WO2007104696A1 - Agents antimalariaux de structure polyaromatique - Google Patents

Agents antimalariaux de structure polyaromatique Download PDF

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Publication number
WO2007104696A1
WO2007104696A1 PCT/EP2007/052176 EP2007052176W WO2007104696A1 WO 2007104696 A1 WO2007104696 A1 WO 2007104696A1 EP 2007052176 W EP2007052176 W EP 2007052176W WO 2007104696 A1 WO2007104696 A1 WO 2007104696A1
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Prior art keywords
phenyl
pyrrolidin
chlorophenyl
imidazole
methyl
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PCT/EP2007/052176
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English (en)
Inventor
Giuseppe Campiani
Sandra Gemma
Caterina Fattorusso
Gagan Kukreja
Bhupendra Prasad Joshi
Orazio Taglialatela Scafati
Luisa Savini
Meri De Angelis
Ernesto Fattorusso
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Sigma-Tau Industrie Farmaceutiche Riunite S.P.A.
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Publication of WO2007104696A1 publication Critical patent/WO2007104696A1/fr

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    • 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
    • C07D295/08—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 bound oxygen or sulfur atoms
    • 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
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • 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
    • 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
    • C07D295/08—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 bound oxygen or sulfur atoms
    • C07D295/096—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 bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing 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
    • C07D417/06—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
    • 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 polyaromatic compounds analogues of clotrimazole useful as active ingredients of antiparasitic drugs.
  • the compounds synthesized present a remarkable biological activity against the chloroquine-resistant Plasmodium falciparum strains. Furthermore, the synthesis
  • the parasite derives all benefits from association and the host may either not be harmed or may suffer the consequences of this association, a parasitic disease.
  • Parasites which live inside the body are termed endoparasites, whereas those which exist on the body surface are called ectoparasites.
  • Parasites that cause harm to the host are pathogenic parasites while those that benefit from the host without causing it any harm are known as commensals.
  • Parasitic diseases i.e. diseases caused by pathogenic parasites
  • diseases include malaria, leishmaniasis, Chagas disease, amebic dysentary, sleeping sickness, river-blindness and elephantiasis.
  • the clinical symptoms and the majority of deaths caused by malaria occur during the intraerythrocytic phase of the parasite's complex life cycle within its human host.
  • hemoglobin is consumed as a primary source of amino acids to fuel the explosive growth of the parasite.
  • heme is released, which is cytotoxic to the parasite in its soluble form.
  • the parasite has developed a means of detoxifying heme through polymerization to non-toxic, insoluble hemozoin or by degradation with GSH, which is found at millimolar concentrations in red blood cells and parasite compartments.
  • CLT inhibits the sarcoplasmic reticulum Ca 2+ pump and capacitative Ca 2+ channels of malaria-infected red blood cells, causing the depletion of intracellular Ca 2+ stores which induces the activation of protein kinase R and phosphorylation of eukaryotic translation initiation factor 2 ⁇ , thereby inhibiting protein synthesis in the parasite.
  • the imidazole moiety of CLT behaves as an axial ligand, binding free heme which protect heme from degradation by reduced glutathione, and the resulting complex damages the cell membrane more than free heme (Tien Huy N. et al. J. Biol. Chem., 227(6), 4152-8, Feb. 8, 2002).
  • a recent report suggests that antimalarial activity of CLT might be
  • Leishmania is a genus of trypanosome protozoa and is the parasite responsible for the disease leishmaniasis. It is spread through sandflies of the genus Phlebotomus in the Old World, and of the genus Lutzomyia in the New World. Their primary hosts are vertebrates; Leishmania commonly infects hyraxes, canids, rodents, and humans. Leishmania currently affects 12 million people in 88 countries.
  • Chagas disease also called American trypanosomiasis
  • Its pathogenic agent is a flagellate protozoan named Trypanosoma cruzi, which is transmitted to humans and other mammals mostly by hematophagous assassin bugs of the subfamily Triatominae (Family Reduviidae).
  • Triatominae Family Reduviidae
  • Those insects are known by numerous common names varying by country, including benchuca, vinchuca, kissing bug, chipo and barbeiro.
