WO2015172196A1 - Composés hétérocycliques et leur utilisation - Google Patents

Composés hétérocycliques et leur utilisation Download PDF

Info

Publication number
WO2015172196A1
WO2015172196A1 PCT/AU2015/050238 AU2015050238W WO2015172196A1 WO 2015172196 A1 WO2015172196 A1 WO 2015172196A1 AU 2015050238 W AU2015050238 W AU 2015050238W WO 2015172196 A1 WO2015172196 A1 WO 2015172196A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
mmol
group
alkyl
phenyl
Prior art date
Application number
PCT/AU2015/050238
Other languages
English (en)
Inventor
Jonathan Baell
Matthew PIGGOTT
Stephanie RUSSELL
Arthur TOYNTON
Raphael RAHMANI
Lori FERRINS
Nghi Nguyen
Original Assignee
Monash University
The University Of Western Australia
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
Priority claimed from AU2014901768A external-priority patent/AU2014901768A0/en
Application filed by Monash University, The University Of Western Australia filed Critical Monash University
Publication of WO2015172196A1 publication Critical patent/WO2015172196A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/16—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
    • C07D231/40—Acylated on said nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/10—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems

Definitions

  • the invention relates to the field of medical treatment. More particularly, this invention relates to novel heterocyclic compounds and their use in treating a disease or condition caused by a trypanosomatid.
  • HAT is caused by the protozoans Trypanosoma brucei rhodesiense and T. b. gambiense, transmitted by the bite of the Tsetse fly.
  • HAT was estimated to cause 48,000 deaths and a disease burden of 1 .5 million disability-adjusted life years (DALYs) annually.
  • DALYs disability-adjusted life years
  • T. cruzi spread by the bite of the kissing bug, is the causative agent of Chagas' disease, and is endemic in 18 countries in Latin America, affecting as many as 8-10 million people. It is responsible for approximately 14,000 deaths and a disease burden of 0.7 million DALYs, annually.
  • stage II Treatment of HAT is difficult, especially in its advanced stage (stage II), when the parasite infects the central nervous system. Only a few treatments are available: suramin and pentamidine for the disease in its early stage (stage I), and eflornithine and melarsoprol for stage II. These treatments are difficult to administer, and they are toxic and expensive. Treatments in clinical trials include pafuramidine and nifurtimox-eflornithine combination therapy. Two therapies are currently used for Chagas disease: nifurtimox and benznidazole, but these also have adverse side-effects, and neither prevents the development of, nor can treat, chronic Chagas' disease.
  • Het is an unsaturated heterocycle selected from the group consisting of thiazole, pyrazole, imidazole, oxazole, isoxazole, triazole, tetrazole, pyrimidine, pyridine and pyrazine;
  • R- ⁇ is selected from the group consisting of alkyl, aryl, heterocyclyl, heteroaryl, cycloalkyi, O-alkyl and O-aryl, amine, amino, amido, all of which may be substituted or unsubstituted, nitro and halo;
  • R 2 is selected from the group consisting of alkyl, aryl, alkylaryl, heterocyclyl, heteroaryl, cycloalkyi, cycloalkenyl, O-alkyl and O-aryl, all of which may be substituted or unsubstituted;
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, alkyl, hydroxyl, alkoxy, cyano, carboxy, carboalkoxy, amino, amido, oxo, halo, alkoxyalkyi, alkyl hydroxyl and alkylamino;
  • W is selected in each instance from the group consisting of carbon, nitrogen and oxygen; m is 1 , 2 or 3;
  • R 5 is one or more substituents independently selected from the group consisting of hydrogen, deuterium, alkyl, hydroxyl, alkoxy, cyano, carboxy, carboalkoxy, amino, amido, halo, alkoxyalkyi, alkyl hydroxyl and alkylamino; with the proviso that when Het is 1 , 3-thiazole, R-, is 3-fluorophenyl at the 2-position of the thiazole ring, R 5 is hydrogen and an ethylamide chain extends from the 4- position of the thiazole ring then R 2 is not terf-butyl; and when Het is 1 ,2,4-triazole, R-, is 3-fluorophenyl at the 3-position of the ring, R 5 is hydrogen and an ethylamide chain extends from the 5-position of the triazole ring then R 2 is not 3-fluorophenyl.
  • a pharmaceutical composition comprising an effective amount of a compound of the first aspect, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent and/or excipient.
  • the pharmaceutical composition is for the treatment or prophylaxis of a disease, disorder or condition caused by a trypanosomatid.
  • a third aspect of the invention resides in a method of treating a disease, disorder or condition caused by a trypanosomatid in a patient including the step of administering an effective amount of a compound of the first aspect, or a pharmaceutically effective salt thereof, or the pharmaceutical composition of the second aspect to the patient, to thereby treat the disease, disorder or condition caused by the trypanosomatid.
  • a fourth aspect of the invention provides for a compound of the first aspect, or a pharmaceutically effective salt thereof, or the pharmaceutical composition of the second aspect for use in the treatment of a disease, disorder or condition caused by a trypanosomatid in a patient.
  • a fifth aspect of the invention provides for use of a compound of the first aspect, or a pharmaceutically effective salt thereof, in the manufacture of a medicament for the treatment of a disease, disorder or condition caused by a trypanosomatid.
  • the disease, disorder or condition is trypanosomiasis.
  • the trypanosomiasis may be HAT or Chagas disease.
  • the trypanosome selected from the group consisting of Trypanosoma brucei rhodesiense, Trypanosoma brucei gambiense, Trypanosoma brucei brucei and Trypanosoma cruzi.
  • the disease, disorder or condition being treated may caused by a protozoa from the trypanosoma genus or the Leishmania genus.
  • the patient is a domestic or livestock animal or a human.
  • FIG 1 is a reaction scheme for the synthesis of certain substituted thiazoles
  • FIG 2 is a further reaction pathway for the synthesis of certain substituted thiazoles
  • FIG 3 is another reaction scheme for the synthesis of certain substituted thiazoles;
  • FIG 4 is a reaction scheme for the synthesis of certain substituted pyrazoles;
  • FIG 5 is a further reaction scheme for the synthesis of certain substituted pyrazoles
  • FIG 6 is an alternative reaction scheme for the synthesis of certain substituted thiazoles
  • FIG 7 is yet a further synthetic pathway for the synthesis of substituted thiazoles
  • FIG 8 is a procedure which may be used to synthesise 3-phenyl pyrazoles
  • FIG 9 is a further reaction pathway for the synthesis of 3-phenyl pyrazoles using a Michael addition approach
  • FIG 10 is reaction scheme for the synthesis of certain substituted pyridyls
  • FIG 1 1 shows a route by which 2-aryl- and 2-hetercyclo thiazoles can be assembled
  • FIG 12 is an alternative approach to the synthesis of 2-aryl- and 2- heterocyclo thiazoles
  • FIG 13 is another approach to the synthesis of 2-aryl- and 2- heterocyclo thiazoles
  • FIG 14 is yet a further approach to the synthesis of 2-aryl- and 2- heterocyclo thiazoles
  • FIG 15 is a reaction scheme to vary placement of the amide containing chain on a thiazole.
  • FIG 16 is a reaction scheme to vary placement of the amide containing chain on a pyrazole.
  • the present invention is predicated, at least in part, on the finding that certain unsaturated heterocyclic compounds display useful efficacy in the treatment of diseases caused by trypanosomatids.
