WO2004000855A1 - Combination of an acid secretion inhibiting agent and a reflux inhibitor for the treatment of gerd - Google Patents

Combination of an acid secretion inhibiting agent and a reflux inhibitor for the treatment of gerd Download PDF

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Publication number
WO2004000855A1
WO2004000855A1 PCT/SE2003/001007 SE0301007W WO2004000855A1 WO 2004000855 A1 WO2004000855 A1 WO 2004000855A1 SE 0301007 W SE0301007 W SE 0301007W WO 2004000855 A1 WO2004000855 A1 WO 2004000855A1
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represents hydrogen
reflux
combination
inhibiting agent
inhibitor
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PCT/SE2003/001007
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French (fr)
Inventor
Anders Lehmann
Michael Wrangstadh
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Astrazeneca Ab
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Priority to AU2003239025A priority Critical patent/AU2003239025A1/en
Publication of WO2004000855A1 publication Critical patent/WO2004000855A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C313/02—Sulfinic acids; Derivatives thereof
    • C07C313/04—Sulfinic acids; Esters thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • the present invention relates to a combination of an acid secretion inhibiting agent and a reflux inhibitor.
  • a further aspect of the invention is prevention of reflux for the treatment of gastro-esophageal reflux disease.
  • the lower esophageal sphincter (LES) is prone to relaxing intermittently. As a consequence, fluid from the stomach can pass into the esophagus since the mechanical barrier is temporarily lost at such times, an event hereinafter referred to as "reflux".
  • Gastro-esophageal reflux disease is the most prevalent upper gastrointestinal tract disease. The major mechanism behind reflux has been considered to depend on a hypotonic lower esophageal sphincter.
  • TLESR transient lower esophageal sphincter relaxations
  • gastric acid secretion usually is normal in patients with GERD.
  • GERD ulcerative colitis
  • the present invention provides a combination comprising, separately or together, (i) at least one acid secretion inhibiting agent; and (ii) at least one reflux inhibitor.
  • the present invention relates to a combination of an acid secretion inhibiting agent and a reflux inhibitor. Further, the invention relates to the use of a combination of an acid secretion inhibiting agent and a reflux inhibitor for the preparation of a medicament for the treatment of gastro-esophageal reflux disease, regurgitation, asthma, failure to thrive and lung disease.
  • Acid secretion inhibiting agents used in accordance with the present invention comprises inter alia H2 blocking agents, such as cimetidine, ranitidine; as well as proton pump inhibitors.
  • H2 blocking agents such as cimetidine, ranitidine
  • proton pump inhibitors include pyridinylmethylsulfinyl benzimidazoles such as omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole or related substances such as leminoprazole.
  • Proton pump inhibitors useful in accordance with the present invention may be reversible or irreversible. Reflux inhibitor
  • reflux inhibitor is defined herein as an agent preventing reflux of gastric contents.
  • GABA B -receptor agonists are examples of reflux inhibitors.
  • GABAs-receptor agonists have been shown to inhibit TLESR, which is disclosed in i.a. WO 98/11885 Al.
  • reflux inhibitors useful in accordance with the present invention are compounds of the formula I
  • Ri represents hydrogen, hydroxy, lower alkyl, lower alkoxy or halogen
  • R 2 represents hydroxy, mercapto, halogen, or an oxo group
  • R 3 represents hydrogen or lower alkyl (optionally substituted by hydroxy, mercapto, lower alkoxy, lower thioalkoxy or aryl);
  • Examples of such compounds are (3-amino-2-fluoropropyl)phosphinic acid, (2R)-(3-amino-2- fluoropropyl)phosphinic acid, (2S)-(3-amino-2-fluoropropyl)phosphinic acid, (3-amino-2- fluoro-l-methylpropyl)phosphinic acid, (3-amino-2-oxopropyl)phosphinic acid, (S)-(3- amino-2-hydroxypropyl)phosphinic acid, ), (R)-(3-amino-2-hydroxypropyl)phosphinic acid and (3-amino- 1 -fluoro-2-hydroxypropyl)phosphinic acid.
  • Lower alkyl is, for example, 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 C 5 -C7 alkyl group such as a pentyl, hexyl or heptyl group.
  • 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 C 5 -C7 alkyl group such as a pentyl, hexyl or heptyl group.
  • Lower alkoxy is, for example, 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.
  • Lower thioalkoxy is, for example, C1-C4 thioalkoxy, such as thiomethoxy, thioethoxy, n- thiopropoxy or n-thiobutoxy, also thioisopropoxy, thioisobutoxy, secondary thiobutoxy or tertiary thiobutoxy, but may also be a C5-C7 thioalkoxy group, such as a thiopentoxy, thiohexoxy or thioheptoxy group.
  • C1-C4 thioalkoxy such as thiomethoxy, thioethoxy, n- thiopropoxy or n-thiobutoxy, also thioisopropoxy, thioisobutoxy, secondary thiobutoxy or tertiary thiobutoxy, but may also be a C5-C7 thioalkoxy group, such as a thiopentoxy, thiohexoxy or thio
  • Halogen is, for example, halogen of an atomic number up to and including 35, such as fluorine, chlorine or bromine.
  • the compounds according to formula I of the invention are of amphoteric nature and may be presented in the form of internal salts. They can also form acid addition salts and salts with bases. Such salts are particularly pharmaceutically acceptable acid addition salts, as well as pharmaceutically acceptable salts formed with bases. Suitable acids for the formation of such salts include, for example, mineral acids such as hydrochloric, hydrobromic, sulfuric, or phosphoric acid or organic acids such as sulfonic acids and carboxylic acids. Salts with bases are, for example, alkali metal salts, e.g. sodium or potassium salts, or alkaline earth metal salts, e.g. calcium or magnesium salts, as well as ammonium salts, such as those with ammonia or organic amines.
  • 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 compounds can also be in the form of solvates, e.g. hydrates.
  • R 5 represents hydrogen, hydroxy, lower alkyl, lower alkoxy or halogen
  • R6 represents hydroxy, mercapto, halogen, or an oxo group
  • R7 represents hydrogen or lower alkyl (optionally substituted by hydroxy, mercapto, lower alkoxy, aryl or lower thioalkoxy);
  • R ⁇ represents hydrogen, lower alkyl (optionally substituted by aryl) or aryl;
  • R9 represents methyl, fluoromethyl, difluoromethyl or trifluorormethyl
  • Examples of such compounds are (3-amino-2-fluoropropyl)(methyl)phosphinic acid, (2R)- (3-amino-2-fluoropropyl)(methyl)phosphinic acid, (2S)-(3-amino-2- fluoropropyl)(methyl)phosphinic acid, (3-Amino-2-fluoro-l- methylpropyl)(methyl)phosphinic acid or pharmaceutically acceptable salts, solvates or the stereoisomers thereof
  • Lower alkyl is, for example, 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.
  • 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.
  • Lower alkoxy is, for example, 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.
  • Lower thioalkoxy is, for example, C1-C4 thioalkoxy, such as thiomethoxy, thioethoxy, n- thiopropoxy or n-thiobutoxy, also thioisopropoxy, thioisobutoxy, secondary thiobutoxy or tertiary thiobutoxy, but may also be a C 5 -C7 thioalkoxy group, such as a thiopentoxy, thiohexoxy or thioheptoxy group.
