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WO2004000856A1 - Combinaison d'un inhibiteur de reflux gastro-oesophagien et imidazopyridine destinee au traitement du reflux gastro-oesophagien pathologique - Google Patents

Combinaison d'un inhibiteur de reflux gastro-oesophagien et imidazopyridine destinee au traitement du reflux gastro-oesophagien pathologique Download PDF

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WO2004000856A1
WO2004000856A1 PCT/SE2003/001008 SE0301008W WO2004000856A1 WO 2004000856 A1 WO2004000856 A1 WO 2004000856A1 SE 0301008 W SE0301008 W SE 0301008W WO 2004000856 A1 WO2004000856 A1 WO 2004000856A1
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alkyl
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halogen
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aryl
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Anders Lehmann
Michael Wrangstadh
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AstraZeneca AB
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AstraZeneca AB
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • 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
    • 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

Definitions

  • the present invention provides a combination comprising, separately or together, (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine.
  • a further aspect of the invention relates to methods of treatment of gastro-esophageal reflux disease, regurgitation, asthma, failure to thrive and lung 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.
  • the present invention provides a combination comprising, separately or together, (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V below.
  • the present invention relates to a combination of a reflux inhibitor and an imidazopyridine. Further, the invention relates to the use of a combination of a reflux inhibitor and an imidazopyridine for the preparation of a medicament for the treatment of gastro- esophageal reflux disease, regurgitation, asthma, failure to thrive and lung disease.
  • reflux inhibitor is defined as an agent preventing reflux of gastric contents.
  • GABAe-receptor agonists are examples of reflux inhibitors useful in accordance with the present invention.
  • GABAs-receptor agonists have been shown to inhibit TLESR, which is disclosed in inter alia 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);
  • R 4 represents hydrogen, lower alkyl (optionally substituted by aryl), or aryl;
  • Examples of such compounds are (3-amino-2-fluoropropyl)phosphinic acid, (2i?)-(3-amino-2- fluoropropyl)phosphinic acid, (25)-(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, ), ( ⁇ )-(3-amino-2-hydroxypropyl)phosphinic acid and (3-amino-l-fluoro-2-hydroxypropyl)phosphinic acid.
  • Lower alkyl is, for example, Ci -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.
  • Ci -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.
  • 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 or chlorine, less prefered, 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.
  • R5 represents hydrogen, hydroxy, lower alkyl, lower alkoxy or halogen
  • R 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 trifluoromethyl; 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, (25 ⁇ -(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, Ci -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.
  • Ci -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-fhiobutoxy, 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.
  • the compounds according to formula II 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
  • Rii represents hydrogen, hydroxy, C1-C7 alkyl, -C7 alkoxy or halogen
  • R !2 represents hydrogen, C1-C7 alkyl (optionally substituted by hydroxy, mercapto, C1-C7 alkoxy, C1-C7 thioalkoxy, aryl or heteroaryl), aryl or heteroaryl;
  • Ri 3 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 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.
  • 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 ⁇ 4 represents hydrogen, hydroxy, C1-C7 alkyl, C1-C7 alkoxy or halogen
  • R ⁇ 5 represents hydrogen, hydroxy, mercapto, halogen, or an oxo group
  • R )6 represents hydrogen or C1 -C7 alkyl (optionally substituted by hydroxy, mercapto, C ⁇ - C7 alkoxy, Ci -C7 thioalkoxy, aryl or heteroaryl), aryl or heteroaryl;
  • R ⁇ 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-ammo-2-fluoropropyl)sulphinic acid, (2R)-(3-amino-2-fluoropropyl)sulphinic acid, (25)-(3-amino-2-hydroxypropyl)sulphinic acid, (2i?)-(3-amino-2- hydroxypropyl)sulphinic acid and (3-amino-2-oxopropyl)sulphinic acid.
  • Cj -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-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, Cj -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 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 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, C1-C7 thioalkoxy, halogen, hydroxy, mercapto, carboxylic acid, carboxylic acid ester, carboxylic acid amide or nitrile.
  • the compounds according to formula IV 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 IV 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 imidazopyridine is a compound of formula V:
  • R and R are the same or different, selected from any one of
  • C ⁇ -C 6 alkyl denotes a straight or branched alkyl group having from 1 to 6 carbon atoms.
  • Examples of said C j -Cg alkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl and straight- and branched-chain pentyl and hexyl.
  • halogen includes fluoro, chloro, bromo and iodo.
  • the drug substance used in accordance with the present invention are both the pure enantiomers, racemic mixtures and unequal mixtures of two enantiomers. It should be understood that all the diastereomeric forms possible (pure enantiomers, racemic mixtures and unequal mixtures of two enantiomers) are within the scope of the present invention as the active drug substance, as well as derivatives of the compounds of the formula V that have the biological function of the compounds of the compounds of the formula V, such as prodrugs. It will also be appreciated by those skilled in the art, although derivatives of compounds of formula V may not possess pharmacological activity as such, they may be administered orally and thereafter metabolised in the body to form compounds that are pharmacologically active.
  • Prodrugs of compounds of formula V are also within the scope of the invention. Depending on the process conditions the end products of the formula V are obtained either in neutral or salt form. Both the free base and the salts of these end products are within the scope of the invention.
  • the active drug substance is a compound of the formula V wherein R 1 is CH 3 or CH 2 OH; R 2 is CH 3 or CH 2 CH 3 ; R 3 is CH 3 or CH 2 CH 3 ; R 4 is CH 3 or CH 2 CH 3 ; R 5 is H, Br, Cl, or F.
  • the active drug substance of the formula V is a compound selected from any one of
  • 6-carboxamide or a pharmaceutically acceptable salt thereof.
  • the imidazopyridine of formula V is a compound selected from any one of 8-(2-ethyl-6-methylbenzylamino)-3-hydroxymethyl-2-methylimidazo[l,2-a]pyridine-6- carboxamide;
  • the present invention provides a combination comprising, separately or together, (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V.
  • 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 reflux inhibitor; and (ii) at least one imidazopyridine of formula V are present in one unit.
  • One example of a “fix combination” is a pharmaceutical composition wherein the (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V 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 reflux inhibitor; and (ii) at least one imidazopyridine of formula V 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 reflux inhibitor; and (ii) at least one imidazopyridine of formula V are present in more than one unit.
