WO2011092505A1 - Inhibiteurs des interactions des liaisons des protéines s100 - Google Patents

Inhibiteurs des interactions des liaisons des protéines s100 Download PDF

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WO2011092505A1
WO2011092505A1 PCT/GB2011/050137 GB2011050137W WO2011092505A1 WO 2011092505 A1 WO2011092505 A1 WO 2011092505A1 GB 2011050137 W GB2011050137 W GB 2011050137W WO 2011092505 A1 WO2011092505 A1 WO 2011092505A1
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hydroxy
phenyl
dihydro
pyrrol
benzoyl
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PCT/GB2011/050137
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English (en)
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Tummala R. K. Reddy
Chan LI
Peter M. Fischer
Lodewijk V. Dekker
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Cancer Research Technology Limited
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to compounds that are inhibitors of SI 00 protein binding interactions, such as, for example, the annexin A2-S100A10 protein binding interaction. More specifically, the present invention concerns certain substituted pyrrole derivatives, as well as processes for preparing these derivatives, pharmaceutical compositions comprising these derivatives and their use in the treatment, prevention or delay of progression of diseases in which SI 00 protein binding interactions are implicated.
  • SI 00 proteins are small acidic proteins which were first isolated from brain by virtue of their solubility in 100% saturated ammonium sulphate at neutral pH. They belong to the larger EF hand family of Ca 2+ binding proteins and have the capacity to form homodimers (two molecules of the same S100 protein), heterodimers (one molecule each of two different S100 protein family members) and oligomers (more complex arrangements) 1 ' 2 ' 3 .
  • the SI 00 protein family consists of over 20 family members which are unique in sequence and also show a degree of unique tissue distribution 1 ' 2 ' 3 .
  • Monomeric S100 proteins contain two non-identical EF hand motifs linked by a linker region.
  • EF hand motifs consist of two alpha helices linked by a 12 amino acid long Ca 2+ binding loop 3 .
  • S100 proteins are generally dimers, such as homodimers. They can also form
  • S100 proteins are responsive to Ca 2+ by virtue of their EF hands.
  • the structure of the S100A4 dimer changes upon Ca 2+ binding, to create potential interfaces for protein interaction 5 .
  • SIOOAIO At least one SI 00 protein, SIOOAIO, does not bind Ca 2+ due to mutations in the Ca 2+ binding sites of the EF hand.
  • the dimer of SIOOAIO is receptive to protein interactions (e.g. with Annexin A2) in the absence of Ca 2+ .
  • SI 00 proteins are thought to play an important role in a number of pathological conditions.
  • the interaction between the annexin A2 protein and SI 00 proteins is of particular interest as a potential therapeutic target.
  • Annexins are calcium and phospholipid binding proteins and some family members directly bind actin 7 .
  • the annexin A2 protein in particular has been implicated in cancer related properties of the tumour cells themselves (including migration, cell adhesion and metastasis) and in processes that regulate the tumour environment such as angiogenesis.
  • Annexin A2 exists in multiple forms, including a monomeric form and a complex with accessory proteins of the SlOO family 7 . This link with SlOO proteins is of interest since these proteins have themselves been proposed as cancer targets 8 .
  • annexin A2 The binding of annexin A2 to S100A10 has been characterized extensively, both biochemically and structurally.
  • Two S100A10 molecules form a dimeric structure that yields two binding pockets each of which accommodates the 14 amino acid N-terminal region of annexin A2 9 ' 10 . It appears that this annexin N-terminus is sufficient to mediate binding with the S100A10 dimer since annexin A2(l-14) as an isolated peptide can dissociate the complex 11 and deletion of residues 1-14 results in a complete loss of the interaction 12 . Similar interactions take place between the N-terminus of annexin A2 and the S100A4 dimer 12 .
  • Peptides representing the annexin A2 N-terminus are expected to prevent the formation of new complexes but in addition have been shown to disrupt completely a preexisting tetramer complex of annexin A2 and S100A10 11 .
  • the annexin A2(l-14) peptide has been used to probe the function of this complex in vivo and to provide important evidence that the interaction is functionally targetable in cancer.
  • the studies so far have only looked at straight effects of the peptide, which cannot penetrate cells and therefore only interrupts complexes localized outside the cell.
  • the peptide gives almost complete block of the FGF and VEGF induced angiogenic response into matrigel plugs implying a major function for these complexes in angiogenesis 13 .
  • the annexin A2(l-14) peptide also inhibits the adhesion of prostate cancer cells to bone marrow endothelial cells and to osteoblasts in vitro and furthermore when this peptide is injected into the animal, it inhibits metastasis of prostate cancer cells thus providing proof of concept that the annexin A2 complex is important in prostate cancer cell metastasis.
  • Inhibitors of the annexin A2-S100 protein binding interaction offer potential new therapies for diseases/conditions in which the annexin A2-S100 protein binding interaction is implicated. In addition, these agents also offer the possibility of disrupting other SlOO protein binding interactions.
  • the present invention provides small molecule inhibitors of SlOO protein binding interactions, especially inhibitors of the annexin A2- SlOO protein binding interaction.
  • the present invention provides novel compounds as defined herein, which are inhibitors of SlOO protein binding interactions.
  • the present invention provides inhibitors of SI 00 protein binding interactions as defined herein for use in therapy.
  • the present invention provides a pharmaceutical composition comprising an inhibitor of SI 00 protein binding interactions as defined herein and a
  • the present invention also provides processes for the preparation of the compounds defined herein and novel synthetic intermediates that are used in these processes.
  • the ability of the compounds of the invention to inhibit SI 00 protein binding interactions means that they are potentially useful agents for the treatment of pathological conditions in which SI 00 proteins play a role. Examples of such conditions are described further herein.
  • the present invention provides an inhibitor of S100 protein binding interactions as defined herein for use in the treatment of diseases/conditions in which SI 00 protein binding interactions are implicated.
  • the present invention provides the use of an inhibitor compound of SI 00 protein binding interactions as defined herein in the manufacture of a medicament for use in the treatment of diseases/conditions in which SI 00 protein binding interactions are implicated.
  • the present invention provides a method of treating a disease or condition in which a SI 00 protein binding interaction is implicated, the method comprising administering to a warm blooded mammal (such as human) in need of such treatment a therapeutically effective amount of an inhibitor compound of SI 00 protein binding interactions as defined herein.
  • S100 protein refers to a member of the S100 family of proteins.
  • S100 protein binding interaction refers to the binding of a protein to an S100 protein or SI 00 protein dimer.
  • alkyl is used herein to refer to a straight or branched chain alkyl moiety.
  • (l-6C)alkyl refers to alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms. This term includes groups such as methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec -butyl or tert-butyl), pentyl, hexyl and the like. Suitably an alkyl group has 1, 2, 3 or 4 carbon atoms.
  • alkyl also includes cycloalkyl or cycloalkyl-alkyl groups.
  • Ci_6 alkyl includes C 3 _ 6 cycloalkyl groups, such as cyclopropyl, cyclobutyl and cyclohexyl and cycloalkyl- alkyl groups such as cyclopropylmethyl.
  • An analogous convention applies to other generic terms, for example “alkenyl” and “alkynyl”.
