WO2007071396A2 - Pyrazinoylguanidine compounds useful in the treatment of inflammatory or allergic conditions - Google Patents

Pyrazinoylguanidine compounds useful in the treatment of inflammatory or allergic conditions Download PDF

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Publication number
WO2007071396A2
WO2007071396A2 PCT/EP2006/012314 EP2006012314W WO2007071396A2 WO 2007071396 A2 WO2007071396 A2 WO 2007071396A2 EP 2006012314 W EP2006012314 W EP 2006012314W WO 2007071396 A2 WO2007071396 A2 WO 2007071396A2
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alkyl
group
alkylene
membered heterocyclic
heterocyclic group
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PCT/EP2006/012314
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French (fr)
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WO2007071396A8 (en
WO2007071396A3 (en
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Stephen Paul Collingwood
Nichola Smith
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Novartis Ag
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Priority to EP06841060A priority Critical patent/EP1968969A2/en
Priority to CA002631347A priority patent/CA2631347A1/en
Priority to US12/158,481 priority patent/US7803804B2/en
Priority to JP2008546249A priority patent/JP2009520728A/en
Priority to AU2006328951A priority patent/AU2006328951B2/en
Priority to BRPI0620177-6A priority patent/BRPI0620177A2/en
Publication of WO2007071396A2 publication Critical patent/WO2007071396A2/en
Publication of WO2007071396A3 publication Critical patent/WO2007071396A3/en
Publication of WO2007071396A8 publication Critical patent/WO2007071396A8/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • 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
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/12—Mucolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • This invention relates to organic compounds, their preparation and use as pharmaceuticals.
  • the present invention provides compounds of formula (I):
  • M, M , and M 2 are independently ;
  • R 1 , R 2 , R 3 , and R 4 are independently selected from H, d-Ce-alkyl, Ci-Cfralkyl-carboxy, CrCg-haloalkyl, C 3 -C 15 -carbocyclic group, CrC ⁇ -alkylcarbonyl, C 1 -C 8 - alkoxycarbonyl, a C 6 -C 15 -membered aromatic carbocyclic group, a4- to 14-membered heterocyclic group, a CrC ⁇ -alkyl substituted by a 4- to 14-membered heterocyclic group, and a C r C r alkyl substituted by a Cs-Curmembered aromatic carbocyclic group , or
  • R 1 and R 2 with the nitrogen atom to which they are attached form a CrC 14 -membered heterocyclic group optionally substituted by R 14 , or
  • R 3 and R 4 with the nitrogen atom to which they are attached form a C 3 -C 14 - membered heterocyclic group optionally substituted by R 14 ;
  • L, L, and L 2 are independently selected from: and
  • R 6 ,R 5 , R 53 , R 5b and R x are independently selected from H, C 1 -C 8 alkyl, C r C ⁇ -alkyl- carboxy, CrC ⁇ -alkyl-alkoxy.C ⁇ -haloalkyl, C r C 1s -carbocyclic group, C r C 8 - alkylcarbonyl, CrC ⁇ -alkoxycarbonyl, nitro, cyano, a C 6 -C 15 - membered aromatic carbocyclic group, a4- to 14-membered heterocyclic group, a Ci-C ⁇ -alkyI substituted by a 4- to 14-membered heterocyclic group, and a C r Ce-alkyl substituted by a C ⁇ rC 15 -membered aromatic carbocyclic group, or R 5 with the nitrogen atom to which it is attached, together with A, form a 4- to 14-membered heterocyclic group when X 1 is C ⁇ -C ⁇ -
  • R 5b with the nitrogen atom to which it is attached, together with A, form a 4- to 14-membered heterocyclic group when X is C ⁇ -C ⁇ -alkylene, O, -NR 7 - or S;
  • W, W 1 and W 2 are independently selected from Co-C ⁇ -alkylene
  • Y, Y 1 and Y 2 are independently -Co-C ⁇ -alkylene-;
  • Z is C r C 4 -alkylene; where W, W h W 2 , Y, Y 1 , Y 2 and Z are optionally substituted by CrC ⁇ -alkyl, halogen , CrC ⁇ -alkoxy, carboxy, C rCg-alkyl-carboxy, C r Ca-haloalkyl, C r C ⁇ -haloalkoxy, CrC 15 -CaIt)OCyCIiC group, C r C r alkylcarbonyl, CrCg-alkoxycarbonyl, nitro, cyano, a C,rC 15 -membered aromatic carbocyclic group, a CrC ⁇ -alkyl substituted by a C 6 -C 15 -membered aromatic carbocyclic group, a 4- to 14-membered heterocyclic group containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulphur, a d-C ⁇ -alkyl substituted by
  • T is selected from H, halogen , CrC ⁇ -alkyl, C r Ce-haloalkyl, d-C ⁇ -haloalkoxy, C 3 -C 15 - carbocyclic group, nitro, cyano, a Cg-d-rmembered aromatic carbocyclic group, a and a C r C 8 -alkyl substituted by a Cg-ds-membered aromatic carbocyclic group; wherein each C ⁇ rC 1s -membered aromatic carbocyclic group and each 4 - to 14-membered heterocyclic group, unless otherwise specified is independently optionally substituted by one or more groups selected from OH, d-Cg-alkoxy, d-C ⁇ -alkyl, halogen, SO 2 NR 11 R 12 , hydroxyCrC ⁇ -alkoxy, optionally substituted by hydroxyl, (C 0 -C 4 - alkylene) CONR 11 R 12 , (Co-dralkylene
  • R 14 is selected from H, halogen, C r C ⁇ -alkyl, OH, C 6 -C 15 -membered aromatic carbocyclic group, CT-d-raralkyl, and O-C ⁇ -Ci4-aralkyl.
  • An aspect of the present invention provides compounds of formula (I) , or tautomers, or stereoisomers, or pharmaceutically acceptable salts thereof, wherein
  • M, M , and M 2 are independently
  • R 1 , R 2 , R 3 , and R 4 are independently selected from H, C,-C r alkyl, d-C ⁇ -alkyl-carboxy;
  • L, L 1 and L 2 are independently selected from: and R 5 , R 5a and R 5b are independently selected from H, and CrC ⁇ -alkyl, or
  • R 5 with the nitrogen atom to which it is attached, together with A, form a 4 - to
  • R 53 WiUi the nitrogen atom to which it is attached, together with A, form a 4- to 14- membered heterocyclic group when X 2 is C ⁇ -C ⁇ -alkylene, O, -NR 7 -, or S, or
  • R 5b with the nitrogen atom to which it is attached, together with A, form a 4- to 14-membered heterocyclic group when X is Co-C ⁇ -alkylene, O, -NR 7 -, or S;
  • R 6 is selected from H, and CrC ⁇ -alkyl
  • W, Wi and W 2 are selected from Co-C ⁇ -alkylene
  • Y, Y 1 and Y 2 are -Co-C ⁇ -alkylene-;
  • Z is C r C 4 -alkylene; where W, W 1 , W 2 , Y, Y 1 , Y 2 , and Z are optionally substituted byCi-Ce-alkyl, halogen, C r C ⁇ -alkoxy, carboxy, C rCg-alkyl-carboxy, CrC ⁇ -haloalkyl, C f C ⁇ -haloalkoxy, C 3 -C 15 -carbocyclic group, C r C ⁇ -alkylcarbonyl, CrC ⁇ -alkoxycarbonyl, nitro, cyano, a C ⁇ rC 15 -membered aromatic carbocyclic group, a CrC ⁇ -alkyl substituted by a C 6 -C 15 -membered aromatic carbocyclic group, a 4- to 14-membered heterocyclic group containing at least one ring heteroatom selected from
  • R 7 , R 8 , R 1 'and R c are independently selected from H, CrCg-alkyl optionally substituted by C ⁇ -C 14 -aralkyl, C t -C ⁇ -haloalkyl, a 5- to 14-membered heterocyclic group, and R 7 and R 8 , independently, by way of an CrC-alkyl group can form a bond with a carbon atom of group W or Y creating a 5 - to 14-membered heterocyclic group; and
  • T is selected from H, halogen , CrQj-alkyl, CrCg-haloalkyl, CrCirhaloalkoxy, C 3 -C 15 - carbocyclic group, nitro, cyano, a C 6 -C,s-membered aromatic carbocyclic group, and a CrCs-alkyl substituted by a C ⁇ -C 1s -membered aromatic carbocyclic group.
  • L, L , and L 2 are suitably ° . Equally suitably, L, L 1 and L 2
  • R 1 is preferably H.
  • R 2 is preferably H.
  • R 3 is preferably H.
  • R 4 is preferably H.
  • M 1 M 1 , and M 2 are preferably
  • R 5 R 53 and R a are H.
  • R 6 is preferably H.
  • A is a CrC ⁇ carbocyclic group
  • this is suitably a 4- to 6-membered carbocyclic group, e.g, cyclobutane and cyclohexane.
  • A can be nitrogen substituted by -Y-X-W-N R 5b -L -M.
  • W, W 1 and W 2 are independently, methylene, ethylene, butylene, pentylene or hexylene, preferably W 1 and W 2 are methylene.
  • R 7 and R 8 are preferably, independently H and CrCg-alkyl.
  • X, X 1 and X 2 are C ⁇ -alkylene, i.e, a bond.
  • Z is suitably -(Co-Cralkylene)-.
  • Z is methylene or ethylene.
  • Y, Y 1 and Y 2 are suitably -(Co-C r alkylene)-.
  • Y i and Y 2 are C 0 , i.e., a bond, methylene or ethylene.
  • 1 T is suitably halogen, preferably chlorine.
  • the present invention provides compounds of formula (Ia)
  • a 2 is selected from
  • the present invention provides for the use of a compound of formula (I) in any of the aforementioned embodiments, in free or pharmaceutically acceptable salt form, for the manufacture of a medicament for the treatment of an inflammatory or allergic condition, particularly an inflammatory or obstructive airways disease.
  • a preferred embodiment of the present invention provides for the use of a compound of formula (I) in any of the aforementioned embodiments, in free or pharmaceutically acceptable salt form, for the manufacture of a medicament for the treatment of an inflammatory or allergic condition selected from cystic fibrosis, primary ciliary dyskinesia, chronic bronchitis, chronic obstructive pulmonary disease, asthma, respiratory tract infections, lung carcinoma, xerostomia, and keratoconjunctivitis sire .
  • an inflammatory or allergic condition selected from cystic fibrosis, primary ciliary dyskinesia, chronic bronchitis, chronic obstructive pulmonary disease, asthma, respiratory tract infections, lung carcinoma, xerostomia, and keratoconjunctivitis sire .
  • Optionally substituted means the group referred to can be substituted at one or more positions by any one or any combination of the radicals listed thereafter.
  • Halo or Tialogen ", as used herein , may be fluorine, chlorine, bromine or iodine.
  • CrC ff -Alkyr denotes straight chain or branched alkyl having 1 -8 carbon atoms.
  • C 1 -C 8 -AIkOXy denotes straight chah or branched alkoxy having 1 -8 carbon atoms.
  • alkylene denotes a straight chain or branched saturated hydrocarbon chain.
  • Amino-Ci-C ⁇ -alkyr and “amino-d-C ⁇ -alkoxy” denote amino attached by a nitrogen atom to C,-C ⁇ -alkyl, e.g., NH 2 -(C 1 -C,))-, or to C rCg-alkoxy, e.g., NHr(C 1 -Cg)-O-.
  • Amino-fhydroxyJ-CrC ⁇ -alkyl denotes amino attached by a nitrogen atom to CrCg-alkyl and hydroxy attached by an oxygen atom to the same C ⁇ Ce-alkyl.
  • CrC ⁇ -Alkylcarbonyl and “CrC ⁇ -alkoxycarbonyr, as used herein, denote CrC ⁇ -alkyl or CrC ⁇ -alkoxy , respectively, as hereinbefore defined, attached by a carbon atom to a carbonyl group.
  • CrC ⁇ -Cycloalkylcarbonyl denotes C 3 -Ca-cycloalkyl, as hereinbefore defined, attached by a carbon atom to a carbonyl group.
  • C ⁇ -C 14 -Aralkyr denotes alkyl, e.g., CrC-alkyl, as hereinbefore defined, substituted by a C 6 -C 1 ⁇ -aromatic carbocyclic group, as herein defined.
  • C ⁇ ds-Carbocyclic group denotes a carbocyclic group having 3- to 15-ring carbon atoms that is saturated or partially saturated, such as a C3-C ⁇ -cycloalkyl.
  • Examples of C 3 -C 1 s-carbocyclic groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl or a bicyclic group, such as bicyclooctyl, bicyclononyl including indanyl and indenyl, and bicyclodecyl.
  • C6-C 1s -Aromatic carbocyclic group denotes an aromatic group having ⁇ - to 15-ring carbon atoms.
  • Examples of C ⁇ rC, 5 -aromatic carbocyclic groups include, but are not limited to, phenyl, phenylene, benzenetriyl, naphthyl, naphthylene , naphthalenetriyl or anthrylene.
  • 4- to 14-Membered heterocyclic group refers to a 4 - to 14-membered heterocyclic ring containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulphur, which may be saturated, partially saturated or unsaturated (aromatic).
  • 3- to 14-membered heterocyclic groups include but are not limited to furan, pyrrole, pyrrolidine, pyrazole, imidazole, triazole, isotriazole, tetrazole, thiadiazole, isothiazole, oxadiazole, pyridine, piperidine, pyrazine, oxazole, isoxazole, pyrazine, pyridazine, pyrimidine, piperazine, pyrrolidine, pyrrolidinone, mo ⁇ holine, triazine, oxazine, tetrahyrofuran, tetrahydrothiophene, tetrahydrothiopyran, tetrahydropyran, 1,4 ⁇ Jioxane, 1,4-oxathiane, indazole, quinoline, indazole, indole or thiazole.
  • the compounds represented by formula (I) may be capable of forming acid addition salts, particularly pharmaceutically acceptable acid addition salts.
  • Pharmaceutically acceptable acid addition salts of the compound of formula (I) include those of inorganic acids, e.g., hydrohalic adds, such as hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; and organic acids, e.g., aliphatic monocarboxylic acids, such as formic add, acetic acid, trifluoroacetic acid, propionic acid and butyric acid; aliphatic hydroxy acids, such as lactic acid, citric acid, tartaric acid or malic add; dicarboxylic acids, such as maleic acid or succinic acid; aromatic carboxylic acids, such as benzoic acid.p-chlorobenzoic acid, diphenylacetic acid, para-biphenyl benzoic acid or triphenylacetic add; aromatic hydroxy acids,
  • Compounds of formula (I) which may contain acidic, e.g, carboxyl, groups, are also capable of forming salts with bases, in particular, pharmaceutically acceptab Ie bases, such as those well-known in the art; suitable such salts include metal salts, particularly alkali metal or alkaline earth metal salts, such as sodium, potassium, magnesium or calcium salts; or salts with ammonia or pharmaceutically acceptable organic amines or heterocyclic bases, such as ethanolamines, benzylamines or pyridine. These salts may be prepared from compounds of formula (I) by known salt-forming procedures.
  • Stereoisomers are those compounds where there is an asymmetric carbon atom.
  • the compounds exist in individual optically active isomeric forms or as mixtures thereof, e.g., as diastereomeric mixtures.
  • the present invention embraces both individual optically active R and S isomers, as well as mixtures thereof.
  • Individual isomers can be separated by methods well known to those skilled in the art, e.g. chiral high performance liquid chromatography (HPLC).
  • Tautomers are one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.
  • the compounds of the invention may exist in both unsolvated and solvated forms.
  • solvate is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, e.g., ethanol.
  • solvent molecules e.g., ethanol.
  • hydrate is employed when said solvent is water.
  • M 1 , M 2 , L 1 , L 2 , NR 5 , NR 5a , W 1 , W 2 , X 1 , X 2 , Y 1 , Y 2 , and A are as defined hereinbefore, which comprises the steps of:
  • L * is L 1 or L 2 ;
  • R 5 , R 53 , W 1 , W 2 , X 1 , X 2 , Y 1 , Y 2 and A are hereinbefore defined, optionally in the presence of a base, e.g., an organic base; and in an organic solvent e.g., a non-protic dipolar solvent; and
  • the compounds of formula (I) can be prepared, e.g., using the reactions and techniques described below and in the Examples.
  • the reactions may be performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention.
  • Compounds of formula (I), in free form, may be converted into salt form, and vice versa, in a conventional manners understood by those skilled in the art.
  • the compounds in free or salt form can be obtained in the form of hydrates or solvates containing a solvent used for crystallisation.
  • Compounds of formula (I) can be recovered from reaction mixtures and purified in a conventional manner. Isomers, such as stereoisomers, may be obtained in a conventional manner, e.g., by fractional crystallisation or asymmetric syntiesis from correspondingly asymmetrically substituted, e.g., optically active, starting materials.
  • kits of the invention are useful in the treatment of conditions which respond to the blockade of the epithelial sodium channel, particularly conditions benefiting from mucosal hydration.
  • Diseases mediated by blockade of the epithelial sodium channel include diseases associated with the regulation of fluid volumes across epithelial membranes.
  • the volume of airway surface liquid is a key regulator of mucociliary clearance and the maintenance of lung health.
