WO2016133888A1 - Composés pour le traitement d'infections par le virus respiratoire syncytial - Google Patents

Composés pour le traitement d'infections par le virus respiratoire syncytial Download PDF

Info

Publication number
WO2016133888A1
WO2016133888A1 PCT/US2016/018044 US2016018044W WO2016133888A1 WO 2016133888 A1 WO2016133888 A1 WO 2016133888A1 US 2016018044 W US2016018044 W US 2016018044W WO 2016133888 A1 WO2016133888 A1 WO 2016133888A1
Authority
WO
WIPO (PCT)
Prior art keywords
optionally substituted
rsv
group
compound
composition according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2016/018044
Other languages
English (en)
Inventor
Alistair Draffan
Jeffrey Mitchell
Gary Pitt
Rosliana Halim
Michael Harding
Daniel A. OFFERMAN
Edward Lee
John Vernachio
Elyse Bourque
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Vaxart Inc
Original Assignee
Biota Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Biota Pharmaceuticals Inc filed Critical Biota Pharmaceuticals Inc
Publication of WO2016133888A1 publication Critical patent/WO2016133888A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/80—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—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 compounds useful in the treatment of viral infections, in particular respiratory syncytial viral (RSV) infections.
  • RSV respiratory syncytial viral
  • the present invention also relates to processes for preparing the compounds and intermediates used in their preparation.
  • Respiratory syncytial virus is the leading cause of acute upper and lower respiratory tract infections (LRTI ) in adults, young children and infants.
  • RSV is primarily considered to be a paediatric disease due to the prevalence and severity of unfavourable outcomes in infants.
  • Acute LRTI are a leading cause of global childhood mortality and morbidity.
  • Serological evidence indicates that in the western world approximately 95% of all children have been infected with RSV by the age of two and 100% of children have been exposed by the time they reach adulthood.
  • RSV is a seasonal infectious disease that generally runs from November to March/April in the Northern Hemisphere. In more tropical climates, the annual epidemics are more variable, often coinciding with the wet season. 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. Further, since the immune response to RSV infection is not protective, RSV infections reoccur throughout adulthood . Annual re-infection rates in adults of 3-6% have been observed . RSV is the predominant cause of acute LRTI in infants.
  • Symptoms of RSV infection include bronchiolitis, cough, wheezing, rales (crackling in the lungs), low grade fever (38.3°C), decreased oral intake and in more advanced cases of infection cyanosis can occur with up to 20% of patients developing an elevated temperature.
  • bronchiolitis bronchiolitis, cough, wheezing, rales (crackling in the lungs), low grade fever (38.3°C), decreased oral intake and in more advanced cases of infection cyanosis can occur with up to 20% of patients developing an elevated temperature.
  • a given year it is estimated that in the United States alone, 4-5 million children under the age of 4 years will develop an acute RSV infection and more than 125,000 infants are hospitalized with an RSV related illness. Between 25-40% of infants with RSV infections will show signs of pneumonia and bronchiolitis.
  • the risk and severity of RSV infections is increased in infants with, for example, chronic co-existing medical conditions such as chronic lung disease, congenital heart disease, those
  • RSV infection has been associated with upper respiratory infection, tracheobronchitis, and otitis media.
  • RSV in the institutionalized elderly can be more serious and is characterized by severe pneumonia and mortality rates of up to 20 and 78%, respectively.
  • Adults with a previous history of heart conditions, such as congestive heart failure, or lung conditions, such as chronic obstructive pulmonary disease (COPD), pneumonia and asthma are at a high risk for RSV infection as are immunocompromised adults, for example those receiving haematopoietic stem cell or lung transplants and leukemia patients.
  • COPD chronic obstructive pulmonary disease
  • RSV infections place a significant burden on the healthcare system. This is particularly so in the case of infants such as, for example, immunodeficient infants which on average spend twice as long in hospital as other patients with an RSV infection (7-8 days compared to 3-4 days). Hospitalisation of infants with acute RSV- related bronchiolitis or RSV-related pneumonia involves supportive care
  • RSV is a member of the order Mononegavirales, which consists of the non- segmented negative strand RNA viruses in the Families Paramyxoviridae,
  • Rhabdoviridae and Filoviridae Rhabdoviridae and Filoviridae.
  • RSV of humans (often also termed RSV or HRSV) is a member of the Pneumovirus genus of the sub-family Pneumovirinae within the Family Paramyxoviridae. Based on genetic and antigenic variations in the structural proteins, RSV is classified into two subgroups, A and B (Mufson, M. et al., J. Gen. Virol. 66:21 1 1 -2124).
  • Other members of the Pneumovirus genus include viruses such as bovine RSV (BRSV), ovine RSV (ORSV) and pneumonia virus of mice (PVM) amongst others.
  • BRSV bovine RSV
  • RSV ovine RSV
  • PVM pneumonia virus of mice
  • 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 Paramyxoviridae viruses of all genera characteristically express a fusion glycoprotein (F) which mediates membrane fusion.
  • F fusion glycoprotein
  • Virazole® ribavirin solution for inhalation
  • This agent has a broad spectrum antiviral with virustatic effects, and acts by inhibiting RSV replication.
  • 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 effects.
  • the agent has a number of adverse effects including sudden deterioration of respiratory function (bronchiospasm).
  • Virazole is rarely prescribed due to its cost and potential toxicity. The efficacy of Virazole has remained controversial.
  • RSV-IGIV RSV-immunoglobulin intravenous, also known as RespiGamTM. RespiGam was licensed by the Food and Drug
  • Synagis® is another immunoglobulin-based therapy, more specifically, a monoclonal antibody which is indicated for the preventing RSV-related serious lower tract disease in high risk paediatric patients.
  • the Food and Drug Administration approved Synagis for administration as a monthly intramuscular injection commencing before the onset of the RSV season and continuing for a total of five doses.
  • difficulties with administration and its high cost are prohibitive to widespread use.
  • R 6 is H or an optional substituent
  • A is 5- or 6- membered monocyclic or 9- or 10-membered bicyclic group wherein the said monocyclic or bicyclic group is optionally substituted with H, Ci- 6 alkyl, C 2- 6 alkenyl, halo, CN, C3- 6 cycloalkyl, optionally substituted aryl or optionally substituted heterocyclyl.
  • R 6 is H or an optional substituent
  • A is selected from
  • the present invention relates to the method of treating RSV comprising administering to a patient in need thereof an effective amount of a compound of Formula II, wherein
  • X is CH 2 or NR 6 ;
  • R 6 is H or an optional substituent
  • A is 5- or 6- membered monocyclic or 9- or 10-membered bicyclic group wherein the said monocyclic or bicyclic group is optionally substituted with H, Ci-6alkyl, C 2- 6alkenyl, halo, CN, C3-6cycloalkyl, optionally substituted aryl or optionally substituted heterocyclyl.
  • the present invention to a compound and a method of treating RSV using said com ound, the compound having the Formula III:
  • Z is a bond or CR 1 ;
