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WO2011061277A1 - Aminoarylacétamides et leur utilisation dans le traitement du paludisme - Google Patents

Aminoarylacétamides et leur utilisation dans le traitement du paludisme Download PDF

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Publication number
WO2011061277A1
WO2011061277A1 PCT/EP2010/067806 EP2010067806W WO2011061277A1 WO 2011061277 A1 WO2011061277 A1 WO 2011061277A1 EP 2010067806 W EP2010067806 W EP 2010067806W WO 2011061277 A1 WO2011061277 A1 WO 2011061277A1
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Prior art keywords
phenyl
trifluoromethyl
compound
formula
pharmaceutically acceptable
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Inventor
Julia Castro-Pichel
Esther Pilar Fernandez-Velando
Jose Maria Fiandor-Roman
Maria De La O Gordo-Lopez
Maria Lourdes Rueda-Benede
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Glaxo Group Ltd
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Glaxo Group Ltd
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    • 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
    • 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
    • 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
    • A61P33/06—Antimalarials
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to amino aryl acetamide compounds and their use in chemotherapy. More specifically, this invention is concerned with amino phenyl acetamide compounds and their use in chemotherapy of certain parasitic protozoal infections such as malaria, in particular infection by Plasmodium falciparum, pharmaceutical compositions including such compounds and processes for the preparation of such compounds..
  • Parasitic protozoal infections are responsible for a wide variety of diseases of medical and veterinary importance, including malaria in man and various coccidioses in birds, fish and mammals. Many of the diseases are life-threatening to the host and cause considerable economic loss in animal husbandry, such as diseases caused by infection by species of Eimeria, Theileria, Babesia, Cryptosporidium, Toxoplasma (such as Toxoplasma brucei, African sleeping sickness and Toxoplasma cruzi, Chagas disease) and Plasmodium (such as Plasmodium falciparum), and the Mastigophora such as species of Leishmania (such as Leishmania donovani).
  • Another parasitic organism of increasing concern is Pneumocytis carinii, which can cause an often fatal pneumonia in immunodeficient or immunocompromised hosts, including those infected with HIV.
  • Malaria is one of the major disease problems of the developing world.
  • the most virulent malaria-causing parasite in humans is the parasite Plasmodium falciparum, which is the cause of hundreds of millions of cases of malaria per annum, and is thought to cause over 1 million deaths each year, Breman, J. G., et al., (2001 ) Am. Trop. Med. Hyg. 64, 1 -1 1.
  • One problem encountered in the treatment of malaria is the build-up of resistance by the parasite to available drugs. Thus, there is a need to develop new antimalarial drugs.
  • US patent 20090163545 discloses certain amino phenyl acetamide derivatives.
  • the present invention is directed to certain amino phenyl acetamide derivatives for use in the chemotherapy of certain parasitic infections such as malaria, and in particular infection by Plasmodium falciparum, processes for their preparation and pharmaceutical compositions comprising such compounds.
  • the present invention provides a compound of Formula (I):
  • R 1 is Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci -6 haloalkoxy or halo;
  • R 2 is -NR 4 R 5 ;
  • R 4 and R 5 are independently Ci -6 alkyl or, together with the N to which they are attached, form C 5 - 7 heteroaryl or C 5-7 heterocyclyl, either of which i) may optionally contain 1 -3 additional heteroatoms, independently selected from the group consisting of N, O and S and ii) may be optionally substituted with Ci -3 alkyl;
  • R 3 is H
  • R a is -X-Y-Z or -CCI 3 ;
  • X is -CR 6 R 7 ;
  • R 6 is H or Ci -6 alkyl
  • R 7 is H or C 1-6 alkyl
  • R 6 and R 7 together with the carbon atom to which they are attached, form cyclopropyl;
  • Y is a direct bond, -O- or -NR 8 -(CH 2 ) P ;
  • R 8 is H or C 1-4 alkyl
  • p is 0 or 1 ;
  • R 9 is H, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci -6 haloalkoxy, halo, cyano or optionally substituted C 5-7 heteroaryl or optionally substituted C 5-7 heterocyclyl, wherein the optional substitutents for C 5-7 heteroaryl and C 5-7 heterocyclyl are selected from C 1-3 alkyl;
  • R 10 is H, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci -6 haloalkoxy halo or cyano;
  • R 9 and R 10 together with the carbon atoms to which they are attached form a C 5-6 membered carbocyclyl which may optionally contain 1 -3 heteroatoms, independently selected from the group consisting of N, O and S;
  • the present invention provides a compound of Formula (ID):
  • R 1 is Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci -6 haloalkoxy or halo;
  • R 2 is -NR 4 R 5 ;
  • R 4 and R 5 are independently Ci -6 alkyl or, together with the N to which they are attached, form C 5 - 7 heteroaryl or C 5-7 heterocyclyl, either of which may optionally contain 1 -3 additional heteroatoms, independently selected from the group consisting of N, O and S;
  • R 3 is H
  • R a is -X-Y-Z or -CCI 3 ;
  • X is -CR 6 R 7 ;
  • R 6 is H or Ci -6 alkyl
  • R 7 is H or Ci -6 alkyl
  • R 6 and R 7 together with the carbon atom to which they are attached, form cyclopropyl;
  • Y is a direct bond, -O- or -NR 8 -(CH 2 ) P ;
  • R 8 is H or C 1-4 alkyl
  • p is 0 or 1 ;
  • R 9 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halo or optionally substituted C 5- 7 heteroaryl or optionally substituted C 5-7 heterocyclyl;
  • R 10 is H, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci -6 haloalkoxy or halo;
  • R 9 and R 10 together with the carbon atoms to which they are attached form a C 5-6 membered carbocyclyl which may optionally contain 1 -3 heteroatoms, independently selected from the group consisting of N, O and S;
  • alkyl refers to straight or branched saturated hydrocarbon chains containing the specified number of carbon atoms.
  • C 1-4 alkyl means a straight or branched alkyl containing at least 1 , and at most 4, carbon atoms.
  • alkyl as used herein include, but are not limited to, methyl, ethyl, n-propyl, 1 -methylethyl (isopropyl), n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or hexyl.
  • alkoxy refers to an -O-alkyI group wherein alkyl is as defined herein.
  • alkoxy as used herein include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy.
  • C 5 - 6 membered carbocyclyl refers to a 5- or 6-membered saturated hydrocarbon ring.