  • Halogen is, for example, halogen of an atomic number up to and including 35, such as flourine, chlorine or bromine.
  • the compounds according to formula II of the invention are of amphoteric nature and may be presented in the form of internal salts. They can also form acid addition salts and salts with bases. Such salts are particularly pharmaceutically acceptable acid addition salts, as well as pharmaceutically acceptable salts formed with bases. Suitable acids for the formation of such salts include, for example, mineral acids such as hydrochloric, hydrobromic, sulfuric, or phosphoric acid or organic acids such as sulfonic acids and carboxylic acids. Salts with bases are, for example, alkali metal salts, e.g. sodium or potassium salts, or alkaline earth metal salts, e.g. calcium or magnesium salts as well as ammonium salts, such as those with ammonia or organic amines.
  • the compounds according to formula 13 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 present compounds can also be in the form of solvates, e.g. hydrates.
  • reflux inhibitors useful in accordance with the present invention are compounds of the formula III
  • R ⁇ represents hydrogen, hydroxy, C1-C7 alkyl, C1-C7 alkoxy or halogen
  • R 12 represents hydrogen, C1-C7 alkyl (optionally substituted by hydroxy, mercapto, C1-C7 alkoxy, C1-C7 thioalkoxy, aryl or heteroaryl), aryl or heteroaryl;
  • R 13 represents hydrogen, C1-C7 alkyl (optionally substituted by aryl or heteroaryl), aryl or heteroaryl;
  • Examples of compounds according to formula III are (3-amino-l-fluoropropyl)phosphinic acid, 3-[(4-chlorobenzyl)amino]propyl(methyl)phosphinic acid and 3-[l-( ⁇ 3-[hydroxy(oxido)phosphino]propyl ⁇ amino)ethyl]benzoic acid.
  • C1-C7 alkyl can be straight, branched or cyclic alkyl and is, for example, 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.
  • C1-C7 alkyl can be straight, branched or cyclic alkyl and is, for example, 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.
  • C1-C7 alkoxy is, for example, 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.
  • C1-C7 thioalkoxy is, for example, C1-C4 thioalkoxy, such as thiomethoxy, thioethoxy, n- thiopropoxy or n-thiobutoxy, also 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 in Formula III 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 benzyl or naphtyl, optionally substituted by 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 carbon 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 by one or more substituents such as alkyl, C1-C7 alkoxy, -C7 thioalkoxy, halogen, hydroxy, mercapto, carboxylic acid, carboxylic acid ester, carboxylic acid amide or nitrile.
  • the compounds according to formula III of the invention are of amphoteric nature and may be presented in the form of internal salts. They can also form acid addition salts and salts with bases. Such salts are particularly pharmaceutically acceptable acid addition salts, as well as pharmaceutically acceptable salts formed with bases. Suitable acids for the formation of such salts include, for example, mineral acids such as hydrochloric, hydrobromic, sulfuric, or phosphoric acid or organic acids such as sulfonic acids and carboxylic acids.
  • Salts with bases are, for example, alkali metal salts, e.g. sodium or potassium salts, or alkaline earth metal salts, e.g. calcium or magnesium salts, as well as ammonium salts, such as those with ammonia or organic amines.
  • the salts may be prepared by conventional methods.
  • the compounds according to formula III 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 compounds can also be in the form of solvates, e.g. hydrates.
  • R 14 represents hydrogen, hydroxy, C1-C7 alkyl, -C7 alkoxy or halogen
  • R 15 represents hydrogen, hydroxy, mercapto, halogen, or an oxo group
  • R 16 represents hydrogen or C1-C7 alkyl (optionally substituted by hydroxy, mercapto, C ⁇ - C7 alkoxy, C1-C7 thioalkoxy, aryl or heteroaryl), aryl or heteroaryl;
  • R 17 represents hydrogen, C1-C7 alkyl (optionally substituted by aryl or heteroaryl), aryl or heteroaryl;
  • Examples of compounds according to formula IV are (3-amino-2-fluoropropyl)sulphinic acid, (2S)-(3-amino-2-fluoropropyl)sulphinic acid, (2R)-(3-amino-2-fluoropropyl)sulphinic acid, (2S)-(3-amino-2-hydroxypropyl)sulphinic acid, (2R)-(3-amino-2- hydroxypropyl)sulphinic acid and (3-amino-2-oxopropyl)sulphinic acid.
  • C1-C7 alkyl can be straight, branched or cyclic alkyl and is, for example, 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.
  • C1-C7 alkyl can be straight, branched or cyclic alkyl and is, for example, 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.
  • C1-C7 alkoxy is, for example, 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.
  • C1-C7 thioalkoxy is, for example, C1-C4 thioalkoxy, such as thiomethoxy, thioethoxy, n- thiopropoxy or n-thiobutoxy, also 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 in Formula TV 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 benzyl or naphtyl, optionally substituted by one or more substituents such as membered rings optionally substituted by one or more substituents such as C1-C7 alkyl, C1-C7 alkoxy, halogen, C1-C7 thioalkoxy, hydroxy, mercapto, carboxylic acid, carboxylic acid ester, carboxylic acid amide or nitrile.
  • heteroaryl as used herein means aromatic rings with 5-14 carbon 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 by one or more substituents such as C1-C7 alkyl, C1-C7 alkoxy, -C7 thioalkoxy, halogen, hydroxy, mercapto, carboxylic acid, carboxylic acid ester, carboxylic acid amide or nitrile.
  • the compounds according to formula TV of the invention are of amphoteric nature and may be presented in the form of internal salts. They can also form acid addition salts and salts with bases. Such salts are particularly pharmaceutically acceptable acid addition salts, as well as pharmaceutically acceptable salts formed with bases. Suitable acids for the formation of such salts include, for example, mineral acids such as hydrochloric, hydrobromic, sulfuric, or phosphoric acid or organic acids such as sulfonic acids and carboxylic acids.
  • Salts with bases are, for example, alkali metal salts, e.g. sodium or potassium salts, or alkaline earth metal salts, e.g. calcium or magnesium salts, as well as ammonium salts, such as those with ammonia or organic amines.
  • the salts may be prepared by conventional methods.
  • the compounds according to formula TV 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 compounds can also be in the form of solvates, e.g. hydrates.
  • the present invention provides a medicament comprising separately, or together, (i) at least one acid secretion inhibiting agent; and (ii) at least one reflux inhibitor.
  • a “combination” according to the invention may be present as a “fix combination” or as a “kit of parts combination”.
  • a “fix combination” is defined as a combination wherein the (i) at least one acid secretion inhibiting agent; and (ii) at least one reflux inhibitor are present in one unit.
  • a “fix combination” is a pharmaceutical composition wherein the (i) at least one acid secretion inhibiting agent; and (ii) at least one reflux inhibitor are present in admixture, such as in a formulation.
  • Another example of a “fix combination” is a pharmaceutical combination wherein the (i) at least one acid secretion inhibiting agent; and (ii) at least one reflux inhibitor are present in one unit without being in admixture.
  • a “kit of parts combination” is defined as a combination wherein the (i) at least one acid secretion inhibiting agent; and (ii) at least one reflux inhibitor are present in more than one unit.