  • alkoxy as used herein include reference to -O-alkyl groups, wherein the alkyl moiety is a straight or branched chain.
  • an alkoxy group has 1 , 2, 3 or 4 carbon atoms. This term includes reference to groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, hexoxy and the like.
  • alkylene is an alkyl group that is positioned between and serves to connect two other chemical groups.
  • “Ci_ 6 alkylene” means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, for example, methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like.
  • halo refers to fluoro, chloro, bromo and iodo.
  • heterocyclyl means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system(s).
  • heterocyclyl includes both monovalent species and divalent species.
  • Monocyclic heterocyclic rings contain from about 3 to 12 (suitably from 3 to 7) ring atoms, with from 1 to 5 (suitably 1 , 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring.
  • Bicyclic heterocycles contain from 7 to 17 member atoms, suitably 7 to 12 member atoms, in the ring.
  • Bicyclic heterocycles contain from about 7 to about 17 ring atoms, suitably from 7 to 12 ring atoms. Bicyclic heterocyclic(s) rings may be fused, spiro, or bridged ring systems.
  • heterocyclic groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers.
  • Heterocycles containing nitrogen include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like.
  • Typical sulfur containing heterocycles include tetrahydrothienyl, dihydro-l ,3-dithiol, tetrahydro- 2H-thiopyran, and hexahydrothiepine.
  • Other heterocycles include dihydro-oxathiolyl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl.
  • the oxidized sulfur heterocycles containing SO or S0 2 groups are also included.
  • examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl such as tetrahydrothiene 1 ,1 -dioxide and thiomorpholinyl 1 ,1 -dioxide.
  • heterocyclyl groups are saturated monocyclic 3 to 7 membered heterocyclyls containing 1 , 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl,
  • any heterocycle may be linked to another group via any suitable atom, such as via a carbon or nitrogen atom.
  • reference herein to piperidino or morpholino refers to a piperidin-l-yl or morpholin-4-yl ring that is linked via the ring nitrogen.
  • HeterocyclylCi_ 6 alkyl means a heterocyclyl group covalently attached to a Ci_ 6 alkylene group, both of which are defined herein.
  • heteroaryl or “heteroaromatic” means an aromatic mono-, bi-, or polycyclic ring incorporating one or more (for example 1-4, particularly 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur.
  • heteroaryl includes both monovalent species and divalent species. Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more usually from five to ten ring members.
  • the heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring, for example a bicyclic structure formed from fused five and six membered rings or two fused six membered rings.
  • Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen.
  • the heteroaryl ring will contain up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
  • the heteroaryl ring contains at least one ring nitrogen atom.
  • the nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.
  • heteroaryl examples include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carb
  • Heteroaryl also covers partially aromatic bi- or polycyclic ring systems wherein at least one ring is an aromatic ring and one or more of the other ring(s) is a non-aromatic, saturated or partially saturated ring, provided at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur.
  • partially aromatic heteroaryl groups include for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-l,2,3,4- tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 2,3-dihydro-benzo[l,4]dioxinyl, benzo[l ,3]dioxolyl, 2,2-dioxo-l ,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl, indolinyl, l ,2,3,4-tetrahydro-l ,8-naphthyridinyl, l ,2,3,4-tetrahydropyrido[2,3- ⁇ ]pyrazinyl and 3,4-dihydro-2H-pyrido[3,2-&] [1 ,4]oxazinyl
  • heteroaryl groups examples include but are not limited to pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
  • heteroaryl groups examples include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.
  • bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzfuranyl, benzthiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl and pyrazolopyridinyl groups.
  • bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl,
  • aryl means a cyclic or polycyclic aromatic ring having from 5 to 12 carbon atoms.
  • aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like.
  • arylCi_ 6 alkyl means an aryl group covalently attached to a group, both of which are defined herein.
  • aryl-Ci- 6 alkyl groups include benzyl, phenylethyl, and the like.
  • oxo is used herein to denote a double bonded oxygen atom.
  • An oxo group is normally attached to a carbon atom so that oxygen atom and carbon together form a carbonyl (-C(O)-) group.
  • treatment used herein encompasses prophlylactic treatment.
  • references to "compounds of the invention” herein refer to the compounds of general formulae I and II as defined herein below, and includes tautomers and pharmaceutically acceptable salts and solvates thereof. Compounds for use in the useful for the treatment of diseases and/or conditions in which S100 protein binding interactions are implicated
  • the present invention provides novel compound useful for the treatment of diseases and/or conditions in which S I 00 protein binding interactions are implicated.
  • Ri is selected from:
  • R z is selected from halo, nitro, cyano, hydroxy, CF 3 , (l-4C)alkyl, (l-4C)alkoxy, C(0)OR a , -OC(0)-R a , -C(0)NR a R b , -NR b C(0)R a , -NR a R b , -S(0) n R a (where n is 0, 1 or 2), or -S0 2 NR a R b ;
  • R 2 , R3, R4 and R 5 are each independently selected from hydrogen, halo, nitro, cyano, hydroxy, CF 3 , (l-5C)alkyl, (l-5C)alkoxy, -C(0)R a , -C(0)OR a , -OC(0)-R a , -C(0)NR a R b , - NR b C(0)R a , -NR a R b , -S(0) n
  • R 2 and R 3 , R 3 and R 4 , or R 4 and R 5 are linked to form a fused phenyl or 5 or 6- membered heterocyclyl ring, which is optionally substituted by hydrogen, halo, nitro, cyano, hydroxy, CF 3 , (l-5C)alkyl, (l-5C)alkoxy, -C(0)R a , -C(0)OR a , -OC(0)-R a , - C(0)NR a R b , -NR b C(0)R a , -NR a R b , -S(0) n R a (where n is 0, 1 or 2), or -S0 2 NR a R b ;
  • Q is aryl or heteroaryl, each of which is optionally substituted by one or more substituents selected from halo, nitro, cyano, hydroxy, CF 3 , (l-4C)alkoxy, -C(0)R a , -C(0)OR a , - OC(0)-R a , -C(0)NR a R b , -NR b C(0)R a , -NR a R b , -S(0) n R a (where n is 0, 1 or 2), or - S(0) 2 NR a R b ;
  • R a and R b are each independently selected from hydrogen or (l-4C)alkyl
  • Particular compounds according to the first aspect of the invention include, for example, compounds of the formula I or II, or pharmaceutically acceptable salts or solvates thereof, wherein, unless otherwise stated, each of Ri, R z , R 2 , R 3 , R 4 , R 5 , R a , R b and Q have any of the meanings defined hereinbefore or in any of paragraphs (1) to (30) hereinafter: -
  • Ri is selected from:
  • aryl-(l-2C)alkyl group which is optionally substituted by one or more R z ; wherein R z is selected from halo, nitro, cyano, hydroxy, CF 3 , (l-4C)alkyl, (1- 4C)alkoxy, -C(0)OR a , -OC(0)-R a , -C(0)NR a R b , -NR b C(0)R a , -NR a R b , S(0) n R a (where n is 0, 1 or 2), or -S0 2 NR a R b .
