WO2016116752A1 - Pyrazolopyrimidines anti-leishmaniose - Google Patents

Pyrazolopyrimidines anti-leishmaniose Download PDF

Info

Publication number
WO2016116752A1
WO2016116752A1 PCT/GB2016/050124 GB2016050124W WO2016116752A1 WO 2016116752 A1 WO2016116752 A1 WO 2016116752A1 GB 2016050124 W GB2016050124 W GB 2016050124W WO 2016116752 A1 WO2016116752 A1 WO 2016116752A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
pharmaceutically acceptable
leishmaniasis
acceptable salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/GB2016/050124
Other languages
English (en)
Inventor
Ian Hugh GILBERT
Michael George Thomas
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Dundee
Original Assignee
University of Dundee
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of Dundee filed Critical University of Dundee
Publication of WO2016116752A1 publication Critical patent/WO2016116752A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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

  • This invention provides a compound, 3,3,3-trifluoro-A/-((l,4-irans)-4-((4-methoxy-3- (2-methoxyphenyl)-l/-/-pyrazolo[3,4-d]pyrimidin-6-yl)amino)cyclohexyl)propane-l-sulfonamide and salts thereof, pharmaceutical compositions comprising it, and its use in therapy, for example in the treatment of the leishmaniasis, particularly visceral leishmaniasis (also known as VL).
  • VL visceral leishmaniasis
  • Leishmaniasis is caused in humans and animals by protozoan parasites from several leishmania species that are transmitted to hosts by the bites of infected female phlebotomine sandflies.
  • leishmaniasis - visceral There are three main human forms of leishmaniasis - visceral (often known as kala- azar and the most serious form of the disease), cutaneous (the most common), and mucocutaneous (the most disfiguring). Most leishmaniases are zoonoses (diseases that can be transmitted from animals to humans) and the reservoir hosts include many species of mammals. Dogs are important reservoirs of L. infantum responsible for visceral leishmaniasis.
  • Animals can also suffer from visceral, cutaneous and mucocutaneous forms of the disease.
  • WO 2005/121107 and US 2005/277655 disclose certain pyrazolo-pyrimidine compounds as cyclin-dependent kinase inhibitors useful for the treatment of cancer.
  • WO 2008/09457, WO 2008/094602 and Bioorganic & Medicinal Chemistry Letters (2011), 21(18), 5633-5637 disclose certain pyrazolo-pyrimidine compounds as protein kinase inhibitors useful for the treatment of cancer.
  • the present invention provides the pyrazolo-pyrimidine compound 3,3,3-trifluoro-/V- ((l,4-trans)-4-((4-methoxy-3-(2-methoxyphenyl)-l/-/-pyrazolo[3,4-d]pyrimidin-6- yl)amino)cyclohexyl)propan -l-sulfonamide, having the Formula (I):
  • the present invention also provides pharmaceutical compositions comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a method of treatment or prevention of leishmaniasis, particularly visceral leishmaniasis, which method comprises administering to a mammal in need thereof, a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the mammal is a human.
  • the invention provides the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy, which therapy is human or veterinary.
  • the invention provides the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of leishmaniasis, particularly visceral leishmaniasis.
  • the invention provides the use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of leishmaniasis, particularly visceral leishmaniasis.
  • the present invention is directed to 3,3,3-trifluoro-/V-((l,4-trans)-4-
  • a compound of the invention is intended for use in pharmaceutical compositions it will readily be understood that it is provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compound of the invention may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1%, more suitably at least 5% and preferably from 10 to 59% of a compound of the invention or pharmaceutically acceptable derivative thereof.
  • a compound of Formula (I) is provided in substantially pure form, preferably at least 60% pure, more suitably at least 75% pure and more preferably at least 85%, and especially at least 98% pure (% are on a weight for weight basis).
  • a compound of Formula (I) is in the form of a free base.
  • a compound of Formula (I) is in the form of a pharmaceutically acceptable salt.
  • Salts of the compounds of Formula (I) include pharmaceutically acceptable salts and salts which may not be pharmaceutically acceptable but may be useful in the preparation of compounds of Formula (I) and pharmaceutically acceptable salts thereof.
  • a compound of Formula (I) is in the form of a pharmaceutically acceptable salt. Salts may be derived from certain inorganic or organic acids or bases. Examples of salts are pharmaceutically acceptable salts. Pharmaceutically acceptable salts include acid addition salts. For a review on suitable salts see Berge et al., J. Pharm. Sci., 66:1-19 (1977).
  • Examples of pharmaceutically acceptable acid addition salts of a compound of Formula (I) include inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, orthophosphoric acid, nitric acid, phosphoric acid, or sulfuric acid, or with organic acids such as, for example, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, acetic acid, propionic acid, lactic acid, citric acid, fumaric acid, malic acid, succinic acid, salicylic acid, maleic acid, glycerophosphoric acid, tartaric, benzoic, glutamic, aspartic, benzenesulfonic, naphthalenesulfonic such as 2-naphthalenesufonic, hexanoic acid or acetylsalicylic acid.
  • inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, orthophosphoric acid, nitric acid
  • a compound of Formula (I) is in the form of a salt independently selected from a hydrochloric acid, hydrobromic acid, orthophosphoric acid, nitric acid, phosphoric acid, maleic acid or a p-toluenesulfonic acid or sulfuric acid salt.
  • a compound of Formula (I) is in the form of a salt independently selected from a hydrochloric acid, maleic acid, sulfuric acid or a p-toluenesulfonic acid salt.
  • Examples of pharmaceutically acceptable inorganic base addition salts of a compound of Formula (I) include salts of ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like.