  • One example of a “kit of parts combination” is a combination wherein the (i) at least one acid secretion inhibiting agent; and (ii) at least one reflux inhibitor are present separately.
  • the components of the "kit of parts combination” may be administered simultaneously, sequentially or separately, i.e. separately or together.
  • the molar ratio of the acid secretion inhibiting agent to the reflux inhibitor used according to the invention in within the range of from 1:100 to 100:1, such as from 1 :50 to 50:1 or from 1 : 20 to 20: 1 or from 1 : 10 to 10: 1.
  • the two drugs may be administered separately in the same ratio.
  • a suitable daily dose of the acid secretion inhibiting agent is in the range of 10 to 400 mg per day, such as 10 or 20 or 50 or 100 or 200 mg per day.
  • a suitable daily dose of the reflux inhibitor is in the range of 1 ⁇ g to 100 mg per day and kg body weight, preferably 10 ⁇ g to 20 mg per day and kg body weight.
  • TLESRs are known to allow gastric juice to flow back into the esophagus.
  • Administration of an acid secretion inhibiting agent such as a proton pump inhibitor can provide control of acid reflux but has little effect on bile reflux.
  • treatment with a reflux inhibitor, such as a GAB A ⁇ receptor agonist can prevent most bile reflux but its effect on acid reflux is relatively small compared with a proton pump inhibitor.
  • a combination of the two classes of agents would provide effective acid control and at the same time reduce bile acid retroflow into the esophagus.
  • reflux inhibitors useful in a "kit of parts” or in a “fix combination” as described above are any reflux inhibitors of formula I, II, III or TV above, used in combination with any acid secretion inhibiting agent(s).
  • Another aspect of the invention is the use of GAB A ( ⁇ -ammobutyric acid) or baclofen as reflux inhibitor.
  • a further aspect of the present invention is a method for the treatment of GERD, whereby a pharmaceutically and pharmacologically effective amount of a combination of an acid secretion inhibiting agent and a reflux inhibitor is administered to a subject in need of such treatment.
  • the acid secretion inhibiting agent and the reflux inhibitor are administered simultaneously, sequentially or separately.
  • a further aspect of the invention is the use of a combination of an acid secretion inhibiting agent and a reflux inhibitor for the manufacture of a medicament for the treatment of regurgitation.
  • the acid secretion inhibiting agent and the reflux inhibitor are administered simultaneously, sequentially or separately.
  • Another aspect of the present invention is a method for the treatment of regurgitation, whereby a pharmaceutically and pharmacologically effective amount of a combination of an acid secretion inhibiting agent and a reflux inhibitor is administered to a subject in need of such treatment.
  • the acid secretion inhibiting agent and the reflux inhibitor are administered simultaneously, sequentially or separately.
  • Still a further aspect of the invention is the use of a combination of an acid secretion inhibiting agent and a reflux inhibitor for the manufacture of a medicament for the treatment or prevention of lung disease.
  • the acid secretion inhibiting agent and the reflux inhibitor are administered simultaneously, sequentially or separately.
  • Still a further aspect of the invention is a method for the treatment or inhibition of lung disease, whereby a pharmaceutically and pharmacologically effective amount of a combination of an acid secretion inhibiting agent and a reflux inhibitor is administered to a subject in need of such treatment.
  • the acid secretion inhibiting agent and the reflux inhibitor are administered simultaneously, sequentially or separately.
  • Another aspect of the invention is the use of a combination of an acid secretion inhibiting agent and a reflux inhibitor for the manufacture of a medicament for the management of failure to thrive due.
  • the acid secretion inhibiting agent and the reflux inhibitor are administered simultaneously, sequentially or separately.
  • Still a further aspect of the invention is a method for the management of failure to thrive, whereby a pharmaceutically and pharmacologically effective amount of a combination of an acid secretion inhibiting agent and a reflux inhibitor is administered to a subject in need of such treatment.
  • the acid secretion inhibiting agent and the reflux inhibitor are administered simultaneously, sequentially or separately.
  • Still a further aspect of the invention is the use of a combination of an acid secretion inhibiting agent and a reflux inhibitor for the manufacture of a medicament for the prevention of reflux.
  • the acid secretion inhibiting agent and the reflux inhibitor are administered simultaneously, sequentially or separately.
  • Another aspect of the present invention is a method for the prevention of reflux, whereby a pharmaceutically and pharmacologically effective amount of a combination of an acid secretion inhibiting agent and a reflux inhibitor is administered to a subject in need of such prevention.
  • the acid secretion inhibiting agent and the reflux inhibitor are administered simultaneously, sequentially or separately.
  • Still a further aspect of the invention is the use of a combination of an acid secretion inhibiting agent and a reflux inhibitor for the manufacture of a medicament for the treatment of esophagitis.
  • the acid secretion inhibiting agent and the reflux inhibitor are administered simultaneously, sequentially or separately.
  • Another aspect of the present invention is a method for the prevention of esophagitis, whereby a pharmaceutically and pharmacologically effective amount of a combination of an acid secretion inhibiting agent and a reflux inhibitor is administered to a subject in need of such treatment.
  • the acid secretion inhibiting agent and the reflux inhibitor are administered simultaneously, sequentially or separately.
  • Still a further aspect of the invention is the use of a combination of an acid secretion inhibiting agent and a reflux inhibitor for the manufacture of a medicament for the treatment of asthma, such as reflux-related asthma or non reflux-related asthma.
  • the acid secretion inhibiting agent and the reflux inhibitor are administered simultaneously, sequentially or separately.
  • Another aspect of the present invention is a method for the treatment of asthma, such as reflux-related asthma or non reflux-related asthma, whereby a pharmaceutically and pharmacologically effective amount of a combination of an acid secretion inhibiting agent and a reflux inhibitor is administered to a subject in need of such treatment.
  • the acid secretion inhibiting agent and the reflux inhibitor are administered simultaneously, sequentially or separately.
  • Still a further aspect of the invention is the use of a combination of an acid secretion inhibiting agent and a reflux inhibitor for the manufacture of a medicament for the treatment of laryngitis, such as chronic laryngitis.
  • the acid secretion inhibiting agent and the reflux inhibitor are administered simultaneously, sequentially or separately.
  • Another aspect of the present invention is a method for the treatment of laryngitis, such as chronic laryngitis, whereby a pharmaceutically and pharmacologically effective amount of a combination of an acid secretion inhibiting agent and a reflux inhibitor is administered to a subject in need of such treatment.
  • the acid secretion inhibiting agent and the reflux inhibitor are administered simultaneously, sequentially or separately.
  • Still a further aspect of the invention is the use of a combination of an acid secretion inhibiting agent and a reflux inhibitor for the manufacture of a medicament for the inhibition of TLESRs.
  • the acid secretion inhibiting agent and the reflux inhibitor are administered simultaneously, sequentially or separately.
  • a further aspect of the present invention is a method for the inhibition of TLESRs, whereby a pharmaceutically and pharmacologically effective amount of a combination of an acid secretion inhibiting agent and a reflux inhibitor is administered to a subject in need of such inhibition.
  • the acid secretion inhibiting agent and the reflux inhibitor are administered simultaneously, sequentially or separately.
  • agonist should be understood as including full agonists as well as partial agonists, whereby a “partial agonist” should be understood as a compound capable of partially, but not fully, activating a receptor.