  • W is S, N or CR 4 ;
  • R 1 and R 4 are independently selected from H, optionally substituted C h alky!, optionally substituted C2-6alkenyl, optionally substituted C3_6cycloalkyl, optionally substituted C6-ioaryl or optionally substituted heterocyclyl;
  • R 2 and R 3 are independently selected from H, halo, CN, optionally substituted Ci- 6alkyl, optionally substituted C2-6alkenyl, optionally substituted C3-6cycloalkyl, optionally substituted C6-ioaryl or optionally substituted heterocyclyl; or R 2 and R 3 , together with the atoms to which they are attached, form an optionally substituted fused 5-membered ring or an optionally substituted fused 6-membered ring; and
  • A is 5- or 6- membered monocyclic or 9- or 10-membered bicyclic group (selected from...?) wherein the said monocyclic or bicyclic group is optionally substituted with H, Ci -6 alkyl, C
  • the present invention relates to the compound and a method of treating RSV using said compound, said compound being a compound of Formula III, wherein A is selected from
  • the present invention relates to the compound and a method of treating RSV using said compound, said compound being a compound of Formula III, wherein
  • R 5 is selected from optionally substituted Ci_6alkyl, optionally substituted C2-6alkenyl, optionally substituted C3-6cycloalkyl, optionally substituted C6-ioaryl or optionally substituted heterocyclyl;
  • n 0, 1 or 2; and R 6 is an optional substituent.
  • the compounds of formulas 1, 11 and III or salts thereof may be in the form of a racemate or a single stereoisomeric form.
  • RSV antiviral agents are useful in the treatment of RSV infections. Accordingly, these compounds of the invention are useful in the treatment of RSV disease, such as bronchiolitis or pneumonia, or in reducing exacerbation of underlying or pre-existing respiratory diseases or conditions wherein RSV infection is a cause of said exacerbation.
  • RSV disease such as bronchiolitis or pneumonia
  • underlying or pre-existing respiratory diseases or conditions may include asthma, chronic obstructive pulmonary disease (COPD) and immunosuppression such as immunosuppression experienced by bone marrow transplant recipients.
  • COPD chronic obstructive pulmonary disease
  • immunosuppression such as immunosuppression experienced by bone marrow transplant recipients.
  • an RSV antiviral agent comprising the compound of formula I or II defined above or its salts, racemates, stereoisomers, isomers or prodrugs thereof.
  • the compound or its salts, racemates, isomers or prodrugs thereof may also be administered in the form of a composition.
  • composition comprising the compound defined above or its salts, racemates, isomers or prodrugs thereof and a carrier.
  • the composition is a pharmaceutical composition and the carrier is a pharmaceutically acceptable carrier.
  • the agent or composition defined above also comprises one or more other RSV antiviral agents.
  • a method of treating an RSV infection comprising the step of administering the compound defined above or its salts, racemates, isomers or prodrugs thereof, or the agent or composition defined above, to a subject in need thereof.
  • a method of treating an RSV disease comprising the step of administering the compound defined above or its salts, racemates, isomers or prodrugs thereof, or the agent or composition defined above, to a subject in need thereof.
  • exacerbation of an underlying or pre-existing respiratory disease wherein RSV infection is a cause of said exacerbation comprising the step of administering the compound defined above or its salts, racemates, isomers or prodrugs thereof, or the agent or composition defined above, to a subject in need thereof.
  • compounds useful as RSV antiviral agents are provided which are suitable for methods of treating RSV infections or other RSV disease conditions including exacerbation of an underlying or pre-existing respiratory disease wherein RSV infection is a cause of said
  • R 6 is H or an optional substituent
  • A is 5- or 6- membered monocyclic or 9- or 10-membered bicyclic group wherein the said monocyclic or bicyclic group is optionally substituted with H, Ci- 6 alkyl, C 2- 6 alkenyl, halo, CN, C3- 6 cycloalkyl, optionally substituted aryl or optionally substituted heterocyclyl;
  • the present invention comtemplates pharmaceutical compositions comprising the above compound and a pharmaceutically acceptable vehicle, excipient or carrier.
  • the present invention comtemplates a method of treating Respiratory Syncytial Virus (RSV) comprising administering to a patient in need thereof an effective amount of this compound or pharmaceutical compositions thereof.
  • RSV Respiratory Syncytial Virus
  • X is CH 2 or NR 6 ;
  • R 6 is H or an optional substituent
  • A is selected from
  • the present invention comtemplates pharmaceutical compositions comprising the above compound and a pharmaceutically acceptable vehicle, excipient or carrier.
  • the present invention comtemplates a method of treating Respiratory Syncytial Virus (RSV) comprising administering to a patient in need thereof an effective amount of this compound or pharmaceutical compositions thereof.
  • RSV Respiratory Syncytial Virus
  • X is CH 2 or NR 6 ;
  • R 6 is H or an optional substituent
  • A is 5- or 6- membered monocyclic or 9- or 10-membered bicyclic group wherein the said monocyclic or bicyclic group is optionally substituted with H, Ci-6alkyl, C 2- 6alkenyl, halo, CN, C3-6cycloalkyl, optionally substituted aryl or optionally substituted heterocyclyl;
  • the present invention comtemplates pharmaceutical compositions comprising the above compound and a pharmaceutically acceptable vehicle, excipient or carrier.
  • the present invention comtemplates a method of treating Respiratory Syncytial Virus (RSV) comprising administering to a patient in need thereof an effective amount of this compound or pharmaceutical compositions thereof.
  • RSV Respiratory Syncytial Virus
  • a compound which has the following Formula III as follows:
  • Z is a bond or CR 1 ;
  • W is S, N or CR 4 ;
  • R 1 and R 4 are independently selected from H, optionally substituted C h alky!, optionally substituted C2- 6 alkenyl, optionally substituted C3- 6 cycloalkyl, optionally substituted C6-ioaryl or optionally substituted heterocyclyl
  • R 2 and R 3 are independently selected from H, halo, CN, optionally substituted Ci_ 6 alkyl, optionally substituted C2- 6 alkenyl, optionally substituted C3- 6 cycloalkyl, optionally substituted C6-ioaryl or optionally substituted heterocyclyl; or R 2 and R 3 , together with the atoms to which they are attached, form an optionally substituted fused 5-membered ring or an optionally substituted fused 6-membered ring; and A is 5- or 6- membered monocyclic or 9- or 10-membered bicyclic group wherein the said monocyclic or bicyclic group is optionally substituted with H, Ci- 6 alkyl, C 2- 6 alkenyl, halo, CN, C3- 6 cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl;
  • A is selected from
  • R 5 is selected from optionally substituted Ci-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C3_6cycloalkyl, optionally substituted C6-ioaryl or optionally substituted heterocyclyl;
  • n 0, 1 or 2;
  • R 6 is an optional substituent.
  • the present invention comtemplates pharmaceutical compositions comprising the above compounds and a pharmaceutically acceptable vehicle, excipient or carrier.
  • the present invention comtemplates a method of treating Respiratory Syncytial Virus (RSV) comprising administering to a patient in need thereof an effective amount of this compound or pharmaceutical compositions thereof.
  • RSV Respiratory Syncytial Virus