  • the invention includes within its scope all possible stoichiometric and non- stoichiometric forms of the salts of the compounds of Formula (I).
  • Salts may be formed using techniques well-known in the art, for example by precipitation from solution followed by filtration, or by evaporation of the solvent.
  • a pharmaceutically acceptable acid addition salt can be formed by reaction of a compound of Formula (I) with a suitable acid (such as hydrobromic, hydrochloric, sulfuric, maleic, p-toluenesulfonic, methanesulfonic, naphthalenesulfonic or succinic acids), optionally in a suitable solvent such as an organic solvent, to give the salt which is usually isolated for example by crystallisation and filtration.
  • a suitable acid such as hydrobromic, hydrochloric, sulfuric, maleic, p-toluenesulfonic, methanesulfonic, naphthalenesulfonic or succinic acids
  • the compound of Formula (I) may also be prepared as the N-oxide.
  • N-oxide examples of N- oxides of the compound of Formula (I) are as follows:
  • solvates complexes with solvents in which they are reacted or from which they are precipitated or crystallised. These complexes are known as "solvates".
  • a complex with water is known as a "hydrate”.
  • Solvents with high boiling points and/or solvents with a high propensity to form hydrogen bonds such as water, ethanol, /so-propyl alcohol, and A/-methyl pyrrolidinone may be used to form solvates.
  • Methods for the identification of solvated compounds include, but are not limited to, NMR and microanalysis. Accordingly compounds of Formula (I) may exist as solvates.
  • the term solvate encompasses solvates of both a free base compound as well as any salt thereof.
  • the compounds of the invention may be in crystalline or amorphous form.
  • the crystalline forms of the compounds of the invention may exist as polymorphs, all of which are included within the scope of the present invention.
  • the most thermodynamically stable polymorphic form or forms of the compounds of the invention are of particular interest.
  • the compound of Formula (I) is crystalline.
  • Polymorphic forms of compounds of the invention may be characterised and differentiated using a number of conventional analytical techniques, including, but not limited to, X-ray powder diffraction (XRPD), infrared spectroscopy (IR), Raman spectroscopy, differential scanning calorimetry (DSC), thermogravi metric analysis (TGA) and solid-state nuclear magnetic resonance (ssNMR).
  • XRPD X-ray powder diffraction
  • IR infrared spectroscopy
  • Raman spectroscopy Raman spectroscopy
  • DSC differential scanning calorimetry
  • TGA thermogravi metric analysis
  • ssNMR solid-state nuclear magnetic resonance
  • the compounds of the invention may also be prepared as an amorphous molecular dispersion of drug substance in a polymer matrix such as HPMCAS (hydroxypropylmethylcellulose acetate succinate) using a process such as spray-dried dispersion (SDD). Such a technique is employed to improve properties such as stability and solubility.
  • HPMCAS hydroxypropylmethylcellulose acetate succinate
  • SDD spray-dried dispersion
  • Compounds of Formula (I) may exist in the form of isotopic variations.
  • An isotopic variation of a compound of Formula (I), or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine such as 2 H, 3 H, 13 C, 1 C, 15 N, 17 0, 18 0, 18 F and 36 CI, respectively.
  • isotopic variations of a compound of Formula (I) or a salt or solvate thereof are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., 3 H, and carbon-14, i.e., 1 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances.
  • Isotopic variations of a compound of Formula (I), or a pharmaceutically salt thereof can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Examples hereafter using appropriate isotopic variations of suitable reagents.
  • each Ri is independently selected from H, C(0)OI_iR 2 , CLiR 3 OLiR 2 , C(0)l_iR 2 or P(0)(OLiR2)(OLiR 3 );
  • each l_i is independently selected from a bond or X;
  • X is Ci- 6 alkylene, Ci- 6 haloalkylene, C 4 - 6 heterocyclylene, phenylene or C 5 - 6heteroarylene, each of which is optionally substituted by 1 to 4 substituents independently selected from Z;
  • Z is H, halo, C(0)l_iR 2 , C(0)OI_iR 2 , C(0)NHI_iR 2 , C(0)N(LiR 2 )(l_iR 3 ), NH 2 , OI_iR 2 , NH(LiR 2 ), N(LiR 2 )(LiR 3 ), or ⁇ (0)( ⁇ _ ⁇ 2 )( ⁇ _ ⁇ 3 );
  • Each R 2 and R 3 is independently selected from H or Y;
  • Y is Ci- 6 alkyl, Ci- 6 haloalkyl, C 4 - 6 heterocyclyl, phenyl or C 5 - 6 heteroaryl, each of which is optionally substituted by 1 to 4 substituents independently selected from Z; or
  • R 2 and R 3 are bound together to form a linker group U, so as to form together with the atoms to which they are attached a C 4 - 6 cycloalkyl or , C 4 - 6 heterocyclyl group.
  • prodrugs of compounds of Formula (I) are shown in compounds of Formula (III) or (IV), or a pharmaceutically acceptable salt thereof:
  • each Ri is independently selected from H, C(0)OI_iR 2 , CH(LiR 3 )OLiR 2 , CH 2 OLiR 2 ,
  • each Li is independently selected from a bond or X;
  • X is Ci- 6 alkylene, C 2 _ 6 alkenylene, C 2 _ 6 alkynylene, C 4 - 7 cycloalkylene, C 5 - 7 cycloalkenylene, C 4 - 7 heterocycloalkylene, C 5 -C 7 heterocycloalkenylene, phenylene or C 5 - 6 heteroarylene; each of which is optionally substituted by 1 to 6 substituents independently selected from Z;
  • each Z is independently selected from halo, C(0)l_iR 2 , C(0)OI_iR 2 , C(0)NHI_iR 2 , C(0)N(LiR2)(LiR 3 ), OLiR 2 , NCUR.XUR,), CN, SCURz), SCOXURz), SO ⁇ UR,) or P(0)(OLiR2)(OLiR 3 );
  • each R 2 , R 3 and R 4 is independently selected from H or Y;
  • each R 2 , R 3 and R 4 is independently selected from Y, wherein two of said R 2 , R 3 and R 4 are bound together through an additional U group so as to form a cyclic group;
  • Y is Z or Ci- 6 alkyl, C 2 - 6 alkenyl, C 2 _ 6 alkynyl, C 4 _ 7 cycloalkyl, C 5 _ 7 cycloalkenyl, C 4 -
  • each Ri is independently selected from H, C(0)OI_iR 2 , CH(LiR 3 )OI_iR 2 , CH 2 OI_iR 2 , C(LiR 3 )(LiR 4 )OI_iR 2 , C(0)l_iR 2 , P(0)(OLiR 2 )(OI_iR 3 ), C(0)OLiOP(0)(OLiR 2 )(OLiR 3 ), or C(0)OLiOC(0)L
  • the term "Ci_6alkyl” means a straight or branched alkyl containing at least one, and at most six, carbon atoms. Examples of include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, neopentyl, or hexyls.