  • Examples of “C 5-6 membered carbocyclyl” as used herein include cyclopropyl or cyclohexyl.
  • haloalkyi refers to an alkyl group as defined herein wherein at least one hydrogen atom is replaced with a halogen atom, for example a fluoro atom.
  • Ci -4 haloalkyl means an alkyl group containing at least 1 , and at most 4, carbon atoms and at least one halogen atom, for example a fluoro atom.
  • haloalkyi as used herein include, but are not limited to, -CF 3 , -CHF 2 and -CH 2 F.
  • haloalkoxy refers to an alkoxy group, as defined herein wherein at least one hydrogen atom is replaced with a halogen atom, for example a fluoro atom.
  • Ci -4 haloalkoxy means an alkoxy group containing at least 1 , and at most 4, carbon atoms and at least one halogen atom, for example a fluoro atom.
  • Examples of "haloalkoxy” as used herein include, but are not limited to, -OCF 3 , -OCHF 2 and -OCH 2 F.
  • halogen refers to a fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo) atom.
  • halogen refers to a fluorine (fluoro), chlorine (chloro) or bromine (bromo) atom.
  • C 5 - 7 heteroary refers to an aromatic monocyclic group containing 5 to 7 ring-atoms, 1 , 2, 3 or 4 of which are heteroatoms independently selected from nitrogen, oxygen and sulphur and the remaining ring-atoms are carbon, e.g. pyridyl.
  • C 5- 7 heteroaryl examples include, but are not limited to, imidazolyl, pyrazolyl, pyrrolyl, pyridyl, pyrazinyl, thiazolyl, thiophenyl, oxadiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, triazolyl and tetrazolyl. All isomers of the above C 5-7 heteroaryl groups are within the scope of this invention.
  • C 5-7 heterocyclyr' refers to a monocyclic group containing 5 to 7 ring-atoms 1 , 2, 3 or 4 of which are heteroatoms independently selected from nitrogen, oxygen and sulphur and the remaining ring-atoms are carbon, wherein said cyclic group is saturated, partially or fully unsaturated but, which is not aromatic.
  • C 5- 7 heterocyclyl examples include, but are not limited to, pyrrolidinyl, pyrrolidinone, imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, hydantoinyl, valerolactamyl, oxathiolanyl, oxathianyl, diazepanyl, dihydrofuranyl, tetrahydrofuranyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, dihydropyranyl, tetrahydropyranyl, dioxanyl and dithianyl. All isomers of the above heterocyclic groups are within the scope of
  • the term "pharmaceutically acceptable” used in relation to an ingredient (such as an active ingredient, a salt thereof or an excipient) which may be included in a pharmaceutical formulation for administration to a patient refers to that ingredient being acceptable in the sense of being compatible with any other ingredients present in the pharmaceutical formulation and not being deleterious to the recipient thereof.
  • R 1 is Ci -6 haloalkyl or halo. In a further aspect, R 1 is Ci_ 4 haloalkyl or halo. In another aspect, when R 1 is or contains halo, halo is selected from fluoro, chloro and bromo. In a further aspect, R 1 is -CF 3 or chloro. In a further aspect, R 1 is -CF 3 . In a further aspect, R 1 is chloro.
  • R 2 is-NR 4 R 5 wherein R 4 and R 5 , together with the N to which they are attached, form C 5 - 6 heteroaryl or C 5 - 6 heterocyclyl, which may optionally contain 1-3 additional heteroatoms, independently selected from the group consisting of N and O.
  • R 2 is -NR 4 R 5 wherein R 4 and R 5 , together with the N to which they are attached, form C 5 heteroaryl or C 6 heterocyclyl, which may optionally contain 1-3 additional heteroatoms, independently selected from the group consisting of N and O.
  • R 2 is -NR 4 R 5 wherein R 4 and R 5 , together with the N to which they are attached, forms one of the following:
  • R is -NR R 5 wherein R and R 5 , together with the N to which they are attached, forms
  • R a is X-Y-Z.
  • R 6 is H. In a further aspect of the invention, R 6 is C 1-4 alkyl. In a further aspect of the invention, R 6 is H, methyl or ethyl. In a further aspect of the invention, R 6 is H or methyl. In a further aspect of the invention, R 6 is methyl.
  • R 7 is H. In a further aspect of the invention, R 7 is Ci -4 alkyl. In a further aspect of the invention, R 7 is H or methyl. In a further aspect of the invention, when R 6 is H, R 7 is methyl. In another aspect, when when R 6 is methyl, R 7 is H.
  • R 6 and R 7 together with the carbon atom to which they are attached, form cyclopropyl.
  • Y is a direct bond, -0-, -NH- or -N(CH 3 )-CH 2 . In a further aspect of the invention , Y is a direct bond, -NH- or -N(CH 3 )-CH 2 . In a further aspect, Y is a direct bond or -0-. In one aspect of the invention, R is H or methyl. In a further aspect of the invention, R is H. In a further aspect of the invention, R 8 is methyl.
  • p is 0. In a further aspect of the invention, p is 1. In one aspect of the invention, Z is
  • Z is
  • R 9 when R 9 is or contains halo, halo is selected from fluoro, chloro and bromo.
  • R 9 is H, Ci -6 alkyl, d. 6 haloalkyl, C 1-6 alkoxy, halo, cyano or optionally substituted C 5-7 heteroaryl.
  • R 9 is H, methyl, CF 3 , methoxy, chloro, fluoro, cyano or
  • R is CF 3 , chloro, fluoro or H.
  • R 9 is CF 3 , chloro or fluoro.
  • R 9 is H, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, halo or optionally substituted C 5-7 heteroaryl.
  • R 9 is H, Ci -6 alkyl or optionally substituted C 5 - 7 heteroaryl. In a further aspect of the invention, R 9 is H, d ⁇ alkyl or optionally substituted heteroaryl. In a further aspect of the invention, R 9 is H, C 1-4 alkyl or
  • R 9 is H, methyl or
  • halo is selected from fluoro, chloro and bromo.
  • R 10 is H, C 1-6 alkyl, C 1-6 alkoxy, halo or cyano. In one aspect of the invention, R 10 is H, C 1-6 alkyl, C 1-6 alkoxy or halo. In another aspect of the invention, R 10 is H, methyl, methoxy, chloro, fluoro or cyano. In a further aspect of the invention, R 10 is H, C 1-4 alkyl or halo. In a further aspect of the invention, R 10 is H, methyl or chloro.