  • the compounds of the invention are useful in the treatment of HAT and/or Chagas disease and/or Animal African trypanosomiasis (AAT).
  • trypanosomatid refers to a protozoan of the order Trypsanomatida. Particularly preferred protozoa within this order are those of the genus Trypanosoma and Leishmania.
  • trypanosome refers to a protozoan of the genus Trypanosoma and including a number of species known to cause trypanosomiasis including, but not limited to, Trypanosoma brucei rhodesiense, Trypanosoma brucei gambiense, Trypanosoma brucei brucei and Trypanosoma cruzi, Trypanosoma vivax, Trypanosoma congolense, Trypanosoma equiperdum and Trypanosoma brucei evansi.
  • T.vivax and T.congolense that are largely associated with the blood compartment and cause severe anemia (Nagana). Tequiperdum is transmitted venereally in horses and donkeys.
  • T.brucei evansi (Surra) is transmitted mechanically by biting flies in horses, cattle and camels in Africa and in cattle, horses, camels, elephants, etc. in Asia.
  • trypanosomes are only transmitted mechanically by biting flies and in this region T.vivax mainly affects cattle and sheep and T.evansi mainly affects horses and dogs but also cattle.
  • Leishmania is a genus of the protist order Trypanosomatida and includes species such as Leishmania major, Leishmania tropica, Leishmania braziliensis, Leishmania donovani, Leishmania infantum, Leishmania aethiopica, Leishmania chagasi and Leishmania mexicana, although without limitation thereto.
  • Leishmaniasis is any disease or condition caused by, or otherwise associated with, parasitic protists of the genus Lesihmania.
  • Primary hosts are mammals such as hyraxes, canids, rodents and humans.
  • Leishmaniasis results from Leishmania transmission by the bite of certain species of sand fly (e.g. Phlebotominae and Lutzomyi).
  • Most human disease is zoonotic (i.e transmissible only from non-human animals), but some can be spread between humans.
  • Leishmaniasis The symptoms of Leishmaniasis include skin sores which erupt weeks to months after the person is bitten by sand flies, fever, damage to the spleen (which may result in an enlarged, palpable spleen) and liver, and anemia. Cutaneous Leishmaniasis is the most common form (typically caused by L. major, L. tropica, L. aethiopica and L. mexicana), which causes a sore at the bite site, healing in a few months to a year, leaving a permanent scar.
  • effective amount refers to the administration of an amount of the relevant active agent sufficient to prevent the occurrence of symptoms of the condition being treated, or to bring about a halt in the worsening of symptoms or to treat and alleviate or at least reduce the severity of the symptoms.
  • the effective amount will vary in a manner which would be understood by a person of skill in the art with patient age, sex, weight etc. An appropriate dosage or dosage regime can be ascertained through routine trial.
  • pharmaceutically acceptable salt refers to salts which are toxicologically safe for systemic or localised administration such as salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
  • the pharmaceutically acceptable salts may be selected from the group including alkali and alkali earth, ammonium, aluminium, iron, amine, glucosamine, chloride, sulphate, sulphonate, bisulphate, nitrate, citrate, tartrate, bitarate, phosphate, carbonate, bicarbonate, malate, maleate, napsylate, fumarate, succinate, acetate, benzoate, terephthalate, palmoate, piperazine, pectinate and S-methyl methionine salts and the like.
  • alkyf refers to a straight-chain or branched alkyl substituent containing from, for example, 1 to about 12 carbon atoms, preferably 1 to about 9 carbon atoms, more preferably 1 to about 6 carbon atoms, even more preferably from 1 to about 4 carbon atoms, still yet more preferably from 1 to 2 carbon atoms.
  • substituents may be selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, te/t-butyl, pentyl, isoamyl, 2-methylbutyl, 3-methylbutyl, hexyl, heptyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-ethylbutyl, 3- ethylbutyl, octyl, nonyl, decyl, undecyl, dodecyl and the like.
  • Substituted alkyl includes alkyl substituted with one or more moieties selected from the group consisting of halo ⁇ e.g., CI, F, Br, and I); halogenated alkyl ⁇ e.g., CF 3 , 2-Br-ethyl, CH 2 F, CF 2 H, CH 2 CI, CH 2 CF 3 , or CF 2 CF 3 ); hydroxyl; amino; carboxylate; carboxamido; alkylamino; arylamino; alkoxy; aryloxy; nitro; azido; cyano; thio; sulfonyl, sulphonamide, sulfonic acid; sulfate; phosphonic acid; phosphate; and phosphon
  • alkenyf refers to optionally substituted unsaturated linear or branched hydrocarbon groups, having 2 to 12 carbon atoms, preferably 2 to 9 carbon atoms, more preferably 2 to 6 carbon atoms and having at least one carbon-carbon double bond.
  • the alkenyl group may have a specified number of carbon atoms, for example, C 2 -C 6 alkenyl which includes alkenyl groups having 2, 3, 4, 5 or 6 carbon atoms in linear or branched arrangements.
  • the number of carbons referred to relates to the carbon backbone and carbon branching but does not include carbon atoms belonging to any substituents.
  • substituents may be selected from the group consisting of ethenyl, propenyl, isopropenyl, butenyl, s- and t-butenyl, pentenyl, hexenyl, hept-l,3-diene, hex-l,3-diene, non-l,3,5-triene and the like.
  • Substituted alkyl includes alkyl substituted with one or more moieties selected from the group consisting of halo ⁇ e.g., CI, F, Br, and I); halogenated alkyl ⁇ e.g., CF 3 , 2-Br-ethyl, CH 2 F, CF 2 H, CH 2 CI, CH 2 CF 3 , or CF 2 CF 3 ); hydroxyl; amino; carboxylate; carboxamido; alkylamino; arylamino; alkoxy; aryloxy; nitro; azido; cyano; thio; sulfonyl, sulphonamide, sulfonic acid; sulfate; phosphonic acid; phosphate; and phosphonate.
  • halo ⁇ e.g., CI, F, Br, and I
  • halogenated alkyl ⁇ e.g., CF 3 , 2-Br-ethyl, CH 2 F
  • carboalkoxy refers to an alkyl ester of a carboxylic acid, wherein alkyl has the same definition as found above. Examples include carbomethoxy, carboethoxy, carboisopropoxy and the like.
  • alkoxy as used herein means straight or branched chain alkyl groups linked by an oxygen atom (i.e., -O-alkyl), wherein alkyl is as described above.
  • alkoxy refers to oxygen-linked groups comprising 1 to 10 carbon atoms ("C1 -10 alkoxy”).
  • alkoxy refers to oxygen-linked groups comprising 1 to 8 carbon atoms ("C1 -8 alkoxy"), 1 to 6 carbon atoms (“C1 -6 alkoxy”), 1 to 4 carbon atoms (“C1 -4 alkoxy") or 1 to 3 carbon atoms ("C1 -3 alkoxy").
  • cycloalkyi and “cycloalkenyl” refers to optionally substituted saturated and unsaturated mono-cyclic, bicyclic or tricyclic carbon groups.
  • the cycloalkyi or cycloalkenyl group may have a specified number of carbon atoms, for example, C 3 -C 6 cycloalkyi or cycloalkenyl includes within its scope a carbocyclic group having 3, 4, 5 or 6 carbon atoms.
  • C 4 -C 7 cycloalkyi or cycloalkenyl may be preferred in embodiments.
  • C 5 -C 6 cycloalkyi or cycloalkenyl may be preferred in certain embodiments.
  • substituents may be selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl and the like.
  • Substituted cycloalkyi or cycloalkenyl includes substitutions with one or more moieties selected from the group consisting of halo ⁇ e.g., CI, F, Br, and I); halogenated alkyl ⁇ e.g., CF 3 , 2-Br-ethyl, CH 2 F,
  • aryl refers to an unsubstituted or substituted aromatic carbocyclic substituent, as commonly understood in the art. It is understood that the term aryl applies to cyclic substituents that are planar and comprise 4n+2 ⁇ electrons, according to Huckel's Rule.