  • Ci_ 6 haloalkyl means wherein one or more of the hydrogen atoms are replaced with halo.
  • Ci_ 6 alkylene means a divalent radical of Ci_ 6 alkyl.
  • Examples of Ci_ 6 alkylene include, but are not limited to, methylene, ethylene, isopropylene, n-butylene, isobutylene, tert-butylene, pentylene, neopentylene, or hexylenes.
  • Ci_ 6 haloalkylene means a means a divalent radical of Ci_6haloalkyl as defined herein.
  • C 4 -6cycloalkyl means a non-aromatic carbocyclic ring containing at least four and at most six carbon atoms.
  • Examples of C 4 _ 6 cycloalkyl groups include cyclobutyl, cyclopentyl and cyclohexyl.
  • C 4 -6heterocyclyl means a saturated ring containing at least four and at most six atoms, which includes one or more (e.g. 2) ring heteroatoms selected from nitrogen, oxygen and sulfur.
  • C 4 _ 6 heterocyclyl groups include, but are not limited to, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, 1,4-dioxanyl, thiomorpholinyl, 1,4-oxathianyl and 1,4- dithanyl.
  • the point of attachment to the rest of the molecule may be by any suitable carbon or nitrogen atom.
  • C 4 _6heterocyclylene means a divalent radical of a C 4 _ 6 heterocyclyl group as defined herein.
  • Cs-eheteroaryl refers to an optionally substituted aromatic ring comprising five or six heteroatoms selected from N, 0 and S.
  • Examples of C 5 - 6 heteroaryl groups include, but are not limited to, furanyl, thiophenyl, pyrrolyl, pyridyl, pyrimidyl, imidazolyl and isoxazolyl.
  • Optional heteroaryl substituents include halo, and alkyl.
  • Cs-6heteroarylene means a divalent radical of C5- 6 heteroaryl as defined herein.
  • phenylene means a means a divalent radical of phenyl.
  • Ci_ 6 alkyl means a straight or branched saturated hydrocarbon group containing at least one, and at most six, carbon atoms. Examples of Ci_ 6 alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, neopentyl, or hexyls.
  • Ci_ 6 alkylene means a divalent radical of Ci-ealkyl as defined herein. Examples of include, but are not limited to, methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, tert- butylene, pentylene, neopentylene, or hexylenes.
  • C 2 _ 6 alkenyl means a straight or branched unsaturated hydrocarbon group containing at least two, and at most six, carbon atoms, wherein the hydrocarbon group has one or more positions of unsaturation each of which is present as a double bond.
  • C 2 _ 6 alkenylene means a divalent radical of C 2 - 6 alkenyl as defined herein.
  • Examples of C 2 -C 6 alkenylene include, but are not limited to, ethenylene, n-propenylene, isopropenylene, n-butenylene, isobutenylene, tert- butenylene, pentenylene, neopentenylene, or hexenylenes.
  • C 2 - 6 alkynyl means a straight or branched unsaturated hydrocarbon group containing at least two, and at most six, carbon atoms, wherein the hydrocarbon group has one or more positions of unsaturation each of which is present as a triple bond.
  • Examples of C 2 -C 6 alkynyl include, but are not limited to, ethynyl (-CH ⁇ CH-), propynyl (-CH 2 -CH ⁇ CH-), butynyl, pentynyl, hexynyl, 1-propynyl, 2- butynyl and 2-methyl-2-butynyl.
  • C 2 _ 6 alkynylene means a divalent radical of C 2 -6alkynyl as defined herein.
  • Examples of C 2 -C 6 alkenylene include, but are not limited to, ethynylene, n-propynylene, n-butynylene, isobutynylene, tert-butynylene, pentynylene, neopentynylene, or hexynylenes.
  • C4- 7 cycloalkyl means a non-aromatic carbocyclic saturated ring containing at least four and at most seven carbon atoms.
  • Examples of C4-7cycloalkyl groups include, but are not limited to, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • C4_ 7 cycloalkylene means a divalent radical of C4-7cycloalkyl as defined herein.
  • C 5 - 7 cycloalkenyl means a non-aromatic carbocyclic unsaturated ring containing at least five and at most seven carbon atoms. Examples of C 5 - 7 cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl and cycloheptenyl.
  • C 5 _ 7 cycloalkenylene means a divalent radical of Cs- 7 cycloalkenyl as defined herein.
  • C 4 - 7 heterocycloalkyl means a saturated ring containing at least four and at most seven atoms, which includes at least one heteroatom in the ring selected from nitrogen, oxygen and sulfur.
  • C 4 _ 7 heterocycloalkyl groups include, but are not limited to, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1,4-dioxanyl, thiomorpholinyl, 1,4-oxathianyl, 1,4-dithanyl, dioxepanyl, azepanyl, oxepanyl and diazepanyl.
  • the point of attachment to the rest of the molecule may be by any suitable carbon or nitrogen atom.
  • C 4 _ 7 heterocycloalkylene means a divalent radical of a C 4 - 7 heterocycloalkyl group as defined herein.
  • C 5 -C 7 heterocycloalkenyl means a non-aromatic unsaturated ring containing at least five and at most seven atoms, which includes at least one heteroatom in the ring selected from nitrogen, oxygen and sulfur.
  • C 5 -C 7 heterocycloalkenyl groups include, but are not limited to, dihydropyranyl, dihydrofuranyl, dihydrothiophenyl, pyrrolinyl, azepinyl, oxepinyl, thiepiny, dioxepinyl, dihydropyrrolyl, dihydropyrazolyl, dihydroimidazolyl, dihydrooxazolyl, dihydrothiazolyl and dihydrothiopyranyl.
  • C 5 - C 7 heterocycloalkenylene means a divalent radical of Cs-C 7 heterocycloalkenyl as defined herein.
  • C 5 - 6 heteroaryl refers to an aromatic ring containing at least five and at most six atoms, and comprising at least one heteroatom in the ring selected from nitrogen, oxygen and sulfur.
  • C5- 6 heteroaryl groups include, but are not limited to, furanyl, thiophenyl, pyrrolyl, pyridyl, pyrimidyl, imidazolyl and isoxazolyl.
  • the point of attachment to the rest of the molecule may be by any suitable carbon or nitrogen atom.
  • C 5 _ 6 heteroarylene means a divalent radical of C5- 6 heteroaryl as defined herein.
  • phenylene means a means a divalent radical of phenyl.
  • halo refers to fluoro, chloro, bromo or iodo.
  • composition comprising a compound of Formula (II), (III) or (IV), or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier.
  • a combination comprising (a) a compound of Formula (II), (III) or (IV), or a pharmaceutically acceptable salt thereof, and (b) at least one additional therapeutic agent.
