EP1831210A1 - Derives de 8-aza-bicyclo (3.2.1) octane possedant une activite de recepteurs de chimiokines ccr5 - Google Patents

Derives de 8-aza-bicyclo (3.2.1) octane possedant une activite de recepteurs de chimiokines ccr5

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Publication number
EP1831210A1
EP1831210A1 EP05813627A EP05813627A EP1831210A1 EP 1831210 A1 EP1831210 A1 EP 1831210A1 EP 05813627 A EP05813627 A EP 05813627A EP 05813627 A EP05813627 A EP 05813627A EP 1831210 A1 EP1831210 A1 EP 1831210A1
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European Patent Office
Prior art keywords
alkyl
compound
formula
atoms
halogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP05813627A
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German (de)
English (en)
Inventor
David Cameron Pfizer Global Res. and Dev. PRYDE
Paul Anthony Pfizer Global Res. and Dev. STUPPLE
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Pfizer Ltd
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Pfizer Ltd
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Priority claimed from GB0428267A external-priority patent/GB0428267D0/en
Application filed by Pfizer Ltd filed Critical Pfizer Ltd
Publication of EP1831210A1 publication Critical patent/EP1831210A1/fr
Withdrawn legal-status Critical Current

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
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Definitions

  • This invention relates to tropane derivatives, to processes for their preparation, to compositions containing them and to their use.
  • the present invention relates to the use of 8-azabicyclo[3.2.1]octane 5 derivatives in the treatment of a variety of disorders, including those in which the modulation, in particular antagonism, of chemokine CCR5 receptors is implicated.
  • compounds of the invention are useful in the treatment of HIV, such as HIV-1 , and genetically related retroviral infections (and the resulting acquired immune deficiency syndrome, AIDS), inflammatory diseases, autoimmune diseases and pain.
  • HIV such as HIV-1
  • retroviral infections and the resulting acquired immune deficiency syndrome, AIDS
  • inflammatory diseases autoimmune diseases and pain.
  • autoimmune diseases and pain '
  • chemokine is a contraction of "chemotactic cytokines”.
  • the chemokines comprise a large family of proteins which have in common important structural features and which have the ability to attract leukocytes.
  • chemokines play an indispensable role in the attraction of leukocytes to various tissues of the body, a process which is essential for both inflammation and the body's response to infection. Because 5 chemokines and their receptors are central to the pathophysiology of inflammatory and infectious diseases, agents which are active in modulating, preferably antagonising, the activity of chemokines and their receptors, are useful in the therapeutic treatment of such inflammatory and infectious diseases.
  • CCR5 The chemokine receptor CCR5 is of particular importance in the context of treating 0 inflammatory and infectious diseases.
  • CCR5 is a receptor for chemokines, especially for the macrophage inflammatory proteins (MIP) designated MIP-1 ⁇ and MIP-1 ⁇ , and for a protein which is regulated upon activation and is normal T-cell expressed and secreted (RANTES).
  • MIP macrophage inflammatory proteins
  • RANTES normal T-cell expressed and secreted
  • R 1 is R 7 , OR 7 or NR 5 R 6 ;
  • R 2 is H or C 1-6 alkyl;
  • R 3 is phenyl substituted by 0 to 3 atoms or groups selected from C 1-6 alkyl, Ci -6 alkylcarbonyl, Ci -6 alkoxy, C 1-6 alkoxycarbonyl, halogen, CF 3 , OH, CN, NR 5 R 6 , CO 2 R 7 or CONR 5 R 6 ;
  • R 4 is a moiety of partial
  • Q is CR 42 or N
  • T is CR 43 or N
  • R 41 is H, C 1-6 alkyl or C 1-6 fluoroalkyl
  • R 42 and R 43 are independently selected from H, C 1-6 alkyl, C 1-6 fluoroalkyl, or halogen; or R 42 and R 43 when taken together with the atoms to which they are attached form a benzene, pyridine, pyrimidine, pyridazine or pyrazine ring, wherein the said benzene pyridine, pyrimidine, pyridazine or pyrazine ring is substituted by 0 to 3 atoms or groups selected from C 1- 6 alkyl, C 1-6 fluoroalkyl or halogen; or form a partially saturated pyridine ring such that R 4 is a moiety of partial formula (1.0.1)
  • R 5 is H or C 1-6 alkyl; C 2-6 alkenyl; C 2 . 6 alkynyl; C 3-7 cycloalkyl; a 5 or 6-membered aromatic heterocycle; or a 4 to 7-membered saturated heterocycle; wherein said alkyl, alkenyl, alkynyl and cycloalkyl are substituted by 0 to 3 atoms or groups selected from oxo, halogen, CF 3 , OR 6 , CN, COR 6 , or CO 2 R 6 ; wherein said heterocycle contains one to three heteroatoms selected from N, O or S; and wherein said heterocycle is substituted by 0 to 3 atoms or groups selected from C 1-6 alkyl, C 1-6 alkylcarbonyl, Ci -6 alkoxy, C 1-6 alkoxycarbonyl, halogen, CF 3 , OH, CN, COR 6 , or CO 2 R 6 ;
  • R 6 is H or C 1-6 alkyl; or, when R 5 and R 6 are both attached to the same N atom, NR 5 R 6 may also represent a 5 to 7 membered, saturated, partially unsaturated or aromatic, heterocycle containing from 0 to 2 additional heteroatoms selected from O, N or S, substituted by 0 to 3 halogen atoms;
  • R 7 is C 1-6 alkyl; C 2-6 alkenyl; C 2 -e alkynyl; C 3-7 cycloalkyl; a 5 or 6-membered aromatic heterocycle; or a 4 to 7-membered saturated heterocycle; wherein said alkyl, alkenyl, alkynyl and cycloalkyl are substituted by 0 to 3 atoms or groups selected from oxo, halogen, CF 3 , OR 6 ,
  • heterocycle contains one to three heteroatoms selected from N, O or S; and wherein said heterocycle is substituted by O to 3 atoms or groups selected from C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, oxo, halogen, CF 3 , OH, CN, NR 5 R 6 , COR 6 , CO 2 R 6 or CONR 5 R 6 ; provided that when R 1 is OR 7 the said heterocycle is carbon bonded to the oxygen of OR 7 ;
  • R 8 is H or C 1-6 alkyl
  • X and Y are selected from CH 2 and NR 9 such that one of X and Y is CH 2 and the other is NR 9 ;
  • R 9 is H; R 7 ; COR 7 ; CO 2 R 7 ; CONR 5 R 6 ; SO 2 R 7 ; or (C 1-6 alkylene)phenyl, wherein phenyl is substituted by O to 3 atoms or groups selected from C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, halogen, CF 3 , OH, CN, NR 5 R 6 , COR 6 , CO 2 R 6 or CONR 5 R 6 .