  • R z is selected from halo, nitro, cyano, hydroxy, CF 3 , (l-4C)alkyl, (1- 4C)alkoxy, -C(0)OR a , -OC(0)-R a , -C(0)NR a R b , -NR b C(0)R a , -NR a R b ,
  • Ri is selected from:
  • aryl-(l -2C)alkyl group which is optionally substituted by one or more R z ; wherein R z is selected from halo, nitro, cyano, hydroxy, CF 3 , (l-3C)alkyl, (1- 3C)alkoxy, -C(0)NR a R b , -NR b C(0)R a , -NR a R b , -S(0) n R a (where n is 0, 1 or 2), or S0 2 NR a R b .
  • Ri is selected from:
  • R z is selected from halo, nitro, cyano, hydroxy, CF 3 , (l-3C)alkyl, (1- 3C)alkoxy, -C(0)NR a R b , -NR b C(0)R a , -NR a R b , -S(0) n R a (where n is 0, 1 or 2), or S0 2 NR a R b .
  • R z is selected from halo, nitro, cyano, hydroxy, CF 3 , (l-3C)alkyl, (1- 3C)alkoxy, -C(0)NR a R b , -NR b C(0)R a , -NR a R b , -S(0) n R a (where n is 0, 1 or 2), or S0 2 NR a R b .
  • Ri is selected from:
  • Ri is selected from:
  • aryl-(l-2C)alkyl group which is optionally substituted by one to five R z . is selected from:
  • Ri is selected from:
  • R z is selected from halo, nitro, cyano, hydroxy, CF 3 , (l-4C)alkyl, (l-4C)alkoxy, - C(0)OR a , -OC(0)-R a , -C(0)NR a R b , -NR b C(0)R a , -NR a R b , -S(0) n R a (where n is 0, 1 or 2) or -S0 2 NR a R b .
  • R z is selected from halo, nitro, cyano, hydroxy, CF 3 , (l-4C)alkyl, (l-4C)alkoxy, - C(0)NR a R b , -NR b C(0)R a , -NR a R b , -S(0) n R a (where n is 0, 1 or 2) or
  • R z is selected from halo, nitro, cyano, hydroxy, CF 3 , (l-4C)alkyl, (l-4C)alkoxy, - NR a R b , or -S(0) n R a (where n is 0, 1 or 2).
  • R z is selected from halo, nitro, cyano, hydroxy, CF 3 , (l-2C)alkyl, (l-2C)alkoxy, - NR a R b , or -S(0) n R a (where n is 0, 1 or 2).
  • R 2 , R 3 , R 4 and R 5 are selected from hydrogen, halo, nitro, cyano, hydroxy, CF 3 , (1- 5C)alkyl, (l-5C)alkoxy, -C(0)R a , -C(0)OR a , -OC(0)-R a , -C(0)NR a R b , -NR b C(0)R a , -NR a R b , -S(0) n R a (where n is 0, 1 or 2), or -S0 2 NR a R b , with the proviso that at least two of R 2 , R 3 , R 4 and R 5 are a substituent other than hydrogen; or R 2 and R 3 , R 3 and R 4 , or R 4 and R 5 are linked to form a fused phenyl or 5 or 6- membered heteroaryl ring, which is optionally substituted by hydrogen, halo, nitro, cyano, hydroxy, CF
  • R 2 , R3, R 4 and R 5 are selected from hydrogen, halo, nitro, cyano, hydroxy, CF 3 , (1- 5C)alkyl, (l-5C)alkoxy, -C(0)R a , -C(0)OR a , -OC(0)-R a , -C(0)NR a R b , -NR b C(0)R a , -NR a R b , -S(0) n R a (where n is 0, 1 or 2), or -S0 2 NR a R b , with the proviso that at least two of R 2 , R 3 , R 4 and R 5 are hydrogen;
  • R 2 and R 3 , R 3 and R 4 , or R 4 and R 5 are linked to form a fused phenyl ring.
  • R 2 , R 3 , R 4 and R 5 are selected from hydrogen, halo, nitro, cyano, CF 3 , amino, (2- 4C)alkyl, or (l-5C)alkoxy, with the proviso that at least two of R 2 , R 3 , R 4 and R 5 are hydrogen.
  • R 2 , R 3 , R 4 and R 5 are selected from hydrogen, halo, CF 3 , (2-4C)alkyl, or (1- 2C)alkoxy.
  • R 2 , R 3 , R 4 and R 5 are selected from hydrogen, halo, CF 3 or isopropyl.
  • R 2 , R 3 , R 4 and R 5 are a substituent other than hydrogen as defiend herein.
  • R 2 is hydrogen.
  • R 2 is hydrogen and one or two of the groups R 3 , R4 and R 5 are a substituent other than hydrogen as defined herein.
  • R 2 and R 4 are hydrogen and one or two of the groups R 3 and R 5 are a substituent other than hydrogen as defined herein.
  • R 3 and R 5 are a substituent other than hydrogen as defined herein.
  • Q is phenyl or heteroaryl, each of which is optionally substituted by one or more substituents selected from halo, nitro, cyano, hydroxy, CF 3 , (l-4C)alkoxy, -C(0)R a , - C(0)OR a , -OC(0)-R a , -C(0)NR a R b , -NR b C(0)R a , -NR a R b , -S(0) n R a (where n is 0, 1 or 2), or -S(0) 2 NR a R b .
  • Q is phenyl optionally substituted by one or more substituents selected from halo, nitro, cyano, hydroxy, CF 3 , (l-4C)alkoxy, -C(0)R a , -C(0)OR a , -OC(0)-R a , - C(0)NR a R b , -NR b C(0)R a , -NR a R b , -S(0) n R a (where n is 0, 1 or 2), or -S(0) 2 NR a R b .
  • Q is phenyl optionally substituted by one, two or three substituents selected from halo, nitro, cyano, hydroxy, CF 3 , (l-4C)alkoxy, -C(0)R a , -C(0)OR a , -OC(0)-R a , - C(0)NR a R b , -NR b C(0)R a , -NR a R b , -S(0) n R a (where n is 0, 1 or 2), or -S(0) 2 NR a R b .
  • R a and R b are each independently selected from hydrogen or (l-2C)alkyl.
  • R a and R b are each independently selected from hydrogen or methyl.
  • Q is phenyl which is para substituted by a substituent group selected from those recited in paragraph (28) above.
  • R 2 is hydrogen, i.e. the compounds have the following formula:
  • R 1; R 3 , R 4 , R 5 and Q each have any one of the definitions set out herein;
  • R 3 and R 5 are hydrogen and R 4 is (l-4C)alkyl (especially isopropyl), and and Q each have any one of the definitions set out herein.
  • R 2 and R4 are hydrogen, i.e. the compounds have the following for
  • R 1; R 3 , R 5 and Q each have any one of the definitions set out herein;
  • R 3 and R 5 are both a substituent as defined hereinbefore other than hydrogen.
  • R 3 and R 5 are both -CF 3 , and Ri and Q each have any one of the definitions set out hereinbefore.
  • R 3 and R 5 are hydrogen, i.e. the compounds have the following formula:
  • R 1; R 2 , R 4 and Q each have any one of the definitions set out herein;
  • R 2 and R 5 are hydrogen, i.e. the compounds have the following formula: or its tautomer:
  • R 1; R 3 , R 4 and Q each have any one of the definitions set out herein;
  • Particular compounds of the invention include any one of the following:
  • the present invention further provides certain novel compounds.