  • TLESR transient lower esophageal sphincter relaxations
  • the wording "reflux” is defined as fluid from the stomach being able to pass into the esophagus, since the mechanical barrier is temporarily lost at such times.
  • the wording "GERD”, gastro-esophageal reflux disease, is defined in accordance with van Heerwarden, M.A., Smout A.J.P.M., 2000; Diagnosis of reflux disease. Bailliere's Clin. Gastroenterol. 14, pp. 759-774.
  • the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
  • the terms “therapeutic” and “therapeutically” should be construed accordingly.
  • the combination of an acid secretion inhibiting agent and a reflux inhibitor are in accordance with the present invention suitably formulated into pharmaceutical formulations for oral administration.
  • rectal, parenteral or any other route of administration may be contemplated to the skilled man in the art of formulations.
  • the combination of an acid secretion inhibiting agent and a reflux inhibitor are formulated with at least one pharmaceutically and pharmacologically acceptable carrier or adjuvant.
  • the carrier may be in the form of a solid, semi-solid or liquid diluent.
  • the acid secretion inhibiting agent and a reflux inhibitor are administered simultaneously, sequentially or separately.
  • an acid secretion inhibiting agent and a reflux inhibitor to be formulated is mixed with solid, powdered ingredients such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
  • disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
  • Soft gelatine capsules may be prepared with capsules containing a mixture of the combination of an acid secretion inhibiting agent and a reflux inhibitor, with vegetable oil, fat, or other suitable vehicle for soft gelatine capsules.
  • Hard gelatine capsules may contain the combination of an acid secretion inhibiting agent and a reflux inhibitor, in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatine.
  • Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain the active substance(s) mixed with a neutral fat base; (ii) in the form of a gelatine rectal capsule which contains the combination of an acid secretion inhibiting agent and a reflux inhibitor, in a mixture with a vegetable oil, paraffin oil, or other suitable vehicle for gelatine rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
  • Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions, containing the combination of an acid secretion inhibiting agent and a reflux inhibitor, and the remainder of the formulation consisting of sugar or sugar alcohols, and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agent.
  • Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.
  • Solutions for parenteral administration may be prepared as a solution of a combination of an acid secretion inhibiting agent and a reflux inhibitor, in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients and/or buffering ingredients and are dispensed into unit doses in the form of ampoules or vials. Solutions for parenteral administration may also be prepared as a dry preparation to be reconstituted with a suitable solvent extemporaneously before use.
  • the combination of an acid secretion inhibiting agent and a reflux inhibitor may be administered once or twice daily, depending on the severity of the patient's condition.
  • the amount of active agent in a dosage form is from 0.1% to 95% by weight of the preparation.

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Abstract

The present invention relates to a medicament comprising, separately or together, (i) at least one acid secretion inhibiting agent; and (ii) at least one reflux inhibitor. A further aspect of the invention relates to methods of treatment of gastro-esophageal reflux disease, regurgitation, asthma, failure to thrive and lung disease.

Description

COMBINATION OF AN ACE) SECRETION INHIBITING AGENT AND A REFLUX INHIBITOR FOR THE TREATMENT OF GERD
Field of the invention
The present invention relates to a combination of an acid secretion inhibiting agent and a reflux inhibitor. A further aspect of the invention is prevention of reflux for the treatment of gastro-esophageal reflux disease.
Background of the invention
The lower esophageal sphincter (LES) is prone to relaxing intermittently. As a consequence, fluid from the stomach can pass into the esophagus since the mechanical barrier is temporarily lost at such times, an event hereinafter referred to as "reflux".
Gastro-esophageal reflux disease (GERD) is the most prevalent upper gastrointestinal tract disease. The major mechanism behind reflux has been considered to depend on a hypotonic lower esophageal sphincter. However, more detailed studies (e.g. Holloway & Dent (1990) Gastroenterol. Clin. N. Amer. 19, pp. 517-535) have shown that most reflux episodes occur during transient lower esophageal sphincter relaxations (TLESR), i.e. relaxations not triggered by swallows. It has also been shown that gastric acid secretion usually is normal in patients with GERD.
GERD is caused by reflux of gastric contents into the esophagus leading to heartburn and other typical symptoms. In many cases, an inflammation develops in the distal esophagus (esophagitis). It has been known for a long time that suppression of production of gastric acid ameliorates both symptoms and esophagitis. However, some patients continue to have symptoms despite adequate control of acid secretion. Reflux of other noxious factors is believed to be responsible for those symptoms. Most focus has been centered on the importance of bile acids, and the development of severe GERD is related to the degree of esophageal bile acid exposure. The combination therapy of idiopathic chronic hiccup with cisapride, omeprazole and baclofen has been described by Petroianu G. et al. Clinical Therapeutics (1997), 19, pp. 1031-1038. The combination therapy of idiopathic chronic hiccup with cisapride, omeprazole and gabapentin has been disclosed by Petroianu G. et al. Journal of Clinical Gastroenterology (2000), 20, pp. 321-324.
Outline of the invention
The present invention provides a combination comprising, separately or together, (i) at least one acid secretion inhibiting agent; and (ii) at least one reflux inhibitor.
The present invention relates to a combination of an acid secretion inhibiting agent and a reflux inhibitor. Further, the invention relates to the use of a combination of an acid secretion inhibiting agent and a reflux inhibitor for the preparation of a medicament for the treatment of gastro-esophageal reflux disease, regurgitation, asthma, failure to thrive and lung disease.
Acid secretion inhibiting agents The wording "acid secretion inhibiting agent" used in accordance with the present invention comprises inter alia H2 blocking agents, such as cimetidine, ranitidine; as well as proton pump inhibitors. Examples of proton pump inhibitors useful in accordance with the present invention are pyridinylmethylsulfinyl benzimidazoles such as omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole or related substances such as leminoprazole. Proton pump inhibitors useful in accordance with the present invention may be reversible or irreversible. Reflux inhibitor
The wording "reflux inhibitor" is defined herein as an agent preventing reflux of gastric contents. GABAB-receptor agonists are examples of reflux inhibitors. GABAs-receptor agonists have been shown to inhibit TLESR, which is disclosed in i.a. WO 98/11885 Al.
Examples of reflux inhibitors useful in accordance with the present invention are compounds of the formula I
Figure imgf000004_0001
wherein
Ri represents hydrogen, hydroxy, lower alkyl, lower alkoxy or halogen;
R2 represents hydroxy, mercapto, halogen, or an oxo group;
R3 represents hydrogen or lower alkyl (optionally substituted by hydroxy, mercapto, lower alkoxy, lower thioalkoxy or aryl);
represents hydrogen, lower alkyl (optionally substituted by aryl), or aryl;
and pharmaceutically acceptable salts, solvates and the stereoisomers thereof. Examples of such compounds are (3-amino-2-fluoropropyl)phosphinic acid, (2R)-(3-amino-2- fluoropropyl)phosphinic acid, (2S)-(3-amino-2-fluoropropyl)phosphinic acid, (3-amino-2- fluoro-l-methylpropyl)phosphinic acid, (3-amino-2-oxopropyl)phosphinic acid, (S)-(3- amino-2-hydroxypropyl)phosphinic acid, ), (R)-(3-amino-2-hydroxypropyl)phosphinic acid and (3-amino- 1 -fluoro-2-hydroxypropyl)phosphinic acid.
