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WO2012131297A1 - Dérivés de pyrido[3',2':4,5]thiéno[3,2-d]pyrimidin-4-ylamine et leur utilisation thérapeutique - Google Patents

Dérivés de pyrido[3',2':4,5]thiéno[3,2-d]pyrimidin-4-ylamine et leur utilisation thérapeutique Download PDF

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WO2012131297A1
WO2012131297A1 PCT/GB2012/000280 GB2012000280W WO2012131297A1 WO 2012131297 A1 WO2012131297 A1 WO 2012131297A1 GB 2012000280 W GB2012000280 W GB 2012000280W WO 2012131297 A1 WO2012131297 A1 WO 2012131297A1
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independently
compound according
present
nhr
compound
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Jonathan Bayldon Baell
Ian Philip Street
Brad Edmund Sleebs
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention pertains generally to the field of therapeutic compounds, and more specifically to certain fused triaryl amine compounds (for convenience, collectively referred to herein as "FTA compounds"), which, inter alia, inhibit LIM kinase (LIMK) activity.
  • FAA compounds fused triaryl amine compounds
  • LIMK LIM kinase
  • the present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit LIMK activity, and in the treatment of diseases and conditions that are mediated by LIMK, that are ameliorated by the inhibition of LIMK activity, etc., including proliferative conditions such as cancer (e.g., breast cancer, prostate cancer, melanoma, glioma, etc.), as well as vasodilation (including, e.g., hypertension, angina, cerebral vasospasm, and ischemia following subarachnoid hemorrhage), neurodegenerative disorders, atherosclerosis, fibrosis, and inflammatory diseases (including, e.g., Crohn's disease and chronic obstructive pulmonary disease (COPD)), and glaucoma (also known as ocular hypertension).
  • cancer e.g., breast cancer, prostate cancer, melanoma, glioma, etc.
  • LIMK LIM kinase
  • Rho family of GTPases There are two members of the family, LIMK1 and LIMK2, both of which are directly involved in regulating multiple cellular processes via their ability to reorganise the actin-cytoskeleton network (see, e.g., Scott et al., 2007).
  • LIMKs share 50% homology (see, e.g., Mizuno et al., 1994; Nunoue et al., 1995). They are composed of two N-terminal LIM domains, each of which contains a double zinc-finger motif.
  • the LIM domains play an important role in regulating kinase activity (see, e.g., Nagata et al., 1999; Tomiyoshi et al., 2004) and may also contribute to LIMK function by mediating protein-to-protein and protein-to- DNA interactions (see, e.g., Hiraoka et al., 1996; Nishiya et al., 1998).
  • a proline/serine rich region then follows with the kinase domain of the protein being located at the extreme C-terminus.
  • the kinase domains of LIMK1 and LIMK2 are 70% identical and phosphorylation within the activation loop enhances their activity.
  • LIMK is activated via a number of signalling networks downstream of growth factors, integrins and cytokines (for a comprehensive review see, e.g., Scott et al., 2007).
  • Rho effector Rho kinase (ROCK) has been shown to phosphorylate LIMK on conserved threonine residues (Thr-508 on LIMK1 or Thr-505 LIMK2), modifications that are essential for kinase activation (see, e.g., Amano et al., 2001 ;
  • Pak1 see, e.g., Edwards et al., 1999
  • Pak4 see, e.g., Dan et al., 2001
  • MRCKa myotonic dystrophy kinase-related Cdc42-binding kinase
  • LIMK1 Transphosphorylation of LIMK1 , following association with HSP90, has been shown to increase the half life of the protein and increases its specific activity (see, e.g., Li et al., 2006). Autophosphorylation of LIMK also occurs, although the site of phosphorylation and functional consequence remains uncertain (see, e.g., Kobayashi et al., 2006; Proschel et al., 1995). Conversely, LIMK is subject to deactivation by the direct action of phosphatases.
  • Slingshotl (SSH1) binds directly to the kinase domain and dephosphorylates LIMK1 on Thr-508 and additional autophosphorylated serine residues resulting in decreased activity (see, e.g., Soosairajah et al., 2005).
  • cofilin 1 non-muscle cofilin
  • cofilin2 muscle cofilin
  • destrin also known as actin depolymerizing factor, ADF.
  • Unphosphorylated active cofilin binds to actin filaments in vivo, depolymerises filamentous actin (F-actin), and produces free barbed ends that serve to nucleate new actin filaments (see, e.g., Ghosh et al., 2004; Lorenz et al., 2004). Ultimately it is a balance between phosphorylated and
  • LIMK dephosphorylated cofilin that determines a cell's ability to reorganise the cytoskeleton, controlling cell shape and influencing its ability to move, invade or metastasise.
  • LIMK reorganises actin-cytoskeleton dynamics through direct phosphorylation of cofilin on serine-3 resulting in its inactivation and subsequent inhibition of its actin-severing activity (see, e.g., Maekawa et al., 1999; Sumi et al., 1999). Through this modulation of the actin- cytoskeleton, LIMK is implicated to play pivotal a role in several human diseases with inhibition via small molecule kinase inhibitors having potential utility.
  • LIMK1 has been found unregulated via chromosomal translocation in malignant melanoma cells (see, e.g., Okamoto et al., 2005), breast cancer tumours (see, e.g., Bagheri-Yarmand et al., 2006) and breast cancer cell lines (see, e.g., Yoshioka et al., 2003), in prostate tumours (see, e.g., Davila et al., 2003) and prostate cancer cell lines (see, e.g., Bagheri-Yarmand et al., 2006; Yoshioka et al., 2003).
  • LIMK expression levels have been linked to tumour cell growth. For example, reduction in LIMK1 caused a decrease in prostate cancer cell proliferation, arresting cells in G2/M (see, e.g., Davila et al., 2003). Similarly, lowering expression of LIMK2 in human fibrosarcoma cells limited their ability to form colonies in a long term growth assay (see, e.g., Suyama et al., 2004). LIMK has been reported to modify the p53 pathway (see, e.g., Freidman et al., 2002).
  • p53 is a potent tumour suppressor protein which is stabilised in response to cellular stress signals to induce cell-cycle arrest or apoptosis depending on signal strength and duration (see, e.g., Vousden et al., 2009).