  • One example of a “kit of parts combination” is a combination wherein the (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V 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 imidazopyridine of formula V 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 imidazopyridine of formula V is in the range of 10 to 60 mg per day, such as 20 or 30 or 40 or 50 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, such as 10 ⁇ g to 20 mg per day and kg body weight.
  • 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 IV above, used in combination with any compound of formula V.
  • Another aspect of the invention is the use of GABA ( ⁇ -aminobutyric 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 (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V is administered to a subject in need of such treatment.
  • the (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V are administered simultaneously, sequentially or separately.
  • a further aspect of the invention is the use of a combination of (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V for the manufacture of a medicament for the treatment of regurgitation.
  • the (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V 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 (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V is administered to a subject in need of such treatment.
  • the (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V are administered simultaneously, sequentially or separately.
  • Still a further aspect of the invention is the use of a combination of (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V for the manufacture of a medicament for the treatment or prevention of lung disease.
  • the (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V are administered simultaneously, sequentially or separately.
  • Still a further aspect of the invention is a method for the treatment or prevention of lung disease, whereby a pharmaceutically and pharmacologically effective amount of a combination of (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V is administered to a subject in need of such treatment.
  • the (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V are administered simultaneously, sequentially or separately.
  • Another aspect of the invention is the use of a combination of (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V for the manufacture of a medicament for the management of failure to thrive due.
  • the (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V 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 (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V is administered to a subject in need of such treatment.
  • the (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V are administered simultaneously, sequentially or separately.
  • Still a further aspect of the invention is the use of a combination of (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V for the manufacture of a medicament for the prevention of reflux.
  • the (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V 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 (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V is administered to a subject in need of such prevention.
  • the (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V are administered simultaneously, sequentially or separately.
  • Still a further aspect of the invention is the use of a combination of (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V for the manufacture of a medicament for the inhibition of TLESRs.
  • the (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V 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 (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V is administered to a subject in need of such inhibition.
  • the (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V are administered simultaneously, sequentially or separately.
  • Still a further aspect of the invention is the use of a combination of (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V for the manufacture of a medicament for the treatment of esophagitis.
  • the (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V 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 (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V is administered to a subject in need of such treatment.
  • the (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V are administered simultaneously, sequentially or separately.
  • Still a further aspect of the invention is the use of a combination of (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V for the manufacture of a medicament for the treatment of asthma, such as reflux-related asthma or non reflux- related asthma.
  • the (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V 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 (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V is administered to a subject in need of such treatment.
  • the (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V are administered simultaneously, sequentially or separately.
  • Still a further aspect of the invention is the use of a combination of (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V for the manufacture of a medicament for the treatment of laryngitis, such as chronic laryngitis.
  • the (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V 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 (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V is admimstered to a subject in need of such treatment.
  • the (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V 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
  • GFD gastro-esophageal reflux disease
  • the combination of (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V is in accordance with the present invention suitably formulated into pharmaceutical formulations for oral administration.
  • parenteral or any other route of administration may be contemplated to the skilled man in the art of formulations.
  • the combination of (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V is 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 (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V are administered simultaneously, sequentially or separately.
  • the combination of (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V, 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 (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V, with vegetable oil, fat, or other suitable vehicle for soft gelatine capsules.
  • Hard gelatine capsules may contain the combination of (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V, 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 (1) in the form of suppositories which contain the active substance(s) mixed with a neutral fat base; (2) in the form of a gelatine rectal capsule which contains the combination of (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V, in a mixture with a vegetable oil, paraffin oil, or other suitable vehicle for gelatine rectal capsules; (3) in the form of a ready- made micro enema; or (4) 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 (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V, 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 (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V, 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 (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V may be administered once or twice daily, depending on the severity of the patient's condition.
  • a reflux inhibitor such as a GAB A ⁇ receptor agonist, and an imidazopyridine of formula V
  • 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 a reflux inhibitor; 3) After treatment with an imidazopyridine of formula V; and 4) After combination treatment with a reflux inhibitor and an imidazopyridine of formula V.

