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US20140051689A1 - Polycyclic Agents for the Treatment of Respiratory Syncytial Virus Infections - Google Patents

Polycyclic Agents for the Treatment of Respiratory Syncytial Virus Infections Download PDF

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Publication number
US20140051689A1
US20140051689A1 US14/062,780 US201314062780A US2014051689A1 US 20140051689 A1 US20140051689 A1 US 20140051689A1 US 201314062780 A US201314062780 A US 201314062780A US 2014051689 A1 US2014051689 A1 US 2014051689A1
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alkyl
optionally substituted
ring
phenyl
aryl
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US14/062,780
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Silas Bond
Vanessa Anne Sanford
John Nicholas Lambert
Chin Yu Lim
Alistair George Draffan
Roland Henry Nearn
Jeffrey Peter Mitchell
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Biota Scientific Management Pty Ltd
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Biota Scientific Management Pty Ltd
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Priority claimed from AU2003907196A external-priority patent/AU2003907196A0/en
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Priority to US14/062,780 priority Critical patent/US20140051689A1/en
Assigned to BIOTA SCIENTIFIC MANAGEMENT PTY LTD. reassignment BIOTA SCIENTIFIC MANAGEMENT PTY LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DRAFFAN, ALISTAIR GEORGE, LIM, CHIN YU, NEARN, ROLAND HENRY, SANFORD, VANESSA ANNE, BOND, SILAS, LAMBERT, JOHN NICHOLAS, MITCHELL, JEFFREY PETER
Publication of US20140051689A1 publication Critical patent/US20140051689A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61P31/12—Antivirals
    • 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
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to antiviral compounds, methods for their preparation and compositions containing them, and use at the compounds and composition in the treatment of viral infections.
  • the invention relates to the use of compounds of formula I for the treatment of respiratory syncytial virus infection.
  • Respiratory syncytial virus is the leading cause of lower respiratory tract infection in adults and in young children. In the western world approximately all children have been infected by the age of two. In most cases the RSV infections will only cause minor upper respiratory illness with symptoms resembling that of the common cold. However, severe infection with the virus may result in bronchiolitis or pneumonia which may result in hospitalization or death. Infants who have been born prematurely or have a pre-existing lung disease are a high risk of severe infection and complications.
  • Respiratory syncytial virus is a member of the order Mononegalirales, which consists of the non-segmented negative strand RNA viruses in the Families Paramyxoviridae, Rhabdoviridae and Filoviridae.
  • RSV of humans (often termed RSV or HRSV) is a member of the Pneumovirus genus of the sub-family Pneumovirinae within the Family Paramyxoviridae.
  • Other members of the Pneumovirus genus include viruses such as bovine RSV (BRSV), ovine RSV (ORSV) and murine pneumonia virus (MPV) amongst others.
  • the sub-family Pneumovirinae also includes the genus Metapneumovirus which contains the recently identified and important human pathogen human metapneumovirus.
  • Family characteristics include a lipid envelope containing one or more glycoprotein species considered to be associated with attachment and entry of the host cell. Entry is considered to require a process by which the viral envelope fuses with the membrane of the host cell. Fusion of infected cells with, for example, their neighbours, can also result in the formation of fused multinucleate cells known as syncytia in some cases. The fusion process is believed to be glycoprotein mediated and is a feature shared with diverse enveloped viruses in other taxonomic groups. In the case of the Paramyxovrldae viruses of all genera characteristically express a fusion glycoprotein (F) which mediates membrane fusion
  • F fusion glycoprotein
  • Virazole also known as Ribavirin.
  • This agent has a broad spectrum antiviral with virustatic effects, and acts by inhibiting RSV replication. It also improves arterial blood oxygenation.
  • the agent is toxic so that administration of the agent is confined to a hospital setting. Its administration is further complicated by the need to follow a strict procedural process when administering the agent in order to minimise the likelihood of certain adverse affects.
  • the agent has a number of adverse effects including sudden deterioration of respiratory function (bronchiospasm).
  • bronchiospasm sudden deterioration of respiratory function
  • A is —NH—, —O— or —S—, and n is 1-3.
  • R 3 is selected from various aromatic substituents.
  • U.S. Pat. No. 4,058,529 discloses anti-inflammatory and anti-convulsive activity polycyclic compounds of the general formula A, and includes compounds of the formula B where R 2 is hydrogen or lower alkyl group (including amino substituted groups) and n is 1-3.
  • CH 482,697 discloses a number of compounds of the general formula B above, where R 2 is —CO—CHR—N 3 and R is hydrogen or alkyl, and intermediates where R 2 is —CO—CHR—NH 2 , —CO—CHR—OH or hydrogen.
  • R 2 is —CO—CHR—NR′R′′.
  • n is 1 to 3
  • R is H or lower alkyl
  • R′ and R′′ may be lower alkyl or benzyl or together form a piperidinyl or morpholinyl ring.
  • the Graf compounds may have anti-inflammatory uses.
  • WO 02/066479 (Banyu Pharmaceutical) lists some compounds of the general formula B, where R 2 is lower alkyl, —CO—C 2 H 5 and selected other moieties. It also appears to suggest a compound of formula B where the fused phenyl ring has been replaced with pyridyl and R 2 is methyl. It is not clear whether all of these compounds have been made. The compounds are for use in the treatment of high blood pressure and diabetes.
  • GB 1,038,735 discloses anti-inflammatory compounds of the general formula B, where n is 1 to 3, R 2 is lower alkyl or, for example, an dimethylaminoethyl group.
  • Canadian patent application no. 2,108,899 (also see family member WO 92/16207) discloses various oxazolo-[2,3-a]-isoindole and imidazo-[2,1-a]-isoindole derivatives for use in antiviral medicaments, particularly for use in the treatment of AIDS and HIV.
  • HIV and RSV viruses There are marked differences between HIV and RSV viruses, the diseases they are associated with, and the respective modes of action of the disclosed compounds.
  • the specification generally describes compounds of the structure below where R is C 1 -C 6 alkyl group or C 1 -C 6 acyl group, and specifically discloses compounds where R is —COCH 3 or —CH 3 .
  • the invention relates to the discovery that certain compounds exhibit favourable anti-RSV activity by inhibition of the RSV virus's essential fusion processes.
  • This invention provides for the use of a compound of formula I
  • R 1 is selected from C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, —(CH 2 ) n C 3-7 cycloalkyl, —(CH 2 ) n C 4-7 cycloalkenyl, —(CH 2 ) aryl, —(CH 2 ) n arylC 1-12 alkyl, —(CH 2 ) n arylC 2-12 alkenyl, —(CH 2 ) n arylC 2-12 alkynyl, and —(CH 2 ) n heterocyclyl; n is 0-6 and said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are optionally substituted; R 2 is selected from —CH 2 R 3 , —C(
  • the invention also provides for the use of compounds of formula I, its salts, and pharmaceutically acceptable derivatives thereof, in the treatment of RSV infections by the inhibition of the virus's fusion processes.
  • the invention also provides novel compounds of formula I, their salts, and pharmaceutically acceptable derivatives thereof.
  • aromatic refers to aryl rings or ring systems and aromatic heterocyclic rings or ring systems, as known as heteroaryl or heteroaromatic rings.
  • aryl refers to carbocyclic (non-heterocyclic) aromatic rings or ring systems.
  • the aromatic rings may be mono- or bi-cyclic ring systems.
  • the aromatic rings or ring systems are generally composed of 5 to 10 carbon atoms.
  • suitable aryl groups include but are not limited to phenyl, biphenyl, naphthyl, tetrahydronaphthyl, and the like.
  • Preferred aryl groups include phenyl, naphthyl, indenyl, azulenyl, fluorenyl or anthracenyl.
  • heterocyclic or “heterocyclyl” as used herein refers to mono or bicyclic rings or ring systems that include one or more heteroatoms selected from N, S and O.
  • the rings or ring systems generally include 1 to 9 carbon atoms in addition to the heteroatom(s) and may be saturated, unsaturated or aromatic (including pseudoaromatic).
  • pseudoaromatic refers to a ring system which is not strictly aromatic, but which is stabilized by means of delocalization of electrons and behaves in a similar manner to aromatic rings.
  • Aromatic includes pseudoaromatic ring systems, such as furyl, thienyl and pyrrolyl rings.
  • Examples of 5-membered monocyclic heterocycles include furyl, thienyl, pyrrolyl, H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl, (including 1,2,3 and 1,2,4 oxadiazolyls) thiazolyl, isoxazolyl, furazanyl, isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, triazolyl (including 1,2,3 and 1,3,4 triazolyls), tetrazolyl, thiadiazolyl (including 1,2,3 and 1,3,4 thiadiazolyls).
  • 6-membered monocyclic heterocycles include pyridyl, pyrimidinyl, pyridazinyl, pyranyl, pyrazinyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, piperazinyl, 1,3,5-trithianyl and triazinyl.
  • the heterocycles may be optionally substituted with a broad range of substituents, and preferably with C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, halo, hydroxy, mercapto, trifluoromethyl, amino, cyano or mono or di(C 1-6 alkyl)amino.
  • the heterocycle may be fused to a carbocyclic ring such as phenyl, naphthyl, indenyl, azulenyl, fluorenyl, and anthracenyl.
  • Examples of 8, 9 and 10-membered bicyclic heterocycles include 1H thieno[2,3-c]pyrazolyl, thieno[2,3-b]furyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, uridinyl, purinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzotriazinyl, naphthyridinyl, pteridinyl and the like.
  • heterocycles may be optionally substituted, for example with C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, halo, hydroxy, mercapto, trifluoromethyl, amino, cyano or mono or di(C 1-6 alkyl)amino.
  • heterocyclic radicals examples include (optionally substituted) isoxazoles, isothiazoles, 1,3,4-oxadiazoles, 1,3,4-thiadiazoles, 1,2,4-oxadiazoles, 1,2,4-thiadiazoles, oxazoles, thiazoles, pyridines, pyridazines, pyrimidines, pyrazines, 1,2,4-triazines, 1,3,5-triazines, benzoxazoles, benzothiazoles, benzisoxazoles, benzisothiazoles, quinolines and quinoxalines.
  • heterocycles can be optionally substituted with, by example, with C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, halo, hydroxy, mercapto, trifluoromethyl, amino, cyano or mono or di(C 1-6 alkyl)amino.
  • heterocyclic radicals include furyl, thienyl, pyridyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, benzo[b]furanyl, benzo[b]thiophenyl and benzoisoxazolyl.
  • Examples of unsaturated 5-membered heterocyclic rings include oxazole, thiazole, imidazole, 1,2,3-triazole, isoxazole, isothiazole, pyrazole, furan, thiophene and pyrrole.
  • Examples of unsaturated 6-membered heterocyclic rings include pyridine, pyrimidine, pyrazine, pyridazine and 1,2,4-triazine.
  • the heterocyclic ring is an aromatic ring.
  • Heteroaryl and heteroaromatic are used herein to refer to this subset of heterocyclic rings.
  • Heteroaryl rings include furyl, thienyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-oxadiazol-5-one, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1H thieno[2,3-c]pyrazolyl, thieno[2,3-b]furyl, indolizinyl, indolyl, isoindolyl, 3H-ind
  • heteroaryl or heteroaromatic is selected from isoxazolyl, oxazolyl, imidazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furazanyl, triazolyl, pyridyl, pyrimidinyl, furyl, pyrazolyl, pyridazinyl, thienyl and aryl fused heteroaromatic rings such as benzfuranyl, benzothiophenyl and benzoisoxazolyl.
  • the heterocyclic ring is a non-aromatic ring selected from the group consisting of pyrrolidine, imidazoline, 2-imidazolidone, 2-pyrrolidone, pyrrolin-2-one, tetrahydrofuran, 1,3-dioxolane, piperidine, tetrahydropyran, oxazoline, 1,3-dioxane, 1,4-piperazine, morpholine and thiomorpholine.
  • the heterocyclic ring containing the linker group B-C may be selected from the above described heterocyclic rings provided the ring meets the requirement of containing at least two nitrogen atoms and excludes aromatic ring systems.
  • the term “optionally substituted” as used herein means that a group may include one or more substituents that do not interfere with the binding activity of the compound of formula I. In some instances the substituent may be selected to improve binding.
  • the group may be substituted with one or more substituents selected from halogens, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —(CH 2 ) p C 3-7 cycloalkyl, —(CH 2 ) p C 4-7 cycloalkenyl, —(CH 2 ) p aryl, —(CH 2 ) p heterocyclyl, —C 6 H 4 S(O) t C 1-6 alkyl, —C(Ph) 3 , —(CH 2 ) p Z, —COZ, —CN, —OR, —O—(CH 2 ) 1-6 —R, —O—(CH 2 ) 1-6 —OR, —OCOR
  • the group may itself be optionally substituted with one to six of the same or different halogen atoms, hydroxy, lower alkyl, lower alkoxy, halo-C 1-6 alkyl (including —CF 3 ), phenyl, benzyl, —CN, —C(O)—C 1-6 alkyl, mercapto, —NH 2 , mono or di (lower alkyl)amino or —NO 2 .
  • optionally substituted includes pyridinium salts and the N-oxide form of suitable ring nitrogens.
  • non-aromatic carbocyclic or heterocyclic compounds unless otherwise defined such compounds may also be optionally substituted with one or two ⁇ O groups, instead of or in addition to the above described optional substituents.
  • optional substituents include halogens, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 haloalkyl, —CF 3 , —OH, phenyl, —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 ) 2 , —CN, mercapto, C 1-4 alkylcarbonyl and C 1-4 alkoxycarbonyl.
  • C 1-12 alkyl refers to straight chain or branched saturated hydrocarbon group having from 1 to 12 carbon atoms.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  • C 1-6 alkyl or “lower alkyl” refers to such groups having from 1 to 6 carbon atoms.
  • C 3-7 cycloalkyl refers to non-aromatic, saturated cyclic groups having from 3 to 7 carbon atoms. Examples include cyclopentyl and cyclohexyl.
  • alkoxy refers to a straight or branched alkyl group covalently bound via an O linkage and the terms “C 1-4 alkoxy” and “lower alkoxy” refer to such groups containing from one to six carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy and the like.
  • C 2-12 alkenyl refers to groups formed from C 2-12 straight chain or branched non-cyclic hydrocarbon containing one or more double bonds.
  • Examples of C 2-12 alkenyl include allyl, 1-methylvinyl, butenyl, iso-butenyl, 1,3-butadienyl, 3-methyl-2-butenyl, 1,3-butadienyl, 1,4-pentadienyl, 1-pentenyl, 1-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl and 1,3,5-hexatrienyl.
  • C 4-7 cycloalkenyl refers to non aromatic carbocycles having 4 to 7 carbon atoms and having one or more double carbon bonds. Examples include cyclopentenyl, 1-methyl-cyclopentenyl, cyclohexenyl, 1,3-cyclopentadienyl, 1,3-cyclohexadienyl and 1,4-cyclohexadienyl.
  • C 2-12 alkynyl refers to C 2-12 straight or branched non-cyclic hydrocarbon containing one or more triple bonds, preferably one or two triple bonds. Examples include 2-propynyl and 2- or 3-butynyl.
  • aryl C 1-12 alkyl refers to carbocyclic aromatic rings or ring systems as previously described and substituted by a C 1-12 alkyl group, also as previously described.
  • aryl C 2-12 alkenyl and “aryl C 2-12 alkynyl” refer to carbocyclic aromatic rings or ring systems as previously described and substituted by a C 2-12 alkenyl or C 2-12 alkynyl group, as previously described.
  • the aryl group and the alkyl, alkenyl or alkynyl group may be optionally substituted. Preferably the aryl group is not optionally substituted.
  • the alkyl, alkenyl or alkynyl group is optionally substituted, and more preferably with a substituent selected from halogens, —CN, —NR′R′′, —COR, —COOR, or —CONR′R′′.
  • R, R′ and R′′ are independently selected from hydrogen or lower alkyl.
  • halo or “halogen” refers to fluoro, chloro, bromo and iodo groups.
  • halo alkyl has one or more of the hydrogen atoms on an alkyl group replaced with halogens.
  • An example includes —CF 3 .
  • Particularly preferred compounds of the invention include those compounds where A is a bivalent link of 3 or 4 atoms selected from C, N, O and S. In that arrangement A and the atoms to which they are attached together form an aromatic ring having five or six ring atoms.
  • the linking atoms are all carbon, the ring formed is a carbocyclic aromatic ring or ring system.
  • the linking atoms include one or more of N, O or S then the ring formed is an aromatic heterocyclic ring. Examples include where the substructure
  • ring A is an optionally substituted aryl or heteroaryl ring, more preferably a phenyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl ring, and most preferably a phenyl or pyridyl ring.
  • the optionally substituents include N-oxides of the ring nitrogen atoms.
  • the aromatic rings may be optionally substituted, preferably by no more than 3 substituents.
  • substituents it is particular preferred to use 1 to 3 substituents selected from halo, lower alkyl, halogenated forms of lower alkyl, hydroxy, lower alkoxy, nitro, amino, loweralkylamino, carboxy, carboxamido, phenyl and benzyl.
  • N-oxide forms of the nitrogen atoms of nitrogen containing rings are also preferred.
  • A is a pyridyl ring
  • the ring nitrogen may be in a N-oxide form, or the ring may be in the form of a pyridinium salt.
  • this ring can not be selected from all of the heterocyclic rings discussed earlier in relation to the meaning of the term due to the atoms to which B-C are attached.
  • This ring is limited to monocyclic, non-aromatic heterocyclic rings that include at least two nitrogen atoms.
  • the ring may include additional hetero atoms and may be partially unsaturated.
  • B-C represents a bivalent link of 1 to 3 atoms.
  • the link B-C together with the atoms to which it is attached forms a non-aromatic heterocyclic ring. Examples include where the substructure:—
  • B-C represents —CH 2 —(CH 2 ) z —, where z is 1-4, more preferably 1, 2 or 3, more preferably 1 or 2 and most preferably z is 1.
  • the atoms forming the link B-C may be optionally substituted, preferably by no more than 3 substituents.
  • substituents include halo, lower alkyl, hydroxy, lower alkoxy, phenyl and benzyl.
  • a preferred form of the invention includes those compounds where B-C represents —CH 2 CH 2 —.
  • X is oxygen or sulphur, more preferably X is oxygen.
  • fused ring A and the ring containing the bivalent link B-C are optionally substituted with one or two substituents independently selected from halogen and C 1-6 alkyl.
  • fused ring A and the ring containing the bivalent link B-C are not substituted.
  • R 1 may be an optionally substituted aryl, alkyl or heterocyclyl.
  • R 1 is an optionally substituted aryl or heterocyclyl group, more preferably a phenyl, thienyl, pyrrolyl or pyridyl ring.
  • R 1 may also be a —C 1-4 alkylphenyl group.
  • the rings of R 1 may b optional substituted with halo, hydroxy, nitro, —NR′R′′ (where R′ and R′′ are independently selected from hydrogen, lower alkyl and —C(O)R, where R is C 1-6 alkyl, phenyl or heterocyclyl), C 1-12 alkyl, phenyl and —O—R a , where R a is —C 1-12 alkyl, —C 3-7 cycloalkyl, —C 1-12 alkylC 3-7 cycloalkyl, phenyl or —C 1-12 alkylphenyl; and the C 1-12 alkyl, phenyl or R a group may be optionally substituted with halo, —CN, —NR′R′′, —CO 2 R or —CONR′R′′, where R, R′ and R′′ are independently selected from hydrogen or lower alkyl.
  • the ring is phenyl and is optionally substituted in the para or 4-position.
  • R 1 may be -phenyl substituted with C 1-10 alkyl chain, where the alkyl chain is substituted with halo, —CN, —NR′R′′, —CO 2 R or —CONR′R′′, where R, R′ and R′′ are independently selected from hydrogen or lower alkyl. More preferably the alkyl chain is in the 4-position of the phenyl ring, and substituents are attached to the carbon at the free end of the alkyl group.
  • R 1 may be phenyl optionally substituted with a substituent selected from halo, —C 1-6 alkyl, —C 1-6 alkylhalo, —C 1-6 alkylCN, —OC 1-6 alkyl, —OC 1-6 alkylhalo, —OC 1-6 alkylCO 2 NH 2 , —OC 1-6 alkylCN, —OC 1-6 alkylC 3-7 cycloalkyl, —OC 1-6 alkylC 6 H 5 , —OC 1-6 alkylOCH 3 , —OC 6 H 5 , —OC 6 H 4 halo, —CF 3 , —OCF 3 , —NR′R′′ (where R′ and R′′ are independently selected from hydrogen, —C(O)C 1-6 alkyl, —C(O)C 6 H 5 , —C(O)CH ⁇ CHCO 2 H, —C(O)C 1-6 alkylCO 2 H, —C(O)C
  • R 1 is halophenyl, most preferably 4-chlorophenyl.
  • R 2 is not an unsubstituted —C 1-6 alkyl or unsubstituted —C(O)—C 1-6 alkyl.
  • R 3 is —(CH 2 ) m aryl or —(CH 2 ) m heterocyclyl, where m is 0 to 3.
  • the ring atoms may by optionally substituted with a broad range of substituents. Preferred substituents are selected from halo, lower alkyl, hydroxy, lower alkoxy and phenyl.
  • R 2 is —C(Y)—R 3
  • Y is O
  • R 3 is preferably —(CH 2 ) m aryl or —(CH 2 ) m heterocyclyl where m is 0 to 3.
  • the heterocycyl may itself be substituted with an oxo group, hydroxy or lower alkyl.
  • R 3 is phenyl, naphthyl, furyl, thienyl, pyrrolyl, H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl, (including 1,2,3 and 1,2,4 oxadiazolyls) thiazolyl, isoxazolyl, furazanyl, isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, triazolyl (including 1,2,3 and 1,3,4 triazolyls), tetrazolyl, thiadiazolyl (including 1,2,3 and 1,3,4 thiadiazolyls), pyridyl, pyrimidinyl, pyridazinyl, pyranyl, pyrazinyl, piperidinyl, 1,4-dioxanyl, morpholinyl
  • the heterocyclic ring may be fused to a carbocyclic ring such as phenyl, naphthyl, indenyl, azulenyl, fluorenyl, and anthracenyl.
  • the aryl or heterocyclic may be optionally substituted with a broad range of substituents, and preferably with C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, halo, hydroxy, mercapto, trifluoromethyl, amino, nitro, cyano and mono or di(C 1-6 alkyl)amino.