  • LIMK regulates p53 signalling however remains unclear.
  • LIMK1 has been shown to increase the motility and invasive capacity of tumour cells in several different systems.
  • Overexpression of LIMK1 increased motility, invasiveness and metastatic ability of human breast cancer cells (see, e.g., Bagheri- Yarmand et al., 2006; Yoshioka et al., 2003) as well as increasing the invasive phenotype of benign prostate cells (see, e.g., Davila et al., 2003).
  • Glaucoma is one of the leading causes of irreversible blindness in the world. It is characterized by degeneration of the optic nerve and progressive visual field loss and is often associated with elevated intraocular pressure (IOP) (see, e.g., Ferrer, 2006).
  • IOP intraocular pressure
  • the actin cytoskeleton network is thought to be an important modulator of IOP and subsequently LIMK has been proposed to play a role in regulating IOP.
  • Downregulation of LIMK1 with short-interfering RNA in cultured corneal fibroblasts was shown to reduce actin polymerization, focal adhesion formation and delay cell migration. In an in vivo mouse model, deletion or downregulation of LIMK1 significantly reduced ocular inflammation (see, e.g., Gorovoy et al., 2008).
  • LIMK inhibitors have been proposed for the treatment of glaucoma (see, e.g., Hizaki et al., 2004; Harrison et al., 2009; Burgoon et al., 2009).
  • One aspect of the invention pertains to certain fused triaryl amine compounds
  • FTA compounds (for convenience, collectively referred to herein as “FTA compounds”), as described herein.
  • compositions e.g., a pharmaceutical composition
  • a composition comprising a FTA compound, as described herein, and a pharmaceutically acceptable carrier or diluent.
  • Another aspect of the invention pertains to method of preparing a composition (e.g., a pharmaceutical composition) comprising the step of admixing a FTA compound, as described herein, and a pharmaceutically acceptable carrier or diluent.
  • a composition e.g., a pharmaceutical composition
  • Another aspect of the present invention pertains to a method of inhibiting LIM kinase (LIMK) activity (e.g., LIMK1 activity and/or LIMK2 activity) in a cell, in vitro or in vivo, comprising contacting the cell with an effective amount of a FTA compound, as described herein.
  • LIMK LIM kinase
  • Another aspect of the present invention pertains to a method of regulating (e.g., inhibiting) cell proliferation (e.g., proliferation of a ce)) ⁇ , inhibiting cell cycle progression, promoting apoptosis, or a combination of one or more these, in vitro or in vivo, comprising contacting a cell with an effective amount of a FTA compound, as described herein.
  • Another aspect of the present invention pertains to a method of treatment comprising administering to a subject in need of treatment a therapeutically-effective amount of a FTA compound, as described herein, preferably in the form of a pharmaceutical composition.
  • Another aspect of the present invention pertains to a FTA compound as described herein for use in a method of treatment of the human or animal body by therapy.
  • Another aspect of the present invention pertains to use of a FTA compound, as described herein, in the manufacture of a medicament for use in treatment.
  • the treatment is treatment of a disease or condition that is mediated by LIM kinase (LIMK) (e.g., LIMK1 and/or LIMK2).
  • LIMK LIM kinase
  • the treatment is treatment of a disease or condition that is ameliorated by the inhibition of LIM kinase (LIMK) activity (e.g., LIMK1 activity and/or LIMK2 activity).
  • LIMK LIM kinase
  • the treatment is treatment of a proliferative condition. ln one embodiment, the treatment is treatment of cancer.
  • the treatment is treatment of cancer characterised by, or further characterised by, cancer cells which overexpress LlM kinase (LIMK) (e.g., LIMK1 and/or LIMK2).
  • LIMK LlM kinase
  • the treatment is treatment of solid tumour cancer. In one embodiment, the treatment is treatment of breast cancer, prostate cancer, melanoma, or glioma.
  • the treatment is treatment of vasodilation. In one embodiment, the treatment is treatment of hypertension, angina, cerebral vasospasm, or ischemia following subarachnoid hemorrhage.
  • the treatment is treatment of a neurodegenerative disorder. In one embodiment, the treatment is treatment of atherosclerosis.
  • the treatment is treatment of fibrosis.
  • the treatment is treatment of an inflammatory disease.
  • the treatment is treatment of Crohn's disease or chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the treatment is treatment of glaucoma (also known as ocular hypertension).
  • kits comprising (a) a FTA compound, as described herein, preferably provided as a pharmaceutical composition and in a suitable container and/or with suitable packaging; and (b) instructions for use, for example, written instructions on how to administer the compound.
  • Another aspect of the present invention pertains to a FTA compound obtainable by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
  • Another aspect of the present invention pertains to a FTA compound obtained by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
  • Another aspect of the present invention pertains to novel intermediates, as described herein, which are suitable for use in the methods of synthesis described herein.
  • Another aspect of the present invention pertains to the use of such novel intermediates, as described herein, in the methods of synthesis described herein.
  • the compounds are also characterized by (a) an amino group at the 4-position of the pyrimidine ring, (b) the lack of a substituent at the 2-position of the pyrimidine ring, and (c) the presence of a heteroatom (i.e., S, N, or O) at the 5-position in the central ring, for example, as shown below:
  • Some embodiments of the invention include the following:
  • -Y- is independently -S-, -NR Y -, or -0-;
  • -R Y is independently -H or saturated aliphatic C 1-6 alkyl
  • -R ze is independently -H, -R us , or -R ,
  • -R Z7 is independently -H, -R QS , or -R QL ;
  • -R Z8 is independently -H, -R QS , or -R QL ;
  • -R 29 is independently -H, -R QS , or -R QL ;
  • -R Z7 is independently -H, -R , or -R ;
  • -R ze is independently -H, -R QS , or -R QL ;
  • -R Z9 is independently -H, -R QS , or -R QL ;
  • each -R is independently -R CA , -R HA , -R cc , or -R ;
  • -R CA is independently phenyl or naphthyl, and is optionally substituted
  • -R HA is independently Cs-ia e eroaryl, and is optionally substituted;
  • -R cc is independently non-aromatic C 3 .7cycloalkyl or non-aromatic
  • -R HC is independently non-aromatic C 3 .7heterocyclyl, and is optionally substituted; and wherein: each - H 2 , -NHR S , -NR S 2
  • each -R s is independently saturated aliphatic Ci- 5 alkyl, phenyl,
  • each phenyl is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -R ss , -CF 3 , -OH, -OR ss , and -OCF3, wherein each -R ss is independently saturated aliphatic
  • the compounds are optionally as defined herein, but with a proviso as defined in this section.