  • the blockade of the epithelial sodium channel will promote fluid accumulation on the mucosal side of the airway epithelium thereby promoting mucus clearance and preventing the accumulation of mucus and sputum in respiratory tissues (including lung airways).
  • diseases include respiratory diseases, such as cystic fibrosis, primary ciliary dyskinesia, chronic bronchitis, chronic obstructive pulmonary disease (COPD), asthma, respiratory tract infections (acute and chronic; viral and bacterial) and lung carcinoma.
  • COPD chronic obstructive pulmonary disease
  • Diseases mediated by blockade of the epithelial sodium channel also include diseases other than respiratory diseases that are associated with abnormal fluid regulation across an epithelium, perhaps involving abnormal physiology of the protective surface liquids on their surface, e.g., xerostomia (dry mouth) or keratoconjunctivitis sire (dry eye).
  • diseases other than respiratory diseases that are associated with abnormal fluid regulation across an epithelium, perhaps involving abnormal physiology of the protective surface liquids on their surface, e.g., xerostomia (dry mouth) or keratoconjunctivitis sire (dry eye).
  • blockade of the epithelial sodium channel in the kidney could be used to promote diuresis and thereby induce a hypotensive effect.
  • Treatment in accordance with the invention may be symptomatic or prophylactic.
  • Asthma includes both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma induced following bacterial infection.
  • Treatment of asthma is also to be understood as embracing treatment of subjects, e.g., of less than 4 or 5 years of age, exhibiting wheezing symptoms and diagnosed or diagnosable as Vhez infants", an established patient category of major medical concern and now often identified as incipient or early-phase asthmatics. (For convenience this particular asthmatic condition is referred to as "whez -infant syndrome ".)
  • Prophylactic efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, e.g., of acute asthmatic or bronchoconstrictor attack, improvement in lung function or improved airways hyperreactivity. It may further be evidenced by reduced requirement for other, symptomatic therapy, i.e., therapy for or intended to restrict or abort symptomatic attack when it occurs.e.g., anti-inflammatory (e.g., cortico-steroid) or bronchodilatory.
  • symptomatic therapy i.e., therapy for or intended to restrict or abort symptomatic attack when it occurs.e.g., anti-inflammatory (e.g., cortico-steroid) or bronchodilatory.
  • Prophylactic benefit in asthma ma y, in particular, be apparent in subjects prone to "morning dipping".
  • “Morning dipping” is a recognized asthmatic syndrome, common to a substantial percentage of asthmatics and characterized by asthma attack, e.g., between the hours of about 4-6 am, i.e., at a time normally substantially distant from any previously administered symptomatic asthma therapy.
  • Chronic obstructive pulmonary disease includes chronic bronchitis or dyspnea associated therewith, emphysema, as well as exacerbation of airways hyperrea ctivity consequent to other drug therapy, in particular, other inhaled drug therapy.
  • the invention is also applicable to the treatment of bronchitis of whatever type or genesis including, e.g., acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis.
  • the suitability of epithelial sodium channel blocker as a treatment of a disease benefiting from mucosal hydration may be tested by determining the inhibitory effect of the channel activating protease inhibitor on: the ion channel/ion transport function in suitable isolated cells or confluent epithelia using the methods described in Bridges et al., Am J Physiol Lung Cell MoI Physiol, Vol. 281 , No. 1 , pp. L16-L23 (2001 ); and Donaldson et al., J Biol Chem, Vol. 277, No. 10, pp. 8338-8345 (2002).
  • Epithelial sodium channel blockers including the compounds of formula (I), are also useful as co -therapeutic agents for use in combination with other drug substances, such as antiinflammatory, bronchodilatory, antihistamine or anti-tussive drug substances, particularly in the treatment of cystic fibrosis or obstructive or inflammatory airways diseases such as those mentioned hereinbefore, e.g., as potentiators of therapeutic activity of such drugs or as a means of reducing required dosaging or potential side effects of such drugs.
  • drug substances such as antiinflammatory, bronchodilatory, antihistamine or anti-tussive drug substances, particularly in the treatment of cystic fibrosis or obstructive or inflammatory airways diseases such as those mentioned hereinbefore, e.g., as potentiators of therapeutic activity of such drugs or as a means of reducing required dosaging or potential side effects of such drugs.
  • the epithelial sodium channel blocker may be mixed with the other drug substance in a fixed pharmaceutical composition or it may be administered separately, before, simultaneously with or after the other drug substance.
  • the invention includes a combination of epithelial sodium channel blocker with an anti-inflammatory, bronchodilatory, antihistamine, anti -tussive, antibiotic or DNase drug substance, said epithelial sodium channel blocker and said drug substance being in the same or different pharmaceutical composition.
  • Suitable antibiotics include macrolide antibiotics, e.g., tobramycin (TOBITM).
  • Suitable DNase drug substances include domase alfa (PulmozymeTM), a highly-purified solution of recombinant human deoxyribonuclease I (rhDNase), which selectively cleaves DNA. Domase alfa is used to treat cystic fibrosis.
  • epithelial sodium channel blockers with anti-inflammatory drugs are those with antagonists of chemokine receptors, e.g., CCR-1 , CCR-2, CCR-3, CCR ⁇ , CCR-5, CCR-6, CCR-7, CCR-8.
  • chemokine receptors e.g., CCR-1 , CCR-2, CCR-3, CCR ⁇ , CCR-5, CCR-6, CCR-7, CCR-8.
  • CCR-9 and CCR10 CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5 antagonists, such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D; Takeda antagonists, such as ⁇ /-[[4-[rj6,7-dihydro-2-(4-methyl- phenyl)-5/-/-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro- ⁇ /, ⁇ /-dimethyl- 2/-/-pyran-4-amin-ium chloride (TAK-770); and CCR-5 antagonists described in USP 6,166037 (particularly claims 18 and 19), WO 00/66558 (particularly claim 8), WO 00/66559 (particularly claim 9), WO 04/018425 and WO 04/026873.
  • Suitable anti -inflammatory drugs include steroids, in particular, glucocorticosteroids, such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate, or steroids described in WO 02/88167, WO 02/12266, WO 02/100879, WO 02/00679 (especially those of Examples 3, 11 , 14, 17, 19, 26, 34, 37, 39, 51, 60, 67, 72, 73, 90, 99 and 101 ), WO 03/35668, WO 03/48181 , WO 03/62259, WO 03/64445, WO 03/72592, WO 04/39827 and WO 04/66920; non-steroidal glucocorticoid receptor agonists, such as those described in DE 10261874, WO 00/00531 , WO 02/10143, WO 03/82280, WO 03/82787, WO 03/86294, WO 03/104
  • Suitable bronchodilatory drugs include anticholinergic or antimuscarinic agents, in particular, ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate, but also those described in EP 424021, USP 3,714,357, USP 5,171 ,744, WO 01/04118, WO 02/00652, WO 02/51841 , WO 02/53564, WO 03/00840, WO 03/33495, WO 03/53966, WO 03/87094, WO 04/018422 and WO 04/05285.
  • anticholinergic or antimuscarinic agents in particular, ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate, but also those described in EP 424021, USP 3,714,357, USP 5,171 ,744, WO 01/04118,
  • Suitable dual anti -inflammatory and bronchodilatory drugs include dual beta-2 adrenoceptor agonist/muscarinic antagonists such as those disclosed in USP 2004/0167167, WO 04/74246 and WO 04/74812.
  • Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine, as well as those disclosed in JP 2004107299, WO 03/099807 and WO 04/026841.
  • agents of the invention with anti-inflammatory drugs are those with antagonists of chemokine receptors, e.g., CCR-1 , CCR-2, CCR -3, CCR-4, CCR-5, CCR-6, CCR -7, CCR-8, CCR-9 and CCR10, CXCR1 , CXCR2, CXCR3.
  • antagonists of chemokine receptors e.g., CCR-1 , CCR-2, CCR -3, CCR-4, CCR-5, CCR-6, CCR -7, CCR-8, CCR-9 and CCR10, CXCR1 , CXCR2, CXCR3.
  • CXCR4, CXCR5, particularly CCR-5 antagonists such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D; Takeda antagonists, such as ⁇ /-[[4-QI6,7-dihydro-2-(4- methylphenyl)-5/-/-benzo-cyclohepten-8-yl]carbonyrjamino]phenyr
  • the invention also provides a method for the treatment of a condition responsive to blockade of the epithelial sodium channel, e.g., diseases associated with the regulation of fluid volumes across epithelial membranes, pa rticularly an obstructive airways disease, which comprises administering to a subject, particularly a human subject, in need thereof a compound of formula (I), in free form or in the form of a pharmaceutically acceptable salt.
  • a condition responsive to blockade of the epithelial sodium channel e.g., diseases associated with the regulation of fluid volumes across epithelial membranes, pa rticularly an obstructive airways disease
  • the invention provides a compound of formula (I), in free form or in the form of a pharmaceutically acceptable salt, for use in the manufacture of a medicament for the treatment of a condition responsive to blockade of the epithelial sodium channel, particularly anobstructive airways disease, e.g., Cystic Fibrosis and COPD.
  • a condition responsive to blockade of the epithelial sodium channel particularly anobstructive airways disease, e.g., Cystic Fibrosis and COPD.
  • the agents of the invention may be administered by any appropriate route, e.g. orally, e.g., in the form of a tablet or capsule; parenterally, e.g., intravenously; by inhalation, e.g., in the treatment of an obstructive airways disease; intranasally, e.g., in the treatment of allergic rhinitis; topically to the skin; or rectally.
  • the invention also provides a pharmaceutical composition comprising a compound of formula (I), in free form or in the form of a pharmaceutically acceptable salt, optionally together with a pharmaceutically acceptable diluent or carrier therefor.
  • compositions may contain a co-therapeutic agent, such as an antiinflammatory, broncho-dilatory, antihistamine or anti -tussive drug as hereinbefore described.
  • a co-therapeutic agent such as an antiinflammatory, broncho-dilatory, antihistamine or anti -tussive drug as hereinbefore described.
  • Such compositions may be prepared using conventional diluents or excipients and techniques known in the galenic art.
  • oral dosage forms may include tablets and capsules.
  • Formulations for topical administration may take the form of creams, ointments, gels or transdermal delivery systems, e.g., patches.
  • Compositions for inhalation may comprise aerosol or other atomizable formulations or dry powder formulations.
  • the composition comprises an aerosol formulation
  • it preferably contains, e.g, a hydro - fluoro -alkane (HFA) propellant, such as HFA134a or HFA227 or a mixture of these, and may contain one or more co -solvents known in the art, such as ethanol (up to 20% by weight), and/or one or more surfactants, such as oleic acid or sorbitan trioleate, and/or one or more bulking agents, such as lactose.
  • HFA hydro - fluoro -alkane
  • the composition comprises a dry powder formulation, it preferably contains, e.g., the compound of formula (I) having a particle diameter up to 10 microns, optionally together with a diluent or carrier, such as lactose, of the desired particle size distribution and a compound that helps to protect against product performance deterioration due to moisture, e.g, magnesium stearate.
  • a diluent or carrier such as lactose
  • the composition comprises a nebulised formulation, it preferably contains, e.g, the compound of formula (I) either dissolved, or suspended, in a vehicle containing water, a co -solvent, such as ethanol or propylene glycol and a stabilizer, which may be a surfactant.
  • the invention includes:
  • Dosages of compounds of formula (0 employed in practising the present invention will of course vary depending, e.g., on the particular condition to be treated, the effect desired and the mode of administration.
  • suitable daily dosages for administration by inhalation are of the order of 0.005-10 mg
  • suitable daily doses are of the order of 0.05 -100 mg.
  • HBECs Human Bronchial Epithelial cells
  • HBECs were cultured using a modification of the method described by Gray and colleagues (Gray et al., 1996). Cells were seeded in plastic T -162 flasks and were grown in bronchial epithelial cell growth medium (BEGM; Cambrex) supplemented with bovine pituitary extract (52 ⁇ g/mL), hydrocortisone (0.5 ⁇ g/mL), human recombinant epidermal growth factor (0.5 ng/mL), epinephrine (0.5 ⁇ g/mL), transferrin (10ug/mL), insulin (5 ⁇ g/ml_), retinoic acid (0.1 ⁇ g/mL), triiodothyronine (6.5 ⁇ g/mL), gentamycin (50 ⁇ g/mL) and amphotericin B (50 ng/mL).
  • BEGM bronchial epithelial cell growth medium
  • Cambrex bronchial epithelial cell growth medium
  • Amphotericin B was removed from all media 3 feeds prior to use in the Ussing Chambers. Cells were used between days 7 and 21 after establishment of the apical-air interface. At all stages of culture, cells were maintained at 37°C in 5% CO 2 in an air incubator.
  • ISC Short circuit current
  • Snapwell inserts were mounted in Vertical Diffusion Chambers (Costar) and were bathed with continuously gassed Ringer solution (5% CO 2 in O 2 ; pH 7.4) maintained at 37°C containing (in mM): 120 NaCI, 25 NaHCO 3 , 3.3 KH 2 PO 4 , 0.8 K 2 HPO* 1.2 CaCI 2 , 1.2 MgCI 2 , and 10 glucose.
  • the solution osmolarity was between 280 and 300 m ⁇ smol/kg H 2 O for all physiological salt solutions used.
  • Cells were voltage clamped to 0 mV (model EVC4000; WPI).
  • RT was measured by applying a 1- or 2-mV pulse at 30-s intervals and calculating RT by Ohm's law. Data were recorded using a PowerLab workstation (ADInstruments).
  • Test compounds were prepared as a 10 mM stock solution in DMSO (95%). Serial 3 -fold dilutions were freshly prepared in an appropriate vehicle (distilled H 2 O or Ringers solution). The initial concentration was added to the apical chamber as a 100Ox concentrate in 5 ⁇ L, resulting in a final 1x concentration the 5 mL volume of the Ussing chamber. Subsequent additions of compound were added in a 3.3 ⁇ L volume of the 100Ox serially diluted stock solution. At the completion of the concentration -response experiment, amiloride (10 ⁇ M) was added into the apical chamber to enable the total amiloride-sensitive current to be measured. An amiloride control IC 50 WaS established at the start of each experiment.
  • Results are expressed as the mean % inhibition of the amiloride-sensitive ISC. Concentration-response curves were plotted and IC 50 values generated using GraphPad Prism 3.02. Cell inserts were typically run in duplicate and the IC a calculated on the mean % inhibition data.
  • Compounds of the Examples, herein below, generally have IC 50 values in the data measurements described above below 10 ⁇ M.
  • the compounds of Examples 2, and 5 have IC 50 values of 0.0057 and 0.0002 ⁇ M, respectively.
  • Examples 2-5 are prepared analogously using the appropriate starting compounds as Example 1.
  • Example 6 N-[2-(Bis42-pj'-(3,5 ⁇ liamino ⁇ hloro-pyrazine-2-carbonyl) guanidino]- ethyl ⁇ -amino)-ethyl]-N'-(3,5-diamino-6-chloro -pyrazine-2-carbonyl)- guanidine
  • Example 7 3 ⁇ -Diamino- €-chloro-pyrazine-2-carboxylic acid 1-amino-1 - ⁇ 4-[N'-(3,5- diamino-6-chloro -pyrazine-2-carbonyl)-guanidino]-piperidin-1-yi ⁇ «meth- (E)-ylideneamide trifluoroacetate
  • Piperidin-4-ylamine (5.0 mg, 0.05 mmol) is treated with a solution of Intermediate A (0.06 g, 0.16 mmol) in DMF (1.0 mL) followed by EtJM (25.3 mg, 0.25 mmol) and the reaction mixture is stirred at RT overnight. Aminomethylpolystyrene and macroporous isocyanate (scavenger resins) are added and the mixture is allowed to shake at RT overnight. The mixtures are filtered and concentrated in vacuo to afford the product.
  • Step 2 3,5-Diamino-6-chloro-pyrazine-2-carboxylic add 1-amino-1 -( ⁇ -[N'- ⁇ .S-diamino- ⁇ - chloro-pyrazine-2-carbonyl)-guanidino]-piperidin-1-yl ⁇ -meth-(E)-ylideneamide trifluoroacetate
  • Step 1 (0.05 mmol) is treated with 10% TFA in DCM (0.9 mL) and allowed to stand at RT for 1 hour. The solvent is removed in vacuo and purification of the crude product by preparative HPLC eluting with 10-100% MeCN in water (0.1 % TFA) affords the title compound.
  • Example 19 N-(3,5-Diamino-6-chloroi3yrazine-2-carbony!)-N 1 - ⁇ 4-tN'-(3,5-diamino-6-chloro-pyrazine-2- carbonyl)-guanidinomethyl]-cyclohexyl ⁇ -guanidine trifluoroacetate (Example 19), are prepared analogously to Example 7 with the appropriate diamine with the exception that mercury dichloride (2 eq) in DMF is added to the reaction mixture. Reaction byproducts are removed during purification by addition of scavenger resins, such as aminomethylpolystyrene, macroporous isocyanate and solid supported silica 1-propanethiol.
  • scavenger resins such as aminomethylpolystyrene, macroporous isocyanate and solid supported silica 1-propanethiol.
  • This compound is prepared from Intermediate A (3 eq) analogously to Example 7 by replacing piperidin4-ylamine with tris (2-aminoethyl)amine.