  • the present invention contemplates that the above compounds will be useful in the treatment of RSV, along with the racemates, isomers and pharmaceutically acceptable salts of said compound.
  • isomers it will be understood thatthis term includes stereoisomers such as enantiomers and structural isomers, such as tautomers.
  • tautomer is used herein in its broadest sense to include compounds of formula (I) which are in a state of rapid equilibrium between two isomeric forms. Such compounds may differ in the nature of the bond connecting two atoms or groups and the position of these atoms or groups in the compound.
  • Ci-6alkyl encompasses optionally substituted straight chain or branched chain hydrocarbon groups having from 1 to 6 carbon atoms . Examples include methyl (Me), ethyl (Et), propyl (Pr), isopropyl (/-Pr), butyl (Bu), isobutyl (/-Bu), sec-butyl (s-Bu), tert-butyl (£-Bu), pentyl, neopentyl, hexyl and the like. Unless the context requires otherwise, the term "C h alky! also encompasses alkyl groups containing one less hydrogen atom such that the group is attached via two positions i.e. divalent. Such groups are also referred to as "Ci- 6 alkylene” groups. Ci- 3 alkyl and Ci- 3 alkylene groups are preferred.
  • C 2 - 6 alkenyl refers to optionally substituted straight chain or branched chain hydrocarbon groups having at least one double bond of either E or Z stereochemistry where applicable and 2 to 6 carbon atoms. Examples include vinyl, 1 -propenyl, 1 - and 2-butenyl, 2-methyl-2-propenyl, hexenyl, butadienyl, hexadienyl, hexatrienyl and the like. Unless the context requires otherwise, the term "Ci- 6 alkenyl” also encompasses alkenyl groups containing one less hydrogen atom such that the group is attached via two positions i.e. divalent. Such groups are also referred to as "C 2-6 alkenylene” groups. C 2 - 3 alkenyl and C 2 - 3 alkenylene groups are preferred.
  • C 2 - 6 alkynyl refers to optionally substituted straight chain or branched chain hydrocarbon groups having at least one triple bond and 2 to 6 carbon atoms. Examples include ethynyl, 1 -propynyl, 1 - and 2-butynyl, 2-methyl-2- propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5- hexynyl and the like.
  • C 2 - 6 alkynyl also encompasses alkynyl groups containing one less hydrogen atom such that the group is attached via two positions i.e. divalent. Such groups are also referred to as “C 2 - 6 alkynylene” groups. C 2 - 3 alkynyl and C 2 - 3 alkynylene groups are preferred.
  • Cs-scycloalkyl refers to non-aromatic cyclic hydrocarbon groups having from 3 to 8 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl and the like. It will be understood that cycloalkyl groups may be saturated such as cyclohexyl or unsaturated such as cyclohexenyl. C 3-6 cycloalkyl groups are preferred.
  • hydroxy and "hydroxyl” refer to the group -OH.
  • Ci- 6 alkylhydroxyl refers to a C h alky! which is substituted with one or more hydroxyl groups. Ci -3 alkyl hydroxyl groups are preferred, such as for example, -CH 2 OH.
  • C-6alkoxyl refers to the group refers to the group OCi-6alkyl. Examples include methoxy, ethoxy, propoxy, isoproxy, butoxy, tert-butoxy, pentoxy and the like.
  • the oxygen atom may be located along the hydrocarbon chain, and need not be the atom linking the group to the remainder of the compound. C-i- 3 alkoxyl groups are preferred.
  • aryloxy refers to the group -Oaryl and may include variations thereof such as “alkoxyaryl”, wherein aryl is defined herein. Examples include, but are not limited to, phenoxy and naphthoxy and benzyloxy.
  • halo refers to fluoro, chloro, bromo and iodo (F, CI, Br, I).
  • Ci- 6 alkylhalo refers to a Ci- 6 alkyl which is substituted with one or more halogens. Ci- 3 alkylhalo groups are preferred, such as for example, -CHF 2 and - CF 3 .
  • Ci- 6 alkoxylhalo refers to a Ci ⁇ alkoxyl which is substituted with one or more halogens. Ci- 3 alkoxylhalo groups are preferred, such as for example, - OCHF 2 and -OCF 3 .
  • carboxylate or “carboxyl” refers to the group -COO " or -COOH.
  • esters refers to a carboxyl group having the hydrogen replaced with, for example a C h alky! group (“carboxylCi- 6 alkyl” or “Ci- 6 alkylester”), an aryl or aralkyl group (“arylester” or “aralkylester”) and so on.
  • C 1 . 3 alkylest.er groups are preferred, such as for example, methylester (-C0 2 Me), ethylester (-C0 2 Et) and propylester (-CO 2 P and includes reverse esters thereof (e.g. -OCOMe, -OCOEt and -OCOPr).
  • cyano refers to the group -CN.
  • nitro refers to the group -NO 2 .
  • amino refers to the group -NH 2 .
  • substituted amino or “secondary amino” refers to an amino group having a hydrogen replaced with, for example a Ci ⁇ alkyl group (“Ci- 6 alkylamino”), an aryl or aralkyl group (“arylamino” or “aralkylamino”) and so on.
  • Ci -3 alkylamino groups are preferred, such as for example, methylamino (-NHMe), ethylamino (-NHEt) and propylamino (-NHPr).
  • disubstituted amino or "tertiary amino” refers to an amino group having the two hydrogens replaced with, for example a Ci_ 6 alkyl group, which may be the same or different (“diCi-6alkylamino"), an aryl and Ci-ealkyl group ("aryl(Ci- 6alkyl)amino") and so on.
  • DiCi-3alkylamino groups are preferred, such as for example, dimethylamino (-NMe 2 ), diethylamino (-NEt 2 ), dipropylamino (-NPr 2 ) and variations thereof (e.g . -N(Me)(Et) and so on).
  • substituted acyl or “ketone” refers to an acyl group having a hydrogen replaced with, for example a Ci- 6 alkyl group ("Ci- 6 alkylacyl” or “Ci- 6 alkylketone” or “ketoCi- 6 alkyl”), an aryl group ("arylketone”), an aralkyl group (“aralkylketone) and so on. Ci ⁇ alkylketone groups are preferred .
  • aminoacyl refers to the group -NHC(0)H.
  • substituted amido or “substituted amide” refers to an amido group having a hydrogen replaced with, for example a Chalky! group ("Ci- 6 alkylamido” or “Ci- 6 alkylamide”), an aryl (“arylamido”), aralkyl group (“aralkylamido”) and so on.
  • Ci_ 3 alkylamide groups are preferred, such as for example, methylamide (-C(O)NHMe), ethylamide (-C(O)NHEt) and propylamide (-C(O)NHPr) and includes reverse amides thereof (e.g. -NHMeC(O)-, -NHEtC(O)- and -NHPrC(O)-).
  • disubstituted amido or “disubstituted amide” refers to an amido group having the two hydrogens replaced with, for example a Chalky! group ("diCi- 6alkylamido” or “diCi-6alkylamide”), an aralkyl and Ci-6alkyl group (“ aralkyl(Ci- 6 alkyl)amido") and so on.
  • DiCi- 3 alkylamide groups are preferred, such as for example, dimethylamide (-C(0)NMe 2 ), diethylamide (-C(0)NEt 2 ) and dipropylamide (-C(0)NPr 2 ) and variations thereof (e.g. -C(0)N(Me)Et and so on) and includes reverse amides thereof.
  • thiol refers to the group -SH .
  • Ci-6alkylthio refers to a thiol group having the hydrogen replaced with a Ci_ 6 alkyl group. Ci-aalkylthio groups are preferred, such as for example, thiolmethyl, thiolethyl and thiolpropyl.
  • substituted sulfinyl or “sulfoxide” refers to a sulfinyl group having the hydrogen replaced with, for example a Chalky! group ("Ci-ealkylsulfinyl” or “d. 6 alkylsulfoxide”), an aryl (“arylsulfinyl”), an aralkyl (“aralkyl sulfinyl”) and so on .
  • Ci- 3 alkylsulfinyl groups are preferred, such as for example, -SOmethyl, -SOethyl and - SOpropyl.
  • sulfonyl refers to the group -S0 2 H.
  • substituted sulfonyl refers to a sulfonyl group having the hydrogen replaced with, for example a Ci- 6 alkyl group (“sulfonylCi- 6 alkyl”), an aryl
  • arylsulfonyl an aralkyi
  • SulfonylCi. 3 alkyl groups are preferred, such as for example, -SC ⁇ Me, -SC ⁇ Et and -S0 2 Pr.
  • sulfonylamido or "sulfonamide” refers to the group -SO 2 NH 2 .
  • substituted sulfonamido or “substituted sulfonamide” refers to a sulfonylamido group having a hydrogen replaced with, for example a C h alky! group (“sulfonylamidoCi- 6 alkyl”), an aryl (“arylsulfonamide”), aralkyi (“aralkylsulfonamide”) and so on.