  • the present invention provides a compound of formula I or II above, wherein:
  • Ri is selected from:
  • R z is selected from halo, nitro, cyano, hydroxy, CF 3 , (l-4C)alkyl, (1- 4C)alkoxy, -C(0)OR a , -OC(0)-R a , -C(0)NR a R b , -NR b C(0)R a , -NR a R b , -S(0) n R a (where n is 0, 1 or 2), or -S0 2 NR a R b ;
  • R 2 , R3, R4 and R 5 are each independently selected from hydrogen -, cyano, hydroxy, CF 3 , (l-5C)alkyl, (l-5C)alkoxy, -C(0)R a , , -OC(0)-R a , -C(0)NR a R b , -NR b C(0)R a , -NR a R b , - S(0) n R a (where n is 0, 1 or 2), or -S0 2 NR a R b , with the proviso that at least one of R 2 , R 3 , R4 and R 5 is a substituent other than H;
  • R 2 and R 3 , R 3 and R 4 , or R 4 and R 5 are linked to form a fused phenyl or 5 or 6- membered heterocyclyl ring, which is optionally substituted by hydrogen, halo, nitro, cyano, hydroxy, CF 3 , (l-5C)alkyl, (l-5C)alkoxy, -C(0)R a , -C(0)OR a , -OC(0)-R a , - C(0)NR a R b , -NR b C(0)R a , -NR a R b , -S(0) n R a (where n is 0, 1 or 2), or -S0 2 NR a R b ;
  • Q is aryl or a mono- or bi-cyclic heteroaryl ring, each of which is optionally substituted by one or more substituents selected from halo, nitro, cyano, hydroxy, CF 3 , (l-5C)alkyl, (l-5C)alkoxy, -C(0)R a , -C(0)OR a , -OC(0)-R a , -C(0)NR a R b , -NR b C(0)R a , -NR a R b , - S(0) n R a (where n is 0, 1 or 2), or -S(0) 2 NR a R b ;
  • R a and R b are selected from hydrogen or (l-4C)alkyl
  • Ri is not -CH 2 -CHOHCH 3 , when R 4 is methyl, ethyl, isopropyl, tert-butyl,
  • R 2 , R 3 and R 5 are H; and Q is /rara-methylphenyl;
  • Ri is not -CH 2 -CHOHCH 3 , when R 2 and R 4 are chloro; R 3 and R 5 are H; and Q is /rara-methylphenyl;
  • Ri is not -CH 2 -CHOHCH 3 , when R 4 is isopropyl; R 2 , R 3 and R 5 are H; and Q is phenyl;
  • novel compounds of the invention include, for example, compounds of the formula I or II, or pharmaceutically acceptable salts or solvates thereof, wherein, unless otherwise stated, each of R z , R 2 , R 3 , R 4 , R 5 , R a , R b and Q are as defined above in relation to the first aspect of the invention, and has any of the meanings defined in any of paragraphs (31) to (39) hereinafter:- Ri is selected from:
  • R z is selected from halo, nitro, cyano, hydroxy, CF 3 , (l-4C)alkyl, (1- 4C)alkoxy, -C(0)OR a , -OC(0)-R a , -C(0)NR a R b , -NR b C(0)R a , -NR a R b , -S(0) n R a (where n is 0, 1 or 2), or -S0 2 NR a R b .
  • Ri is selected from:
  • R z is selected from halo, nitro, cyano, hydroxy, CF 3 , (l-4C)alkyl, (1- 4C)alkoxy, -C(0)OR a , -OC(0)-R a , -C(0)NR a R b , -NR b C(0)R a , -NR a R b , -S(0) n R a (where n is 0, 1 or 2), or -S0 2 NR a R b .
  • Ri is selected from:
  • R z is selected from halo, nitro, cyano, hydroxy, CF 3 , (l-3C)alkyl, (1-
  • Ri is selected from:
  • R z is selected from halo, nitro, cyano, hydroxy, CF 3 , (l-3C)alkyl, (1-
  • Ri is selected from:
  • R z is selected from halo, nitro, cyano, hydroxy, CF 3 , (l-3C)alkyl, (1-
  • Ri is selected from:
  • Ri is selected from:
  • Ri is selected from:
  • Ri is selected from:
  • Q is phenyl which is para substituted by one substiuent group selected from those mentioned in paragraph (28) above.
  • R 1; R 3 , R 5 and Q each have any one of the definitions set out hereinbefore; or a pharmaceutically acceptable salt or solvate thereof.
  • R 3 and R 5 are both a substituent as defined hereinbefore other than hydrogen.
  • R 3 and R 5 are -CF 3 , and Ri and Q each have any one of the definitions set out hereinbefore.
  • compounds of the formula (Ie) and (He) include the definition of provided for the first aspect of the invention above, as well as those set oput above for the second aspect.
  • novel compounds of the invention include any one of the following:
  • the various functional groups and substituents making up the compounds of the present invention are typically chosen such that the molecular weight of the compound of the formula I or II does not exceed 1000. More usually, the molecular weight of the compound will be less than 750, for example less than 700, or less than 650, or less than 600, or less than 550. More preferably, the molecular weight is less than 525 and, for example, is 500 or less.
  • a suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric or maleic acid.
  • a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium or magnesium salt
  • an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation
  • a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxye
  • isomers Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".
  • the compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof.
  • the methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form.
  • Some of the compounds of the invention may have geometric isomeric centres (E- and Z- isomers). It is to be understood that the present invention encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess SI 00 protein binding inhibitory activity.
  • tautomeric forms include keto-, enol-, and enolate -forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro.
  • N-oxides may also form N-oxides.
  • a reference herein to a compound of the formula I that contains an amine function also includes the N-oxide.
  • one or more than one nitrogen atom may be oxidised to form an N-oxide.
  • Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.
  • N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4 th Edition, Wiley Interscience, pages.
  • N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane .
  • MCPBA m-chloroperoxybenzoic acid
  • the compounds of formula I or II may be administered in the form of a pro-drug which is broken down in the human or animal body to release a compound of the invention.
  • a pro-drug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the invention.
  • a pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property-modifying group can be attached.
  • Examples of pro-drugs include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of the formula I or II and in-vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of the formula I or II.
  • the present invention includes those compounds of the formula I or II as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the formula I or II that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the formula I or II may be a synthetically-produced compound or a metabolically-produced compound.
  • a suitable pharmaceutically acceptable pro-drug of a compound of the formula I or II is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.
  • pro-drug Various forms of pro-drug have been described, for example in the following
  • a suitable pharmaceutically acceptable pro-drug of a compound of the formula I or II that possesses a carboxy group is, for example, an in vivo cleavable ester thereof.
  • An in vivo cleavable ester of a compound of the formula I or II containing a carboxy group is, for example, a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid.
  • Suitable pharmaceutically acceptable esters for carboxy include
  • Ci- 6 alkyl esters such as methyl, ethyl and tert-bv&yl
  • Ci_ 6 alkoxymethyl esters such as
  • Ci_ 6 alkanoyloxymethyl esters such as pivaloyloxymethyl esters
  • a suitable pharmaceutically acceptable pro-drug of a compound of the formula I or II that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof.
