WO2014072419A1 - Nouveaux composés anti-vih - Google Patents

Nouveaux composés anti-vih Download PDF

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Publication number
WO2014072419A1
WO2014072419A1 PCT/EP2013/073288 EP2013073288W WO2014072419A1 WO 2014072419 A1 WO2014072419 A1 WO 2014072419A1 EP 2013073288 W EP2013073288 W EP 2013073288W WO 2014072419 A1 WO2014072419 A1 WO 2014072419A1
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Prior art keywords
mmol
list
compounds
dafpy
amino
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PCT/EP2013/073288
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English (en)
Inventor
Philippe Franck
Jan Heeres
Bert Maes
Serguei Sergueev
Ashok Kumar YADAV
Paulus Joannes Lewi
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Universiteit Antwerpen
Heeres Consulting Cv
Shakturana Cv
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Publication of WO2014072419A1 publication Critical patent/WO2014072419A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms

Definitions

  • the present invention relates to the field of HIV-1 infections, and in particular provides novel compounds containing fluorine on the Central ring.
  • the compounds according to this invention are very suitable for the prevention and/or treatment of HIV-1 infection and in particular show a higher activity against NNRTI-resistant strains of HIV-1.
  • HAART consists of the combination of several active components belonging to different classes of anti-HIV compounds such as protease inhibitors (PI), nucleoside reverse transcriptase inhibitors (NRTI) and non-nucleoside reverse transcriptase inhibitors (NNRTI).
  • PI protease inhibitors
  • NRTI nucleoside reverse transcriptase inhibitors
  • NRTI non-nucleoside reverse transcriptase inhibitors
  • HIV-1 reverse transcriptase is one of the most important viral enzymes and plays a unique role in the HIV-1 life cycle. It has two known drug-target sites, the substrate catalytic site and an allosteric site that is distinct from, but located closely to, the substrate site.
  • NRTIs Non-nucleoside reverse transcriptase inhibitors
  • NNRTIs interact with the allosteric site in a non-competitive manner to distort the enzyme's active conformation and thus disrupt the function of the enzyme. It is demonstrated by XRD analysis, that many NNRTIs form a hydrogen bond with a K101 amino acid residue in the reverse transcriptase binding site.
  • DAPY di(arylamino)pyrimidine
  • Etravirine fig.
  • Etravirine exhibits high potency against wild- type and a number of mutated viral strains with nanomolar EC 50 values and has a high genetic barrier to delay the emergence of drug-resistance.
  • the success of Etravirine greatly encouraged further research to explore additional novel NNRTIs.
  • the most advanced NNRTI in development is another DAPY derivative Rilpivirine (fig. 1 B) which was approved by the FDA in May 2011 . It showed better potency and pharmacological profiles than Etravirine, and features the same hydrogen bonding sites as present in the drug Etravirine (WO2002078708).
  • NRTIs non-nucleoside reverse transcriptase inhibitors
  • the proposed new compounds are represented by the general formula (I) as specified herein below; and all contain a central aromatic or azaheteroaromatic ring (Central ring) bearing the two aryl substituents (will be referred to as Eastern and Western rings, according to the terminology used in the literature for analogous compounds) connected to the Central ring by an -NH- or -O- linker. All compounds feature an F atom in the specified position of the Central ring.
  • the novel compounds can be further subdivided into 3 major groups i.e.
  • DAFPY 2,6-di(arylamino)-3-fluoropyridine
  • DAFPYM derivatives featuring central pyrimidine
  • DAFB derivatives featuring central benzene
  • WO2009132202 discloses macrocyclic compounds having a F atom on the central ring, for the treatment of JAK/ALK associated diseases (including HIV), however, these compounds differ from the compounds according to this invention, in the fact that they are macrocyclic, and in that none of said compounds have actually been shown to be effective against HIV.
  • the present invention thus discloses compounds which differ from prior art compounds in both structure and/or pharmacological activity.
  • FIG. 1 Prior Art DAPY compounds.
  • the invention is based on novel compounds, which contain a halogen atom, in particular an F atom on the central ring, at the position as specified herein below. Surprisingly, the novel compounds of this present invention showed higher activity against NNRTI-resistant viruses of HIV-1 .