  • R 9 is other than H and R 10 is H.
  • R 10 is other than H and R 9 is H.
  • R 9 and R 10 together with the carbon atoms to which they are attached form a C 5-6 membered saturated carbocyclyl which may optionally contain 1 -3 heteroatoms, independently selected from the group consisting of N and O.
  • R 9 and R 10 together with the carbon atoms to which they are attached form a C 5-6 membered saturated carbocyclyl which may optionally contain 1 -2 -O- atoms.
  • R 9 and R 10 together with the carbon atoms to which they are attached form
  • Z is
  • the present invention provides a compound of Formula (I) as represented by Formula (IA)
  • R 1 is Ci -6 haloalkyl or halo;
  • R 2 is-NR 4 R 5 ;
  • R 4 and R 5 together with the N to which they are attached, form C 5-6 heteroaryl or C 5- 6 heterocyclyl, either of which may optionally contain 1-3 additional heteroatoms, independently selected from the group consisting of N and O;
  • R 3 is H
  • R a is -X-Y-Z or -CCI 3 ;
  • X is -CR 6 R 7 ;
  • R 6 is H or Ci -4 alkyl
  • R 7 is H or Ci -4 alkyl
  • Y is a direct bond, -0-, -NH- or - N(CH 3 )-CH 2 ;
  • R 9 is H, or optionally substituted heteroaryl
  • R 10 is H, C 1-4 alkyl or halo
  • R 9 and R 10 together with the carbon atoms to which they are attached form a C 5-6 membered carbocyclyl which may optionally contain 1 -3 heteroatoms, independently selected from the group consisting of N, O and S;
  • the present invention provides a compound of Formula (I) as represented by Formula (IB)
  • R 1 is -CF 3 or chloro
  • R 2 is-NR 4 R 5 ;
  • R a is -X-Y-Z or -CCI 3 ;
  • X is -CR 6 R 7 ;
  • R 6 is H or methyl;
  • R 7 is H or methyl
  • Y is a direct bond, -0-, -NH- or - N(CH 3 )-CH 2 ;
  • R 10 is H, methyl or chloro
  • R 9 and R 10 together with the carbon atoms to which they are attached form a C 5 - 6 membered carbocyclyl which may optionally contain 1 -3 heteroatoms, independently selected from the group consisting of N, O and S;
  • the present invention provides a compound of Formula (I) as represented by Formula (IC)
  • R 1 is -CF 3 or chloro
  • R 2 is-NR 4 R 5 ;
  • R a is -X-Y-Z or -CCI 3 ;
  • X is -CR 6 R 7 ;
  • R 6 is H or methyl
  • R 7 is H or methyl
  • R 6 and R 7 together with the C atom to which they are attached, form cyclopropyl;
  • Y is a direct bond, -0-, -NH- or - N(CH 3 )-CH 2 ;
  • the present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group (List A) consisting of:
  • the present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
  • the present invention provides a compound of Formula (I), wherein the compound is selected from the group consisting of:
  • pharmaceutically acceptable salt complexes are included in the present invention.
  • pharmaceutically acceptable salts of the compounds according to Formula (I) may be preferred over the respective free base because such salts impart greater stability or solubility to the molecule thereby facilitating formulation into a dosage form. Therefore, the present invention also covers the pharmaceutically acceptable salts of the compounds of Formula (I).
  • pharmaceutically acceptable salt refers to a salt that retains the desired biological activity of the subject compound and exhibits minimal undesired toxicological effects.
  • pharmaceutically acceptable salt includes any pharmaceutically acceptable acid addition salts. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free base form with a suitable acid, respectively. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. Therefore, according to a further aspect, the invention provides a pharmaceutically acceptable salt of a compound of Formula (I) thereof.
  • compounds according to Formula (I) may contain a basic functional group and may therefore be capable of forming pharmaceutically acceptable acid addition salts by treatment with a suitable acid.
  • a pharmaceutically acceptable acid addition salt may be formed by reaction of a compound of Formula (I) with a suitable strong inorganic or organic acid (such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, perchloric, p- toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, naphthalenesulfonic (e.g.
  • 2-naphthalenesulfonic optionally in a suitable solvent such as an organic solvent, to give the salt which is usually isolated for example by crystallisation and filtration.
  • Pharmaceutically acceptable acid addition salts include a hydrobromide, hydrochloride, hydroiodide, sulfate, bisulfate, nitrate, phosphate, perchlorate, p- toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, 2- hydroxyethanesulfonate or naphthalenesulfonate (e.g. 2-naphthalenesulfonate) salt.
  • a pharmaceutically acceptable acid addition salt of a compound of Formula (I) is a salt of a strong acid, for example a hydrobromide, hydrochloride, hydroiodide, sulfate, nitrate, perchlorate, phosphate p-toluenesulfonic, benzenesulfonic or methanesulfonic salt.
  • a strong acid for example a hydrobromide, hydrochloride, hydroiodide, sulfate, nitrate, perchlorate, phosphate p-toluenesulfonic, benzenesulfonic or methanesulfonic salt.
  • Suitable pharmaceutically acceptable salts of the compounds of Formula (I) include mono- or di- basic salts with the appropriate acid for example organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids and inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids and the like.
  • organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic and succinic acids
  • organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids
  • inorganic acids such as hydrochloric, sulfuric, phosphoric and sul
  • the invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the salts of the compounds of Formula (I).
  • the term "compounds of the invention” means the compounds according to Formula (I) and the pharmaceutically acceptable salts, solvates and pro-drugs thereof, especially pharmaceutically acceptable salts and solvates thereof.
  • a compound of the invention means any one of the compounds of the invention as defined above.
  • the phrase "a compound of the invention” as used herein encompasses a compound of Formula (I), a pharmaceutically acceptable solvate of a compound of Formula (I), a pharmaceutically acceptable salt of a compound of Formula (I), and a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt of a compound of Formula (I).
  • the compounds of the invention may exist as solids or liquids, both of which are included in the invention. In the solid state, the compounds of the invention may exist as either amorphous material or in crystalline form, or as a mixture thereof. It will be appreciated that pharmaceutically acceptable solvates of compounds of the invention may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallisation. Solvates may involve non-aqueous solvents such as ethanol, isopropanol, dimethylsulfoxide (DMSO), acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice.