  • heteroaryl refers to an aryl group containing from one or more (particularly one to four) non-carbon atom(s) (particularly N, O or S) or a combination thereof, which heteroaryl group is optionally substituted at one or more carbon or nitrogen atom(s). It may be a 4, 5, 6 or 7-membered ring, preferably 5 or 6-membered. Heteroaryl rings may also be fused with one or more cyclic hydrocarbon, heterocyclic, aryl, or heteroaryl rings.
  • Heteroaryl includes, but is not limited to, 5-membered heteroaryls having one hetero atom (e.g., thiophenes, pyrroles, furans); 5 membered heteroaryls having two heteroatoms in 1 ,2 or 1 ,3 positions (e.g., oxazoles, pyrazoles, imidazoles, thiazoles, purines); 5-membered heteroaryls having three heteroatoms (e.g., triazoles, thiadiazoles); 5-membered heteroaryls having 3 heteroatoms; 6- membered heteroaryls with one heteroatom (e.g., pyridine, quinoline, isoquinoline, phenanthrine, 5,6-cycloheptenopyridine); 6-membered heteroaryls with two heteroatoms (e.g., pyridazines, cinnolines, phthalazines, pyrazines, pyrimidines, quinazolines); 6-member
  • Heterocyclyl as used herein specifically in relation to certain 'R' groups refers to a non-aromatic ring having 5 to 7 atoms in the ring and of those atoms 1 to 4 are heteroatoms, said ring being isolated or fused to a second ring wherein said heteroatoms are independently selected from O, N and S. 5 to 6 ring atoms may be preferred.
  • Heterocyclic includes partially and fully saturated heterocyclic groups. Heterocyclic systems may be attached to another moiety via any number of carbon atoms or heteroatoms of the radical and may be both saturated and unsaturated.
  • heterocyclic examples include pyrrolidinyl, pyrrolinyl, pyranyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolinyl, dithiolyl, oxathiolyl, dioxanyl, dioxinyl, oxazinyl, azepinyl, diazepinyl, thiazepinyl, oxepinyl and thiapinyl, imidazolinyl, thiomorpholinyl, and the like.
  • a range of the number of atoms in a structure is indicated (e.g., a C1-C12, C1-C10, C1-C9, C1-C6, Ci-C 4 , or C2-C20, C2-C12, C2-C10, C2-C9, C 2 -C 8 , C 2 -C 6 , C 2 -C 4 alkyl, alkenyl, etc.), it is specifically contemplated that any sub-range or individual number of carbon atoms falling within the indicated range also can be used.
  • Substituted or “Optionally substituted” in reference to a substituent group refers to substituent groups optionally substituted with one or more moieties, for example, those selected from the group consisting of optionally substituted C1 -10 alkyi ⁇ e.g., optionally substituted C1 -6 alkyi); optionally substituted C1 -10 alkoxy ⁇ e.g., optionally substituted C1 -6 alkoxy); optionally substituted C2-10 alkenyl; optionally substituted C2-10 alkynyl; optionally substituted C6-C12 aryl; aryloxy; optionally substituted heteroaryl; optionally substituted heterocycle; halo ⁇ e.g., CI, F, Br, and I); hydroxyl; halogenated alkyi ⁇ e.g., CF 3 , 2-Br-ethyl, CH 2 F, CF 2 H, CH 2 CF 3 , and CF 2 CF 3 ); amino (e.
  • the terms "subject” or “individual” or “patient” may refer to any subject, particularly a vertebrate subject, and even more particularly a mammalian subject, for whom therapy is desired.
  • Suitable vertebrate animals include, but are not restricted to, primates, avians, livestock animals (e.g., sheep, cows, horses, donkeys, pigs), laboratory test animals (e.g., rabbits, mice, rats, guinea pigs, hamsters), companion animals (e.g., cats, dogs) and captive wild animals (e.g., foxes, deer, dingoes).
  • a preferred subject is a human in need of treatment for a disease or condition caused by a trypanosome. However, it will be understood that the aforementioned terms do not imply that symptoms are necessarily present.
  • Het is an unsaturated heterocycle selected from the group consisting of thiazole, pyrazole, imidazole, triazole, tetrazole, pyrimidine, pyridine and pyrazine;
  • Ri is selected from the group consisting of alkyl, aryl, heterocyclyl, heteroaryl, cycloalkyi, O-alkyl and O-aryl, amine, amino, amido, all of which may be substituted or unsubstituted, nitro and halo;
  • R 2 is selected from the group consisting of alkyl, aryl, alkylaryl, heterocyclyl, heteroaryl, cycloalkyi, cycloalkenyl, O-alkyl and O-aryl, all of which may be substituted or unsubstituted;
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, alkyl, hydroxyl, alkoxy, cyano, carboxy, carboalkoxy, amino, amido, halo, alkoxyalkyl, alkyl hydroxyl and alkylamino; W is selected in each instance from the group consisting of carbon, nitrogen and oxygen; m is 1 , 2 or 3;
  • R 5 is one or more substituents independently selected from the group consisting of hydrogen, alkyl, hydroxyl, alkoxy, cyano, carboxy, carboalkoxy, amino, amido, halo, alkoxyalkyi, alkyl hydroxyl and alkylamino; with the proviso that when Het is 1 , 3-thiazole, R-, is 3-fluorophenyl at the 2-position of the thiazole ring, R 5 is hydrogen and an ethylamide chain extends from the 4- position of the thiazole ring then R 2 is not terf-butyl; and when Het is 1 ,2,4- triazole, R-, is 3-fluorophenyl at the 3-position of the ring, R 5 is hydrogen and an ethylamide chain extends from the 5-position of the triazole ring then R 2 is not 3-fluorophenyl.
  • Het is selected from the group consisting of thiazole, pyrazole, imidazole, oxazole, isoxazole, pyrimidine, pyridine and pyrazine.
  • Het is selected from thiazole, pyrazole or pyridine.
  • Ri is selected from the group consisting of alkyl, aryl, heterocyclyl, heteroaryl, cycloalkyl, O-alkyl, O-aryl, amine, amino and amido, all of which may be substituted or unsubstituted.
  • R- is selected from the group consisting of phenyl, benzyl, pyridyl, thiophene, amido, amine, amino, and piperidinyl, all of which may be substituted or unsubstituted.
  • R-i is optionally substituted phenyl or pyridyl.
  • R 2 is selected from the group consisting of alkyl, aryl, alkylaryl, heterocyclyl, heteroaryl, cycloalkyl, cycloalkenyl, O-alkyl and O-aryl, all of which may be substituted or unsubstituted.
  • R 2 is selected from the group consisting of alkyl, phenyl, cyclohexyl, cyclopentyl, thiophene, pyridinyl, benzyl, thiazole, tetrahydropyranyl, furanyl, pyrazinyl, piperidinyl, thiophene, alkoxybutyl, pyrrolidinyl, morpholinyl, azepane, isoxazole, all of which may be substituted or unsubstituted, and NR 2 Ri3 wherein R 2 and Ri 3 are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl and hexyl or R 2 and Ri 3 join to form a ring.
  • R 2 is pyrrolidinyl, piperidinyl, azepane, furanyl, phenyl, morpholinyl, all of which may be substituted or unsubstituted, and NR 12 R 13 wherein R 12 and R 3 are as previously described.
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, alkyl, hydroxyl, alkoxy, cyano, carboxy, carboalkoxy and amino.
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, alkyl, hydroxyl and amino.
  • W is selected from carbon or nitrogen.
  • n is 2.
  • R 5 is one or more substituents independently selected from the group consisting of hydrogen, alkyl, hydroxyl, alkoxy, cyano, carboxy, halo and amino.
  • R 5 may be selected from hydrogen, d-C 6 alkyl, chlorine and fluorine.
  • the compound is not either of the following compounds:
  • R 1 ; R 2 and R 5 are as described in any one or more of the above embodiments; and with the proviso that when Het is 1 , 3-thiazole, R-, is 3-fluorophenyl at the 2-position of the thiazole ring, R 5 is hydrogen and an ethylamide chain extends from the 4- position of the thiazole ring then R 2 is not terf-butyl; and when Het is 1 ,2,4- triazole, Ri is 3-fluorophenyl at the 3-position of the ring, R 5 is hydrogen and an ethylamide chain extends from the 5-position of the triazole ring then R 2 is not 3-fluorophenyl.