  • the substituents also include phenyl, benzyl and heterocyclyl.
  • R 3 is selected from phenyl, furyl, thienyl, pyridyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, benzo[b]furanyl, benzo[b]thiophenyl and benzoisoxazolyl.
  • R 3 is —phenylC 1-10 alkyl, where the alkyl is substituted with halo, —CN, —NR′R′′, —CO 2 R or —CONR′R′′, where R, R′ and R′′ are independently selected from hydrogen or lower alkyl. More preferably the alkyl chain is in the 4-position of the phenyl ring, and substituents are attached to the carbon at the free end of the alkyl group.
  • R 4 When R 2 is —CON(R 4 )R 3 it is preferred for R 4 to be hydrogen and R 3 to be —(CH 2 ) m aryl or —(CH 2 ) m heteroaryl.
  • m is 0 to 2, more preferably 0 to 1.
  • the aryl and heteroaryl ring atoms may be optionally substituted with a broad range of substituents. Preferred substituents include halo, lower alkyl, hydroxy, lower alkoxy and phenyl.
  • R 2 is —COR 3 and fused ring A contains at least one ring nitrogen atom.
  • R 1 is unsubstituted phenyl
  • X is O
  • a together with the atoms to which it is attached forms an unsubstituted phenyl ring
  • B-C is —CH 2 CH 2 —
  • R 2 is not unsubstituted C 1-6 alkyl or —C(O)C 1-6 alkyl.
  • compound of formula I and some derivatives thereof may have at least one asymmetric centre, and therefore are capable of existing in more than one stereoisomeric form.
  • the invention extends to each of these forms individually and to mixtures thereof, including racemates.
  • the isomers may be separated conventionally by chromatographic methods or using a resolving agent. Alternatively the individual isomers may be prepared by asymmetric synthesis using chiral intermediates. Where the compound has at least one carbon-carbon double bond, it may occur in Z- and E-forms and all isomeric forms of the compounds being included in the present invention.
  • salts of the compound of formula I are preferably pharmaceutically acceptable, but it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present invention, since these are useful as intermediates in the preparation of pharmaceutically acceptable salts.
  • pharmaceutically acceptable derivatives includes pharmaceutically acceptable esters, prodrugs, solvates and hydrates, and pharmaceutically acceptable addition salts of the compounds or the derivatives.
  • Pharmaceutically acceptable derivatives may include any pharmaceutically acceptable salt, solvate, hydrate or any other compound or prodrug which, upon administration to a subject, is capable of providing (directly or indirectly) a compound of formula I or an antivirally active metabolite or residue thereof.
  • the pharmaceutically acceptable salts include acid addition salts, base addition salts, salts of pharmaceutically acceptable esters and the salts of quaternary amines and pyridiniums.
  • the acid addition salts are formed from a compound of the invention and a pharmaceutically acceptable inorganic or organic acid including but not limited to hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, toluenesulphonic, benzenesulphonic, acetic, propionic, ascorbic, citric, malonic, fumaric, maleic, lactic, salicyclic, sulfamic, or tartartic acids.
  • the counter ion of quarternary amines and pyridiniums include chloride, bromide, iodide, sulfate, phosphate, methansulfonate, citrate, acetate, malonate, fumarate, sulfamate, and tartate.
  • the base addition salts include but are not limited to salts such as sodium, potassium, calcium, lithium, magnesium, ammonium and alkylammonium.
  • basic nitrogen-containing groups may be quaternised with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others.
  • the salts may be made in a known manner, for example by treating the compound with an appropriate acid or base in the presence of a suitable solvent.
  • the compounds of the invention may be in crystalline form or as solvates (e.g. hydrates) and it is intended that both forms be within the scope of the present invention.
  • solvate is a complex of variable stoichiometry formed by a solute (in this invention, a compound of the invention) and a solvent. Such solvents should not interfere with the biological activity of the solute. Solvents may be, by way of example, water, ethanol or acetic acid. Methods of solvation are generally known within the art.
  • pro-drug is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, for example, compounds where a free hydroxy group is converted into an ester derivative or a ring nitrogen atom is converted to an N-oxide. Examples of ester derivatives include alkyl esters, phosphate esters and those formed from amino acids, preferably valine. Any compound that is a prodrug of a compound of the invention is within the scope and spirit of the invention. Conventional procedures for the preparation of suitable prodrugs according to the invention are described in text books, such as “Design of Prodrugs” Ed. H. Bundgaard, Elsevier, 1985.
  • pharmaceutically acceptable ester includes biologically acceptable esters of compound of the invention such as sulphonic, phosphonic and carboxylic acid derivatives.
  • composition that comprises a therapeutically effective amount of one or more of the aforementioned anti-RSV compounds of formula I, including pharmaceutically derivatives thereof, and optionally a pharmaceutically acceptable carrier or diluent.
  • treatment includes both therapeutic and prophylactic treatments.
  • a method of treating RSV by the administration of a compound of formula I including the administration of pharmaceutically acceptable salts, or derivatives such as prodrugs of formula I, or a composition containing at least one compound of formula I, to a patient in need to treatment.
  • a method for treating mammals infected with RSV, and in need thereof which comprises administering to said mammal a therapeutically effective amount of one or more of the aforementioned compounds of formula I or pharmaceutically acceptable derivatives thereof.
  • a method for preventing the infection of mammals with RSV which comprises administering to said mammal a therapeutically effective amount of one or more of the aforementioned compounds of formula I, or pharmaceutically acceptable derivatives thereof.
  • the invention has been described with reference to treating RSV, and in particularly human RSV, it will be appreciated that the invention may also be useful in the treatment of other viruses of the sub-family Pneumovrinae, more particularly, the genera Pneumovirus and Metapneumovirus, more particularly animal and human strains of RSV and metapneumovirus.
  • Scheme 1 depicts a general process for manufacture of compounds of formula III.
  • Compounds of formula III are intermediates, similar to formula I but where R 2 is H.
  • Compounds of formula III may be prepared via appropriate starting materials of formula II.
  • General methods for the preparation of 2-(aroyl)benzoic acids and 3-(aroyl)pyridine-2-carboxylic acids of formula II are described by Yamaguchi, M. et. al, J. Med. Chem. 1993, 36, 4052-4060 and Natsugari, H. et. al, J. Med. Chem. 1995, 38, 3106-3120.
  • one equivalent of an appropriate keto-acid of formula II is reacted with approximately 3 equivalents of an appropriate diamine of the general formula H 2 N—B—C—NH 2 .
  • the mixture is heated under reflux in an inert solvent, such as toluene or xylene, with a Dean-Stark apparatus for 3-10 h.
  • a catalyst such as an acid tosylate, can be used. After this time the reaction is allowed to cool and the product filtered and recrystallised from an appropriate solvent. If no precipitate forms the solvent is evaporated in-vacuo and the residue recrystallised or purified using flash chromatography or preparative HPLC.
  • two equivalents of diisopropylethylamine or triethylamine are added to one equivalent of a compound of formula III in THF at 0° C.
  • An acid chloride, or other acylating agent is added to the mixture and the reaction monitored by HPLC. When the reaction is complete the reaction is quenched with water and the product extracted into a suitable organic solvent and worked up according to standard methods. Similar acylation may also be carried out by reacting one equivalent of the compound of formula III with one equivalent of the appropriate acid chloride in xylene at 120° C. for 1-24 h. The reaction is then allowed to cool and the product isolated.
  • compounds of formula III may be treated with approximately 2.2 equivalents of an appropriate acid chloride or anhydride in pyridine at approximately ⁇ 5° C. The mixture is allowed to arm to room temperature and after stirring for 2-24 h the product is isolated by standard methods. Acylation may also be achieved by treating the appropriate compound of formula III with the appropriate carboxylic acid (3 equivalents), TFFH (3.3 equivalents) and DIEA (3.3 equivalents) in DMF and heating to 45° C. for approximately 14 days. After this time the product is isolated by standard methods.
  • N-alkylated and N-sulfonylated compounds of Formula I are best obtained using suitable N-substituted diamines. These may be prepared by known methods for example that described by Kruse L. I., et. al, J. Med. Chem. 1990, 33, 781-789.
  • R 2 is —CHR 3 or —S(O) 2 R 5 , as earlier defined in the summary of the invention.
  • One equivalent of the appropriate compound of formula III is reacted with one equivalent of the appropriate isocyanate or isothiocyanate in THF or xylene at a temperature ranging from 20.120° C. for 1-24 h.
  • the reaction is then allowed to cool and the product filtered, washed and generally recrystallised from an appropriate solvent. If no precipitate is formed the product can be purified using standard chromatographic methods.
  • Examples of functional group inter-conversions are: —C(O)NR′R′′ from —CO 2 CH 3 by heating with or without catalytic metal cyanide, e.g. NaCN, and HNR′R′′ in CH 3 OH; —OC(O)R from —OH with e.g., ClC(O)R in pyridine; —NC(S)NR′R′′ from —NHR with an alkylisothiocyanate or thiocyanic acid; —NRC(O)OR′ from —NHR with alkyl chloroformate; —NRC(O)NR′R′′ from —NHR by treatment with an isocyanate, e.g.
  • the invention also pertains to therapeutic compositions containing at least one compound of formula I including pharmaceutical acceptable salts or prodrugs.
  • compositions may further contain one or more other compounds having anti-viral activity in respect of RSV, such as Virazole, or other agents such as RespiGam or Synagis.
  • compositions may further contain or be administered in combination with other drugs to treat symptoms of the disease, such as for example anti-inflammatory medicaments.
  • composition is intended to include the formulation of an active ingredient with conventional carriers and excipients, and also with encapsulating materials as the carrier, to give a capsule in which the active ingredient (with or without other carriers) is surrounded by the encapsulation carrier.
  • the route of administration and the nature of the pharmaceutically acceptable carrier will depend on the nature of the condition and the animal to be treated. It is believed that the choice of a particular carrier or delivery system, and route of administration could be readily determined by a person skilled in the art. In the preparation of any formulation containing the compounds care should be taken to ensure that the activity of the compound is not destroyed in the process and that the compound is able to reach its site of action without being destroyed. In some circumstances it may be necessary to protect the compound by means known in the art, such as, for example, micro encapsulation. Similarly the route of administration chosen should be such that the compound reaches its site of action.
  • compositions or formulations include those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. It is envisaged that the compositions should be provided in a form suitable for oral or nasal administration or by inhalation or insufflation.
  • the compounds of the invention may thus be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • Formulations containing ten (10) milligrams of active ingredient or, more broadly, 0.1 to one hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms.
  • the compounds of the present invention can be administrated in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a compound of the invention or a pharmaceutically acceptable salt of a compound of the invention.
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispensable granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilisers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid that is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from five or ten to about seventy percent of the active compound.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term “preparation” is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.
  • a low melting wax such as admixture of fatty acid glycerides or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogenous mixture is then poured into convenient sized moulds, allowed to cool, and thereby to solidify.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions.
  • parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
  • Sterile liquid form compositions include sterile solutions, suspensions, emulsions, syrups and elixirs.
  • the active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a mixture of both.
  • compositions according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulation agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution, for constitution with a suitable vehicle, eg. sterile, pyrogen-free water, before use.
  • compositions suitable for injectable use include sterile injectable solutions or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions. They should be stable under the conditions of manufacture and storage and may be preserved against oxidation and the contaminating action of microorganisms such as bacteria or fungi.
  • Those skilled in the art may readily determine appropriate formulations for the compounds of the present invention using conventional approaches. Identification of preferred pH ranges and suitable excipients, for example antioxidants, is routine in the art (see for example Cleland et al, 1993). Buffer systems are routinely used to provide pH values of a desired range and include carboxylic acid buffers for example acetate, citrate, lactate and succinate. A variety of antioxidants are available for such formulations including phenolic compounds such as BHT or vitamin E, reducing agents such as methionine or sulphite, and metal chelators such as EDTA.
  • phenolic compounds such as BHT or vitamin E
  • reducing agents such as methionine or sulphite
  • metal chelators such as EDTA.
  • the solvent or dispersion medium for the injectable solution or dispersion may contain any of the conventional solvent or carrier systems for the compounds, and may contain, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about where necessary by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like.
  • agents to adjust osmolality for example, sugars or sodium chloride.
  • the formulation for injection will be isotonic with blood.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin.
  • Pharmaceutical forms suitable for injectable use may be delivered by any appropriate route including intravenous, intramuscular, intracerebral, intrathecal, epidural injection or infusion.
  • Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various other ingredients such as these enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilised active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • preferred methods of preparation are vacuum drying or freeze-drying of a previously sterile-filtered solution of the active ingredient plus any additional desired ingredients.
  • the active ingredients When the active ingredients are suitably protected they may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsule, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet.
  • the active compound For oral therapeutic administration, the active compound may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Such compositions and preparations preferably contain at least 1% by weight of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about to about 80% of the weight of the unit. The amount of active compound in therapeutically useful compositions should be sufficient that a suitable dosage will be obtained.
  • the tablets, troches, pills, capsules and the like may also contain the components as listed hereafter: a binder such as gum, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such a sucrose, lactose or saccharin may be added or a flavouring agent such as peppermint, oil of wintergreen, or cherry flavouring.
  • a binder such as gum, acacia, corn starch or gelatin
  • excipients such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, lactose or saccharin may be added or a flavouring agent such as peppermint, oil of winter
  • any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
  • the active compound(s) may be incorporated into sustained-release preparations and formulations, including those that allow specific delivery of the active peptide to specific regions of the gut.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilising and thickening agents, as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
  • viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
  • Pharmaceutically acceptable carriers and/or diluents include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • the use of such media and agents for pharmaceutical active substances is well known in the art. Except in so far as any conventional media or agent is incompatible with the active ingredient, use thereof in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavours, stabilisers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilising agents, and the like.
  • the compounds according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents.
  • Formulations suitable for topical administration in the mouth include lozenges comprising active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray.
  • the formulations may be provided in single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomising spray pump.
  • the compounds according to the invention may be encapsulated with cyclodextrins, or formulated with other agents expected to enhance delivery and retention in the nasal mucosa.
  • Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurised pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • CFC chlorofluorocarbon
  • the aerosol may conveniently also contain a surfactant such as lecithin.
  • the dose of drug may be controlled by provision of a metered valve.
  • the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
  • a powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • the powder carrier will form a gel in the nasal cavity.
  • the powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.
  • the compound In formulations intended for administration to the respiratory tract, including intranasal formulations, the compound will generally have a small particle size for example of the order of to 10 microns or less. Such a particle size may be obtained by means known in the art, for example by micronisation.
  • formulations adapted to give sustained release of the active ingredient may be employed.
  • the pharmaceutical preparations are preferably in unit dosage forms.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the novel dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active material for the treatment of disease in living subjects having a diseased condition in which bodily health is impaired as herein disclosed in detail.
  • the invention also includes the compounds in the absence of carrier where the compounds are in unit dosage form.
  • the amount of compound of formula I administered may be in the range from about 10 mg to 2000 mg per day, depending on the activity of the compound and the disease to be treated.
  • Liquids or powders for intranasal administration, tablets or capsules for oral administration and liquids for intravenous administration are the preferred compositions.
  • One equivalent of an appropriate keto-acid of formula II is reacted with approximately 3 equivalents of an appropriate diamine of the general formula H 2 N—B—C—NH 2 .
  • the mixture is heated under reflux in an inert solvent, such as toluene or xylene, with a Dean-Stark apparatus for 3-10 h.
  • a catalyst such as an acid tosylate, can be used. After this time the reaction is allowed to cool and the product filtered and recrystallised from an appropriate solvent. If no precipitate forms the solvent is evaporated in-vacuo and the residue recrystallised or purified using flash chromatography or preparative HPLC.
  • Compound 1 was prepared using Method A employing 2-(4-chlorobenzoyl)benzoic acid
  • Compound 2 was prepared using Method A from 2-(4-chlorobenzoyl)benzoic acid and 1,3-diaminopropane.
  • Compound 7 was prepared using Method A from 2-(4-chlorobenzoyl)benzoic acid and 1,4-diaminobutane.
  • One equivalent of the appropriate compound of formula II is reacted with one equivalent of the appropriate acid chloride in xylene at 120° C. for 1-24 h. The reaction is then allowed to cool and the product filtered and recrystallised from an appropriate solvent. If no precipitate is formed the reaction is purified using flash chromatography or preparative HPLC.
  • N-alkylated diamines may be prepared according to the procedure outlined in Kruse L. I., et. al, J. Med. Chem. 1990, 33, 781-789.
  • One equivalent of the appropriate compound of formula III is reacted with one equivalent of the appropriate isocyanate or isothiocyanate in THF or xylene at a temperature ranging from 20-120° C. for 1-24 h.
  • the reaction is then allowed to cool and the product filtered, washed and recrystallised from an appropriate solvent. If no precipitate was formed the reaction was purified using flash chromatography or preparative HPLC.
  • Compound 12 was prepared using Method C using Compound 1 and 4-fluorobenzoyl chloride.
  • Compound 13 was prepared using Method C using Compound 1 and benzoyl chloride.
  • Compound 23 was prepared using Method D from 2-(4-chlorobenzoyl)benzoic acid and N-benzyl ethylenediamine.
  • Compound 24 was prepared using Method D from 2-benzoylbenzoic acid and N-benzyl ethylenediamine.
  • Compound 25 was prepared using Method D from 2-(4-toluoyl)benzoic acid and N-benzyl ethylenediamine.
  • Compound 106 was prepared using Method A employing 3-bromo-(4-chlorobenzoyl)benzoic acid and ethylene diamine.
  • Compound 107 was prepared using Method A employing 4-bromo-(4-chlorobenzoyl)benzoic acid and ethylene diamine.
  • the acid chloride or anhydride or isocyanate or isothiocyanate (2.2 eq) is added directly for liquids or as a solution in pyridine ( ⁇ 1M) for solids to a solution of the appropriate compound of formula III (0.1 mmol) in pyridine (500 ⁇ L) at ⁇ 5° C.
  • the reaction is stirred and allowed to warm to room temperature for between 2-24 h after which time the starting material has been consumed.
  • the reaction is subsequently diluted with water and extracted with CH 2 Cl 2 (3 ⁇ ).
  • the combined CH 2 Cl 2 extracts are washed with 1N NaOH (3 ⁇ ) and 10% HCl (3 ⁇ ). In the case of basic products the acid wash is omitted and in the case of acidic products the basic wash is omitted.
  • the crude purity is improved markedly by stirring the combined CH 2 Cl 2 extract in the presence of a carbonate resin (MP-Carbonate ⁇ 3 eq) for 0.5-12 h.
  • the CH 2 Cl 2 extracts are dried (MgSO 4 ) and the solvent evaporated in-vacuo.
  • the crude products are subsequently purified by flash chromatography using a EtOAc/Hexane solvent system.
  • Compound 120 was prepared using Method F employing compound 107 and 4-tolylboronic acid.
  • Compound 132 was prepared using Method G employing compound 107 and n-butylboronic acid.
  • An appropriate substrate of Formula I, wherein R 2 6-fluoronicotinoyl or 6-chloronicotinoyl, was produced using Method H. To this substrate was added an excess of an appropriate amine. In a suitable solvent, such as THF or ethanol, the mixture was heated in a sealed vessel to approximately 150° C. for 1-5 h (or 60° C. for 72 h in the case where the nucleophile was hydrazine). After this time the solvent was evaporated and the residue purified using flash chromatography or preparative HPLC.
  • a suitable solvent such as THF or ethanol
  • a suitable phenolic compound of formula III was acylated according to Method H. Ester hydrolysis was then effected by dissolving the product in a minimal volume of methanol and treating with an excess of 1M NaOH (aq) at ambient temperature. The reaction mixture was then acidified, extracted with dichloromethane and purified by flash chromatography to yield a phenolic compound of formula I.
  • Compound 239 was prepared from 9b-(4-hydroxyphenyl)-1,2,3,9b-tetrahydroimidazo[2,1-a]isoindol-5-one using Method L.
  • the tetrahydroimidazoisoindolone was bis-acylated with 4-fluorobenzoyl chloride according to Method H and the resulting phenolic ester function was converted to a phenol by basic hydrolysis.
  • the product was then treated with chloroacetonitrile and K 2 CO 3 in acetone and heated to reflux for 30 h to yield phenyl ether compound 239.
  • This method involves nucleophilic displacement of R 2 when it represents 2-haloethanoyl.
  • Aluminium chloride (2.88 mol) was added to a stirred suspension of 3,4-pyridine anhydride (1.31 mol) in chlorobenzene (1.2 l) at RT to give an orange suspension and heated to 110° C. for 5 h.
  • the mixture was cooled and carefully hydrolysed with water (2 l), heated to reflux for 1 h, filtered when hot and dried to give a brown solid.
  • the precipitate formed was filtered and refluxed with ethanol (2 l) to give a white solid (67 g).
  • Selected compounds of the invention may be separated into single stereoisomers by HPLC using chromatographic columns with a chiral stationary phase.
  • HPLC chromatographic columns with a chiral stationary phase.
  • racemic compounds were separated into enantiomers under the conditions detailed below.
  • the white salt was suspended in water (25 ml) and basified with 10% NaOH solution (0.7 ml) to pH 11.
  • the aqueous phase was extracted with ethyl acetate (100 ml then 2 ⁇ 75 ml).
  • the combined organic extracts were washed with saturated NaCl solution, dried (MgSO 4 ) and concentrated to yield Compound 153B (0.49 g) as a white powder.
  • Cytopathic effect (CPE) assays were performed essentially as described in the literature (see for example Watanabe et al, J. Virological Methods, 1994, 48, 257). Serial dilutions of the test compounds were made in assay medium.
  • HEp2 cells 1.0 ⁇ 10 4 cells/well
  • RSV at a low multiplicity of infection
  • 100 ⁇ L added to cultures assessing antiviral activity and cells without virus added to those assessing compound cytotoxicity.
  • Assays were incubated for approximately days at 37° C. in a 5% CO 2 atmosphere.
  • the extent of CPE was determined via metabolism of the vital dye 3-(4,5-dimethylthiaxol-2-yl)-2,5-diphenyltetrazolium bromide (MTT).
  • MTT 3-(4,5-dimethylthiaxol-2-yl)-2,5-diphenyltetrazolium bromide
  • Selected compounds of the invention were tested for their ability to inhibit the essential fusion processes of the respiratory syncytial virus.