  • DMSO dimethylsulfoxide
  • Solvates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as "hydrates.” Solvates of the compound of Formula (I) are within the scope of the invention. Therefore, in one aspect of the present invention, there is provided solvates of the compounds of Formula (I), for example hydrates.
  • the salts of a compound of Formula (I) may be prepared by contacting appropriate stoichiometric amounts of the free base with the appropriate acid in a suitable solvent.
  • the free base of a compound of Formula (I) may for example be in solution with the appropriate acid added as a solid or both the free base of a compound of Formula (I) and the appropriate acid may independently be in solution.
  • Suitable solvents for solubilising a compound of Formula (I) free base include for example alcohols such as isopropanol; ketones such as acetone; acetonitrile or toluene. If the base is to be added as a solution in a solvent, the solvent used may include acetone, methanol or water.
  • the salts of a compound of Formula (I) may be isolated in solid form by conventional means from a solution thereof obtained as above.
  • a non-crystalline salt may be prepared by precipitation from solution, spray drying or freeze drying of solutions, evaporating a solution to a glass, or vacuum drying of oils, or solidification of melts obtained from reaction of the free base and the acid.
  • the salts of a compound of Formula (I) may be prepared by directly crystallising from a solvent in which the salt has limited solubility, or by triturating or otherwise crystallising a noncrystalline salt.
  • a solvent in which the salt has limited solubility for example, organic solvents such as acetone, acetonitrile, butanone, 1- butanol, ethanol, 1-propanol or tetrahydrofuran or mixtures of such solvents may be used.
  • An improved yield of the salts may be obtained by the evaporation of some or all of the solvent or by crystallisation at elevated temperature followed by controlled cooling, for example in stages. Careful control of the precipitation temperature and seeding may be used to improve the reproducibility of the production process and the particle size distribution and form of the product.
  • Salts and solvates of compounds of Formula (I) which are suitable for use in medicine are those wherein the counterion or associated solvent is pharmaceutically acceptable.
  • salts and solvates having non-pharmaceutically acceptable counterions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of Formula (I) or salts, solvates or amides thereof and their pharmaceutically acceptable salts and solvates.
  • prodrugs for compounds of Formula (I) or salts or solvates thereof include : amides, carbamates, azo-compounds, phosphamides, glycosides.
  • the present invention also relates to pharmaceutically acceptable amides of the compounds of Formula (I), for example amides from carboxylic acids -COOR, in which R is selected from straight or branched chain alkyl, for example n-propyl, n-butyl, alkoxyalkyl (e.g. methoxymethyl), aralkyl (e.g. benzyl), aryloxyalkyl (e.g. phenoxymethyl), aryl (e.g.
  • any alkyl moiety present in such amides suitably contains 1 to 18 carbon atoms, particularly 1 to 4 carbon atoms.
  • Any aryl moiety present in such amides suitably comprises a phenyl group.
  • the compounds of the present invention may be in the form of their free base or a pharmaceutically acceptable salt, solvate, or prodrug e.g. an amide of a compound of Formula (I), which upon administration to the recipient is capable of providing (directly or indirectly) a compound of Formula (I), or an active metabolite or residue thereof.
  • a pharmaceutically acceptable salt, solvates, and prodrugs are recognizable to those skilled in the art, without undue experimentation. Nevertheless, reference is made to the teaching of Burger's Medicinal Chemistry and Drug Discovery, 5th Edition, Vol 1 : Principles and Practice, which is incorporated herein by reference to the extent of teaching such derivatives.
  • the compounds of the invention are pharmaceutically acceptable salts, solvates or amides. In a further aspect, the compounds of the present invention are pharmaceutically acceptable salts or solvates. In another aspect, the compounds of the present invention are pharmaceutically acceptable salts.
  • crystalline forms of the compounds of Formula (I) or salts and solvates thereof may exist in one or more polymorphic form, which are included in the present invention. It will further be appreciated that certain compounds of the present invention may exist in different tautomeric forms. All possible tautomers are contemplated to be within the scope of the present invention.
  • the compounds of the invention can be useful in the treatment of certain parasitic infections such as parasitic protozoal infections by the malarial parasite Plasmodium falciparum, species of Eimeria, Pneumocytis carinii, Trypanosoma cruzi, Trypanosoma brucei or Leishmania donovani.
  • the compounds of the invention can be useful for treatment of infection by Plasmodium falciparum. Accordingly, the invention is directed to methods of treating such conditions.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a parasitic protozoal infection such as malaria, for example infection by Plasmodium falciparum.
  • a compound of List A or a pharmaceutically acceptable salt thereof for use in the treatment of parasitic protozoal infections such as malaria, for example a condition caused by infection by Plasmodium falciparum.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a parasitic protozoal infection such as malaria, for example infection by Plasmodium falciparum.
  • a compound of List A or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of parasitic protozoal infections such as malaria, for example a condition caused by infection by Plasmodium falciparum.
  • a method for the treatment of a human or animal subject suffering from a parasitic protozoal infection such as malaria, for example infection by Plasmodium falciparum comprises administering to said human or animal subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • a method for the treatment of a human or animal subject suffering from a parasitic protozoal infection such as malaria comprising administering to said human or animal subject an effective amount of a compound of List A or a pharmaceutically acceptable salt thereof.
  • the methods of treatment of the invention comprise administering a safe and effective amount of a compound according to Formula (I), and a pharmaceutically acceptable salt thereof to a patient in need thereof.
  • treatment means: (1 ) the amelioration or prevention of the condition being treated or one or more of the biological manifestations of the condition being treated, (2) the interference with (a) one or more points in the biological cascade that leads to or is responsible for the condition being treated or (b) one or more of the biological manifestations of the condition being treated, or (3) the alleviation of one or more of the symptoms or effects associated with the condition being treated.
  • prevention is not an absolute term. In medicine, “prevention” is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.
  • safe and effective amount means an amount of the compound sufficient to significantly induce a positive modification in the condition to be treated but low enough to avoid serious side effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment.
  • a safe and effective amount of a compound of the invention will vary with the particular compound chosen (e.g. depending on the potency, efficacy, and half-life of the compound); the route of administration chosen; the nature of the infection and/or condition being treated; the severity of the infection and/or condition being treated; the age, size, weight, and physical condition of the patient being treated; the medical history of the patient to be treated; the duration of the treatment; the nature of concurrent therapy; the desired therapeutic effect; and like factors, but can nevertheless be routinely determined by the skilled artisan.
  • patient refers to a human or other animal.