  • R- is selected from the group consisting of phenyl, pyridyl, thiophene, piperidine and amine, each of which may be substituted or unsubstituted.
  • R 2 is selected from the group consisting of CrC 6 alkyl, C C 6 alkoxy, phenyl, pyridyl, thiophene, piperidine, furanyl, C 5 -C 6 cyclyl, benzyl, thiazole, pyrazine, oxazole, pyrrolidinyl, morpholinyl, amine, azepane, pyrrole and isoxazole, each of which may be substituted or unsubstituted.
  • R 2 is piperidine independently substituted at one or more points on the ring with a moiety selected from the group consisting of fluoro, oxo, cyano and hydroxyl.
  • R 5 is selected from hydrogen, fluorine, chlorine and C C 6 alkyl.
  • R-i and R 2 may be as described in any one or more of the above embodiments; and with the proviso that when Het is 1 , 3-thiazole, R-, is 3-fluorophenyl at the 2-position of the thiazole ring, R 5 is hydrogen and an ethylamide chain extends from the 4- position of the thiazole ring then R 2 is not terf-butyl; and when Het is 1 ,2,4- triazole, R-, is 3-fluorophenyl at the 3-position of the ring, R 5 is hydrogen and an ethylamide chain extends from the 5-position of the triazole ring then R 2 is not 3-fluorophenyl.
  • Ri is selected from the group consisting of alkyl, aryl, heterocyclyl, heteroaryl, cycloalkyi, amino, all of which may be substituted or unsubstituted, and halo.
  • R- is selected from the group consisting of phenyl, benzyl, pyridyl, thiophene, amido, amine, amino, and piperidine, all of which may be substituted or unsubstituted
  • R 2 is selected from alkyl, aryl, alkylaryl, heterocyclyl, heteroaryl, cycloalkyi, O-alkyl and O-aryl, all of which may be substituted or unsubstituted.
  • R 2 is selected from the group consisting of alkyl, phenyl, cyclohexyl, cyclopentyl, thiophene, pyridinyl, benzyl, thiazole, tetrahydropyranyl, furanyl, pyrazinyl, piperidinyl, thiophene, alkoxybutyl, pyrrolidinyl, morpholinyl, azepane, isoxazole and NR 12 R 13 , all of which may be substituted or unsubstituted, wherein R 2 and Ri 3 are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl and hexyl or Ri 2 and Ri 3 join to form a ring. [0087] In one embodiment, there is provided a compound of formula (XI), or a pharmaceutically acceptable salt thereof:
  • R ; R 2 and R 5 may be as described in any one or more of the above embodiments; with the proviso that when Het is 1 , 3-thiazole, Ri is 3-fluorophenyl at the 2-position of the thiazole ring, R 5 is hydrogen and an ethylamide chain extends from the 4- position of the thiazole ring then R 2 is not terf-butyl; and when Het is 1 ,2,4- triazole, Ri is 3-fluorophenyl at the 3-position of the ring, R 5 is hydrogen and an ethylamide chain extends from the 5-position of the triazole ring then R 2 is not 3-fluorophenyl.
  • Ri is selected from the group consisting of alkyl, aryl, heterocyclyl, heteroaryl, cycloalkyi, amino, all of which may be substituted or unsubstituted, and halo.
  • R- is selected from the group consisting of phenyl, benzyl, pyridyl, thiophene, amido, amine, amino, and piperidine, all of which may be substituted or unsubstituted.
  • R 2 is selected from alkyl, aryl, alkylaryl, heterocyclyl, heteroaryl, cycloalkyi, O-alkyl and O-aryl, all of which may be substituted or unsubstituted.
  • R 2 is selected from the group consisting of alkyl, phenyl, cyclohexyl, cyclopentyl, thiophene, pyridinyl, benzyl, thiazole, tetrahydropyranyl, furanyl, pyrazinyl, piperidinyl, thiophene, alkoxybutyl, pyrrolidinyl, morpholinyl, azepane, isoxazole and NR 2 R 3 , all of which may be substituted or unsubstituted, wherein R 12 and R 3 are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl and hexyl or R 2 and R 3 join to form a ring.
  • substitution may be substitution selected from the group consisting of CrC 6 alkyl, halo, C C 6 alkoxy, cyano and hydroxyl.
  • the compound of the first aspect is a trypanocidal compound.
  • the compound of the above formula is selected from the group consisting of:
  • R-, and R 2 are as described for any one or more of the above embodiments.
  • Ri is phenyl and R 2 is selected from the group consisting of pyrrolidinyl, piperidinyl and azepane.
  • the compound is selected from the group consisting of:
  • the compound of any of the above formulae is a trypanocidal compound.
  • substitution may be substitution selected from the group consisting of C C 6 alkyl, d-C 6 alkoxy, CrC 6 aryl, CrC 6 cycloalkyl, cyano, halo and hydroxyl.
  • the compound may be selected from those recited in the table below, wherein the core chemical structure with a right hand side moiety missing is shown in the left hand column and the possible replacements envisaged are shown in the adjacent columns.
  • the combined structures are considered to have been disclosed as if each and every structure had been drawn with each of the adjacent moieties (A to F) attached at the relevant point:
  • n 1 , 2 or 3.
  • the compound may be selected from those recited in the table below, wherein the core chemical structure with a right hand side moiety missing is shown in the left hand column and the possible replacements envisaged are shown in the adjacent columns.
  • the combined structures are considered to have been disclosed as if each and every structure had been drawn with each of the adjacent moieties (A to F) attached at the relevant point:
  • R may be selected from hydrogen, fluoro, chloro and C C 6 alkyl.
  • the compound may be selected from those recited in the table below, wherein the core chemical structure with a right hand side moiety missing is shown in the left hand column and the possible replacements envisaged for 'R' are shown in the adjacent columns.
  • the combined structures are considered to have been disclosed as if each and every structure had been drawn with each of the adjacent moieties (A to E) attached at the relevant point:
  • the compound may be selected from those recited in the table below, wherein the core chemical structure with a right hand side moiety missing is shown in the left hand column and the possible replacements envisaged for 'R' are shown in the adjacent columns.
  • the combined structures are considered to have been disclosed as if each and every structure had been drawn with each of the adjacent moieties attached at the relevant point:
  • the compound may be selected from those recited in the table below, wherein the core chemical structure with a right hand side moiety missing is shown in the left hand column and the possible replacements envisaged are shown in the adjacent columns.
  • the combined structures are considered to have been disclosed as if each and every structure had been drawn with each of the ad acent moieties (A to F) attached at the relevant point:
  • the compound of formula (I) to formula (XXV), as appropriate, is selected from the group consisting of:
  • R 1 to R 8 are independently selected from the group consisting of H, CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , OH, OCH 3 ,O(CH 2 CH 3 ), CN, CO 2 H, CO 2 Me, CONH 2 , C(O)NH(CH 3 ), C(O)N(CH 3 ) 2 , F, CI, Br, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , CH 2 OH, CH 2 OCH 3 , CH 2 NH 2 , CH 2 NH(CH 3 ) and CH 2 N(CH 3 ) 2 .
  • heterocyclic compounds shown all show interesting activities, in one embodiment, it is preferred that the heterocyclic ring of the compounds of the invention be selected from the group consisting of thiazole, pyrazole and pyridine.
  • the compound is selected from the group consisting of:
  • the compounds can be synthesised by approaches which are known in the art. Such approaches can be found in reference texts and journal articles including the following: Eriiks, J.; Vandergoot, H.; Sterk, G.; Timmerman, H. J. Med. Chem, 1992, 35, 3239-3246; Walczynski, K.; Timmerman, H.; Zuiderveld, O.; Zhang, M.; Glinka, R. II Farmaco, 1999, 54, 533-541 ; Ahangar, N.; Ayatti, A.; Alipour, E.; Pashapour, A.; Formadi, A.; Emmami, S. Chem Biol Drug Des.
  • FIGs 1 to 16 A number of synthetic pathways to one or more of the compounds of formula (I) to formula (XXV) are shown in FIGs 1 to 16.
  • FIG 1 shows a synthetic scheme to access certain substituted thiazoles (J. Med. Chem, 1992, 35, 3239- 3246; and // Farmaco, 1999, 54, 533-541 ).
  • FIG 2 ⁇ Chem Biol Drug Des. 2011 , 78, 844-852; Caddick. S; Judd. D.; Lewis. A,; Reich. M,; Williams.; M. Tetrahedron, 2003, 59, 5417-5423) shows a synthetic scheme yielding thiazoles with a differing substitution pattern from that in FIG 1 .
  • FIG 3 shows a route to achieve a range of thiazole compounds which can then be further modified to either provide a urea linkage or offer a substituted amino group (Duspara, P. A., et al. JOCS. 2012. 77, 10362-10368).
  • FIG 4 shows a synthesis to achieve a range of substituted pyrazole compounds. The final step shown leaves an ammonium moiety which is easily subsequently converted into a range of desirable functionalities in the manner already shown in FIG 2.
  • FIG 5 presents a varying route to the same intermediate product as seen in FIG 4.
  • FIG 6 indicates another pathway by which the R-, and R 2 moiety of the compounds can be manipulated.
  • FIG 7 relates to modifications of the Ri and R 2 positions of a thiazole heterocycle, once again indicating the flexibility in placing a range of functional groups at these positions.
  • FIG 8 shows a typical procedure used to synthesise 3-phenyl pyrazoles. This is applicable to a wide variation in the 3-position moieties as would be understood by those skilled in the art. Also, as shown, the RHS amine can be diversified to form ureas or amides. Derivatising to other amides and ureas is available to those skilled in the art. Additionally, the bromo ethyl warhead in the phthalimide could be replaced by an alkene, and the same reaction undertaken via Michael addition.
  • FIG 10 indicates, for a pyridyl core, similar synthetic principles, with options including Curtius rearrangement and Hofmann rearrangement routes.
  • a Heck reaction has been used.
  • the chemistry shown is equally applicable to other heterocyclic cores such as the pyrimidines.
  • FIG 1 1 shows a route by which 2-aryl- and 2-heterocyclo thiazoles can be assembled as is demonstrated specifically for 2-phenylthiazole compounds. It will be appreciated by a skilled artisan that manipulation of the 2- bromo moiety can be undertaken to give many variations and this is common to all cores where there is an intermediate aryl halide. Alternatives to this approach to achieve a similar class of end product are shown in FIGs 12, 13 and 14.
  • a thiazole, or like heterocyclic, showing a different substitution pattern in that the ethylamide arm extends from the 2-position as opposed to the 4-position can be synthesized as demonstrated in FIG 15.
  • a similar reversal of the positioning of the and R 2 moieties is seen to be achieved for the pyrazole core in FIG 16.
  • a pharmaceutical composition comprising an effective amount of a compound of the first aspect, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent and/or excipient.
  • the pharmaceutical composition is for the treatment or prophylaxis of a disease, disorder or condition caused by a trypanosomatid, preferably by a trypanosome.
  • the pharmaceutical composition may include more than one compound of the first aspect. When the composition includes more than one compound then the compounds may be in any ratio.
  • the composition may further comprise known co-actives, delivery vehicles or adjuvants.
  • the compound of the first aspect is present in the pharmaceutical composition in an amount sufficient to inhibit or ameliorate the disease, disorder or condition which is the subject of treatment. Suitable dosage forms and rates of the compounds and the pharmaceutical compositions containing such may be readily determined by those skilled in the art.
  • Dosage forms may include tablets, dispersions, suspensions, injections, solutions, syrups, troches, capsules and the like. These dosage forms may also include injecting or implanting devices designed specifically for, or modified to, ensure placement at the site of connective tissue degradation.
  • a hydrogel is a preferred delivery form.
  • a third aspect of the invention resides in a method of treating a disease, disorder or condition caused by a trypanosomatid in a patient including the step of administering an effective amount of a compound of the first aspect, or a pharmaceutically effective salt thereof, or the pharmaceutical composition of the second aspect to the patient, to thereby treat the disease, disorder or condition caused by the trypanosomatid.
  • a fourth aspect of the invention provides for a compound of the first aspect, or a pharmaceutically effective salt thereof, or the pharmaceutical composition of the second aspect for use in the treatment of a disease, disorder or condition caused by a trypanosomatid in a patient.
  • a fifth aspect of the invention provides for use of a compound of the first aspect, or a pharmaceutically effective salt thereof, in the manufacture of a medicament for the treatment of a disease, disorder or condition caused by a trypanosomatid.
  • the disease, disorder or condition is caused by a trypanosome. In one embodiment, the disease, disorder or condition is trypanosomiasis.
  • the trypanosomiasis may be HAT or Chagas disease.
  • the trypanosome selected from the group consisting of Trypanosoma brucei rhodesiense, Trypanosoma brucei gambiense, Trypanosoma brucei brucei and Trypanosoma cruzi.
  • the patient is a domestic or livestock animal or a human.
  • the compound of the first aspect may be selected from any one or more compounds of formula I to formula XXV or any compound disclosed herein by way of a generic structure or exact chemical structure.
  • Boc-deprotection with 4-toluenesulfonic acid [00135] To a solution of carbonate (0.5 mmol) in acetonitrile (2 imL) was added 4-toluenesulfonic acid hydrate (0.55 mmol). The suspension was refluxed until completion by TLC. The solution was then cooled to 0C in an ice bath. The precipitate was filtered, washed with cold acetonitrile (2 imL) and diethylether (2 x 10 imL) and finally dried in a vacuum oven at 50°C for 4h. The material was obtained as an aminium tosylate salt and used in the next step without further purification.
  • 2-Phenyl-6-vinylpyridine 2 [00180] 2-Bromo-6-phenylpyridine (959 mg, 4.10 mmol), tributyl(vinyl) tin (2.40 ml, 8.20 mmol), palladium acetate (138 mg, 0.62 mmol) and triphenylphosphine (323 mg, 1 .23 mmol) were combined in tetrahydrofuran (8.2 ml) and the reaction mixture was thoroughly degassed. The reaction mixture was refluxed for 48 h and monitored for completion. Once complete, the reaction mixture was filtered through celite and the filtrate concentrated.
  • Ethyl (1 ft,2ft)-2-(6-phenylpyridin-2-yl)cyclopropane-1 -carboxylate (310 mg, 1 .16 mmol) was dissolved in tetrahydrofuran (0.8 ml) and this solution was added dropwise to an solution of lithium hydroxide (56 mg, 2.32 mmol) in water (1 ml). The reaction mixture was stirred at 50 °C and monitored by LRMS and TLC for completion. Once complete ( ⁇ 2 h) the reaction mixture was neutralised by addition of an aqueous solution of 1 M hydrochloric acid.