In the definition of formula I above, it is to be understood that when R2 is an oxo group the bond between R2 and the carbon is a double bond. In the definition of formula I above, it is to be understood by "lower" radicals for example those having up to and including 7, especially up to and including 4, carbon atoms. Also the general terms have the following meanings:
Lower alkyl is, for example, 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.
Lower alkoxy is, for example, 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.
Lower thioalkoxy is, for example, C1-C4 thioalkoxy, such as thiomethoxy, thioethoxy, n- thiopropoxy or n-thiobutoxy, also 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 is, for example, halogen of an atomic number up to and including 35, such as fluorine, chlorine or bromine.
The compounds according to formula I of the invention are of amphoteric nature and may be presented in the form of internal salts. They can also form acid addition salts and salts with bases. Such salts are particularly pharmaceutically acceptable acid addition salts, as well as pharmaceutically acceptable salts formed with bases. Suitable acids for the formation of such salts include, for example, mineral acids such as hydrochloric, hydrobromic, sulfuric, or phosphoric acid or organic acids such as sulfonic acids and carboxylic acids. Salts with bases are, for example, alkali metal salts, e.g. sodium or potassium salts, or alkaline earth metal salts, e.g. calcium or magnesium salts, as well as ammonium salts, such as those with ammonia or organic amines. 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 compounds can also be in the form of solvates, e.g. hydrates.
Still further examples of reflux inhibitors useful in accordance with the present invention are compounds of the formula II
Figure imgf000006_0001
wherein
R5 represents hydrogen, hydroxy, lower alkyl, lower alkoxy or halogen;
R6 represents hydroxy, mercapto, halogen, or an oxo group;
R7 represents hydrogen or lower alkyl (optionally substituted by hydroxy, mercapto, lower alkoxy, aryl or lower thioalkoxy);
Rδ represents hydrogen, lower alkyl (optionally substituted by aryl) or aryl;
R9 represents methyl, fluoromethyl, difluoromethyl or trifluorormethyl;
and pharmaceutically acceptable salts, solvates and the stereoisomers thereof.
Examples of such compounds are (3-amino-2-fluoropropyl)(methyl)phosphinic acid, (2R)- (3-amino-2-fluoropropyl)(methyl)phosphinic acid, (2S)-(3-amino-2- fluoropropyl)(methyl)phosphinic acid, (3-Amino-2-fluoro-l- methylpropyl)(methyl)phosphinic acid or pharmaceutically acceptable salts, solvates or the stereoisomers thereof
In the definition of formula II above, it is to be understood that when Rg is an oxo group the bond between Rβ and the carbon is a double bond.
Furthermore, in the definition of formula II above, it is to be understood by "lower" radicals for example those having up to and including 7, especially up to and including 4, carbon atoms. Also the general terms have the following meanings:
Lower alkyl is, for example, 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.
Lower alkoxy is, for example, 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.
Lower thioalkoxy is, for example, C1-C4 thioalkoxy, such as thiomethoxy, thioethoxy, n- thiopropoxy or n-thiobutoxy, also 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 is, for example, halogen of an atomic number up to and including 35, such as flourine, chlorine or bromine.
The compounds according to formula II of the invention are of amphoteric nature and may be presented in the form of internal salts. They can also form acid addition salts and salts with bases. Such salts are particularly pharmaceutically acceptable acid addition salts, as well as pharmaceutically acceptable salts formed with bases. Suitable acids for the formation of such salts include, for example, mineral acids such as hydrochloric, hydrobromic, sulfuric, or phosphoric acid or organic acids such as sulfonic acids and carboxylic acids. Salts with bases are, for example, alkali metal salts, e.g. sodium or potassium salts, or alkaline earth metal salts, e.g. calcium or magnesium salts as well as ammonium salts, such as those with ammonia or organic amines.
When one or more stereocentre is present in the molecule, the compounds according to formula 13 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 present compounds can also be in the form of solvates, e.g. hydrates.
Still further examples of reflux inhibitors useful in accordance with the present invention are compounds of the formula III
Figure imgf000008_0001
wherein
Rio represents hydrogen, methyl, fluoromethyl, difluoromethyl or trifluoromethyl;
Rπ represents hydrogen, hydroxy, C1-C7 alkyl, C1-C7 alkoxy or halogen;
R12 represents hydrogen, C1-C7 alkyl (optionally substituted by hydroxy, mercapto, C1-C7 alkoxy, C1-C7 thioalkoxy, aryl or heteroaryl), aryl or heteroaryl;
R13 represents hydrogen, C1-C7 alkyl (optionally substituted by aryl or heteroaryl), aryl or heteroaryl;
and pharmaceutically acceptable salts, solvates and the stereoisomers thereof. Examples of compounds according to formula III are (3-amino-l-fluoropropyl)phosphinic acid, 3-[(4-chlorobenzyl)amino]propyl(methyl)phosphinic acid and 3-[l-({3-[hydroxy(oxido)phosphino]propyl}amino)ethyl]benzoic acid.
In the definition of formula III above, C1-C7 alkyl can be straight, branched or cyclic alkyl and is, for example, 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.
C1-C7 alkoxy is, for example, 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.
C1-C7 thioalkoxy is, for example, C1-C4 thioalkoxy, such as thiomethoxy, thioethoxy, n- thiopropoxy or n-thiobutoxy, also 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 in Formula III 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 benzyl or naphtyl, optionally substituted by 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 carbon 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 by one or more substituents such as
Figure imgf000010_0001
alkyl, C1-C7 alkoxy, -C7 thioalkoxy, halogen, hydroxy, mercapto, carboxylic acid, carboxylic acid ester, carboxylic acid amide or nitrile.
The compounds according to formula III of the invention are of amphoteric nature and may be presented in the form of internal salts. They can also form acid addition salts and salts with bases. Such salts are particularly pharmaceutically acceptable acid addition salts, as well as pharmaceutically acceptable salts formed with bases. Suitable acids for the formation of such salts include, for example, mineral acids such as hydrochloric, hydrobromic, sulfuric, or phosphoric acid or organic acids such as sulfonic acids and carboxylic acids. Salts with bases are, for example, alkali metal salts, e.g. sodium or potassium salts, or alkaline earth metal salts, e.g. calcium or magnesium salts, as well as ammonium salts, such as those with ammonia or organic amines. The salts may be prepared by conventional methods.
When one or more stereocentre is present in the molecule, the compounds according to formula III 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 compounds can also be in the form of solvates, e.g. hydrates.
Still further examples of reflux inhibitors useful in accordance with the present invention are compounds of the formula IV
Figure imgf000010_0002
wherein R14 represents hydrogen, hydroxy, C1-C7 alkyl, -C7 alkoxy or halogen;
R15 represents hydrogen, hydroxy, mercapto, halogen, or an oxo group; R16 represents hydrogen or C1-C7 alkyl (optionally substituted by hydroxy, mercapto, C\- C7 alkoxy, C1-C7 thioalkoxy, aryl or heteroaryl), aryl or heteroaryl;
R17 represents hydrogen, C1-C7 alkyl (optionally substituted by aryl or heteroaryl), aryl or heteroaryl;
and pharmaceutically acceptable salts, solvates and the stereoisomers thereof.