  • This compound is prepared analogously to Example 1 by replacing 1 -(3,5-diamino-6-chloro- pyrazine-2-carbonyl)-2-methyl-isothiourea hydroiodide with Intermediate A.
  • the boc- protected intermediate that is formed is deprotected using 33% HBr in acetic acid. Reaction by-products are removed during purification by addition of scavenger resins such as aminomethylpolystyrene and macroporous isocyanate.
  • Step 2 N- ⁇ 4 -[N -(3,5 -Diamino - ⁇ -chloro-pyrazine ⁇ -carbonyO-guanidinol-butyl ⁇ - ⁇ 4 -((4-[N 1 - (3,5-diamino-6-chloro-pyrazine-2-carbonyl)-guanidino]*utylcarbamoyl ⁇ -methyl)- phenylj-acetamide trifluoroacetate
  • Example 22 (20 mg, 0.021 mmol) is treated with 10% TFA in DCM (2 mL) and allowed to stand at RT overnight. The solvent is removed in vacuo and purification of the crude product by preparative HPLC eluting with 10-100% MeCN in water (0.1% TFA) affords the title compound.
  • Example 23 1 - ⁇ 4-[N'-(3,5-Diamino-6 ⁇ hloro-pyrazine-2-carbonyl)-guanidino]-butyl)-3- [4-(3- ⁇ 4-[N'-(3,5 -diamino -6-chloro -pyrazine -2-carbonyl)-guanidino]-butyl ⁇ - ureido)-butyl]-urea
  • Yet further preferred compounds of the present invention include compounds of formula(lb) and are as shown in Table 3 below. The method of preparation being described thereinafter.
  • Yet further preferred compounds of the present invention include compounds of formula (Ic) and are as shown in Table 5 below. The method of preparation being described thereinafter.
  • Y 1 A Y 2 may be varied utilising mono protected diamines and the Intermediate 2. This is illustrated in the scheme above.
  • P 1 and P 2 represent different standard amine protecting groups, e.g., Boc, CBz, acetate and deprotection is by standard means.
  • J represents a group capable of reacting with amines, e.g., halogen, carboxylic acid, isocyanate, sulfonyl chlorides, aldehydes and ketones, methanesulfonate.
  • X represents a halogen, OH, an ester or an activated ester species derived from the use of coupling agents, e.g., EDCI. Where these reagents are unavailable commercially they can be synthesized by general methods known in the art.
  • Y1AY2 may be varied utilizing monoamines and the Intermediate 2.
  • J represents a group capable of reacting with amines, e.g., halogen, carboxylic acid.
  • Diphenylphosphorylazide (1 eq) is added to a stirred solution of the di-acid or tri-acid (1 eq) EfeN (2 eq ) and Intermediate H in DCM (40 vol). The reaction is heated to reflux for 8 hours. The product (Intermediate I) is isolated from the cooled reaction mixture by filtration.
  • Sulfonyl chlorides may be obbined by methods known in the literature, e.g.,
  • the compounds shown in Tables 3-5 may be synthesized analogously to Example 1 using the appropriate diamine.
  • the diamines (Intermediates O) are prepared from Intermediates N which may be synthesized using standard methods known in the literature from mono -protected amines via Steps 1a-e, described hereinafter in the Intermediates section. Deprotection by standard methods and concomitant reaction with 1 -(S.S-diamino- ⁇ -chloro-pyrazine ⁇ -carbonyl ⁇ -methyl-isothiourea hydroiodide to produce compound P.
  • Further preferred compounds of the present invention include compounds of formula (X) and are as shown in Table 6 below. These compounds are prepared in a multiparallel sequence of reactions as described belowin Scheme X. Methods of preparing such compounds are described hereinafter.
  • Further preferred compounds of the present invention include compounds of formula Z and are as shown in Table 8 below. These compounds are prepared in a multiparallel sequence of reactions as described below in Scheme Z. Methods of preparing such compounds are described hereinafter.
  • Yet further preferred compounds of the present invention include compounds of formula (T) and are as shown in Table 9 below. Methods of preparing such compounds are described hereinafter.
  • a suspension of Intermediate A and the corresponding Intermediate S in dry DMF is treated with TEA and heated to 65°C for 96 hours.
  • the reaction mixture is cooled to RT and the product is purified by reverse phase column chromatography (IsoluteTM C18, 0-100% acetonitrile in water - 0.1 % TFA). The fractions comprising the product are concentrated in vacuo.
  • the resulting solid is dissolved in 4 M HCI (in dioxane) and stirred overnight. The reaction mixture is reduce in vacuo to afford the title compound.
  • a stirred suspension comprising 1 -(3,5 ⁇ liamino-6-chlorc ⁇ pyrazine-2 ⁇ t>onyl)-2-methyl- isothiourea hydroiodide (11.4 g, 29 mmol), 4-dimethylaminopyridine (0.87 g, 7 mmol), EUM (20 mL) in THF (400 mL) is treated with di-tert butyl dicarbonate (12 g, 55 mmol) in THF (100 mL) in one portion. The resulting mixture is stirred at RT overnight and then concentrated in vacuo. The crude product is partitioned between EtOAc (50 mL) and water (50 mL) and stirred at RT for 10 minutes. The suspension is filtered, washed with water (5 mL), EtOAc (20 mL) and dried under vacuum at 40°C to afford the title compound. (M+H] + 361.05
  • Step 1 ⁇ 4-[4-(4-tert-Butoxycarbonylamino-butylcart)a ⁇ noyl)-benzoylamino]-butyl ⁇ -carbamic acid tert-butyl ester
  • Step 1 3-(BenzyH3- ⁇ benzyl-(2-cyano -ethyl)-amino]-propyl ⁇ -amino)-propionitrile
  • Step 2 N*1 *- ⁇ 3-f(3-Amin ⁇ propyl>t»enzyl-aminoJ-propyl ⁇ -N * 1 *-benzyl-propane-1 ,3- diamine dihydrochloride
  • Methane sulfonyl chloride (1 eq) is added to a stirring solution of Intermediate J (1 eq) and E ⁇ N (3 eq) in DCM. Upon completion the reaction is quenched with NaHCO 3 solution. The DCM layer is dried over magnesium sulfate and concentrated in vacuo to produce a crude residue which is purified by flash column chromatography.
  • the di-acid chloride or tri-a ⁇ d chloride (1 eq) was added to a stirred solution of N-Boc propyldiamine, N-Boc butyldiamine or N-Boc pentyldiamine (2 eq) and Et 3 NI (3 eq) in DMF (10 vol). Upon completion of the reaction the solution was quenched with aqueous NaHCO 3 and the product (Intermediate Na) extracted with DCM and concentrated in vacuo.
  • EDCI (1 eq) was added to a stirred solution of the di-acid or tri-acid (1 eq) in DMF (10 vol).
  • N-ethyl-morpholine (3 eq) and N-Boc propyldiamine, N-Boc butyldiamine or N-Boc pentyldiamine (2 eq) were added and the reaction heated. Upon completion the reaction was quenched with NaHCO 3 solution and the product (Intermediate Nb) extracted with DCM and concentrated in vacuo.
  • Diphenylphosphorylazide (1 eq) was added to a stirred solution of the di-acid or tri-acid (1 eq), EyM (2 eq)and N-Boc propyldiamine, N-Boc butyldiamine or N-Boc pentyldiamine in DCM (40 vol). The reaction was heated to reflux for 8 hours. The product (Intermediate Nd) was isolated fro m the cooled reaction mixture by filtration or purified by flash column chromatography.
  • the diamine (1 eq) is added a solution of bis-4-nitrophenylcarbonate (2 eq) in DMF.
  • the reaction is left to stir for 1 -2 hours and N-Boc propyldiamine, N-Boc butyldiamine or N-Boc pentyldiamine is added and the reaction heated .
  • the reaction is quenched with water and the crude product (Intermediate Ne) isolated by filtration and purified by flash column chromatography.
  • N-Boc propylamine methane sulfonate, N-Boc butylamine methane sulfonate or N-Boc pentylamine methane sulfonate (2 eq) is added to a stirring solution of the diamine (1 eq) and triethylaine (2 eq) in DMF.
  • the reaction is quenched with water and the product (Intermediate Ng) isolated by filtration or extraction with DCM or by flash column chromatography.
  • Methane sulfonyl chloride (0.4 mL, 5.3 mmol) is added to a stirring solution of Boc-amino pentanol (1.0 g, 4.9 mmol) and Et 3 N (1.68 mL, 15 mmol) in DCM (10 mL).
  • the reaction is left to stir at RT for 1 hour and is then quenched with sodium hydrogen carbonate solution and the organic phase washed with 5% citric acid solu tion.
  • the resulting organic phase is dried over magnesium sulphate and concentrated in vacuo to yield the title compound as a viscous yellow oil.
  • Step 2 ⁇ 5- ⁇ 4-(5-tert-Butoxycarbonylamino-pentyl)-piperazin-1-yl]-pentyl ⁇ -carbamic acid tert-butyl ester
  • Step 3 5-[4-(5-Amino-pentyl)-piperazin-1 -yl]-pentylamine trifluoroacetate .
  • 2,4-Dichloro-1,3,5-triazine (15.5 mg, 010 mmol) is dissolved in N-methyl-2-py ⁇ olidone (2 mL) and cooled to 0 0 C.
  • a solution of Intermediate H (90 mg, 0.21 mmol) in N-methyl-2- pyrrolidone (1 mL) is added to the reaction mixture and stirred over night at RT.
  • the reaction mixture is purified by reverse phase column chromatography (IsoluteTM C18, 0-100% acetonitrile in water - 0.1% TFA).

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Abstract

A compound of formula (I) or tautomers, or stereoisomers, or solvates, or pharmaceutically acceptable salts thereof, wherein M1, M1, L1, L2, W1, W2, X1, X2, Y1, Y2, A, R5 and R5a are as defined herein for the for treatment of conditions mediated by the blockade of an epithelial sodium channel, particularly an inflammatory or allergic condition.

Description

ORGANIC COMPOUNDS
This invention relates to organic compounds, their preparation and use as pharmaceuticals.
In one aspect, the present invention provides compounds of formula (I):
Figure imgf000002_0001
or tautomers, or stereoisomers, or solvates, or pharmaceutically acceptable salts thereof, wherein
M, M , and M2 are independently
Figure imgf000002_0002
;
R1, R2, R3, and R4 are independently selected from H, d-Ce-alkyl, Ci-Cfralkyl-carboxy, CrCg-haloalkyl, C3-C 15-carbocyclic group, CrCβ-alkylcarbonyl, C1-C8- alkoxycarbonyl, a C6-C15-membered aromatic carbocyclic group, a4- to 14-membered heterocyclic group, a CrCβ-alkyl substituted by a 4- to 14-membered heterocyclic group, and a CrCralkyl substituted by a Cs-Curmembered aromatic carbocyclic group , or
R1 and R2 with the nitrogen atom to which they are attached form a CrC14-membered heterocyclic group optionally substituted by R14, or
R3 and R4 with the nitrogen atom to which they are attached form a C 3-C14- membered heterocyclic group optionally substituted by R14;
L, L, and L2 are independently selected from:
Figure imgf000002_0003
and
Figure imgf000002_0004
R6,R5, R53, R5band Rx are independently selected from H, C1-C8 alkyl, C rCβ-alkyl- carboxy, CrCβ-alkyl-alkoxy.C^β-haloalkyl, CrC1s-carbocyclic group, CrC8- alkylcarbonyl, CrCβ-alkoxycarbonyl, nitro, cyano, a C 6-C15- membered aromatic carbocyclic group, a4- to 14-membered heterocyclic group, a Ci-Cβ-alkyI substituted by a 4- to 14-membered heterocyclic group, and a C rCe-alkyl substituted by a C<rC15-membered aromatic carbocyclic group, or R5 with the nitrogen atom to which it is attached, together with A, form a 4- to 14-membered heterocyclic group when X1 is Cσ-Cβ-alkylene, O, -NR7- or S, or
R53 with the nitrogen atom to which it is attached, together with A, form a 4- to 14-membered heterocyclic group when X2 is C<j-Cβ-alkylene, O1 -NR7- or S, or
R5b with the nitrogen atom to which it is attached, together with A, form a 4- to 14-membered heterocyclic group when X is Cσ-Cβ-alkylene, O, -NR7- or S;
W, W1 and W2 are independently selected from Co-Cβ-alkylene;
X, X1 and X2 are independently selected from Co-Cβ-alkylene, O, S, -NR7-, -NR7(C=O)-, -NR7(C=O)NR8-, -NR8SOr, -NR^SO2)NR8-, -NR7(C=O)O-, -O(C=O)-, -0(C=O)O-, -0(C=O)NR7-, -<C=S)NR7-, -(C=NR7JNR8-, -(C=O)NR7-. -(C=O)O-, -(SO2)(C0-C8- alkyleneh -(SO2)NR8- and -(SO2)NR7-Z-(SO2)NRβ-;
Y, Y1 and Y2 are independently -Co-Cβ-alkylene-;
Z is CrC4-alkylene; where W, W h W2, Y, Y1, Y2 and Z are optionally substituted by CrCβ-alkyl, halogen , CrCβ-alkoxy, carboxy, C rCg-alkyl-carboxy, CrCa-haloalkyl, C rCβ-haloalkoxy, CrC15-CaIt)OCyCIiC group, C rCralkylcarbonyl, CrCg-alkoxycarbonyl, nitro, cyano, a C,rC15-membered aromatic carbocyclic group, a CrCβ-alkyl substituted by a C6-C15-membered aromatic carbocyclic group, a 4- to 14-membered heterocyclic group containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulphur, a d-Cβ-alkyl substituted by a4-to 14-membered heterocyclic group containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulphur, and a CrCg-alkyl substituted by a C<rC1s-membered aromatic carbocyclic group;
A is selected from a C6-C15-membered aromatic carbocyclic group optionally substituted by -Y-X-W-NR5^L-M, CrC1s-carbocyclic group optionally substituted by -Y-X-W- NR5^L-M, a 4- to 14-membered heterocyclic group optionally substituted by -Y-X-W- NR5b-L-M, a heteroatom selected from nitrogen, oxygen, and sulphur, wherein the nitrogen can be substituted by-Y-X-W-NRa-L-M, a CrCβ-alkyl optionally substituted by -Y-X-W-NR5b-L-M, with the proviso that when R5 and R5a does not form a 4-to 14- membered heterocyclic group with A, then A is not a Cβ-C^-aromatic carbocyclic group, O, C=O or a CrCβ-alkyl group when X1, X2, Y1 and Y2 are Co-Cβ-alkylene unless A is substituted by -Y-X-W-NR5b-L-M; R7, R8, R11and R12, are independently selected from H, CfCβ-alkyl optionally substituted by Cy-CM-aralkyl , d-Cβ-haloalkyl and a 5- to 14-membered heterocyclic group; R 7 and R8, independently, by way of a C rd-alkyl group can form a bond with a carbon atom of group W, W fc W2, Y, Y2, or Y2 to create a 5- b 14-membered heterocyclic group;
T is selected from H, halogen , CrCβ-alkyl, C rCe-haloalkyl, d-Cβ-haloalkoxy, C 3-C15- carbocyclic group, nitro, cyano, a Cg-d-rmembered aromatic carbocyclic group, a and a CrC8-alkyl substituted by a Cg-ds-membered aromatic carbocyclic group; wherein each C<rC1s-membered aromatic carbocyclic group and each 4 - to 14-membered heterocyclic group, unless otherwise specified is independently optionally substituted by one or more groups selected from OH, d-Cg-alkoxy, d-Cβ-alkyl, halogen, SO2NR11R12, hydroxyCrCβ-alkoxy, optionally substituted by hydroxyl, (C0-C4- alkylene) CONR11R12, (Co-dralkylene) N=C(NR11R12J2, -O-(C,-C,-alkylene)- N=C(NR11R12J2, -O-fd-C^alkyleneyCONR^R12, C^C1(raralkoxy, d-do-aralkyl, SH, SfC-Qralkylene), SO^d-Cβ-alkyleneJ SOfd-dralkylene), NR11R12, R15, a C1-C8- alkyl substituted by R15, R16, a C-Ce-alkyl substituted by R16, O(d-C,ralkylene)- NR11C(C=O)O-(CcrC4-alkylene)-R15, cyano, oxo, carboxy, nitro, d-Cβ-alkylcarbonyl, hydroxy-CrCβ-alkyl, C rCβ-haloalkyl, amino-d-Cβ-alkyl, amino(hydroxy JC1-C g-alkyl and d-Cβ-alkoxy optionally substituted by aminocarbonyl, where Rβ is a C6-C15- membered aromatic carbocyclic group, optionally substituted by OH, CrCβ-alkoxy, CrCβ-alkyl, halogen andC^β-haloalkyl, R1βis a 3- to 14-membered heterocyclic group, optionally substituted by OH, CrCβ-alkoxy, CrCβ-alkyl, halogen and C1-C6- haloalkyl, and wherein each alkylene group, unless otherwise specified, is optionally substituted by CrCβ-alkyl, halogen, CrCβ-alkoxy, carboxy, d-Cg-alkyl-carboxy, C rCβ-haloalkyl, CrCβ-haloalkoxy, C rC1s-carbocyclic group, d-Ce-alkylcarbonyl, C rCβ- alkoxycarbonyl, nitro, cyano, R15, a CrCβ-alkyl substituted by R15, R16 or a C1-C8- alkyl substituted by R16; and
R14is selected from H, halogen, CrCβ-alkyl, OH, C6-C15-membered aromatic carbocyclic group, CT-d-raralkyl, and O-Cτ-Ci4-aralkyl. An aspect of the present invention provides compounds of formula (I) , or tautomers, or stereoisomers, or pharmaceutically acceptable salts thereof, wherein
M, M , and M2 are independently
Figure imgf000005_0001
R1, R2, R3, and R4 are independently selected from H, C,-Cralkyl, d-Cβ-alkyl-carboxy;
L, L1 and L2 are independently selected from:
Figure imgf000005_0002
and
Figure imgf000005_0003
R5, R5a and R5b are independently selected from H, and CrCβ-alkyl, or
R5 with the nitrogen atom to which it is attached, together with A, form a 4 - to
14-membered heterocyclic group when X, is Co-Cg-alkylene, O, -NR7-, or S, or
R53WiUi the nitrogen atom to which it is attached, together with A, form a 4- to 14- membered heterocyclic group when X2 is Cα-Cβ-alkylene, O, -NR7-, or S, or
R5bwith the nitrogen atom to which it is attached, together with A, form a 4- to 14-membered heterocyclic group when X is Co-Cβ-alkylene, O, -NR7-, or S;
R6 is selected from H, and CrCβ-alkyl;
W, Wi and W2 are selected from Co-Cβ-alkylene;
X, X1 and X2 are selected from Co-Cβ-alkylene, O, S, -NR7-, -NR7(C=O)-, -NR7(C=O)NR8-, -NR8SO2-, -NR7(SO2)NR8-, -NR7(C=0)0-, -O(C=O)-, -0(C=O)O-, -0(C=O)NR7-, -(C=S)NR7-, -(C=NR7)NR8-, -(C=O)NR7-, -(C=O)O-, -<SO2)(C<rC<ralkylene)-, -(SO2)NR8- and -(SO2)NR7-Z-(SO2)NR8-;
Y, Y1 and Y2 are -Co-Cβ-alkylene-; Z is CrC4-alkylene; where W, W1, W2, Y, Y1, Y2, and Z are optionally substituted byCi-Ce-alkyl, halogen, CrCβ-alkoxy, carboxy, C rCg-alkyl-carboxy, CrCβ-haloalkyl, CfCβ-haloalkoxy, C3-C15-carbocyclic group, C rCβ-alkylcarbonyl, CrCβ-alkoxycarbonyl, nitro, cyano, a C<rC15-membered aromatic carbocyclic group, a CrCβ-alkyl substituted by a C6-C15-membered aromatic carbocyclic group, a 4- to 14-membered heterocyclic group containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulphur, a substituted by a4-to 14-membered heterocyclic group containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulphur, and a C,-Cralkyl substituted by a C6-C15-membered aromatic carbocyclic group;
A is selected from a C6-C1s-membered aromatic carbocyclic group, CrCis-carbocyclic group, a 4- to 14-membered heterocyclic group, a heteoatom selected from nitrogen, oxygen, and sulphur, wherein the nitrogen can be substituted by -Y-X-W- NR^-L-M, a C-Cβ-alkyl optionally substituted by -Y-X-W-NR5b-L-M, with the proviso that when R5 and R * does not form a 4 -to 14-membered heterocyclic group with A, then A is not a C(rC15-aromatic carbocyclic group, O, C=O or a d-Cβ-alkyl group when X1, X2, Y1 and Y2 are Co-Cralkylene unless A is substituted by -Y-X-W-NR5"- L-M;
R7, R8, R1 'and R c, are independently selected from H, CrCg-alkyl optionally substituted by Cτ-C14-aralkyl, Ct-Cβ-haloalkyl, a 5- to 14-membered heterocyclic group, and R7 and R8, independently, by way of an CrC-alkyl group can form a bond with a carbon atom of group W or Y creating a 5 - to 14-membered heterocyclic group; and
T is selected from H, halogen , CrQj-alkyl, CrCg-haloalkyl, CrCirhaloalkoxy, C3-C15- carbocyclic group, nitro, cyano, a C6-C,s-membered aromatic carbocyclic group, and a CrCs-alkyl substituted by a Cβ-C1s-membered aromatic carbocyclic group.
