WO2005016344A1 - Dérivés de pipérazine pour le traitement des infections à vih - Google Patents

Dérivés de pipérazine pour le traitement des infections à vih Download PDF

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Publication number
WO2005016344A1
WO2005016344A1 PCT/IB2004/002562 IB2004002562W WO2005016344A1 WO 2005016344 A1 WO2005016344 A1 WO 2005016344A1 IB 2004002562 W IB2004002562 W IB 2004002562W WO 2005016344 A1 WO2005016344 A1 WO 2005016344A1
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WO
WIPO (PCT)
Prior art keywords
compound
methyl
preparation
piperazin
benzoyl
Prior art date
Application number
PCT/IB2004/002562
Other languages
English (en)
Inventor
Donald Stuart Middleton
Charles Eric Mowbray
Peter Thomas Stephenson
David Howard Williams
Original Assignee
Pfizer Limited
Pfizer Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB0319149A external-priority patent/GB0319149D0/en
Priority claimed from GB0322153A external-priority patent/GB0322153D0/en
Priority claimed from GB0406656A external-priority patent/GB0406656D0/en
Priority to AU2004264724A priority Critical patent/AU2004264724A1/en
Priority to CA002534866A priority patent/CA2534866A1/fr
Priority to JP2006523071A priority patent/JP2007502266A/ja
Priority to EA200600225A priority patent/EA200600225A1/ru
Priority to EP04744202A priority patent/EP1663234A1/fr
Application filed by Pfizer Limited, Pfizer Inc. filed Critical Pfizer Limited
Priority to AP2006003514A priority patent/AP2006003514A0/xx
Priority to MXPA06001762A priority patent/MXPA06001762A/es
Priority to BRPI0413469-9A priority patent/BRPI0413469A/pt
Publication of WO2005016344A1 publication Critical patent/WO2005016344A1/fr
Priority to IL173365A priority patent/IL173365A0/en
Priority to IS8275A priority patent/IS8275A/is
Priority to TNP2006000051A priority patent/TNSN06051A1/fr
Priority to NO20061170A priority patent/NO20061170L/no

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    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
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    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
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Definitions

  • This " invention relates to piperazine derivatives, to processes for their preparation, to compositions containing them and to their use. More particularly, the present invention relates to the use of piperazine derivatives in the treatment of HIV, such as HIV-1 , and genetically related retroviral infections (and the resulting acquired immune deficiency syndrome, AIDS). Entry of HIV-1 into a target cell requires cell-surface CD4 and additional host cell cof actors. It is recognised that for efficient entry into target cells, human immunodeficiency viruses require a chemokine receptor, such as CCR5 or CXCR-4, as well as the primary receptor CD4.
  • chemokine receptor such as CCR5 or CXCR-4
  • the principal cofactor for the entry mediated by the envelope glycoproteins of primary macrophage-trophic strains of HIV-1 is CCR5, a receptor for the ⁇ - chemokines RANTES, MIP-1 ⁇ and MIP-1 ⁇ (Deng et al., 1996, Nature, 38, 661 -666). HIV attaches to the CD4 molecules on target cells through a region of its envelope protein, gp120. It is believed that the CD4 binding site on the gp120 of HIV interacts with the CD4 molecule on the target cell surface and undergoes conformational changes, which allow it to bind to further cell- surface receptors such as CCR5 or CXCR-4.
  • R 1 is phenyl or pyridyl, wherein said phenyl or pyridyl is optionally substituted by 1 or 2 atoms or groups selected from halo, CrC 6 alkoxy, CF 3 , OCF 3 , or CN;
  • R 2 and R 3 are independently H, or CrC 6 alkyl
  • R 4 is C C 6 alkyl
  • R 5 is phenyl; naphthyl; or a C-linked, 6 to 10 membered, mono- or bicyclic, aromatic or partially saturated, heterocycle wherein said heterocycle contains 1 to 4 nitrogen heteroatom(s), 1 or 2 nitrogen and 1 oxygen heteroatoms, or 1 or 2 nitrogen and 1 sulphur heteroatoms; wherein said phenyl, napthyl or heterocycle is optionally substituted by 1 to 3 atoms or groups selected from CrC 6 alkyl, C C 6 fluoroalkyl, C 3 -C 7 cycloalkyl, phenyl, OH, CrC 6 alkoxy, CrC 6 alkoxy C r C 6 alkyl, OC C 6 fluoroalkyl- C 0 -C 2 alkylene NR 6 R 7 , halo, C 0 -C- 2 alkylene CN, C 0 -C 2 alkylene C0 2 R 8 , C 0 -C 2 alkylene CONR 6 R 7 ,
  • R 6 and R 7 are independently H, C r C 6 alkyl, C 3 -C 7 cycloalkyl, phenyl or R 10 ; or when taken together with the nitrogen to which they are attached form an optionally substituted azetidine, pyrrolidine, piperidine, morpholine, or thiomorpholine ring; wherein the said substituents are 1 or 2 groups selected from C ⁇ -C 6 alkyl, or C 0 -C 6 alkylene NH 2 ;
  • R 8 is H, CrC 6 alkyl or phenyl
  • R 9 is C ⁇ -C 6 alkyl or phenyl
  • R > 10 is imidazolyl, pyrazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, indazolyl, quinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl, each optionally substituted by 1 to 3 atoms or groups selected from C C 6 alkyl, C C 6 alkoxy, cyano or halo.
  • alkyl as a group or part of a group includes straight chain - and branched groups. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl.
  • C 3 - 7 cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • halo means fluoro, chloro, bromo or iodo.
  • R 1 is phenyl or pyridyl, wherein said phenyl or pyridyl is optionally substituted by 1 or 2 atoms or groups selected from halo.
  • R 4 s methyl is yet phenyl or pyridyl, wherein said phenyl or pyridyl is optionally substituted by 1 or 2 atoms or groups selected from halo.
