WO2004000856A1 - Combination of a reflux inhibitor and an imidazopyridine for the treatment of gerd - Google Patents

Combination of a reflux inhibitor and an imidazopyridine for the treatment of gerd 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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    • 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

The present invention relates to a medicament 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.

Description

COMBINATION OF A REFLUX INHIBITOR AND AN IMIDAZOPYRIDINE FOR THE TREATMENT OF GERD
Field of the invention
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.
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.
Outline of the invention
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
The wording "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 .
Examples of reflux inhibitors useful in accordance with the present invention are compounds of the formula I
Figure imgf000003_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);
R4 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, (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, ), (Λ)-(3-amino-2-hydroxypropyl)phosphinic acid and (3-amino-l-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 and compounds, 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, 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.
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.
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 imgf000005_0001
wherein
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);
Rδ 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.
In the definition of formula II above, it is to be understood that when R6 is an oxo group the bond between Rg and the carbon is a double bond.
Furthermore, in the definition of formula II above, it is to be understood by "lower" radicals and compounds, 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, 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.
When one or more stereocentre is present in the molecule, 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.
Still further examples of reflux inhibitors useful in accordance with the present invention are compounds of the formula III
Figure imgf000007_0001
wherein
Rio represents hydrogen, methyl, fluoromethyl, difluoromethyl or trifluoromethyl;
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; Ri3 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 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.
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 imgf000009_0001
wherein Rι4 represents hydrogen, hydroxy, C1-C7 alkyl, C1-C7 alkoxy or halogen; Rι5 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;
Rπ 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-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.
In the defmtion of formula IV 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 IV above, 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-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.
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, 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. When one or more stereocentre is present in the molecule, 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.
Imidazopyridines
The imidazopyridine is a compound of formula V:
Figure imgf000012_0001
or a pharmaceutically acceptable salt thereof, wherein
R18 is
(a) H,
(b) CH3, or
(c) CH2OH;
19 R is
(a) CH3
(b) CH2CH3
R20 is
(a) H (b) Cι-C6 alkyl,
(c) hydroxylated C1-C6 alkyl
(d) halogen R21 is
(a) H, (b) Cι-C6 alkyl,
(c) hydroxylated Cj-Cό alkyl, or
(d) halogen;
R22 is
(a) H, or
(b) halogen;
23 24
R and R are the same or different, selected from any one of
(a) H,
(b) Cι-C6 alkyl; (c) hydroxylated Ci-Cβ alkyl (d) Cι-C6 a.koxy-substituted C\ -Cβ alkyl
X is
(a) NH, or
(b) O;
In the definition of formula V above, the term "Cι-C6 alkyl" denotes a straight or branched alkyl group having from 1 to 6 carbon atoms. Examples of said Cj-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.
The term "halogen" includes fluoro, chloro, bromo and iodo.
As 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. Such derivatives may therefore be described as "prodrugs". 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.
In one aspect of the invention, the active drug substance is a compound of the formula V wherein R1 is CH3 or CH2OH; R2 is CH3 or CH2CH3; R3 is CH3 or CH2CH3; R4 is CH3 or CH2CH3; R5 is H, Br, Cl, or F.
In a further aspect of the present invention, the active drug substance of the formula V is a compound selected from any one of
• 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-N-propyl-imidazo[ 1 ,2-a]pyridine-6- carboxamide;