  • 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. T he term "C 3- C 7 cycloalkyl” means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • halogen means fluoro, chloro, bromo or iodo.
  • Ci -6 fluoroalkyl means Ci -6 alkyl substituted by one to three fluoro atoms.
  • R 1 is R 7 or OR 7 .
  • R 7 is C 1-4 alkyl optionally s ubstituted by C 1-3 alkoxy; C 3 . 6 cycloalkyl substituted by O to 2 halogen atoms; or a 4 to 6-membered saturated heterocycle containing one heteroatom selected from N, O, or S, wherein said heterocycle is substituted by O to 2 atoms or groups selected from oxo, halogen, or COC 1-3 alkyl.
  • R 1 is R 7 or OR 7 as defined above in any preceding embodiment or NR 5 R 6 ;
  • R 5 is H, C 1-4 alkyl, a C 3-7 cylcoalkyl;
  • R 6 is H or C 1-6 alkyl; or R 5 and R 6 together with the N to which they are attached form a C 5-7 saturated, partially unsaturated or aromatic heterocycle containing one or two additional heteroatoms selected from O, N or S, substituted by O to 3 halogen.
  • R 2 is H.
  • R 3 is phenyl optionally substituted by one fluorine atom.
  • R is: i) a moiety of partial formula (1.0.1)
  • R 4 is:
  • R 4 is a moiety of partial formula
  • R 4 is a moiety of partial formula
  • R 9 is as defined hereinbefore.
  • R 8 is C 1-3 alkyl. In yet a further embodiment, R 8 is methyl. In yet a further embodiment, R 9 is H; R 7 ; COR 7 ; CO 2 R 7 . In yet a further embodiment, R 9 is C alkyl , CO C 1-4 alkyl or CO 2 -C 1-4 alkyl. In yet a further embodiment there is provided a compound of formula 1 as shown in the first aspect of the invention, wherein R 1 is R 7 or OR 7 ; R 2 is H;
  • R 3 is phenyl optionally substituted by one fluorine;
  • R 4 is i) a moiety of partial form
  • X and Y are selected from CH 2 and NR 9 such that one of X and Y is CH 2 and the other is NR 9 ; or ii) a triazolyl of partial formula (1.0.3)
  • R 7 is C 1-4 alkyi optionally substituted by C 1-3 alkoxy; C 3-6 cycloalkyl substituted by 0 to 2 halogen atoms; or a 4 to 6-membered saturated heterocycle containing one heteroatom selected from N, O, or S, wherein said heterocycle is substituted by 0 to 2 atoms or groups selected from oxo, halogen, or COCi -3 alkyl.
  • R 8 is methyl; and R 9 is C 1-4 alkyl, COC 1-4 alkyl or CO 2 C 1-4 alkyl.
  • R 1 is R 7 , OR 7 or NR 5 R 6 ;
  • R 2 is H or C 1-6 alkyl;
  • R 3 is phenyl substituted by 0 to 3 atoms or groups selected from Ci -6 aikyl, C 1-6 alkylcarbonyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, halogen, CF 3 , OH, CN, NR 5 R 6 , CO 2 R 7 or CONR 5 R 6 ;
  • R 4 is a moiety of partial
  • R 42 and R 43 are independently selected from H, C 1-6 alkyl, C 1-6 fluoroalkyl, or halogen; or R 42 and R 43 when taken together with the atoms to which they are attached form a benzene, pyridine, pyrimidine, pyridazine or pyrazine ring, wherein the said benzene pyridine, pyrimidine, pyridazine or pyrazine ring is substituted by 0 to 3 atoms or groups selected from Ci- ⁇ alkyl, C 1-6 fluoroalkyl or halogen; or form a partially saturated pyridine ring such that R 4 is a moiety of partial formula (1.0.1)
  • R 5 is H or C 1-6 alkyl; C 2-6 alkenyl; C 2-6 alkynyl; C 3-7 cycloalkyl; a 5 or 6-membered aromatic heterocycle; or a 4 to 7-membered saturated heterocycle; wherein said alkyl, alkenyl, alkynyl and cycloalkyl are substituted by 0 to 3 atoms or groups selected from oxo, halogen, CF 3 , OR 6 , CN, COR 6 , or CO 2 R 6 ; wherein said heterocycles contain one to three heteroatoms selected f rom N 1 O or S ; a nd w herein s aid h eterocycles a re s ubstituted b y 0 to 3 atoms or groups s elected from C 1-6 a Ikyl, C 1-6 a Ikylcarbonyl, C
  • R 8 is H or C 1-6 alkyl; X and Y are selected from CH 2 and NR 9 such that one of X and Y is CH 2 and the other is NR 9 ;
  • R 9 is H; R 7 ; COR 7 ; CO 2 R 7 ; CONR 5 R 6 ; SO 2 R 7 ; or (C 1-6 alkylene)phenyl, wherein phenyl is substituted by O to 3 atoms on groups selected from C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, halogen, CF 3 , OH, CN, NR 5 R 6 , COR 6 , CO 2 R 6 or CONR 5 R 6 . It is to be understood that the invention covers all combinations of embodiments of the invention as described hereinabove, consistent with the definition of compounds of formula (I).