  • a method of treatment or prevention of leishmaniasis comprises administering to a mammal in need thereof, a therapeutically effective amount of a compound a compound of Formula (II), (III) or (IV), or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) and salts thereof may be prepared by the methodology described hereinafter, constituting further aspects of this invention.
  • the general procedures which can be used to synthesise the compound of Formula (I) are
  • N-Pg N-protected variant of a compound of Formula I from an intermediate compound A or a salt thereof and the corresponding N-protected compound of Formula 4 wherein the N-Pg group may be any suitable N-protecting group such as for example a THP or SEM group.
  • any suitable salt of intermediate compound A may be used, and an exemplary salt is the TFA salt of A/-((l,4-trans)-4-aminocyclohexyl)-3,3,3-trifluoropropane-l-sulfonamide as utilised in the Examples herein.
  • Scheme 1 Compounds of Formula (I) in Scheme 1 may be prepared from 4,6- dichloro-l/-/-pyrazolo[3,4-d]pyrimidine (la).
  • Compound (la) may be subjected to bromination using a suitable brominating agent, such as A/-bromosuccinimide, to provide compound (1).
  • a suitable brominating agent such as A/-bromosuccinimide
  • the pyrazole NH of compound (1) may be protected with a suitable protecting group Pg such as THP or SEM, under suitable conditions, to give (2).
  • One of the chloro groups on the pyrimidine ring may be replaced by a methoxy group using with a suitable reagent such as sodium methoxide to provide (3).
  • Compound (3) may be reacted with Intermediate A in the presence of a suitable base, such as DIPEA, to provide (4).
  • Compound (4) may be subjected to a coupling reaction, for example a Suzuki or a Buchwald reaction, with a suitable reagent, such as 2-methoxyphenylboronic acid, to introduce a 2-methoxyphenyl group, in the presence of a suitable palladium catalyst, to give compound (5).
  • Compound (5) may be subjected to deprotection using a suitable reagent to give the compound of Formula (I).
  • Scheme 2 Intermediate A in Scheme 2 may be made from cyclohexane-l,4-diamine
  • Compound (14) may be protected with a suitable protecting group (Pg) (such as Boc) to give compound (15) followed by sulfonylation of the remaining free NH 2 to give (16).
  • Pg protecting group
  • Compound (16) may then be deprotected under suitable conditions to give Intermediate A.
  • conventional methods of heating and cooling may be employed, for example temperature-regulated oil-baths or temperature-regulated hot-blocks, and ice/salt baths or dry ice/acetone baths respectively.
  • Conventional methods of isolation for example extraction from or into aqueous or nonaqueous solvents may be used.
  • Conventional methods of drying organic solvents, solutions, or extracts such as shaking with anhydrous magnesium sulfate, or anhydrous sodium sulfate, or passing through a hydrophobic frit, may be employed.
  • Conventional methods of purification for example crystallisation and chromatography, for example silica chromatography or reverse-phase chromatography, may be used as required.
  • Crystallisation may be performed using conventional solvents such as ethyl acetate, methanol, ethanol, or butanol, or aqueous mixtures thereof. It will be appreciated that specific reaction times temperatures may typically be determined by reaction-monitoring techniques, for example thin-layer chromatography and LC-MS.
  • references herein to treatment refer to the treatment of established conditions.
  • the compounds of Formula (I) and pharmaceutically acceptable salts thereof may, depending on the condition, also be useful in the prevention (prophylaxis) of certain diseases.
  • treat means: (1) to ameliorate the disease or one or more of the biological manifestations of the disease (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the disease or (b) one or more of the biological manifestations of the disease, (3) to alleviate one or more of the symptoms or effects associated with the disease, (4) to slow the progression of the disease or one or more of the biological manifestations of the disease, and/or (5) to diminish the likelihood of severity of a disease or biological manifestations of the disease.
  • prevention means the prophylactic administration of a drug to diminish the likelihood of the onset of or to delay the onset of a disease or biological manifestation thereof.
  • 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 disorder or biological manifestation thereof, or to delay the onset of such disorder or biological manifestation thereof.
  • the treatment or prevention of a disease there is provided the treatment or prevention of a disease. In another embodiment, there is provided the treatment of a disease. In a further embodiment, there is provided the prevention of a disease.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in therapy.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use as a medicament in therapy, which therapy is human or veterinary.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of leishmaniasis, particularly visceral leishmaniasis.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of cutaneous leishmaniasis.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of leishmaniasis, particularly visceral leishmaniasis.
  • a method of treatment or prevention of leishmaniasis which method comprises administering to a human subject in need thereof, a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • a method of treatment or prevention of cutaneous leishmaniasis comprises administering to a mammal in need thereof, a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • compositions and formulations are provided.
  • the compound of Formula (I) or a pharmaceutically acceptable salt thereof may be administered as the bulk substance, it is usually preferable to present the active ingredient in a pharmaceutical formulation, for example, wherein the agent is in admixture with at least one pharmaceutically acceptable carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • carrier refers to a diluent, excipient, and/or vehicle with which an active compound is administered.
  • the pharmaceutical compositions of the invention may contain combinations of more than one carrier.