• 8-(2-ethyl-6-methylbenzylamino)-3-hydroxymethyl-2-methylimidazo[ 1 ,2-a]pyridine-6- carboxamide;
• 2,3-dimethyl-8-(2,6-dimethylbenzylamino)-N-hydroxyethyl-imidazo[l,2-a]pyridine-6- carboxamide;
• 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[l,2-a]pyridine-6- carboxamide; • 8-(2-ethyl-6-methylbenzylamino)-N,2,3-trimethylimidazo[l ,2-a]pyridine-6- carboxamide;
• 8-(2-ethyl-6-methylbenzylamino)-N,N,2,3-tetramethylimidazo[l,2-a]pyridine-6- carboxamide;
• 2,3-dimethyl-8-(2,6-dimethylbenzyl-amino)-imidazo[l,2-a]pyridine-6-carboxamide, N-[2-(dimethylamine)-2-oxoethyl]-8-(2-ethyl-6-methylbenzylamino)-N,2,3- trimethylimidazo[ 1 ,2-a]pyridine-6-carboxamide; • 2,3-dimethyl-8-(2-ethyl-4-fluoro-6-methylbenzylamino)-imidazo[l,2-a]pyridine-6- carboxamide mesylate;
• 2,3-dimethyl-8-(2-methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide; 2,3-dimethyl-8-(2,6-dimethyl-4-fluoro-benzylamino)-imidazo[l,2-a]pyridine-6- carboxamide mesylate;
• 2,3-dimethyl-8-(2-methyl-6-isopropylbenzylamino)-imidazo[ 1 ,2-a]pyridine-6- carboxamide mesylate;
• 2,3-dimethyl-8-(2,6-diethyl-benzylamino)-imidazo[l,2-a]pyridine-6-carboxamide;
• 2,3-dimethyl-8-(2-ethylbenzylamino)-imidazo[ 1 ,2-a]pyridine-6-carboxamide; • 2,3 dimethyl-8-(2-ethyl-6-methyl-benzylamino)-N-hydroxyethyl-imidazo[l,2- a]pyridine-6-carboxamide;
• N-(2,3-dihydroxypropyl)-2,3 dimethyl-8-(2-ethyl-6-methylbenzylamino)-[ 1 ,2- a]pyridine-6-carboxamide;
• 2,3 dimethyl-8-(2-ethyl-6-methyl-benzylamino)-N-(2-methoxyethyl)-imidazo[ 1 ,2- a]pyridine-6-carboxamide;
• 2-methyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[ 1 ,2-a]pyridine-6-carboxamide;
• 2,3-dimethyl-8-(2-bromo-6-methylbenzylamino)-imidazo[ 1 ,2-a]pyridine-6- carboxamide;
• 2,3-dimethyl-8-(2-(2-hydroxyethyl)-6-methylbenzylamino)-imidazo[ 1 ,2-a]pyridine-6- carboxamide;
• 8-(2-ethyl-6-methylbenzylamino)-N,N-bis(2-hydroxyethyl)-2,3-dimethylimidazo[l,2- a]pyridine-6-carboxamide;
• 8-(2-ethyl-6-methylbenzylamino)-N-(2-hydroxyethyl)-N,2,3-trimethylimidazo[ 1 ,2- a]pyridine-6-carboxamide; and • 2,3-dimethyl-8-(2-ethyl-6-methylbenzyloxy)-imidazo[l ,2-a]pyridine-
6-carboxamide; or a pharmaceutically acceptable salt thereof.
In still a further aspect of the present invention, 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;
2,3-dimethyl-8-(2,6-dimethylbenzylamino)-N-hydroxyethyl-imidazo[l,2-a]pyridine-6- carboxamide;
2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[l,2-a]pyridine-6- carboxamide;
8-(2-ethyl-6-methylbenzylamino)-N,2,3-trimethylimidazo[l,2-a]pyridine-6- carboxamide;
2,3-dimethyl-8-(2,6-dimethylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide; • 2,3-dimethyl-8-(2-ethyl-4-fluoro-6-methylbenzylamino)-imidazo[ 1 ,2-a]pyridine-6- carboxamide;
2,3-dimethyl-8-(2,6-dimethyl-4-fluoro-benzylamino)-imidazo[l,2-a]pyridine-6- carboxamide;
2,3-dimethyl-8-(2,6-diethylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide; • 2,3 dimethyl-8-(2-ethyl-6-methylbenzylamino)-N-hydroxyethyl-imidazo[l,2- a]pyridine-6-carboxamide; and • 2,3 dimethyl-8-(2-ethyl-6-methylbenzylamino)-N-(2-methoxyethyl)-imidazo[l ,2- a]pyridine-6-carboxamide; or a pharmaceutically acceptable salt thereof.
Compounds of the formula V above and their preparation, are described in the patent application PCT/SE99/00663 (WO 99/55706), which is hereby incorporated in full as reference.
Combination of a reflux inhibitor and an imidazopyridine of formula V
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 μg to 100 mg per day and kg body weight, such as 10 μg to 20 mg per day and kg body weight.
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 IV above, used in combination with any compound of formula V. Another aspect of the invention is the use of GABA (γ-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.
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 (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.
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 (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. 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 (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.
In the preparation of oral pharmaceutical formulations in accordance with the invention, 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. 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 (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.
In one aspect of the present invention, 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. Biological studies
The effect of a reflux inhibitor, such as a GAB Aβ receptor agonist, and an imidazopyridine of formula V, 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 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.