  • Ethyl (1 ft,2S)-2-(6-phenylpyridin-2-yl)cyclopropane-1 -carboxylate (137 mg, 0.51 mmol) was dissolved in tetrahydrofuran (0.3 ml) and this solution was added dropwise to a solution of lithium hydroxide (25 mg, 1 .02 mmol) in water (0.5 ml). The reaction mixture was stirred at 50 °C and monitored by LRMS and TLC for completion. Once complete ( ⁇ 2 h) the reaction mixture was neutralised by addition of an aqueous solution of 1 M hydrochloric acid.
  • the title compound can be prepared from from benzyl (£)-3-(6- phenylpyridin-2-yl)acrylate (495 mg, 1 .57 mmol) which is dissolved in ethanol (12 ml) and 5% Pd/C (8 mg, .0.8 mmol) was added prior to the reaction being flushed with hydrogen gas.
  • the recation mixture was stirred at 60 °C for 18 h, at which point both TLC and LRMS confirmed that the reaction was complete.
  • the reaction mixture was then filtered through celite and the solvent removed in vacuo.
  • Triethylamine (0.35 mL, 2.5 mmol) was added to a suspension of 2- (4-phenyl)thiazol-2-yl ethylamine dihydrochloride (0.24 g, 1 .2 mmol) of in DCM (10 mL) under argon.
  • the reaction mixture was cooled in an ice-bath, then carefully treated with 4-fluorobenzoylchloride (0.17 mL, 1 .5 mmol).
  • the resulting solution was allowed to warm to room temperature and stirring was continued overnight.
  • the solvent was evaporated and the residue was purified using column chromatography.
  • Triethylamine (0.08 imL, 0.59 mmol) was added to a stirred solution of A/-(2-(2-phenylthiazol-4-yl)ethyl)-1 -/-imidazole-1 -carboxamide (0.16 g, 0.54 mmol) and azepane (0.06 imL, 0.54 mmol) in DCM (6 imL) under argon. After 18 h, the solvent was evaporated and the residue was diluted with EtOAc (150 imL), then washed with brine (3 ⁇ 50 ml), dried and the solvent was evaporated. The residue was subjected to column chromatography.
  • Ethyl (1 ft,2S)-2-(6-phenylpyridin-2-yl)cyclopropane-1 -carboxylate (137 mg, 0.51 mmol) was dissolved in tetrahydrofuran (0.3 ml) and this solution was added dropwise to a solution of lithium hydroxide (25 mg, 1 .02 mmol) in water (0.5 ml). The reaction mixture was stirred at 50 °C and monitored by LRMS and TLC for completion. Once complete ( ⁇ 2 h) the reaction mixture was neutralised by addition of an aqueous solution of 1 M hydrochloric acid.
  • the crude product was purified by flash column chromatography, eluting with 0-40% ethyl acetate and petroleum benzine, afforded the desired product, 1 -phenyl-1 -/-pyrazol-3-amine, as a brown solid (1 .53 g, 80%).
  • P. falciparum assay In vitro activity against erythrocytic stages of P. falciparum was determined using a 3H-hypoxanthine incorporation assay, 6,7 using the chloroquine and pyrimethamine resistant K1 strain 8 and the standard drug chloroquine (Sigma C6628).
  • donovani axenic amastigotes assay Amastigotes of L. dono vani strain MHOM/ET/67/L82 were grown in axenic culture at 37 °C in SM medium 10 at pH 5.4 supplemented with 10% heat-inactivated fetal bovine serum under an atmosphere of 5% CO 2 in air. 100 ⁇ _ of culture medium with 10 5 amastigotes from axenic culture with or without a serial drug dilution were seeded in 96-well microtitre plates. Serial drug dilutions of eleven 3-fold dilution steps covering a range from 100 to 0.002 pg/mL were prepared.
  • T. cruzi assay Rat skeletal myoblasts (L-6 cells) were seeded in 96- well microtitre plates at 2000 cells/well in 100 ⁇ _ RPM1 1640 medium with 10% FBS and 2 imM l-glutamine. After 24 h at 37°C/5% CO 2 , the medium was removed and replaced by 100 pl_ per well containing 5000 trypomastigote forms of T. craz/Tulahuen strain C2C4 containing the ⁇ -galactosidase (Lac Z) gene.
  • T. brucei rhodesiense assay This parasite stock was isolated in 1982 from a human patient in Africa and after several mouse passages cloned and adapted to axenic culture conditions. 13 Minimum Essential Medium (50 ⁇ _) supplemented with 25 imM HEPES, 1 g/L additional glucose, 1 % MEM non-essential amino acids (100x), 0.2 imM 2-mercaptoethanol, 1 imM Na- pyruvate and 15% heat inactivated horse serum was added to each well of a 96-well microtiter plate. Serial drug dilutions of eleven 3-fold dilution steps covering a range from 100 to 0.002 pg/mL were prepared.
  • Rat skeletal myoblast cytotoxicity assay Assays were performed in 96-well microtiter plates, each well containing 100 ⁇ _ of RPM1 1640 medium supplemented with 1 % L-glutamine (200 imM) and 10% fetal bovine serum, and 4000 L-6 cells (a primary cell line derived from rat skeletal myoblasts). 15, 16 Serial drug dilutions of eleven 3-fold dilution steps covering a range from 100 to 0.002 g/mL were prepared. After 70 h of incubation at 37°C/5% CO 2 the plates were inspected under an inverted microscope to assure growth of the controls and sterile conditions.
  • T. b. brucei assay Compound activity against T. b. brucei was assessed using a modification of the Alamar blue® viability assay as previously described by Sykes and Avery. 17 in which resazurin was used instead of Alamar Blue (which is made up of resazurin dye 18 ). Briefly, 55 ⁇ _ of HMI-9 media +10% FCS 19 containing 1200 cells/mL of logarithmic phase T. b. brucei 427 bloodstream parasites were added to a 384-well microtiter plate (Greiner, Monroe, NC, USA) and incubated for 24 h at 37°C/5% CO 2 .
  • Serial compound concentrations were prepared in 100% DMSO and diluted 1 :21 in DMEM media. 5 ⁇ _ of this dilution was subsequently added to assay plates to give final compound concentrations ranging from 41 .67 to 0.0004 ⁇ . Plates were incubated for 48 h at 37°C/5% CO 2 . 10 ⁇ _ of 0.49 imM resazurin prepared in HMI-9 media +10% FCS was added to assay plates and plates incubated for a further 2 h at 37 °C/5% CO 2 followed by 22 h at room temperature. Assay plates were read at 535 nm excitation/590 nm emission on an Envision® multiplate reader (PerkinElmer, Massachusetts, USA). Data was analysed and IC 5 o values calculated using the software GraphPad Prism 5. Pentamidine and suramin were used as controls.
  • HEK293 cytotoxicity assay 55 ⁇ _ of DMEM +10% FCS media (Gibco, Waltham, MA, USA) containing 72727 cells/mL of HEK293 cells was added to a 384-well microtiter plate (Greiner) and incubated for 24 h at 37°C/5% CO2. Serial compound concentrations were prepared in 100% DMSO and diluted 1 :21 in DMEM media. 5 ⁇ _ of this dilution was subsequently added to assay plates to give final compound concentrations ranging from 83.34 to 0.0004 ⁇ . Plates were incubated for 48 h at 37°C/5% CO 2 .
  • rhodesiense is a human pathogenic strain; /.. donovani causes leishmaniasis; P. falciparum causes malaria.
  • MRK8 observed activity against 7.
  • b. rhodesiense HAT, 0.024[ig/mL), T cruzi (Chagas, 0. 169 ⁇ g/mL), L donovani (Leishmania 7.7 ⁇ g/mL) and P. falciparum (Malaria, 10.0 ug/mL).
  • Hirumi, H.; Hirumi, K Continuous cultivation of Trypanosoma brucei blood stream forms in a medium containing a low concentration of serum protein without feeder cell layers. Journal of Parasitology 1989, 75, 985-989.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouveaux composés hétérocycliques se révélant efficaces dans le cadre du traitement de maladies provoquées par les trypanosomatides. Les composés de l'invention se révèlent, en particulier, utiles pour le traitement de la trypanosomiase humaine africaine (THA) et/ou de la maladie de Chagas et/ou de la trypanosomiase animale africaine (TAA).
PCT/AU2015/050238 2014-05-13 2015-05-13 Composés hétérocycliques et leur utilisation WO2015172196A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AU2014901768A AU2014901768A0 (en) 2014-05-13 Heterocyclic compounds and use of same
AU2014901768 2014-05-13