  • the most common insect species belong to the genera Triatoma, Rhodnius, and Panstrongylus.
  • Other forms of transmission are possible, though, such as ingestion of food contaminated with parasites, blood transfusion and fetal transmission.
  • Trypanosoma cruzi is a member of the same genus as the infectious agent of African sleeping sickness, but its clinical manifestations, geographical distribution, life cycle and insect vectors are quite different. DESCRIPTION OF THE INVENTION
  • the compounds synthesized present a remarkable biological activity especially against the chloroquine (CQ) resistant strains, which is promising for the development of a new antimalarial drug. Furthermore, the synthesis involves few steps from commercial products with a low cost of production which addresses to the economic burden associated with this orphan disease.
  • CQ chloroquine
  • A is bivalent radical selected from the group comprising phenylene, naphtylene and 5- 6- 10- or 14- membered, mono, bicyclic or tricyclic heteroarylene, containing one or more heteroatoms selected among N, O and S;
  • R is selected from the group comprising hydrogen, halogen, trifluoromethyl, linear
  • B is bivalent radical selected between phenylene unsubstituted and substituted with OH, halogen, cyano, -SO2NH2;
  • R1 is selected from the group comprising di-(Ci-C 4 ) alkylamino, di-(CrC 4 )- alkylaminoalkylene(Ci-C 4 ) and 5- or 6- membered heterocyclyl or heteroaryl, containing one or more heteroatoms selected among O, S, S(O), S(O)2 and N unsubstituted or substituted with acetyl or mesyl;
  • R2 is selected from the group comprising hydrogen, 5- or 6- membered heterocyclyl or heteroaryl, containing one or more heteroatoms selected among N, O and S, and phenyl unsubstituted or substituted with R4; or R4 together with R2 forms a benzodiazolyl group;
  • R3 is selected from the group comprising 5- 6- 11- or 12- membered, mono or bicyclic heterocyclyl, containing one or more heteroatoms selected among N, O and S; and R4 is selected from the group comprising hydrogen, OH, halogen; N-(CrC 4 ) alkyl;
  • heterocyclyl and heterocyclyl-methylene where the heterocyclyl is a 5- 6- membered ring containing one or more heteroatoms selected among N, O and S; with the proviso that R and R2 are never both H;.
  • Compounds of Formula (I) also comprise tautomers, geometrical isomers, optically active forms as enantiomers, diastereomers and racemate forms, as well as pharmaceutically acceptable salts of the compounds of Formula (I).
  • each of the products of formula (I) can exist both as a racemic mixture R/S, and in the separate isomeric forms R and S.
  • Preferred pharmaceutically acceptable salts of the Formula (I) are acid addition salts formed with pharmaceutically acceptable acids like hydrochloride, hydrobromide, sulfate or bisulfate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, gluconate, methanesulfonate, benzenesulfonate, and para-toluenesulfonate salts.
  • pharmaceutically acceptable acids like hydrochloride, hydrobromide, sulfate or bisulfate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, gluconate, methanesulfonate, benzenesulfonate, and para-toluenesulfonate salts.
  • Suitable pharmaceutically acceptable base addition salts for the compound of the present invention include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N, N'- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine ( ⁇ /-methylglucamine) and procaine.
  • Sodium salts are particularly preferred.
  • examples of the linear or branched (Ci-C4) alkyl group are understood to include methyl, ethyl, propyl and butyl as well as their possible isomers, such as, for example, isopropyl, isobutyl, and ter-butyl.
  • the expression "lower alkyl” is herein used as a synonym of (CrC 4 )
  • heterocyclyl alone or in combination, means saturated or unsaturated (but not aromatic) five-, six- or seven-membered rings containing one or two nitrogen, oxygen or sulfur atoms which may be the same or different and which rings may be substituted with lower alkyl, lower alkenyl, aryl; examples of such rings are morpholinyl, piperazinyl, tetrahydropyranyl, dihydropyranyl, dioxanyl, pyrrolidinyl, tetrahydrofuranyl, dihydropyrrolyl, imidazolidinyl,
  • heteroaryl alone or in combination, means six-membered
  • aromatic rings containing one to four nitrogen atoms benzofused six-membered aromatic rings containing one to three nitrogen atoms; five-membered aromatic rings containing one oxygen, one nitrogen or one sulfur atom; benzo-fused
  • Halogen refers to fluoro, chloro, bromo and iodo atoms.