  • the compounds are optionally as defined herein, but without the proviso as defined in this section.
  • a reference to a particular group of compounds "without the recited proviso" is intended to be a reference to the compounds as defined, but wherein the definition no longer includes the indicated proviso.
  • the definition no longer includes the indicated proviso.
  • it is as if the indicated proviso has been deleted from the definition of compounds, and the definition has been expanded to encompass those compounds which otherwise would have been excluded by the indicated proviso.
  • -R 26 is independently -H, -R QS , or -R QL ;
  • -R Z7 is independently -H, -R QS , or -R QL ;
  • -R Z8 is independently -H, -R QS , or -R QL ;
  • -R Z9 is independently -H, -R QS , or -R QL ;
  • -R Z6 is independently -H or -R QS ;
  • -R Z7 is independently -R QL ;
  • -R Z8 is independently -H or -R QS ;
  • -R Z9 is independently -H or -R QS .
  • -R Z6 is independently -H
  • -R Z7 is independently -R QL ;
  • -R ze is independently -H
  • -R 29 is independently -H or -R QS .
  • -R Z6 is independently -H
  • -R ZT is independently -R QL ;
  • -R ze is independently -H
  • -R Z9 is independently -H. Examples of the previous embodiment include the following:
  • -R Z7 is independently -H, -R QS , or -R QL ;
  • -R ze is independently -H, -R QS , or -R QL ;
  • -R Z9 is independently -H, -R QS , or -R QL ;
  • -R Z7 is independently -R QL ;
  • -R Z8 is independently -H or -R QS ;
  • -R Z9 is independently -H or -R QS
  • -R Z7 is independently -R QL ;
  • -R Z8 is independently -H
  • -R Z9 is independently -H or -R QS .
  • -R Z7 is independently -R QL ;
  • -R ZB is independently -H
  • -R Z9 is independently -H.
  • a compound according to (1) selected from compounds of the following formula, and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • -R ze is independently -H or -R QS ;
  • -R Z8 is independently -H or -R QS ;
  • -R Z9 is independently -H or -R QS .
  • a compound according to (1) selected from compounds of the following formula, and pharmaceutically acceptable salts, hydrates, and solvates thereof, wherein -R Z9 is independently -H or -R QS :
  • each -R QS if present, is independently -F, -CI, -Br, -I, -R s , -CF 3 , -OH, -OR s , -OCF 3 , -NH 2 , -NHR S , -NR S 2 ,
  • each -R QS if present, is independently -F, -CI, -Br, -I, -R s , -CF 3 , -OH, -OR s , or -OCF 3 .
  • each -R s if present, is independently saturated aliphatic or phenyl, wherein said phenyl is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -R sss , -CF 3 , -OH, -OR sss , or -OCF 3 , wherein each -R S5S is independently saturated aliphatic Ci. 4 alkyl.
  • each -R s is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
  • each -R s is independently -Me.
  • each of -R , -R , -R , -R P5 , and -R is independently -H or a ring substituent; for example, wherein each ring substituent is independently -R x .
  • each of -R , -R , and -R P5 is independently -H or a ring substituent
  • each ring substituent is independently -R x .
  • each of -R P3 and -R w is independently -H or a ring substituent; for example, wherein each ring substituent is independently -R x
  • -R is independently a ring substituent; for example, wherein the ring substituent is independently -R x
  • -R is independently a ring substituent; for example, wherein the ring substituent is independently -R x .
  • each of -R P3 and -R P4 is independently a ring substituent; for example, wherein each ring substituent is independently -R*
  • each of -R and -R is independently -H or a ring substituent; for example, wherein each ring substituent is independently -R x .
  • each of -R P3 and -R P5 is independently a ring substituent; for example, wherein each ring substituent is independently -R x .
  • each of -R P2 and -R is independently a ring substituent; for example, wherein each ring substituent is independently -R x (58)
  • each of -R and -R is independently a ring substituent; for example, wherein each ring substituent is independently -R x .
  • -R is independently a ring substituent; for example, wherein the ring substituent is independently -R x .
  • each of -R , -R , and -R is independently a ring substituent; for example, wherein each ring substituent is independently -R x .
  • the Group -R' (62) A compound according to any one of (1) to (61), wherein -R , if present, or each -R HA , if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazoiyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzoisoxazolyl, quinolinyl, isoquinolinyl, dihydroisoquinolinyl, cinnolinyl, or quinazolinyl; and is optionally substituted
  • two or more adjacent substituents -R X1 may together form -OCH 2 0-, -OCH 2 CH 2 0-, or -OCH 2 CH 2 CH 2 0-;
  • each -R ZL - is independently saturated aliphatic C- ⁇ alkylene
  • each -R NZ is independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted with one or more substitutents selected from saturated aliphatic C ⁇ alkyl;
  • each -R z is independently saturated aliphatic C ⁇ alkyl, phenyl, benzyl, or
  • each pyrrolidinyl, piperidinyl, morpholinyl, piperizinyl, pyrrolidino, piperidino, morpholino, and piperizino is optionally substituted with one or more groups
  • each -R A1 is independently saturated aliphatic C 1-4 alkyl
  • each -R A2 is independently phenyl, C 5 . 6 heteroaryl, or non-aromatic
  • each -NR K3 R K4 is independently:
  • each -R A3 is independently saturated aliphatic C ⁇ alkyl, optionally substituted with one or more groups independently selected from -OH, -OR A ", -NH 2 , -NHR A4 , -NR M 2 , pyrrolidino, piperidino, morpholino, and piperizino;
  • each -R is independently saturated aliphatic C ⁇ alkyl; and wherein each -R KS is independently saturated aliphatic Ci. 4 alkyl, and is optionally substituted with one or more groups independently selected from: -F, -CI, -Br, -I, -CF 3 , -OH, -OR A5 , -OCF 3 , -NH 2 , -NHR A5 , and -NR A5 2 , wherein each -R AS is independently saturated aliphatic C ⁇ alkyl; and wherein each -R is independently saturated aliphatic C 1-4 alkyl, and is optionally substituted with one or more groups independently selected from: -F, -CI, -Br, -I, -CF 3l -OH, -OR A6 , -OCF 3 , -NH 2 , -NHR A6 , and -NR AS 2 , wherein each -R A6 is independently saturated aliphatic C
  • each -R X if present, is independently -R z , -F, -CI, -Br, -OH, or -OR z .