  • the compounds of the invention include compounds of formula (I) and pharmaceutically acceptable salts, solvates or derivatives thereof (wherein derivatives include complexes, prodrugs and isotopically-labelled compounds, as well as salts and solvates 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, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, ste
  • 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. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • the compounds of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline.
  • the term 'amorphous' refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid.
  • a change from solid to liquid properties occurs which is characterised by a change of state, typically second order ('glass transition').
  • 'crystalline' refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterised by a phase change, typically first order ('melting point').
  • compositions of formula (I) may be prepared by one ( or more of three methods:
  • the compounds of the invention may also exist in unsolvated and solvated forms.
  • 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • solvent molecules for example, ethanol.
  • 'hydrate' is employed when said solvent is water.
  • Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules.
  • channel hydrates the water molecules lie in lattice channels where they a re n ext to other water m olecules.
  • I n m etal-ion coordinated hydrates the water molecules are bonded to the metal ion.
  • the complex When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.
  • multi-component complexes other than salts and solvates
  • the drug a nd at l east one other component a re p resent i n stoichiometric or non-stoichiometric amounts.
  • Complexes of this type include clathrates (drug- host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes o f n eutral m olecular c onstituents w hich a re b ound t ogether t hrough non-covalent interactions, but could also be a complex of a neutral molecule with a salt.
  • Co-crystals may be prepared by melt crystallisation, by recrystallisation from solvents, or by physically grinding the components together - see Chem Commun, ,17, 1889-1896, by O. Almarsson and M. J. Zaworotko (2004), incorporated herein by reference.
  • Chem Commun ,17, 1889-1896
  • O. Almarsson and M. J. Zaworotko (2004), incorporated herein by reference.
  • the compounds of the invention may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to sapproprible conditions.
  • the m esomorphic s tate is i ntermediate between the true crystalline state and the true liquid state (either meit or solution).
  • Mesomorphism arising as the result of a change in temperature is described as 'thermotropic' and that resulting from the addition of a second component, such as water or another solvent, is described as 'lyotropic'.
  • references to compounds of formula (I) include references to salts, solvates, multi- component complexes and liquid crystals thereof and to solvates, multi-component complexes and liquid crystals of salts thereof.
  • the compounds of the invention include compounds of formula (I) as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically- labeled compounds of formula (I).
  • so-called 'prodrugs' of the compounds of formula (I) are also within the scope of the invention.
  • 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.
  • Such derivatives are referred to as 'prodrugs'.
  • Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems. Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (Ed. E. B. Roche, American Pharmaceutical Association), incorporated herein by reference.
  • 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).
  • Some examples of prodrugs in accordance with the invention include:
  • metabolites of compounds of formula (I), that is, compounds formed in vivo upon administration of the drug are also included within the scope of the invention.
  • Some examples of metabolites in accordance with the invention include:
  • the compound of formula (I) contains an amide group, a carboxylic acid derivative thereof (-CONH 2 -> COOH).
  • Compounds of formula (I) contain at least two asymmetric carbon atoms (the carbon atom from which R 3 is a substituent and the adjacent carbon from which the methylene tropane is a substituent), and may contain one or more further asymmetric carbon atoms, and therefore exist as four or more stereoisomers.
  • R 4 substitution of the tropane ring in compounds of formula (I) can be in either endo- or exo- configuration, and therefore geometric cisltrans (or Z/E) isomers are possible.
  • the compound contains, for example, a keto group, tautomeric isomerism ('tautomerism') may occur. It follows that a single compound may exhibit more than one type of isomerism.
  • stereoisomers of the compounds of formula (I) including all optical isomers, geometric isomers and tautomeric forms as well as compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof.
  • acid addition or base salts wherein the counterion is optically active for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL- arginine.
  • Imidazole substitution of the tropane ring in the endo- configuration is preferred.
  • Triazole substitution of the tropane ring in the exo- configuration is preferred.
  • Endo/exo isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.
  • the 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 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 O and 18 O, 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-f14, 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-labelled 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 Preparations using an appropriate isotopically- labelled reagent in place of the non-labelled reagent previously employed.
  • Preferred compounds of formula (I) include the compounds of Examples 1-29; and pharmaceutically acceptable salts, solvates or derivatives thereof.
  • R 9 are as previously defined unless otherwise stated;
  • Z is OH, or a carboxylic acid activating group such as chloro or 1 H-imidazol-1-yl;
  • Pg is an amino protecting group, such as boc;
  • DMF is N,N-dimethylformamide;
  • DCM is dichloromethane;
  • THF is tetrahydrofuran;
  • Lg is a leaving group appropriate to aliphatic nucleophilic substitution, such as those disclosed in Jerry March, ibid, page 352 (incorporated herein by reference), including Cl, Br, I and sulfonic esters (e.g.
  • 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 O-benzotriazol-i-yl- ⁇ /./V. ⁇ /'./V- tetramethyluronium hexafluorophosphate.
  • compounds of formula (I) may be prepared by reacting a compound of formula (II)
  • the coupling is effected under the conditions described hereinafter in connection with scheme 1 , step (c).
  • the coupling is effected under the conditions described hereinafter in connection with scheme 1 , step (ci).
  • compounds of formula (I) wherein R 1 is OR 7 may be prepared by reacting a compound of formula (II) with a compound of formula (VIII)
  • the coupling is effected under the conditions described hereinafter in connection with scheme 1 , step (cii).
  • alkylation is effected in a suitable solvent, such as an haloalkane (e.g. DCM), an alcohol (e.g. ethanol) or an ether (e.g. THF); optionally in the presence of a base, such as an amine (e.g. triethylamine or ⁇ /-ethyl- ⁇ /, ⁇ /- diisopropylamine); and at from ambient to elevated temperature (e.g. reflux).
  • a suitable solvent such as an haloalkane (e.g. DCM), an alcohol (e.g. ethanol) or an ether (e.g. THF); optionally in the presence of a base, such as an amine (e.g. triethylamine or ⁇ /-ethyl- ⁇ /, ⁇ /- diisopropylamine); and at from ambient to elevated temperature (e.g. reflux).