  • SulfonylamidoCi- 3 alkyl groups are preferred, such as for example, - S0 2 NHMe, -SC ⁇ NHEt and -SC ⁇ NHPr and includes reverse sulphonamide groups thereof (e.g. -NHS0 2 Me, -NHS0 2 Et and -NHS0 2 Pr).
  • disubstituted sufonamido or "disubstituted sulfonamide” refers to a sulfonylamido group having the two hydrogens replaced with, for example a Ci- 6 alkyl group, which may be the same or different (“sulfonylamidodiCi- 6 alkyl”), an aralkyi and Ci- 6 alkyl group (“sulfonamido(aralkyl)Ci- 6 alkyl”) and so on.
  • SulfonylamidodiCi- 3 alkyl groups are preferred, such as for example, -S0 2 NMe 2 , - S0 2 NEt 2 and -S0 2 NPr 2 and variations thereof (e.g. -SC> 2 N(Me)Et and so on) and includes reserve sulphonamide groups thereof.
  • sulfate refers to the group -OS(0) 2 0H and includes groups having the hydrogen replaced with, for example a C h alky! group ("Ci-
  • Ci_ 3alkylsulfate groups are preferred, such as for example, -OS(0) 2 0Me, -OS(0) 2 0Et and -OS(0) 2 OPr.
  • sulfonate refers to the group -SO3H and includes groups having the hydrogen replaced with, for example a Ci_ 6 alkyl group ("Ci- 6 alkylsulfonate”), an aryl (“arylsulfonate”), an aralkyi (“aralkylsulfonate”) and so on.
  • Ci- 3 alkylsulfonate groups are preferred, such as for example, -SC e, -SOsEt and -SOsPr.
  • aryl refers to any group containing a carbocyclic (non- heterocyclic) aromatic ring and may be a mono-, bi- or tri-cyclic ring system.
  • the aromatic ring or ring system is generally composed of 6 to 10 carbon atoms.
  • Such groups may contain fused ring systems (such as napthyl, tetrahydronapthyl, fluorenyl, indenyl, azulenyl, anthracenyl and the like), linked ring systems (such as biphenyl groups), and may be substituted or unsubstituted.
  • fused ring systems such as napthyl, tetrahydronapthyl, fluorenyl, indenyl, azulenyl, anthracenyl and the like
  • linked ring systems such as biphenyl groups
  • Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and te
  • aralkyl refers to an aryl group substituted with a C h alky! group. Examples include benzyl and phenethyl.
  • heterocyclyl encompasses aromatic heterocyclyls and non- aromatic heterocyclyls. Such groups may be substituted or unsubstituted.
  • Particularly preferred optional substituents in the case of heterocycles containing N include C h alky! particularly A/-Ci- 3 alkyl, more preferably methyl particularly N- methyl.
  • aromatic heterocyclyl may be used interchangeably with the term
  • heteroaryl or the term “heteroaryl” or “hetaryl”.
  • aromatic or the term "aromatic
  • heterocyclyl also encompasses pseudoaromatic heterocyclyls.
  • aromatic 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.
  • the heteroatoms in the aromatic heterocyclyl group may be selected from N, S and O.
  • Aromatic heterocyclyl groups may be 5-membered or 6-membered monocyclic aromatic ring systems.
  • 5-membered mono-cyclic aromatic ring systems include furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl (including 1 ,2,3 and 1 ,2,4 oxadiazolyls and furazanyl i.e. 1 ,2,5-oxadiazolyl), thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl (including 1 ,2,3, 1 ,2,4 and 1 ,3,4 triazolyls), tetrazolyl, thiadiazolyl (including 1 ,2,3 and 1 ,3,4 thiadiazolyls) and the like.
  • 6-membered mono-cyclic aromatic ring systems include pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl and the like.
  • 6- membered aromatic heterocyclyls containing 1 nitrogen include pyridyl.
  • 6-membered aromatic heterocyclyls containing 2 nitrogens include pyrazinyl, pyrimidinyl and pyridazinyl.
  • Aromatic heterocyclyl groups may also be bicyclic or polycyclic
  • heteroaromatic ring systems such as fused ring systems (including purine, pteridinyl, napthyridinyl, 1 H thieno[2,3-c]pyrazolyl, thieno[2,3-b]furyl and the like) or linked ring systems (such as oligothiophene, polypyrrole and the like).
  • Fused ring systems may also include aromatic 5-membered or 6-membered heterocyclyls fused to carbocyclic aromatic rings such as phenyl, napthyl, indenyl, azulenyl, fluorenyl, anthracenyl and the like, such as 5-membered aromatic heterocyclyls containing nitrogen fused to phenyl rings, 5-membered aromatic heterocyclyls containing 1 or 2 nitrogens fused to phenyl ring.
  • aromatic 5-membered or 6-membered heterocyclyls fused to carbocyclic aromatic rings such as phenyl, napthyl, indenyl, azulenyl, fluorenyl, anthracenyl and the like, such as 5-membered aromatic heterocyclyls containing nitrogen fused to phenyl rings, 5-membered aromatic heterocyclyls containing 1 or 2 nitrogens fused to phenyl ring.
  • aromatic heterocyclyls fused to carbocyclic aromatic rings include benzothiophenyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,
  • benzisothiazolyl benzimidazolyl, indazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzotriazinyl, phthalazinyl, carbolinyl and the like.
  • suitable derivatives of aromatic heterocyclyls containing nitrogen include N-oxides thereof.
  • non-aromatic heterocyclyl encompasses optionally substituted saturated and unsaturated rings which contain at least one heteroatom selected from the group consisting of N, S and O.
  • Non-aromatic heterocyclyls may be 5-membered, 6-membered or 7- membered mono-cyclic rings.
  • Examples of 5-membered non-aromatic heterocyclyl rings include 2H- pyrrolyl, 1 -pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1 -pyrrolidinyl, 2- pyrrolidinyl, 3-pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolinyl, 2- pyrazolinyl, 3-pyrazolinyl, pyrazolidinyl, 2-pyrazolidinyl, 3-pyrazolidinyl,
  • 6-membered non-aromatic heterocyclyls include piperidinyl, piperidinonyl, pyranyl, dihyrdopyranyl, tetrahydropyranyl, 2H pyranyl, 4H pyranyl, thianyl, thianyl oxide, thianyl dioxide, piperazinyl, diozanyl, 1 ,4-dioxinyl, 1 ,4-dithianyl, 1 ,3,5-triozalanyl, 1 ,3,5-trithianyl, 1 ,4-morpholinyl, thiomorpholinyl, 1 ,4-oxathianyl, triazinyl, 1 ,4-thiazinyl and the like.
  • Examples of 7-membered non-aromatic heterocyclyls include azepanyl, oxepanyl, thiepanyl and the like.
  • Non-aromatic heterocyclyl rings may also be bicyclic heterocyclyl rings such as linked ring systems (for example uridinyl and the like) or fused ring systems.
  • Fused ring systems include non-aromatic 5-membered, 6-membered or 7-membered heterocyclyls fused to carbocyclic aromatic rings such as phenyl, napthyl, indenyl, azulenyl, fluorenyl, anthracenyl and the like.
  • non-aromatic 5-membered, 6-membered or 7-membered heterocyclyls fused to carbocyclic aromatic rings include indolinyl, benzodiazepinyl, benzazepinyl, dihydrobenzofuranyl and the like.
  • the term "optionally substituted” or “optional substituent” as used herein refers to a group which may or may not be further substituted with 1 , 2, 3, 4 or more groups, preferably 1 , 2 or 3, more preferably 1 or 2 groups selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkylhydroxyl, oxo, alkoxy, aryloxy, alkoxyaryl, halo, alkylhalo, alkoxyhalo, carboxylate, esters, cyano, nitro, amino, substituted amino, disubstituted amino, acyl, ketone, amido, aminoacyl, substituted amido, disubstituted amido, thiol, alkylthio, thioxo, sulfate, sulfonate, sulfinyl, substituted sulfinyl, sulfonyl, substituted
  • the compounds of the invention may also be prepared as salts which are pharmaceutically acceptable. 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.
  • Examples of pharmaceutically acceptable salts include salts of pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, ammonium, alkylammonium and the like; acid addition salts of pharmaceutically acceptable inorganic acids such as hydrochloric, orthophosphoric, sulfuric, phosphoric, nitric, carbonic, boric, sulfamic, hydrobromic acids and the like; and salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulfonic, trihalomethanesulfonic,
  • Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl, aralkyl moiety and the like.
  • the salts may be formed by conventional means, such as by reacting the free base form of the compound with one or more equivalents of the appropriate acid. It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with
  • solvents such as water, alcohols such as methanol, ethanol or isopropyl alcohol, DMSO, acetonitrile, dimethyl formamide (DMF) and the like with the solvate forming part of the crystal lattice by either non-covalent binding or by occupying a hole in the crystal lattice. Hydrates are formed when the solvent is water; alcoholates are formed when the solvent is alcohol. Solvates of the compounds of the present invention can be conveniently prepared or formed during the processes described herein.
  • the compounds of the present invention can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like.
  • the solvated forms of the compounds of the present invention are also considered to be disclosed herein.
  • compounds of the present invention may possess a chiral centre and may therefore exist as a racemate or an R- or S-enantiomer.
  • the compounds may therefore be used as a purified enantiomer or diastereomer, or as a mixture of any ratio thereof.
  • a compound of formula (I) as defined above or a compound of formula (I I) as defined above in a single stereoisomeric form 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.
  • the compound has a carbon-carbon double bond, it may occur in Z- or E- form and all isomeric forms of the compounds being included in the present invention.
  • This invention also encompasses prodrugs of the compounds of formula (I).
  • prodrug is used herein in its broadest sense to include those compounds which are converted in vivo to the compound of formula (I). Use of the prodrug strategy optimises the delivery of the drug to its site of action. Compounds having free amino, amido, hydroxyl, or carboxylic acid groups can be converted into prodrugs. Prodrugs may also include N-oxides, appropriate nitrogen atoms in compounds of formula (I).
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable vehicle, excipient or carrier.
  • the pharmaceutical composition may further comprise or be administered in combination with one or more other RSV antiviral agents such as Virazole ® , BMS- 4337715, TMC3531216, MDT-637 (formerly VP-14637), GS-5806, RSV604,
  • RSV antiviral agents such as Virazole ® , BMS- 4337715, TMC3531216, MDT-637 (formerly VP-14637), GS-5806, RSV604,
  • ALNRSV01 AL-8176 (or ALS-8176) and/or other agents that may be developed as inhibitors of viral entry, assembly, replication, egress or host-virus interactions
  • composition is intended to include the formulation of an active ingredient with conventional vehicles, 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.
  • Any carrier must be “pharmaceutically acceptable” meaning that it is compatible with the other ingredients of the composition and is not deleterious to a subject.
  • compositions of the present invention may contain other therapeutic agents as described above, and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavours and the like) according to techniques such as those well known in the art of pharmaceutical formulation (see, for example, Remington: The Science and Practice of Pharmacy, 21 st Ed., 2005, Lippincott Williams & Wilkins).
  • the pharmaceutical composition includes 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.
  • 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.
  • 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.
  • Suitable vehicles, carriers or excipients include 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 an encapsulating material as the carrier by 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.
  • 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 (for example, 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, for example, 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.
  • 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.
  • compositions 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 they may be enclosed in hard or soft shell gelatin capsule, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet.
  • 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.
  • 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; 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
  • a flavouring agent such as peppermint, oil of wintergreen, or cherry
  • tablets, pills, or capsules may be coated with shellac, sugar or both.
  • a syrup or elixir may contain the active
  • 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.
  • 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.
  • 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.
  • 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
  • a suitable propellant such as a chlorofluorocarbon (CFC) for example
  • dichlorodifluoromethane trichlorofluoromethane, or dichlorotetrafluoroethane
  • HFC hydrofluorocarbon
  • HFA hydrofluoroalkanes
  • 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).
  • 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, for example 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 5 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 viral infection 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.
  • Liquids or powders for intranasal administration, tablets or capsules for oral administration and liquids for intravenous administration are the preferred.
  • compositions compositions.
  • the compounds of formulas (I), (II) and (I II) have demonstrated potency as inhibitors of RSV and therefore offer a method of treating an RSV infection. These compounds can also be used to treat an RSV disease or reduce exacerbation of an underlying or pre-existing respiratory disease wherein RSV infection is a cause of said exacerbation.
  • the RSV disease may include brochiolitis or pneumonia.
  • the underlying or pre-existing respiratory diseases or conditions may include asthma, chronic obstructive pulmonary disease (COPD) and immunosuppression such as immunosuppression experienced by bone marrow transplant recipients.
  • COPD chronic obstructive pulmonary disease
  • Treatment may be therapeutic treatment or prophylactic treatment.
  • the term "treating" means affecting a subject, tissue or cell to obtain a desired pharmacological and/or physiological effect and includes: (a) inhibiting the viral infection or RSV disease, such as by arresting its development or further development; (b) relieving or ameliorating the effects of the viral infection or RSV disease, such as by causing regression of the effects of the viral infection or RSV disease; (c) reducing the incidence of the viral infection or RSV disease or (d) preventing the viral infection or RSV disease from occurring in a subject, tissue or cell predisposed to the viral infection or RSV disease or at risk thereof, but has not yet been diagnosed with a protective pharmacological and/or physiological effect so that the viral infection or RSV disease does not develop or occur in the subject, tissue or cell.
  • subject refers to any animal, in particular mammals such as humans, having a disease which requires treatment with the compound of formula (I).
  • Particularly preferred treatment groups include at risk populations such as hospitalised subjects, the elderly, high-risk adults and infants.
  • an effective amount of the above compounds, or pharmaceutical compositions thereof, is administered to a patient or subject in need thereof.