  • Single-stranded synthetic DNA oligonucleotides encoding the portions of RSV A2 F glycoprotein incorporating optimal codons and without potential poly(A) addition or splice sites were generated synthetically (Mason et al, WO0242326).
  • a membrane-anchored full-length F was generated essentially according to the method described therein and in Morton et al, Virology, 2003, 31, 275.
  • Fusion activity of the RSV-F constructs was measured in 293 cells essentially according to the method described in Morton et al, Virology, 2003, 311, 275. For example: cells in six well plates at approximately 80% confluency were transfected by adding plasmid DNA (2 ⁇ g/well) carrying the constructs of interest in CaPO 4 solution for 4 hours. After glycerol shock and wash, the transfected cells were trypsinized and 1.5 ⁇ 10 4 cells/well added to 96-well plates containing half-log serial dilutions of the test compound.
  • Syncytium formation was evaluated by visual inspection and quantified at 48 hours post-transfection by addition of 20 ⁇ L of CellTiter 96 One Solution (Promega) followed by incubation for 4 hours at 37° C. The colour reaction was then stopped by addition of 25 ⁇ L 10% SDS to each well and absorbance measured at 492 nm. The compound concentration that reduced absorbance relative to untreated control cultures by 50% (EC50) was calculated using an Excel curve fitting program.
  • the cotton rat model was performed essentially as described in the literature (Wyde et al, Antiviral Res. 2003, 60, 221). Briefly, cotton rats weighing 50-100 g were lightly anesthetized with isoflurane and dosed orally with 100 mg/kg/day of compound or vehicle control. Viral infection followed 2 hours post-treatment in similarly anesthetized rats by intranasal instillation with approximately 1000 TCID50 of RSV A2 per animal. Four days after virus inoculation, each cotton rat was sacrificed and their lungs removed and RSV titres determined by plaque assay.
  • mice The mouse model was performed essentially as described by Clanci et al ( Antimicroblal Agents and Chemotherapy. 2004, 48, 413). Briefly, eight week old female Balb/c mice were weighed, anesthetized intraperitoneally with AvertinTM and compound or vehicle administered orally 6 hours preinfection. Mice were inoculated intranasally with approximately 10000 TCID50 RSV A2 per animal. Three days after virus inoculation, each mouse was sacrificed and their lungs removed and RSV titres determined by plaque assay.

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Abstract

Compounds of formula (I), and their use as in the treatment of infections involving viruses of the Pneumovirinae sub-family (RSV) are disclosed. In the formula ring (A) may be phenyl, pyridyl etc., (B-C) may be CH2—CH2 etc., (R1) may be phenyl and substituted forms thereof, (R2) may be assorted substituents.
Figure US20140051689A1-20140220-C00001

Description

    FIELD OF THE INVENTION
  • The present invention relates to antiviral compounds, methods for their preparation and compositions containing them, and use at the compounds and composition in the treatment of viral infections. In particular, the invention relates to the use of compounds of formula I for the treatment of respiratory syncytial virus infection.
    • BACKGROUND ART
  • Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection in adults and in young children. In the western world approximately all children have been infected by the age of two. In most cases the RSV infections will only cause minor upper respiratory illness with symptoms resembling that of the common cold. However, severe infection with the virus may result in bronchiolitis or pneumonia which may result in hospitalization or death. Infants who have been born prematurely or have a pre-existing lung disease are a high risk of severe infection and complications.
  • Respiratory syncytial virus (RSV) is a member of the order Mononegalirales, which consists of the non-segmented negative strand RNA viruses in the Families Paramyxoviridae, Rhabdoviridae and Filoviridae. RSV of humans (often termed RSV or HRSV) is a member of the Pneumovirus genus of the sub-family Pneumovirinae within the Family Paramyxoviridae. Other members of the Pneumovirus genus include viruses such as bovine RSV (BRSV), ovine RSV (ORSV) and murine pneumonia virus (MPV) amongst others. The sub-family Pneumovirinae also includes the genus Metapneumovirus which contains the recently identified and important human pathogen human metapneumovirus.
  • In addition to the genome features described above, Family characteristics include a lipid envelope containing one or more glycoprotein species considered to be associated with attachment and entry of the host cell. Entry is considered to require a process by which the viral envelope fuses with the membrane of the host cell. Fusion of infected cells with, for example, their neighbours, can also result in the formation of fused multinucleate cells known as syncytia in some cases. The fusion process is believed to be glycoprotein mediated and is a feature shared with diverse enveloped viruses in other taxonomic groups. In the case of the Paramyxovrldae viruses of all genera characteristically express a fusion glycoprotein (F) which mediates membrane fusion
  • The only drug currently approved for the treatment of severe RSV is the antiviral medication, Virazole, also known as Ribavirin. This agent has a broad spectrum antiviral with virustatic effects, and acts by inhibiting RSV replication. It also improves arterial blood oxygenation. Unfortunately, the agent is toxic so that administration of the agent is confined to a hospital setting. Its administration is further complicated by the need to follow a strict procedural process when administering the agent in order to minimise the likelihood of certain adverse affects. The agent has a number of adverse effects including sudden deterioration of respiratory function (bronchiospasm). The efficacy of the agent has remained controversial and thus there is a real need to find an alternative agent for the treatment of RSV infection.
  • A number of agents are known to inhibit RSV. Published patent applications WO 01/95910 and WO 02/26228 (Bristol Myers Squib Company), the contents of which are incorporated by cross reference, describe a number of different types of compounds which exhibit anti-RSV activity in their description of the background art. Moreover, these applications describe compounds having antiviral activity against RSV of the formula
  • Figure US20140051689A1-20140220-C00002
  • There are also a number of patent specifications that disclose imidazo-[2,1-a]-isoindole derivatives for uses other than treating RSV. U.S. Pat. No. 3,507,863 describes a number of polycyclic compounds that have anti-inflammatory and anti-convulsive activity. These compounds have the following general structure
  • Figure US20140051689A1-20140220-C00003
  • where A is —NH—, —O— or —S—, and n is 1-3.
  • U.S. Pat. No. 3,770,766 describes polycyclic compounds that have antidepressant activity, and have the following general structure
  • Figure US20140051689A1-20140220-C00004
  • where R3 is selected from various aromatic substituents.
  • U.S. Pat. No. 4,058,529 discloses anti-inflammatory and anti-convulsive activity polycyclic compounds of the general formula A, and includes compounds of the formula B where R2 is hydrogen or lower alkyl group (including amino substituted groups) and n is 1-3.
  • Figure US20140051689A1-20140220-C00005
  • CH 482,697 (Graf) discloses a number of compounds of the general formula B above, where R2 is —CO—CHR—N3 and R is hydrogen or alkyl, and intermediates where R2 is —CO—CHR—NH2, —CO—CHR—OH or hydrogen. Likewise U.S. Pat. No. 3,590,043 (Graf) relates to compounds of the formula B where R2 is —CO—CHR—NR′R″. In this document n is 1 to 3, R is H or lower alkyl, R′ and R″ may be lower alkyl or benzyl or together form a piperidinyl or morpholinyl ring. The Graf compounds may have anti-inflammatory uses.
  • WO 02/066479 (Banyu Pharmaceutical) lists some compounds of the general formula B, where R2 is lower alkyl, —CO—C2H5 and selected other moieties. It also appears to suggest a compound of formula B where the fused phenyl ring has been replaced with pyridyl and R2 is methyl. It is not clear whether all of these compounds have been made. The compounds are for use in the treatment of high blood pressure and diabetes.
  • GB 1,038,735 discloses anti-inflammatory compounds of the general formula B, where n is 1 to 3, R2 is lower alkyl or, for example, an dimethylaminoethyl group.
  • Canadian patent application no. 2,108,899 (also see family member WO 92/16207) discloses various oxazolo-[2,3-a]-isoindole and imidazo-[2,1-a]-isoindole derivatives for use in antiviral medicaments, particularly for use in the treatment of AIDS and HIV. There are marked differences between HIV and RSV viruses, the diseases they are associated with, and the respective modes of action of the disclosed compounds. The specification generally describes compounds of the structure below where R is C1-C6 alkyl group or C1-C6 acyl group, and specifically discloses compounds where R is —COCH3 or —CH3.
  • Figure US20140051689A1-20140220-C00006
  • A number of documents disclose compounds of the above formula or substituted forms thereof, where R is hydrogen. See for example the herbicidal compounds disclosed in U.S. Pat. Nos. 4,726,838 and 4,846,876.
    • SUMMARY OF THE INVENTION
  • The invention relates to the discovery that certain compounds exhibit favourable anti-RSV activity by inhibition of the RSV virus's essential fusion processes.
  • This invention provides for the use of a compound of formula I
  • Figure US20140051689A1-20140220-C00007
  • its salts, and pharmaceutically acceptable derivatives thereof, in the treatment of respiratory syncytial virus (RSV) infections, wherein
    R1 is selected from C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, —(CH2)nC3-7 cycloalkyl, —(CH2)nC4-7 cycloalkenyl, —(CH2) aryl, —(CH2)n arylC1-12 alkyl, —(CH2)n arylC2-12 alkenyl, —(CH2)n arylC2-12 alkynyl, and —(CH2)n heterocyclyl; n is 0-6 and said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are optionally substituted;
    R2 is selected from —CH2R3, —C(Y)R3, —C(Y)OR3, —C(Y)N(R4)R3, —C(Y)CH2N(R4)R3, —C(Y)CH2SR3 and —S(O)wR5, where R3 is selected from hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, —(CH2)mC3-7 cycloalkyl, —(CH2)mC4-7 cycloalkenyl, —(CH2)m aryl, —(CH2)m arylC1-12 alkyl, —(CH2)m arylC2-12 alkenyl, —(CH2)m arylC2-12 alkynyl and —(CH2)m heterocyclyl; and when R2 is —CH2R3, or —C(Y)R3, R3 may also be selected from —S—R5 and —O—R5; m is 0-6; R4 is hydrogen or C1-6 alkyl; R5 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, benzyl, aryl or heterocyclyl; w is 0, 1 or 2, and the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are optionally substituted;
    X and Y are independently selected from O, S and NR6, where R6 is independently selected from hydrogen, lower alkyl, hydroxy and lower alkoxy;
    A together with the atoms to which it is attached, forms an optionally substituted aromatic ring;
    B-C together with the atoms to which they are attached, forms an optionally substituted heterocyclic ring having from 5 to 8 ring atoms.
  • The invention also provides for the use of compounds of formula I, its salts, and pharmaceutically acceptable derivatives thereof, in the treatment of RSV infections by the inhibition of the virus's fusion processes.
  • The invention also provides novel compounds of formula I, their salts, and pharmaceutically acceptable derivatives thereof.
    • DESCRIPTION OF PREFERRED EMBODIMENTS
  • As used herein the term “aromatic” refers to aryl rings or ring systems and aromatic heterocyclic rings or ring systems, as known as heteroaryl or heteroaromatic rings.
  • As used herein the term “aryl” refers to carbocyclic (non-heterocyclic) aromatic rings or ring systems. The aromatic rings may be mono- or bi-cyclic ring systems. The aromatic rings or ring systems are generally composed of 5 to 10 carbon atoms. Examples of suitable aryl groups include but are not limited to phenyl, biphenyl, naphthyl, tetrahydronaphthyl, and the like.
  • Preferred aryl groups include phenyl, naphthyl, indenyl, azulenyl, fluorenyl or anthracenyl.
  • The term “heterocyclic” or “heterocyclyl” as used herein refers to mono or bicyclic rings or ring systems that include one or more heteroatoms selected from N, S and O. The rings or ring systems generally include 1 to 9 carbon atoms in addition to the heteroatom(s) and may be saturated, unsaturated or aromatic (including pseudoaromatic). The term “pseudoaromatic”*refers to a ring system which is not strictly aromatic, but which is stabilized by means of delocalization of electrons and behaves in a similar manner to aromatic rings. Aromatic includes pseudoaromatic ring systems, such as furyl, thienyl and pyrrolyl rings.
  • Examples of 5-membered monocyclic heterocycles include furyl, thienyl, pyrrolyl, H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl, (including 1,2,3 and 1,2,4 oxadiazolyls) thiazolyl, isoxazolyl, furazanyl, isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, triazolyl (including 1,2,3 and 1,3,4 triazolyls), tetrazolyl, thiadiazolyl (including 1,2,3 and 1,3,4 thiadiazolyls). Examples of 6-membered monocyclic heterocycles include pyridyl, pyrimidinyl, pyridazinyl, pyranyl, pyrazinyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, piperazinyl, 1,3,5-trithianyl and triazinyl. The heterocycles may be optionally substituted with a broad range of substituents, and preferably with C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, halo, hydroxy, mercapto, trifluoromethyl, amino, cyano or mono or di(C1-6alkyl)amino.
  • The heterocycle may be fused to a carbocyclic ring such as phenyl, naphthyl, indenyl, azulenyl, fluorenyl, and anthracenyl.
  • Examples of 8, 9 and 10-membered bicyclic heterocycles include 1H thieno[2,3-c]pyrazolyl, thieno[2,3-b]furyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, uridinyl, purinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzotriazinyl, naphthyridinyl, pteridinyl and the like. These heterocycles may be optionally substituted, for example with C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, halo, hydroxy, mercapto, trifluoromethyl, amino, cyano or mono or di(C1-6alkyl)amino.
  • Examples of preferred heterocyclic radicals include (optionally substituted) isoxazoles, isothiazoles, 1,3,4-oxadiazoles, 1,3,4-thiadiazoles, 1,2,4-oxadiazoles, 1,2,4-thiadiazoles, oxazoles, thiazoles, pyridines, pyridazines, pyrimidines, pyrazines, 1,2,4-triazines, 1,3,5-triazines, benzoxazoles, benzothiazoles, benzisoxazoles, benzisothiazoles, quinolines and quinoxalines. These heterocycles can be optionally substituted with, by example, with C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, halo, hydroxy, mercapto, trifluoromethyl, amino, cyano or mono or di(C1-6alkyl)amino.
  • Examples of particularly preferred heterocyclic radicals include furyl, thienyl, pyridyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, benzo[b]furanyl, benzo[b]thiophenyl and benzoisoxazolyl.
  • Examples of unsaturated 5-membered heterocyclic rings include oxazole, thiazole, imidazole, 1,2,3-triazole, isoxazole, isothiazole, pyrazole, furan, thiophene and pyrrole. Examples of unsaturated 6-membered heterocyclic rings include pyridine, pyrimidine, pyrazine, pyridazine and 1,2,4-triazine.
  • In a preferred embodiment, the heterocyclic ring is an aromatic ring. Heteroaryl and heteroaromatic are used herein to refer to this subset of heterocyclic rings. Heteroaryl rings include furyl, thienyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-oxadiazol-5-one, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1H thieno[2,3-c]pyrazolyl, thieno[2,3-b]furyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, benzo[b]thiophenyl, 1H-indazolyl, benzimidazolyl, tetrazolyl, uridinyl, and cytosinyl.
  • More preferably heteroaryl or heteroaromatic is selected from isoxazolyl, oxazolyl, imidazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furazanyl, triazolyl, pyridyl, pyrimidinyl, furyl, pyrazolyl, pyridazinyl, thienyl and aryl fused heteroaromatic rings such as benzfuranyl, benzothiophenyl and benzoisoxazolyl.
  • In another preferred embodiment, the heterocyclic ring is a non-aromatic ring selected from the group consisting of pyrrolidine, imidazoline, 2-imidazolidone, 2-pyrrolidone, pyrrolin-2-one, tetrahydrofuran, 1,3-dioxolane, piperidine, tetrahydropyran, oxazoline, 1,3-dioxane, 1,4-piperazine, morpholine and thiomorpholine.
  • The heterocyclic ring containing the linker group B-C may be selected from the above described heterocyclic rings provided the ring meets the requirement of containing at least two nitrogen atoms and excludes aromatic ring systems.
  • Unless otherwise defined, the term “optionally substituted” as used herein means that a group may include one or more substituents that do not interfere with the binding activity of the compound of formula I. In some instances the substituent may be selected to improve binding. The group may be substituted with one or more substituents selected from halogens, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, —(CH2)pC3-7 cycloalkyl, —(CH2)pC4-7 cycloalkenyl, —(CH2)p aryl, —(CH2)p heterocyclyl, —C6H4S(O)tC1-6 alkyl, —C(Ph)3, —(CH2)pZ, —COZ, —CN, —OR, —O—(CH2)1-6—R, —O—(CH2)1-6—OR, —OCOR, —COR, —COOR, —OCONR′R″, —NR′R″, —NRCOR′, —NRCONR′R″, —NRC(S)NR′R″, —NRSO2R′, —NRCOOR′, —C(NR)NR′R″, —CRNOR′, —C(═NOH)NR′R″, —CONR′R″, —C(═NCN)—NR′R″, —C(═NR)NR′R″, —C(═NR′)SR″, —NR′C(═NCN)SR″, —CONRSO2R′, —C(S)NR′R″, —S(O)tR, —SO2NR′R″, —SO2NRCOR′, —OS(O)2R, —PO(OR)2 and —NO2; where p is 0-6, t is 0-2, Z is an N-linked amino acid selected from the group consisting of alanine, asparagine, aspartic acid, glutamic acid, glutamine, glycine, pipecolic acid, α-amino-butyric acid, α-amino-propanoic acid, and iminodiacetic acid, Z being linked through a nitrogen atom of said N-linked amino acid to the carbon atom, and each R, R′ and R″ is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, aryl, heterocyclyl, C1-6 alkylaryl abd C1-6 alkylheterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, C1-6 alkylaryl or C1-6 alkylheterocyclyl, may be optionally substituted with one to six of same or different selected from halogen, hydroxy, lower alkyl, lower alkoxy, —CO2H, CF3, CN, phenyl, NH2 and —NO2; or when R′ and R″ are attached to the same nitrogen atom, they may, together with the atom to which they are attached, form a 5 to 7 membered nitrogen containing heterocyclic ring.
  • When the optional substituent is or contains an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclyl group, the group may itself be optionally substituted with one to six of the same or different halogen atoms, hydroxy, lower alkyl, lower alkoxy, halo-C1-6 alkyl (including —CF3), phenyl, benzyl, —CN, —C(O)—C1-6 alkyl, mercapto, —NH2, mono or di (lower alkyl)amino or —NO2.
  • In relation to nitrogen containing heterocyclic rings, unless otherwise defined optionally substituted includes pyridinium salts and the N-oxide form of suitable ring nitrogens.
  • In relation to non-aromatic carbocyclic or heterocyclic compounds, unless otherwise defined such compounds may also be optionally substituted with one or two ═O groups, instead of or in addition to the above described optional substituents.
  • Examples of optional substituents include halogens, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, —CF3, —OH, phenyl, —NH2, —NHC1-4 alkyl, —N(C1-4)2, —CN, mercapto, C1-4 alkylcarbonyl and C1-4 alkoxycarbonyl.
  • As used herein the term “C1-12 alkyl” refers to straight chain or branched saturated hydrocarbon group having from 1 to 12 carbon atoms. Examples of such alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl. Similarly “C1-6 alkyl” or “lower alkyl” refers to such groups having from 1 to 6 carbon atoms.
  • As used herein the term “C3-7 cycloalkyl” refers to non-aromatic, saturated cyclic groups having from 3 to 7 carbon atoms. Examples include cyclopentyl and cyclohexyl.
  • As used herein the term “alkoxy” refers to a straight or branched alkyl group covalently bound via an O linkage and the terms “C1-4 alkoxy” and “lower alkoxy” refer to such groups containing from one to six carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy and the like.
  • As used herein the term “C2-12 alkenyl” refers to groups formed from C2-12 straight chain or branched non-cyclic hydrocarbon containing one or more double bonds. Examples of C2-12 alkenyl include allyl, 1-methylvinyl, butenyl, iso-butenyl, 1,3-butadienyl, 3-methyl-2-butenyl, 1,3-butadienyl, 1,4-pentadienyl, 1-pentenyl, 1-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl and 1,3,5-hexatrienyl.
  • As used herein the term “C4-7 cycloalkenyl” refers to non aromatic carbocycles having 4 to 7 carbon atoms and having one or more double carbon bonds. Examples include cyclopentenyl, 1-methyl-cyclopentenyl, cyclohexenyl, 1,3-cyclopentadienyl, 1,3-cyclohexadienyl and 1,4-cyclohexadienyl.
  • As used herein the term “C2-12 alkynyl” refers to C2-12 straight or branched non-cyclic hydrocarbon containing one or more triple bonds, preferably one or two triple bonds. Examples include 2-propynyl and 2- or 3-butynyl.
  • The term “aryl C1-12 alkyl” refers to carbocyclic aromatic rings or ring systems as previously described and substituted by a C1-12 alkyl group, also as previously described.
  • Likewise the terms “aryl C2-12 alkenyl” and “aryl C2-12 alkynyl” refer to carbocyclic aromatic rings or ring systems as previously described and substituted by a C2-12 alkenyl or C2-12 alkynyl group, as previously described.
  • The aryl group and the alkyl, alkenyl or alkynyl group may be optionally substituted. Preferably the aryl group is not optionally substituted.
  • Preferably the alkyl, alkenyl or alkynyl group is optionally substituted, and more preferably with a substituent selected from halogens, —CN, —NR′R″, —COR, —COOR, or —CONR′R″. Preferably R, R′ and R″ are independently selected from hydrogen or lower alkyl.
  • As used herein the term “halo” or “halogen” refers to fluoro, chloro, bromo and iodo groups.
  • As used herein a “halo alkyl” group has one or more of the hydrogen atoms on an alkyl group replaced with halogens. An example includes —CF3.
  • Particularly preferred compounds of the invention include those compounds where A is a bivalent link of 3 or 4 atoms selected from C, N, O and S. In that arrangement A and the atoms to which they are attached together form an aromatic ring having five or six ring atoms. When the linking atoms are all carbon, the ring formed is a carbocyclic aromatic ring or ring system. When the linking atoms include one or more of N, O or S then the ring formed is an aromatic heterocyclic ring. Examples include where the substructure
  • Figure US20140051689A1-20140220-C00008
  • is:—
  • Figure US20140051689A1-20140220-C00009
  • Preferably ring A is an optionally substituted aryl or heteroaryl ring, more preferably a phenyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl ring, and most preferably a phenyl or pyridyl ring. The optionally substituents include N-oxides of the ring nitrogen atoms.