  • a suitable solvent such as an haloalkane (e.g. DCM), an alcohol (e.g
  • compounds of formula (I) wherein R 4 is a moiety of partial formula (1.0.1) and X is NCOR 7 may be prepared by reacting a compound of formula (XIII) with a compound of formula (XIX)
  • the coupling is effected under the conditions described hereinafter in connection with scheme 2, step (e).
  • the coupling is effected under the conditions described hereinafter in connection with scheme 2, step (e).
  • reaction is carried out in the presence of an acid, such as organic acid (e.g. acetic acid); in a solvent, such as a haloalkane (e.g. DCM) or an ether (e.g. THF); using an alkali metal hydride reducing agent, such as sodium triacetoxyborohydride, sodium cyanoborohydride or sodium borohydride; and at ambient temperature.
  • an acid such as organic acid (e.g. acetic acid)
  • a solvent such as a haloalkane (e.g. DCM) or an ether (e.g. THF)
  • an alkali metal hydride reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride or sodium borohydride
  • the protecting group is benzyl its removal is conveniently effected by a transition metal catalyst (e.g. 20% (w/w) palladium on carbon), either hydrogen gas or ammonium formate in a suitable solvent, such as an alcohol (e.g. ethanol or methanol); and from ambient temperature to reflux.
  • a transition metal catalyst e.g. 20% (w/w) palladium on carbon
  • hydrogen gas or ammonium formate in a suitable solvent, such as an alcohol (e.g. ethanol or methanol); and from ambient temperature to reflux.
  • the acid/amine coupling is conveniently effected using an amine of formula (II) and an acid chloride/alkyl chloroformate of formula (III); an excess of an acid acceptor, such as triethylamine or ⁇ /-ethyl- ⁇ /, ⁇ /-diisopropylamine; a solvent, such as a haloalkane (e.g. DCM) or an ether (e.g. THF); and at ambient temperature.
  • an acid acceptor such as triethylamine or ⁇ /-ethyl- ⁇ /, ⁇ /-diisopropylamine
  • a solvent such as a haloalkane (e.g. DCM) or an ether (e.g. THF); and at ambient temperature.
  • the acid/amine coupling is effected using an acid of formula (III) activated by reagents such as WSCDI or DCC and HOBt or HOAt; an excess of an acid acceptor such as triethylamine or ⁇ /-ethyl- ⁇ /, ⁇ /-diisopropylamine; a solvent, such as a haloalkane (e.g. DCM) or an ether (e.g. THF); and at ambient temperature.
  • a haloalkane e.g. DCM
  • an ether e.g. THF
  • compounds of formula (I) wherein R 1 is NR 5 R 6 and R 5 or R 6 is H can be conveniently prepared by treatment of an amine of formula (II) with an isocyanate of formula
  • T he carbamoyl chloride can itself be prepared by treatment of an amine with triphosgene or phosgene in a suitable solvent such as a haloalkane (e.g. dichloromethane) or an ether (e.g. THF) at reduced (e.g. 0 0 C) to ambient temperature.
  • a suitable solvent such as a haloalkane (e.g. dichloromethane) or an ether (e.g. THF) at reduced (e.g. 0 0 C) to ambient temperature.
  • a methyl formate protecting group can be conveniently effected by the use of trimethylsilyliodide in a suitable organic solvent, such as a haloalkane (e.g. DCM) or an ether (e.g. THF); at ambient to elevated temperature (e.g. 50 0 C).
  • a suitable organic solvent such as a haloalkane (e.g. DCM) or an ether (e.g. THF); at ambient to elevated temperature (e.g. 50 0 C).
  • compounds of formula (X) may be prepared using an amine of formula (Xl) and an acid chloride/alkyl chloroformate of formula (XIX) according to the conditions described with respect to Scheme 1 , step (c).
  • compounds of formula (X) where R 9 is R 7 can be conveniently prepared by reductive amination by an amine of formula (Xl) with an aldehyde/ketone, in the presence of an acid, such as organic acid (e.g. acetic acid); in a solvent, such as a haloalkane (e.g. DCM) or an ether (e.g. THF); using an alkali metal hydride reducing agent, such as sodium triacetoxyborohydride, sodium cyanoborohydride or sodium borohydride; and at ambient temperature.
  • an acid such as organic acid (e.g. acetic acid)
  • a solvent such as a haloalkane (e.g. DCM) or an ether (e.g. THF)
  • an alkali metal hydride reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride or sodium borohydride
  • alkylation of a compound of formula (Xl) can be effected by use of an alkyl halide or alkyl sulfonate of formula (XX), in the presence of a base, such as an inorganic base (e.g. potassium carbonate); optionally in the presence of an metal iodide salt (e.g. potassium iodide); an organic solvent (e.g. DMF or NMP); and at ambient temperature to elevated temperature (up to 100 0 C).
  • a base such as an inorganic base (e.g. potassium carbonate); optionally in the presence of an metal iodide salt (e.g. potassium iodide); an organic solvent (e.g. DMF or NMP); and at ambient temperature to elevated temperature (up to 100 0 C).
  • a base such as an inorganic base (e.g. potassium carbonate); optionally in the presence of an metal iodide salt (e.g. potassium iodide); an organic solvent (e.g.
  • Step (g) may be carried out according to the conditions described with respect to scheme 1 , step (c).
  • compounds of formula (I) may be prepared by carrying out steps (d) to (g) in a different order, for example in the order (f), (g), (d), (e).
  • Pyrrolidines of formula (Vl) can be prepared by methods previously described in the literature, e.g. US2002/0198178 incorporated herein by reference.
  • Tropanes of formula (V) can also be prepared by methods previously described in the literature (WO00/038680, WO03/084954 and WO01/90106).
  • the compounds of formula (I) and their pharmaceutically acceptable salts, solvates and derivatives are useful because they have pharmacological activity in animals, including humans. More particularly, they are useful in the treatment of a disorder in which the modulation, in particular antagonism, of CCR5 receptors is implicated.
  • Disease states of particular interest include HIV, retroviral infections genetically related to HIV, AIDS, inflammatory diseases, autoimmune diseases and pain.