  • the invention provides a compound of Formula (I) or a stereoisomer, tautomer, racemic, metabolite, pro-or predrug, salt, hydrate, or solvate thereof,
  • X and Y are each independently selected from the list comprising N or C;
  • Z is selected from the list comprising -O- and -NH-;
  • R 7 is selected from the list comprising -OR 8 , NR 9 R 10 ;
  • R 8 , R 9 and R 10 are each independently selected from the list comprising -H and C-i- 6 alkyl; and Wherein either
  • R 1 , R 5 and R 6 are not -H ;
  • R 2 , R 3 and R 4 are not -H
  • this invention provides a compound of formula (la) or a stereoisomer, tautomer, racemic, metabolite, pro-or predrug, salt, hydrate, or solvate thereof,
  • X and Y are each independently selected from the list comprising N or C;
  • Z is selected from the list comprising -O- and -NH-;
  • R 7 is selected from the list comprising -OR 8 , NR 9 R 10 ;
  • R 8 , R 9 and R 10 are each independently selected from the list comprising -H and Ci-ealkyl.
  • this invention provides a compound of Formula (lb) or a stereoisomer, tautomer, racemic, metabolite, pro-or predrug, salt, hydrate, or solvate thereof,
  • X and Y are each independently selected from the list comprising N or C;
  • Z is selected from the list comprising -O- and -NH-;
  • R 7 is selected from the list comprising -OR 8 , NR 9 R 10 ;
  • R 8 , R 9 and R 10 are each independently selected from the list comprising -H and Ci. 6 alkyl.
  • this invention provides a compound as defined herein above, wherein the optionally substituted Ci-ealkyl, -C 2 . 6 alkenyl, -C 2 . 6 alkynyl or -C-
  • . 6 alkoxy as defined in any one of R 1 -R 6 is substituted with one or more substituents selected from the list comprising -halo, -CN, and -(C 0)-R 11 : wherein R 11 is selected from the list comprising -OR 12 and -NR 13 R 14 ; and wherein R 2 , R 3 and R 4 are each independently selected from the list comprising -H and d- 6 alkyl.
  • this invention provides a compound as specified above, wherein at least one of the following applies:
  • X and Y are each N;
  • X and Y are each C
  • X is N and Y is C;
  • the present invention provides a compound as specified above, wherein R is -CN.
  • this invention provides a composition comprising a compound according to this invention.
  • This invention further provides a compound or a composition according to this invention, for use as a medicament.
  • This invention in particular provides a compound or composition according to this invention, for use in the prevention and/or treatment of HIV infections in a subject in need thereof.
  • this invention provides the use of a compound or composition according to this invention as a non-nucleoside reverse transcriptase inhibitor.
  • this invention provides a method for the prevention and/or treatment of HIV infections; said method comprising administering to a subject in need thereof a compound or a composition according to this invention.
  • the present invention provides a compound of Formula (I) or a stereoisomer, tautomer, racemic, metabolite, pro-or predrug, salt, hydrate, or solvate thereof,
  • X and Y are each independently selected from the list comprising N or C;
  • Z is selected from the list comprising -O- and -NH-;
  • R 7 is selected from the list comprising -OR 8 , NR 9 R 10 ;
  • R 8 , R 9 and R 10 are each independently selected from the list comprising -H and Ci. 6 alkyl; and Wherein either
  • R , R 5 and R 6 are not -H ;
  • R 2 , R 3 and R 4 are not -H
  • alkyl by itself or as part of another substituent refers to fully saturated hydrocarbon radicals.
  • alkyl groups of this invention comprise from 1 to 6 carbon atoms.
  • Alkyl groups may be linear or branched and may be substituted as indicated herein.
  • the subscript refers to the number of carbon atoms that the named group may contain.
  • C h alky! means an alkyl of one to six carbon atoms.
  • alkyl groups are methyl, ethyl, n-propyl, i-propyl, butyl, and its isomers (e.g.
  • C C 6 alkyl includes all linear, branched, or cyclic alkyl groups with between 1 and 6 carbon atoms, and thus includes methyl, ethyl, n-propyl, i-propyl, butyl and its isomers (e.g. n-butyl, i-butyl and t-butyl); pentyl and its isomers, hexyl and its isomers, cyclopentyl, and cyclohexyl.
  • alkenyl means straight-chain, cyclic, or branched-chain hydrocarbon radicals containing at least one carbon-carbon double bond.