  • each -R NZ is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted with one or more substitutents selected from saturated aliphatic Ci. 4 alkyl.
  • each -R K if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu.
  • each -R ⁇ if present, is independently -Me or -Et.
  • each -R A1 is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu.
  • the Group -R A2 (130) A compound according to any one of (98) to (129), wherein each -R* 2 , if present, is independently phenyl or C 5-6 heteroaryl.
  • each -NR K3 R 4 is independently pyrrolidine piperidino, morpholino, or piperizino.
  • each -R A3 is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu.
  • each -R A4 is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu.
  • the Group -R KS (140) A compound according to any one of (98) to (139), wherein each -R KS , if present, is independently saturated aliphatic d. 4 alkyl, and is optionally substituted with one or more groups independently selected from: -OH, -OR A5 , -NH 2 , -NHR AS , and -NR A5 2 .
  • each -R A5 is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu.
  • the Group -R K6 (145) A compound according to any one of (98) to (144), wherein each -R K6 , if present, is independently saturated aliphatic Ci. 4 alkyl, and is optionally substituted with one or more groups independently selected from: -OH, -OR A6 , -NH 2 , -NHR A6 , and -NR A6 2 .
  • each -R A6 is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu.
  • a compound according to (1) selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • a compound according to (1) selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • a compound according to (1) selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • a compound according to (1) selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • a compound according to (1) selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • a compound according to (1) selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • a compound according to (1) selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • a compound according to (1) selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • a compound according to (1) selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • the substantially purified form is at least 50% by weight, e.g., at least 60% by weight, e.g., at least 70% by weight, e.g., at least 80% by weight, e.g., at least 90%) by weight, e.g., at least 95% by weight, e.g., at least 97% by weight, e.g., at least 98% by weight, e.g., at least 99% by weight.
  • the substantially purified form refers to the compound in any
  • the substantially purified form refers to a mixture of stereoisomers, i.e., purified with respect to other compounds. In one embodiment, the substantially purified form refers to one
  • the substantially purified form refers to a mixture of enantiomers. In one embodiment, the substantially purified form refers to a equimolar mixture of enantiomers (i.e., a racemic mixture, a racemate). In one embodiment, the substantially purified form refers to one enantiomer, e.g., optically pure enantiomer.
  • the contaminants represent no more than 50% by weight, e.g., no more than 40% by weight, e.g., no more than 30% by weight, e.g., no more than 20% by weight, e.g., no more than 10% by weight, e.g., no more than 5% by weight, e.g., no more than 3% by weight, e.g., no more than 2% by weight, e.g., no more than 1% by weight.
  • the contaminants refer to other compounds, that is, other than stereoisomers or enantiomers. In one embodiment, the contaminants refer to other compounds and other stereoisomers. In one embodiment, the contaminants refer to other compounds and the other enantiomer.
  • the substantially purified form is at least 60% optically pure (i.e., 60% of the compound, on a molar basis, is the desired stereoisomer or enantiomer, and 40% is the undesired stereoisomer or enantiomer), e.g., at least 70% optically pure, e.g., at least 80% optically pure, e.g., at least 90% optically pure, e.g., at least 95% optically pure, e.g., at least 97% optically pure, e.g., at least 98% optically pure, e.g., at least 99% optically pure.
  • 60% optically pure i.e., 60% of the compound, on a molar basis, is the desired stereoisomer or enantiomer, and 40% is the undesired stereoisomer or enantiomer
  • at least 70% optically pure e.g., at least 80% optically pure, e.g., at least 90% optically pure, e
  • Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diastereoisomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; a- and ⁇ -forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as "isomers” (or "isomeric forms").
  • a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., d -7 alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).
  • d -7 alkyl includes n-propyl and iso-propyl
  • butyl includes n-, iso-, sec-, and tert-butyl
  • methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl
  • reference to a specifc group or substitution pattern is not intended to include other structural (or constitutional isomers) which differ with respect to the connections between atoms rather than by positions in space.
  • a reference to a methoxy group, -OCH 3 is not to be construed as a reference to its structural isomer, a
  • keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hydroxyazo, and nitro/aci-nitro.
  • keto enol enolate Note that specifically included in the term “isomer” are compounds with one or more isotopic substitutions.
  • H may be in any isotopic form, including 1 H, 2 H (D), and 3 H (T);
  • C may be in any isotopic form, including 12 C, 13 C, and 4 C;
  • O may be in any isotopic form, including 16 0 and 18 0; and the like.
  • a reference to a particular compound includes all such isomeric forms, including mixtures (e.g., racemic mixtures) thereof.
  • Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner.
  • Salts It may be convenient or desirable to prepare, purify, and/or handle a corresponding salt of the compound, for example, a pharmaceutically-acceptable salt.
  • a pharmaceutically-acceptable salt examples include pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts are discussed in Berge ei a/., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci.. Vol. 66, pp. 1-19.
  • the compound is anionic, or has a functional group which may be anionic (e.g., -COOH may be -COO " )
  • a salt may be formed with a suitable cation.
  • suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K + , alkaline earth cations such as Ca 2+ and Mg 2+ , and other cations such as Af 3 .
  • suitable organic cations include, but are not limited to, ammonium ion (i.e., NH ) and substituted ammonium ions (e.g., NH 3 R + , NH 2 R 2 + , NHR 3 ⁇ NR graffiti + ).
