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006050472A2 (en) * 2004-11-03 2006-05-11 Xenoport, Inc. Acyloxyalkyl carbamate prodrugs of 3-aminopropylphosphonous and -phosphinic acids
WO2006050472A3 (en) * 2004-11-03 2006-08-03 Xenoport Inc Acyloxyalkyl carbamate prodrugs of 3-aminopropylphosphonous and -phosphinic acids
US7494985B2 (en) 2004-11-03 2009-02-24 Xenoport, Inc. Acyloxyalkyl carbamate prodrugs, methods of synthesis, and use
US7566738B2 (en) 2004-11-03 2009-07-28 Xenoport, Inc. Acyloxyalkyl carbamate prodrugs of sulfinic acids, methods of synthesis, and use
US7935686B2 (en) 2004-11-03 2011-05-03 Xenoport, Inc. Acyloxyalkyl carbamate prodrugs, methods of synthesis, and use
WO2006071185A1 (en) * 2004-12-27 2006-07-06 Astrazeneca Ab New use of gabab receptor agonists
WO2006071186A1 (en) * 2004-12-27 2006-07-06 Astrazeneca Ab Use of gabab receptor agonists
US7585996B2 (en) 2006-09-15 2009-09-08 Xenoport, Inc. Acyloxyalkyl carbamate prodrugs, methods of synthesis and use
US7749985B2 (en) 2006-09-15 2010-07-06 Xenoport, Inc. Acyloxyalkyl carbamate prodrugs, methods of synthesis and use
WO2012009646A1 (en) 2010-07-15 2012-01-19 Xenoport, Inc. Methods of treating fragile x syndrome, down's syndrome, autism and related disorders
US11905286B2 (en) 2018-08-09 2024-02-20 Antabio Sas Diazabicyclooctanones as inhibitors of serine beta-lactamases

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