  • Such pharmaceutical carriers can be sterile liquids, such as water, saline solutions, aqueous dextrose solutions, aqueous glycerol solutions, and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • Water or aqueous solution saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W.
  • compositions may comprise, in addition to the carrier, any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), and/or solubilizing agent(s).
  • pharmaceutically acceptable refers to salts, molecular entities and other ingredients of compositions that are generally physiologically tolerable and do not typically produce untoward reactions when administered to a mammal (e.g., human).
  • pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government for use in mammals, and more particularly in humans, or listed in the U.S. Pharmacopoeia or other generally recognized texts, for example the International Union of Pure and Applied Chemistry (lUPAC) Handbook of Pharmaceutical Salts, 2011 Edition.
  • a “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes an excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • a “pharmaceutically acceptable excipient” as used in the present application includes both one and more than one such excipient.
  • the compounds of the invention may be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with formulation of antibacterials, such as anti-tubercular agents, or formulation of antimalarial agents.
  • the compounds of the invention will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient.
  • the invention is directed to a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the invention is directed to a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and together with at least one or more pharmaceutically acceptable carrier.
  • the carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the present invention further provides a pharmaceutical composition as defined herein for use as a medicament, for example for use as a medicament for use in the treatment or prevention of leishmaniasis, such as for use as a medicament for use in the treatment or prevention of visceral leishmaniasis.
  • a therapeutically effective amount of the compound of the present invention can be determined by methods known in the art.
  • the therapeutically effective quantities will depend on the age and on the general physiological condition of the subject, the route of administration and the pharmaceutical formulation used.
  • the therapeutic doses will generally be between about 1 and 2000 mg/day, for example between about 500 mg and 2000 mg/day.
  • the daily dose as employed for human treatment will range from 1 to 2000 mg, which may be administered in one or two daily doses, for example, depending on the route of administration and the condition of the subject.
  • each unit will contain 1 mg to 2000 mg of active ingredient.
  • the dosage form is a tablet
  • the total weight of the tablet is suitably lOOOmg or lower.
  • the present invention is further related to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the present invention is further related to a pharmaceutical composition for the treatment of leishmaniasis, particularly visceral leishmaniasis (VL), comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition for the treatment of leishmaniasis particularly visceral leishmaniasis (VL)
  • VL visceral leishmaniasis
  • the present invention is yet further related to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier.
  • the present invention is even further related to a pharmaceutical composition
  • a pharmaceutical composition comprising a) a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and b) one or more pharmaceutically acceptable carriers.
  • the present invention is even further related to a pharmaceutical composition
  • a pharmaceutical composition comprising a) 1 to 2000 mg of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, and b) 1 mg and 2000 mg of one or more pharmaceutically acceptable carriers.
  • compositions for use in accordance with the present invention may be in the form of oral, parenteral, transdermal, inhalation, sublingual, topical, implant, nasal, or enterally administered (or other mucosally administered) suspensions, capsules or tablets, which may be formulated in conventional manner using one or more pharmaceutically acceptable carriers or excipients.
  • the pharmaceutical composition is formulated for oral administration.
  • compositions of the invention include those in a form adapted for oral use in mammals including humans.
  • compositions of the invention include those in a form adapted for oral use and may be used for the treatment of leishmaniasis, particularly visceral leishmaniasis, in mammals including humans.
  • the compound of the invention can be administered for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications for example as a single or sole-therapeutic agent or may be administered as part of a combination therapy as detailed herein.
  • the composition may be formulated for administration by any convenient route.
  • the compositions may be in the form of tablets, capsules, powders, granules, lozenges, aerosols or liquid preparations, for oral use.
  • Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulfate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof may be the sole therapeutic agent in the compositions of the invention, or it may be present in the formulation in combination with one or more additional therapeutic agents.
  • the invention thus provides in a further aspect, a combination comprising (a) a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and (b) at least one additional therapeutic agent.
  • the combination optionally further comprises at least one pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier and one or more additional therapeutic agents.
  • the present invention further provides a combination of (a) and (b) as defined herein for use as a medicament, for example for use as a medicament for use in the treatment or prevention of leishmaniasis, such as for use as a medicament for use in the treatment or prevention of visceral leishmaniasis.
  • additional therapeutic agents are anti-leishmania agents, including, but not limited to, miltefosine, paromomycin, sodium stibugluconate, meglumine antimoniate, amphotericin B deoxycholate or liposomal amphotericin B.