  • The aromatic rings may be optionally substituted, preferably by no more than 3 substituents. Of the optional substituents, it is particular preferred to use 1 to 3 substituents selected from halo, lower alkyl, halogenated forms of lower alkyl, hydroxy, lower alkoxy, nitro, amino, loweralkylamino, carboxy, carboxamido, phenyl and benzyl. N-oxide forms of the nitrogen atoms of nitrogen containing rings are also preferred. When A is a pyridyl ring, the ring nitrogen may be in a N-oxide form, or the ring may be in the form of a pyridinium salt.
  • In respect of the heterocyclic ring formed by B-C, it will be understood that this ring can not be selected from all of the heterocyclic rings discussed earlier in relation to the meaning of the term due to the atoms to which B-C are attached. This ring is limited to monocyclic, non-aromatic heterocyclic rings that include at least two nitrogen atoms. The ring may include additional hetero atoms and may be partially unsaturated.
  • Particularly preferred are compounds in which B-C represents a bivalent link of 1 to 3 atoms. The link B-C together with the atoms to which it is attached forms a non-aromatic heterocyclic ring. Examples include where the substructure:—
  • Figure US20140051689A1-20140220-C00010
  • Figure US20140051689A1-20140220-C00011
  • In a preferred form of the invention, B-C represents —CH2—(CH2)z—, where z is 1-4, more preferably 1, 2 or 3, more preferably 1 or 2 and most preferably z is 1.
  • The atoms forming the link B-C may be optionally substituted, preferably by no more than 3 substituents. A broad range of substituents are possible and include halo, lower alkyl, hydroxy, lower alkoxy, phenyl and benzyl.
  • A preferred form of the invention includes those compounds where B-C represents —CH2CH2—.
  • Preferably X is oxygen or sulphur, more preferably X is oxygen.
  • In an embodiment of the invention fused ring A and the ring containing the bivalent link B-C are optionally substituted with one or two substituents independently selected from halogen and C1-6 alkyl. Preferably fused ring A and the ring containing the bivalent link B-C are not substituted.
  • R1 may be an optionally substituted aryl, alkyl or heterocyclyl. Preferably R1 is an optionally substituted aryl or heterocyclyl group, more preferably a phenyl, thienyl, pyrrolyl or pyridyl ring. R1 may also be a —C1-4 alkylphenyl group. The rings of R1 may b optional substituted with halo, hydroxy, nitro, —NR′R″ (where R′ and R″ are independently selected from hydrogen, lower alkyl and —C(O)R, where R is C1-6 alkyl, phenyl or heterocyclyl), C1-12alkyl, phenyl and —O—Ra, where Ra is —C1-12alkyl, —C3-7cycloalkyl, —C1-12alkylC3-7cycloalkyl, phenyl or —C1-12alkylphenyl; and the C1-12alkyl, phenyl or Ra group may be optionally substituted with halo, —CN, —NR′R″, —CO2R or —CONR′R″, where R, R′ and R″ are independently selected from hydrogen or lower alkyl. Preferably, the ring is phenyl and is optionally substituted in the para or 4-position.
  • R1 may be -phenyl substituted with C1-10 alkyl chain, where the alkyl chain is substituted with halo, —CN, —NR′R″, —CO2R or —CONR′R″, where R, R′ and R″ are independently selected from hydrogen or lower alkyl. More preferably the alkyl chain is in the 4-position of the phenyl ring, and substituents are attached to the carbon at the free end of the alkyl group.
  • R1 may be phenyl optionally substituted with a substituent selected from halo, —C1-6alkyl, —C1-6alkylhalo, —C1-6alkylCN, —OC1-6alkyl, —OC1-6alkylhalo, —OC1-6alkylCO2NH2, —OC1-6alkylCN, —OC1-6alkylC3-7cycloalkyl, —OC1-6alkylC6H5, —OC1-6alkylOCH3, —OC6H5, —OC6H4halo, —CF3, —OCF3, —NR′R″ (where R′ and R″ are independently selected from hydrogen, —C(O)C1-6alkyl, —C(O)C6H5, —C(O)CH═CHCO2H, —C(O)C1-6alkylCO2H, —C(O)C1-6alkylCO2CH3, —C(O)C1-6alkylC6H5, —C(O)C1-6alkylC6H4CH3, —C(O)C1-6alkylC6H4OCH3 and —C(O)C1-6alkylC6H4halo), —CO2H, —CO2C1-6alkyl, —NO2, —OH, —C6H5, —C6H4C1-6alkyl, —C6H4halo and —OC(O)C1-6alkyl.
  • Preferably R1 is halophenyl, most preferably 4-chlorophenyl.
  • Compounds where R2 is hydrogen do not form part of the present invention. These compounds are useful as intermediates for the production of compounds of the invention in which R2 is not hydrogen.
  • Preferably R2 is not an unsubstituted —C1-6alkyl or unsubstituted —C(O)—C1-6alkyl.
  • When R2 is —CH2—R3, it is preferred that R3 is —(CH2)m aryl or —(CH2)m heterocyclyl, where m is 0 to 3. R3 may be benzyl (m=1). The ring atoms may by optionally substituted with a broad range of substituents. Preferred substituents are selected from halo, lower alkyl, hydroxy, lower alkoxy and phenyl.
  • When R2 is —C(Y)—R3, it is preferred that Y is O. It is also preferred that R3 is —(CH2)m aryl or —(CH2)m heteroaryl, where m is 0 to 3. It is particularly preferred for R3 to be aryl or heteroaryl (m=0), and more preferably a or 6 membered monocyclic heterocycle or 9 or 10 membered bicyclic heterocycle or an aryl group.
  • When R2 is —C(Y)CH2N(R4)R3 or —C(Y)CH2SR3, R3 is preferably —(CH2)m aryl or —(CH2)m heterocyclyl where m is 0 to 3. The heterocycyl may itself be substituted with an oxo group, hydroxy or lower alkyl.
  • More preferably R3 is phenyl, naphthyl, furyl, thienyl, pyrrolyl, H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl, (including 1,2,3 and 1,2,4 oxadiazolyls) thiazolyl, isoxazolyl, furazanyl, isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, triazolyl (including 1,2,3 and 1,3,4 triazolyls), tetrazolyl, thiadiazolyl (including 1,2,3 and 1,3,4 thiadiazolyls), pyridyl, pyrimidinyl, pyridazinyl, pyranyl, pyrazinyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, piperazinyl, 1,3,5-trithianyl, triazinyl, 1H thieno[2,3-c]pyrazolyl, thieno[2,3-b]furyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, uridinyl, purinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzotriazinyl, naphthyridinyl or pteridinyl.
  • The heterocyclic ring may be fused to a carbocyclic ring such as phenyl, naphthyl, indenyl, azulenyl, fluorenyl, and anthracenyl.
  • The aryl or heterocyclic may be optionally substituted with a broad range of substituents, and preferably with C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, halo, hydroxy, mercapto, trifluoromethyl, amino, nitro, cyano and mono or di(C1-6alkyl)amino. The substituents also include phenyl, benzyl and heterocyclyl.
  • Most preferably R3 is selected from phenyl, furyl, thienyl, pyridyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, benzo[b]furanyl, benzo[b]thiophenyl and benzoisoxazolyl.
  • When R2 is —COR3, it is also preferred for R3 to be -phenylC1-10 alkyl, where the alkyl is substituted with halo, —CN, —NR′R″, —CO2R or —CONR′R″, where R, R′ and R″ are independently selected from hydrogen or lower alkyl. More preferably the alkyl chain is in the 4-position of the phenyl ring, and substituents are attached to the carbon at the free end of the alkyl group.
  • When R2 is —CON(R4)R3 it is preferred for R4 to be hydrogen and R3 to be —(CH2)m aryl or —(CH2)m heteroaryl. Preferably m is 0 to 2, more preferably 0 to 1. The aryl and heteroaryl ring atoms may be optionally substituted with a broad range of substituents. Preferred substituents include halo, lower alkyl, hydroxy, lower alkoxy and phenyl.
  • Another preferred embodiment of the invention are those compounds where R2 is —COR3 and fused ring A contains at least one ring nitrogen atom.
  • When the invention relates to compounds of formula I per se, it is preferred that when R1 is unsubstituted phenyl, X is O, A together with the atoms to which it is attached forms an unsubstituted phenyl ring and B-C is —CH2CH2—, R2 is not unsubstituted C1-6 alkyl or —C(O)C1-6 alkyl.
  • It will be appreciated that compound of formula I and some derivatives thereof may have at least one asymmetric centre, and therefore are capable of existing in more than one stereoisomeric form. The invention extends to each of these forms individually and to mixtures thereof, including racemates. The isomers may be separated conventionally by chromatographic methods or using a resolving agent. Alternatively the individual isomers may be prepared by asymmetric synthesis using chiral intermediates. Where the compound has at least one carbon-carbon double bond, it may occur in Z- and E-forms and all isomeric forms of the compounds being included in the present invention.
  • The salts of the compound of formula I are preferably pharmaceutically acceptable, but it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present invention, since these are useful as intermediates in the preparation of pharmaceutically acceptable salts.
  • The term “pharmaceutically acceptable derivatives” includes pharmaceutically acceptable esters, prodrugs, solvates and hydrates, and pharmaceutically acceptable addition salts of the compounds or the derivatives. Pharmaceutically acceptable derivatives may include any pharmaceutically acceptable salt, solvate, hydrate or any other compound or prodrug which, upon administration to a subject, is capable of providing (directly or indirectly) a compound of formula I or an antivirally active metabolite or residue thereof.
  • The pharmaceutically acceptable salts include acid addition salts, base addition salts, salts of pharmaceutically acceptable esters and the salts of quaternary amines and pyridiniums. The acid addition salts are formed from a compound of the invention and a pharmaceutically acceptable inorganic or organic acid including but not limited to hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, toluenesulphonic, benzenesulphonic, acetic, propionic, ascorbic, citric, malonic, fumaric, maleic, lactic, salicyclic, sulfamic, or tartartic acids. The counter ion of quarternary amines and pyridiniums include chloride, bromide, iodide, sulfate, phosphate, methansulfonate, citrate, acetate, malonate, fumarate, sulfamate, and tartate. The base addition salts include but are not limited to salts such as sodium, potassium, calcium, lithium, magnesium, ammonium and alkylammonium. Also, basic nitrogen-containing groups may be quaternised with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others. The salts may be made in a known manner, for example by treating the compound with an appropriate acid or base in the presence of a suitable solvent.
  • The compounds of the invention may be in crystalline form or as solvates (e.g. hydrates) and it is intended that both forms be within the scope of the present invention. The term “solvate” is a complex of variable stoichiometry formed by a solute (in this invention, a compound of the invention) and a solvent. Such solvents should not interfere with the biological activity of the solute. Solvents may be, by way of example, water, ethanol or acetic acid. Methods of solvation are generally known within the art.
  • The term “pro-drug” is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, for example, compounds where a free hydroxy group is converted into an ester derivative or a ring nitrogen atom is converted to an N-oxide. Examples of ester derivatives include alkyl esters, phosphate esters and those formed from amino acids, preferably valine. Any compound that is a prodrug of a compound of the invention is within the scope and spirit of the invention. Conventional procedures for the preparation of suitable prodrugs according to the invention are described in text books, such as “Design of Prodrugs” Ed. H. Bundgaard, Elsevier, 1985.
  • The term “pharmaceutically acceptable ester” includes biologically acceptable esters of compound of the invention such as sulphonic, phosphonic and carboxylic acid derivatives.
  • Thus, in another aspect of the invention, there is provided a prodrug or pharmaceutically acceptable ester of a compound of formula I.
  • In another aspect of the invention, there is provided a pharmaceutical composition that comprises a therapeutically effective amount of one or more of the aforementioned anti-RSV compounds of formula I, including pharmaceutically derivatives thereof, and optionally a pharmaceutically acceptable carrier or diluent.
  • Unless otherwise specified the terms “treatment” or “treating”, in the context of a method or use of the invention, includes both therapeutic and prophylactic treatments.
  • In further aspect of the present invention, there is provided the use of a compound of formula I, its salts or pharmaceutically acceptable derivatives thereof in the preparation of a medicament for the treatment (therapeutic or prophylactic) of RSV infections.
  • In another aspect of the invention, there is provided a method of treating RSV by the administration of a compound of formula I, including the administration of pharmaceutically acceptable salts, or derivatives such as prodrugs of formula I, or a composition containing at least one compound of formula I, to a patient in need to treatment.
  • In another aspect of the invention, there is provided a method for treating mammals infected with RSV, and in need thereof, which comprises administering to said mammal a therapeutically effective amount of one or more of the aforementioned compounds of formula I or pharmaceutically acceptable derivatives thereof.
  • In another aspect of the invention, there is provided a method for preventing the infection of mammals with RSV, which comprises administering to said mammal a therapeutically effective amount of one or more of the aforementioned compounds of formula I, or pharmaceutically acceptable derivatives thereof.
  • Although the invention has been described with reference to treating RSV, and in particularly human RSV, it will be appreciated that the invention may also be useful in the treatment of other viruses of the sub-family Pneumovrinae, more particularly, the genera Pneumovirus and Metapneumovirus, more particularly animal and human strains of RSV and metapneumovirus.
  • In a further form of the invention there is provided a process for the production of compounds of formula I. These compounds may be prepared using the procedure outlined in the following methods.
  • Scheme 1 depicts a general process for manufacture of compounds of formula III. Compounds of formula III are intermediates, similar to formula I but where R2 is H. Compounds of formula III may be prepared via appropriate starting materials of formula II. General methods for the preparation of 2-(aroyl)benzoic acids and 3-(aroyl)pyridine-2-carboxylic acids of formula II are described by Yamaguchi, M. et. al, J. Med. Chem. 1993, 36, 4052-4060 and Natsugari, H. et. al, J. Med. Chem. 1995, 38, 3106-3120.
  • Figure US20140051689A1-20140220-C00012
  • In general, one equivalent of an appropriate keto-acid of formula II is reacted with approximately 3 equivalents of an appropriate diamine of the general formula H2N—B—C—NH2. The mixture is heated under reflux in an inert solvent, such as toluene or xylene, with a Dean-Stark apparatus for 3-10 h. A catalyst, such as an acid tosylate, can be used. After this time the reaction is allowed to cool and the product filtered and recrystallised from an appropriate solvent. If no precipitate forms the solvent is evaporated in-vacuo and the residue recrystallised or purified using flash chromatography or preparative HPLC.
  • Compounds of formula III can also be produced by the methods described in U.S. Pat. No. 4,058,529, Sulkowski, T. S., et. al, J. Org. Chem. 1967, 32, 2180-2184 and Houlihan, W. J., et. al, J. Med. Chem. 1975, 18, 182-185. Other (novel) compounds of formula I may be obtained by acylating compounds of formula III as described in Scheme 2.
  • Figure US20140051689A1-20140220-C00013
  • In one method, two equivalents of diisopropylethylamine or triethylamine are added to one equivalent of a compound of formula III in THF at 0° C. An acid chloride, or other acylating agent, is added to the mixture and the reaction monitored by HPLC. When the reaction is complete the reaction is quenched with water and the product extracted into a suitable organic solvent and worked up according to standard methods. Similar acylation may also be carried out by reacting one equivalent of the compound of formula III with one equivalent of the appropriate acid chloride in xylene at 120° C. for 1-24 h. The reaction is then allowed to cool and the product isolated. Alternatively, compounds of formula III may be treated with approximately 2.2 equivalents of an appropriate acid chloride or anhydride in pyridine at approximately −5° C. The mixture is allowed to arm to room temperature and after stirring for 2-24 h the product is isolated by standard methods. Acylation may also be achieved by treating the appropriate compound of formula III with the appropriate carboxylic acid (3 equivalents), TFFH (3.3 equivalents) and DIEA (3.3 equivalents) in DMF and heating to 45° C. for approximately 14 days. After this time the product is isolated by standard methods.
  • N-alkylated and N-sulfonylated compounds of Formula I are best obtained using suitable N-substituted diamines. These may be prepared by known methods for example that described by Kruse L. I., et. al, J. Med. Chem. 1990, 33, 781-789.
  • Figure US20140051689A1-20140220-C00014
  • In which R2 is —CHR3 or —S(O)2R5, as earlier defined in the summary of the invention.
  • Hence, the appropriate keto-acid (2 equivalents) and N-substituted diamine (1 equivalent) in chlorobenzene, toluene or xylene are placed in a flask equipped with a stirrer and Dean-Stark water separator and heated at reflux until no further water is seen to separate (1-8 h). The solvent is then removed by distillation and the residue cooled. The residue can be purified using standard methods.
  • Compounds of Formula I where R2 is a urea or thiourea are prepared using the following method.
  • One equivalent of the appropriate compound of formula III is reacted with one equivalent of the appropriate isocyanate or isothiocyanate in THF or xylene at a temperature ranging from 20.120° C. for 1-24 h. The reaction is then allowed to cool and the product filtered, washed and generally recrystallised from an appropriate solvent. If no precipitate is formed the product can be purified using standard chromatographic methods.
  • Other compounds of formula I can be prepared by the addition, removal or modification of existing substituents. This could be achieved by using standard techniques for functional group inter-conversion, well known in the industry such as those described in Comprehensive organic transformations: a guide to functional group preparations by Larock R C, New York, VCH Publishers, Inc. 1989.
  • Examples of functional group inter-conversions are: —C(O)NR′R″ from —CO2CH3 by heating with or without catalytic metal cyanide, e.g. NaCN, and HNR′R″ in CH3OH; —OC(O)R from —OH with e.g., ClC(O)R in pyridine; —NC(S)NR′R″ from —NHR with an alkylisothiocyanate or thiocyanic acid; —NRC(O)OR′ from —NHR with alkyl chloroformate; —NRC(O)NR′R″ from —NHR by treatment with an isocyanate, e.g. HN═C═O or RN═C═O; —NRC(O)R′ from —NHR by treatment with ClC(O)R′ in pyridine; —C(═NR)NR′R″ from —C(NR′R″)SR with H3NR+OAc− by heating in alcohol; —C(NR′R″)SR from —C(S)NR′R″ with R—I in an inert solvent, e.g. acetone; —C(S)NR′R″ (where R′ or R″ is not hydrogen) from —C(S)NH2 with HNR′R″; —C(═NCN)—NR′R″ from —C(═NR′R″)—SR with NH2CN by heating in anhydrous alcohol, alternatively from —C(═NH)—NR′R″ by treatment with BrCN and NaOEt in EtOH; —NR—C(═NCN)SR from —NHR′ by treatment with (RS)2C═NCN; —NR″SO2R from —NHR′ by treatment with CISO2R by heating in pyridine; —NR′C(S)R from —NR′C(O)R by treatment with Lawesson's reagent [2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide]; —NRSO2CF3 from —NHR with triflic anhydride and base, —CH(NH2)CHO from —CH(NH2)C(O)OR′ with Na(Hg) and HCl/EtOH; —CH2C(O)OH from —C(O)OH by treatment with SOCl2 then CH2N2 then H2O/Ag2O; —C(O)OH from —CH2C(O)OCH3 by treatment with PhMgX/HX then acetic anhydride then CrO3; R—OC(O)R′ from RC(O)R′ by R″CO3H; —CCH2OH from —C(O)OR′ with Na/R′OH; —CHCH2 from —CH2CH2OH by the Chugaev reaction; —NH2 from —C(O)OH by the Curtius reaction; —NH2 from —C(O)NHOH with TsCl/base then H2O; —CHC(O)CHR from —CHCHOHCHR by using the Dess-Martin Periodinane regent or CrO3/aqH2SO4/acetone; —C6H5CHO from —C6H5CH3 with CrO2Cl2; —CHO from —CN with SnCl2/HCl; —CN from —C(O)NHR with PCl5; —CH2R from —C(O)R with N2H4/KOH.
  • During the reactions a number of the moieties may need to be protected. Suitable protecting groups are well known in industry and have been described in many references such as Protecting Groups in Organic Synthesis, Greene T W, Wiley-Interscience, New York, 1981.
  • The abbreviations that may be used herein, including in Schemes I-II, and experimental section are as follows unless indicated otherwise:
  • DCM: dichloromethane
    DIEA: diisopropylethylamine
    DMF: dimethylformamide
    Et: ethyl
    EtOAc: ethyl acetate
    Me: methyl
    MeOH: methyl alcohol
    MS: mass spectrometry
    NMR: nuclear magnetic resonance
    Ph: phenyl
    HPLC: high performance liquid chromatography
    TEA: triethylamine
    TFA: Trifluoroacetic acid
    TFFH: Fluoro-N,N,N″,N″-tetramethylformamidinium hexafluorophosphate
    THF: tetrahydrofuran
    TsCl: Tosyl chloride
    TsOH: Toluenesulphonic acid
  • The invention also pertains to therapeutic compositions containing at least one compound of formula I including pharmaceutical acceptable salts or prodrugs.
  • The compositions may further contain one or more other compounds having anti-viral activity in respect of RSV, such as Virazole, or other agents such as RespiGam or Synagis.
  • The compositions may further contain or be administered in combination with other drugs to treat symptoms of the disease, such as for example anti-inflammatory medicaments.
  • The term “composition” is intended to include the formulation of an active ingredient with conventional carriers and excipients, and also with encapsulating materials as the carrier, to give a capsule in which the active ingredient (with or without other carriers) is surrounded by the encapsulation carrier.
  • As will be readily appreciated by those skilled in the art, the route of administration and the nature of the pharmaceutically acceptable carrier will depend on the nature of the condition and the animal to be treated. It is believed that the choice of a particular carrier or delivery system, and route of administration could be readily determined by a person skilled in the art. In the preparation of any formulation containing the compounds care should be taken to ensure that the activity of the compound is not destroyed in the process and that the compound is able to reach its site of action without being destroyed. In some circumstances it may be necessary to protect the compound by means known in the art, such as, for example, micro encapsulation. Similarly the route of administration chosen should be such that the compound reaches its site of action.
  • The pharmaceutical compositions or formulations include those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. It is envisaged that the compositions should be provided in a form suitable for oral or nasal administration or by inhalation or insufflation.
  • The compounds of the invention, together with a conventional adjuvant, carrier, or diluent, may thus be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. Formulations containing ten (10) milligrams of active ingredient or, more broadly, 0.1 to one hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms.
  • The compounds of the present invention can be administrated in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a compound of the invention or a pharmaceutically acceptable salt of a compound of the invention.
  • For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispensable granules. A solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilisers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • In powders, the carrier is a finely divided solid that is in a mixture with the finely divided active component.