  • R 5 s an optionally substituted phenyl, naphthyl, pyridyl, indazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, benzopiperidinyl or benzoxazolyl; wherein said substituents are 1 to 3 atoms or groups selected from C C 6 alkyl, C C 6 alkoxy, halo, CN, CO 2 R 8 , CONR 6 R 7 , or R 10 .
  • R 5 is an optionally substituted phenyl or pyridyl, wherein said substituents are 1 to 3 groups selected from C C 6 alkoxy, C0 2 R 8 , or CONR 6 R 7 .
  • R 6 is H or C 1 -C 4 alkyl.
  • R 7 is H, C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl.
  • R 8 is C C alkyl.
  • R 10 is imidazolyl, pyrazolyl, triazolyl or oxadiazolyl, each optionally substituted by 1 to 3 atoms or groups selected from C 1 -C 4 alkyl, C C 4 alkoxy, cyano or halo.
  • a compound of formula (la) is imidazolyl, pyrazolyl, triazolyl or oxadiazolyl, each optionally substituted by 1 to 3 atoms or groups selected from C 1 -C 4 alkyl, C C 4 alkoxy, cyano or halo.
  • the compounds of the invention include compounds of formula (I) and pharmaceutically acceptable salts, solvates or derivatives thereof (wherein derivatives include complexes, polymorphs, prodrugs and isotopically-labeled compounds, as well as salts, solvates and salt solvates thereof), and isomers thereof.
  • the compounds of the invention are the compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof, in particular the compounds of formula (I). It is to be understood that the aforementioned compounds of the invention include polymorphs and isomers thereof.
  • Pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts.
  • Examples include the acetate, aspartate, benzoate, besylate, bicarbonate, bisulphate, borate, bromide, camsylate, carbonate, chloride, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrobromide, hydrochloride, hydroiodide, iodide, isethionate, lactate, malate, maleate, malonate, mesylate, " methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, sulphate, tartrate, tosylate and trifluoroacetate salts.
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • suitable salts see “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
  • Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one or more of three methods:
  • drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts.
  • complexes of the pharmaceutical drug which contain two or more organic and/or inorganic components which may be in stoichiometric or non- stoichiometric amounts.
  • the resulting complexes may be ionised, partially ionised, or non-ionised.
  • the compounds of the present invention may have the ability to crystallize in more than one form, a characteristic known as polymorphism, and all such polymorphic forms (“polymorphs”) are encompassed within the scope of the invention.
  • Polymorphism generally can occur as a response to changes in temperature or pressure or both, and can also result from variations in the crystallization process.
  • Polymorphs can be distinguished by various physical characteristics, and typically the x-ray diffraction patterns, solubility behavior, and melting point of the compound are used to distinguish polymorphs.
  • Certain derivatives of compounds of formula (I) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (I) having the desired activity, for example, by hydrolytic cleavage.
  • prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (I) with certain moieties known to those skilled in the art as 'pro- moieties' as described, for example, in "Design of Prodrugs" by H Bundgaard (Elsevier, 1985).
  • prodrugs in accordance with the invention include: (i) where the compound of formula (I) contains a carboxylic acid functionality (-COOH), an ester thereof, for example, replacement of the hydrogen with (C ⁇ -C 6 )alkyl; (ii) where the compound of formula (I) contains an alcohol functionality (-OH), an ether thereof, for example, replacement of the hydrogen with (C ⁇ -C 6 )alkanoyloxymethyl; and (iii) where the compound of formula (I) contains a primary or secondary amino functionality (-NH 2 or -NHR where R ⁇ H), an amide thereof, for example, replacement of one or both hydrogens with (C C ⁇ o)alkanoyl.
  • Some examples of metabolites in accordance with the invention include: (i) where the compound of formula (I) contains a methyl group, an hydroxymethyl derivative thereof (-CH 3 -> -CH 2 OH): (ii) where the compound of formula (I) contains an alkoxy group, an hydroxy derivative thereof (-OR -> -OH); (iii) where the compound of formula (I) contains a tertiary amino group, a secondary amino derivative thereof (-NR 1 R 2 -> -NHR 1 or -NHR 2 );
  • a compound of formula (I) contains an alkenyl or alkenylene group
  • geometric cis/trans (or Z/E) isomers are possible, and where the compound contains, for example, a keto or oxime group or an aromatic moiety, tautomeric isomerism ('tautomerism') may occur. It follows that a single compound may exhibit more than one type of isomerism. Included within the scope of the present invention are all optical isomers, geometric isomers and tautomeric forms of the compounds of formula (I), including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof.
  • Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).
  • HPLC high pressure liquid chromatography
  • racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine.
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
  • Chiral compounds of the invention may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture.
  • Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art - see, for example, "Stereochemistry of Organic Compounds" by E L Eliel (Wiley, New York, 1994).
  • the present invention also includes all pharmaceutically acceptable isotopically-labelled compounds of formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 l and 125 l, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 0 and 18 0, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • isotopically-labelled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease- of incorporation and ready means of detection.
  • Substitution with heavier 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.
  • Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and
  • Particularly preferred compounds of formula (I) include:
  • (2S)-1-[(2/ ?)-4-Benzoyl-2-methyl-piperazin-1-yl]-2-[2-(2H-pyrazol-3-ylamino)- quinolin-5-yloxy]-propan-1 -one; 5- ⁇ (1 S)-2-[(2 ?)-4-Benzoyl-2-methyl-piperazin-1 -yl]-1 -methyl-2-oxo-ethoxy ⁇ - isoquinoline-1 -carboxylic acid methylamide;
  • R 1 to R 9 are as previously defined unless otherwise stated;
  • X is halo or hydroxy;
  • Y is a leaving group, such as chloro, bromo, tosylate, mesylate or hydroxy;
  • DMF is N,N-dimethylformamide;
  • DMSO is dimethylsulphoxide;
  • THF is tetrahydrofuran;
  • WSCDI is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride;
  • DCC is N,N'-dicyclohexylcarbodiimide;
  • HOAT is 1-hydroxy-7- azabenzotriazole;
  • HOBt is 1-hydroxybenzotriazole hydrate;
  • HBTU is 0(1 H- benzotriazol-1-yl)- ⁇ , ⁇ /- ⁇ / ⁇ ,V-tetramethyluronium hexafluorophosphate;
  • PyBOP® is benzo
  • Compounds of formula (I) may be prepared by any methods known for the preparation of compounds of analogous structure.