Examples of compounds according to formula IV are (3-amino-2-fluoropropyl)sulphinic acid, (2S)-(3-amino-2-fluoropropyl)sulphinic acid, (2R)-(3-amino-2-fluoropropyl)sulphinic acid, (2S)-(3-amino-2-hydroxypropyl)sulphinic acid, (2R)-(3-amino-2- hydroxypropyl)sulphinic acid and (3-amino-2-oxopropyl)sulphinic acid.
In the definition of formula TV above, it is to be understood that when R15 is an oxo group the bond between R15 and the carbon is a double bond.
In the definition of formula TV above, C1-C7 alkyl can be straight, branched or cyclic alkyl and is, for example, 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.
C1-C7 alkoxy is, for example, 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.
C1-C7 thioalkoxy is, for example, C1-C4 thioalkoxy, such as thiomethoxy, thioethoxy, n- thiopropoxy or n-thiobutoxy, also 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 in Formula TV 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 benzyl or naphtyl, optionally substituted by one or more substituents such as membered rings optionally substituted by one or more substituents such as C1-C7 alkyl, C1-C7 alkoxy, halogen, C1-C7 thioalkoxy, hydroxy, mercapto, carboxylic acid, carboxylic acid ester, carboxylic acid amide or nitrile.
The term heteroaryl as used herein means aromatic rings with 5-14 carbon 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 by one or more substituents such as C1-C7 alkyl, C1-C7 alkoxy, -C7 thioalkoxy, halogen, hydroxy, mercapto, carboxylic acid, carboxylic acid ester, carboxylic acid amide or nitrile.
The compounds according to formula TV of the invention are of amphoteric nature and may be presented in the form of internal salts. They can also form acid addition salts and salts with bases. Such salts are particularly pharmaceutically acceptable acid addition salts, as well as pharmaceutically acceptable salts formed with bases. Suitable acids for the formation of such salts include, for example, mineral acids such as hydrochloric, hydrobromic, sulfuric, or phosphoric acid or organic acids such as sulfonic acids and carboxylic acids. Salts with bases are, for example, alkali metal salts, e.g. sodium or potassium salts, or alkaline earth metal salts, e.g. calcium or magnesium salts, as well as ammonium salts, such as those with ammonia or organic amines. The salts may be prepared by conventional methods.
When one or more stereocentre is present in the molecule, the compounds according to formula TV 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 compounds can also be in the form of solvates, e.g. hydrates. Combination of an acid secretion inhibiting agent and a reflux inhibitor
The present invention provides a medicament comprising separately, or together, (i) at least one acid secretion inhibiting agent; and (ii) at least one reflux inhibitor.
A "combination" according to the invention may be present as a "fix combination" or as a "kit of parts combination".
A "fix combination" is defined as a combination wherein the (i) at least one acid secretion inhibiting agent; and (ii) at least one reflux inhibitor are present in one unit. One example of a "fix combination" is a pharmaceutical composition wherein the (i) at least one acid secretion inhibiting agent; and (ii) at least one reflux inhibitor are present in admixture, such as in a formulation. Another example of a "fix combination" is a pharmaceutical combination wherein the (i) at least one acid secretion inhibiting agent; and (ii) at least one reflux inhibitor are present in one unit without being in admixture.
A "kit of parts combination" is defined as a combination wherein the (i) at least one acid secretion inhibiting agent; and (ii) at least one reflux inhibitor are present in more than one unit. One example of a "kit of parts combination" is a combination wherein the (i) at least one acid secretion inhibiting agent; and (ii) at least one reflux inhibitor are present separately. The components of the "kit of parts combination" may be administered simultaneously, sequentially or separately, i.e. separately or together.
The molar ratio of the acid secretion inhibiting agent to the reflux inhibitor used according to the invention in within the range of from 1:100 to 100:1, such as from 1 :50 to 50:1 or from 1 : 20 to 20: 1 or from 1 : 10 to 10: 1. The two drugs may be administered separately in the same ratio.
A suitable daily dose of the acid secretion inhibiting agent is in the range of 10 to 400 mg per day, such as 10 or 20 or 50 or 100 or 200 mg per day. A suitable daily dose of the reflux inhibitor is in the range of 1 μg to 100 mg per day and kg body weight, preferably 10 μg to 20 mg per day and kg body weight. TLESRs are known to allow gastric juice to flow back into the esophagus. Administration of an acid secretion inhibiting agent such as a proton pump inhibitor can provide control of acid reflux but has little effect on bile reflux. On the other hand, treatment with a reflux inhibitor, such as a GAB Aβ receptor agonist can prevent most bile reflux but its effect on acid reflux is relatively small compared with a proton pump inhibitor. Thus, a combination of the two classes of agents would provide effective acid control and at the same time reduce bile acid retroflow into the esophagus.
Examples of reflux inhibitors useful in a "kit of parts" or in a "fix combination" as described above, are any reflux inhibitors of formula I, II, III or TV above, used in combination with any acid secretion inhibiting agent(s). Another aspect of the invention is the use of GAB A (γ-ammobutyric acid) or baclofen as reflux inhibitor.
A further aspect of the present invention is a method for the treatment of GERD, whereby a pharmaceutically and pharmacologically effective amount of a combination of an acid secretion inhibiting agent and a reflux inhibitor is administered to a subject in need of such treatment. The acid secretion inhibiting agent and the reflux inhibitor are administered simultaneously, sequentially or separately.
Effective management of regurgitation would be an important way of preventing, as well as curing lung disease due to aspiration of regurgitated gastric contents, and for managing failure to thrive due to excessive loss of ingested nutrient. Thus, a further aspect of the invention is the use of a combination of an acid secretion inhibiting agent and a reflux inhibitor for the manufacture of a medicament for the treatment of regurgitation. The acid secretion inhibiting agent and the reflux inhibitor are administered simultaneously, sequentially or separately.
Another aspect of the present invention is a method for the treatment of regurgitation, whereby a pharmaceutically and pharmacologically effective amount of a combination of an acid secretion inhibiting agent and a reflux inhibitor is administered to a subject in need of such treatment. The acid secretion inhibiting agent and the reflux inhibitor are administered simultaneously, sequentially or separately.
Still a further aspect of the invention is the use of a combination of an acid secretion inhibiting agent and a reflux inhibitor for the manufacture of a medicament for the treatment or prevention of lung disease. The acid secretion inhibiting agent and the reflux inhibitor are administered simultaneously, sequentially or separately.
Still a further aspect of the invention is a method for the treatment or inhibition of lung disease, whereby a pharmaceutically and pharmacologically effective amount of a combination of an acid secretion inhibiting agent and a reflux inhibitor is administered to a subject in need of such treatment. The acid secretion inhibiting agent and the reflux inhibitor are administered simultaneously, sequentially or separately.
Another aspect of the invention is the use of a combination of an acid secretion inhibiting agent and a reflux inhibitor for the manufacture of a medicament for the management of failure to thrive due. The acid secretion inhibiting agent and the reflux inhibitor are administered simultaneously, sequentially or separately.
Still a further aspect of the invention is a method for the management of failure to thrive, whereby a pharmaceutically and pharmacologically effective amount of a combination of an acid secretion inhibiting agent and a reflux inhibitor is administered to a subject in need of such treatment. The acid secretion inhibiting agent and the reflux inhibitor are administered simultaneously, sequentially or separately.