  • In tablets, the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
  • The powders and tablets preferably contain from five or ten to about seventy percent of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term “preparation” is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.
  • For preparing suppositories, a low melting wax, such as admixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized moulds, allowed to cool, and thereby to solidify.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
  • Sterile liquid form compositions include sterile solutions, suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a mixture of both.
  • The compositions according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulation agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution, for constitution with a suitable vehicle, eg. sterile, pyrogen-free water, before use.
  • Pharmaceutical forms suitable for injectable use include sterile injectable solutions or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions. They should be stable under the conditions of manufacture and storage and may be preserved against oxidation and the contaminating action of microorganisms such as bacteria or fungi.
  • Those skilled in the art may readily determine appropriate formulations for the compounds of the present invention using conventional approaches. Identification of preferred pH ranges and suitable excipients, for example antioxidants, is routine in the art (see for example Cleland et al, 1993). Buffer systems are routinely used to provide pH values of a desired range and include carboxylic acid buffers for example acetate, citrate, lactate and succinate. A variety of antioxidants are available for such formulations including phenolic compounds such as BHT or vitamin E, reducing agents such as methionine or sulphite, and metal chelators such as EDTA.
  • The solvent or dispersion medium for the injectable solution or dispersion may contain any of the conventional solvent or carrier systems for the compounds, and may contain, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about where necessary by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like. In many cases, it will be preferable to include agents to adjust osmolality, for example, sugars or sodium chloride. Preferably, the formulation for injection will be isotonic with blood. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin. Pharmaceutical forms suitable for injectable use may be delivered by any appropriate route including intravenous, intramuscular, intracerebral, intrathecal, epidural injection or infusion.
  • Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various other ingredients such as these enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilised active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, preferred methods of preparation are vacuum drying or freeze-drying of a previously sterile-filtered solution of the active ingredient plus any additional desired ingredients.
  • When the active ingredients are suitably protected they may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsule, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet. For oral therapeutic administration, the active compound may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations preferably contain at least 1% by weight of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about to about 80% of the weight of the unit. The amount of active compound in therapeutically useful compositions should be sufficient that a suitable dosage will be obtained.
  • The tablets, troches, pills, capsules and the like may also contain the components as listed hereafter: a binder such as gum, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such a sucrose, lactose or saccharin may be added or a flavouring agent such as peppermint, oil of wintergreen, or cherry flavouring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier.
  • Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavouring such as cherry or orange flavour. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the active compound(s) may be incorporated into sustained-release preparations and formulations, including those that allow specific delivery of the active peptide to specific regions of the gut.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilising and thickening agents, as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
  • Pharmaceutically acceptable carriers and/or diluents include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except in so far as any conventional media or agent is incompatible with the active ingredient, use thereof in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavours, stabilisers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilising agents, and the like.
  • For topical administration to the epidermis the compounds according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents.
  • Formulations suitable for topical administration in the mouth include lozenges comprising active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The formulations may be provided in single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomising spray pump. To improve nasal delivery and retention the compounds according to the invention may be encapsulated with cyclodextrins, or formulated with other agents expected to enhance delivery and retention in the nasal mucosa.
  • Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurised pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by provision of a metered valve.
  • Alternatively the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). Conveniently the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.
  • In formulations intended for administration to the respiratory tract, including intranasal formulations, the compound will generally have a small particle size for example of the order of to 10 microns or less. Such a particle size may be obtained by means known in the art, for example by micronisation.
  • When desired, formulations adapted to give sustained release of the active ingredient may be employed.
  • The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the novel dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active material for the treatment of disease in living subjects having a diseased condition in which bodily health is impaired as herein disclosed in detail.
  • The invention also includes the compounds in the absence of carrier where the compounds are in unit dosage form.
  • The amount of compound of formula I administered may be in the range from about 10 mg to 2000 mg per day, depending on the activity of the compound and the disease to be treated.
  • Liquids or powders for intranasal administration, tablets or capsules for oral administration and liquids for intravenous administration are the preferred compositions.
    • EXPERIMENTAL DATA
  • 1H NMR spectra were recorded on either a Bruker Avance DRX 400, AC 200 or AM 300 spectrometer. Spectra were recorded in CDCl3, d6-acetone, CD3OD or d6-DMSO using the residual solvent peak as a reference. Chemical shifts are reported on the 8 scale in parts per million (ppm) using the following conventions to assign the multiplicity: s (singlet), d (doublet), t (triplet), q (quartet) m (multiplet) and prefixed b (broad). Mass spectra (ESI) were recorded on either a Micromass Platform QMS or Finnigan LCQ Advantage spectrometer. Flash chromatography was performed on 40-63 μm silica gel 60 (Merck No. 9385). Analytical HPLC was carried out using a Waters 600 Pump, Waters 717 Autosampler and a Waters 490E UV detector. Preparative HPLC was carried out using a Gilson 322 pump with a Gilson 215 liquid handler and a HP1100 PDA detector. Both HPLC systems employed Phenomonex C8(2) columns using either acetonitrile or acetonitrile containing 0.06% TFA in water or water containing 0.1% TFA.
    • Method A
  • One equivalent of an appropriate keto-acid of formula II, is reacted with approximately 3 equivalents of an appropriate diamine of the general formula H2N—B—C—NH2. The mixture is heated under reflux in an inert solvent, such as toluene or xylene, with a Dean-Stark apparatus for 3-10 h. A catalyst, such as an acid tosylate, can be used. After this time the reaction is allowed to cool and the product filtered and recrystallised from an appropriate solvent. If no precipitate forms the solvent is evaporated in-vacuo and the residue recrystallised or purified using flash chromatography or preparative HPLC.
    • Compound 1
  • Compound 1 was prepared using Method A employing 2-(4-chlorobenzoyl)benzoic acid
  • Figure US20140051689A1-20140220-C00015
  • and ethylene diamine.
  • 1H NMR (300 MHz, CDCl3) δ 2.05 (bs, 1H), 3.11-3.26 (m, 2H), 3.61-3.68 (m, 1H), 3.76-3.84 (m, 1H), 7.22-7.26 (m, 1H), 7.30 (d, J=8.9 Hz, 2H), 7.42-7.48 (m, 2H), 7.62 (d, J=8.8 Hz, 2H), 7.74-7.80 (m, 1H).
  • MS m/z 285 ([M+H+]
    • Compound 2
  • Figure US20140051689A1-20140220-C00016
  • Compound 2 was prepared using Method A from 2-(4-chlorobenzoyl)benzoic acid and 1,3-diaminopropane.
  • 1H NMR (300 MHz, CDCl3) 1.48-1.62 (m, 2H), 2.83-2.96 (m, 1H), 2.97-3.13 (m, 2H), 4.47-4.60 (m, 1H), 7.22-7.29 (m, 1H), 7.31-7.37 (m, 2H), 7.38-7.47 (m, 2H), 7.48-7.56 (m, 2H), 7.82-7.89 (m, 1H).
  • MS m/z ([M+H+] 299
    • Compound 7
  • Figure US20140051689A1-20140220-C00017
  • Compound 7 was prepared using Method A from 2-(4-chlorobenzoyl)benzoic acid and 1,4-diaminobutane.
  • 1H NMR (300 MHz, CDCl3) δ 1.13-1.32 (m, 2H), 1.33-1.57 (m, 2H), 2.15-2.44 (m, 2H), 2.73-2.90 (m, 1H), 3.32-3.49 (m, 1H), 7.10-7.20 (m, 1H), 7.21-7.34 (m, 4H), 7.35-7.49 (m, 2H), 7.60-7.71 (m, 1H).
  • MS m/z ([M+H+]313
  • The methods for forming compounds of formula III are based on those described in U.S. Pat. No. 4,058,529, Sulkowski, T. S., et. al, J. Org. Chem. 1967, 32, 2180-2184 and Houlihan, W. J., et. al, J. Med. Chem. 1975, 18, 182-185.
    • Method B
  • Two equivalents of diisopropylethylamine or triethylamine are added to one equivalent of compound of formula III in THF at 0° C. An acid chloride, or other acylating agent, is added to the mixture and the reaction monitored by HPLC. When the reaction is complete the reaction is quenched with water and the product extracted into EtOAc. The EtOAc is subsequently washed with a 1:1 solution of sat. NH4Cl(aq):water, 1:1 sat. Na2CO3(aq):water and sat. Na2CO3(aq). The EtOAc was dried (Na2SO4), the solvent evaporated in vacuo and the residue either crystallised or purified by flash chromatography using EtOAc/hexanes or by preparative HPLC.
    • Method C
  • One equivalent of the appropriate compound of formula II is reacted with one equivalent of the appropriate acid chloride in xylene at 120° C. for 1-24 h. The reaction is then allowed to cool and the product filtered and recrystallised from an appropriate solvent. If no precipitate is formed the reaction is purified using flash chromatography or preparative HPLC.
    • Method D
  • N-alkylated diamines may be prepared according to the procedure outlined in Kruse L. I., et. al, J. Med. Chem. 1990, 33, 781-789.
  • Appropriate keto-acid (2 equivalents) and N-substituted diamine (1 equivalent) in chlorobenzene, toluene or xylene are placed in a flask equipped with a stirrer and Dean-Stark water separator. The mixture is refluxed until no further water is seen to separate (1-8 h) after which time the solvent is then distilled off and the residue cooled. The residue is purified using flash chromatography or preparative HPLC.
    • Method E
  • One equivalent of the appropriate compound of formula III is reacted with one equivalent of the appropriate isocyanate or isothiocyanate in THF or xylene at a temperature ranging from 20-120° C. for 1-24 h. The reaction is then allowed to cool and the product filtered, washed and recrystallised from an appropriate solvent. If no precipitate was formed the reaction was purified using flash chromatography or preparative HPLC.
    • Compound 12
  • Figure US20140051689A1-20140220-C00018
  • Compound 12 was prepared using Method C using Compound 1 and 4-fluorobenzoyl chloride.
  • 1H NMR (300 MHz, CDCl3) δ 3.22-3.34 (m, 1H), 3.73-3.82 (m, 1H), 3.91-4.03 (m, 1H), 4.28-4.36 (m, 1H), 7.05-7.13 (m, 2H), 7.17 (d, J=7.8 Hz, 2H), 7.33 (d, J=7.8 Hz, 2H), 7.43-7.52 (m, 2H), 7.54-7.65 (m, 2H), 7.84-7.90 (m, 1H), 8.00-8.06 (m, 1H).
  • MS m/z 407 ([M+H+]
    • Compound 13
  • Figure US20140051689A1-20140220-C00019
  • Compound 13 was prepared using Method C using Compound 1 and benzoyl chloride.
  • 1H NMR (300 MHz, CDCl3) δ 3.21-3.31 (m, 1H), 3.72-3.79 (m, 1H), 3.91-4.00 (m, 1H), 4.26-4.33 (m, 1H), 7.20 (d, J=8.8 Hz, 2H), 7.34 (d, J=8.8 Hz, 2H), 7.38-7.48 (m, 5H), 7.56-7.61 (m, 2H), 7.85-7.88 (m, 1H), 8.04-8.07 (m, 1H).
  • MS m/z 389 ([M+H+]
    • Compound 23
  • Figure US20140051689A1-20140220-C00020
  • Compound 23 was prepared using Method D from 2-(4-chlorobenzoyl)benzoic acid and N-benzyl ethylenediamine.
  • 1H NMR (300 MHz, CDCl3) δ 2.97 (d, JAB 13 Hz, 1H), 3.07-3.32 (m, 3H), 3.42 (d, JAB 13 Hz, 1H), 3.83-3.96 (m, 1H), 7.04-7.09 (m, 1H), 7.17-7.38 (m, 8H), 7.39-7.46 (m, 1H), 7.66-7.73 (m, 2H), 7.81-7.86 (m, 1H).
  • MS m/z ([M+H+] 375
    • Compound 24
  • Figure US20140051689A1-20140220-C00021
  • Compound 24 was prepared using Method D from 2-benzoylbenzoic acid and N-benzyl ethylenediamine.
  • 1H NMR (300 MHz, CDCl3) δ 2.99 (d, JAB 13 Hz, 1H), 3.10-3.29 (m, 3H), 3.44 (d, JAB 13 Hz, 1H), 3.84-3.99 (m, 1H), 7.07-7.13 (m, 1H), 7.18-7.44 (m, 10H), 7.73-7.81 (m, 2H), 7.82-7.87 (m, 1H).
  • MS m/z ([M+H+]341
    • Compound 25
  • Figure US20140051689A1-20140220-C00022
  • Compound 25 was prepared using Method D from 2-(4-toluoyl)benzoic acid and N-benzyl ethylenediamine.
  • 1H NMR (300 MHz, CDCl3) δ 2.36 (s, 3H), 3.00 (d, JAB 13 Hz, 1H), 3.11-3.29 (m, 3H), 3.45 (d, JAB 13 Hz, 1H), 3.86-3.98 (m, 1H), 7.08-7.14 (m, 1H), 7.15-7.21 (m, 2H), 7.22-7.44 (m, 7H), 7.63-7.69 (m, 2H), 7.81-7.86 (m, 1H).
  • MS m/z ([M+H+]355
    • Compound 106
  • Compound 106 was prepared using Method A employing 3-bromo-(4-chlorobenzoyl)benzoic acid and ethylene diamine.
  • 1H NMR (300 MHz, CDCl3): δ 3.12-3.25 (m, 2H), 3.64-3.71 (m, 1H), 3.76-3.83 (m, 1H), 7.13, (dd, J 8.1, 0.6 Hz, 1H), 7.33 (d, J=8.7 Hz, 2H), 7.57-7.61 (m, 3H), 7.91 (dd, J 1.8, 0.6 Hz, 1H).
  • MS m/z ([M+H]+) 365
    • Compound 107
  • Compound 107 was prepared using Method A employing 4-bromo-(4-chlorobenzoyl)benzoic acid and ethylene diamine.
  • 1H NMR (300 MHz, CDCl3): δ 3.11-3.24 (m, 2H), 3.69-3.63 (m, 1H), 3.76-3.82 (m, 1H), 7.34, (d, J=8.7 Hz, 1H), 7.39 (dd, J 1.5, 0.6 Hz, 1H), 7.59-7.66 (m, 4H).
  • MS m/z ([M+H]+) 365
    • Method F
  • Two equivalents of boronic acid or ester, five equivalents of Na2CO3 and palladium on charcoal (catalytic) or 0.1 equivalents of [PdCl2(dppf)](dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct) are added to the appropriate bromo-substituted compound of formula III in DME/H2O (93:7). The reaction is heated to 50° C. for 1-4 h. The reaction is then cooled, filtered and evaporated in vacuo to give a solid or oily residue. The residue is then either recrystallised or purified by flash chromatography using EtOAc/hexanes or by preparative HPLC.
    • Method G
  • Three equivalents of boronic acid or ester, six equivalents of K2CO3 and 0.3 equivalents of tetrakis(tripheynylphosphine)palladium are added to the appropriate bromo-substituted compound of formula III in toluene. The reaction is heated to 100° C. for 1-24 h. The reaction is then quenched with CH2Cl2 and washed with water. The CH2Cl2 layer was dried (Na2SO4) and evaporated in vacuo to give a solid or oily residue. The residue is then either recrystallised or purified by flash chromatography using EtOAc/hexanes or by preparative HPLC.
    • Method H
  • The acid chloride or anhydride or isocyanate or isothiocyanate (2.2 eq) is added directly for liquids or as a solution in pyridine (˜1M) for solids to a solution of the appropriate compound of formula III (0.1 mmol) in pyridine (500 μL) at −5° C. The reaction is stirred and allowed to warm to room temperature for between 2-24 h after which time the starting material has been consumed. The reaction is subsequently diluted with water and extracted with CH2Cl2 (3×). The combined CH2Cl2 extracts are washed with 1N NaOH (3×) and 10% HCl (3×). In the case of basic products the acid wash is omitted and in the case of acidic products the basic wash is omitted. For neutral or basic products the crude purity is improved markedly by stirring the combined CH2Cl2 extract in the presence of a carbonate resin (MP-Carbonate˜3 eq) for 0.5-12 h. The CH2Cl2 extracts are dried (MgSO4) and the solvent evaporated in-vacuo. The crude products are subsequently purified by flash chromatography using a EtOAc/Hexane solvent system.
    • Compound 120
  • Compound 120 was prepared using Method F employing compound 107 and 4-tolylboronic acid.
  • 1H NMR (300 MHz, CDCl3): δ 3.19-3.26 (m, 2H), 3.65-3.72 (m, 1H), 3.86-3.89 (m, 1H), 7.23, (d, J=8.1 Hz, 2H), 7.34 (d, J=8.7 Hz, 2H), 7.39-7.45 (m, 3H), 7.65-7.71 (m, 3H), 7.82 (dd, J 8.1, 0.6 Hz, 4H).
  • MS m/z ([M+H]+) 375
    • Compound 132
  • Compound 132 was prepared using Method G employing compound 107 and n-butylboronic acid.
  • 1H NMR (300 MHz, CDCl3): δ 0.89 (t, J=7.5 Hz, 3H), 1.23-1.37 (m, 3H), 1.48-1.56 (m, 2H), 2.59 (t, J=7.8 Hz, 2H), 3.12-3.26 (m, 2H), 3.62-3.69 (m, 1H), 3.83-3.78 (m, 1H), 7.26-7.35 (m, 3H), 7.62-7.69 (m, 3H).
  • MS m/z ([M+H]+) 341
    • Method I
  • A mixture of an appropriate carboxylic acid (3 eq) and TFFH (3.3 eq) was suspended in anhydrous DMF (0.25M) and DIEA (3.3 eq) under nitrogen. The mixture was heated at 45° C. for 30 min. This solution was added to the appropriate compound of Formula III (1 eq) under nitrogen and heated at 45° C. for 14 days. The reaction mixture was transferred to a 10 mL tube and diluted with CH2Cl2 (2 mL). The organic phase was washed with 10% citric acid (2 mL), sat. NaHCO3 (aq) (2 mL) and evaporated to dryness. The residue was purified by flash chromatography over silica, using 0.4% methanol/CH2Cl2 as eluent, to isolate the desired product.
    • Method J
  • This method is an adaptation of the method described by Copéret, C. et al., J. Org. Chem., 1998, 63, 1740-1741.30% Hydrogen peroxide (100 eq) was added to a solution of either an appropriate compound of Formula I or Formula III (1 eq) and trioxorhenium 2.5 mol % in CH2Cl2 (4× volume of hydrogen peroxide solution) at rt. The mixture was stirred overnight after which time the mixture was diluted with water and stirred for a further 30 mins. After this time the CH2Cl2 was separated and the aqueous layer extracted further with CH2Cl2 (2×). The combined extracts were dried and the solvent evaporated in-vacuo to yield the desired product which was purified by crystallisation or chromatography as required.
    • Method K
  • An appropriate substrate of Formula I, wherein R2=6-fluoronicotinoyl or 6-chloronicotinoyl, was produced using Method H. To this substrate was added an excess of an appropriate amine. In a suitable solvent, such as THF or ethanol, the mixture was heated in a sealed vessel to approximately 150° C. for 1-5 h (or 60° C. for 72 h in the case where the nucleophile was hydrazine). After this time the solvent was evaporated and the residue purified using flash chromatography or preparative HPLC.
    • Method L
  • A suitable phenolic compound of formula III was acylated according to Method H. Ester hydrolysis was then effected by dissolving the product in a minimal volume of methanol and treating with an excess of 1M NaOH (aq) at ambient temperature. The reaction mixture was then acidified, extracted with dichloromethane and purified by flash chromatography to yield a phenolic compound of formula I.
  • If desired, conversion of this phenol to a phenyl ether was then performed using standard techniques known in the industry such as those described in Vogel's Textbook of Practical Organic Chemistry by B. S. Furniss et al., Harlow, Longman Scientific & Technical, 1989 or Mitsunobu, O. Synthesis 1981, 1. The crude products were subsequently purified using flash chromatography or preparative HPLC.
    • Compound 239
  • Figure US20140051689A1-20140220-C00023
  • Compound 239 was prepared from 9b-(4-hydroxyphenyl)-1,2,3,9b-tetrahydroimidazo[2,1-a]isoindol-5-one using Method L. The tetrahydroimidazoisoindolone was bis-acylated with 4-fluorobenzoyl chloride according to Method H and the resulting phenolic ester function was converted to a phenol by basic hydrolysis. The product was then treated with chloroacetonitrile and K2CO3 in acetone and heated to reflux for 30 h to yield phenyl ether compound 239.
  • 1H NMR (300 MHz, d6-acetone) δ 3.28-3.38 (m, 1H), 3.91-3.97 (m, 1H), 4.09-4.27 (m, 2H), 5.12 (s, 2H), 7.08 (d, J=9.0 Hz, 2H), 7.17-7.26 (m, 2H), 7.30 (d, J=9.0 Hz, 2H), 7.61-7.71 (m, 4H), 7.79-7.82 (m, 1H), 8.05-8.08 (m, 1H).
    • Method M
  • This method involves nucleophilic displacement of R2 when it represents 2-haloethanoyl. A solution or suspension of an appropriate compound of Formula I (R2=COCH2Br) (1 eq) and an appropriate amine (3 eq) were allow to stand at room temperature for 3 days. The mixture was allowed to evaporate to dryness, the residue lyophilised from 30% acetonitrile/water and the resultant crude product purified by preparative HPLC.
    • Method N
  • This method was used to prepare compound 153.
  • Figure US20140051689A1-20140220-C00024
  • Aluminium chloride (2.88 mol) was added to a stirred suspension of 3,4-pyridine anhydride (1.31 mol) in chlorobenzene (1.2 l) at RT to give an orange suspension and heated to 110° C. for 5 h. The mixture was cooled and carefully hydrolysed with water (2 l), heated to reflux for 1 h, filtered when hot and dried to give a brown solid. The solid was suspended in water (3.5 l) and basified with 10% NaOH solution (350 ml). The resulting solution was filtered, acidified to pH=3.1 with 2N HCl. The precipitate formed was filtered and refluxed with ethanol (2 l) to give a white solid (67 g). This material was dissolved in 10% NaOH (400 ml), acidified to pH 6.3 with 2N HCl and filtered to yield 3-(4-Chloro-benzoyl)-isonicotinic acid (53 g) as a white solid.