  • administering should be understood to mean providing a compound or pharmaceutical composition of the invention to a subject suffering from or at risk of the disease or condition to be treated or prevented.
  • RSV infections and diseases more particularly human and animal RSV infections or diseases
  • the invention may also be useful in the treatment of other viruses of the sub-family Pneumovirinae, more particularly, the genera Pneumovirus and Metapneumovirus.
  • terapéuticaally effective amount refers to the amount of the compound of formula (I) that will elicit the biological or medical response of a subject, tissue or cell that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • effective amount is generally considered that amount that will be effective to treat the condition sought to be treated, and this effective amount is variable based on a variety of factors including age, size and condition of the patient being treated. Accordingly, one skilled in the art would be readily able to determine the specific effective amount for each patient being treated.
  • an appropriate dosage level will generally be about 0.01 to about 500 mg per kg subject body weight per day which can be administered in single or multiple doses.
  • the dosage may be selected, for example, to any dose within any of these ranges, for therapeutic efficacy and/or symptomatic adjustment of the dosage to the subject to be treated.
  • the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the subject undergoing therapy.
  • the compounds of the invention may generally be prepared by the following methods. Unless otherwise stated, the groups of each of the compounds are as previously defined.
  • Step 1 Coupling to a pyrimidinone derivative by nucleophilic substitution.
  • a base such as Cs 2 C0 3 or K 2 C0 3 (2.0 eq)
  • an electrophile of formula LG-CH 2 -A wherein LG is a leaving group such as bromine, chlorine or a sulfonate (2.0 eq).
  • LG is a leaving group such as bromine, chlorine or a sulfonate (2.0 eq).
  • the resulting reaction mixture is stirred, generally at room temperature or a temperature between 55°C and 85°C.
  • the product may be partially purified by liquid-liquid work up and then isolated by chromatography to obtain the desired product.
  • Scheme 2 General Method B, illustrated for preparation of compounds of Formula III Step 1 : A suitable 2-amino-substituted aromatic ester of the form shown in Scheme 2 (1 eq) and an aminomethyl-substituted aromatic derivative (1 -2 eq) are suspended in triethyl orthoformate and heated at 140°C. After reaction is complete the mixture is cooled, diluted with dichloromethane and washed with water. The organic layer is dried (MgS0 4 ) and concentrated and the target compound may be isolated by chromatography.
  • a suitable 2-amino-substituted aromatic ester of the form shown in Scheme 2 (1 eq) and an aminomethyl-substituted aromatic derivative (1 -2 eq) are suspended in triethyl orthoformate and heated at 140°C. After reaction is complete the mixture is cooled, diluted with dichloromethane and washed with water. The organic layer is dried (MgS0 4 ) and concentrated and the target compound may be isolated by chromatography.
  • Step 1 A suitable ester, such as ethyl (4-oxo-6,7-dihydro-4H- cyclopenta[4,5]thieno[2,3-d]pyrimidin-3(5H)-yl)acetate or of the generalised form illustrated in Scheme 3, is treated with an optionally substituted 2-hydrazinopyridine in xylenes at reflux. Upon completion of the reaction, the mixture is concentrated and the residue may be purified by chromatography to yield the required
  • Step 1 To a solution of tert-butyl 4-oxo-3,4,5,7-tetrahydro-6H- pyrrolo[3',4':4,5]thieno[2,3-d]pyrimidine-6-carboxylate (1.0 eq, prepared as described in Representative Example 4, Step 1 ) in a solvent such as DMF is added a base such as CS2CO3 or K2CO3 (2.0 eq), followed by an electrophile of formula LG-CH2-A, wherein LG is a leaving group such as bromine, chlorine or a sulfonate (2.0 eq). The resulting reaction mixture is stirred, generally at room temperature or a temperature between 55°C and 85°C. After the reaction is complete (LCMS monitoring), the product may be partially purified by liquid-liquid work up and then isolated by chromatography to obtain the desired product.
  • a base such as CS2CO3 or K2CO3
  • LG-CH2-A an electrophile of formula LG-CH2-A, wherein
  • Step 2 Hydrogen chloride solution, 4 M in dioxane (typically 10-100 eq) is added to a solution of the tert-butoxycarbonyl derivative from the previous step and stirred at ambient temperature for 1 h. The solution is then concentrated to dryness to give the target amine as a hydrochloride salt.
  • dioxane typically 10-100 eq
  • the amine may then be optionally alkylated, acylated or carbamylated by methods known to those skilled in the art.
  • Representative Example IV provides a specific example of the use of General Method D.
  • Step 1 5-tert-Butyl 3-ethyl 2-amino-4,6-dihydro-5H-thieno[2,3-c]pyrrole-3,5- dicarboxylate (1 eq) and an aminomethyl-substituted aromatic derivative (1 -2 eq) are suspended in triethyl orthoformate and heated at a temperature typically between 80°C and 140°C. If necessary, additional amine may be added. After reaction is complete the mixture is cooled and the target compound may be isolated by chromatography.
  • Step 2 Hydrogen chloride solution, 4 M in dioxane (typically 10-100 eq) is added to a solution of the tert-butoxycarbonyl derivative from the previous step and stirred at ambient temperature for 1 h. The solution is then concentrated to dryness to give the target amine as a hydrochloride salt.
  • dioxane typically 10-100 eq
  • the amine may then be optionally alkylated, acylated or carbamylated by methods known to those skilled in the art.
  • Example V provides a specific example of the use of General Method E.
  • Scheme 6 General Method F, illustrated for preparation of compounds of Formula III Step 1 : Suzuki Coupling.
  • a bromopyridine derivative of the form shown in Scheme 6 is suspended in dioxane and water with a suitable boronic acid derivative (1 -3 eq) and CS2CO3 (1 - 3 eq).
  • This mixture is deoxygenated by bubbling nitrogen for 20 min.
  • [1 , 1 '-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) dichloromethane complex (0.05 - 0.1 eq) is added and the mixture is sealed in a vial and heated in a microwave reactor to 100°C with stirring until reaction is complete (typically 2 - 5 h).
  • the mixture may be subjected to a liquid-liquid work up (for example, using EtOAc and water) and the residue from the organic phase may be purified by chromatography to yield the target compound.
  • Example VI provides a specific example of the use of General Method F.
  • Step 1 Alkylation.
  • a base such as CS2CO3 or K2CO3 (1 -3 eq
  • a suitable electrophile To a solution of a free phenol derivative of the form shown in Scheme 7 in a solvent such as DMF is added a base such as CS2CO3 or K2CO3 (1 -3 eq), followed by a suitable electrophile.
  • the resulting reaction mixture is stirred, generally at room temperature or a temperature between 55°C and 85°C, depending on the reactivity of the chosen electrophile.
  • the product may be partially purified by liquid-liquid work up and then isolated by chromatography to obtain the desired product.
  • Suitable electrophiles may include alkyi halides and alkyi sulfonates. In the case wherein R is -CH2CH2OH, ethyl carbonate is a preferred electrophile.
  • Representative Example I I, Step 2 provides a specific example of the use of General Method G.
  • Flash chromatography was performed on 100-200 mesh silica gel or using a Biotage SP4 (GraceResolvTM Silica Flash cartridges or C18 silica cartridges plugged in).