Still a further aspect of the invention is the use of a combination of an acid secretion inhibiting agent and a reflux inhibitor for the manufacture of a medicament for the prevention of reflux. The acid secretion inhibiting agent and the reflux inhibitor are administered simultaneously, sequentially or separately.
Another aspect of the present invention is a method for the prevention of reflux, whereby a pharmaceutically and pharmacologically effective amount of a combination of an acid secretion inhibiting agent and a reflux inhibitor is administered to a subject in need of such prevention. The acid secretion inhibiting agent and the reflux inhibitor are administered simultaneously, sequentially or separately.
Still a further aspect of the invention is the use of a combination of an acid secretion inhibiting agent and a reflux inhibitor for the manufacture of a medicament for the treatment of esophagitis. The acid secretion inhibiting agent and the reflux inhibitor are administered simultaneously, sequentially or separately.
Another aspect of the present invention is a method for the prevention of esophagitis, whereby a pharmaceutically and pharmacologically effective amount of a combination of an acid secretion inhibiting agent and a reflux inhibitor is administered to a subject in need of such treatment. The acid secretion inhibiting agent and the reflux inhibitor are administered simultaneously, sequentially or separately.
Still a further aspect of the invention is the use of a combination of an acid secretion inhibiting agent and a reflux inhibitor for the manufacture of a medicament for the treatment of asthma, such as reflux-related asthma or non reflux-related asthma. The acid secretion inhibiting agent and the reflux inhibitor are administered simultaneously, sequentially or separately.
Another aspect of the present invention is a method for the treatment of asthma, such as reflux-related asthma or non reflux-related asthma, whereby a pharmaceutically and pharmacologically effective amount of a combination of an acid secretion inhibiting agent and a reflux inhibitor is administered to a subject in need of such treatment. The acid secretion inhibiting agent and the reflux inhibitor are administered simultaneously, sequentially or separately.
Still a further aspect of the invention is the use of a combination of an acid secretion inhibiting agent and a reflux inhibitor for the manufacture of a medicament for the treatment of laryngitis, such as chronic laryngitis. The acid secretion inhibiting agent and the reflux inhibitor are administered simultaneously, sequentially or separately. Another aspect of the present invention is a method for the treatment of laryngitis, such as chronic laryngitis, whereby a pharmaceutically and pharmacologically effective amount of a combination of an acid secretion inhibiting agent and a reflux inhibitor is administered to a subject in need of such treatment. The acid secretion inhibiting agent and the reflux inhibitor are administered simultaneously, sequentially or separately.
Still a further aspect of the invention is the use of a combination of an acid secretion inhibiting agent and a reflux inhibitor for the manufacture of a medicament for the inhibition of TLESRs. The acid secretion inhibiting agent and the reflux inhibitor are administered simultaneously, sequentially or separately.
A further aspect of the present invention is a method for the inhibition of TLESRs, whereby a pharmaceutically and pharmacologically effective amount of a combination of an acid secretion inhibiting agent and a reflux inhibitor is administered to a subject in need of such inhibition. The acid secretion inhibiting agent and the reflux inhibitor are administered simultaneously, sequentially or separately.
For the purpose of this invention, the term "agonist " should be understood as including full agonists as well as partial agonists, whereby a "partial agonist" should be understood as a compound capable of partially, but not fully, activating a receptor.
The wording "TLESR", transient lower esophageal sphincter relaxations, is herein defined in accordance with Mittal, R.K., Holloway, R.H., Penagini, R., Blackshaw, L.A., Dent, J., 1995; Transient lower esophageal sphincter relaxation. Gastroenterology 109, pp. 601-610.
The wording "reflux" is defined as fluid from the stomach being able to pass into the esophagus, since the mechanical barrier is temporarily lost at such times. The wording "GERD", gastro-esophageal reflux disease, is defined in accordance with van Heerwarden, M.A., Smout A.J.P.M., 2000; Diagnosis of reflux disease. Bailliere's Clin. Gastroenterol. 14, pp. 759-774.
The term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be construed accordingly.
Pharmaceutical formulations
For clinical use, the combination of an acid secretion inhibiting agent and a reflux inhibitor, are in accordance with the present invention suitably formulated into pharmaceutical formulations for oral administration. Also rectal, parenteral or any other route of administration may be contemplated to the skilled man in the art of formulations. Thus, the combination of an acid secretion inhibiting agent and a reflux inhibitor, are formulated with at least one pharmaceutically and pharmacologically acceptable carrier or adjuvant. The carrier may be in the form of a solid, semi-solid or liquid diluent. The acid secretion inhibiting agent and a reflux inhibitor are administered simultaneously, sequentially or separately.
In the preparation of oral pharmaceutical formulations in accordance with the invention, the combination of an acid secretion inhibiting agent and a reflux inhibitor, to be formulated is mixed with solid, powdered ingredients such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture is then processed into granules or compressed into tablets.
Soft gelatine capsules may be prepared with capsules containing a mixture of the combination of an acid secretion inhibiting agent and a reflux inhibitor, with vegetable oil, fat, or other suitable vehicle for soft gelatine capsules. Hard gelatine capsules may contain the combination of an acid secretion inhibiting agent and a reflux inhibitor, in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatine.
Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain the active substance(s) mixed with a neutral fat base; (ii) in the form of a gelatine rectal capsule which contains the combination of an acid secretion inhibiting agent and a reflux inhibitor, in a mixture with a vegetable oil, paraffin oil, or other suitable vehicle for gelatine rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions, containing the combination of an acid secretion inhibiting agent and a reflux inhibitor, and the remainder of the formulation consisting of sugar or sugar alcohols, and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agent. Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.
Solutions for parenteral administration may be prepared as a solution of a combination of an acid secretion inhibiting agent and a reflux inhibitor, in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients and/or buffering ingredients and are dispensed into unit doses in the form of ampoules or vials. Solutions for parenteral administration may also be prepared as a dry preparation to be reconstituted with a suitable solvent extemporaneously before use.
In one aspect of the present invention, the combination of an acid secretion inhibiting agent and a reflux inhibitor, may be administered once or twice daily, depending on the severity of the patient's condition. Usually, the amount of active agent in a dosage form is from 0.1% to 95% by weight of the preparation.
Biological studies The effect of an acid secretion inhibiting agent, such as a proton pump inhibitor, and a reflux inhibitor, such as a GABAβ receptor agonist, on acid and bile reflux is studied in freely moving dogs. An esophagostomy is formed surgically, and after recovery, the dog is equipped with a vest. A pH electrode as well as a bile acid sensor (Bilitec) are positioned 3 cm above the lower esophageal spincter, the location of which is determined manometrically. The data loggers are placed in pockets in the vest. Acid and bile reflux is measured in four conditions: 1) After placebo treatment; 2) After treatment with an acid secretion inhibiting agent; 3) After treatment with a reflux inhibitor; and 4) After combination treatment with an acid secretion inhibiting agent and a reflux inhibitor.

Claims

Claims
1. A combination comprising, separately or together, (i) at least one acid secretion inhibiting agent; and (ii) at least one reflux inhibitor.