  • the compounds of this invention may be used for treatment of respiratory disorders, including adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis, chronic sinusitis, sarcoidosis, farmer's lung, nasal polyposis, fibroid lung or idiopathic interstitial pneumonia.
  • ARDS adult respiratory distress syndrome
  • bronchitis chronic bronchitis
  • chronic obstructive pulmonary disease cystic fibrosis
  • cystic fibrosis asthma
  • emphysema chronic obstructive pulmonary disease
  • cystic fibrosis cystic fibrosis
  • asthma emphysema
  • rhinitis chronic sinusitis
  • sarcoidosis farmer's lung
  • nasal polyposis fibroid lung or idiopathic interstitial pneumonia.
  • the compounds of this invention may be
  • CCR5 or CCR5 chemokines have been established, and more particularly, but not limited to, the following: multiple sclerosis; Behcet's disease, Sjogren's syndrome or systemic sclerosis; arthritis, such as rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, and juvenile arthritis; and graft rejection, in particular, but not limited to, solid organ transplants, such as heart, lung, liver, kidney and pancreas transplants (e.g.
  • kidney and lung allografts kidney and lung allografts
  • graft versus host rejection inflammatory bowel disease, including Crohn's disease and ulcerative colitis
  • inflammatory lung conditions endometriosis
  • renal diseases such as glomerular disease (e.g. glomerulonephritis); fibrosis, such as liver, pulmonary and renal fibrosis; encephalitis, such as HIV encephalitis; chronic heart failure; myocardial infarction; hypertension; stroke; ischaemic heart disease; atherosclerotic plaque ; restenosis; obesity; psoriasis; atopic dermatitis; CNS diseases, such as AIDS related dementias and Alzheimer's disease; anaemia; chronic pancreatitis; Hashimoto's thyroiditis; type I diabetes; cancer, such as non-Hodgkin's lymphoma, Kaposi's sarcoma, melanoma and breast cancer; pain, such as nociceptive pain and neur
  • Infectious diseases where modulation of the CCR5 receptor is implicated include acute and chronic hepatitis B Virus (HBV) and hepatitis C Virus (HCV) infection; bubonic, septicemic, and pneumonic plague; pox virus infection, such as smallpox; toxoplasmosis infection; mycobacterium infection; trypanosomal infection such as Chagas' Disease; pneumonia; and cytosporidiosis.
  • HBV hepatitis B Virus
  • HCV hepatitis C Virus
  • 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 the treatment of a disorder in which the modulation of CCR5 receptors is implicated.
  • the invention provides the use of a compound of formula (I) or of a pharmaceutically acceptable salt, solvate or derivative thereof, in the manufacture of a medicament for the treatment of a disorder in which the modulation of CCR5 receptors is implicated.
  • the invention provides a method of treatment of a disorder in which the modulation of CCR5 receptors is implicated which comprises administering to a patient in need thereof (e.g a human patient or an animal patient) a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof.
  • the compounds of the invention are useful in the treatment of the diseases, disorders or conditions mentioned above; diseases of particular interest include HIV, retroviral infections genetically related to HIV, AIDS, inflammatory diseases, autoimmune diseases and pain.
  • diseases of particular interest include HIV, retroviral infections genetically related to HIV, AIDS, inflammatory diseases, autoimmune diseases and pain.
  • references herein to "treatment” include references to curative, palliative and prophylactic treatment.
  • the invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof, for the treatment of a respiratory disorder including adult respiratory d istress syndrome (ARDS), b ronchitis, chronic b ronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis, chronic sinusitis, sarcoidosis; farmer's lung, nasal polyposis, fibroid lung or idiopathic interstitial pneumonia
  • ARDS adult respiratory d istress syndrome
  • b ronchitis chronic b ronchitis
  • chronic obstructive pulmonary disease cystic fibrosis
  • asthma emphysema
  • rhinitis chronic sinusitis
  • sarcoidosis farmer's lung, nasal polyposis, fibroid lung or idiopathic interstitial pneumonia
  • the invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof, for the treatment of multiple sclerosis, Behcet's disease, Sjogren's syndrome, systemic sclerosis, rheumatoid arthritis or graft rejection.
  • the invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof, for the treatment of inflammatory bowel d isease; e ndometriosis; type I diabetes; renal diseases; fibrosis such as liver fibrosis; chronic pancreatitis; inflammatory lurig conditions; encephalitis; chronic heart failure; myocardial infarction; ischaemic heart disease; psoriasis; stroke; obesity; CNS diseases; anaemia; restenosis; atherosclerotic plaque; atopic dermatitis; chronic pancreatitis; Hashimotos thyroiditis; cancer; pain; or stress response resulting from surgery, infection, injury or other traumatic insult.
  • the invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof, for the treatment of HBV, HCV, plague, pox virus, toxoplasmosis, mycobacterium, trypanosomal, pneumonia, or cytosporidiosis.
  • 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 disorder in which the modulation of CCR5 receptors is implicated.
  • the invention provides a method of treatment of a mammalian disorder in which the modulation of CCR5 receptors is implicated which comprises treating said mammal with an effective amount of a compound of formula (I) or with 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.
  • 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 a nd m ethods 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 0.1 wt% to 80 wt%, more typically from 1 wt% to 60 wt%, such as 5 wt% to 50 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 0.1 wt% to 25 wt%, more typically from 0.5 wt% to 20 wt%, such as 1 wt% to 15 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, calcium carbonate and dibasic calcium phosphate dihydrate.
  • lactose monohydrate, spray-dried monohydrate, anhydrous and the like
  • mannitol xylitol
  • dextrose sucrose
  • sorbitol microcrystalline cellulose
  • starch calcium carbonate 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.
  • surface active agents m ay 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.
  • 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.
  • 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 1 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.
  • Solid formulations for o ral administration m ay 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 On-line, 25(2), 1-14 (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298.
  • the compounds of the invention may also be administered directly into the blood stream, i nto m uscle, o r i nto a n internal organ.
  • Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrastemal, 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.