  • An in vivo cleavable ester or ether of a compound of the formula I or II containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound.
  • Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters).
  • ester forming groups for a hydroxy group include Ci_i 0 alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, Ci_i 0 alkoxycarbonyl groups such as ethoxycarbonyl, N,N -(Ci-6) 2 carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups.
  • Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include OC-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.
  • a suitable pharmaceutically acceptable pro-drug of a compound of the formula I or II that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a Ci_ 4 alkylamine such as methylamine, a (Q. 4 alkyl) 2 amine such as dimethylamine, N-ethyl-N-methylamine or diethylamine, a Ci_ 4 alkoxy- C 2 . 4 alkylamine such as 2-methoxyethylamine, a phenyl-Ci_ 4 alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.
  • an amine such as ammonia
  • a Ci_ 4 alkylamine such as methylamine
  • a (Q. 4 alkyl) 2 amine such as dimethylamine, N-ethyl-N-methylamine or diethylamine
  • a suitable pharmaceutically acceptable pro-drug of a compound of the formula I or II that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof.
  • Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with Ci-ioalkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups.
  • ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, Af,Af-dialkylaminomethyl, morpholinomethyl, piperazin-l-ylmethyl and
  • the in vivo effects of a compound of the formula I or II may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the formula I or II. As stated hereinbefore, the in vivo effects of a compound of the formula I or II may also be exerted by way of metabolism of a precursor compound (a pro-drug).
  • the present invention provides a process for preparing a compound of the invention as defined herein.
  • Any mixtures of final products or intermediates obtained can be separated on the basis of the physico-chemical differences of the constituents, in a known manner, into the pure final products or intermediates, for example by chromatography, distillation, fractional crystallisation, or by the formation of a salt if appropriate or possible under the circumstances.
  • the present invention provides a method of synthesising a compound of formula I as defined herein, the method comprising reacting a compound of formula A:
  • R 2 , R 3 , R 4 and R 5 each have any one of the definitions set out herein;
  • the above reaction may be carried out in the presence of a suitable solvent.
  • suitable solvents are known in the art and include 1,4-dioxane.
  • compound D is prepared by reaction Q-methyl ketones with dimethyl oxalate in 2M MeONa in MeOH solution under microwave irradiation (250 W) for 5 minutes at 30 °C. With most Q-methyl ketones this reaction gave rise to a precipitate of the sodium enolate Claisen adduct, which upon acidification to pH 3-4 provided Compound D in maximally 52% isolated yields.
  • the pyruvate compound D is subjected to a three -component coupling reaction with the appropriate amines (compound B) and aldehydes (compound A). 19"21
  • the three -component reaction of an amine (compound B), aldehyde (compound A), and compound D occurs through the initial formation of an imine (compound C), which then undergoes cyclocondensation with compound D.
  • ketone dimethyl oxalate a Reagents and conditions: (a); 1,4-dioxane, 15 min; (b) 1,4-dioxane, overnight reaction; (c) i, microwave irradiation, 250W, 30 °C, 5 min, 2 M NaOMe/MeOH; ii, H + (pH 3 ⁇ ).
  • the compounds of the invention will normally be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, by any other parenteral route, as an oral or nasal spray or via inhalation,
  • the compounds may be administered in the form of pharmaceutical preparations comprising prodrug or active compound either as a free compound or, for example, a pharmaceutically acceptable non-toxic organic or inorganic acid or base addition salt, in a pharmaceutically acceptable dosage form.
  • the compositions may be administered at varying doses.
  • the pharmaceutical compounds of the invention may be administered orally or parenterally ("parenterally” as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion) to a host.
  • parenterally refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion
  • the compounds may be administered alone or as compositions in combination with pharmaceutically acceptable diluents, excipients or carriers.
  • Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration.
  • the selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses.
  • the dosage level is about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day.
  • a suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day.
  • compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0 and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • the compounds may be administered on a regimen of 1 to 4 times per day, e.g. once or twice per day. The dosage regimen may be adjusted to provide the optimal therapeutic response.
  • composition including a compound of the invention as defined herein, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • compositions of this invention for parenteral injection suitably comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol or phenol sorbic acid. It may also be desirable to include isotonic agents such as sugars or sodium chloride, for example. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents (for example aluminum monostearate and gelatin) which delay absorption.
  • adjuvants such as preservative, wetting agents, emulsifying agents and dispersing agents.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is typically mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or one or more: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate;
  • the dosage form may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycol, for example.
  • oral formulations contain a dissolution aid.
  • the dissolution aid is not limited as to its identity so long as it is pharmaceutically acceptable. Examples include nonionic surface active agents, such as sucrose fatty acid esters, glycerol fatty acid esters, sorbitan fatty acid esters (e.g.
  • sorbitan trioleate polyethylene glycol, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene alkyl ethers, methoxypolyoxy ethylene alkyl ethers, polyoxyethylene alkylphenyl ethers, polyethylene glycol fatty acid esters, polyoxyethylene alkylamines, polyoxyethylene alkyl thioethers, polyoxyethylene polyoxypropylene copolymers, polyoxyethylene glycerol fatty acid esters, pentaerythritol fatty acid esters, propylene glycol monofatty acid esters, polyoxyethylene propylene glycol monofatty acid esters, polyoxyethylene sorbitol fatty acid esters, fatty acid alkylolamides, and alkylamine oxides; bile acid and salts thereof (e.g.,
  • ionic surface active agents such as sodium laurylsulfate, fatty acid soaps, alkylsulfonates, alkylphosphates, ether phosphates, fatty acid salts of basic amino acids; triethanolamine soap, and alkyl quaternary ammonium salts; and amphoteric surface active agents, such as betaines and aminocarboxylic acid salts.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, and/or in delayed fashion. Examples of embedding compositions include polymeric substances and waxes.
  • the active compounds may also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • the active compounds may be in finely divided form, for example they may be micronised.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.
  • inert diluents commonly used in the art such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, is
  • the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth and mixtures thereof.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolisable lipid capable of forming liposomes can be used.
  • the present compositions in liposome form can contain, in addition to a compound of the present invention, stabilisers, preservatives, excipients and the like.
  • the preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p 33 et seq.
  • Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which may be required.
  • Ophthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • the compounds of the present invention act as inhibitors of the interaction between members of the SlOO protein family and their respective protein binding partners.
  • the present invention provides a compound of the invention as defined herein for use in the inhibition of the interaction between SlOO proteins and their protein binding partners.
  • the present invention provides a method of inhibiting the interaction between a SlOO protein and its protein binding partner, the method comprising administering a compound of the invention as defined herein.
  • the present invention provides the use of a compound of the invention as defined herein for use in the manufacture of a medicament for use in the inhibition of the interaction between SlOO proteins and their protein binding partners.
  • Protein binding partners include the endogenous mammalian (e.g. human) proteins that interact with SlOO proteins in vivo.
  • the method comprises administering the compound of the invention as defined herein to a warm blooded mammal in need of such inhibition.
  • the compounds of the invention inhibit the protein binding interaction between SlOO proteins and binding partner proteins.