  • suitable substituted ammonium ions are those derived from:
  • ethylamine diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine.
  • An example of a common quaternary ammonium ion is N(CH 3 )4 +
  • a salt may be formed with a suitable anion.
  • suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.
  • Suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, trifluoroacetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric.
  • Suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose. Unless otherwise specified, a reference to a particular compound also includes salt forms thereof.
  • Solvates and Hydrates It may be convenient or desirable to prepare, purify, and/or handle a corresponding solvate of the compound.
  • solvate is used herein in the conventional sense to refer to a complex of solute (e.g., compound, salt of compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.
  • a reference to a particular compound also includes solvate and hydrate forms thereof.
  • chemically protected form is used herein in the conventional chemical sense and pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions under specified conditions (e.g., pH, temperature, radiation, solvent, and the like).
  • specified conditions e.g., pH, temperature, radiation, solvent, and the like.
  • well known chemical methods are employed to reversibly render unreactive a functional group, which otherwise would be reactive, under specified conditions.
  • one or more reactive functional groups are in the form of a protected or protecting group (also known as a masked or masking group or a blocked or blocking group).
  • a compound which has two nonequivalent reactive functional groups may be derivatized to render one of the functional groups "protected,” and therefore unreactive, under the specified conditions; so protected, the compound may be used as a reactant which has effectively only one reactive functional group.
  • the protected group may be "deprotected” to return it to its original functionality.
  • a hydroxy group may be protected as an ether (-OR) or an ester
  • the aldehyde or ketone group is readily regenerated, for example, by hydrolysis using water in the presence of acid.
  • an amine group may be protected, for example, as an amide (-NRCO-R) or a urethane (-NRCO-OR), for example, as: a methyl amide (-NHCO-CH 3 ); a benzyloxy amide (-NHCO-OCH 2 C 6 H 5 , -NH-Cbz); as a t-butoxy amide (-NHCO-OC(CH 3 ) 3 , -NH-Boc); a 2-biphenyl-2-propoxy amide (-NHCO-OC(CH 3 ) 2 C 6 H 4 C 6 H 5 , -NH-Bpoc), as a
  • 9-fluorenylmethoxy amide (-NH-Fmoc), as a 6-nitroveratryloxy amide (-NH-Nvoc), as a 2-trimethylsilylethyloxy amide (-NH-Teoc), as a 2,2,2-trichloroethyloxy amide (-NH-Troc), as an allyloxy amide (-NH-Alloc), as a 2-(phenylsulfonyl)ethyloxy amide (-NH-Psec); or, in suitable cases (e.g., cyclic amines), as a nitroxide radical (> ⁇ -0 ⁇ ).
  • a carboxylic acid group may be protected as an ester for example, as: an Ci. 7 alkyl ester (e.g., a methyl ester; a t-butyl ester); a C 1-7 haloalkyl ester (e.g., a
  • Ci. 7 trihaloalkyl ester a triC 1-7 alkylsilyl-C 1-7 alkyl ester; or a C 5-20 aryl-Ci. 7 alkyl ester (e.g., a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as a methyl amide.
  • prodrug refers to a compound which yields the desired active compound in vivo. Typically, the prodrug is inactive, or less active than the desired active compound, but may provide advantageous handling, administration, or metabolic properties.
  • prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound (for example, as in antibody directed enzyme prodrug therapy (ADEPT), gene directed enzyme prodrug therapy (GDEPT), lipid directed enzyme prodrug therapy (LIDEPT), etc.).
  • the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.
  • compositions e.g., a pharmaceutical composition
  • a composition comprising a FTA compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • compositions e.g., a pharmaceutical composition
  • a composition comprising admixing a FTA compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • LIMK LIM kinase
  • LIMK LIM kinase
  • One aspect of the present invention pertains to a method of inhibiting LIM kinase (LIMK) activity (e.g., LIMK1 activity and/or LIMK2 activity), in vitro or in vivo, comprising contacting LIMK (e.g., LIMK1 and/or LIMK2) with an effective amount of a LIMK (e.g., LIMK1 and/or LIMK2) with an effective amount of a
  • LIMK LIM kinase
  • a method of inhibiting LIM kinase (LIMK) activity comprising contacting the cell with an effective amount of a FTA compound, as described herein.
  • LIMK activity e.g., LIMK1 activity and/or LIMK2 activity
  • Suitable assays for determining LI K activity inhibition are described herein and/or are known in the art.
  • the FTA compounds described herein e.g., (a) regulate (e.g., inhibit) cell proliferation; (b) inhibit cell cycle progression; (c) promote apoptosis; or (d) a combination of one or more of these.
  • One aspect of the present invention pertains to a method of regulating (e.g., inhibiting) cell proliferation (e.g., proliferation of a cell), inhibiting cell cycle progression, promoting apoptosis, or a combination of one or more these, in vitro or in vivo, comprising contacting a cell with an effective amount of a FTA compound, as described herein.
  • the method is a method of regulating (e.g., inhibiting) cell proliferation (e.g., proliferation of a cell), in vitro or in vivo, comprising contacting a cell with an effective amount of a FTA compound, as described herein.
  • the method is performed in vitro.
  • the method is performed in vivo.
  • the FTA compound is provided in the form of a pharmaceutically acceptable composition.
  • Any type of cell may be treated, including but not limited to, lung, gastrointestinal
  • a candidate compound regulates (e.g., inhibits) cell proliferation, etc.
  • assays which may conveniently be used to assess the activity offered by a particular compound are described herein.
  • a sample of cells e.g., from a tumour
  • a compound brought into contact with said cells, and the effect of the compound on those cells observed.
  • effect the morphological status of the cells (e.g., alive or dead, etc.) may be determined.
  • this may be used as a prognostic or diagnostic marker of the efficacy of the compound in methods of treating a patient carrying cells of the same cellular type.
  • Another aspect of the present invention pertains to a FTA compound, as described herein, for use in a method of treatment of the human or animal body by therapy.
  • Another aspect of the present invention pertains to use of a FTA compound, as described herein, in the manufacture of a medicament for use in treatment.
  • the medicament comprises the FTA compound.