  • 1H-NMR (400 MHz, DMSO-d6) δ 7.59 (d, J=8.6 Hz, 2H), 7.68 (d, J=8.6 Hz, 2H), 7.88 (dd, J 0.7, 5.0 Hz, 1H), 8.74 (d, J=0.7 Hz, 1H), 8.93 (d, J=5.0 Hz, 1H), 13.9 (bs, 1H) ppm.
  • 3-(4-Chloro-benzoyl)-isonicotinic acid (53 g) and ethylene diamine (67.7 ml) in xylenes (1.8 l) were refluxed for 4 h. The solution was filtered when hot and the filtrate evaporated under reduced pressure to give a yellow solid (58 g). This material was recrystallised from ethanol to give Compound 153 as a white solid (46.4 g).
  • 1H-NMR (400 MHz, CDCl3) δ 2.12 (bs, 1H, NH), 3.19 (m, 1H), 3.21 (m, 1H), 3.71 (m, 1H), 3.83 (m, 1H), 7.36 (d, J=8.8 Hz, 2H), 7.63 (d, J=8.8 Hz, 2H), 7.66 (dd, J 1.1, 4.9 Hz, 1H), 8.64 (d, J=1.1 Hz, 1H), 8.79 (d, J=4.9 Hz, 1H) ppm. MS m/z ([M+H]+) 286
  • The above described methods were used to make the compounds described in tables 1 to 3 below. All compounds depicted in the tables were obtained. The tables set out a compound reference number, structure, observed mass (not calculated) and the method used to make the compound (based on correspondingly varied starting materials). The observed mass for the two compounds marked with * has not been included.
  • TABLE I
    Compounds of Formula III (Intermediates).
    m/z
    No Structure M + H+ Mtd
    1
    Figure US20140051689A1-20140220-C00025
         		285 A
    2
    Figure US20140051689A1-20140220-C00026
         		299 A
    3
    Figure US20140051689A1-20140220-C00027
         		265 A
    4
    Figure US20140051689A1-20140220-C00028
         		251 A
    5
    Figure US20140051689A1-20140220-C00029
         		265 A
    6
    Figure US20140051689A1-20140220-C00030
         		279 A
    7
    Figure US20140051689A1-20140220-C00031
         		313 A
    8
    Figure US20140051689A1-20140220-C00032
         		252 A
    9
    Figure US20140051689A1-20140220-C00033
         		286 A
    10
    Figure US20140051689A1-20140220-C00034
         		286 A
    11
    Figure US20140051689A1-20140220-C00035
         		252 A
    96
    Figure US20140051689A1-20140220-C00036
         		331 A
    7
    Figure US20140051689A1-20140220-C00037
         		331 A
    100
    Figure US20140051689A1-20140220-C00038
         		257 A
    102
    Figure US20140051689A1-20140220-C00039
         		281 A
    103
    Figure US20140051689A1-20140220-C00040
         		341 F
    106
    Figure US20140051689A1-20140220-C00041
         		365 A
    107
    Figure US20140051689A1-20140220-C00042
         		365 A
    110
    Figure US20140051689A1-20140220-C00043
         		279 A
    111
    Figure US20140051689A1-20140220-C00044
         		296 A
    112
    Figure US20140051689A1-20140220-C00045
         		266 A
    115
    Figure US20140051689A1-20140220-C00046
         		308 H
    116
    Figure US20140051689A1-20140220-C00047
         		388 H
    120
    Figure US20140051689A1-20140220-C00048
         		375 F
    121
    Figure US20140051689A1-20140220-C00049
         		429 F
    122
    Figure US20140051689A1-20140220-C00050
         		364 H
    126
    Figure US20140051689A1-20140220-C00051
         		336 H
    127
    Figure US20140051689A1-20140220-C00052
         		380 H
    128
    Figure US20140051689A1-20140220-C00053
         		366 H
    130
    Figure US20140051689A1-20140220-C00054
         		414 B
    131
    Figure US20140051689A1-20140220-C00055
         		350 H
    132
    Figure US20140051689A1-20140220-C00056
         		341 G
    133
    Figure US20140051689A1-20140220-C00057
         		362 F
    134
    Figure US20140051689A1-20140220-C00058
         		285 A
    136
    Figure US20140051689A1-20140220-C00059
         		267 A
    140
    Figure US20140051689A1-20140220-C00060
         		300 A
    142
    Figure US20140051689A1-20140220-C00061
         		307 A
    150
    Figure US20140051689A1-20140220-C00062
         		269 A
    151
    Figure US20140051689A1-20140220-C00063
         		267 A
    152
    Figure US20140051689A1-20140220-C00064
         		339 A
    153
    Figure US20140051689A1-20140220-C00065
         		286 N
    154
    Figure US20140051689A1-20140220-C00066
         		287 A
    155
    Figure US20140051689A1-20140220-C00067
         		280 A
    156
    Figure US20140051689A1-20140220-C00068
         		279 A
    157
    Figure US20140051689A1-20140220-C00069
         		* A
    158
    Figure US20140051689A1-20140220-C00070
         		330 A
    159
    Figure US20140051689A1-20140220-C00071
         		293 A
    160
    Figure US20140051689A1-20140220-C00072
         		293 A
    161
    Figure US20140051689A1-20140220-C00073
         		329 A
    162
    Figure US20140051689A1-20140220-C00074
         		286 A
    163
    Figure US20140051689A1-20140220-C00075
         		319 A
    164
    Figure US20140051689A1-20140220-C00076
         		320 A
    165
    Figure US20140051689A1-20140220-C00077
         		287 A
    166
    Figure US20140051689A1-20140220-C00078
         		282 A
    167
    Figure US20140051689A1-20140220-C00079
         		332 A
    168
    Figure US20140051689A1-20140220-C00080
         		332 A
    169
    Figure US20140051689A1-20140220-C00081
         		286 A
    170
    Figure US20140051689A1-20140220-C00082
         		280 A
    171
    Figure US20140051689A1-20140220-C00083
         		321 A
    176
    Figure US20140051689A1-20140220-C00084
         		437 A
    177
    Figure US20140051689A1-20140220-C00085
         		437 A
  • TABLE 2
    Compounds of the Invention (Formula I where A is Aryl)
    m/z
    No Structure M + H+ Mtd
    12
    Figure US20140051689A1-20140220-C00086
         		407 B
    13
    Figure US20140051689A1-20140220-C00087
         		389 B
    14
    Figure US20140051689A1-20140220-C00088
         		404 E
    15
    Figure US20140051689A1-20140220-C00089
         		418 E
    16
    Figure US20140051689A1-20140220-C00090
         		341 B
    17
    Figure US20140051689A1-20140220-C00091
         		355 B
    18
    Figure US20140051689A1-20140220-C00092
         		397 B
    19
    Figure US20140051689A1-20140220-C00093
         		439 B
    20
    Figure US20140051689A1-20140220-C00094
         		381 B
    21
    Figure US20140051689A1-20140220-C00095
         		361 B
    22
    Figure US20140051689A1-20140220-C00096
         		526 B
    23
    Figure US20140051689A1-20140220-C00097
         		375 D
    24
    Figure US20140051689A1-20140220-C00098
         		341 D
    25
    Figure US20140051689A1-20140220-C00099
         		355 D
    26
    Figure US20140051689A1-20140220-C00100
         		389 D
    27
    Figure US20140051689A1-20140220-C00101
         		355 D
    28
    Figure US20140051689A1-20140220-C00102
         		369 D
    29
    Figure US20140051689A1-20140220-C00103
         		375 D
    30
    Figure US20140051689A1-20140220-C00104
         		409 D
    31
    Figure US20140051689A1-20140220-C00105
         		389 D
    32
    Figure US20140051689A1-20140220-C00106
         		393 D
    33
    Figure US20140051689A1-20140220-C00107
         		359 D
    34
    Figure US20140051689A1-20140220-C00108
         		373 D
    35
    Figure US20140051689A1-20140220-C00109
         		389 D
    36
    Figure US20140051689A1-20140220-C00110
         		355 D
    37
    Figure US20140051689A1-20140220-C00111
         		369 D
    38
    Figure US20140051689A1-20140220-C00112
         		407 D
    39
    Figure US20140051689A1-20140220-C00113
         		373 D
    40
    Figure US20140051689A1-20140220-C00114
         		387 D
    41
    Figure US20140051689A1-20140220-C00115
         		469 C
    42
    Figure US20140051689A1-20140220-C00116
         		515 C
    43
    Figure US20140051689A1-20140220-C00117
         		423 D
    44
    Figure US20140051689A1-20140220-C00118
         		421 D
    45
    Figure US20140051689A1-20140220-C00119
         		387 D
    46
    Figure US20140051689A1-20140220-C00120
         		401 D
    47
    Figure US20140051689A1-20140220-C00121
         		468 D
    48
    Figure US20140051689A1-20140220-C00122
         		403 D
    49
    Figure US20140051689A1-20140220-C00123
         		423 C
    50
    Figure US20140051689A1-20140220-C00124
         		403 C
    51
    Figure US20140051689A1-20140220-C00125
         		419 C
    52
    Figure US20140051689A1-20140220-C00126
         		473 C
    53
    Figure US20140051689A1-20140220-C00127
         		457 C
    54
    Figure US20140051689A1-20140220-C00128
         		495 C
    55
    Figure US20140051689A1-20140220-C00129
         		481 C
    56
    Figure US20140051689A1-20140220-C00130
         		431 C
    57
    Figure US20140051689A1-20140220-C00131
         		435 C
    58
    Figure US20140051689A1-20140220-C00132
         		439 D
    59
    Figure US20140051689A1-20140220-C00133
         		390 C
    60
    Figure US20140051689A1-20140220-C00134
         		373 C
    61
    Figure US20140051689A1-20140220-C00135
         		387 C
    62
    Figure US20140051689A1-20140220-C00136
         		486 D
    64
    Figure US20140051689A1-20140220-C00137
         		417 C
    65
    Figure US20140051689A1-20140220-C00138
         		397 C
    66
    Figure US20140051689A1-20140220-C00139
         		413 C
    67
    Figure US20140051689A1-20140220-C00140
         		433 C
    68
    Figure US20140051689A1-20140220-C00141
         		417 C
    69
    Figure US20140051689A1-20140220-C00142
         		437 C
    70
    Figure US20140051689A1-20140220-C00143
         		428 C
    71
    Figure US20140051689A1-20140220-C00144
         		448 C
    72
    Figure US20140051689A1-20140220-C00145
         		401 C
    73
    Figure US20140051689A1-20140220-C00146
         		421 C
    74
    Figure US20140051689A1-20140220-C00147
         		395 C
    75
    Figure US20140051689A1-20140220-C00148
         		415 C
    76
    Figure US20140051689A1-20140220-C00149
         		425 C
    77
    Figure US20140051689A1-20140220-C00150
         		445 C
    79
    Figure US20140051689A1-20140220-C00151
         		374 C
    80
    Figure US20140051689A1-20140220-C00152
         		374 C
    81
    Figure US20140051689A1-20140220-C00153
         		384 E
    82
    Figure US20140051689A1-20140220-C00154
         		398 E
    83
    Figure US20140051689A1-20140220-C00155
         		477 E
    84
    Figure US20140051689A1-20140220-C00156
         		497 E
    85
    Figure US20140051689A1-20140220-C00157
         		434 E
    86
    Figure US20140051689A1-20140220-C00158
         		414 E
    87
    Figure US20140051689A1-20140220-C00159
         		436 E
    88
    Figure US20140051689A1-20140220-C00160
         		416 E
    89
    Figure US20140051689A1-20140220-C00161
         		432 E
    91
    Figure US20140051689A1-20140220-C00162
         		365 D
    94
    Figure US20140051689A1-20140220-C00163
         		429 B
    98
    Figure US20140051689A1-20140220-C00164
         		453 B
    99
    Figure US20140051689A1-20140220-C00165
         		453 B
    101
    Figure US20140051689A1-20140220-C00166
         		379 B
    104
    Figure US20140051689A1-20140220-C00167
         		418 B
    105
    Figure US20140051689A1-20140220-C00168
         		463 B
    108
    Figure US20140051689A1-20140220-C00169
         		487 C
    109
    Figure US20140051689A1-20140220-C00170
         		551 H
    114
    Figure US20140051689A1-20140220-C00171
         		327 H
    117
    Figure US20140051689A1-20140220-C00172
         		321 B
    118
    Figure US20140051689A1-20140220-C00173
         		307 B
    124
    Figure US20140051689A1-20140220-C00174
         		335 H
    125
    Figure US20140051689A1-20140220-C00175
         		406 H
    129
    Figure US20140051689A1-20140220-C00176
         		562 H
    135
    Figure US20140051689A1-20140220-C00177
         		341 H
    137
    Figure US20140051689A1-20140220-C00178
         		379 H
    138
    Figure US20140051689A1-20140220-C00179
         		323 L
    139
    Figure US20140051689A1-20140220-C00180
         		484 C
    143
    Figure US20140051689A1-20140220-C00181
         		350 H
    144
    Figure US20140051689A1-20140220-C00182
         		407 H
    145
    Figure US20140051689A1-20140220-C00183
         		429 H
    146
    Figure US20140051689A1-20140220-C00184
         		455 H
    147
    Figure US20140051689A1-20140220-C00185
         		548 H
    172
    Figure US20140051689A1-20140220-C00186
         		447 D
    173
    Figure US20140051689A1-20140220-C00187
         		461 C
    174
    Figure US20140051689A1-20140220-C00188
         		501 B
    175
    Figure US20140051689A1-20140220-C00189
         		501 B
    178
    Figure US20140051689A1-20140220-C00190
         		412 E
    179
    Figure US20140051689A1-20140220-C00191
         		428 E
    180
    Figure US20140051689A1-20140220-C00192
         		448 E
    181
    Figure US20140051689A1-20140220-C00193
         		434 E
    182
    Figure US20140051689A1-20140220-C00194
         		414 E
    183
    Figure US20140051689A1-20140220-C00195
         		380 H
    184
    Figure US20140051689A1-20140220-C00196
         		411 H
    185
    Figure US20140051689A1-20140220-C00197
         		394 H
    186
    Figure US20140051689A1-20140220-C00198
         		463 H
    187
    Figure US20140051689A1-20140220-C00199
         		497 H
    188
    Figure US20140051689A1-20140220-C00200
         		410 H
    189
    Figure US20140051689A1-20140220-C00201
         		389 L
    190
    Figure US20140051689A1-20140220-C00202
         		427 H
    191
    Figure US20140051689A1-20140220-C00203
         		401 H
    192
    Figure US20140051689A1-20140220-C00204
         		335 H
    193
    Figure US20140051689A1-20140220-C00205
         		337 H
    194
    Figure US20140051689A1-20140220-C00206
         		403 H
    195
    Figure US20140051689A1-20140220-C00207
         		429 H
    196
    Figure US20140051689A1-20140220-C00208
         		492 H
    197
    Figure US20140051689A1-20140220-C00209
         		426 H
    198
    Figure US20140051689A1-20140220-C00210
         		384 H
    199
    Figure US20140051689A1-20140220-C00211
         		349 H
    200
    Figure US20140051689A1-20140220-C00212
         		415 H
    201
    Figure US20140051689A1-20140220-C00213
         		441 H
    202
    Figure US20140051689A1-20140220-C00214
         		349 H
    203
    Figure US20140051689A1-20140220-C00215
         		415 H
    204
    Figure US20140051689A1-20140220-C00216
         		441 H
    205
    Figure US20140051689A1-20140220-C00217
         		473 C
    206
    Figure US20140051689A1-20140220-C00218
         		456 C
    207
    Figure US20140051689A1-20140220-C00219
         		475 C
    208
    Figure US20140051689A1-20140220-C00220
         		421 C
    209
    Figure US20140051689A1-20140220-C00221
         		411 I
    210
    Figure US20140051689A1-20140220-C00222
         		510 I
    211
    Figure US20140051689A1-20140220-C00223
         		447 I
    212
    Figure US20140051689A1-20140220-C00224
         		433 I
    213
    Figure US20140051689A1-20140220-C00225
         		437 I
    214
    Figure US20140051689A1-20140220-C00226
         		369 I
    215
    Figure US20140051689A1-20140220-C00227
         		423 I
    216
    Figure US20140051689A1-20140220-C00228
         		395 I
    217
    Figure US20140051689A1-20140220-C00229
         		449 I
    218
    Figure US20140051689A1-20140220-C00230
         		415 I
    219
    Figure US20140051689A1-20140220-C00231
         		379 I
    220
    Figure US20140051689A1-20140220-C00232
         		367 I
    221
    Figure US20140051689A1-20140220-C00233
         		353 I
    222
    Figure US20140051689A1-20140220-C00234
         		383 I
    223
    Figure US20140051689A1-20140220-C00235
         		433 I
    224
    Figure US20140051689A1-20140220-C00236
         		395 I
    225
    Figure US20140051689A1-20140220-C00237
         		493 I
    226
    Figure US20140051689A1-20140220-C00238
         		357 I
    227
    Figure US20140051689A1-20140220-C00239
         		431 I
    228
    Figure US20140051689A1-20140220-C00240
         		470 I
    229
    Figure US20140051689A1-20140220-C00241
         		401 I
    230
    Figure US20140051689A1-20140220-C00242
         		390 H
    231
    Figure US20140051689A1-20140220-C00243
         		391 H
    232
    Figure US20140051689A1-20140220-C00244
         		417 H
    233
    Figure US20140051689A1-20140220-C00245
         		325 H
    234
    Figure US20140051689A1-20140220-C00246
         		453 H
    235
    Figure US20140051689A1-20140220-C00247
         		479 H
    236
    Figure US20140051689A1-20140220-C00248
         		387 H
    237
    Figure US20140051689A1-20140220-C00249
         		511 H
    238
    Figure US20140051689A1-20140220-C00250
         		447 L
    239
    Figure US20140051689A1-20140220-C00251
         		428 L
    240
    Figure US20140051689A1-20140220-C00252
         		428 L
    241
    Figure US20140051689A1-20140220-C00253
         		352 I
    242
    Figure US20140051689A1-20140220-C00254
         		481 I
    243
    Figure US20140051689A1-20140220-C00255
         		397 I
    244
    Figure US20140051689A1-20140220-C00256
         		442 I
    245
    Figure US20140051689A1-20140220-C00257
         		447 I
    246
    Figure US20140051689A1-20140220-C00258
         		384 I
    247
    Figure US20140051689A1-20140220-C00259
         		409 I
    248
    Figure US20140051689A1-20140220-C00260
         		455 I
    249
    Figure US20140051689A1-20140220-C00261
         		397 I
    250
    Figure US20140051689A1-20140220-C00262
         		367 I
    251
    Figure US20140051689A1-20140220-C00263
         		423 I
    252
    Figure US20140051689A1-20140220-C00264
         		405 I
    253
    Figure US20140051689A1-20140220-C00265
         		453 I
    254
    Figure US20140051689A1-20140220-C00266
         		443 I
    255
    Figure US20140051689A1-20140220-C00267
         		451 I
    256
    Figure US20140051689A1-20140220-C00268
         		509 I
    257
    Figure US20140051689A1-20140220-C00269
         		389 L
    258
    Figure US20140051689A1-20140220-C00270
         		447 L
    259
    Figure US20140051689A1-20140220-C00271
         		461 L
    260
    Figure US20140051689A1-20140220-C00272
         		456 L
    261
    Figure US20140051689A1-20140220-C00273
         		465 L
    262
    Figure US20140051689A1-20140220-C00274
         		479 L
    263
    Figure US20140051689A1-20140220-C00275
         		498 L
    264
    Figure US20140051689A1-20140220-C00276
         		479 L
    265
    Figure US20140051689A1-20140220-C00277
         		451 L
    266
    Figure US20140051689A1-20140220-C00278
         		446 L
    267
    Figure US20140051689A1-20140220-C00279
         		443 L
    268
    Figure US20140051689A1-20140220-C00280
         		445 L
    269
    Figure US20140051689A1-20140220-C00281
         		447 L
    270
    Figure US20140051689A1-20140220-C00282
         		454 M
    271
    Figure US20140051689A1-20140220-C00283
         		439 M
    272
    Figure US20140051689A1-20140220-C00284
         		439 M
    273
    Figure US20140051689A1-20140220-C00285
         		453 M
    274
    Figure US20140051689A1-20140220-C00286
         		447 M
    275
    Figure US20140051689A1-20140220-C00287
         		447 M
    276
    Figure US20140051689A1-20140220-C00288
         		467 M
    277
    Figure US20140051689A1-20140220-C00289
         		450 M
    278
    Figure US20140051689A1-20140220-C00290
         		455 M
    279
    Figure US20140051689A1-20140220-C00291
         		469 M
    280
    Figure US20140051689A1-20140220-C00292
         		447 M
    281
    Figure US20140051689A1-20140220-C00293
         		433 M
    282
    Figure US20140051689A1-20140220-C00294
         		490 M
    283
    Figure US20140051689A1-20140220-C00295
         		433 M
    284
    Figure US20140051689A1-20140220-C00296
         		433 M
    285
    Figure US20140051689A1-20140220-C00297
         		419 M
    286
    Figure US20140051689A1-20140220-C00298
         		409 M
    287
    Figure US20140051689A1-20140220-C00299
         		426 M
    288
    Figure US20140051689A1-20140220-C00300
         		469 M
    289
    Figure US20140051689A1-20140220-C00301
         		425 M
    290
    Figure US20140051689A1-20140220-C00302
         		419 M
    291
    Figure US20140051689A1-20140220-C00303
         		419 M
    292
    Figure US20140051689A1-20140220-C00304
         		420 M
    293
    Figure US20140051689A1-20140220-C00305
         		409 M
    294
    Figure US20140051689A1-20140220-C00306
         		469 M
    295
    Figure US20140051689A1-20140220-C00307
         		469 M
    296
    Figure US20140051689A1-20140220-C00308