  • 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 stents 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, s ponges, fibres, bandages and m icroemulsions.
  • L iposomes m ay 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.
  • 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 ifor dispersing, solubiiising, 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). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
  • comminuting method such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
  • 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.
  • Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
  • a s Preble 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, vaginal ring or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
  • the compounds of the invention can also be applied topically to mucosa, such as vaginal and rectal mucosa. Typical formulations for this purpose include gels, creams, ointments, foams, wafers, implants and sponges.
  • 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. a bsorbable g el s ponges, collagen) a nd n on-biodegradable (e.g.
  • s ilicone implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.
  • a polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride.
  • Such formulations may also be delivered by iontophoresis.
  • Formulations for ocular/aural administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release.
  • 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 a uxiliary additive, i.e. as a carrier, diluent, or solubiliser.
  • compositions may conveniently be combined in the form of a kit suitable for coadministration of the compositions.
  • 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.
  • the total daily dose of a compound of the invention is typically in the range 1 to 10,000mg, such as 10 to
  • 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
  • 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 co-administration 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 any of the diseases or conditions mediated by or associated with CCR5 chemokine receptor modulation, particularly infection by human immunodeficiency virus, HIV.
  • the use of such combination therapy is especially p ertinent 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 co-administered in combination with one or more additional therapeutic agents such as those described in detail further herein.
  • the therapeutic agents that may be used in combination with the compounds of the present invention include, but are not limited to, those useful as HIV protease inhibitors (PIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), CCR5 antagonists, agents which inhibit the interaction of gp120 with CD4, other agents which inhibit the entry of HIV into a target cell, inhibitors of HIV integrase, RNaseH inhibitors, prenylation inhibitors, maturation inhibitors which act by interfering with production of the HIV capsid protein, compounds useful as anti-infectives, and others as described below.
  • PIs HIV protease inhibitors
  • NRTIs non-nucleoside reverse transcriptase inhibitors
  • NRTIs nucleoside/nucleotide reverse transcriptase inhibitors
  • CCR5 antagonists agents which inhibit the interaction of gp120 with CD4
  • a combination drug treatment may comprise two or more compounds having the same, or different, mechanism of action.
  • a combination may comprise a compound of the invention and: one or more NRTIs; one or more NRTIs and a Pl; one or more NRTIs and another CCR5 antagonist; a Pl; a Pl and an NNRTI; an NNRTI; and so on.
  • PIs include, but are not limited to, amprenavir (141W94), CGP-73547, CGP-61755, D MP-450 ( mozenavir), n elfinavir, ritonavir, saquinavir (invirase), lopinavir, TMC- 126, atazanavir, palinavir, GS-3333, KN 1-413, KNI-272, LG-71350, CGP-61755, PD 173606, PD 177298, PD 178390, PD 178392, U-140690, ABT-378, DMP-450, AG-1776, MK-944, VX- 478, indinavir, tipranavir, TMC-114, DPC-681 , DPC-684, fosamprenavir calcium (Lexiva), benzenesulfonamide derivatives disclosed in WO 03/053435, R-944, Ro-03-34649, VX-385, GS-224338, O
  • NRTIs include, but are not limited to, abacavir, GS-840, lamivudine, adefovir dipivoxil, beta-fluoro-ddA, zalcitabine, didanosine, stavudine, zidovudine, tenofovir disoproxii fumarate, amdoxovir (DAPD), SPD-754, SPD-756, racivir, reverset (DPC-817), MIV-
  • NNRTIs include, but are not limited to, efavirenz, HBY-097, nevirapine,
  • TMC-120 (dapivirine), TMC-125, etravirine, delavirdine, DPC-083, DPC-961 , capravirine, rilpivirine, 5- ⁇ [3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy ⁇ isophthalonitrile or pharmaceutically a cceptable s alts, s olvates o r d erivatives t hereof; GW-678248, GW -695634,
  • CCR5 antagonists include, but are not limited to, TAK-779, SC-351125, SCH-C (ancriviroc), SCH-D (vicriviroc), maraviroc, PRO-140, aplaviroc, AMD-887 CMPD-167, methyl 1 -enc/o- ⁇ 8-[(3S)-3-(acetylamino)-3-(3-fluorophenyl)propyl]-8-azabicyclo[3.2.1]oct-3-yl ⁇ -2- methyl-4,5,6,7-tetrahydro-1 /-/-imidazo[4,5-c]pyridine-5-carboxylate or pharmaceutically acceptable salts, solvates or derivatives thereof, methyl 3-enofo- ⁇ 8-[(3S)-3-(acetamido)-3-(3- fluorophenyl)propyl]-8-azabicyclo[3.2.1]oct-3-yl ⁇ -2-methyl-4,5,6,7-tetrahydro-
  • entry and fusion inhibitors include, but are not limited to, BMS-806, BMS- 488043, 5- ⁇ (1 S)-2-[(2R)-4-Benzoyl-2-methyl-piperazin-1 -yl]-1 -methyl-2-oxo-ethoxy ⁇ -4-methoxy- pyridine-2-carboxylic acid methylamide and 4- ⁇ (1S)-2-[(2R)-4-Benzoyl-2-methyl-piperazin-1-yl]- 1-methyl-2-oxo-ethoxy ⁇ -3-methoxy-N-methyl-benzamide, enfuvirtide (T-20), SP-01A, T1249, PRO 542, AMD-3100, soluble CD4, compounds disclosed in JP 2003171381 , and compounds disclosed in JP 2003119137.
  • inhibitors of HIV integrase include, but are not limited to, L-000870810 GW- 810781 , 1 ,5-naphthyridine-3-carboxamide derivatives disclosed in WO 03/062204, compounds disclosed in WO 03/047564, compounds disclosed in WO 03/049690, and 5-hydroxypyrimidine- 4-carboxamide derivatives disclosed in WO 03/035076.
  • p renylation inhibitors include, but are not limited to, HMG CoA reductase inhibitors, such as statins (e.g. atorvastatin).