  • Compounds of formula (I), and intermediates thereto may be prepared according to the schemes that follow. It will be appreciated by those skilled in the art that certain of the procedures described in the schemes for the preparation of compounds of formula (I) or intermediates thereto may not be applicable to some of the possible substituents. It will be further appreciated by those skilled in the art that it may be necessary or desirable to carry out the transformations described in the schemes in a different order from that described, or to modify one or more of the transformations, to provide the desired compound of formula (I).
  • the transformations depicted therein may be effected as follows: (a)-(e) Acid-amine coupling reactions Typically the acid chloride or acid bromide of formulae (V), (VI) or (VIII), and the appropriate piperazine of formulae (IV), (VII) or (IX), optionally with an excess of an acid acceptor such as triethylamine or A/-ethyl- ⁇ /,/V- diisopropylamine, are reacted in a solvent, such as an haloalkane (e.g. dichloromethane) or an ether (e.g. THF) at room temperature for 1-24 hours.
  • a solvent such as an haloalkane (e.g. dichloromethane) or an ether (e.g. THF)
  • the reactions may conveniently be carried out by reacting the relevant piperazine with 1.1 equivalents of the relevant acid chloride in dichloromethane at room temperature for 1 hour.
  • the acid of formulae (V), (VI) or (VIII) activated by suitable reagents such as WSCDI/DCC and HOBt/HOAt, the appropriate piperazine of formulae (IV), (VII) or (IX), and an excess of an acid acceptor such as triethylamine or ⁇ /-ethyl- ⁇ /, ⁇ /-diisopropylamine, are reacted in a solvent such as an haloalkane (e.g. dichloromethane), an ether (e.g.
  • the reactions may conveniently be carried out by reacting the relevant piperazine, 1.4 equivalents of WSCDI, 1.4 equivalents of HOBt, 2.2 equivalents of triethylamine and 1.1 equivalents of the relevant carboxylic acid in dichloromethane at room temperature for 18 hours.
  • the acid of formulae (V), (VI) or (VIII), the appropriate piperazine of formulae (IV), (VII) or (IX), and either HBTU, PyBOP, PyBrOP or Mukaiyama's reagent, and an excess of an acid acceptor such as triethylamine or A/-ethyl- ⁇ /,/V-diisopropyIamine, may be reacted in a solvent such as an haloalkane (e.g. dichloromethane) or an ether (e.g. THF) at room temperature for 4-24 hours.
  • a solvent such as an haloalkane (e.g. dichloromethane) or an ether (e.g. THF)
  • R is a lower alkyl such as d-C ⁇ alkyl.
  • nucleophilic substitution may be effected according to the conditions described for step (f) hereinabove.
  • Ester hydrolysis Typically, compounds of formula (XI), aqueous alkali metal hydroxide solution or aqueous hydrochloric acid solution, and an optional co-solvent such as ethanol or dioxane, are heated at a temperature between 60 and 100°C for 1-18 hours. The reactions may conveniently be carried out by heating compounds of formula (XI) in aqueous 1 N sodium hydroxide solution and dioxane heated at 60 °C for 2 hours.
  • Compounds of formulae (II), (IV) and (VII) are key intermediates and represent a particular aspect of the present invention.
  • Compounds of formulae (III), (V), (VIII), (IX) and (X) are either known compounds or may be prepared by conventional chemistry.
  • the invention provides the following processes for preparing compounds of formula (I). According to a first process (A), compounds of formula (I) may be prepared by coupling an acid of formula (V)
  • compounds of formula (I) may be prepared from other compounds of formula (I) by functional group interconversion under conventional conditions.
  • compounds of formula (I) which contain an ester group may be converted to corresponding compounds of formula (I) which contain a primary or secondary amide group by reacting the former with ammonia or a primary amine respectively.
  • the compounds of the invention inhibit the interaction of gp120 with
  • the invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof for use as a medicament.
  • the invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof for use in the treatment of a HIV, a retroviral infection genetically related to HIV, or AIDS.
  • the invention provides the use of a compound of formula (I) or of a pharmaceutically acceptable salt, solvate or derivative thereof for the manufacture of a medicament for the treatment of a HIV, a retroviral infection genetically related to HIV, or AIDS.
  • the invention provides a method of treatment of a mammal suffering from HIV, a retroviral infection genetically related to HIV, or AIDS which comprises treating said mammal with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof.
  • the compounds of the invention may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose. They may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or in any combination thereof).
  • excipient is used herein to describe any ingredient other than the compound(s) of the invention.
  • excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
  • Pharmaceutical compositions suitable for the delivery of compounds of the invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in 'Remington's Pharmaceutical Sciences', 19th Edition (Mack Publishing Company, 1995).
  • the compounds of the invention may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films (including muco-adhesive), ovules, sprays and liquid formulations.
  • Liquid formulations include suspensions, solutions, syrups and elixirs.
  • Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents.
  • Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • the compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, H (6), 981 -986 by Liang and Chen (2001).
  • the drug may make up from 1 wt% to 80 wt% of the dosage form, more typically from 5 wt% to 60 wt% of the dosage form.
  • tablets generally contain a disintegrant.
  • disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate.
  • the disintegrant will comprise from 1 wt% to 25 wt%, preferably from 5 wt% to 20 wt% of the dosage form.
  • Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose.
  • Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents may comprise from 0.2 wt% to 5 wt% of the tablet, and glidants may comprise from 0.2 wt% to 1 wt% of the tablet.
  • diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. Tablets may
  • Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.
  • Lubricants generally comprise from 0.25 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt% of the tablet.
  • Other possible ingredients include anti-oxidants, colourants, flavours, preservatives and taste-masking agents.
  • Exemplary tablets contain up to about 80% drug, from about 10 wt% to about 90 wt% binder, from about 0 wt% to about 85 wt% diluent, from about 2 wt% to about 10 wt% disintegrant, and from about 0.25 wt% to about 10 wt% lubricant. Tablet blends may be compressed directly or by roller to form tablets.
  • Tablet blends or portions of blends may alternatively be wet-, dry-, or melt- granulated, melt congealed, or extruded before tabletting.
  • the final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.
  • the " formulation of tablets is discussed in "Pharmaceutical Dosage Forms: Tablets, Vol. 1", by H. Lieberman and L. Lachman, Marcel Dekker- N.Y., N.Y., 1980 (ISBN 0-8247-6918-X).
  • Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Verma et al, Pharmaceutical Technology
  • the compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ.
  • Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • a suitable vehicle such as sterile, pyrogen-free water.
  • the preparation of parenteral formulations under sterile conditions for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • the solubility of compounds of the invention used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
  • Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the compound.
  • examples of such formulations include drug- coated sterits and PGLA microspheres.
  • the compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol.
  • Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999).
  • Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. PowderjectTM, BiojectTM, etc.) injection.
  • Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane.
  • a suitable propellant such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane.
  • the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
  • the pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound comprising, for example, ethanol (optionally, aqueous ethanol) or a suitable alternative agent for dispersing, solubilising, or extending release of the compound, the propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • the drug product Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns).
  • Capsules made, for example, from gelatin or HPMC
  • blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as /-leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate, preferably the latter.
  • suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
  • a suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1 ⁇ g to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1 ⁇ l to 100 ⁇ l.
  • a typical formulation may comprise a compound of the invention, propylene glycol, sterile water, ethanol and sodium chloride.
  • Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
  • Suitable flavours such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium
  • Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, poly(DL-lactic- coglycolic acid (PGLA).
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the dosage unit is determined by means of a valve which delivers a metered amount.
  • Units in accordance with the invention are typically arranged to administer a metered dose or "puff" containing from 1 ⁇ g to 10mg of the compound of the invention.
  • the overall daily dose will typically be in the range 1 ⁇ g to 200mg which may be administered in a single dose or, more usually, as divided doses throughout the day.
  • the compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
  • Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline.
  • Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.
  • the compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
  • Drug-cyclodextrin complexes for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used.
  • the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser.
  • the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
  • the kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit typically comprises directions for administration and may be provided with a so-called memory aid.
  • For administration to human patients having a weight of about 65 to
  • the total daily dose of a compound of the invention is typically in the range 1 to lOOOOmg, such as 10 to 1000mg, for example 25 to 500mg, depending, of course, on the mode of administration, the age, condition and weight of the patient, and will in any case be at the ultimate discretion of the physician.
  • the total daily dose may be administered in single or divided doses.
  • the invention provides a pharmaceutical composition including a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof together with one or more pharmaceutically acceptable excipients, diluents or carriers.
  • the compounds of formula (I) and their pharmaceutically acceptable salts, solvates and derivatives have the advantage that they are more selective, have a more rapid onset of action, are more potent, are better absorbed, are more stable, are more resistant to metabolism, have a reduced 'food effect', have an improved safety profile or have other more desirable properties (e.g. with respect to solubility or hygroscopicity) than the compounds of the prior art.
  • the compounds of formula (I) and their pharmaceutically acceptable salts, solvates and derivatives may be administered alone or as part of a combination therapy.
  • embodiments comprising coadministration of, and compositions which contain, in addition to a compound of the invention, one or more additional therapeutic agents.
  • Such multiple drug regimens may be used in the treatment and prevention of infection by human immunodeficiency virus, HIV.
  • the use of such combination therapy is especially pertinent with respect to the treatment and prevention of infection and multiplication of the human immunodeficiency virus, HIV, and related pathogenic retroviruses within a patient in need of treatment or one at risk of becoming such a patient.
  • the ability of such retroviral pathogens to evolve within a relatively short period of time into strains resistant to any monotherapy which has been administered to said patient is well known in the literature.
  • a recommended treatment for HIV is a combination drug treatment called Highly Active Anti-Retroviral Therapy, or HAART.
  • HAART combines three or more HIV drugs.
  • the methods of treatment and pharmaceutical compositions of the present invention may employ a compound of the invention in the form of monotherapy, but said methods and compositions may also be used in the form of combination therapy in which one or more compounds of the invention are coadministered in combination with one or more additional therapeutic agents such as those described in detail further herein.
  • combinations of the present invention include treatment with a compound of formula (I), or a pharmaceutically acceptable salt, solvate or derivative thereof, and one or more additional therapeutic agents selected from the following: HIV protease inhibitors, including but not limited to indinavir, ritonavir, saquinavir, nelfinavir, lopinavir, amprenavir, atazanavir, tipranavir, AG1859 and TMC 114; non- nucleoside reverse transcriptase inhibitors (NNRTIs), including but not limited to nevirapine, delavirdine, capravirine, efavirenz, GW-8248, GW-5634 and TMC125; nucleoside/nucleotide reverse transcriptase inhibitors, including but not limited to zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, adefovir dipi
  • NK1 antagonists and various forms of interferon or interferon derivatives; agents which substantially inhibit, disrupt or decrease viral transcription or RNA replication such as inhibitors of tat (transcriptional trans activator) or nef (negative regulatory factor); agents which substantially inhibit, disrupt or decrease translation of one or more proteins expressed by the virus (including, but not limited to, down regulation of protein expression or antagonism of one or more proteins) other than reverse transcriptase, such as Tat or Nef; agents which influence, in particular down regulate, CCR5 receptor expression; chemokines that induce CCR5 receptor intemalisation such MIP-1 ⁇ , MIP-1 ⁇ , RANTES and derivatives thereof; and other agents that inhibit viral infection or improve the condition or outcome of HIV-infected individuals through different mechanisms.