In compounds of formula (I), the following meanings are preferred independently, collectively or in any combination:
According to formula (I), L, L , and L2 are suitably
Figure imgf000006_0001
° . Equally suitably, L, L1 and L2
Figure imgf000006_0002
According to formula (I), R1 is preferably H.
According to formula (I), R2 is preferably H. According to formula (I), R3 is preferably H.
According to formula (I), R4 is preferably H. M1 M1, and M2are preferably
Figure imgf000007_0001
According to formula (I), preferably R5 R53 and Ra are H.
According to formula (I), R6 is preferably H.
According to formula (I), where A is a CrC^carbocyclic group, this is suitably a 4- to 6-membered carbocyclic group, e.g, cyclobutane and cyclohexane.
According to formula (I), A can be nitrogen substituted by -Y-X-W-N R5b-L -M.
According to formula (I), W, W1 and W2are independently, methylene, ethylene, butylene, pentylene or hexylene, preferably W1 and W2 are methylene.
According to formula (I), X, X1 and X2 are suitably Cø-Cβ-alkylene, -NR7-, -NR7(C=O)-, -NR7(C=O)NR8-, -NR8SOr, -NR7(SO2)NR8-, -NR7(C=O)O-, -0(C=O)-, -0(C=O)O-, -0(C=O)NR7-, -(C=S)NR7-, -(C=NR7JNR8-, -(C=O)NR7-, -(C=O)O-, -(SOj-XCo-Cs-alkylene)-, -(SO2)NR18-, -(SO2)NR8-Z-<SO2)NR8-, or R7 and R8, independently, by way of a CrC^alkyl group can form a bond with a carbon atom of group W1 or W2 or Y1 or Y2 to create a 5- to
14-membered heterocyclic group.e.g.,
Figure imgf000007_0002
R7 and R8are preferably, independently H and CrCg-alkyl.
Preferably X, X1 and X2 are Cσ-alkylene, i.e, a bond.
According to formula (I), Z is suitably -(Co-Cralkylene)-. Preferably Z is methylene or ethylene.
According to formula (I), Y, Y1 and Y2 are suitably -(Co-Cralkylene)-. Preferably Y i and Y2 are C0, i.e., a bond, methylene or ethylene.
According to formula (I)1 T is suitably halogen, preferably chlorine. In a more preferred embodiment, the present invention provides compounds of formula (Ia)
Figure imgf000008_0001
or tautomers, or stereoisomers, or pharmaceutically acceptable salts thereof, wherein
A2 is selected from
Figure imgf000008_0002
Figure imgf000008_0003
Figure imgf000009_0001
In another embodiment, the present invention provides for the use of a compound of formula (I) in any of the aforementioned embodiments, in free or pharmaceutically acceptable salt form, for the manufacture of a medicament for the treatment of an inflammatory or allergic condition, particularly an inflammatory or obstructive airways disease.
A preferred embodiment of the present invention provides for the use of a compound of formula (I) in any of the aforementioned embodiments, in free or pharmaceutically acceptable salt form, for the manufacture of a medicament for the treatment of an inflammatory or allergic condition selected from cystic fibrosis, primary ciliary dyskinesia, chronic bronchitis, chronic obstructive pulmonary disease, asthma, respiratory tract infections, lung carcinoma, xerostomia, and keratoconjunctivitis sire .
It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment to describe additional embodiments of the present invention. Furthermore, any elements of an embodiment are meant to be combined with any and all other elements from any of the embodiments to describe additional embodiments. It is understood by those skilled in the art that combinations of substituents where not possible are not an aspect of the present invention. Definitions
Terms used in the speάfication have the following meanings:
"Optionally substituted" means the group referred to can be substituted at one or more positions by any one or any combination of the radicals listed thereafter.
"Halo" or Tialogen ", as used herein , may be fluorine, chlorine, bromine or iodine.
"CrCff-Alkyr, as used herein, denotes straight chain or branched alkyl having 1 -8 carbon atoms.
"C1-C8-AIkOXy", as used herein , denotes straight chah or branched alkoxy having 1 -8 carbon atoms.
The term "alkylene" denotes a straight chain or branched saturated hydrocarbon chain.
"Amino-Ci-Cβ-alkyr and "amino-d-Cβ-alkoxy" denote amino attached by a nitrogen atom to C,-Cβ-alkyl, e.g., NH2-(C1-C,))-, or to C rCg-alkoxy, e.g., NHr(C1-Cg)-O-.
"Amino-fhydroxyJ-CrCβ-alkyl" denotes amino attached by a nitrogen atom to CrCg-alkyl and hydroxy attached by an oxygen atom to the same C^Ce-alkyl.
"CrCβ-Alkylcarbonyl" and "CrCβ-alkoxycarbonyr, as used herein, denote CrCβ-alkyl or CrCβ-alkoxy , respectively, as hereinbefore defined, attached by a carbon atom to a carbonyl group.
"CrCβ-Cycloalkylcarbonyl", as used herein, denotes C3-Ca-cycloalkyl, as hereinbefore defined, attached by a carbon atom to a carbonyl group.
"Cτ-C14-Aralkyr, as used herein, denotes alkyl, e.g., CrC-alkyl, as hereinbefore defined, substituted by a C6-C1α-aromatic carbocyclic group, as herein defined.
"C^ds-Carbocyclic group", as used herein, denotes a carbocyclic group having 3- to 15-ring carbon atoms that is saturated or partially saturated, such as a C3-Cβ-cycloalkyl. Examples of C3-C1 s-carbocyclic groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl or a bicyclic group, such as bicyclooctyl, bicyclononyl including indanyl and indenyl, and bicyclodecyl. "C6-C1s-Aromatic carbocyclic group", as used herein, denotes an aromatic group havingθ- to 15-ring carbon atoms. Examples of C<rC,5-aromatic carbocyclic groups include, but are not limited to, phenyl, phenylene, benzenetriyl, naphthyl, naphthylene , naphthalenetriyl or anthrylene.
"4- to 14-Membered heterocyclic group" refers to a 4 - to 14-membered heterocyclic ring containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulphur, which may be saturated, partially saturated or unsaturated (aromatic). Examples of 3- to 14-membered heterocyclic groups include but are not limited to furan, pyrrole, pyrrolidine, pyrazole, imidazole, triazole, isotriazole, tetrazole, thiadiazole, isothiazole, oxadiazole, pyridine, piperidine, pyrazine, oxazole, isoxazole, pyrazine, pyridazine, pyrimidine, piperazine, pyrrolidine, pyrrolidinone, moφholine, triazine, oxazine, tetrahyrofuran, tetrahydrothiophene, tetrahydrothiopyran, tetrahydropyran, 1,4<Jioxane, 1,4-oxathiane, indazole, quinoline, indazole, indole or thiazole.
Throughout this specification and in the claims that follow, unless the context requires otherwise, the word "comprise", or variations, such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
Especially preferred specific compounds of formula (I) are those described hereinafter in the Examples.
The compounds represented by formula (I) may be capable of forming acid addition salts, particularly pharmaceutically acceptable acid addition salts. Pharmaceutically acceptable acid addition salts of the compound of formula (I) include those of inorganic acids, e.g., hydrohalic adds, such as hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; and organic acids, e.g., aliphatic monocarboxylic acids, such as formic add, acetic acid, trifluoroacetic acid, propionic acid and butyric acid; aliphatic hydroxy acids, such as lactic acid, citric acid, tartaric acid or malic add; dicarboxylic acids, such as maleic acid or succinic acid; aromatic carboxylic acids, such as benzoic acid.p-chlorobenzoic acid, diphenylacetic acid, para-biphenyl benzoic acid or triphenylacetic add; aromatic hydroxy acids, such as o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1 -hydroxynaphthalene-2 -carboxylic acid or 3-hydroxynaphthalene-2- carboxylic acid; cinnamic acids, such as 3-(2-naphthalenyl)propenoic add, para -methoxy cinnamic acid or para -methyl cinnamic acid; and sulfonic acids, such as methanesulfonic acid or benzenesulfonic acid. These salts may be prepared from compounds of formula (I) by known salt-forming procedures.
Compounds of formula (I) which may contain acidic, e.g, carboxyl, groups, are also capable of forming salts with bases, in particular, pharmaceutically acceptab Ie bases, such as those well-known in the art; suitable such salts include metal salts, particularly alkali metal or alkaline earth metal salts, such as sodium, potassium, magnesium or calcium salts; or salts with ammonia or pharmaceutically acceptable organic amines or heterocyclic bases, such as ethanolamines, benzylamines or pyridine. These salts may be prepared from compounds of formula (I) by known salt-forming procedures.
Stereoisomers are those compounds where there is an asymmetric carbon atom. The compounds exist in individual optically active isomeric forms or as mixtures thereof, e.g., as diastereomeric mixtures. The present invention embraces both individual optically active R and S isomers, as well as mixtures thereof. Individual isomers can be separated by methods well known to those skilled in the art, e.g. chiral high performance liquid chromatography (HPLC).
Tautomers are one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.
The compounds of the invention may exist in both unsolvated and solvated forms. The term "solvate " is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, e.g., ethanol. The term "hydrate" is employed when said solvent is water.
Synthesis
An embodiment of the present invention provides a process for the preparation of compounds of f
Figure imgf000012_0001
or tautomers, or stereoisomers, or pharmaceutically acceptable salts thereof, wherein M1, M2, L1, L2, NR5, NR5a, W1, W2, X1, X2, Y1, Y2, and A are as defined hereinbefore, which comprises the steps of:
(i) reacting a compound of formula (M)
Figure imgf000013_0002
wherein
MNs M1 Or M2:
L* is L1 or L2; and
M1, M2, L1, L2 and T are as hereinbefore defined, with compounds of formula (V):
Figure imgf000013_0001
wherein R5, R53, W1, W2, X1, X2, Y1, Y2and A are hereinbefore defined, optionally in the presence of a base, e.g., an organic base; and in an organic solvent e.g., a non-protic dipolar solvent; and
(ii) recovering the resultant compound of formula(l), in free or pharmaceutically acceptable salt form.
The compounds of formula (I) can be prepared, e.g., using the reactions and techniques described below and in the Examples. The reactions may be performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention.
The various substituents on the synthetic intermediates and final products shown in the following reaction schemes can be present in their fully elaborated forms, with suitable protecting groups where required as understood by one skilled in the art, or in precursor forms which can later be elaborated into their final forms by methods familiar to one skilled in the art. The substituents can also be added at various stages throughout the synthetic sequence or after completion of the synthetic sequence. In many cases, commonly used functional group manipulations can be used to transform one intermediate into another intermediate, or one compound of formula (I) into another compound of formula (I). Examples of such manipulations are conversion of an ester or a ketone to an alcohol; conversion of an ester to a ketone; interconversions of esters, acids and amides; alkylation, acylation and sulfonylation of alcohols and amines; and many others. Substituents can also be added using common reactions, such as alkylation, acylation, halogenation or oxidation. Such manipulations are well-known in the art, and many reference works summarize procedures and methods for such manipulations. Some reference works which gives examples and references to the primary literature of organic synthesis for many functional group manipulations, as well as other transformations commonly used in the art of organic synthesis are March's Organic Chemistry, 5th Edition, Wiley and Chichester, Eds. (2001); Comprehensive Organic Transformations, Larock, Ed., VCH (1989); Comprehensive Organic Functional Group Transformations, Katritzky et al. (series editors), Pergamon (1995); and Comprehensive Organic Synthesis, Trost and Fleming (series ed itors), Pergamon (1991 ). It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. Multiple protecting groups within the same molecule can be chosen such that each of these protecting groups can either be removed without removal of other protecting groups in the same molecule, or several protecting groups can be removed using the same reaction step, depending upon the outcome desired. An authoritative account describing many alternatives to the trained practioner is Greene and Wuts, Protective Groups in Organic Synthesis, Wiley and Sons (1999).
Generally, compounds described in the scope of this patent application can be synthesized by the routes described in Scheme 1 and Scheme 2 and the Examples.
In Scheme 1 , compounds of formula (I) can be prepared according to the processes described by Cragoe etal., J Med Chem, Vol. 10, pp.66-73 (1967); and European Patent EP 0017 152 and U.S. Patent No. 3,544,571 . For instance, intermediate 1 can be reacted with intermediate 2, where A is as defined hereinbefore, in the presence of triethylamine in organic solvent to provide compound 3 as the free base. The free base can then be converted to a salt form by treatment with an appropriate acid. Intermediates can be prepared from methods known by those skilled in the art or are commercially-available.
Scheme 1
Figure imgf000015_0001
Compounds of formula (I) can also be prepared according to Scheme 2 by reacting Intermediate 1 with a mono protected diamine (Intermediate 2) in the presence of triethylamine in organic solvent to provide Intermediate 3. Subsequent deprotection of Intermediate 3 using conventional deprotection techniques affords Intermediate 4. Intermediate 4 may be reacted with MrJ where M2 is hereinbefore defined to provide compound 5. P represents a standard amine protecting group , e g . , Boc, CBz, acetate, and deprotection is by standard means. J represents a group capable of reacting with amines, eg., halogen, thioether, carboxylic acid, isocyanate, sulfonyl chlorides, aldehydes and ketones.