  • Methods of Treatment pertains to a method of treatment comprising administering to a patient in need of treatment a therapeutically effective amount of a FTA compound, as described herein, preferably in the form of a pharmaceutical composition.
  • Conditions Treated - Conditions Mediated by LIM Kinase (LIMK) are described herein, preferably in the form of a pharmaceutical composition.
  • the treatment is treatment of a disease or condition that is mediated by LIM kinase (LIMK) (e.g., LIMK1 and/or LIMK2).
  • LIMK LIM kinase
  • the treatment is treatment of. a disease or condition that is ameliorated by the inhibition of LIM kinase (LIMK) activity (e.g., LIMK1 activity and/or LIMK2 activity).
  • LIMK LIM kinase
  • the treatment is treatment of: a proliferative condition.
  • proliferative condition pertains to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth.
  • the treatment is treatment of: a proliferative condition characterised by benign, pre-malignant, or malignant cellular proliferation, including but not limited to, neoplasms, hyperplasias, and tumours (e.g., histocytoma, glioma, astrocyoma, osteoma), cancers (see below), psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissues), pulmonary fibrosis, atherosclerosis, smooth muscle cell proliferation in the blood vessels, such as stenosis or restenosis following angioplasty.
  • a proliferative condition characterised by benign, pre-malignant, or malignant cellular proliferation, including but not limited to, neoplasms, hyperplasias, and tumours (e.g., histo
  • the treatment is treatment of cancer.
  • the treatment is treatment of cancer characterised by, or further characterised by, cancer cells which overexpress LIM kinase (LIMK) (e.g., LIMK1 and/or LIMK2).
  • LIMK LIM kinase
  • the treatment is treatment of lung cancer, small cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, stomach cancer, bowel cancer, colon cancer, rectal cancer, colorectal cancer, thyroid cancer, breast cancer, ovarian cancer, endometrial cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, renal cell carcinoma, bladder cancer, pancreatic cancer, brain cancer, glioma, sarcoma, osteosarcoma, bone cancer, nasopharyngeal cancer (e.g., head cancer, neck cancer), skin cancer, squamous cancer, Kaposi's sarcoma, melanoma, malignant melanoma, lymphoma, or leukemia.
  • lung cancer small cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, stomach cancer, bowel cancer, colon cancer
  • rectal cancer colorectal cancer, thyroid cancer, breast cancer, ovarian cancer, endometrial cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, renal cell carcinoma, bladder cancer
  • the treatment is treatment of:
  • a carcinoma for example a carcinoma of the bladder, breast, colon (e.g., colorectal carcinomas such as colon adenocarcinoma and colon adenoma), kidney, epidermal, liver, lung (e.g., adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas), oesophagus, gall bladder, ovary, pancreas (e.g., exocrine pancreatic carcinoma), stomach, cervix, thyroid, prostate, skin (e.g., squamous cell carcinoma); a hematopoietic tumour of lymphoid lineage, for example leukemia, acute lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non- Hodgkin's lymphoma, hairy cell lymphoma, or Burkett's lymphoma;
  • hematopoietic tumor of myeloid lineage for example acute and chronic myelogenous leukemias, myelodysplastic syndrome, or promyelocytic leukemia;
  • tumour of mesenchymal origin for example fibrosarcoma or habdomyosarcoma
  • a tumor of the central or peripheral nervous system for example astrocytoma, neuroblastoma, glioma or schwannoma
  • melanoma melanoma; seminoma; teratocarcinoma; osteosarcoma; xenoderoma
  • pigmentoum pigmentoum
  • keratoctanthoma thyroid follicular cancer
  • Kaposi's sarcoma Kaposi's sarcoma
  • the treatment is treatment of solid tumour cancer. ln one embodiment, the treatment is treatment of breast cancer, prostate cancer, melanoma, or glioma. In one embodiment, the treatment is treatment of cancer metastasis.
  • the cancer is characterised by, or further characterised by, cancer stem cells.
  • the anti-cancer effect may arise through one or more mechanisms, including but not limited to, the regulation of cell proliferation, the inhibition of cell cycle progression, the inhibition of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a tumour from its origin), the inhibition of cell migration (the spread of cance cells to other parts of the body), the inhibition of invasion (the spread of tumour cells into neighbouring normal structures), or the promotion of apoptosis
  • the compounds of the present invention may be used in the treatment of the cancers described herein, independent of the mechanisms discussed herein. Conditions Treated - Additional Conditions
  • the treatment is treatment of vasodilation.
  • the treatment is treatment of hypertension, angina, cerebral vasospasm, or ischemia following subarachnoid hemorrhage.
  • the treatment is treatment of a neurodegenerative disorder.
  • the treatment is treatment of atherosclerosis.
  • the treatment is treatment of fibrosis.
  • the treatment is treatment of an inflammatory disease. In one embodiment, the treatment is treatment of Crohn's disease or chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the treatment is treatment of glaucoma (also known as ocular hypertension).
  • treatment refers generally to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, alleviatiation of symptoms of the condition, amelioration of the condition, and cure of the condition.
  • Treatment as a prophylactic measure i.e., prophylaxis
  • treatment is also included. For example, use with patients who have not yet developed the condition, but who are at risk of developing the condition, is encompassed by the term "treatment.”
  • treatment includes the prophylaxis of cancer, reducing the incidence of cancer, alleviating the symptoms of cancer, etc.
  • terapéuticaally-effective amount refers to that amount of a compound, or a material, composition or dosage form comprising a compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.
  • treatment includes combination treatments and therapies, in which two or more treatments or therapies are combined, for example, sequentially or simultaneously.
  • the compounds described herein may also be used in combination therapies, e.g., in conjunction with other agents, for example, cytotoxic agents, anticancer agents, etc.
  • treatments and therapies include, but are not limited to, chemotherapy (the administration of active agents, including, e.g., drugs, antibodies (e.g., as in immunotherapy), prodrugs (e.g., as in photodynamic therapy, GDEPT, ADEPT, etc.); surgery; radiation therapy; photodynamic therapy; gene therapy; and controlled diets.