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Abstract

La présente invention concerne un médicament qui comprend, séparés ou rassemblés, (i) au moins un inhibiteur de reflux gastro-oesophagien et (ii) au moins une imidazopyridine. Un autre aspect de cette invention concerne des techniques de traitement du reflux gastro-oesophagien pathologique, de la régurgitation, de l'asthme, d'un arrêt ou d'un retard très prononcé de la croissance et d'une maladie pulmonaire.
PCT/SE2003/001008 2002-06-20 2003-06-16 Combinaison d'un inhibiteur de reflux gastro-oesophagien et imidazopyridine destinee au traitement du reflux gastro-oesophagien pathologique Ceased WO2004000856A1 (fr)

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AU2003237739A AU2003237739A1 (en) 2002-06-20 2003-06-16 Combination of a reflux inhibitor and an imidazopyridine for the treatment of gerd

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SE0201940-4 2002-06-20
SE0201940A SE0201940D0 (sv) 2002-06-20 2002-06-20 New combination II

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Cited By (14)

* Cited by examiner, † Cited by third party
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WO2004105795A1 (fr) * 2003-05-27 2004-12-09 Altana Pharma Ag Combinaisons pharmaceutiques d'un inhibiteur de la pompe a protons et d'un compose modifiant la motilite gastro-intestinale
WO2005077345A1 (fr) * 2004-02-03 2005-08-25 Astrazeneca Ab Composes pour le traitement de la maladie du reflux gastro-oesophagien
WO2006050471A3 (fr) * 2004-11-03 2006-07-13 Xenoport Inc Prodrogues d'acyloxyalkyl carbamate de l'acide 3-aminopropylsulfinique, et procedes de synthese et d'utilisation
US7494985B2 (en) 2004-11-03 2009-02-24 Xenoport, Inc. Acyloxyalkyl carbamate prodrugs, methods of synthesis, and use
US7585996B2 (en) 2006-09-15 2009-09-08 Xenoport, Inc. Acyloxyalkyl carbamate prodrugs, methods of synthesis and use
EP1799695A4 (fr) * 2004-10-08 2010-03-10 Astrazeneca Ab Nouveau procede pour la preparation d'acides alkyl-phosphiniques
WO2010084050A2 (fr) 2009-01-13 2010-07-29 Novartis Ag Dérivés de quinazolinone utiles comme antagonistes vanilloïdes
EP2305652A2 (fr) 2005-12-08 2011-04-06 Novartis AG Dérivés de quinazolinone trisubstituée en tant qu'agonistes de vanilloïde
WO2011092290A1 (fr) 2010-02-01 2011-08-04 Novartis Ag Dérivés de pyrazolo[5,1-b] utilisés en tant qu'antagonistes du récepteur de crf-1
WO2011092293A2 (fr) 2010-02-01 2011-08-04 Novartis Ag Dérivés de cyclohexylamide utilisés en tant qu'antagonistes du récepteur du crf
WO2011095450A1 (fr) 2010-02-02 2011-08-11 Novartis Ag Dérivés de cyclohexylamide à titre d'antagonistes du récepteur crf
WO2012164473A1 (fr) 2011-05-27 2012-12-06 Novartis Ag Dérivés de pipéridine 3-spirocyclique comme agonistes du récepteur de la ghréline
WO2013164790A1 (fr) 2012-05-03 2013-11-07 Novartis Ag Sel de l-malate de dérivés de 2,7-diaza-spiro[4.5]déc-7-yle et ses formes cristallines à titre d'agonistes des récepteurs de ghreline
US9968628B2 (en) 2000-05-26 2018-05-15 Idenix Pharmaceuticals Llc Methods and compositions for treating flaviviruses and pestiviruses