  • alkenyl radicals include ethenyl, E- and Z-propenyl, isopropenyl, E- and Z-butenyl, E- and Z-isobutenyl, E- and Z-pentenyl, E- and Z-hexenyl, ⁇ , ⁇ -, ⁇ , ⁇ -, ⁇ , ⁇ -hexadienyl, and the like.
  • An optionally substituted alkenyl refers to an alkenyl having optionally one or more substituents (for example 1 , 2, 3 or 4), selected from those defined above for substituted alkyl.
  • alkynyl as used herein, unless otherwise indicated, means straight-chain or branched- chain hydrocarbon radicals containing at least one carbon-carbon triple bond. Examples of alkynyl radicals include ethynyl, propynyl, isopropynyl, butynyl, pentynyl, hexynyl, and the like.
  • An optionally substituted alkynyl refers to an alkynyl having optionally one or more substituents (for example 1 , 2, 3 or 4), selected from those defined above for substituted alkyl.
  • alkoxy refers to a radical having the Formula -OR b wherein R b is alkyl.
  • alkoxy is C1-C10 alkoxy, C C 6 alkoxy, or C1-C4 alkoxy.
  • suitable alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec- butoxy, tert-butoxy, pentyloxy and hexyloxy.
  • halo or halogen as a group or part of a group is generic for fluoro, chloro, bromo, or iodo, as well as any suitable isotope thereof.
  • substituted is meant to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group, provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic and/or diagnostic agent
  • groups may be optionally substituted, such groups may be substituted once or more, and preferably once, or twice. Substituents may be selected from, those defined above for substituted alky I.
  • alkyl, aryl, or cycloalkyl each being optionally substituted with” or “alkyl, aryl, or cycloalkyl, optionally substituted with” refers to optionally substituted alkyl, optionally substituted aryl and optionally substituted cycloalkyl.
  • the compounds of the invention may exist in the form of different isomers and/or tautomers, including but not limited to geometrical isomers, conformational isomers, E/Z-isomers, stereochemical isomers (i.e. enantiomers and diastereoisomers) and isomers that correspond to the presence of the same substituents on different positions of the rings present in the compounds of the invention. All such possible isomers, tautomers and mixtures thereof are included within the scope of the invention.
  • the term "compounds of the invention” or a similar term is meant to include the compounds of general Formula I and any subgroup thereof.
  • This term also refers to the compounds as depicted in Tables 2-5, their derivatives, /v-oxides, salts, solvates, hydrates, stereoisomeric forms, racemic mixtures, tautomeric forms, optical isomers, analogues, pro-drugs, esters, and metabolites, as well as their quaternized nitrogen analogues.
  • the /V-oxide forms of said compounds are meant to comprise compounds wherein one or several nitrogen atoms are oxidized to the so-called /v-oxide.
  • a compound means one compound or more than one compound.
  • the present invention provides compounds of (la) or a stereoisomer, tautomer, racemic, metabolite, pro-or predrug, salt, hydrate, or solvate thereof,
  • X and Y are each independently selected from the list comprising N or C;
  • Z is selected from the list comprising -O- and -NH-;
  • R 7 is selected from the list comprising -OR 8 , NR 9 R 10 ;
  • R 8 , R 9 and R 10 are each independently selected from the list comprising -H and Ci. 6 alkyl.
  • the present invention provides compounds compound of Formula (lb) or a stereoisomer, tautomer, racemic, metabolite, pro-or predrug, salt, hydrate, or solvate thereof,
  • X and Y are each independently selected from the list comprising N or C;
  • Z is selected from the list comprising -O- and -NH-;
  • R 7 is selected from the list comprising -OR 8 , NR 9 R 10 ;
  • R 8 , R 9 and R 10 are each independently selected from the list comprising -H and Ci. 6 alkyl.
  • the present invention provides compounds as defined herein above wherein X and Y are each N.
  • X and Y are each N.
  • Exemplary compounds and reaction schemes for synthesis of compounds according to this embodiment are detailed in table 5.
  • the present invention provides compounds as defined herein above wherein X and Y are each C.
  • X and Y are each C.
  • Exemplary compounds and reaction schemes for synthesis of compounds according to this embodiment are detailed in table 4.
  • the present invention provides compounds as defined herein above, wherein R 1 is -CN.
  • R 1 is -CN.