Publications (1)

Publication Number Publication Date
WO2015172196A1 true WO2015172196A1 (fr) 2015-11-19

Family

ID=54479049

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/AU2015/050238 WO2015172196A1 (fr) 2014-05-13 2015-05-13 Composés hétérocycliques et leur utilisation

Country Status (1)

Country Link
WO (1) WO2015172196A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018033467A1 (fr) 2016-08-15 2018-02-22 Bayer Cropscience Aktiengesellschaft Procédé de préparation de 3-amino-1-(2,6-disubstitué-phényl)pyrazoles
WO2019207548A1 (fr) * 2018-04-27 2019-10-31 Ahammune Biosciences Private Limited Procédé de préparation d'un composé thiazole puissant, formulation pharmaceutique et utilisations associées
WO2019240671A1 (fr) * 2018-06-11 2019-12-19 Ministerio De Educación, Ciencia Y Tecnología Procédé de fabrication pour la production de benznidazole et sa mise à l'échelle industrielle
CN111655256A (zh) * 2017-10-29 2020-09-11 中国医药大学 Adam9抑制剂及其用途
US11116760B2 (en) 2018-10-30 2021-09-14 Gilead Sciences, Inc. Quinoline derivatives
US11174256B2 (en) 2018-10-30 2021-11-16 Gilead Sciences, Inc. Imidazopyridine derivatives
US11179383B2 (en) 2018-10-30 2021-11-23 Gilead Sciences, Inc. Compounds for inhibition of α4β7 integrin
US11224600B2 (en) 2018-10-30 2022-01-18 Gilead Sciences, Inc. Compounds for inhibition of alpha 4 beta 7 integrin
US11578069B2 (en) 2019-08-14 2023-02-14 Gilead Sciences, Inc. Compounds for inhibition of α4 β7 integrin

Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0676396A1 (fr) * 1994-03-10 1995-10-11 Wakamoto Pharmaceutical Co., Ltd. Dérivés de tetrazolylphényl-pivalate et composition médicinale les contenant comme ingrédients actifs
WO2002039997A2 (fr) * 2000-11-01 2002-05-23 Millennium Pharmaceuticals, Inc. Composes modulant ace-2 et procedes d'utilisation associes
EP1254901A1 (fr) * 2000-01-26 2002-11-06 Ono Pharmaceutical Co., Ltd. Composes cycliques a 5 chainons, contenant de l'azote, et medicaments contenant ces composes comme ingredients actifs
WO2004013130A1 (fr) * 2002-08-02 2004-02-12 Argenta Discovery Limited Acides substitues thienylhydroxamiques utilises en tant qu'inhibiteurs d'histone desacetylase
EP1428817A1 (fr) * 2001-09-18 2004-06-16 Ishihara Sangyo Kaisha, Ltd. Derives d'amides acides, procedes de production et agent antiparasitaire contenant ces derives
WO2004058176A2 (fr) * 2002-12-20 2004-07-15 Pharmacia Corporation Composes de pyrazole acyclique pour l'inhibition d'une proteine kinase activee par mitogene / d'une proteine kinase 2 activee
WO2005121130A2 (fr) * 2004-06-02 2005-12-22 Schering Corporation Composes pour le traitement de troubles inflammatoires
WO2006002099A2 (fr) * 2004-06-18 2006-01-05 Millennium Pharmaceuticals, Inc. Inhibiteurs du facteurs xa
WO2007029035A2 (fr) * 2005-09-07 2007-03-15 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Derives de trifluoroethanone a substitution thiophene et thiazole utilises comme inhibiteurs de l'histone desacetylase (hdac)
WO2009074743A1 (fr) * 2007-09-27 2009-06-18 Ipsen Pharma S.A.S. Derives des pyrazolo-pyrazines comme inhibiteurs de proteines g
WO2011051540A1 (fr) * 2009-10-27 2011-05-05 Orion Corporation Composés modulateurs de récepteurs des androgènes
WO2013009830A1 (fr) * 2011-07-13 2013-01-17 Tempero Pharmaceuticals, Inc. Méthodes de traitement
US20130059833A1 (en) * 2011-09-06 2013-03-07 Stephan Bachmann Pde10 modulators
WO2014152604A1 (fr) * 2013-03-14 2014-09-25 Janssen Pharmaceutica Nv Modulateurs du récepteur p2x7