         		469 M
    297
    Figure US20140051689A1-20140220-C00309
         		475 M
    298
    Figure US20140051689A1-20140220-C00310
         		408 M
    299
    Figure US20140051689A1-20140220-C00311
         		436 M
    300
    Figure US20140051689A1-20140220-C00312
         		475 M
    301
    Figure US20140051689A1-20140220-C00313
         		492 M
    302
    Figure US20140051689A1-20140220-C00314
         		425 M
    303
    Figure US20140051689A1-20140220-C00315
         		437 M
    304
    Figure US20140051689A1-20140220-C00316
         		467 H
    305
    Figure US20140051689A1-20140220-C00317
         		375 H
    306
    Figure US20140051689A1-20140220-C00318
         		408 H
    307
    Figure US20140051689A1-20140220-C00319
         		441 H
    308
    Figure US20140051689A1-20140220-C00320
         		417 L
    309
    Figure US20140051689A1-20140220-C00321
         		459 L
    310
    Figure US20140051689A1-20140220-C00322
         		431 L
    311
    Figure US20140051689A1-20140220-C00323
         		431 L
    312
    Figure US20140051689A1-20140220-C00324
         		424 H
    313
    Figure US20140051689A1-20140220-C00325
         		425 H
    314
    Figure US20140051689A1-20140220-C00326
         		392 H
    315
    Figure US20140051689A1-20140220-C00327
         		513 H
    316
    Figure US20140051689A1-20140220-C00328
         		444 H
    317
    Figure US20140051689A1-20140220-C00329
         		419 K
    318
    Figure US20140051689A1-20140220-C00330
         		445 K
    319
    Figure US20140051689A1-20140220-C00331
         		405 K
    320
    Figure US20140051689A1-20140220-C00332
         		448 K
    321
    Figure US20140051689A1-20140220-C00333
         		449 K
    322
    Figure US20140051689A1-20140220-C00334
         		473 H
    323
    Figure US20140051689A1-20140220-C00335
         		480 H
    324
    Figure US20140051689A1-20140220-C00336
         		478 H
    325
    Figure US20140051689A1-20140220-C00337
         		407 H
    326
    Figure US20140051689A1-20140220-C00338
         		379 H
    327
    Figure US20140051689A1-20140220-C00339
         		395 H
    328
    Figure US20140051689A1-20140220-C00340
         		429 H
    329
    Figure US20140051689A1-20140220-C00341
         		439 H
    330
    Figure US20140051689A1-20140220-C00342
         		424 H
    331
    Figure US20140051689A1-20140220-C00343
         		466 H
    332
    Figure US20140051689A1-20140220-C00344
         		486 H
    333
    Figure US20140051689A1-20140220-C00345
         		461 H
    334
    Figure US20140051689A1-20140220-C00346
         		396 H
    335
    Figure US20140051689A1-20140220-C00347
         		395 H
    503
    Figure US20140051689A1-20140220-C00348
         		489 J
  • TABLE 3
    Compounds of the Invention (Formula I where A is Heteroaryl)
    m/z
    M +
    No. Structure H+ Mtd
     63
    Figure US20140051689A1-20140220-C00349
         		408 C
     78
    Figure US20140051689A1-20140220-C00350
         		408 C
    123
    Figure US20140051689A1-20140220-C00351
         		342 H
    336
    Figure US20140051689A1-20140220-C00352
         		408 C
    337
    Figure US20140051689A1-20140220-C00353
         		342 H
    338
    Figure US20140051689A1-20140220-C00354
         		388 H
    339
    Figure US20140051689A1-20140220-C00355
         		322 H
    340
    Figure US20140051689A1-20140220-C00356
         		409 H
    341
    Figure US20140051689A1-20140220-C00357
         		435 H
    342
    Figure US20140051689A1-20140220-C00358
         		343 H
    343
    Figure US20140051689A1-20140220-C00359
         		414 H
    344
    Figure US20140051689A1-20140220-C00360
         		408 H
    345
    Figure US20140051689A1-20140220-C00361
         		342 H
    346
    Figure US20140051689A1-20140220-C00362
         		434 H
    347
    Figure US20140051689A1-20140220-C00363
         		442 H
    348
    Figure US20140051689A1-20140220-C00364
         		468 H
    349
    Figure US20140051689A1-20140220-C00365
         		468 H
    350
    Figure US20140051689A1-20140220-C00366
         		376 H
    351
    Figure US20140051689A1-20140220-C00367
         		434 H
    352
    Figure US20140051689A1-20140220-C00368
         		424 J
    353
    Figure US20140051689A1-20140220-C00369
         		409 H
    354
    Figure US20140051689A1-20140220-C00370
         		343 H
    355
    Figure US20140051689A1-20140220-C00371
         		389 H
    356
    Figure US20140051689A1-20140220-C00372
         		323 H
    357
    Figure US20140051689A1-20140220-C00373
         		404 H
    358
    Figure US20140051689A1-20140220-C00374
         		452 H
    359
    Figure US20140051689A1-20140220-C00375
         		454 H
    360
    Figure US20140051689A1-20140220-C00376
         		408 H
    361
    Figure US20140051689A1-20140220-C00377
         		402 H
    362
    Figure US20140051689A1-20140220-C00378
         		336 H
    363
    Figure US20140051689A1-20140220-C00379
         		391 H
    364
    Figure US20140051689A1-20140220-C00380
         		425 H
    365
    Figure US20140051689A1-20140220-C00381
         		426 H
    366
    Figure US20140051689A1-20140220-C00382
         		455 H
    367
    Figure US20140051689A1-20140220-C00383
         		455 H
    368
    Figure US20140051689A1-20140220-C00384
         		409 H
    369
    Figure US20140051689A1-20140220-C00385
         		409 H
    370
    Figure US20140051689A1-20140220-C00386
         		409 H
    371
    Figure US20140051689A1-20140220-C00387
         		428 H
    372
    Figure US20140051689A1-20140220-C00388
         		418 J
    373
    Figure US20140051689A1-20140220-C00389
         		444 J
    374
    Figure US20140051689A1-20140220-C00390
         		352 J
    375
    Figure US20140051689A1-20140220-C00391
         		403 H
    376
    Figure US20140051689A1-20140220-C00392
         		483 H
    377
    Figure US20140051689A1-20140220-C00393
         		479 H
    378
    Figure US20140051689A1-20140220-C00394
         		450 H
    379
    Figure US20140051689A1-20140220-C00395
         		446 H
    380
    Figure US20140051689A1-20140220-C00396
         		441 H
    381
    Figure US20140051689A1-20140220-C00397
         		474 H
    382
    Figure US20140051689A1-20140220-C00398
         		395 H
    383
    Figure US20140051689A1-20140220-C00399
         		476 H
    384
    Figure US20140051689A1-20140220-C00400
         		464 H
    385
    Figure US20140051689A1-20140220-C00401
         		462 H
    386
    Figure US20140051689A1-20140220-C00402
         		412 H
    387
    Figure US20140051689A1-20140220-C00403
         		471 H
    388
    Figure US20140051689A1-20140220-C00404
         		472 H
    389
    Figure US20140051689A1-20140220-C00405
         		474 H
    390
    Figure US20140051689A1-20140220-C00406
         		488 H
    391
    Figure US20140051689A1-20140220-C00407
         		473 H
    392
    Figure US20140051689A1-20140220-C00408
         		409 H
    393
    Figure US20140051689A1-20140220-C00409
         		H
    394
    Figure US20140051689A1-20140220-C00410
         		470 H
    395
    Figure US20140051689A1-20140220-C00411
         		517 H
    396
    Figure US20140051689A1-20140220-C00412
         		501 H
    397
    Figure US20140051689A1-20140220-C00413
         		451 H
    398
    Figure US20140051689A1-20140220-C00414
         		437 H
    399
    Figure US20140051689A1-20140220-C00415
         		493 H
    400
    Figure US20140051689A1-20140220-C00416
         		499 H
    401
    Figure US20140051689A1-20140220-C00417
         		465 H
    402
    Figure US20140051689A1-20140220-C00418
         		513 H
    403
    Figure US20140051689A1-20140220-C00419
         		425 H
    404
    Figure US20140051689A1-20140220-C00420
         		483 H
    405
    Figure US20140051689A1-20140220-C00421
         		471 H
    406
    Figure US20140051689A1-20140220-C00422
         		491 H
    407
    Figure US20140051689A1-20140220-C00423
         		449 H
    408
    Figure US20140051689A1-20140220-C00424
         		471 H
    409
    Figure US20140051689A1-20140220-C00425
         		473 H
    410
    Figure US20140051689A1-20140220-C00426
         		489 H
    411
    Figure US20140051689A1-20140220-C00427
         		493 H
    412
    Figure US20140051689A1-20140220-C00428
         		408 H
    413
    Figure US20140051689A1-20140220-C00429
         		380 H
    414
    Figure US20140051689A1-20140220-C00430
         		380 H
    415
    Figure US20140051689A1-20140220-C00431
         		408 H
    416
    Figure US20140051689A1-20140220-C00432
         		480 H
    417
    Figure US20140051689A1-20140220-C00433
         		501 H
    418
    Figure US20140051689A1-20140220-C00434
         		504 H
    419
    Figure US20140051689A1-20140220-C00435
         		500 H
    420
    Figure US20140051689A1-20140220-C00436
         		408 H
    421
    Figure US20140051689A1-20140220-C00437
         		408 H
    422
    Figure US20140051689A1-20140220-C00438
         		422 H
    423
    Figure US20140051689A1-20140220-C00439
         		456 H
    424
    Figure US20140051689A1-20140220-C00440
         		498 H
    425
    Figure US20140051689A1-20140220-C00441
         		450 H
    426
    Figure US20140051689A1-20140220-C00442
         		488 H
    427
    Figure US20140051689A1-20140220-C00443
         		502 H
    428
    Figure US20140051689A1-20140220-C00444
         		484 H
    429
    Figure US20140051689A1-20140220-C00445
         		470 H
    430
    Figure US20140051689A1-20140220-C00446
         		396 H
    431
    Figure US20140051689A1-20140220-C00447
         		396 H
    432
    Figure US20140051689A1-20140220-C00448
         		452 H
    433
    Figure US20140051689A1-20140220-C00449
         		473 H
    434
    Figure US20140051689A1-20140220-C00450
         		441 H
    435
    Figure US20140051689A1-20140220-C00451
         		491 H
    436
    Figure US20140051689A1-20140220-C00452
         		460 H
    437
    Figure US20140051689A1-20140220-C00453
         		476 H
    438
    Figure US20140051689A1-20140220-C00454
         		506 H
    439
    Figure US20140051689A1-20140220-C00455
         		474 H
    440
    Figure US20140051689A1-20140220-C00456
         		493 H
    441
    Figure US20140051689A1-20140220-C00457
         		426 H
    442
    Figure US20140051689A1-20140220-C00458
         		430 H
    443
    Figure US20140051689A1-20140220-C00459
         		508 H
    444
    Figure US20140051689A1-20140220-C00460
         		411 H
    445
    Figure US20140051689A1-20140220-C00461
         		476 H
    446
    Figure US20140051689A1-20140220-C00462
         		478 H
    447
    Figure US20140051689A1-20140220-C00463
         		446 H
    448
    Figure US20140051689A1-20140220-C00464
         		381 H
    449
    Figure US20140051689A1-20140220-C00465
         		440 H
    450
    Figure US20140051689A1-20140220-C00466
         		444 H
    451
    Figure US20140051689A1-20140220-C00467
         		471 H
    452
    Figure US20140051689A1-20140220-C00468
         		449 H
    453
    Figure US20140051689A1-20140220-C00469
         		425 H
    454
    Figure US20140051689A1-20140220-C00470
         		472 H
    455
    Figure US20140051689A1-20140220-C00471
         		391 H
    456
    Figure US20140051689A1-20140220-C00472
         		398 H
    457
    Figure US20140051689A1-20140220-C00473
         		474 H
    458
    Figure US20140051689A1-20140220-C00474
         		489 H
    459
    Figure US20140051689A1-20140220-C00475
         		430 H
    460
    Figure US20140051689A1-20140220-C00476
         		431 H
    461
    Figure US20140051689A1-20140220-C00477
         		465 H
    462
    Figure US20140051689A1-20140220-C00478
         		487 H
    463
    Figure US20140051689A1-20140220-C00479
         		457 H
    464
    Figure US20140051689A1-20140220-C00480
         		440 H
    465
    Figure US20140051689A1-20140220-C00481
         		487 H
    466
    Figure US20140051689A1-20140220-C00482
         		491 H
    467
    Figure US20140051689A1-20140220-C00483
         		462 H
    468
    Figure US20140051689A1-20140220-C00484
         		488 H
    469
    Figure US20140051689A1-20140220-C00485
         		487 H
    470
    Figure US20140051689A1-20140220-C00486
         		493 H
    471
    Figure US20140051689A1-20140220-C00487
         		507 H
    472
    Figure US20140051689A1-20140220-C00488
         		457 H
    473
    Figure US20140051689A1-20140220-C00489
         		488 H
    474
    Figure US20140051689A1-20140220-C00490
         		473 H
    475
    Figure US20140051689A1-20140220-C00491
         		516 H
    476
    Figure US20140051689A1-20140220-C00492
         		503 H
    477
    Figure US20140051689A1-20140220-C00493
         		487 H
    478
    Figure US20140051689A1-20140220-C00494
         		394 H
    479
    Figure US20140051689A1-20140220-C00495
         		491 H
    480
    Figure US20140051689A1-20140220-C00496
         		425 J
    481
    Figure US20140051689A1-20140220-C00497
         		392 H
    482
    Figure US20140051689A1-20140220-C00498
         		506 J
    483
    Figure US20140051689A1-20140220-C00499
         		397 H
    484
    Figure US20140051689A1-20140220-C00500
         		396 H
    485
    Figure US20140051689A1-20140220-C00501
         		437 H
    486
    Figure US20140051689A1-20140220-C00502
         		H
    487
    Figure US20140051689A1-20140220-C00503
         		447 H
    488
    Figure US20140051689A1-20140220-C00504
         		435 H
    489
    Figure US20140051689A1-20140220-C00505
         		460 H
    490
    Figure US20140051689A1-20140220-C00506
         		* H
    491
    Figure US20140051689A1-20140220-C00507
         		457 H
    492
    Figure US20140051689A1-20140220-C00508
         		512 H
    493
    Figure US20140051689A1-20140220-C00509
         		394 A
    494
    Figure US20140051689A1-20140220-C00510
         		366 A
    495
    Figure US20140051689A1-20140220-C00511
         		342 A
    497
    Figure US20140051689A1-20140220-C00512
         		377 A
    498
    Figure US20140051689A1-20140220-C00513
         		419 H
    499
    Figure US20140051689A1-20140220-C00514
         		405 H
    500
    Figure US20140051689A1-20140220-C00515
         		435 H
    501
    Figure US20140051689A1-20140220-C00516
         		421 H
    502
    Figure US20140051689A1-20140220-C00517
         		440 D
    • Method O: Separation of Stereoisomers by Chiral Chromatography
  • Selected compounds of the invention may be separated into single stereoisomers by HPLC using chromatographic columns with a chiral stationary phase. For example, the following racemic compounds were separated into enantiomers under the conditions detailed below.
    • Column: Chirex 3014 (Chirex (S)-VAL and (R)-NEA)) 250×10.0 mm
  • Detector wavelength: 220 nm
    • Separation of Compound 12 Mobile Phase A: Hexane Mobile Phase B: Isopropanol
  • Flow Rate: 4 mL/min
    • Isocratic Elution: 93% Mobile Phase A, 7% Mobile Phase B
  • Run Time: 20 mins
    • Column Temperature: 35° C. Injection Volume: 20 μl Separation of Compound 188 Mobile Phase A: Hexane Mobile Phase B: Isopropanol
  • Flow Rate: 4 mL/min
    • Isocratic Elution: 93% Mobile Phase A, 7% Mobile Phase B
  • Run Time: 26 mins
    • Column Temperature: 35° C. Injection Volume: 15 μl Separation of Compound 306 Mobile Phase A: Hexane Mobile Phase B: Ethanol
  • Flow Rate: 4 mL/min
    • Column Temperature: 25° C. Injection Volume: 20 μl Gradient Timetable:
  • % Mobile
    Time (min) Phase B
    0 5
    15 25
    15 25
    17 5
    22 5
    • Separation of Compound 336 Mobile Phase A: Hexane Mobile Phase B: Isopropanol
  • Flow Rate: 4 mL/min
    • Isocratic Elution: 93% Mobile Phase A, 7% Mobile Phase B
  • Run Time: 50 mins
    • Column Temperature: 35° C. Injection Volume: 25 μl Separation of Compound 352 Mobile Phase A: Hexane Mobile Phase B: Ethanol
  • Flow Rate: 4 mL/min
    • Column Temperature: 25° C. Injection Volume: 15 μl Gradient Timetable:
  • % Mobile
    Time (min) Phase B
    0 15
    15 20
    23 20
    24 15
    29 15
    • Separation of Compound 363 Mobile Phase A: Hexane Mobile Phase B: Isopropanol
  • Flow Rate: 4 mL/min
    • Column Temperature: 50° C. Injection Volume: 15 μl Gradient Timetable:
  • % Mobile
    Time (min) Phase B
    0 17
    25 35
    26 17
    31 17
    • Separation of Compound 368 Mobile Phase A: Hexane Mobile Phase B: Ethanol
  • Flow Rate: 4 mL/min
    • Column Temperature: 25° C. Injection Volume: 15 μl Gradient Timetable:
  • % Mobile
    Time (min) Phase B
    0 5
    15 25
    24 25
    25 5
    30 5
    • Separation of Compound 381 Mobile Phase A: Hexane Mobile Phase B: Ethanol
  • Flow Rate: 4 mL/min
    • Column Temperature: 30° C. Injection Volume: 20 μl Gradient Timetable:
  • % Mobile
    Time (min) Phase B
    0 3
    15 20
    24 20
    25 3
    30 3
    • Separation of Compound 414 Mobile Phase A: Hexane Mobile Phase B: Ethanol
  • Flow Rate: 4 mL/min
    • Isocratic Elution: 92% Mobile Phase A, 8% Mobile Phase B
  • Run Time: 25 mins
    • Column Temperature: 40° C. Injection Volume: 20 μl
  • TABLE 4
    Separation of Enantiomers Using Chirex 3014 Column
    Compound Retention Time of Retention Time of
    Number Enantiomer A (mins) Enantiomer B (mins)
    12 13.1 14.6
    188 13.4 14.8
    306 12.9 13.7
    336 6.7 7.4
    352 20.4 21.3
    363 17.6 19.5
    368 15.8 16.9
    381 20.8 21.9
    414 21.5 22.3

    Column: Chiracel OD-H (250 mm×4.6 mm)
    IS Isocratic Elution: hexane:ethanol (70:30)
    Detector wavelength: 254 nm
    Flow rate: 0.7 ml/min
    • Injection Volume: 20 μl Column Temperature: 25° C.
  • TABLE 5
    Separation of Enantiomers Using Chiracel OD-H Column
    Compound Retention Time of Retention Time of
    Number Enantiomer A (mins) Enantiomer B (mins)
    153 15.4 12.4
    363 89.6 55.1
    414 23.8 17.6
    • Method P: Resolution of Compounds of Type III by Diastereomeric Salt Formation
  • A mixture of Compound 153 (1.0 g, 3.5 mmol) and (R)-(−)-1,1′-Binaphthyl-2,2′-diyl hydrogen phosphate (0.85 g, 2.44 mmol, 0.7 eq) in ethanol (90 ml) was refluxed until a clear solution was formed. After 15 minutes, the mixture was allowed to cool to room temperature for 1 h and then continued stirring under ice cooling for 1.5 h. The white crystalline salt was filtered, rinsed with ethanol (5 ml) and dried under suction for 30 minutes to yield 1.09 g of salt.
  • The white salt was suspended in water (25 ml) and basified with 10% NaOH solution (0.7 ml) to pH 11. The aqueous phase was extracted with ethyl acetate (100 ml then 2×75 ml). The combined organic extracts were washed with saturated NaCl solution, dried (MgSO4) and concentrated to yield Compound 153B (0.49 g) as a white powder.
  • The (R)-(−)-1,1′-Binaphthyl-2,2′-diyl hydrogen phosphate was recovered from the acidified aqueous layer (pH 2) by extraction with ethyl acetate (2×100 ml). The combined organic phases were washed with saturated NaCl solution, dried (MgSO4) and concentrated to afford a white powder (0.54 g).
    • RSV Antiviral Assays Method Q: RSV Antiviral Assay Protocol
  • Compounds of the invention were tested for their antiviral activity against respiratory syncytial virus. Cytopathic effect (CPE) assays were performed essentially as described in the literature (see for example Watanabe et al, J. Virological Methods, 1994, 48, 257). Serial dilutions of the test compounds were made in assay medium. HEp2 cells (1.0×104 cells/well) were infected with RSV at a low multiplicity of infection (e.g. RSV A2 at an moi of 0.01) and 100 μL added to cultures assessing antiviral activity and cells without virus added to those assessing compound cytotoxicity. Assays were incubated for approximately days at 37° C. in a 5% CO2 atmosphere. The extent of CPE was determined via metabolism of the vital dye 3-(4,5-dimethylthiaxol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). A 3 mg/ml stock of MTT was made in assay medium and 100 μL added to each well, taking the final MTT concentration to 1 mg/ml. After 2 hours incubation at 37° C., the media-MTr solution was removed and 200 L of isopropanol was added to dissolve the vital dye crystals. Plates were shaken and the absorbance read at 540 nm. The compound concentrations that inhibited CPE by 50% (EC50) and developed cytotoxicity (CC50) were calculated using an Excel curve fitting program.
  • Representative data for compounds of the invention against RSV A2 is show in Tables 6-8 where EC50 values lie in the ranges A: <100 ng/ml, B: 100-250 ng/ml and C: 250-1000 ng/ml.