  • Exemplary compounds and reaction schemes for synthesis of compounds according to this embodiment are detailed in tables 2-5.
  • the present invention provides compounds as defined herein above, wherein Z is N .
  • Exemplary compounds and reaction schemes for synthesis of compounds according to this embodiment are detailed in tables 2, 4 and 5.
  • the present invention provides compounds as defined herein above, wherein Z is O.
  • Exemplary compounds and reaction schemes for synthesis of compounds according to this embodiment are detailed in table 3.
  • the present invention provides the compounds of formula (I), (la) or (lb) as defined herein above, wherein one or more of the following restrictions apply;
  • e alkenyl
  • R 7 is -OR 8 with R 8 representing - C-
  • the present invention provides the compounds of formula (la) as defined herein above, wherein one or more of the following restrictions apply;
  • R 7 is -OR 8 with R 8 representing - Ci_ 6 alkyl, in particular R 8 representing -CH 3
  • the present invention provides the compounds of formula (lb) as defined herein above, wherein one or more of the following restrictions apply;
  • R 1 , R 2 , R 3 , and R 4 are each independently selected from the list comprising -CN, -halo, -
  • R 7 is -OR 8 with R 8 representing - Ci_ 6 alkyl, in particular R 8 representing -CH 3
  • the compounds of the present invention can be prepared according to the reaction schemes provided in the examples hereinafter, but those skilled in the art will appreciate that these are only illustrative for the invention and that the compounds of this invention can be prepared by any of several standard synthetic processes commonly used by those skilled in the art of organic chemistry.
  • This invention further provides a composition comprising a compound according to this invention.
  • this invention provides a compound or composition according to this invention for use as a medicament.
  • This invention also provides a compound or composition according to this invention for use in the prevention and/or treatment of HIV infections in a subject in need thereof.
  • this invention provides the use of a compound or composition according to this invention as a non-nucleoside reverse transcriptase inhibitor.
  • this invention provides a method for the prevention and/or treatment of HIV infections; said method comprising administering to a subject in need thereof a compound or composition according to this invention.
  • Compounds of formula (I), (la) and (lb) a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, are inhibitors of non-nucleoside reverse transcriptase inhibitor and are thus believed to be of potential use in the prevention and/or treatment of HIV infections.
  • the methods of the present invention can be utilized in a variety of settings, including, for example, in selecting the optimal treatment course for a patient, in predicting the likelihood of success when treating an individual patient with a particular treatment regimen, in assessing disease progression, in monitoring treatment efficacy, in determining prognosis for individual patients and in assessing predisposition of an individual to benefit from a particular therapy.
  • the compounds of the invention may be used as a free acid or base, and/or in the form of a pharmaceutically acceptable acid-addition and/or base-addition salt (e.g. obtained with non-toxic organic or inorganic acid or base), in the form of a hydrate, solvate and/or complex, and/or in the form or a pro-drug or pre-drug, such as an ester.
  • a pharmaceutically acceptable acid-addition and/or base-addition salt e.g. obtained with non-toxic organic or inorganic acid or base
  • solvate includes any combination which may be formed by a compound of this invention with a suitable inorganic solvent (e.g. hydrates) or organic solvent, such as but not limited to alcohols, ketones, esters and the like.
  • suitable inorganic solvent e.g. hydrates
  • organic solvent such as but not limited to alcohols, ketones, esters and the like.
  • the pharmaceutically acceptable salts of the compounds according to the invention include the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases.
  • acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalene-sulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tos, to
  • Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.
  • the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl-bromides and others.
  • Other pharmaceutically acceptable salts include the sulfate salt ethanolate and sulfate salts.
  • the compounds of the inventions may be formulated as a pharmaceutical preparation or pharmaceutical composition comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and optionally one or more further pharmaceutically active compounds.
  • such a formulation may be in a form suitable for oral administration, for parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), for administration by inhalation, by a skin patch, by an implant, by a suppository, etc..
  • Such suitable administration forms which may be solid, semi- solid or liquid, depending on the manner of administration - as well as methods and carriers, diluents and excipients for use in the preparation thereof, will be clear to the skilled person; reference is again made to for instance US-A-6,372,778, US-A-6,369,086, US-A-6,369,087 and US-A-6,372,733, as well as to the standard handbooks, such as the latest edition of Remington's Pharmaceutical Sciences.