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Publication number Priority date Publication date Assignee Title
WO1998011885A1 (fr) * 1996-09-18 1998-03-26 Astra Aktiebolag Inhibiteurs du reflux gastro-oesophagien
WO2001042252A1 (fr) * 1999-12-09 2001-06-14 Astrazeneca Ab Nouveaux acides aminopropylphosphiniques
WO2001041743A1 (fr) * 1999-12-09 2001-06-14 Astrazeneca Ab Acides (aminopropyl)methylphosphiniques
US6313136B1 (en) * 1998-04-29 2001-11-06 Astrazeneca Ab Imidazo pyridine derivatives which inhibit gastric acid secretion

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998011885A1 (fr) * 1996-09-18 1998-03-26 Astra Aktiebolag Inhibiteurs du reflux gastro-oesophagien
US6313136B1 (en) * 1998-04-29 2001-11-06 Astrazeneca Ab Imidazo pyridine derivatives which inhibit gastric acid secretion
WO2001042252A1 (fr) * 1999-12-09 2001-06-14 Astrazeneca Ab Nouveaux acides aminopropylphosphiniques
WO2001041743A1 (fr) * 1999-12-09 2001-06-14 Astrazeneca Ab Acides (aminopropyl)methylphosphiniques

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9968628B2 (en) 2000-05-26 2018-05-15 Idenix Pharmaceuticals Llc Methods and compositions for treating flaviviruses and pestiviruses
WO2004105795A1 (fr) * 2003-05-27 2004-12-09 Altana Pharma Ag Combinaisons pharmaceutiques d'un inhibiteur de la pompe a protons et d'un compose modifiant la motilite gastro-intestinale
WO2005077345A1 (fr) * 2004-02-03 2005-08-25 Astrazeneca Ab Composes pour le traitement de la maladie du reflux gastro-oesophagien
EP1799695A4 (fr) * 2004-10-08 2010-03-10 Astrazeneca Ab Nouveau procede pour la preparation d'acides alkyl-phosphiniques
WO2006050471A3 (fr) * 2004-11-03 2006-07-13 Xenoport Inc Prodrogues d'acyloxyalkyl carbamate de l'acide 3-aminopropylsulfinique, et procedes de synthese et d'utilisation
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
EP2305652A2 (fr) 2005-12-08 2011-04-06 Novartis AG Dérivés de quinazolinone trisubstituée en tant qu'agonistes de vanilloïde
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
WO2010084050A2 (fr) 2009-01-13 2010-07-29 Novartis Ag Dérivés de quinazolinone utiles comme antagonistes vanilloïdes
WO2011092293A2 (fr) 2010-02-01 2011-08-04 Novartis Ag Dérivés de cyclohexylamide utilisés en tant qu'antagonistes du récepteur du crf
WO2011092290A1 (fr) 2010-02-01 2011-08-04 Novartis Ag Dérivés de pyrazolo[5,1-b] utilisés en tant qu'antagonistes du récepteur de crf-1
WO2011095450A1 (fr) 2010-02-02 2011-08-11 Novartis Ag Dérivés de cyclohexylamide à titre d'antagonistes du récepteur crf
WO2012164473A1 (fr) 2011-05-27 2012-12-06 Novartis Ag Dérivés de pipéridine 3-spirocyclique comme agonistes du récepteur de la ghréline
WO2013164790A1 (fr) 2012-05-03 2013-11-07 Novartis Ag Sel de l-malate de dérivés de 2,7-diaza-spiro[4.5]déc-7-yle et ses formes cristallines à titre d'agonistes des récepteurs de ghreline

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TW200403059A (en) 2004-03-01
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AR040203A1 (es) 2005-03-16

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