  • the additional therapeutic agent is miltefosine.
  • Such chemotherapy is determined by the judgment of the treating physician using preferred drug combinations.
  • future anti-leishmania therapeutic agents emerging from clinical studies may also be employed as the one or more additional therapeutic agents in a combination with a compound of Formula (I).
  • the invention provides a combination comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, together with one or more additional therapeutic agents, such as an anti-leishmaniasis agent, an anti-AIDS or anti-HIV agent, or an anti-TB agent.
  • additional therapeutic agents such as an anti-leishmaniasis agent, an anti-AIDS or anti-HIV agent, or an anti-TB agent.
  • the one or more additional therapeutic agent is, for example, an agent useful for the treatment of leishmaniasis in a mammal, therapeutic vaccines, anti- leishmaniasis agents and/or agents for the treatment of HIV / AIDS.
  • the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and further therapeutic agent(s) may be employed in combination by administration simultaneously in a unitary pharmaceutical composition including both agents.
  • the combination may be administered separately in separate pharmaceutical compositions, each including one of the agents in a sequential manner wherein, for example, the compound of Formula (I) or a pharmaceutically acceptable salt, thereof is administered first and the other agent second and vice versa.
  • Such sequential administration may be close in time (e.g. simultaneously) or remote in time.
  • administration of the other agent several minutes to several dozen minutes after the administration of the first agent, and administration of the other agent several hours to several days after the administration of the first agent are within the scope of the invention, wherein the lapse of time is not limited.
  • one agent may be administered once a day, and the other agent may be administered 2 or 3 times a day, or one agent may be administered once a week, and the other agent may be administered once a day.
  • either the compound of the present invention or one or more additional therapeutic agent may be administered first.
  • the combination may be administered either in the same or different pharmaceutical composition.
  • the compound and agents must be stable and compatible with each other and the other components of the formulation.
  • they may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art.
  • each agent of the combination may be repeated one or more times.
  • agents may be administered in the same or different dosage forms, e.g. one agent may be administered topically and the other compound may be administered orally. Suitably, both agents are administered orally.
  • kits or kit of parts
  • the combination kit can contain the agents in a single pharmaceutical composition, such as a tablet, or in separate pharmaceutical compositions.
  • the combination kit will contain each agent in separate pharmaceutical compositions either in a single package or in separate pharmaceutical compositions in separate packages.
  • the combination kit can also be provided with instructions, such as dosage and administration instructions.
  • dosage and administration instructions can be of the kind that are provided to a doctor, for example by a drug product label, or they can be of the kind that are provided by a doctor, such as instructions to a patient.
  • the one or more additional therapeutic agent is a therapeutic vaccine.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof may thus be administered in conjunction with vaccination against leishmaniasis infection.
  • Existing veterinary vaccines include canileish and leishmune.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof may be either i) administered to an individual who has previously been vaccinated against leishmaniasis infection; ii) administered to an individual who is subsequently vaccinated against leishmaniasis infection; or iii) may be co-administered with a vaccine against leishmaniasis infection, either by administering the compound of the invention and the vaccine together in the same dosage form or co-administering the compound of the invention and the vaccine in separate dosage forms.
  • the dose of the compound or agent may differ from that when the compound or agent 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 and the one or more additional therapeutic agents 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.
  • Reactions involving metal hydrides (including sodium hydride) and organo-metallic reagents are carried out under argon or nitrogen unless otherwise specified.
  • This reaction was run five times with 1 g each batch. The amounts shown are a total of each of the five batches.
  • the intra macrophage Leishmania assay was performed exactly as described in de Rycker et al (Antimicrob Agents Chemother. 2013 Jul;57(7):2913-22. doi: 10.1128/AAC.02398-12. Epub 2013 Apr 9. Comparison of a high-throughput high-content intracellular Leishmania donovani assay with an axenic amastigote assay.
  • De Rycker M Hallyburton I, Thomas J, Campbell L, Wyllie S, Joshi D, Cameron S, Gilbert IH, Wyatt PG, Frearson JA, Fairlamb AH, Gray DW.
  • 1 ⁇ of compound was pre-dispensed into 384 well sterile intermediary plates.
  • amphotericin B was added to all wells of column 24 as a positive control (final concentration 2 ⁇ ) and DMSO to column 23.
  • final concentration 2 ⁇ final concentration 2 ⁇
  • DMSO final concentration 2 ⁇
  • the plates were incubated at 37 °C under 5% C0 2 in a humidified incubator for 75 h.
  • the cells were then washed with 450 ⁇ sterile phosphate buffered saline (PBS) supplemented with 1 mM CaCI 2 , 0.5 mM MgCI 2 , 0.1% (w/v) bovine serum albumin (PBS-A) and amastigotes were added to all wells at a multiplicity of infection of 5 (40,000 amastigotes per well).
  • PBS-A bovine serum albumin
  • the compound of Formula (I) was tested in the Intramacrophage Leishmania donovani assay.
  • the compound of Formula (I) is found to have an average pEC 50 value of 6.5 against amastigotes and pECso value of 4.6 against THP-1 cells in the Intramacrophage Leishmania donovani assay.