  • the compounds of the present invention inhibit the interaction between S100A10 and binding partner proteins.
  • the compounds of the present invention inhibit the interaction between S100A4 and binding partner proteins. In a particular embodiment, the compounds of the present invention inhibit the interaction between SlOO proteins and Annexin A2.
  • the compounds of the present invention inhibit the interaction between S100A10 and Annexin A2 or S100A4 and Annexin A2.
  • the compounds of the present invention inhibit the interaction between S100A10 and Annexin A2.
  • the compounds of the present invention inhibit the interaction between S100A4 and Annexin A2.
  • the compounds of the present invention inhibit the interaction between S100A4 and Myosin IIA.
  • the compounds of the present invention may also act as any one of the following:
  • Inhibitors of cellular surface proteases regulated by Annexin A2 and/or SlOO proteins such as, for example:
  • Inhibitors of ion channel expression on the plasma membrane such as, for example:
  • tumour cells ii) By tumour cells
  • the present invention provides a compound as defined herein for any one of the uses defined in paragraphs 1 to 8 above.
  • Compounds of the invention may be useful in the therapy of a variety of diseases and conditions.
  • the subject of said therapy may be a human or an animal.
  • Compounds of the invention may exhibit desirable potency, selectivity and microsomal stability.
  • the compounds may be useful in the therapy of diseases or conditions in which SI 00 protein binding interactions are implicated.
  • cancer as used herein includes reference to cellular proliferative or differentiative disorders, including all types of cancerous growths or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues, or organs, irrespective of histopathologic type or stage of invasiveness.
  • malignancies of the various organ systems such as those affecting lung, breast, thyroid, lymphoid, gastrointestinal, and genitourinary tract, as well as adenocarcinomas which include malignancies such as most colon cancers, renal-cell carcinoma, prostate cancer and/or testicular tumors, non-small cell carcinoma of the lung, cancer of the small intestine and cancer of the esophagus.
  • adenocarcinomas refers to malignancies of epithelial or endocrine tissues including respiratory system carcinomas, gastrointestinal system carcinomas, genitourinary system carcinomas, testicular carcinomas, breast carcinomas, prostatic carcinomas, endocrine system carcinomas, and melanomas.
  • Exemplary carcinomas include those forming from tissue of the cervix, lung, prostate, breast, head and neck, colon and ovary. This term also includes carcinosarcomas, e. g., which include malignant tumors composed of carcinomatous and sarcomatous tissues.
  • An "adenocarcinoma” refers to a carcinoma derived from glandular tissue or in which the tumor cells form recognizable glandular structures.
  • the term “sarcoma” is art recognized and refers to malignant tumors of mesenchymal derivation.
  • the compounds of the invention may also be useful in the treatment of a variety of proliferative disorders.
  • Such disorders include hematopoietic neoplastic disorders.
  • hematopoietic neoplastic disorders includes diseases involving hyperplastic/neoplastic cells of hematopoietic origin, e.g., arising from myeloid, lymphoid or erythroid lineages, or precursor cells thereof.
  • the diseases may arise from poorly differentiated acute leukemias, e.g. erythroblastic leukemia and acute megakaryoblastic leukemia.
  • Additional exemplary myeloid disorders include acute promyeloid leukemia, acute myelogenous leukemia and chronic myelogenous leukemia; lymphoid malignancies such as acute lymphoblastic leukemias, including B-lineage and T-lineage types, chronic lymphocytic leukemia, prolymphocytic leukemia, hairy cell leukemia and Waldenstrom's macroglobulineniia. Additional forms of malignant lymphomas include non-Hodgkin lymphoma and variants thereof, peripheral T cell lymphomas, adult T cell leukemia/lymphoma, cutaneous T-cell lymphoma, large granular lymphocytic leukemia, Hodgkin's disease and Reed-Stemberg disease.
  • the compounds may be used in the therapy of haematologic cancers such as leukaemia, non-small cell lung cancers, colonic cancers, breast cancers, ovarian cancers, renal cancers, melanoma, carcinoma, sarcoma and metastatic disorders.
  • haematologic cancers such as leukaemia, non-small cell lung cancers, colonic cancers, breast cancers, ovarian cancers, renal cancers, melanoma, carcinoma, sarcoma and metastatic disorders.
  • cancerous disorders of the colon include, but are not limited to, nonneoplastic polyps, adenomas, familial syndromes, colorectal carcinogenesis, colorectal carcinoma, and carcinoid tumors.
  • cancerous disorders of the liver include, but are not limited to, nodular hyperplasias, adenomas, and malignant tumors, including primary carcinoma of the liver and metastatic tumors.
  • cancerous disorders of the ovary include, but are not limited to, ovarian tumors such as, tumors of coelomic epithelium, serous tumors, mucinous tumors, endometeriod tumors, clear cell adenocarcinoma, cystadenofibroma, brenner tumor, surface epithelial tumors; germ cell tumors such as mature (benign) teratomas, monodermal teratomas, immature malignant teratomas, dysgerminoma, endodermal sinus tumor, choriocarcinoma; sex cord-stomal tumors such as, granulosa-theca cell tumors, thecoma-fibromas, androblastomas, hill cell tumors, and gonadoblastoma; and metastatic tumors such as Krukenberg tumors.
  • ovarian tumors such as, tumors of coelomic epithelium, serous tumors, mucinous tumors, endometeriod tumors, clear
  • cancerous disorders of the breast include, but are not limited to, proliferative breast disease including, e.g. epithelial hyperplasia, sclerosing adenosis, and small duct papillomas; tumors, e.g.
  • carcinoma of the breast including in situ (noninvasive) carcinoma that includes ductal carcinoma in situ (including Paget's disease) and lobular carcinoma in situ, and invasive (infiltrating) carcinoma including, but not limited to, invasive ductal carcinoma, invasive lobular 'carcinoma, medullary carcinoma, colloid (mucinous) carcinoma, tubular carcinoma, and invasive papillary carcinoma, and miscellaneous malignant neoplasms.
  • disorders in the male breast include, but are not limited to, gynecomastia and carcinoma.
  • the compounds may be useful in the therapy of a disorder selected from leukaemia, colonic cancer, melanoma and non-small cell lung cancer.
  • the present invention provides a compound of the invention as defined herein for use in the treatment of a hyper-proliferative disorder.
  • the present invention provides the use of a compound of the invention as defined herein in the manufacture of medicament for use in the treatment of a hyper- proliferative disorder.
  • the present invention provides a method of treating a hyper- proliferative disorder comprising administering to a warm blooded mammal in need of such treatment a therapeutically effective amount of a compound of the invention as defined herein.
  • the hyper-proliferative disorder is a cancer as discussed above.
  • the present invention provides a compound of the invention as defined herein for use in the treatment of cancer.
  • the present invention provides the use of a compound of the invention as defined herein in the manufacture of medicament for use in the treatment of cancer.
  • the present invention provides a method of treating cancer comprising administering to a warm blooded mammal in need of such treatment a therapeutically effective amount of a compound of the invention as defined herein.
  • the cancer may be any cancer in which S100 protein binding interactions are known to play a role.