  • a compound as described herein may be beneficial to combine treatment with a compound as described herein with one or more other (e.g., 1 , 2, 3, 4) agents or therapies that regulates cell growth or survival or differentiation via a different mechanism, thus treating several characteristic features of cancer development.
  • one or more other agents or therapies that regulates cell growth or survival or differentiation via a different mechanism
  • One aspect of the present invention pertains to a compound as described herein, in combination with one or more additional therapeutic agents, as described below.
  • the particular combination would be at the discretion of the physician who would select dosages using his common general knowledge and dosing regimens known to a skilled practitioner.
  • the agents i.e., the compound described herein, plus one or more other agents
  • the agents can be administered at closely spaced intervals (e.g., over a period of 5-10 minutes) or at longer intervals (e.g., 1, 2, 3, 4 or more hours apart, or even longer periods apart where required), the precise dosage regimen being commensurate with the properties of the therapeutic agent(s).
  • agents i.e., the compound described here, plus one or more other agents
  • the agents may be formulated together in a single dosage form, or alternatively, the individual agents may be formulated separately and presented together in the form of a kit, optionally with instructions for their use.
  • the FTA compounds described herein may also be used as cell culture additives to inhibit (LIMK) activity (e.g., LIMK1 activity and/or LIMK2 activity), e.g., to inhibit cell proliferation, etc.
  • LIMK e.g., LIMK1 activity and/or LIMK2 activity
  • the FTA compounds described herein may also be used as part of an in vitro assay, for example, in order to determine whether a candidate host is likely to benefit from treatment with the compound in question.
  • the FTA compounds described herein may also be used as a standard, for example, in an assay, in order to identify other compounds, other LIMK activity inhibitors, other anti-proliferative agents, other anti-cancer agents, etc.
  • kits comprising (a) a FTA compound as described herein, or a composition comprising a FTA compound as described herein, e.g., preferably provided in a suitable container and/or with suitable packaging; and (b) instructions for use, e.g., written instructions on how to administer the compound or composition.
  • the written instructions may also include a list of indications for which the active ingredient is a suitable treatment.
  • the FTA compound or pharmaceutical composition comprising the FTA compound may be administered to a subject by any convenient route of administration, whether systemically/peripherally or topically (i.e., at the site of desired action).
  • Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eyedrops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal,
  • the subject/patient may be a chordate, a vertebrate, a mammal, a placental mammal, a marsupial (e.g., kangaroo, wombat), a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), a lagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., a pig), ovine (e.g., a sheep), bovine (e.g., a cow), a primate, simian (e.g., a monkey or ape), a monkey (e.g., marmoset, baboon), an a rodent (e.
  • the subject/patient may be any of its forms of development, for example, a foetus.
  • the subject/patient is a human.
  • Formulations While it is possible for the FTA compound to be administered alone, it is preferable to present it as a pharmaceutical formulation (e.g., composition, preparation, medicament) comprising at least one FTA compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, including, but not limited to, pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents.
  • pharmaceutically acceptable carriers e.g., composition, preparation, medicament
  • diluents diluents, excipients, adjuvants, fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers, solubilisers, surfactants (e.
  • the formulation may further comprise other active agents, for example, other therapeutic or prophylactic agents.
  • the present invention further provides pharmaceutical compositions, as defined above, and methods of making a pharmaceutical composition comprising admixing at least one FTA compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, e.g., carriers, diluents, excipients, etc. If formulated as discrete units (e.g., tablets, etc.), each unit contains a predetermined amount (dosage) of the compound.
  • pharmaceutically acceptable pertains to compounds, ingredients, materials, compositions, dosage forms, etc., which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject in question (e.g., human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit risk ratio.
  • Each carrier, diluent, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.
  • Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical texts, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pa., 1990; and Handbook of Pharmaceutical Excipients, 5th edition, 2005.
  • the formulations may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the compound with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the compound with carriers (e.g., liquid carriers, finely divided solid carrier, etc.), and then shaping the product, if necessary.
  • carriers e.g., liquid carriers, finely divided solid carrier, etc.
  • the formulation may be prepared to provide for rapid or slow release; immediate, delayed, timed, or sustained release; or a combination thereof.
  • Formulations may suitably be in the form of liquids, solutions (e.g., aqueous, nonaqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, mouthwashes, drops, tablets (including, e.g., coated tablets), granules, powders, losenges, pastilles, capsules (including, e.g., hard and soft gelatin capsules), cachets, pills, ampoules, boluses, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, mists, or aerosols.
  • solutions e.g., aqueous, nonaqueous
  • suspensions e.g., aqueous, non-aqueous
  • emulsions
  • Formulations may suitably be provided as a patch, adhesive plaster, bandage, dressing, or the like which is impregnated with one or more compounds and optionally one or more other pharmaceutically acceptable ingredients, including, for example, penetration, permeation, and absorption enhancers. Formulations may also suitably be provided in the form of a depot or reservoir. The compound may be dissolved in, suspended in, or admixed with one or more other pharmaceutically acceptable ingredients. The compound may be presented in a liposome or other microparticulate which is designed to target the compound, for example, to blood components or one or more organs.
  • Formulations suitable for oral administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, tablets, granules, powders, capsules, cachets, pills, ampoules, boluses.
  • Formulations suitable for buccal administration include mouthwashes, losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.
  • Losenges typically comprise the compound in a flavored basis, usually sucrose and acacia or tragacanth.
  • Pastilles typically comprise the compound in an inert matrix, such as gelatin and glycerin, or sucrose and acacia.
  • Mouthwashes typically comprise the compound in a suitable liquid carrier.
  • Formulations suitable for sublingual administration include tablets, losenges, pastilles, capsules, and pills.
  • Formulations suitable for oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil- in-water, water-in-oil), mouthwashes, losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.
  • solutions e.g., aqueous, non-aqueous
  • suspensions e.g., aqueous, non-aqueous
  • emulsions e.g., oil- in-water, water-in-oil
  • mouthwashes e.g., gluges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.
  • Formulations suitable for non-oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g. , oil-in-water, water-in-oil), suppositories, pessaries, gels, pastes, ointments, creams, lotions, oils, as well as patches, adhesive plasters, depots, and reservoirs.