  • the compounds of the invention may be administered by any suitable route of administration, including systemic administration.
  • Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation.
  • Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion.
  • Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion.
  • Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages.
  • the compounds of the invention may be administered once only, or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect.
  • the dosage will also vary according to the nature of the intended treatment, wherein "treatment” is as hereinbelow defined, for example a greater dose of compound may be given for amelioration as compared with prevention of a condition being treated.
  • Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan.
  • suitable dosing regimens for a compound of the invention including the duration such regimens are administered, depend on the route of administration of the compound, on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of any concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change.
  • the dosing regimen of the compounds of the invention may also vary according to the nature and amount of the one or more additional active therapeutic agents as necessary.
  • Typical daily dosages may vary depending upon the particular route of administration chosen. Typical daily dosages for oral administration range from about 0.01 to about 25 mg/kg, in one embodiment from about 0.1 to about 14 mg/kg. Typical daily dosages for parenteral administration range from about 0.001 to about 10 mg/kg; in one embodiment from about 0.01 to about 6 mg/kg. In one embodiment, the daily dose range of the compounds is from 100-1000 mg per day.
  • the compounds of the invention may also be used in combination with other active therapeutic agents.
  • the invention thus provides, in a further aspect, a combination comprising a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof together with a further active therapeutic agent.
  • a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof is used in combination with a second active therapeutic agent which is active against the same disease state the dose of each compound may differ from that when the compound is used alone.
  • Appropriate doses will be readily appreciated by those skilled in the art. It will be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian.
  • the compounds of the present invention may be used alone or in combination with one or more additional active therapeutic agents, such as other antiparasitic drugs, for example antimalarial drugs.
  • additional active therapeutic agents such as other antiparasitic drugs, for example antimalarial drugs.
  • Such other active therapeutic agents include antimalarial drugs such as (e.g. chloroquine, mefloquine, primaquine, pyrimethamine, quinine, artemisinin, halofantrine, doxycycline, amodiaquine, atovaquone ,tafenoquinedapsone, proguanil, sulfadoxine, cycloguanil) and fansidar.
  • antimalarial drugs such as (e.g. chloroquine, mefloquine, primaquine, pyrimethamine, quinine, artemisinin, halofantrine, doxycycline, amodiaquine, atovaquone ,tafenoquinedapsone, proguanil, sulfadoxine, cycloguanil) and fansidar.
  • antimalarial drugs such as (e.g. chloroquine, mefloquine, primaquine, pyrimethamine, quin
  • compositions comprising a combination as defined above together with a pharmaceutically acceptable carrier and/or excipient comprise a further aspect of the invention.
  • the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations by any convenient route.
  • either the compound of the present invention or the one or more additional active therapeutic agent(s) may be administered first.
  • administration is simultaneous the combination may be administered either in the same or different pharmaceutical composition.
  • the compound of the present invention and the one or more additional active therapeutic agent(s) must be stable and compatible with each other and the other components of the formulation.
  • the compound of the present invention and the one or more additional active therapeutic agent(s) may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art.
  • the invention is directed to pharmaceutical compositions comprising a compound of the invention.
  • the invention is directed to a pharmaceutical composition comprising (a) a compound of the invention and (b) one or more pharmaceutically acceptable carriers and/or excipients.
  • the invention provides a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention provides a pharmaceutical composition comprising (a) a compound of Formula (I) or a pharmaceutically acceptable salt thereof and (b) one or more pharmaceutically acceptable carriers and/or excipients.
  • the carrier and/or excipient must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • compositions of the invention may be prepared and packaged in bulk form wherein a safe and effective amount of a compound of the invention can be extracted and then given to the patient such as with powders or syrups.
  • the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a safe and effective amount of a compound of the invention.
  • the pharmaceutical compositions of the invention typically contain from about 0.1 to 1000mg, in another aspect 0.1 mg to about 500 mg of a compound of the invention.
  • the pharmaceutical compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. For example, in certain embodiments the pharmaceutical compositions of the invention contain two compounds of the invention. In addition, the pharmaceutical compositions of the invention may optionally further comprise one or more additional active therapeutic compounds.
  • the pharmaceutical compositions of the invention typically contain more than one pharmaceutically acceptable excipient. However, in certain embodiments, the pharmaceutical compositions of the invention contain one pharmaceutically acceptable excipient.
  • dosage forms include those adapted for (1 ) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; and (5) inhalation such as aerosols and solutions.
  • oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets
  • parenteral administration such as sterile solutions, suspensions, and powders for reconstitution
  • transdermal administration such as transdermal patches
  • rectal administration such as suppositories
  • inhalation such as aerosols and solutions.
  • Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form chosen.
  • suitable pharmaceutically acceptable excipients may be chosen for a particular function that they may serve in the composition.
  • certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms.
  • Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms.
  • Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the carriage or transport of the compound or compounds of the invention from one organ, or portion of the body, to another organ, or portion of the body, once administered to the patient.
  • Certain pharmaceutically acceptable excipients may be chosen for their ability to enhance patient compliance.
  • Suitable pharmaceutically acceptable excipients include the following types of excipients: binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavouring agents, flavour masking agents, coloring agents, anticaking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents.
  • excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.
  • the invention is directed to a solid or liquid oral dosage form such as a liquid, tablet, lozenge or a capsule, comprising a safe and effective amount of a compound of the invention and a carrier.
  • the carrier may be in the form of a diluent or filler.
  • Suitable diluents and fillers in general include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate.
  • a liquid dosage form will generally consist of a suspension or solution of the compound or pharmaceutically acceptable derivative in a liquid carrier for example, ethanol, olive oil, glycerine, glucose (syrup) or water (e.g. with an added flavouring, suspending, or colouring agent).
  • a liquid carrier for example, ethanol, olive oil, glycerine, glucose (syrup) or water (e.g. with an added flavouring, suspending, or colouring agent).
  • a liquid carrier for example, ethanol, olive oil, glycerine, glucose (syrup) or water (e.g. with an added flavouring, suspending, or colouring agent).
  • a liquid carrier for example, ethanol, olive oil, glycerine, glucose (syrup) or water (e.g. with an added flavouring, suspending, or colouring agent).
  • any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc,
  • any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums or oils, and may be incorporated in a soft capsule shell.
  • An oral solid dosage form may further comprise an excipient in the form of a binder.
  • Suitable binders include starch (e.g. corn starch, potato starch, and pre-gelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g. microcrystalline cellulose).