  • A is phenylene or quinoline, R is chloro or methoxy; when A is phenylene preferably R is in para- or meta- position; R1 is pyrrolidinyl; R3 is imidazolyl; R2 and B are phenylene and R4 is H.
  • the compounds of the present invention contain three phenyl or phenylene groups or two phenyl or phenylene groups and one thiazolyl group.
  • the most preferred compounds are 1-((3-chlorophenyl)(phenyl)(4-
  • Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimisation procedures. Specific reference is made to the methods described in the Examples and to the Schemes 1-6.
  • compounds of Formula (I), in which R2 is H and both A and B are phenylene groups, (4) according to Scheme 1 may be obtained by a process comprising:
  • Compounds of Formula (I), in which R2 is 1H-imidazolyl, both A and B are phenylene groups and R1 is pyrrolidin-1-yl, (24) according to Scheme 5, may be obtained by a process comprising: a. reacting the heteroaromatic carboxaldehyde (21) with 4-chloro, 3-chloro or 4-fluorophenylmagnesium bromide to afford the phenyl ketone (22); b. reacting the phenyl ketone (22) with (4-(pyrrolidin-1- ylmethyl)phenyl)magnesium bromide to obtain the carbinol (23); c.
  • a method of treating a mammal suffering from a parasitic disease or at risk of being infected by a pathogenic parasite, comprising administering a therapeutically effective amount of a compound of Formula (I) as described above represents one of the aspects of the present invention.
  • therapeutically effective amount refers to an amount of a therapeutic agent needed to treat, ameliorate a targeted disease or condition, or to exhibit a detectable therapeutic effect.
  • the therapeutically effective dose can be estimated initially either in cell culture assays, for example, Plasmodium falciparum strains, or in animal models, usually mice, rats, guinea pigs, rabbits, dogs, pigs or monkeys.
  • the animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.
  • the precise effective amount for a human subject will depend upon the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination
  • compositions may be administered individually to a patient or may be administered in combination with other agents, drugs or hormones.
  • the medicament may also contain a pharmaceutically acceptable carrier, for administration of a therapeutic agent.
  • a pharmaceutically acceptable carrier for administration of a therapeutic agent.
  • Such carriers include antibodies and other polypeptides, genes and other therapeutic agents such as liposomes, provided that the carrier does not itself induce the production of antibodies harmful to the individual receiving the composition, and which may be administered without undue toxicity.
  • Suitable carriers may be large, slowly metabolised macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers and inactive virus particles.
  • Pharmaceutically acceptable carriers in therapeutic compositions may additionally contain liquids such as water, saline, glycerol and ethanol. Additionally, auxiliary substances, such as wetting or emulsifying agents, pH
  • Such carriers enable the pharmaceutical compositions to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for ingestion by the patient.
  • compositions of the invention can be administered directly to the subject.
  • the subjects to be treated can be animals; in particular, human subjects can be treated.
  • the medicament of this invention may be administered by any number of routes including, but not limited to, oral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, intraventricular, transdermal or transcutaneous applications, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, intravaginal, rectal means or locally on the diseased tissue after surgical operation.
  • routes including, but not limited to, oral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, intraventricular, transdermal or transcutaneous applications, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, intravaginal, rectal means or locally on the diseased tissue after surgical operation.
  • Dosage treatment may be a single dose schedule or a multiple dose schedule.
  • a further object of the present invention are pharmaceutical compositions containing one or more of the compounds of formula (I) described earlier, in combination with excipients and/or pharmacologically acceptable diluents.
  • compositions in question may, together with the compounds of formula (I), contain known active principles.
  • the invention also includes the use of the compounds of Formula (I) for the preparation of drugs useful in the treatment and/or prevention of a parasitic
  • Parasitic diseases include malaria, leishmaniasis, Chagas disease, amebic dysentary, sleeping sickness, river-blindness and elephantiasis.