  • agents which substantially inhibit, disrupt or decrease viral transcription or RNA replication such as inhibitors of tat (transcriptional trans activator) or nef (negative regulatory factor)
  • agents which substantially inhibit, disrupt or decrease translation of one or more proteins expressed by the virus including, but
  • Agents which influence (in particular down regulate) CCR5 receptor expression include immunosupressants, such as calcineurin inhibitors (e.g. tacroli ' mus and cyclosporin A); steroids; agents which interfere with cytokine production or signalling, such as Janus Kinase (JAK) inhibitors (e.g. JAK-3 inhibitors, including 3- ⁇ (3R,4R)-4-methyl-3-[methyl-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl ⁇ -3-oxo-propionithle) and pharmaceutically acceptable salts, solvates or derivatives thereof; cytokine antibodies (e.g.
  • IL-2 receptor antibodies that inhibit the interleukin-2 (IL-2) receptor, including basiliximab and daclizumab); and agents which interfere with cell activation or cell cycling, such as rapamycin.
  • Increasing the exposure in such a manner is known as boosting. This has the benefit of increasing the efficacy of the compound of the invention or reducing the dose required to achieve the same efficacy as an unboosted dose.
  • the metabolism of the compounds of the invention includes oxidative processes carried out by P450 (CYP450) enzymes, particularly CYP 3A4 and conjugation by UDP glucuronosyl transferase and sulphating enzymes.
  • P450 P450
  • CYP450 cytochrome P450
  • the isoforms of CYP450 that may be beneficially inhibited include, but are not limited to, CYP1A2, CYP2D6, CYP2C9, CYP2C19 and CYP3A4.
  • Suitable agents that may be used to inhibit CYP 3A4 include, but are not limited to, ritonavir, saquinavir or ketoconazole. It will be appreciated by a person skilled in the art, that a combination drug treatment, as described herein above, may comprise two or more compounds having the same, or different, mechanism of action. Thus, by way of illustration only, a combination may comprise a compound of the invention and: one or more NNRTIs; one or more NRTIs and a PI; one or more NRTIs and a CCR5 antagonist; a PI; a PI and an NNRTI; and so on.
  • HCV Hepatitis C Virus
  • HBV Hepatitis B Virus
  • HPV Human Papillomavirus
  • opportunistic infections including bacterial and fungal infections
  • neoplasms and other conditions which occur as the result of the immune-compromised state of the patient being treated.
  • therapeutic agents may be used with the compounds of the invention, e.g., in order to provide immune stimulation or to treat pain and inflammation which accompany the initial and fundamental HIV infection.
  • therapeutic agents for use in combination with the compounds of formula (I) and their pharmaceutically acceptable salts, solvates and derivatives also include: interferons, pegylated interferons (e.g.
  • CMV cytomegalovirus
  • a compound of formula (I), or a pharmaceutically acceptable salt, solvate or derivative thereof with a CCR1 antagonist, such as BX-471 ; a beta adrenoceptor agonist, such as salmeterol; a corticosteroid agonist, such fluticasone propionate; a LTD4 antagonist, such as montelukast; a muscarinic antagonist, such as tiotropium bromide; a PDE4 inhibitor, such as cilomilast or roflumilast; a COX-2 inhibitor, such as celecoxib, valdecoxib or rofecoxib; an alpha-2-delta ligand, such as gabapentin or pregabalin; a beta-interferon, such as REBIF; a TNF receptor modulator, such as a TNF-alpha inhibitor (e.g.
  • the compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof and other therapeutic agent(s) may be administered, in terms of dosage forms, either separately or in conjunction with each other; and in terms of their time of administration, either simultaneously or sequentially.
  • the administration of one component agent may be prior to, concurrent with, or subsequent to the administration of the other component agent(s).
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof and one or more additional therapeutic agents.
  • all references herein to treatment include curative, palliative and prophylactic treatment.
  • the invention is illustrated by the following Examples and
  • Examples 13-45 were prepared by the method described above for Example 2, using the corresponding compound of formula (II) and R 5 OH. LRMS was by APCI+ and data quoted are for [M+H] + , unless otherwise stated.
  • Example 54 phenol prepared as described in Preparation 67
  • Example 55 phenol prepared as described in Preparation 68
  • Example 56 6-methoxy-2-naphthol is commercially available
  • Example 57 5-hydroxy-1 -naphthalene sulfonamide is commercially available
  • Example 58 1 -r(2/?)-4-Benzoyl-2-methyl-piperazin-1 -vn-2-(4-methanesulfonyl-2-methoxy- phenoxy)-p " ropan-1 -one
  • Triethylamine (0.08mL, 0.57mmol) was added to a solution of the compound of Preparation 30 (150mg, 0.38mmol) in dichloromethane (3mL) and the mixture was cooled in an ice bath.
  • Methanesufonyl chloride (0.03mL, 0.42mmol) was added dropwise and the reaction mixture was allowed to stir at room temperature for 18 hours. The mixture was then diluted with further dichloromethane (20mL) and washed with water. The organic phase was dried over magnesium sulfate and concentrated in vacuo.
  • Examples 68 and 69 were purified by column chromatography on silica gel, eluting with dichloromethane:methanol, 99:1 to 96:4
  • the compounds were prepared from the compound of Preparation 60 and 1- chloromethyl-4-fluoro-1 ,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), using a similar preparation to Example 67.
  • the compounds were purified by HPLC using a Phenomenex Luna C18(2) column 150x15mm (10 micron particle size, 10 ⁇ A porosity), using a 2 solvent eluent of acetonitrile:water:trifluoroacetic acid (5:95:0.1) [solvent A] and acetonitile [solvent B].
  • a solvent gradient is run at a flow-rate of 20 ml/min as in the table below.