Claims

Claims
1. A combination comprising, separately or together, (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V:
Figure imgf000025_0001
or a pharmaceutically acceptable salt thereof, wherein
R18 is
(a) H,
(b) CH3, or
(c) CH2OH;
19 R is
(a) CH3
(b) CH2CH3
R20 is
(a) H (b) Cι-C6 alkyl,
(c) hydroxylated Ci-Cβ alkyl
(d) halogen R21 is
(a) H,
(b) Cι-C6 alkyl,
(c) hydroxylated Cj-Cό alkyl, or
(d) halogen;
R22 is
(a) H, or
(b) halogen;
23 24
R and R are the same or different, selected from any one of
(a) H,
(b) Cι-C6 alkyl;
(c) hydroxylated Cj-Cg alkyl (d) Cj-Cβ alkoxy-substituted Ci-Cg alkyl
X is
(a) NH, or
(b) O;
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 reflux inhibitor is a compound according to formula I
Figure imgf000026_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.
4. A combination according to claim 1 or 2, wherein the reflux inhibitor is a compound according to formula II
Figure imgf000027_0001
wherein
R5 represents hydrogen or lower alkyl;
R 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.
5. A combination according to claim 1 or 2, wherein the reflux inhibitor is a compound according to formula III
Figure imgf000028_0001
wherein
Rio represents hydrogen, methyl, fluoromethyl, difluoromethyl or trifluoromethyl;
Ri i represents hydrogen, hydroxy, Ci -C7 alkyl, C1 -C7 alkoxy or halogen;
Rι2 represents hydrogen, C1-C7 alkyl (optionally substituted by hydroxy, mercapto, Ci -C7 alkoxy, Ci -C7 thioalkoxy, aryl or heteroaryl), aryl or heteroaryl;
R)3 represents hydrogen, Ci -C7 alkyl (optionally substituted by aryl or heteroaryl), aryl or heteroaryl; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
6. A combination according to claim 1 or 2, wherein the reflux inhibitor is a compound according to formula IV
Figure imgf000028_0002
wherein
Rj4 represents hydrogen, hydroxy, C1-C7 alkyl, -C7 alkoxy or halogen;
R15 represents hydrogen, hydroxy, mercapto, halogen, or an oxo group;
R)6 represents hydrogen or Ci -C7 alkyl (optionally substituted by hydroxy, mercapto, C1-C7 alkoxy, C1-C7 thioalkoxy, aryl or heteroaryl), aryl or heteroaryl; Rπ 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 1-6, wherein the combination is a combined preparation for simultaneous, sequential or separate administration.
8. Use of (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V:
Figure imgf000029_0001
or a pharmaceutically acceptable salt thereof, wherein
R18 ιs
(a) H,
(b) CH3, or
(c) CH2OH;
19 R is
(a) CH3
(b) CH2CH3
R20 is
(a) H
(b) Cι-C6 alkyl, (c) hydroxylated Ci-Cg alkyl
(d) halogen
R21 is (a) H,
(b) Cι-C6 alkyl,
(c) hydroxylated Cι-C6 alkyl, or
(d) halogen;
R22 is
(a) H, or
(b) halogen;
23 24
R and R are the same or different, selected from any one of (a) H,
(b) Cι-C6 alkyl;
(c) hydroxylated Ci-Cβ alkyl
(d) Ci-Cό alkoxy-substituted Ci-Cg alkyl
X is
(a) NH, or
(b) O;
for the manufacture of a combination for the inhibition of transient lower esophageal sphincter relaxations (TLESRs).
Use of (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V:
Figure imgf000031_0001
or a pharmaceutically acceptable salt thereof, wherein
R18is (a)H,
(b)CH3,or (c)CH2OH;
19 R is
(a)CH3
(b)CH2CH3
R20is
(a)H (b)Cι-C6 alkyl,
(c) hydroxylated C1-C6 alkyl
(d) halogen
R21is (a)H, (b)Cι-C6 alkyl,
(c) hydroxylated Cj-Cg alkyl, or
(d) halogen; R22is (a)H,or
(b) halogen;
23 24
R and R are the same or different, selected from any one of
(a)H, (b)Cι-C6 alkyl;
(c) hydroxylated Ci-Cg alkyl
(d) Cj-C6 alkoxy-substituted
Figure imgf000032_0001
alkyl
Xis
(a) NH, or
(b)O;
for the manufacture of a combination for the treatment of gastro-esophageal reflux disease (GERD).
10. Use of (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V:
Figure imgf000032_0002
or a pharmaceutically acceptable salt thereof, wherein
R18is (a)H, (b) CH3, or (c) CH2OH;
19 R is
(a)CH3 (b) CH2CH3
R20is (a)H
(b)Cι-C6 alkyl, (c) hydroxylated C j -Cg alkyl
(d) halogen
R21is (a)H, (b)Cι-C6 alkyl,
(c) hydroxylated Cj-Cβ alkyl, or
(d) halogen;
R22is (a) H, or
(b) halogen;
23 24
R and R are the same or different, selected from any one of
(a)H, (b)Cι-C6 alkyl;
(c) hydroxylated
Figure imgf000033_0001
alkyl
(d) Ci-Cό alkoxy-substituted C1-C6 alkyl
Xis (a) NH, or
(b)O;
for the manufacture of a combination for the prevention of reflux.
11. Use according to any one of claims 8-10, wherein the reflux inhibitor is a GABAB receptor agonist.
12. Use according to any one of claims 8-10, wherein the reflux inhibitor is a compound according to formula I
Figure imgf000034_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.
13. Use according to any one of claims 8-10, wherein the reflux inhibitor is a compound according to formula II
Figure imgf000034_0002
wherein
Rζ represents hydrogen or lower alkyl;
Rβ represents a fluoro group;
R7 represents hydrogen;
Rg represents hydrogen;
R9 represents methyl, fluoromethyl, difluoromethyl or trifluoromethyl; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
14. Use according to any one of claims 8-10, wherein the reflux inhibitor is a compound according to formula III
Figure imgf000035_0001
wherein
Rio 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;
Rι3 represents hydrogen, Ci -C7 alkyl (optionally substituted by aryl or heteroaryl), aryl or heteroaryl; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
15. Use according to any one of claims 8-10, wherein the reflux inhibitor is a compound according to formula IV
Figure imgf000036_0001
wherein
Rι4 represents hydrogen, hydroxy, C1-C7 alkyl, C1-C7 alkoxy or halogen;
R15 represents hydrogen, hydroxy, mercapto, halogen, or an oxo group;
Ri6 represents hydrogen or C1-C7 alkyl (optionally substituted by hydroxy, mercapto, C1-C7 alkoxy, C1-C7 thioalkoxy, aryl or heteroaryl), aryl or heteroaryl;
R1 represents hydrogen, C1-C7 alkyl (optionally substituted by aryl or heteroaryl), aryl or heteroaryl;
or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
16. A method for the inhibition of transient lower esophageal sphincter relaxations (TLESRs), whereby a pharmaceutically and pharmacologically effective amount of (i) at least one reflux inhibitor; and (ii) at least one imidazopyridine of formula V:
Figure imgf000036_0002
or a pharmaceutically acceptable salt thereof, wherein
R18is (a)H,
(b) CH3, or
(c) CH2OH;
19 R is (a)CH3
(b) CH2CH3
R20is (a)H (b)Cι-C6 alkyl,
(c) hydroxylated Ci-Cβ alkyl
(d) halogen
R21is (a) H,
(b)Cι-C6 alkyl,
(c) hydroxylated C1-C6 alkyl, or
(d) halogen;
R22 is
(a) H, or
(b) halogen;
23 24
R and R are the same or different, selected from any one of (a) H,
(b)C!-C6 alkyl;
(c) hydroxylated Cj-Cg alkyl
(d) Ci-Cgalkoxy-substituted C\ -Cβ alkyl
X is
(a) NH, or (b) O;
is administered to a subject in need of such inhibition.
PCT/SE2003/001008 2002-06-20 2003-06-16 Combination of a reflux inhibitor and an imidazopyridine for the treatment of gerd Ceased WO2004000856A1 (en)