  • the oral solid dosage form may further comprise an excipient in the form of a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose.
  • the oral solid dosage form may further comprise an excipient in the form of a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.
  • a process of preparing a pharmaceutical composition which process comprises mixing at least one compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable carrier and/or excipient.
  • a process of preparing a pharmaceutical composition which process comprises mixing at least one compound of Formula (I) or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier and/or excipient.
  • Preparations for oral administration may be suitably formulated to give controlled/extended release of the active compound.
  • R a is as herein described
  • R 1 and R 2 are as herein described, in the presence of a suitable solvent and under suitable conditions, for example ACN under elevated temperature, optionally in the presence of a base such as NaHC0 3 , optionally in the presence of microwaves.
  • a suitable solvent and under suitable conditions for example ACN under elevated temperature, optionally in the presence of a base such as NaHC0 3 , optionally in the presence of microwaves.
  • R a is as herein described, with a chlorinating agent e.g. COCI 2 (phosgene) or oxalyl chloride and a suitable solvent and under suitable conditions, for example DMF and/or DCM, at room temperature under an inert atmosphere.
  • a chlorinating agent e.g. COCI 2 (phosgene) or oxalyl chloride and a suitable solvent and under suitable conditions, for example DMF and/or DCM, at room temperature under an inert atmosphere.
  • R 11 is methyl or ethyl and R a is X-Y-Z
  • an inorganic base such as sodium hydroxide or lithium hydroxide
  • an alcohol solvent such as methanol or ethanol
  • Certain compounds of Formula (IV) may be prepared from certain other compounds of Formula (IV).
  • compounds of Formula (IV) wherein R a is -X-Y-Z, in which X is -CH(Ci -6 alkyl)-, Y is a direct bond and Z is as defined for Formula (I) may be prepared from compounds of Formula (IV) wherein R a is -X-Y-Z, in which X is -CH 2 -, Y is a direct bond and Z is as defined for Formula (I), in the presence of an alkylating agent such as C 1-6 alkyl iodide, in the presence of a strong base such as LDA, in a suitable solvent such as THF, at reduced temperature, such as -78°C, as illustrated below.
  • R a is -X-Y-Z or -CCI 3 ;
  • X is -CR 6 R 7 ;
  • R 6 is H or Ci -6 alkyl
  • R 7 is H or C 1-6 alkyl
  • R 6 and R 7 together with the carbon atom to which they are attached, form cyclopropyl;
  • Y is a direct bond, -O- or -NR 8 -(CH 2 ) P ;
  • R 8 is H or C ⁇ alkyl
  • p 1 ;
  • R a is -X-Y-Z or -CCI 3 ;
  • X is -CR 6 R 7 ;
  • R 6 is H
  • R 7 is H or Ci -6 alkyl
  • R 6 and R 7 together with the carbon atom to which they are attached, form cyclopropyl;
  • Y is -NR 8 -(CH 2 ) P ;
  • R 8 is H or C 1-4 alkyl
  • Compounds of Formula (I) may alternatively be prepared by reaction of a compound of Formula (IV) as described above, with a compound of Formula (III) as described above, in the presence of a suitable activating agent such as i) a mixture of 1-hydroxy-1 H-benzotriazol hydrate (HOBt) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI), or ii) N,N,N',N'-tetramethyl-0-(7-azabenzotriazol-1 -yl)uronium hexafluorophosphate (HATU), optionally in the presence of a suitable base such as NaHC0 3 or DIPEA, DI PEA or Et 3 N, in a suitable solvent such as DMF or DCM, under suitable conditions such as elevated temperature and/or microwaves.
  • a suitable activating agent such as i) a mixture of 1-hydroxy-1 H-benzotriazol hydrate (HOBt
  • Compounds of Formula (I) may alternatively be prepared by reaction of a compound of Formula (VII), wherein R 1 and R a are rmula (I),
  • R 2 H wherein R 2 is as described for Formula (I)
  • a suitable base such as Cs 2 C0 3
  • a suitable activating agent such as copper (I) iodide
  • a suitable catalyst such as 8-hydroxyquinoline
  • DMF suitable solvent
  • suitable conditions such as elevated temperature and/or microwaves.
  • Compounds of Formula (IX) may be prepared by reaction of a compound of Formula (III) as described above, with a commercially available compound of Formula (XI), wherein X is as described for Formula (I)
  • Table 1 provides Example compounds of the invention (List A):
  • Example 7 Method of preparation of Example 7: /V 2 -(2,3-dihydro-1 H-inden-5-yl)-/V 1 -[2-(4-morpholinyl) 5-(trifluoromethyl)-phenyl]alaninamid
  • Example 46 Title compound was prepared by a method analogous to that described for Example 46, replacing 2-Bromo-N-[2-(1 /-/-1 ,2,4-triazol-1-yl)-5-(trifluoromethyl)phenyl]propanamidewith
  • Example 8 2-[(4-chlorophenyl)oxy]-/V-[2-(1 H-1 ,2,4-triazol-1 -yl)-5- (trifluoromethyl)-phenyl]propanamid
  • Example 24 ⁇ /-[2-(1 H-1 ,2,4-triazol-1 -yl)-5-(trifluoromethyl)phenyl]-2-[3-(trifluoromethyl)- phenyl]propanamide
  • the crude material was dissolved in DCM and washed with NH 4 CI (aq. sat.), NaHC0 3 and brine.
  • the crude was purified first by chromatography on silica gel with hexane:EtOAc 100:0 to 40:60 as eluents and second by preparative HPLC (column: Sunfire 19x150 mm, gradient 40%-100% ACN/water) to obtain 47 mg of a white solid as the desired product (29.7% yield).
  • Examples 25-27 were prepared by methods analogous to that described for Example 24 but replacing Intermediate 1 with the carboxylic acid indicated in Table 3. Reaction time: from 1 hour to 2 hours. Other modifications are also indicated.
  • Example 28 A -[2-(1 H-1 ,2,4-triazol-1 -yl)-5-(trifluoromethyl)phenyl]-1-[3-(trifluoromethyl ⁇ phenyl]cyclopropanecarboxamid
  • Examples 29-34 were prepared by methods analogous to that described for Example 28, replacing 1-[3-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid with the carboxylic acid indicated in Table 4. Reaction time: from 30 minutes to 2h 30min. In most cases only one silica chromatography was necessary. Other modifications are also indicated.