  • compositions characterised by mixing one or more compounds of formula (I) with suitable excipients, stabilizers and/or pharmaceutically acceptable diluents.
  • the Grignard reagent was prepared as described above from 1-(4- bromobenzyl)pyrrolidine (1.19 g, 4.98 mmol) and magnesium turnings (120 mg, 4.98 mmol) which was reacted further with 1b (700 g, 4.98 mmol) to give 3d as a light yellow oil (970 g, 65%); 1 H NMR (200 MHz, CDCI 3 ) ⁇ 7.49-7.32 (m, 6H), 7.25- 7.20 (m, 2H), 5.77 (s, 1 H), 3.96 (s, 2H), 3.71 (bs, 1 H), 2.97 (m, 4H), 1.96 (m, 4H); ESI MS m/z (M+1 ) + 302. (4-Chlorophenyl)(4-(pyrrolidin-1 -ylmethyl)phenyl)methanol (3e)
  • the Grignard reagent was prepared as described above from 1-(4- bromobenzyl)pyrrolidine (1.02 g, 4.27 mmol) and magnesium turnings (100 mg, 4.27 mmol) which was reacted further with 4-chlorobenzaldehyde 1c (600 mg, 4.27 mmol) to give 3e as a light yellow oil (0.95 g, 74%); 1 H NMR (200 MHz, CDCI 3 ) ⁇ 7.76-7.68 (m, 4H), 7.48-7.39 (m, 4H), 6.08 (s, 1 H), 3.89 (s, 2H), 3.58 (bs, 1 H), 2.52 (m, 4H), 1.77 (m, 4H); ESI MS m/z (M+1) + 302. (4-Methoxyphenyl)(4-(pyrrolidin-1-ylmethyl)phenyl)methanol (3f)
  • the Grignard reagent was prepared as described above from 1-(4- bromobenzyl)pyrrolidine (1.23 g, 5.15 mmol) and magnesium turnings (120 mg, 5.15 mmol) which was reacted further with 4-methoxybenzaldehyde 1d (700 mg, 5.15 mmol) to give 3f as a light yellow oil (1.10 g, 72%); 1 H NMR (200 MHz, CDCI 3 ) ⁇ 7.29-7.24 (m, 6H), 6.88-6.82 (m, 2H), 5.76 (s, 1 H), 3.77 (s, 3H), 3.60 (s, 2H), 2.63 (s, 1 H), 2.51 (m, 4H), 1.77 (m, 4H); ESI MS m/z (M+1) + 298.
  • the Grignard reagent was prepared in the usual manner as described for 3a from and 4-bromotoluene (8.0 g, 46.77 mmol), magnesium turnings (1.13 g, 46.77 mmol) and a catalytic amount of iodine in anhydrous tetrahydrofuran (100 ml_).
  • a solution of 3-chlorobenzaldehyde (1b, 10.0 ml_, 93.54 mmol ) in dry THF (70 ml_) was added drop wise and the resulting solution was heated at 75 0 C for 4h.
  • the reaction mixture was quenched with 50 ml_ of 20% of ammonium chloride solution.
  • CDCI 3 ⁇ 7.73-7.69 (m, 4H), 7.43-7.40 (m, 4H), 3.55 (s, 2H), 3.43-3.40 (m, 4H),
  • the Grignard reagent was prepared in the usual manner as described for 3a from and bromobenzene (600 ⁇ l_, 5.70 mmol), magnesium turnings (140 mg, 5.70 mmol) and a catalytic amount of iodine in anhydrous tetrahydrofuran (35 ml_).
  • a solution of 8a (1.14 g, 3.80 mmol) in anhydrous tetrahydrofuran (25 ml_) was added drop wise and the resulting solution was heated at 75 0 C for 8h.
  • the reaction mixture was quenched with 25 ml_ of 20% of ammonium chloride solution.
  • the resulting hydrochloride salt (570 mg, 1.32 mmol) was suspended in 10 ml_ of dry acetonitrile and to this was added slowly a solution containing triethylamine (550 ⁇ l_, 3.95 mmol) and imidazole (270 mg, 3.95 mmol) in acetonitrile (5 ml_) at O 0 C. Thereafter, the reaction mixture was heated at 80 0 C for 4 h. The solvent was evaporated under reduced pressure and the residue was treated with water and extracted with ethyl acetate (2 x 30 ml_). The combined organic layers were dried over Na2SO 4 and concentrated in vacuo.