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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 (en) * 2003-05-27 2004-12-09 Altana Pharma Ag Pharmaceutical combinations of a proton pump inhibitor and a compound which modifies gastrointestinal motility
WO2005077345A1 (en) * 2004-02-03 2005-08-25 Astrazeneca Ab Compounds for the treatment of gastro-esophageal reflux disease
EP1799695A4 (en) * 2004-10-08 2010-03-10 Astrazeneca Ab New process for the preparation of alkyl phosphinic acids
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
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 (en) 2005-12-08 2011-04-06 Novartis AG Trisubstituted quinazolinone derivatives as vanilloid antagonists
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 (en) 2009-01-13 2010-07-29 Novartis Ag Quinazolinone derivatives useful as vanilloid antagonists
WO2011092293A2 (en) 2010-02-01 2011-08-04 Novartis Ag Cyclohexyl amide derivatives as crf receptor antagonists
WO2011092290A1 (en) 2010-02-01 2011-08-04 Novartis Ag Pyrazolo[5,1b]oxazole derivatives as crf-1 receptor antagonists
WO2011095450A1 (en) 2010-02-02 2011-08-11 Novartis Ag Cyclohexyl amide derivatives as crf receptor antagonists
WO2012164473A1 (en) 2011-05-27 2012-12-06 Novartis Ag 3-spirocyclic piperidine derivatives as ghrelin receptor agonists
WO2013164790A1 (en) 2012-05-03 2013-11-07 Novartis Ag L-malate salt of 2, 7 - diaza - spiro [4.5 ] dec- 7 - yle derivatives and crystalline forms thereof as ghrelin receptor agonists

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