  • TABLE 6
    RSV A2 Antiviral Data for Compounds of Table 2
    Cpd No. Activity Range
    12 B
    66 B
    82 C
    85 B
    86 B
    87 B
    88 A
    117 C
    144 B
    178 C
    179 C
    180 C
    183 B
    184 A
    188 C
    190 C
    191 A
    192 C
    199 C
    200 A
    201 C
    203 C
    205 A
    211 C
    214 C
    216 C
    217 B
    218 C
    219 A
    224 A
    227 C
    228 C
    230 A
    231 C
    232 C
    234 A
    235 8
    236 B
    237 C
    238 B
    239 B
    242 B
    243 A
    245 C
    250 C
    260 B
    261 B
    262 B
    263 B
    264 C
    265 B
    266 C
    267 A
    268 C
    299 C
    303 C
    304 C
    305 C
    306 A
    307 B
    308 B
    309 C
    310 C
    311 B
    312 C
    314 B
    316 A
    319 C
    320 C
    323 C
    324 B
    325 A
    326 B
    327 B
    328 B
    329 B
    330 B
    331 C
    332 A
    333 A
    334 B
    335 A
  • TABLE 7
    RSV A2 Antiviral Data for Compounds of Table 3
    Cpd No. Activity Range
    336 B
    344 C
    351 C
    352 B
    358 B
    360 C
    361 B
    363 A
    364 C
    366 A
    367 C
    368 A
    369 B
    370 C
    371 C
    372 C
    377 A
    379 B
    381 A
    382 C
    385 A
    386 B
    387 B
    391 A
    392 B
    394 C
    395 C
    397 B
    398 B
    399 C
    401 B
    404 C
    405 B
    406 C
    408 C
    409 B
    412 A
    413 A
    414 A
    415 C
    416 C
    420 C
    421 C
    422 C
    423 C
    430 A
    431 A
    434 C
    436 B
    437 C
    438 C
    441 B
    442 A
    444 B
    445 A
    448 B
    449 A
    450 B
    453 A
    454 B
    455 C
    456 A
    457 C
    458 B
    461 A
    462 A
    463 A
    464 C
    465 C
    467 A
    468 C
    474 B
    480 A
    481 C
    482 A
    483 A
    484 A
  • TABLE 8
    RSV A2 Antiviral Data for Compounds
    of Tables 4 and 5 (the B enantiomer)
    Cpd No. Activity Range
     12B A
    188B B
    306B A
    336B A
    352B A
    363B A
    368B A
    381B A
    414B A
    • Method R: RSV Fusion Assay
  • Selected compounds of the invention were tested for their ability to inhibit the essential fusion processes of the respiratory syncytial virus.
    • Generation of RSV-F Constructs
  • Single-stranded synthetic DNA oligonucleotides encoding the portions of RSV A2 F glycoprotein incorporating optimal codons and without potential poly(A) addition or splice sites were generated synthetically (Mason et al, WO0242326). A membrane-anchored full-length F was generated essentially according to the method described therein and in Morton et al, Virology, 2003, 31, 275.
    • Syncytium Formation Assay
  • Fusion activity of the RSV-F constructs was measured in 293 cells essentially according to the method described in Morton et al, Virology, 2003, 311, 275. For example: cells in six well plates at approximately 80% confluency were transfected by adding plasmid DNA (2 μg/well) carrying the constructs of interest in CaPO4 solution for 4 hours. After glycerol shock and wash, the transfected cells were trypsinized and 1.5×104 cells/well added to 96-well plates containing half-log serial dilutions of the test compound. Syncytium formation was evaluated by visual inspection and quantified at 48 hours post-transfection by addition of 20 μL of CellTiter 96 One Solution (Promega) followed by incubation for 4 hours at 37° C. The colour reaction was then stopped by addition of 25 μL 10% SDS to each well and absorbance measured at 492 nm. The compound concentration that reduced absorbance relative to untreated control cultures by 50% (EC50) was calculated using an Excel curve fitting program.
  • Representative data for compounds of the invention is show in Table 9 where EC50 values lie in the ranges A: <750 ng/ml, B: 750-1500 ng/ml and C: 1500-2250 ng/ml.
  • TABLE 9
    RSV Fusion Assay Data
    Compound Number RSV Fusion Assay EC50
    12 C
    16 B
    66 B
    336 A
    • Method S: RSV Cotton Rat Model
  • The cotton rat model was performed essentially as described in the literature (Wyde et al, Antiviral Res. 2003, 60, 221). Briefly, cotton rats weighing 50-100 g were lightly anesthetized with isoflurane and dosed orally with 100 mg/kg/day of compound or vehicle control. Viral infection followed 2 hours post-treatment in similarly anesthetized rats by intranasal instillation with approximately 1000 TCID50 of RSV A2 per animal. Four days after virus inoculation, each cotton rat was sacrificed and their lungs removed and RSV titres determined by plaque assay.
  • TABLE 10
    RSV Cotton Rat Model Data
    Compound Number % Reduction of virus Control
    352 68
    306 72
    336 96
    • Method T: RSV Balb/c Mouse Model
  • The mouse model was performed essentially as described by Clanci et al (Antimicroblal Agents and Chemotherapy. 2004, 48, 413). Briefly, eight week old female Balb/c mice were weighed, anesthetized intraperitoneally with Avertin™ and compound or vehicle administered orally 6 hours preinfection. Mice were inoculated intranasally with approximately 10000 TCID50 RSV A2 per animal. Three days after virus inoculation, each mouse was sacrificed and their lungs removed and RSV titres determined by plaque assay.
  • TABLE 11
    RSV Balb/c Mouse Model Data
    Compound Number % reduction of virus control
    336 80
  • It would be appreciated by a person skilled in the art the numerous variations and/or modifications may be made to the invention as shown the specific embodiments without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.
  • Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “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.
  • The reference to any prior art in this specification is not, and should not be taken as an acknowledgment or any form or suggestion that that prior art forms part of the common general knowledge in Australia.

Claims (41)

1. A method for treating a mammal infected with respiratory syncytial (RSV), which comprises administering to the mammal a therapeutically effective amount of one or more compounds of formula I
Figure US20140051689A1-20140220-C00518
or pharmaceutically acceptable salts or derivatives thereof, in the treatment of infections involving viruses of the Pneumovirinae sub-family, wherein
A together with the atoms to which it is attached, forms an optionally substituted aromatic ring;
linker B-C together with the atoms to which they are attached, forms an optionally substituted heterocyclic ring having from 5 to 8 ring atoms;
R1 is selected from C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, —(CH2)nC3-7 cycloalkyl, —(CH2)nC4-7 cycloalkenyl, —(CH2)n aryl, —(CH2)n arylC1-12 alkyl, —(CH2)n arylC2-12 alkenyl, —(CH2)n arylC2-12 alkynyl, and —(CH2)n heterocyclyl; n is 0-6 and the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are optionally substituted;
R2 is selected from —CH2R3, —C(Y)R3, —C(Y)OR3, —C(Y)N(R4)R3, —C(Y)C2H2N(R4)R3, —C(Y)CH2SR3 and —S(O)wR3, where R3 is selected from hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, —(CH2)m arylC3-7 cycloalkyl, —(CH2)mC4-7 cycloalkenyl, —(CH2)m aryl, —(CH2)m arylC1-12 alkyl, —(CH2)m arylC2-12 alkenyl, —(CH2)m arylC2-12 alkynyl and —(CH2)m heterocyclyl; and when R2 is —CH2R3, or —C(Y)R3, R3 may also be selected from —S—R5 and —O—R5; m is 0-6; R4 is hydrogen or C1-6 alkyl; R5 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, benzyl, aryl or heterocyclyl; w is 0, 1 or 2, and the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are optionally substituted; and
X and Y are independently selected from O, S and NR6, where R6 is independently selected from hydrogen, lower alkyl, hydroxy and lower alkoxy.
2. The method according to claim 1 wherein R2 is not an unsubstituted —C1-6alkyl or unsubstituted —C(O)—C1-6alkyl.
3. The method according to claim 1 wherein ring A is an optionally substituted aryl ring.
4. The method according to claim 1 wherein ring A is an optionally substituted phenyl ring.
5. The method according to claim 1 wherein ring A is an optionally substituted heteroaryl ring.
6. The method according to claim 1 wherein ring A together with the atoms to which it is attached, represents an optionally substituted pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl or isoxazolyl ring.
7. The method according to claim 1 wherein ring A is an optionally substituted pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl ring.
8. The method according to claim 1 wherein ring A is optionally substituted pyridyl ring.
9. The method according to claim 1 wherein ring A is optionally substituted with one or more substituents independently selected from halo, —NH2, NO2, C1-6 alkyl, aryl and heterocyclyl, the aryl and heterocyclyl groups optionally substituted with halo, C1-6alkyl or halo substituted C1-6 alkyl and, when ring A contains one or more ring nitrogens, the optional substituents include N-oxides of one or more of the ring nitrogens and pyridinium salts thereof.
10. The method according to claim 1 wherein ring A is optionally substituted with a substituent selected from halo, alkyl, C6H5—CH3—C6H4—, CF3—C6H4—, pyridyl, NO2 and when ring A contains one or more ring nitrogens, the optional substituent also include an N-oxide form of a ring nitrogen, and pyridinium salts thereof.
11. The method according to claim 1 wherein ring A is not substituted.
12. The method according to claim 1 of a compound of the formula IV
Figure US20140051689A1-20140220-C00519
its salts, N-oxides and pharmaceutically acceptable derivatives thereof, wherein B-C, X, R1 and R2 are as defined in claim 1.
13. The method according to claim 1, wherein R2 is selected from —CH2R3, —C(Y)R3, —C(Y)OR3, —C(Y)N(R4)R3, —C(Y)CH2N(R4)R3, —C(Y)CH2SR3 and —S(O)wR5, where R3 is selected from hydrogen, —C1-12alkyl, —C2-12alkenyl, —C2-12alkynyl, —(CH2)mC3-7cycloalkyl, —(CH2)mC4-7 cycloalkenyl, —(CH2)maryl, —(CH2)marylC1-12 alkyl, —(CH2)marylC2-12alkenyl, —(CH2)marylC2-12 alkynyl, —(CH2)mheterocyclyl, and when R2 is —CH2R3, or —C(Y)R3, R3 may also be selected from —S—R5 and —O—R5; m is 0-6, R4 is hydrogen or is C1-6 alkyl, R5 is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C4-7 cycloalkenyl, benzyl, aryl and heterocyclyl, w is 0, 1 or 2, and the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are optionally substituted with one or more substituents selected from C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6alkynyl, halo, halo-C1-6 alkyl (including CF3), hydroxy, mercapto, nitro, cyano, NH2, mono or di((C1-6alkyl)amino, phenyl, benzyl and heterocyclyl.
14. The method according to claim 1 wherein R2 is —CH2—R3, and R3 is —(CH2)maryl or —(CH2)m heterocyclyl and m is 0 to 3 and the aryl or heterocyclyl ring is optionally substituted.
15. The method according to claim 1 wherein R2 is —COR3 and R3 is aryl or heterocyclyl and is optionally substituted.
16. The method according to claim 1 wherein R3 is optionally substituted phenyl, naphthyl, furyl, thienyl, pyrrolyl, H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl, (including 1,2,3 and 1,2,4 oxadiazolyls) thiazolyl, isoxazolyl, furazanyl, isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, triazolyl (including 1,2,3 and 1,3,4 triazolyls), tetrazolyl, thiadiazolyl (including 1,2,3 and 1,3,4 thiadiazolyls), pyridyl, pyrimidinyl, pyridazinyl, pyranyl, pyrazinyl, piperidinyl. 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, piperazinyl, 1,3,5-trithianyl, triazinyl, 1H thieno[2,3-c]pyrazolyl, thieno[2,3-b]furyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, uridinyl, purinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzotriazinyl, naphthyridinyl or pteridinyl.
17. The method according to claim 16, wherein R3 is optionally substituted with one or more substituents selected from C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, halo, halo-C1-6 alkyl (including CF3), hydroxy, mercapto, nitro, cyano. NH2, mono or di(C1-6alkyl)amino, phenyl, benzyl and heterocyclyl.
18. The method according to claim 1 wherein R2 is —CON(H)R3, and R3 is —(CH2)m aryl or —(CH2)m heteroaryl and m is 0 to 2 and the aryl or heteroaryl ring is optionally substituted with one or more substituents independently selected from halo, lower alkyl, hydroxy, lower alkoxy and phenyl.
19. The method according to claim 1 wherein link -B-C- is an optionally substituted link of the formula —CH2—(CH)z—, where z is 1-4.
20. The method according to claim 19 wherein z is 1 or 2.
21. The method according to claim 1 wherein -B-C- is a linker of the formula —CH2CH2—.
22. The method according to claim 1 wherein linker -B-C- is optionally substituted no more than three optional substituents, the substituents selected from halo, lower alkyl, hydroxy, lower alkoxy, phenyl and benzyl.
23. The method according to claim 1 wherein linker -B-C- is not substituted.
24. The method according to claim 1 wherein X is oxygen or sulphur.
25. The method according to claim 1 wherein R1 is an optionally substituted aryl or heterocyclyl group.
26. The method according to claim 1 wherein R1 represents phenyl, thienyl, pyrrolyl, pyridyl ring or a —C1-6 alkylphenyl group, the rings being optional substituted with halo, hydroxy, nitro, —NR′R″ (where R′ and R″ are independently selected from hydrogen, lower alkyl and —C(O)R, where R is C1-6 alkyl, phenyl or heterocyclyl), C1-12alkyl, phenyl and —O—Ra, where Ra is —C1-12alkyl, —C3-7cycloalkyl, —C1-12alkylC3-7cycloalkyl, phenyl or —C1-12alkylphenyl; and the C1-12alkyl, phenyl or Ra group may be optionally substituted with halo, —CN, —NR′R″; —CO2R or —CONR′R″, where R, R′ and R″ are independently selected from hydrogen or lower alkyl.
27. The method according to claim 1 wherein R1 is phenyl optionally substituted with a substituent selected from halo, —C1-6alkyl, —C1-6alkylhalo, —C1-6alkylCN, —OC1-6alkyl, —OC1-6alkylhalo, —OC1-6alkylCO2NH2, —OC1-6alkylCN, —OC1-6alkylC3-7cycloalkyl, —OC1-6alkylC6H5, —OC1-6alkylOCH3, —OC6H5, —OC6H4halo, —CF3, —OCF3, —NR′R″ (where R′ and R″ are independently selected from hydrogen, —C(O)C1-6alkyl, —C(O)C6H5, —C(O)CH═CHCO2H, —C(O)C1-6alkylCO2H, —C(O)C1-6alkylCO2CH3, —C(O)C1-6alkylC6H5, —C(O)C1-6alkylC6H4CH3, —C(O)C1-6alkylC6H4OCH3 and —C(O)C1-6alkylC6H4halo), —CO2H, —CO2C1-6alkyl, —NO2, —OH, —C6H5, —C6H4C1-6alkyl, —C6H4halo and —OC(O)C1-6alkyl.
28. The method according to claim 1 wherein R1 is phenyl substituted with halo, —OC1-6alkyl, —OC1-6alkylhalo, —OC1-6alkylCO2NH2, —OC1-6alkylCN, —OC1-6alkylC3-7cycloalkyl, —OC1-6alkylC6H5 or —OC1-6alkylOCH3.
29. The method according to claim 1 wherein R1 is 4-chlorophenyl.
30. A method for the treatment of infections involving respiratory syncytial viruses (RSV) by the inhibition of the virus's fusion processes by the administration of a therapeutically effective amount of a compound of formula I as defined in claim 1, or a pharmaceutically acceptable salt or derivative thereof to a patient in need to treatment.
31. A pharmaceutical formulation for the treatment of infections involving respiratory syncytial viruses (RSV) comprising a compound of formula I as defined in claim 1, or a pharmaceutically acceptable salt or derivative thereof.
32-37. (canceled)
38. A compound of formula I
Figure US20140051689A1-20140220-C00520
or a salt or pharmaceutically acceptable derivative thereof, wherein
A together with the atoms to which it is attached, represents an optionally substituted phenyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl ring;
B-C is an optionally substituted link of the formula —CH2—(CH)z—, where z is 1-4;
R1 is selected from C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, —(CH2)nC3-7 cycloalkyl, —(CH2)nC4-7 cycloalkenyl, —(CH2)n aryl, —(CH2)n arylC1-12 alkyl, —(CH2)n arylC2-12 alkenyl, —(CH2)n arylC2-12, alkynyl, and —(CH2)n heterocyclyl; n is 0-6 and the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are optionally substituted;
R2 is selected from —CH2R3, —C(Y)R3, —C(Y)OR3, —C(Y)N(R4)R3 and —S(O)wR5, where R3 is selected from hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, —(CH)mC3-7cycloalkyl, —(CH2)mC4-7 cycloalkenyl, —(CH2)m aryl, —(CH2)m arylC1-12 alkyl, —(CH2)m arylC2-12 alkenyl, —(CH2)m arylC2-12 alkynyl and —(CH2)m heterocyclyl; and when R2 is —CH2R3, or —C(Y)R3, R3 may also be selected from —S—R5 and —O—R5; m is 0-6; R4 is hydrogen or C1-6alkyl; R5 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, benzyl, aryl or heterocyclyl; w is 0, 1 or 2, and the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are optionally substituted,
X and Y are independently selected from O, S and NR6, where R6 is independently selected from hydrogen, lower alkyl, hydroxy and lower alkoxy;
with the provisos that when A is phenyl and R1 is 4-chlorophenyl or unsubstituted phenyl
(i) R1 is not unsubstituted cyclopropyl, halomethyl, unsubstituted phenyl or phenyl with only halo, —CH3 and/or —OCH3 substituents when R2 is COR3;
(ii) R3 is not unsubstituted phenyl or phenyl with only halo, —CH3, —OCH3 and/or —C(O)OCH2CH3 substituents when R2 is C(O)NHR3;
(iii) R3 is not unsubstituted phenyl or phenyl with only halo, —CH3, —OCH3 and/or —C(O)OCH2CH3 substituents when R2 is C(S)NHR3;
and with the provisos
(iv) when A is phenyl and R2 is CH2R3; R3 is not hydrogen, unsubstituted C1-6 alkyl or C1-6 alkyl only substituted with NH2, mono or di C1-6 alkyl amino groups;
(v) when A is phenyl and R1 is 4-methoxyphenyl, R2 is not CHO;
(vi) when A is phenyl and R1 is phenyl optionally substituted with only halo, C1-6 alkyl and/or C1-6 alkoxy and R2 is COR3, R3 is not methylene substituted with NH2, mono or di C1-6 alkyl amino. N-piperidinyl or N-morpholinyl;
(vii) when A is phenyl and R1 is 3-CH3,4-CH3CH2CH2NHC(O)CH2O-phenyl, R2 is not —S(O)2CH2SO2CH3, —CHO, —COCH2CH3, —CH2CH2OH, —CH2CH2OCH3, —CH2CO2C(CH3)3 or C1-6 alkyl;
(viii) when A is pyridyl and R1 is 3-CH3,4-CH3CH2CH2NHC(O)CH2O-phenyl, R2 is not CH3.
39-64. (canceled)
65. A compound selected from the group consisting of
Figure US20140051689A1-20140220-C00521
Figure US20140051689A1-20140220-C00522
Figure US20140051689A1-20140220-C00523
Figure US20140051689A1-20140220-C00524
Figure US20140051689A1-20140220-C00525
Figure US20140051689A1-20140220-C00526
Figure US20140051689A1-20140220-C00527
Figure US20140051689A1-20140220-C00528
Figure US20140051689A1-20140220-C00529
Figure US20140051689A1-20140220-C00530
Figure US20140051689A1-20140220-C00531
Figure US20140051689A1-20140220-C00532
Figure US20140051689A1-20140220-C00533
Figure US20140051689A1-20140220-C00534
Figure US20140051689A1-20140220-C00535
Figure US20140051689A1-20140220-C00536
Figure US20140051689A1-20140220-C00537
Figure US20140051689A1-20140220-C00538
Figure US20140051689A1-20140220-C00539
Figure US20140051689A1-20140220-C00540
Figure US20140051689A1-20140220-C00541
Figure US20140051689A1-20140220-C00542
Figure US20140051689A1-20140220-C00543
Figure US20140051689A1-20140220-C00544
Figure US20140051689A1-20140220-C00545
Figure US20140051689A1-20140220-C00546
Figure US20140051689A1-20140220-C00547
Figure US20140051689A1-20140220-C00548
Figure US20140051689A1-20140220-C00549
Figure US20140051689A1-20140220-C00550
Figure US20140051689A1-20140220-C00551
Figure US20140051689A1-20140220-C00552
Figure US20140051689A1-20140220-C00553
Figure US20140051689A1-20140220-C00554
Figure US20140051689A1-20140220-C00555
Figure US20140051689A1-20140220-C00556
Figure US20140051689A1-20140220-C00557
Figure US20140051689A1-20140220-C00558
Figure US20140051689A1-20140220-C00559
Figure US20140051689A1-20140220-C00560
Figure US20140051689A1-20140220-C00561
Figure US20140051689A1-20140220-C00562
Figure US20140051689A1-20140220-C00563
Figure US20140051689A1-20140220-C00564
Figure US20140051689A1-20140220-C00565
Figure US20140051689A1-20140220-C00566
Figure US20140051689A1-20140220-C00567
Figure US20140051689A1-20140220-C00568
Figure US20140051689A1-20140220-C00569
Figure US20140051689A1-20140220-C00570
Figure US20140051689A1-20140220-C00571
Figure US20140051689A1-20140220-C00572
Figure US20140051689A1-20140220-C00573
Figure US20140051689A1-20140220-C00574
Figure US20140051689A1-20140220-C00575
Figure US20140051689A1-20140220-C00576
and salts thereof.
66. A pharmaceutical formulation for the treatment of infections involving respiratory syncytial viruses (RSV) comprising a compound of formula I as defined in claim 38, or a pharmaceutically acceptable salt or derivative thereof.
67. A compound of formula
Figure US20140051689A1-20140220-C00577
or a salt thereof, wherein
the pyridyl ring is optionally substituted;
B-C is an optionally substituted linker of the formula —CH2—(CH2)z—, where z is 1-4;
R1 is selected from C1-12alkyl, C2-12alkenyl, C2-12alkynyl, —(CH2)nC3-7cycloalkyl, —(CH2)nC4-7cycloalkenyl, —(CH2)naryl, —(CH2)narylC1-12alkyl, —(CH2)narylC2-12alkenyl, —(CH2)narylC2-12alkynyl, and —(CH2)nheterocyclyl; n is 0-6; and the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are optionally substituted;
X is selected from O, S and NR6, where R6 is independently selected from hydrogen, lower alkyl, hydroxy and lower alkoxy;
with the proviso that when -B-C- is —CH2CH(CH(CH3)2)—, R1 is not 3-CH3,4-CH3CH2CH2NHC(O)CH2O-phenyl-.
68-77. (canceled)
78. Use of a compound of formula III,
Figure US20140051689A1-20140220-C00578
and salts thereof, wherein R1, ring A, -B-C- and X are as defined in claim 38, as an intermediate for the production of a compound of formula I as defined in claim 38.
79. A method of separating the enantiomers of a compound of formula III by forming diastereomeric salts of the compounds using an enantiomerically enriched chiral hydrogen phosphate.
80-82. (canceled)
US14/062,780 2003-12-24 2013-10-24 Polycyclic Agents for the Treatment of Respiratory Syncytial Virus Infections Abandoned US20140051689A1 (en)

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