  • Example 36 1-phenyl-/V-[2-(1 -pyrrolidinyl)-5-(trifluoromethyl)phenyl]cyclopropane- carboxamide
  • Title compound was prepared by a method analogous to that described for Example 35 replacing (4-fluorophenyl)acetyl chloride with 1 -phenylcyclopropanecarbonyl chloride (CHEMCOLLECT, 52 mg, 0.288 mmol) and the corresponding aniline with (1-pyrrolidinyl)-5- (trifluoromethyl)aniline (APOLLO, 68 mg, 0.295 mmol) to yield 1 -phenyl-A -[2-(1 -pyrrolidinyl)- 5-(trifluoromethyl)phenyl]cyclopropanecarboxamide (21 .1 mg, yield 19.8 %).
  • Example 37 1-(4-methylphenyl)-/V-[2-(1 H-1 ,2,4-triazol-1 -yl)-5-(trifluoromethyl)phenyl]- cylopropanecarboxamide
  • 1-(4-methylphenyl)cyclopropanecarboxylic acid (ACROS, 34.3 mg, 0.195 mmol) was dissolved in DMF (2 mL) under N 2 atmosphere.
  • 1-Hydroxy-1 H-benzotriazol hydrate (ALDRICH, 29.8 mg, 0.195 mmol)
  • N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI) (ALDRICH, 37.3 mg, 0.195 mmol)
  • sodium bicarbonate (16.4 mg, 0.195 mmol) were added. This mixture was heated at 80°C under MW irradiation during 10 min.
  • Example 38 1-[4-(methyloxy)phenyl]-/V-[2-(1 H-1 ,2,4-triazol-1 -yl)-5-(trifluoromethyl)- phenyl]cyclopropanecarboxamide
  • Example 39 /V-[2-(4-methyl-1-piperazinyl)-5-(trifluoromethyl)phenyl]-1 -phenylcyclo- propanecarboxamide bromohydrate salt
  • N-Methylpiperazine (ALDRICH, 0.032 mL, 0.292 mmol) was added to a mixture of N-[2- bromo-5-(trifluoromethyl)phenyl]-1 -phenylcyclopropanecarboxamide (Intermediate 4, 80 mg, 0.208 mmol), caesium carbonate (ALDRICH, 136 mg, 0.416 mmol) and copper (I) iodide (ALDRICH, 7.93 mg, 0.042 mmol) in DMF (3 mL). The mixture was heated at 80 °C under nitrogen overnight.
  • ADRICH More caesium carbonate (ALDRICH, 136 mg, 0.416 mmol), copper(l) iodide (ALDRICH, 7.93 mg, 0.042 mmol) and N-methylpiperazine (ALDRICH, 0.032 mL, 0.292 mmol) were added.
  • the reaction mixture under N 2 was heated at 80°C during the weekend. Solids were filtered off and the solvent was removed under vacuum. Crude was purified by preparative HPLC (column: XBRIDGE 30x150 mm.
  • Example 40 /V-[2-(1 H-imidazol-1 -yl)-5-(trifluoromethyl)phenyl]-1-phenylcyclopropane- carboxamide
  • Example 39 Title compound was prepared by a method analogous to that described for Example 39, replacing N-methylpiperazine with imidazole (MERCK, 28.2 mg, 0.414 mmol). Also 8- hydroxyquinoline (ALDRICH, 4.01 mg, 0.028 mmol) was used as catalyst and reaction was heated under MW irradiation at 120°C during 3 hours. Reaction was diluted with EtOAc and washed twice with NH 4 CI (aq., sat.) and once with NaCI, dried over Mg 2 S0 4 , filtered and concentrated to dryness. Crude was purified by silica chromatography using hexane/EtOAc as eluents.
  • Example 41 1-phenyl-/V-[2-(1 /-/-pyrazol-1-yl)-5-(trifluoromethyl)phenyl]cyclopropane- carboxamide
  • Example 40 Title compound was prepared by a method analogous to that described for Example 40, replacing N-methylpiperazine with pyrazole (ALDRICH, 36 mg, 0.518 mmol). Also 8- hydroxyquinoline (ALDRICH, 3.02 mg, 0.021 mmol) was used as catalyst and reaction was heated under MW irradiation at 130°C during 3 h. 14 mg (yield 36.2%) of 1 -phenyl-/V-[2-(1 H- pyrazol-1-yl)-5-(trifluoromethyl)phenyl]cyclopropane-carboxamide was obtained.
  • Examples 43-45 were prepared by methods analogous to that described for Example 8 or 42 replacing the carboxylic acid 2-[(4-chlorophenyl)oxy]propanoic acid in Example 8, or the acid chloride 2-phenoxypropionyl chloride (Intermediate 5) in Example 42 with that indicated in Table 5. Modifications in the reaction conditions are also indicated.
  • Example 46 /V 2 -(2,3-dihydro-1 H-inden-5-yl)-/V 1 -[2-(1 H-1 ,2,4-triazol-1 -yl)-5-(trifluoro- methyl)phenyl]alaninamide
  • Example 47 /V 2 -(2,3-dihydro-1 H-inden-5-yl)-/V 1 -[2-(1 H-1 ,2,4-triazol-1 -yl)-5-(trifluoro- methyl)phenyl]glycinamide
  • the compounds of this invention may be tested in one of several biological assays to determine the concentration of compound which is required to have a given pharmacological effect. Three assays are described below. It should be noted that the results obtained using any one of the following three assays is directly comparable with those obtained using either of the other two assays. Assays 1 and 2
  • Plasmodium falciparum A simple, rapid method for detecting parasite clones in microtiter plates.
  • NBT NiroBlue Tetrazolium
  • Diaphorase Prepare a solution of 5 mg/ml in Tris-HCI pH 8.0, 0.5 % Tween 20, freshly prepared before initiation of the assay.
  • Antimalarial whole cell screening (AWCI) - Absorbance - TCS - XC 50 determination P. falciparum 3D7 - to determinate XC50 for antimalarial whole cell screening hits.
  • Dilutions are done using an inter-plate approach (5 concentrations assayed, 5-fold dilution).
  • Reaction mix solution (1.43x final assay concentration) 143 mM Sodium L-Lactate - 143 ⁇ APAD, 178.75 ⁇ NBT, 286 ⁇ / ⁇ Diaphorase (2.83 U/ml), 0.7% Tween 20, 100 mM Tris-HCI pH 8.0
  • Assay plates (384 well plates) are prepared by stamping 0.05 ⁇ of compound from master plates in each well. Final volume assay is 25 ⁇ - and final compound concentrations are 2 ⁇ , 0.4 ⁇ , 0.08 ⁇ , 0.016 ⁇ and 0.0032 ⁇ .