  • the compounds of the invention may be used to treat metastatic lung carcinoma, prostate cancer, colorectal cancer, vascular intima carcinoma, glioma, bladder carcinoma, breast cancer, bronchial cancer, cervical cancer, colon cancer, colorectal cancer, gastric cancer, head and neck carcinoma, laryngeal squamous cell carcinoma, leukemia (acute leukemia, acute lymphoblastic leukemia, acute promyelocytic leukaemia), hepatocellular carcinoma, lymphoma, myeloma, oesophageal carcinoma, osteosarcoma, pancreatic cancer (including pancreatic ductal carcinoma), prostate cancer, renal cell carcinoma, thyroid carcinoma, thyroid neoplasm, and vascular intima carcinomatosis.
  • leukemia acute leukemia, acute lymphoblastic leukemia, acute promyelocytic leukaemia
  • pancreatic cancer including pancreatic ductal carcinoma
  • prostate cancer renal cell carcinoma, thyroid carcinoma, thyroid neoplasm, and
  • the compounds of the invention may be used to treat solid tumours, drug-resistant tumours and/or metastatic tumours.
  • the compounds of the invention are used to treat pancreatic cancers.
  • the compounds of the invention are used to treat capecitabine resistant pancreatic tumours.
  • the compounds of the present invention may also provide anti-angiogenic effects.
  • the compounds of the invention may be used to treat solid tumour angiogenesis and tumours resistant to other anti-angiogenesis therapies.
  • the present invention provides a compound of the invention as defined herein for use in production of an anti-angiogenic effect in a warm blooded mammal (e.g. in the treatment of solid tumours).
  • the present invention provides the use of a compound of the invention as defined herein in the manufacture of medicament for use in the production of an anti- angiogenic effect in a warm blooded mammal.
  • the present invention provides a method of producing an anti- angiogenic effect comprising administering to a warm blooded mammal in need of such treatment a therapeutically effective amount of a compound of the invention as defined herein.
  • the compounds of the invention may be used to treat tumour angiogenesis.
  • the compounds of the invention may be used to modulate tumour angiogenesis and normalise the tumour angiogenic network. Such normalised network may allow better penetration of anti tumour drugs into the tumour.
  • the compounds of this invention may be used to increase the efficacy of existing anti tumour therapies.
  • the compounds of the invention may be used to treat diseases associated with excessive angiogenesis, such as, for example, arthritic diseases and macular degeneration.
  • the compounds of the invention may also be used in the treatment of pain.
  • the analgesic effects may be imparted by virtue of the inhibition of Navl.8 expression on the plasma membrane.
  • the compounds of the invention may be used to treat neuropathic pain, inflammatory pain, hyperalgesia and allodynia.
  • the compounds of the invention may also be used in the treatment of hypoaldosterism. Without wishing to be bound by any particular theory, the effects on the treatment of hypoaldosterism is thought to be caused by modulating TASK1 expression on the plasma membrane.
  • the compounds of the invention may also be used in the treatment of depression. Without wishing to be bound by any particular theory, the anti-depressive effects of the compounds of the invention are thought to due to modulating 5HT1B expression on the plasma membrane.
  • Infrared spectra were recorded using AVATAR 360 FT-IR system. Samples were prepared as KBr discs and scanned from 4000 to 500 cm "1 .
  • Thin layer chromatography was performed using aluminum-backed silica gel 60 plates (0.20 mm layer), the ascending technique was used with a variety of solvents. Visualization was by UV light at either 254 or 365 nm.
  • HPLC HPLC was carried out using two different methods:
  • Method 1 Kromasil (250 mm X 4.6mm, 5 ⁇ particle size) column with MeCN / H 2 0 (5% to 95% organic over 20min at 1 mL/min).
  • Method A After 5 min of the microwave reaction, for some products, precipitation was observed immediately (intermediates 1, 4, 5, and 7 to 11). For other products (intermediates 2 and 3), precipitation occurred after standing the solution for 15 min. The precipitate was collected by filtration and was washed with Et 2 0. The resulting solid was dissolved in H 2 0 (volume depending on amount of precipitate obtained) and stirred for 1 h at room temperature. The solution was acidified by addition of glacial AcOH to pH 3 ⁇ 1 and kept at 0 °C for 1 h. The precipitate was filtered, washed with distilled H 2 0, and dried in a freeze-dryer.
  • Method B No precipitate was observed at the end of 5 min of the microwave reaction (intermediate 6).
  • the reaction mixture was poured into 50 mL of ice-cold H 2 0 and acidified with glacial AcOH to pH 3-4. Precipitation was observed and the reaction mixture was kept at 0 °C for 1 h.
  • the precipitate was filtered, washed with distilled H 2 0, and dried in a freeze-dryer.
  • Example 8 5-(2,4-Bis-trifluoromethyl-phenyl)-3-hvdroxy-l-(2-hvdroxy-propyl)-4-(4-methyl- benzoyl) - 1 ,5-dihydro-p yrrol-2-one
  • Example 13 l-Allyl-3-hvdroxy-5-(4-isopropyl-phenyl)-4-(4-methyl-benzoyl)-l,5-dihvdro- pyrrol-2-one
  • Example 17 4-(4-Chloro-benzoyl)-3-hvdroxy-l-(2-hydroxy-propyl)-5-(4-isopropyl-phenyl)- l,5-dihydro-pyrrol-2-one
  • Example 18 l-Allyl-3-hvdroxy-4-(6-methyl-pyridine-3-carbonyl)-5-(4-trifluoromethyl- phenyl)-l,5-dihvdro-pyrrol-2-one
  • Example 22 4-(2-Ethoxy-benzoyl)-3-hvdroxy-l-(2-hydroxy-propyl)-5-(4-isopropyl-phenyl)- l,5-dihydro-pyrrol-2-one
  • Example 23 4-(2-Ethoxy-benzoyl)-3-hvdroxy-l-(3-methoxy-propyl)-5-(4-trifluoromethyl- phenyl)-l,5-dihvdro-pyrrol-2-one
  • Example 24 4-(2-Ethoxy-benzoyl)-5-(3-fluoro-4-trifluoromethyl-phenyl)-3-hvdroxy-l-(3- methoxy-propyl)-l,5-dihvdro-pyrrol-2-one
  • Example 28 l-(2,3-Dihvdroxy-propyl)-3-hvdroxy-5-(4-isopropyl-phenyl)-4-(4-methyl- benzoyl) - 1 ,5-dihydro-p yrrol-2-one
  • Example 25 As Example 25 above except using 4-(Trifluoromethyl) aniline (127 ⁇ , 1.0 mmol, 1.0 eq.) and the reaction mixture was allowed to stir at room temperature overnight. No precipitation was observed after the overnight reaction. The reaction mixture was poured into cold H 2 0 (30 mL) and allowed to stand for 4h. No precipitate was observed and was extracted thoroughly with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under vacuum. The desired product was isolated as a pale yellow powder (18% yield).
  • Example 25 As Example 25 above except using 4-isopropyl aniline (144 ⁇ , 1.0 mmol, 1.0 eq.) and the reaction mixture was allowed to stir at room temperature overnight. No precipitation was observed after the overnight reaction. The reaction mixture was poured into cold H 2 0 (50 mL) and allowed to stand for 4h. No precipitate was observed and was extracted thoroughly with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under vacuum. The yellow residue obtained was recrystallized from ethanol. The desired product was isolated as a white powder (10% yield).