Landscapes

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

Abstract

L'invention concerne le 3,3,3-trifluoro-N-((1,4-trans)-4-((4-méthoxy-3-(2-méthoxyphényl)-1H-pyrazolo[3,4-d] pyrimidin-6-yl)amino)cyclohexyl)propane-1-sulfonamide, de formule (I) : (I) ou un sel de celui-ci, des compositions contenant le composé, son utilisation dans le traitement ou la prévention de la leishmaniose et, en particulier, de la leishmaniose viscérale.
PCT/GB2016/050124 2015-01-23 2016-01-21 Pyrazolopyrimidines anti-leishmaniose Ceased WO2016116752A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB1501115.8 2015-01-23
GBGB1501115.8A GB201501115D0 (en) 2015-01-23 2015-01-23 Compounds

Publications (1)

Publication Number Publication Date
WO2016116752A1 true WO2016116752A1 (fr) 2016-07-28

Family

ID=52673821

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2016/050124 Ceased WO2016116752A1 (fr) 2015-01-23 2016-01-21 Pyrazolopyrimidines anti-leishmaniose

Country Status (2)

Country Link
GB (1) GB201501115D0 (fr)
WO (1) WO2016116752A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020123272A1 (fr) 2018-12-12 2020-06-18 Merck Sharp & Dohme Corp. Inhibiteurs pde9 de pyrazolopyrimidine
WO2025133395A1 (fr) 2023-12-22 2025-06-26 Forx Therapeutics Ag Composés inhibiteurs bicycliques (hétéro)arylène wrn

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050277655A1 (en) 2004-06-09 2005-12-15 Qingjie Ding Pyrazolopyrimidines
WO2008009457A1 (fr) 2006-07-21 2008-01-24 Aleris Aluminum Koblenz Gmbh Procédé et appareil d'assemblage laser de deux composants d'aluminium et/ou d'alliages d'aluminium au moyen d'un flux de gaz laminaire inerte coaxial à un fil d'apport métallique
WO2008094602A2 (fr) 2007-01-30 2008-08-07 Biogen Idec Ma Inc. Modulateurs de kinases mitotiques

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050277655A1 (en) 2004-06-09 2005-12-15 Qingjie Ding Pyrazolopyrimidines
WO2005121107A1 (fr) 2004-06-09 2005-12-22 F. Hoffmann-La Roche Ag Pyrazolopyrimidines
WO2008009457A1 (fr) 2006-07-21 2008-01-24 Aleris Aluminum Koblenz Gmbh Procédé et appareil d'assemblage laser de deux composants d'aluminium et/ou d'alliages d'aluminium au moyen d'un flux de gaz laminaire inerte coaxial à un fil d'apport métallique
WO2008094602A2 (fr) 2007-01-30 2008-08-07 Biogen Idec Ma Inc. Modulateurs de kinases mitotiques

Non-Patent Citations (19)