Scheme 2
Figure imgf000016_0001
Compounds of formula (I), in free form, may be converted into salt form, and vice versa, in a conventional manners understood by those skilled in the art. The compounds in free or salt form can be obtained in the form of hydrates or solvates containing a solvent used for crystallisation. Compounds of formula (I) can be recovered from reaction mixtures and purified in a conventional manner. Isomers, such as stereoisomers, may be obtained in a conventional manner, e.g., by fractional crystallisation or asymmetric syntiesis from correspondingly asymmetrically substituted, e.g., optically active, starting materials.
Pharmacological activity Having regard to their blockade of the epithelial sodium channel (ENaC), compounds of formula (I), in free or pharmaceutically acceptable salt form, hereinafter alternately referred to as "agents of the invention", are useful in the treatment of conditions which respond to the blockade of the epithelial sodium channel, particularly conditions benefiting from mucosal hydration.
Diseases mediated by blockade of the epithelial sodium channel, include diseases associated with the regulation of fluid volumes across epithelial membranes. For example, the volume of airway surface liquid is a key regulator of mucociliary clearance and the maintenance of lung health. The blockade of the epithelial sodium channel will promote fluid accumulation on the mucosal side of the airway epithelium thereby promoting mucus clearance and preventing the accumulation of mucus and sputum in respiratory tissues (including lung airways). Such diseases include respiratory diseases, such as cystic fibrosis, primary ciliary dyskinesia, chronic bronchitis, chronic obstructive pulmonary disease (COPD), asthma, respiratory tract infections (acute and chronic; viral and bacterial) and lung carcinoma. Diseases mediated by blockade of the epithelial sodium channel also include diseases other than respiratory diseases that are associated with abnormal fluid regulation across an epithelium, perhaps involving abnormal physiology of the protective surface liquids on their surface, e.g., xerostomia (dry mouth) or keratoconjunctivitis sire (dry eye). Furthermore, blockade of the epithelial sodium channel in the kidney could be used to promote diuresis and thereby induce a hypotensive effect.
Treatment in accordance with the invention may be symptomatic or prophylactic.
Asthma includes both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma induced following bacterial infection. Treatment of asthma is also to be understood as embracing treatment of subjects, e.g., of less than 4 or 5 years of age, exhibiting wheezing symptoms and diagnosed or diagnosable as Vheezy infants", an established patient category of major medical concern and now often identified as incipient or early-phase asthmatics. (For convenience this particular asthmatic condition is referred to as "wheezy -infant syndrome ".)
Prophylactic efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, e.g., of acute asthmatic or bronchoconstrictor attack, improvement in lung function or improved airways hyperreactivity. It may further be evidenced by reduced requirement for other, symptomatic therapy, i.e., therapy for or intended to restrict or abort symptomatic attack when it occurs.e.g., anti-inflammatory (e.g., cortico-steroid) or bronchodilatory. Prophylactic benefit in asthma ma y, in particular, be apparent in subjects prone to "morning dipping". "Morning dipping" is a recognized asthmatic syndrome, common to a substantial percentage of asthmatics and characterized by asthma attack, e.g., between the hours of about 4-6 am, i.e., at a time normally substantially distant from any previously administered symptomatic asthma therapy.
Chronic obstructive pulmonary disease includes chronic bronchitis or dyspnea associated therewith, emphysema, as well as exacerbation of airways hyperrea ctivity consequent to other drug therapy, in particular, other inhaled drug therapy. The invention is also applicable to the treatment of bronchitis of whatever type or genesis including, e.g., acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis.
The suitability of epithelial sodium channel blocker as a treatment of a disease benefiting from mucosal hydration, may be tested by determining the inhibitory effect of the channel activating protease inhibitor on: the ion channel/ion transport function in suitable isolated cells or confluent epithelia using the methods described in Bridges et al., Am J Physiol Lung Cell MoI Physiol, Vol. 281 , No. 1 , pp. L16-L23 (2001 ); and Donaldson et al., J Biol Chem, Vol. 277, No. 10, pp. 8338-8345 (2002).
Epithelial sodium channel blockers, including the compounds of formula (I), are also useful as co -therapeutic agents for use in combination with other drug substances, such as antiinflammatory, bronchodilatory, antihistamine or anti-tussive drug substances, particularly in the treatment of cystic fibrosis or obstructive or inflammatory airways diseases such as those mentioned hereinbefore, e.g., as potentiators of therapeutic activity of such drugs or as a means of reducing required dosaging or potential side effects of such drugs.
The epithelial sodium channel blocker may be mixed with the other drug substance in a fixed pharmaceutical composition or it may be administered separately, before, simultaneously with or after the other drug substance.
Accordingly, the invention includes a combination of epithelial sodium channel blocker with an anti-inflammatory, bronchodilatory, antihistamine, anti -tussive, antibiotic or DNase drug substance, said epithelial sodium channel blocker and said drug substance being in the same or different pharmaceutical composition. Suitable antibiotics include macrolide antibiotics, e.g., tobramycin (TOBI™).
Suitable DNase drug substances include domase alfa (Pulmozyme™), a highly-purified solution of recombinant human deoxyribonuclease I (rhDNase), which selectively cleaves DNA. Domase alfa is used to treat cystic fibrosis.
Other useful combinations of epithelial sodium channel blockers with anti-inflammatory drugs are those with antagonists of chemokine receptors, e.g., CCR-1 , CCR-2, CCR-3, CCR^, CCR-5, CCR-6, CCR-7, CCR-8. CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5 antagonists, such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D; Takeda antagonists, such as Λ/-[[4-[rj6,7-dihydro-2-(4-methyl- phenyl)-5/-/-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-Λ/,Λ/-dimethyl- 2/-/-pyran-4-amin-ium chloride (TAK-770); and CCR-5 antagonists described in USP 6,166037 (particularly claims 18 and 19), WO 00/66558 (particularly claim 8), WO 00/66559 (particularly claim 9), WO 04/018425 and WO 04/026873.
Suitable anti -inflammatory drugs include steroids, in particular, glucocorticosteroids, such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate, or steroids described in WO 02/88167, WO 02/12266, WO 02/100879, WO 02/00679 (especially those of Examples 3, 11 , 14, 17, 19, 26, 34, 37, 39, 51, 60, 67, 72, 73, 90, 99 and 101 ), WO 03/35668, WO 03/48181 , WO 03/62259, WO 03/64445, WO 03/72592, WO 04/39827 and WO 04/66920; non-steroidal glucocorticoid receptor agonists, such as those described in DE 10261874, WO 00/00531 , WO 02/10143, WO 03/82280, WO 03/82787, WO 03/86294, WO 03/104195, WO 03/101932, WO 04/05229, WO 04/18429, WO 04/19935 and WO 04/26248; LTD4 antagonists, such as montelukast and zafirlukast; PDE4 inhibitors, such as cilomilast (Ariflo® GlaxoSmithKline), Roflumilast (Byk Gulden),V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Arofylline (Almirall Prodesfarma), PD 189659/PD168787 (Parke -Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SeICID(TM) CC-10004 (Celgene), VM554/UM565 (Vernalis), T440 (Tanabe), KW4490 (Kyowa Hakko Kogyo), and those disclosed in WO 92/19594, WO 93/19749, WO 93/19750, WO 93/19751, WO 98/18796, WO 99/16766, WO 01/13953, WO 03/104204, WO 03/104205, WO 03/39544, WO 04/000814, WO 04/000839, WO 04/005258, WO 04/018450, WO 04/018451, WO 04/018457. WO 04/018465, WO 04/018431, WO 04/018449, WO 04/018450, WO 04/018451, WO04/018457, WO 04/018465, WO 04/019944, WO 04/019945, WO 04/045607 and WO 04/037805; adenosine A2B receptor antagonists such as those described in WO 02/42298; and beta -2 adrenoceptor agonists, such as albuterol (salbutamol), metaproterenol, terbutaline, salmeterol fenoterol, procaterol and especially, formoterol, carmoterol and pharmaceutically acceptable salts thereof, and compounds (in free or salt or solvate form) of formula (I) of WO 0075114, which document is incorporated herein by reference, preferably compounds of the Examples thereof, especially a compound of formula
Figure imgf000020_0001
corresponding to indacaterol and pharmaceutically acceptable salts thereof, as well as compounds (in free or salt or solvate form) of formula (I) of WO 04/16601, and also compounds of EP 1440966, JP 05025045, WO 93/18007, WO 99/64035,
USP 2002/0055651 , WO 01/42193, WO 01/83462, WO 02/66422, WO 02/70490,
WO 02/76933, WO 03/24439, WO 03/42160, WO 03/42164, WO 03/72539, WO 03/91204,
WO 03/99764, WO 04/16578, WO 04/22547, WO 04/32921 , WO 04/33412, WO 04/37768,
WO 04/37773, WO 04/37807, WO 04/39762, WO 04/39766, WO 04/45618, WO 04/46083,
WO 04/80964, WO 04/108765 and WO 04/108676.
Suitable bronchodilatory drugs include anticholinergic or antimuscarinic agents, in particular, ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate, but also those described in EP 424021, USP 3,714,357, USP 5,171 ,744, WO 01/04118, WO 02/00652, WO 02/51841 , WO 02/53564, WO 03/00840, WO 03/33495, WO 03/53966, WO 03/87094, WO 04/018422 and WO 04/05285.
Suitable dual anti -inflammatory and bronchodilatory drugs include dual beta-2 adrenoceptor agonist/muscarinic antagonists such as those disclosed in USP 2004/0167167, WO 04/74246 and WO 04/74812.
Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine, as well as those disclosed in JP 2004107299, WO 03/099807 and WO 04/026841.
Other useful combinations of agents of the invention with anti-inflammatory drugs are those with antagonists of chemokine receptors, e.g., CCR-1 , CCR-2, CCR -3, CCR-4, CCR-5, CCR-6, CCR -7, CCR-8, CCR-9 and CCR10, CXCR1 , CXCR2, CXCR3. CXCR4, CXCR5, particularly CCR-5 antagonists, such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D; Takeda antagonists, such as Λ/-[[4-QI6,7-dihydro-2-(4- methylphenyl)-5/-/-benzo-cyclohepten-8-yl]carbonyrjamino]phenyr|-methyl]tetrahydro-Λ/,Λ/- dimethyl-2/-/-pyran-4-amin-ium chloride (TAK-770), and CCR-5 antagonists described in USP 6,166 J037 (particularly claims 18 and 19), WO 00/66558 (particularly claim 8), WO 00/66559 (particularly claim 9), WO 04/018425 and WO 04/026873.
In accordance with the foregoing, the invention also provides a method for the treatment of a condition responsive to blockade of the epithelial sodium channel, e.g., diseases associated with the regulation of fluid volumes across epithelial membranes, pa rticularly an obstructive airways disease, which comprises administering to a subject, particularly a human subject, in need thereof a compound of formula (I), in free form or in the form of a pharmaceutically acceptable salt. In another aspect the invention provides a compound of formula (I), in free form or in the form of a pharmaceutically acceptable salt, for use in the manufacture of a medicament for the treatment of a condition responsive to blockade of the epithelial sodium channel, particularly anobstructive airways disease, e.g., Cystic Fibrosis and COPD.
The agents of the invention may be administered by any appropriate route, e.g. orally, e.g., in the form of a tablet or capsule; parenterally, e.g., intravenously; by inhalation, e.g., in the treatment of an obstructive airways disease; intranasally, e.g., in the treatment of allergic rhinitis; topically to the skin; or rectally. In a further aspect, the invention also provides a pharmaceutical composition comprising a compound of formula (I), in free form or in the form of a pharmaceutically acceptable salt, optionally together with a pharmaceutically acceptable diluent or carrier therefor. The composition may contain a co-therapeutic agent, such as an antiinflammatory, broncho-dilatory, antihistamine or anti -tussive drug as hereinbefore described. Such compositions may be prepared using conventional diluents or excipients and techniques known in the galenic art. Thus oral dosage forms may include tablets and capsules. Formulations for topical administration may take the form of creams, ointments, gels or transdermal delivery systems, e.g., patches. Compositions for inhalation may comprise aerosol or other atomizable formulations or dry powder formulations. When the composition comprises an aerosol formulation, it preferably contains, e.g, a hydro - fluoro -alkane (HFA) propellant, such as HFA134a or HFA227 or a mixture of these, and may contain one or more co -solvents known in the art, such as ethanol (up to 20% by weight), and/or one or more surfactants, such as oleic acid or sorbitan trioleate, and/or one or more bulking agents, such as lactose. When the composition comprises a dry powder formulation, it preferably contains, e.g., the compound of formula (I) having a particle diameter up to 10 microns, optionally together with a diluent or carrier, such as lactose, of the desired particle size distribution and a compound that helps to protect against product performance deterioration due to moisture, e.g, magnesium stearate. When the composition comprises a nebulised formulation, it preferably contains, e.g, the compound of formula (I) either dissolved, or suspended, in a vehicle containing water, a co -solvent, such as ethanol or propylene glycol and a stabilizer, which may be a surfactant.
The invention includes:
(a) a compound of formula (I) in inhalable form, e.g., in an aerosol or other atomisable composition or in inhalable particulate, e.g., micronised form;
(b) an inhalable medicament comprising a compound of formula (I) in inhalable form;
(c) a pharmaceutical product comprising a compound of formula (I) in inhalable form in association with an inhalation device; and
(d) an inhalation device containing a compound of formula I in inhalable form.
Dosages of compounds of formula (0 employed in practising the present invention will of course vary depending, e.g., on the particular condition to be treated, the effect desired and the mode of administration. In general, suitable daily dosages for administration by inhalation are of the order of 0.005-10 mg, while for oral administration suitable daily doses are of the order of 0.05 -100 mg.
Pharmaceutical Use and Assay
Compounds of formula (I) and their pharmaceutically acceptable salts, hereinafter referred to alternatively as 'agents of the invention", are useful as pharmaceuticals. In particular, the compounds have good ENaC blocker activity and may be tested in the following assays. CeII culture
Human Bronchial Epithelial cells (HBECs) (Cambrex) were cultured under air-liquid interfaoe conditions to provide a well differentiated mucociliary phenotype.
HBECs were cultured using a modification of the method described by Gray and colleagues (Gray et al., 1996). Cells were seeded in plastic T -162 flasks and were grown in bronchial epithelial cell growth medium (BEGM; Cambrex) supplemented with bovine pituitary extract (52 μg/mL), hydrocortisone (0.5 μg/mL), human recombinant epidermal growth factor (0.5 ng/mL), epinephrine (0.5 μg/mL), transferrin (10ug/mL), insulin (5μg/ml_), retinoic acid (0.1 μg/mL), triiodothyronine (6.5 μg/mL), gentamycin (50 μg/mL) and amphotericin B (50 ng/mL). Medium was changed every 48 hours until cells were 90% confluent. Cells were then passaged and seeded (8.25 x 105 cells/insert) on polycarbonate Snapwell inserts (Costar) in differentiation media containing 50% DMEM in BEGM with the same supplements as above but without triiodothyronine and a final retinoic acid concentration of 50 nM (all- trans retinoic acid). Cells were maintained submerged for the first 7 days in culture, after which time they were exposed to an apical air interface for the remainder of the culture period. At this time, media was changed to DMEM:F12 media containing 2% v/v Ultroser G for the remainder of culture. Amphotericin B was removed from all media 3 feeds prior to use in the Ussing Chambers. Cells were used between days 7 and 21 after establishment of the apical-air interface. At all stages of culture, cells were maintained at 37°C in 5% CO2 in an air incubator.
Short circuit current (ISC) measurements
Snapwell inserts were mounted in Vertical Diffusion Chambers (Costar) and were bathed with continuously gassed Ringer solution (5% CO2 in O2; pH 7.4) maintained at 37°C containing (in mM): 120 NaCI, 25 NaHCO3, 3.3 KH2PO4, 0.8 K2HPO* 1.2 CaCI2, 1.2 MgCI2, and 10 glucose. The solution osmolarity was between 280 and 300 mθsmol/kg H2O for all physiological salt solutions used. Cells were voltage clamped to 0 mV (model EVC4000; WPI). RT was measured by applying a 1- or 2-mV pulse at 30-s intervals and calculating RT by Ohm's law. Data were recorded using a PowerLab workstation (ADInstruments).
Test compounds were prepared as a 10 mM stock solution in DMSO (95%). Serial 3 -fold dilutions were freshly prepared in an appropriate vehicle (distilled H2O or Ringers solution). The initial concentration was added to the apical chamber as a 100Ox concentrate in 5 μL, resulting in a final 1x concentration the 5 mL volume of the Ussing chamber. Subsequent additions of compound were added in a 3.3 μL volume of the 100Ox serially diluted stock solution. At the completion of the concentration -response experiment, amiloride (10 μM) was added into the apical chamber to enable the total amiloride-sensitive current to be measured. An amiloride control IC50WaS established at the start of each experiment.
Results are expressed as the mean % inhibition of the amiloride-sensitive ISC. Concentration-response curves were plotted and IC50 values generated using GraphPad Prism 3.02. Cell inserts were typically run in duplicate and the IC a calculated on the mean % inhibition data.