  • the Grignard reagent was prepared as described for 3a from 1-(4- bromobenzyl)pyrrolidine (680 mg, 2.83 mmol) and magnesium turnings (69.0 mg, 2.83 mmol) which was reacted further with 22a (410 mg, 1.89 mmol).
  • the Grignard reagent was prepared as described above from 1-(4- bromobenzyl)pyrrolidine (490 mg, 2.02 mmol) and magnesium turnings (50.0 mg, 2.02 mmol) which was reacted further with 22b (300 mg, 1.30 mmol).to give 23b as a white solid (340 mg, 66%); 1 H NMR (300 MHz, CDCI 3 ) ⁇ 7.43-7.42 (m, 1 H), 7.38-7.22 (m, 8H), 6.96-6.93 (m, 1 H), 6.72-6.71 (m, 1 H), 3.73 (s, 2H), 3.10 (bs, 1 H), 2.57-2.53 (m, 4H), 1.79-1.75 (m, 4H); ESI MS m/z (M+1) + 384. (3-Chlorophenyl)(furan-3-yl)(4-(pyrrolidin-1-ylmethyl)phenyl)methanol (23c)
  • the resulting hydrochloride salt was suspended in 10 ml_ of dry acetonitrile and to this was added slowly a solution containing triethylamine (430 ⁇ l_, 3.12 mmol) and imidazole (210 mg, 3.12 mmol) in acetonitrile (10 ml_) at 0 0 C. Thereafter the reaction mixture was heated at 80 0 C for 3 h. The solvent was evaporated under reduced pressure and the residue was treated with water and extracted with ethyl acetate (4 x 30 ml_). The combined organic layer was dried over Na 2 SO 4 and concentrated in vacuo.
  • the resulting hydrochloride salt (200.0 mg, 0.47 mmol) was dissolved in 8 mL of dry DCM and was treated with trimethylsilyl cyanide (80 ⁇ L, 0.50 mmol) and titanium tetrachloride (705 ⁇ L, 1.0 M in CH 2 CI 2 ) at 0 0 C and was allowed to stir at room temperature for 4 h.
  • the reaction was quenched with 1 mL of MeOH and extracted with DCM.
  • the organic phase was washed with water, NaHCO 3 solution, water and then dried over Na 2 SO 4 . Removal of the solvent and purification by flash column chromatography (1 % methanol in chloroform) afforded 20 as a brown oil.
  • yeast and filamentous fungi from international collection (Candida krusei ATCC® 6258, Candida parapsilosis ATCC® 22019 [both quality control strains], Aspergillus flavus ATCC® 204304 [reference strain]) and the following clinical isolates (Candida albicans MGMM , Cryptococcus neoformans MGMI3, and two Aspergillus fumigatus MGMI4 and MGMI5, one (MGMI5) itraconazole (ITRA) resistant (MIC > 16 mcg/ml)) against compounds 4c-e, 10b, i and 24g using the CLSI protocols for yeast and filamentous fungi (see: National Committee for Clinical Laboratory Standards. (2002). Reference method for broth

Abstract

La présente invention concerne des agents antimalariaux comportant un nouveau pharmacophore de formule (I). Ces composés polycycliques sont susceptibles d'inhiber les souches sensibles à la chloroquine et résistantes à la chloroquine de Plasmodium falciparum (Pf). En outre, la synthèse de ces composés est peu onéreuse et implique peu d'étapes à partir des produits commerciaux.
PCT/EP2007/052176 2006-03-15 2007-03-08 Agents antimalariaux de structure polyaromatique WO2007104696A1 (fr)

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US9353122B2 (en) 2013-02-15 2016-05-31 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US9353123B2 (en) 2013-02-20 2016-05-31 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US9688688B2 (en) 2013-02-20 2017-06-27 Kala Pharmaceuticals, Inc. Crystalline forms of 4-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)butan-1-one and uses thereof
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