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0676396A1 (fr) * 1994-03-10 1995-10-11 Wakamoto Pharmaceutical Co., Ltd. Dérivés de tetrazolylphényl-pivalate et composition médicinale les contenant comme ingrédients actifs
EP1254901A1 (fr) * 2000-01-26 2002-11-06 Ono Pharmaceutical Co., Ltd. Composes cycliques a 5 chainons, contenant de l'azote, et medicaments contenant ces composes comme ingredients actifs
WO2002039997A2 (fr) * 2000-11-01 2002-05-23 Millennium Pharmaceuticals, Inc. Composes modulant ace-2 et procedes d'utilisation associes
EP1428817A1 (fr) * 2001-09-18 2004-06-16 Ishihara Sangyo Kaisha, Ltd. Derives d'amides acides, procedes de production et agent antiparasitaire contenant ces derives
WO2004013130A1 (fr) * 2002-08-02 2004-02-12 Argenta Discovery Limited Acides substitues thienylhydroxamiques utilises en tant qu'inhibiteurs d'histone desacetylase
WO2004058176A2 (fr) * 2002-12-20 2004-07-15 Pharmacia Corporation Composes de pyrazole acyclique pour l'inhibition d'une proteine kinase activee par mitogene / d'une proteine kinase 2 activee
WO2005121130A2 (fr) * 2004-06-02 2005-12-22 Schering Corporation Composes pour le traitement de troubles inflammatoires
WO2006002099A2 (fr) * 2004-06-18 2006-01-05 Millennium Pharmaceuticals, Inc. Inhibiteurs du facteurs xa
WO2007029035A2 (fr) * 2005-09-07 2007-03-15 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Derives de trifluoroethanone a substitution thiophene et thiazole utilises comme inhibiteurs de l'histone desacetylase (hdac)
WO2009074743A1 (fr) * 2007-09-27 2009-06-18 Ipsen Pharma S.A.S. Derives des pyrazolo-pyrazines comme inhibiteurs de proteines g
WO2011051540A1 (fr) * 2009-10-27 2011-05-05 Orion Corporation Composés modulateurs de récepteurs des androgènes
WO2013009830A1 (fr) * 2011-07-13 2013-01-17 Tempero Pharmaceuticals, Inc. Méthodes de traitement
US20130059833A1 (en) * 2011-09-06 2013-03-07 Stephan Bachmann Pde10 modulators
WO2014152604A1 (fr) * 2013-03-14 2014-09-25 Janssen Pharmaceutica Nv Modulateurs du récepteur p2x7

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10738012B2 (en) 2016-08-15 2020-08-11 Bayer Cropscience Aktiengesellschaft Process for the preparation of amino-pyrazoles
WO2018033467A1 (fr) 2016-08-15 2018-02-22 Bayer Cropscience Aktiengesellschaft Procédé de préparation de 3-amino-1-(2,6-disubstitué-phényl)pyrazoles
US11357759B2 (en) 2017-10-29 2022-06-14 China Medical University Composition including ADAM9 inhibitor and the use thereof
CN111655256A (zh) * 2017-10-29 2020-09-11 中国医药大学 Adam9抑制剂及其用途
EP3700521A4 (fr) * 2017-10-29 2021-09-08 China Medical University Inhibiteurs d'adam9 et utilisations de ceux-ci
CN111655256B (zh) * 2017-10-29 2023-12-29 洪明奇 包含adam9抑制剂化合物的组合物
WO2019207548A1 (fr) * 2018-04-27 2019-10-31 Ahammune Biosciences Private Limited Procédé de préparation d'un composé thiazole puissant, formulation pharmaceutique et utilisations associées
IL278322B1 (en) * 2018-04-27 2023-04-01 Ahammune Biosciences Private Ltd Process for preparing a potent thiazole compound, pharmaceutical composition and uses thereof
WO2019240671A1 (fr) * 2018-06-11 2019-12-19 Ministerio De Educación, Ciencia Y Tecnología Procédé de fabrication pour la production de benznidazole et sa mise à l'échelle industrielle
US11116760B2 (en) 2018-10-30 2021-09-14 Gilead Sciences, Inc. Quinoline derivatives
US11224600B2 (en) 2018-10-30 2022-01-18 Gilead Sciences, Inc. Compounds for inhibition of alpha 4 beta 7 integrin
US11179383B2 (en) 2018-10-30 2021-11-23 Gilead Sciences, Inc. Compounds for inhibition of α4β7 integrin
US11174256B2 (en) 2018-10-30 2021-11-16 Gilead Sciences, Inc. Imidazopyridine derivatives
US11578069B2 (en) 2019-08-14 2023-02-14 Gilead Sciences, Inc. Compounds for inhibition of α4 β7 integrin

Similar Documents

Publication Publication Date Title
WO2015172196A1 (fr) Composés hétérocycliques et leur utilisation
TWI461197B (zh) 2-mercaptoquinoline-3-carboxamide as a KCNQ2 / 3 modifier
TWI475020B (zh) The substituted nicotine amide as a KCNQ2 / 3 modifier
CN104352492B (zh) 以芳基磺酰基衍生物作为有效成分的长链脂肪酸延长酶抑制剂
KR100589032B1 (ko) 질소 함유 방향환 유도체
US20050171101A1 (en) Phenanthridinones as parp inhibitors
US20100144722A1 (en) Novel heterocyclic compounds as gata modulators
CN108558889A (zh) 布罗莫结构域抑制剂
EP3038612B1 (fr) Amides vinylogues cycliques en tant qu'inhibiteurs de bromodomaine
KR20100014845A (ko) 심혈관 질환을 예방 및 치료하기 위한 화합물
JP2006124387A (ja) 新規なキノリン、テトラヒドロキナゾリン、及びピリミジン誘導体と、これらを使用することに関連した治療方法
JP5583148B2 (ja) Ｋｃｎｑ２／３モジュレータとしての置換された２−メルカプト−アミノピリジン
TWI504395B (zh) Substituted 3-amino-2-mercaptoquinoline as a KCNQ2 / 3 modifier
WO2012085003A1 (fr) 2 -hydroxyisoquinoline- 1, 3 ( 2h, 4h) - diones et composés associés servant d'inhibiteurs de la réplication du vih
MX2015004247A (es) Derivados de n-prop-2-inil carboxamida y su uso como antagonistas del receptor transitorio potencial de la subfamilia a, miembro 1.
KR20120043058A (ko) 함질소환 아실구아니딘 유도체
WO2018160845A1 (fr) Nouveaux analogues d'oxaborole et utilisations de ces derniers
WO2008018529A1 (fr) Nouveau composé pyrimidine comportant une structure benzyl(pyridylméthyl)amine et produit pharmaceutique le comprenant
EP0979823B1 (fr) Nouveaux composes d'amide et medicaments contenant ces derniers
ES2907746T3 (es) Compuestos de amida y uso de los mismos
EP3472141B1 (fr) Agents anti-infectieux
Madhav et al. Development of diphenylmethylpiperazine hybrids of chloroquinoline and triazolopyrimidine using Petasis reaction as new cysteine proteases inhibitors for malaria therapeutics
US20030119876A1 (en) Compounds for the treatment of protozoal diseases
US20210087187A1 (en) Antimalarial heterocyclic compounds and a process for the preparation thereof
CN102643230B (zh) 一种7-位取代喹诺酮类化合物及其在制备抗肿瘤药物中的应用

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: 15792301

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: 15792301

Country of ref document: EP

Kind code of ref document: A1