Compounds of the Examples, herein below, generally have IC50 values in the data measurements described above below 10 μM. For example, the compounds of Examples 2, and 5 have IC50 values of 0.0057 and 0.0002 μM, respectively.
The invention is illustrated by the following Examples.
EXAMPLES
General Conditions
LCMS are recorded on an Agilent 1100 LC system with a Waters Xterra MS C184.6 x 100 5 μM column, eluting with 5-95% 10 mM aqueous ammonium bicarbonate in acetonitrile over 2.5 minutes, with negative ion electrospray ionization or 5 -95% water + 0.1% TFA in acetonitrile with positive ion electrospray ionization. [M+ H]+ and [M-H]" refer to monoisotopic molecular weights
DMF dimethylformamide
DMSO dimethyl sulfoxide
EfeN triethylamine
EtOAc ethyl acetate
HPLC high performance liquid chromatography
MeOH methanol
RT room temperature
TFA trifluoroacetic acid
HATU O-(7-azabenzotriazol-1 -ylJ-N.N.-N'.N'-tetramethyl-uronium hexafluorophophate
The following examples have been prepared using the process described herein .
Figure imgf000025_0001
Table 1
Figure imgf000026_0001
-Example 1 3,5 -Diamino-6-chloro-pyrazine-2<arboxylic acid ({4 -[N'-(3,5-diamino -6 - chloro-pyrazine-2 -carbonyl)-guanidino methyl] -piperidin-1-yl)-imino- methyl)-amide .
To a solution of 1-(3,5diamino-6-chloropyrazinoyl)-2-methyl-2-thioseuclourea (II) (100 mg, 0.26 mmol) dissolved in DMF (1 ml_) is added 4 -aminomethyl piperidine (14.8 mg, 0.13 mmol) and EyM (146 μL, 1.04 mmol). Stiπing is continued at RT for 18 hours. The product is purified by reverse phase column chromatography (0-100% acetonitrile gradient over 20 minutes and 0.05% TFA modifier in both aqueous and organic phases) to give the title product as the trifluoroace tate salt.
Examples 2-5 are prepared analogously using the appropriate starting compounds as Example 1. Example 6 N-[2-(Bis42-pj'-(3,5<liamino^^hloro-pyrazine-2-carbonyl) guanidino]- ethyl}-amino)-ethyl]-N'-(3,5-diamino-6-chloro -pyrazine-2-carbonyl)- guanidine
To a solution of 1-(3,5-diamino-6-chloropyrazinoyl)-2H7iethyl-2-thioseudourea (II) (1 g, 2.58 mmol) dissolved in DMF (5 mL) is added tris(2-aminoethyl)amine (125.8 mg, 0.86 mmol) and EfeN (386 μL, 1.04 mmol). Stirring is continued at RT for 18 hours. The reaction is filtered in vacuoanά the filtrate concentrated and the product is purified by reverse phase column chromatography (0-100% acetonitrile gradient over 20 minutes to give the title product as the free base.
Further preferred compounds of formula (la)and are as shown in Table 2 below. The method of preparation being described thereinafter.
Figure imgf000027_0001
Table 2
Figure imgf000027_0002
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0002
Example 7 3^ -Diamino-€-chloro-pyrazine-2-carboxylic acid 1-amino-1 -{4-[N'-(3,5- diamino-6-chloro -pyrazine-2-carbonyl)-guanidino]-piperidin-1-yi}«meth- (E)-ylideneamide trifluoroacetate
S/ep ϊ;
Figure imgf000030_0001
Piperidin-4-ylamine (5.0 mg, 0.05 mmol) is treated with a solution of Intermediate A (0.06 g, 0.16 mmol) in DMF (1.0 mL) followed by EtJM (25.3 mg, 0.25 mmol) and the reaction mixture is stirred at RT overnight. Aminomethylpolystyrene and macroporous isocyanate (scavenger resins) are added and the mixture is allowed to shake at RT overnight. The mixtures are filtered and concentrated in vacuo to afford the product.
Step 2: 3,5-Diamino-6-chloro-pyrazine-2-carboxylic add 1-amino-1 -(^-[N'-β.S-diamino-θ- chloro-pyrazine-2-carbonyl)-guanidino]-piperidin-1-yl}-meth-(E)-ylideneamide trifluoroacetate
Example 7, Step 1 (0.05 mmol) is treated with 10% TFA in DCM (0.9 mL) and allowed to stand at RT for 1 hour. The solvent is removed in vacuo and purification of the crude product by preparative HPLC eluting with 10-100% MeCN in water (0.1 % TFA) affords the title compound.
Examples 8-15
These examples namely,
N^S.S-Diamino-θ-chloro-pyrazine^-carbonyO-NHS-lN'-tS.S-diamino-β-chloro-pyrazin^- carbonylJ-guanidinomethylJ-cyclohexylmethyO-guanidine trifluoroacetate (Example 8),
N^S.S-Diamino-e-chloro-pyrazine^-carbonylJ-N'^R.SSJ-δ-tN'^a.δ-diamino-e-chloro- pyrazine -2-carbonyl)-guanidinomethyl]-[1 ,4]dioxan -2 -ylmethyl}-guanidine trifluoroacetate (Example 9),
N,N'-Bis-{2-[N-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-guanidino]-ethyl}-2,3-dihydroxy- terephthalamide trifluoroacetate (Example 10),
N-(3,5-Diamino -6-chloro-pyrazine-2-carbonyl)-N -β-(4-{3-[N'-(3,5 -diamino-6-chlono -pyrazine- 2-carbonyl)-guanidino]-propoxy}-phenoxy)-propyl]-guanidine trifluoroacetate (Example 11 ),
N-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-N-P-(4-{3-[N'-(3,5-diamino-6-chloroi3yrazine- 2-carbonyl)-guanidino]-propyl}-piperazin-1-yl)-propyl]-guanidine trifluoroacetate (Example 12),
N-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-N'-[5-(5-{5-[N'-(3,5-diamino-6-chloro -pyrazine- 2-carbonyl)-guanidino]-pentyl}-pyrazin-2-yl)-pentyl]-guanidine trifluoroacetate (Example 13),
N^S.S-Diamino-e-chloro-pyrazine^-carbonyO-N'-p-tθ-iS-INXS.S-diamino-θ-chloro -pyrazine- 2-carbonyl)-guanidino]-propyl}-2,4,8,10-tetraoxa -spiro[5.5]undeo-3-yl)-propyl]-guanidine trifluoroacetate (Example 14) and N-<3-{Benzyl-[3-(benzyl-{3-[N'-(3,5-diamino-6-chloro-pyrazine-2-caιt>onyl)-guanidino]-propyl}- annino>propylJ-amino}-propyl)-NI-(3,5-diamino-6-chloro-pyrazine-2-carbonyl>-guanicline trifluoroacetate (Example 15), are prepared analogously to Example 7 with the appropriate diamine.
Examples 16-19
These compounds namely,
3,5-Diaminc>-6-chloro-pyrazine-2-cait>oxylic acid 1 -amino-1-{(R>3-[Nl-(3,5-diamino-6-chloro- pyrazine -2-carbonyl)-guanidino]-pyrrolidin-1 -yl}-meth-(E)-ylideneamide trifluoroacetate (Example 16),
3,5 -Diaminc>-6-chloro-pyrazine-2-carboxylic acid 1 -amino-1-{(S)-3-[N'-(3,5-diamino-6-chloro- pyrazine-2-carbonyl)-guanidino]-pyrrolidin-1-yl}-meth-(E)-ylideneamide trifluoroacetate (Example 17),
N-(3,5-Diamino-6-chloroi3yrazine-2-carbonyl)-N'-{4-[N1-(3,5-diamino-6-chloro-pyrazine-2- carbonyl>guanidino]-cyclohexyl}-guanidine trifluoroacetate (Example 18) and
N-(3,5-Diamino-6-chloroi3yrazine-2-carbony!)-N1-{4-tN'-(3,5-diamino-6-chloro-pyrazine-2- carbonyl)-guanidinomethyl]-cyclohexyl}-guanidine trifluoroacetate (Example 19), are prepared analogously to Example 7 with the appropriate diamine with the exception that mercury dichloride (2 eq) in DMF is added to the reaction mixture. Reaction byproducts are removed during purification by addition of scavenger resins, such as aminomethylpolystyrene, macroporous isocyanate and solid supported silica 1-propanethiol.
Example 20 N-IS-fBis-β-IN'-β.S -diamino-β-chloro-pyrazine^ -carbonyl)-guanidino]- propyl}-amino)^3ropyl]-N'-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)- guanidine trifluoroacetate
This compound is prepared from Intermediate A (3 eq) analogously to Example 7 by replacing piperidin4-ylamine with tris (2-aminoethyl)amine.
Example 21 N,N'-Bis-{4-[N'-(3,5-diamino-€-chloro-pyrazine-2-carbonyl)-guanidino]- butyl}-terephthalamide bromide
This compound is prepared analogously to Example 1 by replacing 1 -(3,5-diamino-6-chloro- pyrazine-2-carbonyl)-2-methyl-isothiourea hydroiodide with Intermediate A. The boc- protected intermediate that is formed is deprotected using 33% HBr in acetic acid. Reaction by-products are removed during purification by addition of scavenger resins such as aminomethylpolystyrene and macroporous isocyanate.
Example 22 N-{4-[N'-(3,5 -Diamino-6-chloro-pyrazine-2-carbonyl)-guanidino]-butyl}-2- [4-({4-[Nf-(3,5-diamino-6-chloro -pyrazine-2-carbonyl)-guanidino> butylcarbamoyl}-methyl)-phenyl]-acetamide trifluoroacetate
Step 1: Preparation of following compound
Figure imgf000033_0001
Asolution of 1,4-phenylenediacetic acid (24 mg, 0.125 mmol) in DMF (0.75 mL) and Et3N (0.2 mL) is treated with HATU (95 mg, 0.25 mmol) and stirred at RT for 30 minutes. To this mixture is added Intermediate B (0.1 g, 0.25 mmol) and stirring continued for a further 30 minutes. The reaction mixture is passed through a 1 g AL-B Solid Phase Extraction cartridge, eluting with DMF (1.5 mL). The solvent is removed in vacuo and recrystallisation of the crude residue from MeOH affords the product. [M+H]+ 959.74.
Step 2: N-{4 -[N -(3,5 -Diamino -θ-chloro-pyrazine^-carbonyO-guanidinol-butyl}^ -{4 -((4-[N1- (3,5-diamino-6-chloro-pyrazine-2-carbonyl)-guanidino]*utylcarbamoyl}-methyl)- phenylj-acetamide trifluoroacetate
Example 22, Step 1 (20 mg, 0.021 mmol) is treated with 10% TFA in DCM (2 mL) and allowed to stand at RT overnight. The solvent is removed in vacuo and purification of the crude product by preparative HPLC eluting with 10-100% MeCN in water (0.1% TFA) affords the title compound.
Example 23 1 -{4-[N'-(3,5-Diamino-6<hloro-pyrazine-2-carbonyl)-guanidino]-butyl)-3- [4-(3-{4-[N'-(3,5 -diamino -6-chloro -pyrazine -2-carbonyl)-guanidino]-butyl}- ureido)-butyl]-urea
A solution of Intermediate B (0.1 g, 0.25 mmol) in DMF (1 mL) is treated with 1,4-diisocyanatobutane (17.5 mg, 0.125 mmol) and stirred at RT over night. The reaction mixture is treated with 0.1 g aminomethylpolystyrene and (0.1 g) macroporous isocyanate (scavenger resins) and stirred at RT for 3 days. The mixture is filtered and purification by preparative HPLC affords the title compound. [M+H]* 741.34
Example 24 N-(3,5-Diamino-6-chloro -pyrazine-2-carbonyl>-N45-(4-{5-[N>-(3,5-diamino- 6<hloro-pyrazine-2-carbonyl)-guanidino}-pentyr}-piperazin -1 -yl)-pentyl]- guanidine
5-{4-{5-Amino-pentyl>-piperazin-1 -yl]-pentylamine trifluoroacetate (Intermediate P) (172 mg, 0.24 mmol) is added to a stirring solution of 1 -(3,5-diamino-6-chloro -pyrazine-2-carbonyl)-2- methyHsothiourea hydroiodide (93 mg, 0.48 mmol) in DMF (1 mL). The resulting mixture is heated to 500C for 8 hours and then allowed to cool to RT . The reaction mixture is quenched with 5% citric acid solution and addition of DCM results in the formation of a gum. The gum is isolated and dissolved in MeOH (2 mL) The solution is passed through a "capture release" SCX-2 cartridge eluting with 1 N ammonia in MeOH followed by 1 :1 MeOH:ammonia solution to afford the title compound.
Yet further preferred compounds of the present invention include compounds of formula(lb) and are as shown in Table 3 below. The method of preparation being described thereinafter.
Figure imgf000034_0001
=1-3
Table 3
Figure imgf000034_0002
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0002
Yet further preferred compounds of the present invention are shown in Table4 below. The method of preparation being described thereinafter.
Table 4
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Yet further preferred compounds of the present invention include compounds of formula (Ic) and are as shown in Table 5 below. The method of preparation being described thereinafter.
Figure imgf000086_0001
Table 5
Figure imgf000086_0002
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
The examples shown in Tables 3-5 are prepared according to the schemes shown below: Scheme 3
Figure imgf000092_0001
The preparations of the intermediates shown in the schemes are described in the Intermediates section.
Y1A Y2 may be varied utilising mono protected diamines and the Intermediate 2. This is illustrated in the scheme above. Where P1 and P2 represent different standard amine protecting groups, e.g., Boc, CBz, acetate and deprotection is by standard means. Where J represents a group capable of reacting with amines, e.g., halogen, carboxylic acid, isocyanate, sulfonyl chlorides, aldehydes and ketones, methanesulfonate. X represents a halogen, OH, an ester or an activated ester species derived from the use of coupling agents, e.g., EDCI. Where these reagents are unavailable commercially they can be synthesized by general methods known in the art.
Scheme 4
Figure imgf000094_0001
Y1AY2 may be varied utilizing monoamines and the Intermediate 2. J represents a group capable of reacting with amines, e.g., halogen, carboxylic acid.
The examples shown in Tables 3-5 are prepared according to Schemes 3 and 4 using the routes assigned in the table which are described hereinafter with the appropriate Intermediates G, H or K. Route 1
The di-acid chloride or tri-aάd chloride (1 eq) is added to a stirred solution of Intermediate H (2 eq) and Et3N (3 eq) in DMF (10 vol). Upon completion of the reaction the solution is quenched with water and the product (Intermediate I) isolated by filtration.
Route 2
EDCI (1 eq) is added to a stirred solution of the di-acid or tri-acid (1 eq) in DMF (10 vol). N-Ethyl-morpholine (3 eq) and Intermediate G (2 eq) are added and the reaction heated. Upon completion the reaction is quenched with NaHCO3solution and the product (Intermediate I) isolated by filtration.
Route 3
The di-isocyanate (1 eq) is added to a stirred solution of Intermediate H (2 eq) and EtJvJ (2.5 eq) in DCM (40 vol). The reaction is heated to reflux for 8 hours and the product (Intermediate I) isolated by filtration.
Route 4
Diphenylphosphorylazide (1 eq) is added to a stirred solution of the di-acid or tri-acid (1 eq) EfeN (2 eq ) and Intermediate H in DCM (40 vol). The reaction is heated to reflux for 8 hours. The product (Intermediate I) is isolated from the cooled reaction mixture by filtration.
Route 5
The diamine (1 eq) is added to a solution of bis-4-nitrophenyl carbonate (2 eq) in DMF. The reaction is left to stir for 1 -2 hours and Intermediate H is added and the reaction heated. Upon completion the reaction is quenched with water and the crude product (Intermediate I) isolated by filtration and purified by flash column chromatography.
Route 6
Intermediate K (2 eq) is added to a stirring solution of the diamine (1 eq) and triethylaine (2 eq) in DMF. Upon completion the reaction is quenched with water and the product (Intermediate L) isolated by filtration or extraction with DCM. Route7
The di-sulfonyl chloride (1 eq) is added to a stirring solution of Intermediate H (2 eq) in DMF. Upon completion the reaction is quenched with water the product (Intermediate I) isolated by filtration.
Note: Sulfonyl chlorides may be obbined by methods known in the literature, e.g.,
Org Synth, coll Vo1 1 , p.84 (1941 ) by reaction of sulfonic acids with a chlorinating agents, eg., SOCI2PCI5, POCI3
Examples of general methods for the deprotection of Intermediate I and Intermediate L to afford the Examples shown in Tables 3-5 are described in Methods 1 and 2:
Method 1
Intermediate I or Intermediate L (1 eq) is dissolved in 33% HBr/Acetic acid (50 vol) and heated at 50°C forδ hours. Upon cooling the product is isolated by filtration orby trituration with THF.
Method 2
Intermediate I or Intermediate L is suspended in DCM (20 vol) and TMSI (1.5 eq) added. The reaction was heated to 400C for 2 -4 hours and then quenched at RT with MeOH. The solution was left to stir at RT for 2-3 hours and the resulting precipitate is filtered and dried under vacuum to produce the product.