  • Example 60 The compound of Example 60 (200mg, 0.46mmol) and acetic acid (3mL) were dissolved in water and the solution was heated under reflux for 24 hours. The reaction mixture was then diluted with water and washed with dichloromethane (3x1 OmL). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. The oil was purified by column chromatography on silica gel, eluting with dichloromethane:methanol, 95:5 to afford the title compound as pale yellow solid in 40% yield, 76mg. LRMS (APCI + ): m/z [M+H] + 418
  • the compound of Preparation 65 (80mg, 0.18mmol), dichloro- bis(triphenylphosphine)palladium (15mg, 0.018mmol) and triethylamine (51 ⁇ L, 0.37mmol) were dissolved in methanol (5mL) and transferred to a sealed vessel. The vessel was heated to 100°C and the mixture was stirred under 100psi of carbon monoxide gas for 42 hours. The reaction mixture was then filtered through Arbocel , washing through with methanol and the filtrate was concentrated in vacuo.
  • reaction mixture was allowed to warm to room temperature and additional di-tert-butyl azodicarboxylate (0.14 g, 0.6 mmol) and polymer supported triphenylphosphine (0.2 ⁇ g, 0.7 ⁇ mmol) were added.
  • reaction mixture was filtered through Arbocel ® , washing through with dichloromethane (10 mL). The filtrate was washed with saturated aqueous sodium hydrogencarbonate solution (20 ml), then the organic phase separated, dried (MgS0 4 ) and evaporated under reduced pressure.
  • Triphenylphosphine (2.17 g, 8.27 mmol) was added to a stirred suspension of di-isopropyl azodicarboxylate (1.47 ml, 7.66 mmol) in THF (26 ml) at - ⁇ °C.
  • ⁇ -Hydroxyquinoline 1.0 g, 6.90 mmol
  • methyl (R)-lactate 0.66 ml, 6.90 mmol
  • the reaction mixture was diluted with ethyl acetate (60 ml), washed with water (30 ml), saturated potassium carbonate solution (30 ml) and brine (30 ml).
  • the reaction mixture was stirred at room temperature for 48 hours and then washed with water (50 ml), 10 % w/v aqueous citric acid solution (50 ml) and saturated aqueous sodium hydrogencarbonate solution (60 ml). The solution was dried (MgS0 4 ) and solvent evaporated under reduced pressure.
  • the 1 crude product was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane: methanol (99:1) changing to dichloromethane : methanol (9 ⁇ : ⁇ ).
  • Lithium hydroxide monohydrate (4.2g, lOOmmol) was added portionwise to a solution of the compound of Preparation 6 (32g, 120mmol) in methanol (1 ⁇ 0mL) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then evaporated under reduced pressure and the residue was dissolved in water and washed with diethyl ether. The aqueous mixture was acidified with 2M hydrochloric acid to pH4 and was then extracted with ethyl acetate (3x160mL). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The resulting foam was dried under reduced pressure to afford the title compound in 91% yield, 23g. LRMS (ES + ): m/z [M+H] + 25 ⁇
  • H ⁇ nig's base (1.8mL, 10. ⁇ mmol) was added to a solution of the compound of Preparation 7 (1.8g, 7mmol), (3F?)-(3-methyl-piperazin-1 -yl)-phenyl- methanone [(1.6g, 7.7mmol), J. Med. Chem. 43(23), 4499; 2000], and 3- (diethoxyphosphoryloxy)-1 ,2,3-benzotriazin-4(3H)-one (2.75g, 9.1 mmol) in dichloromethane (16mL). The mixture was stirred for 4 hours and was then evaporated under reduced pressure.
  • Preparation 11 uses 1-(3-methoxy-2-methyl-phenyl)-ethanone, prepared as described in Tetrahedron 26(18), 4249; 1969.
  • Preparation " 14 uses 1-(3-methoxy-2-methyl-phenyl)-ethanone, prepared as described in Tetrahedron 26(18), 4249; 1969.
  • the compound of Preparation 11 (2.0 ⁇ g, 9.3 ⁇ mmol) was added portionwise to a solution of methylhydrazine (647 ⁇ L, 10.28mmol) in acetic acid (1 ⁇ mL) and the mixture was heated at 90°C for 2.6 hours. The solvent was then evaporated under reduced pressure and the residue was dissolved in dichloromethane and washed with 10% sodium carbonate solution and saturated sodium hydrogen carbonate solution. The organic phase was dried over magnesium sulfate and concentrated in vacuo to give an orange oil. The oil was purified firstly by column chromatography on silica gel, eluting with dichloromethane:ethyl acetate, 99:1 to 97:3.
  • Preparation 18 title compound is prepared by dealkylation of 3-methoxy-2- methylbenzamide (J.Chem.Soc.Perkin Trans.1 , 2389-2396; 1984)
  • Diisopropyl azodicarboxylate (295 ⁇ L, 1.50mmol) was added dropwise to an ice-cooled solution of the compound of Preparation 20 (240mg, 1.5mmol) methyl (R)-lactate (1 ⁇ 6mg, l . ⁇ Ommol) and triphenyl phosphine (393mg, l . ⁇ mmol) in tetrahydrofuran ( ⁇ mL).
  • the reaction mixture was stirred at room temperature for 18 hours and was then diluted with diethyl ether ( ⁇ OmL) and washed with water (2x1 OmL). The organic phase was dried over magnesium sulfate and concentrated in vacuo to give a yellow oil.
  • Lithium hydroxide monohydrate (80.9mg, 1.93mmol) was added portionwise to a solution of the compound of Preparation 21 (190mg, 0.77mmol) in methanol (6mL) and the mixture was stirred at 60°C for 8 hours. The reaction mixture was then evaporated under reduced pressure and the residue was dissolved in water and washed with diethyl ether. The aqueous mixture was - acidified with 2M hydrochloric acid to pH4 and was then extracted with ethyl acetate (3x30mL). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The resulting foam was dried under reduced pressure to afford the title compound in 76% yield, 13 ⁇ mg. LRMS (ES " ): m/z [M-H] ' 231
  • Triphenylphosphine (2.17g, 8.27mmol) was added to a stirred suspension of diisopropyl azodicarboxylate (1.47mL, 7.56mmol) in tetrahydrofuran (25mL) at -5°C.