2. A combination according to claim 1, said combination being a pharmaceutical composition, further comprising pharmaceutically and pharmacologically acceptable carriers and/or diluents.
3. A combination according to claim 1 or 2, wherein the acid secretion inhibiting agent is a proton pump inhibitor.
4. A combination according to any one of claims 1-3, wherein the reflux inhibitor is a compound according to formula I
Figure imgf000021_0001
wherein
Ri represents hydrogen;
R2 represents hydroxy, fluoro or an oxo group;
R3 represents hydrogen;
R4 represents hydrogen; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
5. A combination according to any one of claims 1-3, wherein the reflux inhibitor is a compound according to formula II
Figure imgf000022_0001
wherein
R5 represents hydrogen or lower alkyl;
Rg represents a fluoro group;
R7 represents hydrogen;
Rδ represents hydrogen;
R9 represents methyl, fluoromethyl, difluoromethyl or trifluoromethyl; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
6. A combination according to any one of claims 1-3, wherein the reflux inhibitor is a compound according to formula III
Figure imgf000022_0002
wherein
R10 represents hydrogen, methyl, fluoromethyl, difluoromethyl or trifluoromethyl;
Rπ represents hydrogen, hydroxy, C1-C7 alkyl, -C7 alkoxy or halogen; R1 represents hydrogen, C1-C7 alkyl (optionally substituted by hydroxy, mercapto, C1-C7 alkoxy, C1-C7 thioalkoxy, aryl or heteroaryl), aryl or heteroaryl;
R13 represents hydrogen, C1-C7 alkyl (optionally substituted by aryl or heteroaryl), aryl or heteroaryl; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
7. A combination according to any one of claims 1-3, wherein the reflux inhibitor is a compound according to formula IV
Figure imgf000023_0001
wherein
R14 represents hydrogen, hydroxy, C1-C7 alkyl, C1-C7 alkoxy or halogen;
R15 represents hydrogen, hydroxy, mercapto, halogen, or an oxo group;
R16 represents hydrogen or -C7 alkyl (optionally substituted by hydroxy,
mercapto, C1-C7 alkoxy, -C7 thioalkoxy, aryl or heteroaryl), aryl or heteroaryl;
R17 represents hydrogen, C1-C7 alkyl (optionally substituted by aryl or heteroaryl), aryl or heteroaryl;
or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
8. A combination according to any one of claims 1-7, wherein the combination is a combined preparation for simultaneous, sequential or separate administration.
9. Use of (i) at least one acid secretion inhibiting agent; and (ii) at least one reflux inhibitor for the manufacture of a combination for the inhibition of transient lower esophageal sphincter relaxations (TLESRs).
10. Use of (i) at least one acid secretion inhibiting agent; and (ii) at least one reflux inhibitor for the manufacture of a combination for the treatment of gastro- esophageal reflux disease (GERD).
11. Use of (i) at least one acid secretion inhibiting agent; and (ii) at least one reflux inhibitor for the manufacture of a combination for the prevention of reflux.
12. Use of (i) at least one acid secretion inhibiting agent; and (ii) at least one reflux inhibitor for the manufacture of a combination for the treatment of, or prevention of, regurgitation.
13. Use of (i) at least one acid secretion inhibiting agent; and (ii) at least one reflux inhibitor for the manufacture of a combination for the treatment of, or prevention of, asthma.
14. Use according to claim 13, wherein the asthma is reflux-related asthma.
15. Use of (i) at least one acid secretion inhibiting agent; and (ii) at least one reflux inhibtor for the manufacture of a combination for the treatment of, or prevention of, lung disease.
16. Use of (i) at least one acid secretion inhibiting agent; and (ii) at least one reflux inhibitor for the manufacture of a combination for managing failure to thrive.
17. Use according to any one of claims 9-16, wherein the acid secretion inhibiting agent is a proton pump inhibitor.
18. Use according to any one of claims 9-17, wherein the reflux inhibitor is a GABAB receptor agonist.
19. Use according to any one of claims 9-18, wherein the reflux inhibitor is a compound according to formula I
Figure imgf000025_0001
wherein
Ri represents hydrogen;
R2 represents hydroxy, fluoro or an oxo group;
R3 represents hydrogen;
R represents hydrogen; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
20. Use according to any one of claims 9-18, wherein the reflux inhibitor is a compound according to formula II
Figure imgf000025_0002
wherein
R5 represents hydrogen or lower alkyl;
Rg represents a fluoro group;
R7 represents hydrogen;
Rδ represents hydrogen;
R9 represents methyl, fluoromethyl, difluoromethyl or trifluoromethyl; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
21. Use according to any one of claims 9-18, wherein the reflux inhibitor is a compound according to formula III
Figure imgf000026_0001
wherein
R10 represents hydrogen, methyl, fluoromethyl, difluoromethyl or trifluoromethyl;
Rπ represents hydrogen, hydroxy, C1-C7 alkyl, C1-C7 alkoxy or halogen;
Rι2 represents hydrogen, C1-C7 alkyl (optionally substituted by hydroxy, mercapto, C1-C7 alkoxy, C1-C7 thioalkoxy, aryl or heteroaryl), aryl or heteroaryl;
R13 represents hydrogen, C1-C7 alkyl (optionally substituted by aryl or heteroaryl), aryl or heteroaryl; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
22. Use according to any one of claims 9-18, wherein the reflux inhibitor is a compound according to formula TV
Figure imgf000027_0001
wherein
R14 represents hydrogen, hydroxy, C1-C7 alkyl, C1-C7 alkoxy or halogen;
R15 represents hydrogen, hydroxy, mercapto, halogen, or an oxo group;
R16 represents hydrogen or C1-C7 alkyl (optionally substituted by hydroxy, mercapto, C1-C7 alkoxy, C1-C7 thioalkoxy, aryl or heteroaryl), aryl or heteroaryl;
Rι7 represents hydrogen, C1-C7 alkyl (optionally substituted by aryl or heteroaryl), aryl or heteroaryl;
or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
23. A method for the inhibition of transient lower esophageal sphincter relaxations (TLESRs), whereby a pharmaceutically and pharmacologically effective amount of (i) at least one acid secretion inhibiting agent; and (ii) at least one reflux inhibitor, is administered to a subject in need of such inhibition.
24. A method for the treatment of gastro-esophageal reflux disease (GERD), whereby a pharmaceutically and pharmacologically effective amount of (i) at least one acid secretion inhibiting agent; and (ii) at least one reflux inhibitor, is administered to a subject in need of such treatment.
PCT/SE2003/001007 2002-06-20 2003-06-16 Combination of an acid secretion inhibiting agent and a reflux inhibitor for the treatment of gerd WO2004000855A1 (en)

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WO2006050471A3 (en) * 2004-11-03 2006-07-13 Xenoport Inc Acyloxyalkyl carbamate prodrugs of sulfinic acids, methods of synthesis, and use
US7494985B2 (en) 2004-11-03 2009-02-24 Xenoport, Inc. Acyloxyalkyl carbamate prodrugs, methods of synthesis, and use
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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
WO2009014490A1 (en) * 2007-07-25 2009-01-29 Astrazeneca Ab Combination of (3-amino-2-fluoropropyl)phosphinic acid and omeprazole for treating tlesr, gerd, and nerd

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