Route 8
Alternatively, the compounds shown in Tables 3-5 may be synthesized analogously to Example 1 using the appropriate diamine. The diamines (Intermediates O) are prepared from Intermediates N which may be synthesized using standard methods known in the literature from mono -protected amines via Steps 1a-e, described hereinafter in the Intermediates section. Deprotection by standard methods and concomitant reaction with 1 -(S.S-diamino-δ-chloro-pyrazine^-carbonyl^-methyl-isothiourea hydroiodide to produce compound P.
Figure imgf000097_0001
Compounds prepared from Intermediate M are prepared as follows:
Intermediate O (1 eq) is added to a stirring solution of 1 -(3J5-diamino-6-chloro-pyrazine-2- carbonyl)-2-fnethyl-isothiourea hydroiodide (2 eq) in DMF (10 vol). The resulting mixture is heated to 500C for 8 hours and then allowed to cool to RY. The reaction mixture is quenched with 5% citric acid solution and the crude product (P) isolated after addition of DCM. Purification by dissolution in MeOH and "capture release" utilizing SCX-2 cartridges affords the title compound upon elution with 1 N ammonia in MeOH. Compounds prepared from Mono -protected amines are prepared as follows:
Intermediate O (1 eq) is added to a stirring solution of 1 -(3,5-diamino-6-chloro-pyrazine-2- carbonyl)-2-methyl-isothiourea hydroiodide (2 eq) in DMF (10 vol). The resulting mixture is heated to 500C. Upon completion the reaction is quenched with water and the product (P) isolated by filtration.
Further preferred compounds of the present invention include compounds of formula (X) and are as shown in Table 6 below. These compounds are prepared in a multiparallel sequence of reactions as described belowin Scheme X. Methods of preparing such compounds are described hereinafter.
Figure imgf000098_0001
Figure imgf000098_0002
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Scheme X
ed
Figure imgf000106_0001
Step 1:
Reaction of Intermediate H with a Boc-protected amino acid (commercially available or prepared from a commercially-available amino acid) using a standard peptide coupling reagent gives the Intermediate X1.
Deprotection of Intermediate X1 with TFA gives Intermediate X2.
Step 3:
Reaction of Intermediate X2 with Intermediate H using a urea forming reagent (e.g., CDI, bis(p-nitrophenyl)carbonate) gives Intermediate X3.
Step 4:
Deprotection of Intermediate X3 with HBr/Acetic acid gives compounds of formula (X).
Further preferred compounds of the present invention include compounds of formula (Y) are as shown in Table 6 below. They are prepared in a multiparallel sequence of reactions as described below in Scheme Y:
Figure imgf000107_0001
Table 7
Figure imgf000107_0002
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0002
Scheme Y
Figure imgf000115_0001
Step 1:
Reaction of Intermediate F2 with a tertbutyl aminoalkane carboxylate (commercially- available or prepared from a commercially available amino acid) gives htermediate Y1.
Step 2:
Deprotection of htermediate Y1 with TFA gives htermediate Y2.
Step 3:
Reaction of Intermediate Y2 with Intermediate X2 using a peptide coupling reagent gives Intermediate Y3.
Deprotection of htermediate Y3 with HBr/Acetic acid gives the final compound Y.
Further preferred compounds of the present invention include compounds of formula Z and are as shown in Table 8 below. These compounds are prepared in a multiparallel sequence of reactions as described below in Scheme Z. Methods of preparing such compounds are described hereinafter.
Figure imgf000116_0001
Table 8
Figure imgf000116_0002
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0002
Scheme Z
Figure imgf000124_0001
Stepi:
Reaction of Intermediate H with the appropriate isocyanate [prepared according to JOC, Vol. 68, No. 19, p. 7274 (2003)] gives Intermediate Z1.
Step 2:
Removal of the protecting group from Intermediate Z1 with piperidine gives htermediateZ2.
Step 3:
Reaction of Intermediate Z2 with Intermediate H using a urea forming reagent (e .g. CDI, bis(p-nitrophenyl)carbonate) gives the Intermediate Z3.
Step 4:
Deprotection of htermediate Z3 with HBr/Acetic acid gives the final compound Z.
Yet further preferred compounds of the present invention include compounds of formula (T) and are as shown in Table 9 below. Methods of preparing such compounds are described hereinafter.
Figure imgf000125_0001
Table 9
Figure imgf000125_0002
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Example 857
Intermediate R (15 mg, 16 μmol) is dissolved in (0.75 ml) hydrogen bromide (33% w/w solution in acetic acid) and stirred at RT overnight. The title compound is obtained after purification by reverse phase column chromatography (Isolute™ C18, 0-30% acetonitrile in water -0.1% TFA). (MH+ 678.28).
Examples 857-897
These examples are prepared as follows:
A suspension of Intermediate A and the corresponding Intermediate S in dry DMF is treated with TEA and heated to 65°C for 96 hours. The reaction mixture is cooled to RT and the product is purified by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water - 0.1 % TFA). The fractions comprising the product are concentrated in vacuo. The resulting solid is dissolved in 4 M HCI (in dioxane) and stirred overnight. The reaction mixture is reduce in vacuo to afford the title compound.
Yet further preferred compounds of the present invention are shown in Table 10 below. The method of preparation being described thereinbefore . TablelO
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Preparation of Intermediates
Intermediate A
Figure imgf000131_0002
A stirred suspension comprising 1 -(3,5<liamino-6-chlorc^pyrazine-2^ιt>onyl)-2-methyl- isothiourea hydroiodide (11.4 g, 29 mmol), 4-dimethylaminopyridine (0.87 g, 7 mmol), EUM (20 mL) in THF (400 mL) is treated with di-tert butyl dicarbonate (12 g, 55 mmol) in THF (100 mL) in one portion. The resulting mixture is stirred at RT overnight and then concentrated in vacuo. The crude product is partitioned between EtOAc (50 mL) and water (50 mL) and stirred at RT for 10 minutes. The suspension is filtered, washed with water (5 mL), EtOAc (20 mL) and dried under vacuum at 40°C to afford the title compound. (M+H]+ 361.05
Intermediate B
Figure imgf000132_0001
A solution comprising Intermediate A (6.55 g, 18.2 mmol), N-Z-1,4-diaminobutane hydrochloride (4.7 g, 18.2 mmol) and Et3N (20 mL) in DMF (300 mL) is stirred at RT overnight. The solvent is removed in vacuo and the crude residue is dissolved in EtOAc (700 mL) and washed with water (2 x 200 mL), brine (100 mL), dried (MgSO4) and concentrated in vacuo. Purification by recrystallisation of the product from EtOAc (400 mL) affords the product as a yellow solid.
A suspension (6.7 g, 12.5 mmol) in MeOH (500 mL) is warmed to 400C to form a turbid solution. The solution is placed under an atmosphere of argon and treated with 10% palladium on carbon. The mixture is then placed under an atmosphere of hydrogen overnight and then filtered. The filtrate is concentrated in vacuo and the resulting solid is suspended in EtOAc (20 mL) and filtered to afford the title compound as a green solid. [M+H]+ 401.34 lntermediate C N,N'-Bis-(4-amino-butyl)-terephthalamide
Step 1: {4-[4-(4-tert-Butoxycarbonylamino-butylcart)aπnoyl)-benzoylamino]-butyl}-carbamic acid tert-butyl ester
A solution of terephthaloyl chloride (5.0 g, 0.0246 mol) in dry DMF (100 mL) is treated with N-Boc-1 ,4-diaminobutane (9.418 mL, 0.0493 mol) and stirred at RT for 30 minutes. Et3N (10.298 mL, 0.0739 mol) is added and stirring continues overnight. The resulting mixture is diluted with deionised water (100 mL) and after stirring at RT for 30 minutes, the mixture is filtered. The filter cake is washed with water and dried in vacuo (400C) to afford the title compound.
Step 2: N,N'-Bis-(4-amino-butyl)-terephthalamide
{4-[4-(4-tert-Butoxycarbonylamino-butylcarbamoyl)-benzoylamino}butyl}-carbamic acid tert- butyl ester (0.49 g) is treated with neat TFA (5 mL) and allowed to stand at RT overnight. The acid is removed in vacuo to afford the title compound as a ye How solid. Alternatively, deprotection can be carried out using 33% HBr is acetic acid. [M+H]+ 307.22
Intermediate D N*1 *-{3 -[(3-Amino-propyl)-benzyl-amino] -propyl}-N*1 *-benzyl- propane-1 ,3 -diamine dihydrochloride
Step 1: 3-(BenzyH3-{benzyl-(2-cyano -ethyl)-amino]-propyl}-amino)-propionitrile
A suspension comprising N,N*-dibenzyl-propane -1,3 -diamine dihydrochloride (31 g, 95 mmol) and sodium acetate (15.6 g, 190 mmol) in MeOH (315 mL) is treated with acetic acid (5.7 mL) followed by dropwise addition of acrylonitrile over 20 minutes. The resulting suspension is stirred at 700C for 10 hours and then at RT for 10 hours. The suspension is removed by filtration and washed with a small volume of MeOH. The filtrate is concentrated in vacuo and the crude residue is dissolved in ether and washed with sodium carbonate solution. The organic portion is dried (MgSO4) and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 1:1 hexane:EtOAc affords the title compound as a yellow oil.
Step 2: N*1 *-{3-f(3-Aminαpropyl>t»enzyl-aminoJ-propyl}-N*1 *-benzyl-propane-1 ,3- diamine dihydrochloride
A solution of 3-(benzyl-{3-rj3enzyl-(2-cyano-ethyl>-amino]-propyr}-amino)-propionitrile (26.6 g, 73.8 mmol)) in EtOH (500 mL) is treated with Raney Nickel (10 g) and placed under an atmosphere of hydrogen at RT for 20 hours. The reaction mixture is filtered and the filtrate is concentrated in vacuo. The crude residue is dissolved in EtOH (100 mL) and treated with 1.8 M ethanolic HCI. The resulting suspension is cooled to 00C and collected by filtration. The solid is washed with cold EtOH/ether and dried under vacuum to afford the title compound.
Intermediate E N,N'-Bis-(2-amino-ethyl)-2,3-dihydroxy-terephthalamide dihydrochloride
A solution of 2,3 -dihydroxy-terephthalic acid dimethyl ester (2.26 g, 10 mmol) in ethylenediamine (50 mL) is heated at reflux overnight. After cooling to RT, the solvent is removed in vacuo and the crude residue is dissolved in MeOH (50 mL). The solution is cooled with an ice -bath and HCI gas is passed through the solution until the pH is adjusted to pH7. The resulting suspension is filtered and washed with cold MeOH to afford the title compound.
Intermediate F
To a stirred solution of 1 -(S.δ-diamino-β-chloro-pyrazine^-carbonyl^-methyl-isothiourea hydroiodide (50 g, 0.129 mol) in dry THF (1 L) is added Et^ (18 mL, 0.129 mol), followed by N-(benzyloxycarbonyloxy)-succinimide (32.1 g, 0.129 mol). The reaction mixture is then heated to reflux (66°C) for 6 hours. The reaction is allowed to cool to RT, then concentrated in vacuo to a yellow solid. The crude is suspended in EtOAc (500 mL) and water (500 mL) and is triturated vigorously for a period of 30 minutes. The resulting suspension is filtered and dried in a vacuum oven (40°C) over P2O5 to give the product as a pale yellow solid. A second crop (10 g) was obtained from then EtOAc layer after it was cooled (4 °C} over a 48 hour period. (MhT; 394.77 and 396.79 )
Intermediate G
Figure imgf000134_0001
Intermediate F (1 eq) is added to a stirring solution of the appropriate mono-Boc protected amine (e.g., propane diamine, butane diamine or pentane diamine) (1 eq) in THF (20 vol). The reaction is heated at 600C for 8 hours. The crude product is isolated by filtration from the cooled reaction mixture and purified by flash column chromatography eluting with (9:1 DCM:MeOH). lntermediate H
Figure imgf000135_0001
Intermediate G is deprotected using a 1 :1 solution of TFA and DCM (20 vol). Neutralisation with NaHCO3 solution and extraction with DCM yields the desired product upon concentration in vacuo .
Intermediate J
Amino propanol or amino butanol or amino pentanol (1 eq) is added to a stirring solution of Intermediate F (1 eq) in THF (10 vol). On completion the reaction mixture is diluted with EtOAc and washed with 5% citric acid solution, brine and water. The organic phase is concentrated in vacuo and the resulting material is used crude or purified using flash column chromatography.
Intermediate K
Methane sulfonyl chloride (1 eq) is added to a stirring solution of Intermediate J (1 eq) and E^N (3 eq) in DCM. Upon completion the reaction is quenched with NaHCO3 solution. The DCM layer is dried over magnesium sulfate and concentrated in vacuo to produce a crude residue which is purified by flash column chromatography.
Intermediate M
Methane sulfonyl chloride (1 eq) was added to a stirring solution of N-Boc propan-1 -ol, N-Boc butan-1-ol or N-Boc pentan-1-ol (1 eq) and EtJM (3 eq) in DCM. Upon completion the reaction was quenched with NaHCO3 solution. The DCM layer was dried over magnesium sulfate and concentrated in vacuo to produce a crude residue which was used crude or purified by flash column chromatography. lntermediate N
The di-acid chloride or tri-aάd chloride (1 eq) was added to a stirred solution of N-Boc propyldiamine, N-Boc butyldiamine or N-Boc pentyldiamine (2 eq) and Et3NI (3 eq) in DMF (10 vol). Upon completion of the reaction the solution was quenched with aqueous NaHCO3 and the product (Intermediate Na) extracted with DCM and concentrated in vacuo.
Step 1b
EDCI (1 eq) was added to a stirred solution of the di-acid or tri-acid (1 eq) in DMF (10 vol). N-ethyl-morpholine (3 eq) and N-Boc propyldiamine, N-Boc butyldiamine or N-Boc pentyldiamine (2 eq) were added and the reaction heated. Upon completion the reaction was quenched with NaHCO3solution and the product (Intermediate Nb) extracted with DCM and concentrated in vacuo.
The di-isocyanate (1 eq) was added to a stirred solution of N-Boc propyldiamine, N-Boc butyldiamine or N-Boc pentyldiamine (1 eq) and Et3N (2.5 eq) in DCM (40 vol). The reaction was heated to reflux for 8 hours and the product (Intermediate Nc) isolated by filtration.
Steoid
Diphenylphosphorylazide (1 eq) was added to a stirred solution of the di-acid or tri-acid (1 eq), EyM (2 eq)and N-Boc propyldiamine, N-Boc butyldiamine or N-Boc pentyldiamine in DCM (40 vol). The reaction was heated to reflux for 8 hours. The product (Intermediate Nd) was isolated fro m the cooled reaction mixture by filtration or purified by flash column chromatography.
Step 1e
The diamine (1 eq) is added a solution of bis-4-nitrophenylcarbonate (2 eq) in DMF. The reaction is left to stir for 1 -2 hours and N-Boc propyldiamine, N-Boc butyldiamine or N-Boc pentyldiamine is added and the reaction heated . Upon completion the reaction is quenched with water and the crude product (Intermediate Ne) isolated by filtration and purified by flash column chromatography.
N-Boc propylamine methane sulfonate, N-Boc butylamine methane sulfonate or N-Boc pentylamine methane sulfonate (2 eq) is added to a stirring solution of the diamine (1 eq) and triethylaine (2 eq) in DMF. Upon completion the reaction is quenched with water and the product (Intermediate Ng) isolated by filtration or extraction with DCM or by flash column chromatography.
Intermediate N (prepared from Intermediate M)
The di-sulfonyl chloride (1 eq) is added to a stirring solution of Intermediate M (2 eq) in DMF. Upon completion the reaction was quenched with water the product (Intermediate N) isolated by filtration or by flash column chromatography.
Intermediate O
Intermediate N is dissolved in DCM (5 vol) and TFA (2-5 vol) is added. Upon completion the product (Intermediate O) is isolated by concentration and toluene azeotrope.
Intermediate P 5-[4-(5-Amino-pentyl)-piperazin-1 -yfj-pentylamine Step 1: (δ-Methanesulfonylamino-pentylVcarbamic acid tert-butyl ester
Methane sulfonyl chloride (0.4 mL, 5.3 mmol) is added to a stirring solution of Boc-amino pentanol (1.0 g, 4.9 mmol) and Et3N (1.68 mL, 15 mmol) in DCM (10 mL). The reaction is left to stir at RT for 1 hour and is then quenched with sodium hydrogen carbonate solution and the organic phase washed with 5% citric acid solu tion. The resulting organic phase is dried over magnesium sulphate and concentrated in vacuo to yield the title compound as a viscous yellow oil.
Step 2: {5-{4-(5-tert-Butoxycarbonylamino-pentyl)-piperazin-1-yl]-pentyl}-carbamic acid tert-butyl ester
(5-Methanesulfonylamino-pentyl)-carbamic acid tert-butyl ester (500 mg, 1.7 mmol) is dissolved in DMF(IO mL) and Et3N (0.286 mL, 2.6 mmol) and piperazine (73 mg, 0.85 mmol) added. The reaction was heated to 1000C for 4 hours and then quenched with water on cooling. The reaction mixture is extracted with DCM and the organic portion is concentrated in vacuo and dried under vacuum to afford the title compound as a solid.
Step 3: 5-[4-(5-Amino-pentyl)-piperazin-1 -yl]-pentylamine trifluoroacetate .