  • Such preparations include tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, creams, lotions, soft and hard gelatin capsules, suppositories, eye drops, sterile injectable solutions and sterile packaged powders (which are usually reconstituted prior to use) for administration as a bolus and/or for continuous administration, which may be formulated with carriers, excipients, and diluents that are suitable per se for such formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, methyl- and propy
  • the formulations can optionally contain other pharmaceutically active substances (which may or may not lead to a synergistic effect with the compounds of the invention) and other substances that are commonly used in pharmaceutical formulations, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, desintegrants, bulking agents, fillers, preserving agents, sweetening agents, flavoring agents, flow regulators, release agents, etc..
  • the compositions may also be formulated so as to provide rapid, sustained or delayed release of the active compound(s) contained therein, for example using liposomes or hydrophilic polymeric matrices based on natural gels or synthetic polymers.
  • the present invention encompasses a pharmaceutical composition comprising an effective amount of a compound according to the invention with a pharmaceutically acceptable cyclodextrin.
  • co-solvents such as alcohols may improve the solubility and/or the stability of the compounds.
  • addition of salts of the compounds of the invention can be more suitable due to their increased water solubility.
  • the preparations may be prepared in a manner known per se, which usually involves mixing at least one compound according to the invention with the one or more pharmaceutically acceptable carriers, and, if desired, in combination with other pharmaceutical active compounds, when necessary under aseptic conditions.
  • a manner known per se which usually involves mixing at least one compound according to the invention with the one or more pharmaceutically acceptable carriers, and, if desired, in combination with other pharmaceutical active compounds, when necessary under aseptic conditions.
  • the pharmaceutical preparations of the invention are preferably in a unit dosage form, and may be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable single-dose or multi-dose holder or container (which may be properly labeled); optionally with one or more leaflets containing product information and/or instructions for use.
  • unit dosages will contain between 1 and 1000 mg, and usually between 5 and 500 mg, of the at least one compound of the invention, e.g. about 10, 25, 50, 100, 200, 300 or 400 mg per unit dosage.
  • the compounds can be administered by a variety of routes including the oral, rectal, ocular, transdermal, subcutaneous, intravenous, intramuscular or intranasal routes, depending mainly on the specific preparation used and the condition to be treated or prevented, and with oral and intravenous administration usually being preferred.
  • the at least one compound of the invention will generally be administered in an "effective amount", by which is meant any amount of a compound of Formula or any subgroup thereof that, upon suitable administration, is sufficient to achieve the desired therapeutic or prophylactic effect in the individual to which it is administered.
  • such an effective amount will usually be between 0.01 to 1000 mg per kilogram body weight day of the patient per day, more often between 0.1 and 500 mg, such as between 1 and 250 mg, for example about 5, 10, 20, 50, 100, 150, 200 or 250 mg, per kilogram body weight day of the patient per day, which may be administered as a single daily dose, divided over one or more daily doses, or essentially continuously, e.g. using a drip infusion.
  • the amount(s) to be administered, the route of administration and the further treatment regimen may be determined by the treating clinician, depending on factors such as the age, gender and general condition of the patient and the nature and severity of the disease/symptoms to be treated.
  • said pharmaceutical composition can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms.
  • the present invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly.
  • compositions of the present invention can be mixed with suitable additives, such as excipients, stabilizers, or inert diluents, and brought by means of the customary methods into the suitable administration forms, such as tablets, coated tablets, hard capsules, aqueous, alcoholic, or oily solutions.
  • suitable inert carriers are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, or starch, in particular, corn starch.
  • the preparation can be carried out both as dry and as moist granules.
  • Suitable oily excipients or solvents are vegetable or animal oils, such as sunflower oil or cod liver oil.
  • Suitable solvents for aqueous or alcoholic solutions are water, ethanol, sugar solutions, or mixtures thereof.
  • Polyethylene glycols and polypropylene glycols are also useful as further auxiliaries for other administration forms.
  • these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.
  • the compounds and compositions of the invention are used orally or parenterally.
  • Example 1 General synthesis route of DAFPY compounds (DiAminoarvlFluoroPYridines)
  • anilines used in the synthesis of the DAFPY compounds were commercially available, such as 4-cyano, 4-fluoro and 4-chloro anilines (2a-c).