  • 5-Hydroxyquinoline (1.0g, 6.90mmol) and methyl-(fi)-lactate (0.66mL, 6.90mmol) were added and the solution was allowed to stir at room temperature for 14 hours.
  • the reaction mixture was then diluted with ethyl acetate (50mL), washed with water (30mL), saturated potassium carbonate solution (30mL) and brine (30mL). The solution was dried over magnesium sulfate and concentrated in vacuo.
  • Tetrakis(triphenylphosphine)palladium(0) (6mg, cat), 1-[[(2- (trimethylsilyl)ethoxy]methyI]pyrazolyl-5-boronic acid [(50mg, 0.1 mmol), J. Med. Chem. 41 2019-2028; 1998] and sodium carbonate (175mg, 1.6mmol) in water (O. ⁇ mL) were added to the compound of Preparation 44 (50mg, 0.1 mmol) in tetrahydrofuran (2mL) and the mixture was heated under reflux for 18 hours. The reaction mixture was then evaporated under reduced pressure and the residue was dissolved in dichloromethane and washed with water (5mL) and brine (2x5mL).
  • the chloro compound of Preparation 66 (130mg, 0.3mmol), dichloro- bis(triphenylphosphine)palladium (24mg, 0.03mmol) and triethylamine (83 ⁇ L, 0.6mmol) were dissolved in a mixture of methanol (3mL) and N,N- dimethylformamide (0.5mL), and transferred to a sealed vessel. The vessel was heated to 100°C and the mixture was stirred under 100psi of carbon monoxide gas for 42 hours. The reaction mixture was then filtered through Arbocel ® , washing through with methanol and the filtrate was concentrated in vacuo.
  • 1-Hydroxybenzotriazole hydrate (249mg, 1.87mmol) was added to a suspension of the compound of Preparation 40 (400mg, 1.7mmol) in N,N- dimethylformamide to form a solution.
  • 1-Ethyl-3-(3-dimethyl amino propyl) carbodiimide (351 mg, 1.87mmol) and triethylamine (0.7mL, 5.1 mmol) were added and the solution was stirred for 5 minutes.
  • (3S)-3-Methyl-piperazine-1- carboxylic acid tert-butyl ester (335 mg, 1.7mmol) was added and the mixture was stirred for 18 hours.
  • Diisopropyl azodicarboxylate (414 ⁇ L, 2.14mmol) was added dropwise to an ice-cooled solution of the compound of Preparation 55 (500mg, 1.95mmol) methyl (R)-lactate (202mg, 1.95mmol) and triphenyl phosphine (614mg, 2.34mmol) in tetrahydrofuran (20mL).
  • the reaction mixture was stirred at room temperature for 18 hours and was then evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with 10% potassium carbonate solution (2x1 OmL). The organic phase was dried over magnesium sulfate and concentrated in vacuo.
  • the compound of Preparation 58 (190mg, 0.37mmol), dichloro- bis(triphenylphosphine)palladium (30mg, 0.04mmol) and triethylamine (0.1 OmL, 0.74mmo! were dissolved in methanol (10mL) and transferred to a sealed vessel. The vessel was heated to 100°C and the mixture was stirred under 100psi of carbon monoxide gas for 42 hours. The reaction mixture was then filtered through Arbocel ® , washing through with methanol and the filtrate was concentrated in vacuo.
  • Phosphorus oxychloride (0.20mL, 2.18mmol) was added to a solution of the compound of Preparation 64 (305mg, 0.73mmol) in dichloromethane (15mL) and the reaction mixture was heated at 100°C for two hours. The mixture was then cooled to room temperature and poured onto water (75mL). The resulting aqueous mixture was basified with concentrated ammonia solution and extracted with dichloromethane (2x75mL). The combined organic extracts were then dried over magnesium sulfate and concentrated in vacuo.
  • Acetic anhydride (22.6mL, 0.24mol) was added to an ice-cooled solution of 3,5-dihydroxytoluene (9.93g, O.O ⁇ mol) and triethylamine (56mL, 0.40mol) in dichloromethane (86mL). The reaction mixture was warmed to room temperature and was stirred for 60 hours. Water (100mL) was then added and the mixture was stirred vigorously for 3 hours. The organic layer was separated and the aqueous layer was re-extracted with dichloromethane (3x80mL). The combined organic extracts were washed with brine (80mL), dried over magnesium sulfate and concentrated in vacuo.
  • terf-Butyldimethylchlorosilane (511 mg, 3.39mmol) and imidazole (1.05g, 15.4mmol) were added to a solution of the compound of Preparation 71 (500mg, 3.08mmol) in N,N-dimethylformamide and the reaction mixture was stirred at 0°C for 1 hour and at room temperature for 18 hours. Additional tert- butyldimethylchlorosilane (511 mg, 3.39mmol) was added and the reaction mixture was heated at 80°C for 48 hours. The solvent was then evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water.
  • Tetrabutylammonium fluoride solution (1M in tetrahydrofuran, 21 mL, 2.1 mmol) was added dropwise to a solution of the compound of Preparation 73 (527mg, 1.4mmol) in tetrahydrofuran (9mL) and the solution was stirred at 0°C for 30 minutes and at room temperature for 5 minutes. Water was then added to t e mixture and the aqueous mixture was extracted with ethyl acetate (2x1 OmL). The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated in vacuo.