  • 0.05 uL of DMSO are dispensed (positive controls).
  • 50 ⁇ artemisinin stock solutions are dispensed (negative controls).
  • P. falciparum 3D7 strain is cultivated using standard procedures as described in Trager et al. (1976). Science 193:673-675.
  • An inoculum of parasitized red blood cells (pRBC) with a parasitaemia of 0.25% and 2% haematocrit in RPMI-1640, albumax and 150 ⁇ hypoxanthine is prepared and used for the assay.
  • 25 ⁇ of parasite inoculum is dispensed in assay plates with compounds using a multidrop combi dispenser. Plates are shaken for 10 sec. to ensure mixing of the compound with the parasites. Plates are incubated at 37 °C for 72 h in an atmosphere of 5% C0 2 , 5% 0 2 , 95% N 2 .
  • HTS QA target is value at which assay meets quality requirements: Z'-Factor Target 0.7- 0.8.
  • Assay plates (384 well plates) are prepared by stamping 0.05 ⁇ of compound from master plates in each well. Final volume assay is 25 ⁇ - and higher compound concentration tested is 20 ⁇ .
  • 0.05 ⁇ - of DMSO are dispensed (positive controls).
  • 50 ⁇ artemisinin stock solutions are dispensed (negative controls).
  • P. falciparum 3D7 strain is cultivated using standard procedures as described in Trager et al. (1976). Science 193:673-675.
  • An inoculum of parasitized red blood cells (pRBC) with a parasitaemia of 0.25% and 2% haematocrit in RPMI-1640, albumax and 150 ⁇ hypoxanthine is prepared and used for the assay.
  • 25 ⁇ of parasite inoculum is dispensed in assay plates with compounds using a multidrop combi dispenser. Plates are shaken for 10 sec. to ensure mixing of the compound with the parasites. Plates are incubated at 37 °C for 72 h in an atmosphere of 5% C0 2 , 5% 0 2 , 95% N 2 .
  • HTS QA target is value at which assay meets quality requirements
  • Assay 3 IC sn (hypoxanthine) Assay
  • the following assay determines potency of hits from antimalarial whole cell screening against P. falciparum using incorporation of radiolabelled hypoxanthine as surrogate of parasitic growth. Results for the assays are provided in Table 1 above. Literature References
  • DMSO DMSO to 0.039 mM (from 1 to 9 wells) (dilution factor 2).
  • DMSO to wells 10 to 12.
  • This culture represents the negative control of the assay.
  • Examples 1-1 1 which are the compounds shown in Table 1 (compounds of List A) were all found to give an XC 50 of less than 1. ⁇ in Assay 1 .
  • Examples 14 and 19, which are the tested compounds shown in Table 2 (List B) were found to give an XC 50 of greater than 1. ⁇ in Assay 1 .
  • Examples 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 40, 41 , 43, 45, 46 and 47 were found to give an IC 50 of less than 5.0 ⁇ in Assay 3.
  • Examples 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 37, 38, 40, 41 , 43, 45 and 46 were found to give an IC 50 of less than 2.0 ⁇ in Assay 3.
  • Examples 23, 24, 25, 28, 29, 30, 31 , 32, 33, 37, 38, 40, 41 , 43, 45 and 46 were found to give an IC 50 of less than 1. ⁇ in Assay 3.
  • Example 28 was found to give an IC 50 of 0.001 ⁇ in Assay 3.
  • Examples 39, 42, 44, 48, 49 and 50 gave an IC 50 of greater than 5.0 ⁇ in Assay 3. These Examples may have utility in the preparation of other compounds of Formula (I) described herein.

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Abstract

La présente invention concerne des composés d'aminophénylacétamide de formule (I) : et des sels pharmaceutiquement acceptables de ceux-ci : dans lesquels R1, R2, R3 et Ra sont tels que définis dans la description, l'utilisation de tels composés dans la chimiothérapie de certaines infections protozoaires parasitaires telles que le paludisme, des compositions pharmaceutiques comprenant de tels composés et des procédés pour la préparation de tels composés.
PCT/EP2010/067806 2009-11-20 2010-11-19 Aminoarylacétamides et leur utilisation dans le traitement du paludisme Ceased WO2011061277A1 (fr)

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WO2016169906A1 (fr) * 2015-04-21 2016-10-27 Glaxosmithkline Intellectual Property Development Limited Dérivés de 2,4-dioxo-1,2-dihydropyrido[3,4-d]pyrimidine
CN109705060A (zh) * 2019-01-16 2019-05-03 华东理工大学 一种n-(2-吗啉基-5-三氟甲基苯基)-2-(3-甲基苯氧基)丙酰胺的制备方法
WO2022183111A1 (fr) * 2021-02-26 2022-09-01 Brown University Compositions et méthodes pour le traitement de la malaria liée à plasmodium falciparum

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016169906A1 (fr) * 2015-04-21 2016-10-27 Glaxosmithkline Intellectual Property Development Limited Dérivés de 2,4-dioxo-1,2-dihydropyrido[3,4-d]pyrimidine
US9624219B2 (en) 2015-04-21 2017-04-18 Glaxosmithkline Intellectual Property Development Limited Compound (S) and (R)-N-(2-fluoropyridin-4-yl)-3-methyl-2-(5-methyl-2,4-dioxo-1,2-dihydropyrido[3,4-d]pyrimidin-3(4H)-yl)butanamide and use
CN109705060A (zh) * 2019-01-16 2019-05-03 华东理工大学 一种n-(2-吗啉基-5-三氟甲基苯基)-2-(3-甲基苯氧基)丙酰胺的制备方法
CN109705060B (zh) * 2019-01-16 2023-04-14 华东理工大学 一种n-(2-吗啉基-5-三氟甲基苯基)-2-(3-甲基苯氧基)丙酰胺的制备方法
WO2022183111A1 (fr) * 2021-02-26 2022-09-01 Brown University Compositions et méthodes pour le traitement de la malaria liée à plasmodium falciparum
EP4298089A4 (fr) * 2021-02-26 2025-01-01 Brown University Compositions et méthodes pour le traitement de la malaria liée à plasmodium falciparum

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