  • Other anilines were prepared from commercial precursors via a Heck coupling with the corresponding bromo derivatives 5. The latter were commercially available with the exception of 4-bromo-2-fluoro-6-methylaniline 5d, which was prepared by bromination of commercially available 2-fluoro-6-methylaniline (Scheme 3).
  • DAFPY analogues featuring an O rather than an NH linkage between western and central rings were prepared using a Pd- catalyzed C-0 bond formation reaction of 3a with phenol and 2,4,6-trimethylphenol, respectively, instead of an aniline (Scheme 4).
  • DAFB compounds according to this invention were prepared, starting from commercially available 2-bromo-4-chloro-1 -fluorobenzene (6), as shown below (Scheme 5) and is based on the difference in reactivities of a bromine atom and a chlorine atom in Pd-catalyzed amination reactions.
  • the bromine atom in 6 was selectively substituted to produce 4-(5-chloro-2- fluorophenylamino)benzonitrile (7).
  • the chlorine in 7 was substituted to produce the DAFB derivatives.
  • cheme 5 Synthesis of di(arylamino)fluorobenzene derivatives (DAFB).
  • DAFPYM DAFPY analogues featuring a pyrimidine as central ring
  • DAFPYM DAFPYM
  • Two derivatives have been prepared via a route which is similar to that for the DAFPYs (pyridine series described above).
  • reaction of 2,4-dichloro-5-fluoropyrimidine (8) with 4-aminobenzonitrile 2a produced the intermediate 2-arylamino-6-chloro-3-fluoropyridine 9 as a single regioisomer.
  • a second Pd- catalyzed amination reaction with the corresponding aniline provided the target DAFPYM-1 and DAFPYM-2 (Scheme 6).
  • Scheme 6 Synthesis of DAFPY analogues featuring a central pyrimidine ring.
  • Example 5 In vitro screening against wild type and/or mutant HIV and cytotoxicity Activity and cytotoxicity of DAFPYs and their analogues.
  • the JC53-BL cell line also known as the TZM-bl cell line (NIH AIDS Research and Reference Reagent Program, Germantown, USA), was used for the evaluation of drug susceptibility of wild type.
  • TZM-bl cells were cultured in Dulbecco's Minimum Essential Medium (DMEM) (Lonza) containing 10% heat-inactivated FBS and 50 pg gentamycin/mL at 37°C in a humidified 5% C02, 95% air environment. Twice a week the cells were treated with 0.25% trypsin - 1 mM EDTA (Lonza) for 10 minutes.
  • DMEM Dulbecco's Minimum Essential Medium
  • the antiviral activity of the newly designed compounds was measured by pre-incubating ten thousand TZM-bl cells (at 105 cells/mL in culture medium supplemented with 30 g/mL DEAE dextran) in a 96-well plate for 30 minutes at 37°C, 5% C02 in the presence or absence of serial dilutions of the respective compound. Subsequently, 200 TCID50 of wild type or NNRTI-resistant HI -1 was added to each well and cultures were incubated for 48 hours before quantifying luciferase activity. Each condition was evaluated in triplicate wells and in at least three independent experiments. The antiviral activity of the compound was expressed as the percentage of viral inhibition compared to the untreated controls and subsequently plotted against the compound concentration. Non-linear regression analysis was used to calculate the 50% inhibitory concentration (IC50) based on at least three independent measurements and using GraphPad Prism version 5.03 for Windows (GraphPad Software, San Diego, CA, USA).
  • the Water Soluble Tetrazolium-1 (WST-1 ) Cell Proliferation Assay is a colorimetric assay for the measurement of cell proliferation and viability.
  • the assay is based on the cleavage of the tetrazolium salt WST-1 ((4-[3-(4-iodophenyl)-2-(4-nitrophenyl)- 2H-5-tetrazolio]-1 ,3-benzene disulfonate)) to a formazan dye by a complex cellular mechanism. This bioreduction is largely dependent on the glycolytic production of NAD(P)H in viable cells.
  • the amount of formazan dye formed correlates directly to the number of viable cells in the culture, and can be quantified by measuring the absorbance at 450nm in a multiwell plate reader.
  • TZM-bl cells were seeded in a 96-well plate and cultured for 2 days in the presence of a serial dilution of compound. After this 48h exposure, Cell Proliferation Reagent, WST-1 , was added and absorbance at 450 nm was quantified after 90 min using a microplate reader (BioRad, Tokio, Japan). Each compound was tested in three replicate wells and in at least three independent experiments. The percentage cell viability, compared to untreated controls, was plotted against the compound concentration and non-linear regression analysis was performed using GraphPad Prism version 5.02 for Windows (GraphPad Software, San Diego, CA, USA) to calculate the 50% cytotoxic concentration (CC50).