  • Example 1 As Example 1 above except using 4-(Trifluoromethyl) aniline (127 ⁇ , 1.0 mmol, 1.0 eq.) and the reaction mixture was allowed to stir at room temperature overnight. No precipitation was observed after the overnight reaction. The reaction mixture was poured into cold H 2 0 (50 mL) and allowed to stand overnight. The yellow precipitate formed was filtered, washed with distilled H 2 0 and was then freeze dried. The yellow precipitate was further washed with EtOH, followed by Et 2 0, and was then dried in vacuo. The desired product was obtained as a pale white powder (19% yield).
  • the following assay can be used to measure biological activity of the compounds of the invention as inhibitors of SlOO protein binding inter actions.
  • a Cy5-labelled S100A10 tracer used to identify inhibitors of the protein interaction with Annexin A2.
  • Annexin A2(l-14)-Cy3 (AA2(1-14)-Cy3) was synthesized by Peptide Protein Research (Wickham, UK) with the Cy3 label linked to a cysteine residue introduced at the C-terminal end of the peptide.
  • Labelling kits for Cy5 conjugation were obtained from GE Healthcare/ Amersham (Buckinghamshire, UK). All molecular biology reagents and protein reagents were obtained from Promega, New England Biolabs, Qiagen or Merck/Novagen. Chemicals were obtained from Sigma or Fisher.
  • S100A10 was amplified from a humana placenta cDNA library (Biochain Institute, Inc.) and cloned into pET14b (Merck-Novagen).
  • pET14b Merck-Novagen
  • IPTG isopropyl-beta-D-thiogalactopyranoside
  • Pellets were resuspended in 30 ml buffer A (50 mM NaH 2 P0 4 pH 8, 0.3 M NaCl, 2 mM ⁇ -mercaptoethanol) containing 10 mM imidazole pH 8.0 and EDTA-free Complete Mini Protease cocktail (Roche). Cells were lysed in a French press at 700 psi, the lysate was spun at 15,000 rpm at 4°C for 40 min, the supernatant was incubated with Ni-NTA-agarose beads (Promega) for 1 hr at 4 °C and the beads were collected in a column cartridge.
  • buffer A 50 mM NaH 2 P0 4 pH 8, 0.3 M NaCl, 2 mM ⁇ -mercaptoethanol
  • 10 mM imidazole pH 8.0 and EDTA-free Complete Mini Protease cocktail Roche. Cells were lysed in a French press at 700 psi, the lysate was spun at 15,000 rpm at
  • the beads were washed twice in buffer A containing 20 and 30 mM imidazole pH 8.0, respectively, and proteins were eluted in buffer A containing 250 mM imidazole pH 8.0. Purity of the sample was checked on 15% SDS-PAGE and pure fractions were pooled.
  • S100A10 was exchanged to buffer B (137 mM NaCl, 2.7 mM KC1, 4.3 mM Na 2 HP0 4 , 1.47 mM KH 2 P0 4 pH 7.4 plus 2 mM ⁇ -mercaptoethanol), adjusted to a concentration of 1 mg/ml and incubated with 2 U thrombin (Haematologic Technologies Inc.) per mg S100A10 at 20 °C for 16 hrs, at which point thrombin was removed on p-aminobenzamidine-agarose (Sigma).
  • buffer B 137 mM NaCl, 2.7 mM KC1, 4.3 mM Na 2 HP0 4 , 1.47 mM KH 2 P0 4 pH 7.4 plus 2 mM ⁇ -mercaptoethanol
  • AA2(1-14)-Cy3 was obtained as powder in 1 mg batches and kept at 4 °C. When required, batches were reconstituted in buffer C to a concentration of 1 mg/ml and stored in aliquots at -20 °C until needed. For the purpose of the assay, batches were matched onto each other based on the amount of peptide.
  • Binding of the Cy3-labelled annexin A2(l-14) peptide ligand to the Cy5-labelled S100A10 tracer was assessed using a fluorescence resonance energy transfer readout. Assays were carried out in Nunc black non-treated 384-well plates at 20 °C in 50 ⁇ buffer C. All incubations were performed in quadruplicate. Compounds, peptide and buffer controls were added to the wells in a 10 ⁇ volume in 5% DMSO.
  • Cy5-labelled S100A10 tracer (407 nM) and Cy3-labelled annexin A2(l-14) peptide ligand (1.33 ⁇ ) were pre -incubated for 5 min at 20 °C and 40 ⁇ of the preformed complex was then added to the wells and mixed for 10 s to yield a final DMSO concentration of 1%. After 5 min incubation at 20 °C, readings were taken on a Perkin Elmer Envision by excitation at 488 nm and emission at 695 nm. Each screening plate contained as controls the individual labelled proteins, as well as the two protein partners with and without 12.8 ⁇ of the non-labelled AA2(1-14) competitor (all in quadruplicate).
  • Fluorescence resonance energy transfer was calculated by subtracting the sum of the fluorescence emission of S100A10-Cy5 and AA2(1-14)-Cy3 individually from that measured for the co-incubated partners. Compound binding was calculated as percentage of non-treated control and data were analysed by non-linear regression (dose response - variable slope) using Graphpad Prism Software to determine the IC 50 of binding (primary assay).
  • Compound binding was calculated as percentage of non-treated control and data were analysed by non-linear regression (dose response - variable slope) using Graphpad Prism Software to determine the IC 50 of binding. A floating fit was generally used and the midpoint of inhibition is shown. *Compounds were analysed in the same way, except that the bottom of the regression curve was fixed at 0%. **Compounds were analysed in the same way, except that the bottom of the regression curve was fixed at 0% and the top at 100%.
  • the compounds of the invention were found to possess good activity in the above screen.
  • the compounds of the invention exhibit an IC 50 in the above Annexin A2-S100A10 inhibition screen of less than 100 ⁇ .
  • Preferred compounds possess an IC 50 of less than 40 ⁇ .
  • Further preferred compounds possess an IC 50 of less than 20 ⁇ .
  • the most preferred compounds have an IC 50 of less than 10 ⁇ , especially less than 5 ⁇ .

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Abstract

Cette invention concerne des composés qui sont des inhibiteurs des interactions des liaisons des protéines S100, telles que, par exemple, l'interaction de la liaison de la protéine d'annexine A2-S100A10. Plus spécifiquement, la présente invention concerne certains dérivés de pyrrole substitués de formule générale I ou II telle que définie dans ce document, ainsi que des procédés de préparation de ces dérivés, des compositions pharmaceutiques contenant ces dérivés et leur utilisation dans le traitement, la prévention ou le retardement de la progression de maladies dans lesquelles des interactions des liaisons des protéines S100 sont impliquées (telles que le cancer).
PCT/GB2011/050137 2010-02-01 2011-01-28 Inhibiteurs des interactions des liaisons des protéines s100 WO2011092505A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102603717A (zh) * 2012-01-09 2012-07-25 中国人民解放军第二军医大学 吡咯酮类化合物及其作为药物的用途

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102603717A (zh) * 2012-01-09 2012-07-25 中国人民解放军第二军医大学 吡咯酮类化合物及其作为药物的用途

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