  • Step 1 2-Aminopyridine (100 mg, 1 .06 mmol) and 1 ,3-dichloroacetone (135 mg, 1 .06 mmol) were suspended in THF (1 mL) and stirred in a sealed vial at 80°C for 16 h. LCMS showed formation of the target 2-(chloromethyl)imidazo[1 ,2-a]pyridine.
  • Step 1 Methyl 2-amino-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylate (600 mg, 3.0 mmol) and 2-(aminomethyl)phenol (450 mg, 1.2 eq) were suspended in triethylorthoformate (6 ml_) and heated at 140°C. After 44 h the mixture was cooled, diluted with dichloromethane (100 ml_) and washed with water (2 x 50 ml_). The organic layer was dried over MgS0 4 and concentrated.
  • Step 2 A solution of 3-(2-hydroxybenzyl)-3,5,6,7-tetrahydro-4H- cyclopenta[4,5]thieno[2,3-d]pyrimidin-4-one (24 mg) in DMA (350 ⁇ _) was treated with CS2CO3 (24 mg, 1 eq) and 4-(2-chloroethyl)morpholine hydrochloride (30 mg, 3 eq). The mixture was heated to 80°C with stirring. After 1 h 45 min, the mixture was filtered through a 0.45 ⁇ filter and purified by reverse-phase chromatography (5- 100% gradient of MeCN in water) to yield the title compound as an off-white solid after freeze-drying (13 mg, 44%).
  • Step 1 A mixture of 3,5,6, 7-tetrahydro-4H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-4- one (0.53 g), ethyl bromoacetate (0.56 g, 1 .2 eq) and cesium carbonate (2.75 g) in acetonitrile (10 ml_) was heated and stirred at 80°C for 1.5 h. The cooled mixture was diluted with EtOAc and filtered. The filtrate was washed with water and brine, dried over MgS0 4 and concentrated. The residue was purified by silica
  • Step 2 A suspension of ethyl (4-oxo-6,7-dihydro-4H-cyclopenta[4,5]thieno[2,3- d]pyrimidin-3(5H)-yl)acetate (50 mg), [3-(trifluoromethyl)-2-pyridyl]hydrazine (100 mg, 4 eq) and toluenesulfonic acid (100 mg, 3 eq) were suspended in xylenes and heated at reflux. After 24 h the mixture was concentrated and the residue purified by reverse-phase chromatography (5-100% gradient of MeCN in water) to yield the title compound as a tan solid (42 mg, 60%).
  • Step 1 5-tert-butyl 3-ethyl 2-amino-4,6-dihydro-5H-thieno[2,3-c]pyrrole-3,5- dicarboxyiate (0.10 g, 0.32 mmol) and formamidine acetate (0.12 g, 1 .2 mmol) was combined and heated at 80°C in DMA (2.5 ml_) for 48 h.
  • Step 2 To a solution of tert-butyl 4-oxo-3,4,5,7-tetrahydro-6H- pyrrolo[3',4':4,5]thieno[2,3-d]pyrimidine-6-carboxylate (28 mg) in THF (3 ml_) was added CS2CO3 (78 mg, 2.5 eq) and 2-(chloromethyl)imidazo[1 ,2-a]pyridine-8- carbonitrile hydrochloride (33 mg, 1 .2 eq). The mixture was stirred at 80°C in a sealed vessel for 16 h. The mixture was diluted with EtOAc and filtered to remove the salts.
  • Step 3 Hydrogen chloride solution, 4M in dioxane ( 4 mL, 16 mmol) was added to tert-butyl 3-[(8-cyanoimidazo[1 ,2-a]pyridin-2-yl)methyl]-4-oxo-3,4,5,7-tetrahydro-6H- pyrrolo[3',4':4,5]thieno[2,3-d]pyrimidine-6-carboxylate (40 mg). The mixture was stirred at ambient temperature for 2 h before evaporating the solvent. The residue was dissolved in water (5 mL) and the solution washed with EtOAc (2 x 5 mL). The aqueous layer was filtered and freeze dried to afford the title compound as the hydrochloride salt (20 mg, 58%).
  • Step 1 1 -[2-(morpholin-4-yl)phenyl]methanamine (92.3 mg, 0.4802 mmol) and 5- tert-butyl 3-ethyl 2-amino-4,6-dihydro-5H-thieno[2,3-c]pyrrole-3,5-dicarboxylate (100 mg, 0.3201 mmol) were suspended in triethyl orthoformate (1 mL) and heated at 80°C for 18 h. LCMS showed ⁇ 60% product and -30% SM remaining. Further (2- morpholinophenyl)methanamine (92.3 mg, 0.4802 mmol) was added and the suspension heated for a further 18 h.
  • Step 2 Hydrogen chloride solution, 4M in dioxane ( 4 mL, 16 mmol) was added to a solution of tert-butyl 3-[2-(morpholin-4-yl)benzyl]-4-oxo-3,4,5,7-tetrahydro-6H- pyrrolo[3',4':4,5]thieno[2,3-d]pyrimidine-6-carboxylate (30 mg, 0.06402 mmol) in 1 ,4- dioxane (1 mL) and stirred at rt for 1 h.
  • Step 1 3-[(5-Bromopyridin-2-yl)methyl]-3,5,6,7-tetrahydro-4H- cyclopenta[4,5]thieno[2,3-d]pyrimidin-4-one (23 mg, 0.064 mmol; prepared from 3,5,6,7-tetrahydro-4H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-4-one using General
  • Step 1 To a suspension of 3,5,6,7-tetrahydro-4H-cyclopenta[4,5]thieno[2,3- d]pyrimidin-4-one (1 .00 g, 5.20 mmol) and Cs 2 C0 3 (2.54 g, 7.80 mmol) in DMF (10 mL) was added bromoacetaldehyde diethyl acetal (3.94 mL, 26.0 mmol) and the reaction mixture was stirred at 70 °C for 4 h. The reaction was cooled, diluted with EtOAc and washed with water and brine. The organic fraction was dried (Na 2 S0 4 ) and concentrated to dryness under reduced pressure. The resulting residue was purified by silica chromatography (gradient of 25-100% EtOAc/heptane) to afford the desired acetal (600 mg, 37%) as a colourless oil.
  • Step 2 3-(2,2-diethoxyethyl)-3,5,6,7-tetrahydro-4H-cyclopenta[4,5]thieno[2,3- d]pyrimidin-4-one (590 mg, 1 .91 mmol) was dissolved in acetonitrile (10 ml_) and 1 M HCI (5 ml_, 5 mmol) was added. The reaction mixture was stirred at reflux for 2 h. LCMS analysis indicated complete consumption of the starting acetal. The reaction mixture was taken to dryness under reduced pressure. The resulting residue was washed with MeCN and filtered to afford the crude target aldehyde (518 mg, 45%) as an off-white solid.
  • Step 3 (4-oxo-6,7-dihydro-4H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-3(5H)- yl)acetaldehyde (95 mg, 0.41 mmol), 40% methylglyoxal (124 ⁇ _, 0.81 mmol) and 28% NH 3 in water (137 ⁇ _, 2.03 mmol) were dissolved in ethanol (1 ml_) and stirred at 60 °C for 16 h. The reaction mixture was concentrated to dryness and the residue was purified by silica chromatography (95:5:0.25 ChbC /MeOH/TEA). The resulting product was further purified by reverse-phase chromatography, eluting with a gradient of 0-100% MeCN in water to afford the title product as an off-white solid (22 mg, 19%).
  • the in vivo and in vitro antiviral activity of the compounds of the invention may be determined using the following methods.
  • Cytopathic effect (CPE) assays were performed essentially as described in the literature (see, for example, Watanabe et al, 1994, J. Viroiogical Methods, 48:257). Serial dilutions of the test compounds were made in 96 well plates. HEp2 cells (1 .0 x 10 4 cells/well) were infected with RSV at a low multiplicity of infection (e.g. RSV A2 at an moi of -0.01 ) and added to plates to assess antiviral activity. Uninfected HEp2 cells were used to assess compound cytotoxicity.
  • CPE Cytopathic effect
  • Assays were incubated for 5 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 (1 mg/ml) was added to each well and plates incubated for 2 hours incubation at 37°C. Wells were aspirated, so-propanol (200 ⁇ _) was added and absorbance values read at
  • RSV A2 EC50 mean values lie in the ranges A: ⁇ 0.10 ⁇ , B: 0.10 ⁇ to ⁇ 0.40 ⁇ , C: 0.40 to ⁇ 1 .6 ⁇ , D: 1 .6 ⁇ to ⁇ 6.4 ⁇ , E: 6.4 ⁇ to ⁇ 20 ⁇ .
  • replicate EC50 values usually fall within three standard deviations of the mean.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés utiles dans le traitement d'infections virales, en particulier d'infections par le virus respiratoire syncytial (VRS). Dans un aspect, l'invention concerne des composés de formule (I) : Ces composés et des composés supplémentaires décrits sont avantageusement utilisés dans des procédés de traitement du VRS où une quantité efficace d'un composé ou d'un composé pharmaceutique de celui-ci est administrée à un patient en ayant besoin. Des procédés de préparation des composés et des intermédiaires utilisés dans leur préparation sont également décrits.
PCT/US2016/018044 2015-02-16 2016-02-16 Composés pour le traitement d'infections par le virus respiratoire syncytial Ceased WO2016133888A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201562116746P 2015-02-16 2015-02-16
US62/116,746 2015-02-16