* Cited by examiner, † Cited by third party
Title
"Handbook of Pharmaceutical Salts", 2011
"Topics in Chemistry", pages: 306 - 316
ALEX M. ARONOV ET AL: "Selective Tight Binding Inhibitors of Trypanosomal Glyceraldehyde-3-phosphate Dehydrogenase via Structure-Based Drug Design", JOURNAL OF MEDICINAL CHEMISTRY, vol. 41, no. 24, 1 November 1998 (1998-11-01), pages 4790 - 4799, XP055054326, ISSN: 0022-2623, DOI: 10.1021/jm9802620 *
ALVAR J. ET AL., PLOS ONE, vol. 7, no. 5, 2012, pages E35671
BERGE ET AL., J. PHARM. SCI., vol. 66, 1977, pages 1 - 19
BERMAN JD; BADARO R; THAKUR CP; WASUNNA KM; BEHBEHANI K ET AL.: "Efficacy and safety of liposomal amphotericin B (AmBisome) for visceral leishmaniasis in endemic developing countries", BULL WORLD HEALTH ORGAN, vol. 76, 1998, pages 25 - 32
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 21, no. 18, 2011, pages 5633 - 5637
DE MELLO H ET AL: "Antileishmanial Pyrazolopyridine Derivatives: Synthesis and Structure?Activity Relationship Analysis", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 47, no. 22, 1 January 2004 (2004-01-01), pages 5427 - 5432, XP002545174, ISSN: 0022-2623, DOI: 10.1021/JM0401006 *
DE RYCKER ET AL., ANTIMICROB AGENTS CHEMOTHER., vol. 57, no. 7, 9 April 2013 (2013-04-09), pages 2913 - 22
DRUGS OF TODAY, vol. 19, no. 9, 1983, pages 499 - 538
E.W. MARTIN: "Remington's Pharmaceutical Sciences"
ELTAHIR A. G. KHALIL; TEKLU WELDEGEBREAL; BRIMA M. YOUNIS ET AL.: "Safety and Efficacy of Single Dose versus Multiple Doses of AmBisome@ for Treatment of Visceral Leishmaniasis in Eastern Africa: A Randomised Trial", PLOS NEGLECTED TROPICAL DISEASES, 16 January 2014 (2014-01-16)
H. BUNDGAARD: "Design of Prodrugs", 1985, ELSEVIER
HAILU A; MUSA A; WASUNNA M; BALASEGARAM M; YIFRU S ET AL.: "Geographical Variation in the Response of Visceral Leishmaniasis to Paromomycin in East Africa: A Multicentre, Open-Label, Randomized Trial", PLOS NEGL TROP DIS, vol. 4, no. 10, 2010, pages E709
LAURA A. T. CLEGHORN ET AL: "Identification of Inhibitors of the Leishmania cdc2-Related Protein Kinase CRK3", CHEMMEDCHEM, vol. 6, no. 12, 9 December 2011 (2011-12-09), pages 2214 - 2224, XP055022427, ISSN: 1860-7179, DOI: 10.1002/cmdc.201100344 *
RADEK JORDA ET AL: "Anti-leishmanial activity of disubstituted purines and related pyrazolo[4,3-]pyrimidines", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, AMSTERDAM, NL, vol. 21, no. 14, 20 May 2011 (2011-05-20), pages 4233 - 4237, XP028234387, ISSN: 0960-894X, [retrieved on 20110527], DOI: 10.1016/J.BMCL.2011.05.076 *
RAM VISHNU J ET AL: "Synthesis of functionalized pyrazoles and pyrazolo(3,4-d)pyrimidines as potential leishmanicides", INDIAN JOURNAL OF CHEMISTRY. SECTION B, COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH (C S I R), IN, vol. 34, no. 6, 1 January 1995 (1995-01-01), pages 521 - 524, XP009188765, ISSN: 0376-4699 *
SEIFERT K.: "Structures, Targets and Recent Approaches in Anti-Leishmanial Drug Discovery and Development", OPEN MED CHEM J., vol. 5, 2011, pages 31 - 39
T. W. GREENE: "Protective Groups in Organic Synthesis", 2006, J. WILEY AND SONS

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020123272A1 (fr) 2018-12-12 2020-06-18 Merck Sharp & Dohme Corp. Inhibiteurs pde9 de pyrazolopyrimidine
WO2025133395A1 (fr) 2023-12-22 2025-06-26 Forx Therapeutics Ag Composés inhibiteurs bicycliques (hétéro)arylène wrn

Also Published As

Publication number Publication date
GB201501115D0 (en) 2015-03-11

Similar Documents

Publication Publication Date Title
CN111163766A (zh) Ahr抑制剂和其用途
JP2023540081A (ja) キノリンｃｇａｓアンタゴニスト化合物
KR20070026414A (ko) Ｈｉｖ 인테그라제 억제제
JP7777596B2 (ja) Ｃｄ３８阻害剤としてのキノリン及びアザキノリン
IL307258A (en) NEK7 inhibitors
EP4217356B1 (fr) Inhibiteurs non covalents de la kinase cycline-dépendante 7 (cdk7)
AU2016269626B2 (en) Imidazo[1,2-b][1,2,4]triazine derivatives as antiparasitic agents
CA2994997C (fr) Composes pour traiter des maladies parasites
WO2016116752A1 (fr) Pyrazolopyrimidines anti-leishmaniose
EP3247713B1 (fr) Dérivé de pyrazolo [3,4-d]pyrimidine et son utilisation pour le traitement de la leishmaniose
HK1238643B (en) Pyrazolo[3,4-d]pyrimidin derivative and its use for the treatment of leishmaniasis

Legal Events

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

Ref document number: 16702443

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16702443

Country of ref document: EP

Kind code of ref document: A1