  • maturation inhibitors include 3-O-(3'3'-dimethylsuccinyl) betulic acid (otherwise known as PA-457) and alphaHGA.
  • Anti-infectives that may be used in combination with the compounds of the present invention include antibacterials and antifungals.
  • antibacterials include, but are not limited to, atovaquone, azithromycin, clarithromycin, trimethoprim, trovafloxacin, pyrimethamine, daunorubicin, clindamycin with primaquine, fluconazole, pastill, ornidyl, eflornithine pentamidine, rifabutin, spiramycin, intraconazole-R51211 , trimetrexate, daunorubicin, recombinant human erythropoietin, recombinant human growth hormone, megestrol acetate, testerone, and total enteral nutrition.
  • antifungals include, but are not limited to, anidulafungin, C31G, caspofungin, DB-289, fluconazaole, itraconazole, ketoconazole, micafungin, posaconazole, and voriconazole.
  • - Proliferation inhibitors e.g. hydroxyurea.
  • - Immunomodulators such as AD-439, AD-519, alpha interferon, AS-101 , bropirimine, acemannan, CL246.738, EL10, FP-21399, gamma interferon, granulocyte macrophage colony stimulating factor (e.g.
  • IL-2 immune globulin intravenous, IMREG-1 , IMREG-2, imuthiol diethyl dithio carbamate, alpha-2 interferon, methionine-enkephalin, MTP-PE, remune, rCD4, recombinant soluble human CD4, interferon alfa-2, SK&F106528, soluble T4 thymopentin, tumor necrosis factor (TNF), tucaresol, recombinant human interferon beta, interferon alfa n-3.
  • TNF tumor necrosis factor
  • - Tachykinin receptor modulators e.g. NK1 antagonists
  • various forms of interferon or interferon derivatives e.g. NK1 antagonists
  • chemokine receptor agonists/antagonists such as CXCR4 antagonists (e.g AMD070 and AMD3100) or CD4 antagonists (e.g. TNX-355).
  • 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 influence, in particular down regulate, CCR5 receptor expression chemokines that induce CCR5 receptor intemalisation such MIP-1 ⁇ , MIP-1 ⁇ , RANTES and derivatives thereof; examples of such agents include, but are not limited to, immunosupressants, such as calcineurin inhibitors (e.g. tacrolimus 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-propionitrile) and pharmaceutically acceptable salts, solvates or derivatives thereof; cytokine antibodies (e.g. antibodies that inhibit the interleukin-2 (IL-2) receptor, including basiliximab and daclizumab); - Agents which interfere with cell activation or cell cycling, such as rapamycin.
  • cytokine antibodies e.g. antibodies that inhibit the interleukin-2 (IL-2) receptor, including basiliximab and daclizumab
  • - Agents which interfere with cell activation or cell cycling such as rapamycin.
  • the basic CCR5 chemokine receptor modulated disease or condition is HIV infection and multiplication it may be necessary or at least desirable to treat Hepatitis C Virus (HCV), Hepatitis B Virus (HBV), Human Papillomavirus (HPV), neoplasms, and other conditions which occur as the result of the immune-compromised state of the patient being treated.
  • HCV Hepatitis C Virus
  • HBV Hepatitis B Virus
  • HPV Human Papillomavirus
  • neoplasms and other conditions which occur as the result of the immune-compromised state of the patient being treated.
  • Other 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: -
  • albumin-interferon alfa TLR7 inhibitors; reverse transcriptase i nhibitors, s uch a s I amivudine a nd e mtricitabine; IMP dehydrogenase inhibitors such as ribavirin and viramidine; polymerase inhibitors (including NS5B polymerase inhibitors) such as valopicitabine, HCV-086, HCV-796 purine nucleoside analogues as disclosed in WO 05/009418, and imidazole derivatives as disclosed in WO 05/012288; alpha glucosidase inhibitors such as celgosivir; interferon enhancers such as EMZ- 702; serine protease inhibitors such as B1LN-2061 , SCH-6, VX-950, aza-peptide-based macrocyclic derivatives as disclosed in WO 05/010029 and those disclosed in WO 05/007681; caspase inhibitor
  • Agents useful in the treatment of AIDS related Kaposi's sarcoma such as interferons, daunorubicin, doxorubicin, paclitaxel, metallo-matrix proteases, A-007, bevacizumab, BMS- 275291 , halofuginone, interleukin-12, rituximab, porfimer sodium, rebimastat, COL-3.
  • CMV cytomegalovirus
  • agents useful in the treatment of cytomegalovirus such as fomivirsen, oxetanocin G, cidofovir, cytomegalovirus immune globin, foscarnet sodium, lsis 2922, valacyclovir, valganciclovir, ganciclovir.
  • HSV herpes simplex virus
  • 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.
  • adalimumab a compound of formula (I), or a pharmaceutically acceptable salt, solvate or derivative thereof, together with one or more additional therapeutic agents which slow down the rate of metabolism of the compound of the invention, thereby leading to increased exposure in patients.
  • 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 unb ⁇ osted 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 oxidative processes carried out by P450 (CYP450) enzymes, particularly CYP 3A4 and conjugation by UDP glucuronosyl transferase and sulphating enzymes:
  • CYP450 enzymes.
  • 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.
  • 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 comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof and one or more additional therapeutic agents.
  • NMR nuclear magnetic resonance tic - thin layer chromatography
  • Example 1 i-fO-encfoV. ⁇ -irOS ⁇ SVI-acetyl ⁇ -phenylpyrrolidin-a-yllmethylV ⁇ -azabicyclora. ⁇ .iloct-S-vO- ⁇ - isobutyryl-2-methyl-4,5,6,7-tetrahvdro-1H-imidazor4,5-cipyridine
  • Examples 2-20 were prepared according to the method described above in Example 1 using the appropriate acid chloride/chloroformate and the amine as specified.
  • Example 2 Prepared using the amine of Preparation
  • Examples 23-26 were prepared according to the method described above in Example 22 using the appropriate carboxylic acid and the amine as specified.