  • the selectivity index (SI) is defined as CC 50 /EC 50 , where EC 50 is the 50%-effective concentration vs. H IV virus, and CC 50 is the concentration causing death of 50% of the cells.
  • the EC 50 value was determined in Ba-L (subtype B, CCR5) cells and the cytotoxicity CC 50 value in WST-1 cells.
  • 6-Chloro-3-fluoro-A/-mesitylpyridin-2-amine (3g) The general procedure B was followed using Pd(OAc) 2 (0.1 mmol, 22 mg), xantphos (0.120 mmol, 0.069 g), 2,5-dichloro-5-fluoropyridine (2.0 mmol, 0.332 g), 2,4,6-trimethylaniline (2.0 mmol, 0.332 g) and Cs 2 C0 3 (10.0 mmol, 3.26 g).
  • DAFB- 1 4- ⁇ 5-[4-(2-cyanovinyl)-2,6-dimethylphenyl]amino ⁇ -2-fluorophenylaminobenzonitrile (DAFB- 1): The general procedure C was followed using Pd(OAc) 2 (0.025 mmol, 5.61 mg), X-phos (0.03 mmol, 14 mg), 4-(5-chloro-2-fluorophenylamino)benzonitrile 7 (0.5 mmol, 123 mg), 3-(4-amino-3,5- dimethylphenylacrylonitrile (0.6 mmol, 103 mg) and Cs 2 C0 3 (2.50 mmol, 0.82 g).
  • WO2009132202 Macrocyclic compounds as kinase inhibitors and their preparation, pharmaceutical compositions and their use in the treatment of JAK/ALK-associated diseases.

Abstract

La présente invention concerne le domaine des infections par le VIH-1, et en particulier de nouveaux composés contenant du fluor sur le cycle central. Les composés selon la présente invention sont très appropriés pour la prévention et/ou le traitement d'infections par le VIH-1 et présentent en particulier une plus grande activité contre des souches du VIH-1 résistantes aux NNRTI.
PCT/EP2013/073288 2012-11-08 2013-11-07 Nouveaux composés anti-vih WO2014072419A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2016050171A1 (fr) * 2014-09-29 2016-04-07 山东轩竹医药科技有限公司 Inhibiteur de la kinase du lymphome anaplasique polycyclique
CN106008506A (zh) * 2016-06-27 2016-10-12 山东大学 取代嘌呤类衍生物及其制备方法与应用
CN106279150A (zh) * 2015-06-10 2017-01-04 中国人民解放军军事医学科学院毒物药物研究所 吡啶稠环类化合物及其制备方法和用途
CN111187222A (zh) * 2020-01-16 2020-05-22 山东大学 一种取代嘧啶类衍生物及其制备方法和应用

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016050171A1 (fr) * 2014-09-29 2016-04-07 山东轩竹医药科技有限公司 Inhibiteur de la kinase du lymphome anaplasique polycyclique
JP2017530139A (ja) * 2014-09-29 2017-10-12 シュエンジュウ・ファーマ・カンパニー・リミテッド 未分化リンパ腫キナーゼの多環状阻害剤
US10011592B2 (en) 2014-09-29 2018-07-03 Xuanzhu Pharma Co., Ltd. Polycyclic inhibitor of anaplastic lymphoma kinase
CN106279150A (zh) * 2015-06-10 2017-01-04 中国人民解放军军事医学科学院毒物药物研究所 吡啶稠环类化合物及其制备方法和用途
CN106279150B (zh) * 2015-06-10 2018-02-09 中国人民解放军军事医学科学院毒物药物研究所 吡啶稠环类化合物及其制备方法和用途
CN106008506A (zh) * 2016-06-27 2016-10-12 山东大学 取代嘌呤类衍生物及其制备方法与应用
CN111187222A (zh) * 2020-01-16 2020-05-22 山东大学 一种取代嘧啶类衍生物及其制备方法和应用
CN111187222B (zh) * 2020-01-16 2021-09-24 山东大学 一种取代嘧啶类衍生物及其制备方法和应用

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