Publications (1)

Publication Number Publication Date
WO2016133888A1 true WO2016133888A1 (fr) 2016-08-25

Family

ID=56692305

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2016/018044 Ceased WO2016133888A1 (fr) 2015-02-16 2016-02-16 Composés pour le traitement d'infections par le virus respiratoire syncytial

Country Status (1)

Country Link
WO (1) WO2016133888A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021074196A1 (fr) * 2019-10-15 2021-04-22 Boehringer Ingelheim International Gmbh Thiénopyrimidones en tant qu'inhibiteurs de trpa1
WO2021074197A1 (fr) * 2019-10-15 2021-04-22 Boehringer Ingelheim International Gmbh Thiénopyrimidones en tant qu'inhibiteurs de trpa1
US12180223B2 (en) 2021-04-14 2024-12-31 Boehringer Ingelheim International Gmbh 3H,4H-thieno[2,3-d]pyrimidin-4-one derivatives as TRPA1 inhibitors
US12227516B1 (en) 2023-09-21 2025-02-18 King Faisal University Selective COX-2 inhibition of 2-(substituted benzyl)-3,5,6,7-tetrahydro-4H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-4-ones and 4-fluoro-n-(4-oxo-3,5,6,7-tetrahydro-4H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-2-yl)benzamide as anti-inflammatory agents
US12497401B2 (en) 2019-10-15 2025-12-16 Boehringer Ingelheim International Gmbh Substituted tetrazoles as TRPA1 inhibitors

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110021493A1 (en) * 2007-09-14 2011-01-27 Bayer Schering Pharma Aktiengesellschaft Substituted tricyclic compounds and methods of use thereof
US20120122889A1 (en) * 2008-12-23 2012-05-17 President And Fellows Of Harvard College Small molecule inhibitors of necroptosis
US20130102601A1 (en) * 2011-10-21 2013-04-25 F. Hoffmann-La Roche Ltd Pyrimidin-4-one derivatives and their use in the treatment, amelioration or prevention of a viral disease
US20140051689A1 (en) * 2003-12-24 2014-02-20 Biota Scientific Management Pty Ltd. Polycyclic Agents for the Treatment of Respiratory Syncytial Virus Infections

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140051689A1 (en) * 2003-12-24 2014-02-20 Biota Scientific Management Pty Ltd. Polycyclic Agents for the Treatment of Respiratory Syncytial Virus Infections
US20110021493A1 (en) * 2007-09-14 2011-01-27 Bayer Schering Pharma Aktiengesellschaft Substituted tricyclic compounds and methods of use thereof
US20120122889A1 (en) * 2008-12-23 2012-05-17 President And Fellows Of Harvard College Small molecule inhibitors of necroptosis
US20130102601A1 (en) * 2011-10-21 2013-04-25 F. Hoffmann-La Roche Ltd Pyrimidin-4-one derivatives and their use in the treatment, amelioration or prevention of a viral disease

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LI, H ET AL.: "Synthesis and Bioevaluation of Thieno[2,3-d]pyrimidinone Derivatives as Potential Tumor Cell Growth Inhibitors", JOURNAL OF CHEMISTRY, vol. 2013, pages 1 - 6 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021074196A1 (fr) * 2019-10-15 2021-04-22 Boehringer Ingelheim International Gmbh Thiénopyrimidones en tant qu'inhibiteurs de trpa1
WO2021074197A1 (fr) * 2019-10-15 2021-04-22 Boehringer Ingelheim International Gmbh Thiénopyrimidones en tant qu'inhibiteurs de trpa1
US11136336B2 (en) 2019-10-15 2021-10-05 Boehringer Ingelheim International Gmbh Thienopyrimidones
CN114929712A (zh) * 2019-10-15 2022-08-19 勃林格殷格翰国际有限公司 作为trpa1抑制剂的噻吩并嘧啶酮
CN114945408A (zh) * 2019-10-15 2022-08-26 勃林格殷格翰国际有限公司 作为trpa1抑制剂的噻吩并嘧啶酮
US11578080B2 (en) 2019-10-15 2023-02-14 Boehringer Ingelheim International Gmbh Thienopyrimidones
CN114945408B (zh) * 2019-10-15 2024-04-16 勃林格殷格翰国际有限公司 作为trpa1抑制剂的噻吩并嘧啶酮
US12497401B2 (en) 2019-10-15 2025-12-16 Boehringer Ingelheim International Gmbh Substituted tetrazoles as TRPA1 inhibitors
US12180223B2 (en) 2021-04-14 2024-12-31 Boehringer Ingelheim International Gmbh 3H,4H-thieno[2,3-d]pyrimidin-4-one derivatives as TRPA1 inhibitors
US12227516B1 (en) 2023-09-21 2025-02-18 King Faisal University Selective COX-2 inhibition of 2-(substituted benzyl)-3,5,6,7-tetrahydro-4H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-4-ones and 4-fluoro-n-(4-oxo-3,5,6,7-tetrahydro-4H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-2-yl)benzamide as anti-inflammatory agents

Similar Documents

Publication Publication Date Title
EP2643323B1 (fr) Composés destinés au traitement d'infections par le virus respiratoire syncytial
JP2019521980A (ja) Ｊａｋ阻害剤としてのピロロピリミジン化合物の結晶
BR112018008966B1 (pt) Compostos inibidores de jak quinase, hidrato cristalino, composição farmacêutica, processos, método de preparação do hidrato cristalino e uso dos referidos compostos e hidrato cristalino no tratamento de doença respiratória
WO2016133888A1 (fr) Composés pour le traitement d'infections par le virus respiratoire syncytial
WO2017196970A1 (fr) Dérivés hétérocycliques pour le traitement de rsv
JP2017530992A (ja) 呼吸器合胞体ウイルス感染症（ｒｓｖ）の治療又は予防のためのスピロインドリン
JP5955778B2 (ja) 呼吸器合胞体ウイルス感染症を治療するための化合物
AU2022412821A1 (en) Aromatic heterocyclic compounds, preparation method therefor and uses thereof
US9359377B2 (en) Substituted imidazo[1,2-a]imidazo[4′,5′:4,5]pyrrolo[1,2-d]pyrazines for treating respiratory syncytial virus infections
WO2017196982A1 (fr) Dérivés pyrazole condensés bicycliques pour le traitement de rsv
KR20170094180A (ko) 호흡기 세포융합 바이러스 （ｒｓｖ）의 복제에 대하여 저해 활성을 갖는 피페리딘 치환된 삼환식 피라졸로［１，５―ａ］피리미딘 유도체
HK1195562A (en) Compounds for treating respiratory syncytial virus infections
HK1195562B (en) Compounds for treating respiratory syncytial virus infections
HK1189884B (en) Compounds for treating respiratory syncytial virus infections

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16752894

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16752894

Country of ref document: EP

Kind code of ref document: A1