  • the crude product mixture was purified by silica gel column chromatography eluting with dichloromethane:methanol:concentrated aqueous ammonia (98:2:0.2 then 90:10:1 , by volume) to give the title compound as a white solid (170mg, 64%).
  • Example 29 was isolated as a by-product during the purification of Example 28 1-((3-e/?c/o)-8- ⁇ [(3S,4S)-1-acetyl-4-phenylpyrrolidin-3-yl]methyl ⁇ -8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-4,5,6,7- tetrahydro-1 H-imidazo[4,5-c]pyridine and was isolated as a white solid (43mg, 16%).
  • Preparations 4-6 were prepared according to the method described in Preparation 3 using the aldehydes from Preparations 1 or 2 as appropriate and the amine as specified.
  • reaction mixture was stirred at room temperature for 3 days.
  • the reaction mixture was heated at 5O 0 C for 4 hours. Further portions of the palladium on carbon (20% w/w; 20mg) and ammonium formate were added (1.0g, 15.9mmol) and the mixture was heated at 5O 0 C for 6 hours. After cooling to room temperature the reaction mixture was filtered through Arbocel, the filtrate was concentrated and purified by silica gel column chromatography eluting with dichloromethane:methanol:concentrated aqueous ammonia (90:10:1 , by volume) to give the title compound as a colourless oil (0.45g, 46%).
  • LRMS atmospheric pressure chemical ionisation
  • Preparations 8-11 were prepared according to the method described in Preparation 7 using the pyrrolidine as specified.
  • Preparation 17 was prepared according to the method described in Preparation 16 using the carbamate of Preparation 4, Methyl 1-((3-e/7cfo)-8- ⁇ [(3R,4S)-1-benzyl-4-phenylpyrrolidin-3- yl]methyl ⁇ -8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 ,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate.
  • Preparations 19-20 were prepared according to the method described in Preparation 18 using the amine as specified.
  • the reaction mixture was stirred at 50 0 C for 48 hours, during which time acetone (5 x 100 ⁇ l, 5 x 1.36mmol) and dichloromethane (5 x 2 ml) were added.
  • the reaction mixture was quenched by addition of 10% aqueous potassium carbonate solution (10ml) and extracted with dichloromethane (2 x 20ml). The combined organic components were dried (MgSO 4 ), filtered and concentrated.
  • the reaction mixture was heated at reflux for 88 hours during which time more BH 3 -THF complex (2.0ml of a 1.0M solution in THF) was added in portions. After cooling to room temperature the mixture was diluted by dropwise addition of 2M HCI (10ml) and the mixture was heated at 80 0 C for 4 hours. After cooling to room temperature 10% aqueous K 2 CO 3 solution was carefully added (20ml). The THF was removed under reduced pressure and the aqueous mixture was extracted with dichloromethane (2 X 15ml). The organic components were combined passed through a phase separation cartridge.
  • Cell lines expressing the receptor of interest include those naturally expressing the receptor, such as PM- 1 , or IL-2 stimulated peripheral b lood lymphocytes ( PBL), o r a cell e ngineered to express a recombinant receptor, such as CHO, 300.19, L1.2 or HEK-293.
  • PBL peripheral b lood lymphocytes
  • o r a cell e ngineered to express a recombinant receptor, such as CHO, 300.19, L1.2 or HEK-293.
  • the pharmacological activity of the compounds of formula (I) and their pharmaceutically acceptable salts, solvates and derivatives is further demonstrated using a gp160 induced cell-cell fusion assay to determine the IC 50 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.
  • 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 R PM11640 (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.
  • 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 Compounds that inhibit fusion will give rise to a reduced signal and, following solubilisation in an appropriate solvent and dilution in culture medium, a dose-response curve for each compound can be used to calculate IC 50 values. All the compounds of the Examples of the invention have IC 50 values, according to the above method, of less than 15OnM. The compounds of Examples 4, 7, 15, 22 and 25 have, respectively, IC 50 values of 18pM, 556pM, 5.1 nM, 6.7nM and 5.7 nM.

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Abstract

La présente invention concerne des composés ayant la formule (I) dans laquelle R1, R2, R3 et R4 sont définis dans la description. Les composés de la présente invention sont des modulateurs, et plus particulièrement des antagonistes, de l'activité des récepteurs de chimiokines CCR5. Les modulateurs du récepteur de CCR5 peuvent être utiles dans le traitement de divers états et maladies inflammatoires et dans le traitement de l'infection par le VIH et par des rétrovirus qui y sont liés génétiquement.
EP05813627A 2004-12-23 2005-12-12 Derives de 8-aza-bicyclo (3.2.1) octane possedant une activite de recepteurs de chimiokines ccr5 Withdrawn EP1831210A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB0428267A GB0428267D0 (en) 2004-12-23 2004-12-23 Chemical compounds
US65664805P 2005-02-24 2005-02-24
PCT/IB2005/003822 WO2006067584A1 (fr) 2004-12-23 2005-12-12 Derives de 8-aza-bicyclo (3.2.1) octane possedant une activite de recepteurs de chimiokines ccr5

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JP5898196B2 (ja) * 2010-08-05 2016-04-13 シガ・テクノロジーズ・インコーポレーテッド Ｓｔ−２４６液体製剤および方法
ES2740399T3 (es) 2011-03-09 2020-02-05 Richard G Pestell Líneas de células de cáncer de próstata, firmas genéticas y usos de estas
CA2873743C (fr) 2012-05-14 2022-12-06 Prostagene, Llc Utilisation de modulateurs de ccr5 dans le traitement du cancer
GB201321748D0 (en) * 2013-12-09 2014-01-22 Ucb Pharma Sa Therapeutic agents
EP3389787B1 (fr) 2015-12-17 2024-05-15 Thomas Jefferson University Dérivés de sulfonamide comme agents antiviraux pour la grippe a résistante aux médicaments

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US6531484B2 (en) * 2000-10-11 2003-03-11 Merck & Co., Inc. Pyrrolidine modulators of CCR5 chemokine receptor activity

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JP2008525418A (ja) 2008-07-17
CA2594602A1 (fr) 2006-06-29

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