A solution of {δ-μ-p-tert-butoxycarbonylamino-pentylj-piperazin-i-yfj-pentylj-carbamic acid tert-butyl ester (329 mg, 0.72 mmol) in DCM (10 mL) is treated with trifluoracetic acid (1mL). The reaction was left to stir at RT for 4 days and then the solvent is removed n vacuo. The material was used crude and conversion was assumed quantitative to produce 5-{4-(5- amino-pentyl)-piperazin-1 -yl]-pentylamine.
Intermediate Q
Figure imgf000138_0001
2,4-Dichloro-1,3,5-triazine (15.5 mg, 010 mmol) is dissolved in N-methyl-2-pyσolidone (2 mL) and cooled to 00C. A solution of Intermediate H (90 mg, 0.21 mmol) in N-methyl-2- pyrrolidone (1 mL) is added to the reaction mixture and stirred over night at RT. The reaction mixture is purified by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water - 0.1% TFA). The acetonitrile is then removed from the clean fractions in vacuo and the resulting aqueous solution is partitioned between dichloromethane and NaHC03(aq> The solid that forms between the two layers is filtered off and dried in vacuo to yield the title compound. (MH+ 946.4)
Intermediates R
Figure imgf000138_0002
Intermediates R are prepared using the procedure of Rankovic, Zoran; Cai, Jiaqiang; Cumming, lain. Preparation o f 2 -cyano-1 ,3,5 -triazine-4,6-diamine derivatives for the treatment of osteoporosis and atherosclerosis. (WO 2005/011703 A1 , page 6 ). lntermediates S
Figure imgf000139_0001
These lntemriecliates are prepared by reacting Intermediates R with 2 equivalents of (4-amino-butyl)-carbamic acid tert-butyl ester at 600C for 1 hour in N-methyl-2-pyπOlidone followed by addition of 4 M HCI (in dioxane) and stirring overnight. Purification by conventional techniques afford the required triazine diamine product

Claims

CLΛIMS
1. A compound of formula (I)
Figure imgf000140_0004
or tautomers, or stereoisomers, or solvates, or pharmaceutically acceptable salts thereof, wherein
M, M , and M2 are independently
Figure imgf000140_0001
;
R1, R2, R3, and R4 a re independently selected from H, Ci-Cβ-alkyI, Ci-Cβ-alkyl-carboxy, CrCg-haloalkyl, CrC15-carbocyclic group, CrCβ-alkylcarbonyl, C1-C8- alkoxycarbonyl, a C6-C15-membered aromatic carbocyclic group, a4- to 14-membered heterocyclic group, a CrCβ-alkyl substituted by a 4- to 14-membered heterocyclic group, and a CrCβ-alkyl substituted by a Ce-C^membered aromatic carbocyclic group, or
R1 and R2 with the nitrogen atom to which they are attached form a CyC^-membered heterocyclic group optionally substituted by R14, or
R3 and R4 with the nitrogen atom to which they are attached form a C 3-C14-membered heterocyclic group optionally substituted by R14;
L, L1 and L2 are independently selected from:
Figure imgf000140_0002
and
Figure imgf000140_0003
R6, R5, R^1 R5" and R* are independently selected from H. C1-C8 alkyl, CrCβ-alkyl- carboxy, C-Cβ-alkyl-alkoxy.C-Cβ-haloalkyl, C3-C1s-carbocyclic group, CrC8- alkylcarbonyl, CrCβ-alkoxycarbonyl, nitro, cyano, a C6-C1s-membered aromatic carbocyclic group, a 4- to 14-membered heterocyclic group, a Ct-Cg-alkyl substituted by a 4- to 14-membered heterocyclic group, and a CrCβ-alkyl substituted by a Ce-C^membered aromatic carbocyclic group, or R5 with the nitrogen atom to which it is attached, together with A, forma 4 - to
14-membered heterocyclic group when X1 is Cσ-Cβ-alkylene, O, -NR7- or S, or
R53 with the nitrogen atom to which it is attached, together with A, form a 4- to 14-membered heterocyclic group when X2 is Cø-Cβ-alkylene, O, -NR7- or S, or
R5b with the nitrogen atom to which it is attached, together with A, form a 4- to 14-membered heterocyclic group when X is Co-Cβ-alkylene, O, -NR7- or S;
W, W1 and W2 are independently selected from Cσ-Cβ-alkylene;
X, X1 and X2 are independently selected from Co-Cg-alkylene, O, S, -NR7-, -NR7(C=O)-, -NR7(C=O)NR8-, -NR8SOr, -NR^SO2)NR8-, -NR7(C=O)O-, -O(C=O)-, -O(C=OP-, -0(C=O)NR7-, -(C=S)NR7-, -(C=NR7JNR8-, -(C=O)NR7-, -(C=O)O-, ^SO2)(Co-C8- alkylene)-, -(Sa)NR8- and -(SO2)NR7-Z-(SO2)NR8-;
Y, Y1 and Y2 are independently -Cø-Cβ-alkylene-; Z is CrGj-alkylene; where W, W1, W2, Y, Y1, Y2 and Z are optionally substituted by d-Cβ-alkyl, halogen, CrCβ-alkoxy, carboxy, C rCg-alkyl-carboxy, CrCβ-haloalkyl, C rCβ-haloalkoxy, C3-C15-carbocyclic group, C rCg-alkylcarbonyl, CrCg-alkoxycarbonyl, nitro, cyano, a C6-C15-membered aromatic carbocyclic group, a C^Ce-alkyl substituted by a C6-C15-membered aromatic carbocyclic group, a 4- to 14-membered heterocyclic group containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulphur, a CrCβ-alkyl substituted by a4-to 14-membered heterocyclic group containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulphur, and a CrCβ-alkyl substituted by a C6-C15-membered aromatic carbocyclic group;
A is selected from a C6-C15-membered aromatic carbocyclic group optionally substituted by -Y-X-W-NR5b-L-M, CrC1s-carbocyclic group optionally substituted by -Y-X-W- NR5b-L-M, a 4- to 14-membered heterocyclic group optionally substituted by -Y-X-W- NR5b-L-M, a heteroatom selected from nitrogen, oxygen, and sulphur, wherein the nitrogen can be substituted by -Y-X-W-NR^-L-M, a CrCg-alkyl optionally substituted by -Y-X-W-NR5b-L-M, with the proviso that when R5 and R5a does not form a 4-to 14- membered heterocyclic group with A, then A is not a CrC1s-aromatic carbocyclic group, O, C=O or a CrCβ-alkyl group when X1, X2, Y1 and Y2 are Cσ-Cβ-alkylene unless A is substituted by -Y-X-W-NR5b-L-M; R7, R8, R11and R'2, are independently selected from H1 d-C^alky! optionally substituted by CrCio-aralkyl, d-Cβ-haloalkyl and a 5- to 14-membered heterocyclic group; R7 and R8, independently, by way of a C rC4-alkyl group can form a bond with a carbon atom of group W, W ,, W2, Y, Y2, or Y2 to create a 5- b 14-membered heterocyclic group;
T is selected from H, halogen , d-Cβ-alkyl, C rCβ-haloalkyl, d-Cβ-haloalkoxy, C 3-C15- carbocyclic group, nitro, cyano, a Ce-ds-membered aromatic carbocyclic group, a and a C rCValkyl substituted by a Ce-C15-membered aromatic carbocyclic group; wherein each Cg-C1s-membered aromatic carbocyclic group and each 4 -to 14-membered heterocyclic group, unless otherwise specified is independently optionally substituted by one or more groups selected from OH, d-Cβ-alkoxy, C,-Cfralkyl, halogen, SO2NR11R12, hydroxyC-Cβ-alkoxy, optionally substituted by hydroxyl, (C0-C4- alkylene) CONR11R12, (Cσ-dralkylene) N=C(NR11R12)2, -0-(d-C4-alkylene)- N=C(NR11R12J2, -O-(CrC4-alkylene>CONR11R12, Ce-do-aralkoxy, CrC1(raralkyl. SH, S(C-Cralkylene), SOz fd-Ce-alkyleneJ SOfd-Cfralkylene), NR11R12, R15, a C1-C8- alkyl substituted by R15, R1β, a C-Cβ-alkyl substituted by R16, O(d-Cfralkylene)- NR11C(C=0)0-(Co-C4-alkylene)-R15 , cyano, oxo, carboxy, nitro, d-Cβ-alkylcarbonyl, hydiOxy-CrCralkyl, C rCβ-haloalkyl, amino-d-Cβ-alkyl, amino(hydroxy)d-C<ralkyl and C,-C8-alkoxy optionally substituted by aminocarbonyl, where R6 is a C6-C15- membered aromatic carbocyclic group, optionally substituted by OH, d-Cβ-alkoxy, d-Cβ-alkyl, halogen andd-Cβ-haloalkyl, R16 is a 3- to 14-membered heterocyclic group, optionally substituted by OH, C,-Cs-alkoxy, C rCβ-alkyl, halogen and C1-C8- haloalkyl, and wherein each alkylene group, unless otherwise specified, is optionally substituted by d-Cg-alkyl, halogen, d-Cβ-alkoxy, carboxy, d-Ce-alkyl-carboxy, C rC8-haloalkyl, CrCβ-haloalkoxy, C 3-C15-carbocyclic group, CrC8-alkylcarbonyl, C rCr alkoxycarbonyl, nitro, cyano, R15, a CrCβ-alkyl substituted by R15, R16or a C1-Cr alkyl substituted by R1β; and
R14is selected from H, halogen, C rCralkyl, OH, C6-C 15-membered aromatic carbocyclic group, C7-d4-aralkyl, and O-Cτ-Ci4-aralkyl.
2. A compound of formula (I) according to claim 1 , or tautomers, or stereoisomers, or pharmaceutically acceptable salts thereof, wherein M, M ( and M2 are independentl
Figure imgf000143_0001
R1, R2, R3, and R4 are independently selected from H, d-Cβ-alkyl, d-Cβ-alkyl-carboxy;
L, L1 and L2 are independently selected from: and ■
Figure imgf000143_0002
Figure imgf000143_0003
R5, R53 and R5b are independently selected from H, and d-Cβ-alkyl, or
R5 with the nitrogen atom to which it is attached, together with A, form a 4 - to
14-membered heterocyclic group when Xi is Co-Cβ-alkylene, O, -NR7-, or S, or
R5a with the nitrogen atom to which it is attached, together with A, form a 4- to 14- membered heterocyclic group when X2 is Cσ-Cβ-alkylene, O1 -NR7-, or S, or
R5bwith the nitrogen atom to which it is attached, together with A, form a 4- to 14-membered heterocyclic group when X is Cσ-Cβ-alkylene, O1 -NR7-, or S;
R6 is selected from H, and d-Cβ-alkyl;
W, W1 and W2 are selected from Co-Cβ-alkylene;
X, X1 and X2 are selected from Co-Cβ-alkylene, O, S, -NR7-, -NR7(C=0)-, -NR7(C=O)NR8-, -NR8SO2-, -NR7(SO2)NR8-. -NR7(C=O)O-, O(C=OV, -0(C=OP-, -0(C=O)NR7-, -(C=S)NR7-, -(C=NR7JNR8-, -(C=O)NR7-, -(C=O)O-, -(SO^Co-Cg-alkyleneK -(SO2)NR8- and -(SO2)NR7-Z-(SO2)NR8-;
Y1 Y1 and Y2 are -Co-Cβ-alkylene-;
Z is d-d-alkylene; where W, W1, W2, Y1 Y1, Y2, and Z are optionally substituted by d-Cβ-alkyl, halogen, d-Cβ-alkoxy, carboxy, C rCβ-alkyl-carboxy, d-Qrhaloalkyl, C rCg-haloalkoxy, d-ds-carbocyclic group, C rCβ-alkylcarbonyl, d-Cg-alkoxycarbonyl, nitro, cyano, a C6-C15-membered aromatic carbocyclic group, a d-Ce-alkyl substituted by a C6-C1 s-membered aromatic carbocyclic group, a 4- to 14-membered heterocyclic group containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulphur, a d-Cyalkyl substituted by a4-to 14-membered heterocyclic group containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulphur, and a d-Cβ-alkyl substituted by a C6-C1s-membered aromatic carbocyclic group; A is selected from a C<rC15-membered aromatic carbocyclic group, C3-C15-carbocyclic group, a 4- to 14-membered heterocyclic group, a heteoatom selected from nitrogen, oxygen, and sulphur, wherein the nitrogen can be substituted by -Y-X-W- NR5b-L-M, a C,-C8-alkyl optionally substituted by -Y-X-W-NR^-L-M, with the proviso that when R5 and R a does not form a 4 -to 14-membered heterocyclic group with A, then A is not a C6-C15-aromatic carbocyclic group, O, C=O or a d-Cβ-alkyl group when X1, X2, Y1 and Y2 are Co-Cβ-alkylene unless A is substituted by -Y-X-W-NR56- L-M;;
R7, R8, R11and R c, are independently selected from H, CVCe-alkyl optionally substituted by CrCM-aralkyl, C^-Cβ-haloalkyl, a 5- to 14-membered heterocyclic group, and R7 and R8, independently, by way of an CrC4-alkyl group can form a bond with a carbon atom of group W or Y creating a 5 - to 14-membered heterocyclic group; and
T is selected from H, halogen , d-Cβ-alkyl, C rCβ-haloalkyl, C-Cβ-haloalkoxy, C 3-C15- carbocyclic group, nitro, cyano, a C<rC15-membered aromatic carbocyclic group, and a CrCff-alkyl substituted by a Cg-C^membered aromatic carbocyclic group.
3. A compound of formula (I) according to claim 1 , or tautomers, or stereoisomers, or pharmaceutically acceptable salts thereof, wherein
M, M1 and M2 are
Figure imgf000144_0001
R1, R2, R3, R4, R5, R a and R6 are H;
L, L1 and L2 are independently selected from:
Figure imgf000144_0002
and
Figure imgf000144_0003
A is a C3-C15-carbocyclic group or A is a heteroatom selected from nitrogen, oxygen, and sulphur wherein said nitrogen is substituted by -Y-X-W-N R5b-L -M;
W, W1 and W2 are independently selected from Co-Cg-alkylene;
X, X, and X2 are independently Co-Gralkylene, -NR7-, -NR7(C=0)-, -NR7(C=O)NR7-, -NR8SO2-, -NR8CSO2)NR8-, -NR7(C=O)O-, O(C=O)-, -0(C=O)O-, -0(C=O)NR7-, -(C=S)NR7-, -(C=NR7)NR7-, -(C=O)NR7-, -(C=O)O-, -(SO^Co-CralkyleneK -(SO2)NR18-, -(SO2)NR "-Z-(SO2)NR8-, or R7and R8, independently, by way of a CrC4-alkyl group can form a bond with a carbon atom of group W or Y to create a 5 ■ to 14-membered heterocyclic group; R7 and R8 are independently selected from H, and CrCg-alkyl; Y1 Y, and Y2 are independently selected from -(Co-Cβ-alkylene)-; Z is C,-C2-alkylene; and T is a halogen .
4. A compound of formula (I) according to claim 1 , wherein the compound is of formula (Ia):
Figure imgf000145_0001
or tautomers, or stereoisomers, or pharmaceutically acceptable salts thereof, wherein
A2 is selected from:
Figure imgf000145_0002
Figure imgf000145_0003
Figure imgf000146_0001
5. A compound according to Claim 1 , substantially as herein described, with reference to any one of the Examples.
6. A compound according to any one of Claims 1-5 for use as a pharmaceutical.
7. Pharmaceutical compositions comprising a compound according to any one of Claims 1 -5.
8. The use of a compound according to any one of Claims 1 -5, in the manufacture of a medicament for treatment of a disease media ted by the blockade of an epithelial sodium channel.
9. The use of a compound according to any one of Claims 1 -4, in the manufacture of a medicament for treatment of an inflammatory or allergic condition, particularly an inflammatory or obstructive airways disease.
10. The use of a compound according to any of Claims 1 -4, in the manufacture of a medicament for the treatment of an inflammatory or allergic condition selected from cystic fibrosis, primary ciliary dyskinesia, chronic bronchitis, chronic obstructive pulmonary disease, asthma, respiratory tract infections, lung carcinoma, xerostomia, and keratoconjunctivitis sire.
11. A combination of a compound according to any one of Claims 1 -4 with an antiinflammatory, bronchodilatory, antihistamine or anti-tussive drug substance.
12. A process for the preparation of compounds of formula (I):
Figure imgf000147_0001
wherein
M1, M2, L1, L2, NR5, NR5a, W1, W2, X1, X2. Y1, Y2 and A are as defined hereinbefore, which comprises the steps of:
(i) reacting a compound of formula (K/):
wherein
Figure imgf000147_0003
M* is M1 or Ma
L* is L1 or L2; and
M1, M2, L1, L2 and T are as hereinbefore defined, with compounds of formula (V):
Figure imgf000147_0002
wherein R5, R53, W1, W2, X1, X2, Y1, Y2and A are hereinbefore defined, optionally in the presence of a base, e.g., an organic base; and in an organic solvent; e.g., a non-protic dipolar solvent; and
(ii) recovering the resultant compound of formula (I), in free or pharmaceutically acceptable salt form
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