  • the compound of Preparation 76 (70mg, 0.25mmol), di-tert-butyl azodicarboxylate (233mg, 1.01 mmol) and polymer supported triphenyl phosphine (380mg, 1.13mmol) were added to a solution of the compound of Preparation 74 (70mg, 0.25mmol) in dichloromethane (3mL) and the reaction mixture was stirred 0°C for 30 minutes and at room temperature for 18 hours. The reaction mixture was then filtered through a filter tube, washing through with dichloromethane. The filtrate was washed with sodium hydroxide solution, dried over magnesium sulfate and concentrated in vacuo.
  • the ability of the compounds of formula (I) and their pharmaceutically acceptable salts, solvates and derivatives to modulate gp120 activity, in particular inhibit the interaction of gp120 with CD4, is demonstrated using a gp160 induced cell-cell fusion assay to determine the IC 5 o values of compounds against HIV-1 fusion.
  • the gp160 induced cell-cell fusion assay uses a HeLa P4 cell line and a CHO-Tat10 cell line.
  • the HeLa P4 cell line expresses CCR5 and CD4 and has been transfected with HIV-1 LTR- ⁇ -Galactosidase.
  • the media for this cell line is Dulbecco modified eagle's medium (D-MEM) (without L-glutamine) containing 10% foetal calf serum (FCS), 2mM L-glutamine penicillin/streptomycin (Pen/Strep; 100U/mL penicillin + 10mg/mL streptomycin), and 1 ⁇ g/ml puromycin.
  • D-MEM Dulbecco modified eagle's medium
  • FCS foetal calf serum
  • Pen/Strep 2mM L-glutamine penicillin/streptomycin
  • the CHO cell line is a Tat (transcriptional trans activator)-expressing clone from a CHO JRR17.1 cell line that has been transfected with pTat puro plasmid.
  • the media for this cell line is rich medium for mammalian cell culture originally developed at Roswell Park Memorial Institute RPMI1640 (without L-glutamine) containing 10% FCS, 2mM L-glutamine, 0.5 mg/ml Hygromycin B and 12 ⁇ g/ml puromycin.
  • the CHO JRR17.1 line expresses gp160 (JRFL) and is a clone that has been selected for its ability to fuse with a CCR5/CD4 expressing cell line.
  • Tat present in the CHO cell is able to transactivate the HIV-1 long terminal repeat (LTR) present in the HeLa cell leading to the expression of the ⁇ -Galactosidase enzyme.
  • LTR HIV-1 long terminal repeat
  • This expression is then measured using a Fluor AceTM ⁇ -Galactosidase reporter assay kit (Bio-Rad cat no. 170-3150).
  • This kit is a quantitative fluorescent assay that determines the level of expression of ⁇ -galactosidase using 4-methylumbelliferul- galactopyranoside (MUG) as substrate.
  • ⁇ -Galactosidase hydrolyses the fluorogenic substrate resulting in release of the fluorescent molecule 4-methylumbelliferone (4MU). Fluorescence of 4-methylumbelliferone is then measured on a fluorometer using an excitation wavelength of 360nm and emission wavelength of 460nm.
  • IC 50 values for the compounds of Examples 12, 29 and 44 are, respectively, 15nM, 134nM and 825nM.
  • ELISA enzyme linked immunosorbent assay
  • gp120 100 ⁇ l of gp120 (dilution predetermined by titration) is added to each well and incubated for 90 minutes at room temperature. The sample is removed and the wells are washed with PBS (phosphate buffered saline) + 0.01% TWEEN® (polyethylene glycol sorbitan monolaurate). 50 ⁇ l/well of compound is added followed by 50 ⁇ l (0.1 ⁇ g) of soluble CD4 conjugated to horseradish peroxidase (Autogen Bioclear). The plate is incubated for 90 minutes at room temperature before the wells are washed again.
  • PBS phosphate buffered saline
  • TWEEN® polyethylene glycol sorbitan monolaurate
  • the substrate OPD o-phenylenediamine, Sigma
  • OPD o-phenylenediamine, Sigma
  • IC 50 values according to the above method, of less than 15 ⁇ M.
  • IC 50 values for the compounds of Examples 1 , 11 and 12 are, respectively, 0.92 ⁇ M, 1.0 ⁇ M and 0.75 ⁇ M.

Abstract

La présente invention concerne un composé de formule (I) ou bien ses sels, solvates ou dérivés pharmaceutiquement acceptables, formule dans laquelle R1 à R5 sont tels que définis dans la description. L'invention concerne également des procédés pour leur préparation, des intermédiaires utilisés dans leur préparation, des compositions les contenant, ainsi que les utilisations de tels dérivés. Les composés décrits inhibent l'interaction de gp120 avec CD4 et sont donc utiles dans le traitement du VIH, des infections rétrovirales génétiquement apparentées au VIH, et du sida.
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AP2006003514A AP2006003514A0 (en) 2003-08-14 2004-08-04 Piperazine derivatives for the treatment of HIV infections.
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BRPI0413469-9A BRPI0413469A (pt) 2003-08-14 2004-08-04 derivados de piperazina para o tratamento de infecções por hiv
CA002534866A CA2534866A1 (fr) 2003-08-14 2004-08-04 Derives de piperazine pour le traitement des infections a vih
JP2006523071A JP2007502266A (ja) 2003-08-14 2004-08-04 Ｈｉｖ感染症を治療するためのピペラジン誘導体
EA200600225A EA200600225A1 (ru) 2003-08-14 2004-08-04 Производные пиперазина для лечения вич инфекций
EP04744202A EP1663234A1 (fr) 2003-08-14 2004-08-04 Derives de piperazine pour le traitement des infections vih
AU2004264724A AU2004264724A1 (en) 2003-08-14 2004-08-04 Piperazine derivatives for the treatment of HIV infections
IL173365A IL173365A0 (en) 2003-08-14 2006-01-25 Piperazine derivatives for the treatment of hiv infections
IS8275A IS8275A (is) 2003-08-14 2006-01-31 Píperasín afleiður til meðhöndlunar á HIV sýkingum
TNP2006000051A TNSN06051A1 (fr) 2003-08-14 2006-02-14 Derives de piperazine pour le traitement d'infections par le hiv
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