  • solutions e.g., aqueous, non-aqueous
  • suspensions e.g., aqueous, non-aqueous
  • emulsions e.g. , oil-in-water, water-in-oil
  • suppositories e.g. , oil-in-water, water-in-oil
  • pessaries e.g., oil-in-water, water-in-oil
  • suppositories e
  • Formulations suitable for transdermal administration include gels, pastes, ointments, creams, lotions, and oils, as well as patches, adhesive plasters, bandages, dressings, depots, and reservoirs.
  • Tablets may be made by conventional means, e.g., compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g., povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, silica); disintegrants (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose); surface-active or dispersing or wetting agents (e.g., sodium lauryl sulfate); preservatives (e.g., ethy] p-hydroxybenzoate, prop
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the compound therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile.
  • Tablets may optionally be provided with a coating, for example, to affect release, for example an enteric coating, to provide release in parts of the gut other than the stomach.
  • Ointments are typically prepared from the compound and a paraffinic or a water-miscible ointment base.
  • Creams are typically prepared from the compound and an oil-in-water cream base.
  • the aqueous phase of the cream base may include, for example, at least about 30% w/w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1 ,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof.
  • the topical formulations may desirably include a compound which enhances absorption or penetration of the compound through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues.
  • Emulsions are typically prepared from the compound and an oily phase, which may optionally comprise merely an emulsifier (otherwise known as an emulgent), or it may comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.
  • an emulsifier also known as an emulgent
  • a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabiliser. It is also preferred to include both an oil and a fat.
  • the emulsifier(s) with or without stabilisers make up the so-called emulsifying wax
  • the wax together with the oil and/or fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • Suitable emulgents and emulsion stabilisers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.
  • suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the compound in most oils likely to be used in pharmaceutical emulsion formulations may be very low.
  • the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
  • Formulations suitable for intranasal administration, where the carrier is a liquid include, for example, nasal spray, nasal drops, or by aerosol administration by nebuliser, include aqueous or oily solutions of the compound.
  • Formulations suitable for intranasal administration, where the carrier is a solid include, for example, those presented as a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Formulations suitable for pulmonary administration include those presented as an aerosol spray from a pressurised pack, with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases.
  • a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases.
  • Formulations suitable for ocular administration include eye drops wherein the compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the compound.
  • Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, for example, cocoa butter or a salicylate; or as a solution or suspension for treatment by enema.
  • a suitable base comprising, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, for example, cocoa butter or a salicylate; or as a solution or suspension for treatment by enema.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the compound, such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous or non-aqueous, isotonic, pyrogen-free, sterile liquids (e.g., solutions, suspensions), in which the compound is dissolved, suspended, or otherwise provided (e.g., in a liposome or other microparticulate).
  • sterile liquids e.g., solutions, suspensions
  • Such liquids may additional contain other pharmaceutically acceptable ingredients, such as anti-oxidants, buffers, preservatives, stabilisers, bacteriostats, suspending agents, thickening agents, and solutes which render the formulation isotonic with the blood (or other relevant bodily fluid) of the intended recipient.
  • excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like.
  • suitable isotonic carriers for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection.
  • the concentration of the compound in the liquid is from about 1 ng/ml to about 10 g/ml, for example from about 10 ng/ml to about 1 g/ml.
  • the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.
  • FTA compounds, and compositions comprising the FTA compounds can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects.
  • the selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular FTA compound, the route of administration, the time of administration, the rate of excretion of the FTA compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, the severity of the condition, and the species, sex, age, weight, condition, general health, and prior medical history of the patient.
  • the amount of FTA compound and route of administration will ultimately be at the discretion of the physician, veterinarian, or clinician, although generally the dosage will be selected to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.
  • Administration can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell(s) being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician, veterinarian, or clinician.
  • a suitable dose of the FTA compound is in the range of about 10 pg to about 250 mg (more typically about 100 pg to about 25 mg) per kilogram body weight of the subject per day.
  • the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately.
  • N,N-dimethylformamide (0.025 mmol) in phosphorous oxychloride (6 mL) was allowed to stir at 90°C for 20 h.
  • the phosphorous oxychloride was removed in vacuo. Ice-water was added and the solution neutralized by portionwise addition of solid sodium hydrogen carbonate. The resulting precipitate was filtered off, washed with water and dried in a vacuum oven to give the chloro pyrimidine as a tanned solid (86%).
  • N,N-dimethylformamide (3 mL) containing under nitrogen was stirred at 0°C for 45 min and then warmed to 25°C for 2 h. After this time, water was added and a precipitate formed. This was filtered, washed with water and then oven dried to give the
  • N,N-dimethylformamide (3 mL) was allowed to stir for 1 h at room temperature. Ice-water was added to the reaction mixture. The precipitate that formed was filtered off, washing with water and dried in a vacuum oven to obtain a white solid (the solid was a mixture of acyclic and cyclic product). The solid was dissolved in N,N-dimethylformamide (3 mL) and potassium carbonate (0.7 mmol) was added. The mixture was allowed to stir at 50°C for 8 h. Ice-water was added to the reaction mixture. The precipitate that formed was filtered off, washing with water and dried in a vacuum oven to obtain the thieno pyridine as a white solid (68 %).
  • Morpholine (36.3 mmol) is added to a solution of 2-cyanothioacetamide (36.3 mmol) in ethanol (20 mL) and the solution stirred at 25°C for 5 min.
  • Ethyl acetoacetate (36.3 mmol) is added and the solution was then stirred at 25°C for 24 h.
  • Acetone was added to the solution and the precipitate that formed was filtered off washing with acetone to afford the pyridine as a white solid (61%).
  • the serine kinases LIMK-1 and LIMK-2 are kinases which have LIM domains or protein- motifs that are frequently found in cytosolic proteins which interact with the actin cytoskeleton involved in cell division and motility.
  • the purpose of the assay was to screen for inhibitors of LIMK-1 whereby kinase activity was measured by a luminescence ATP detection system in a single-point 384 well screening assay measuring ATP consumption by the kinase-substrate phosphorylation reaction.
  • the reaction measured was characterized by two steps as outlined below: APT/Mg ⁇
  • the first step LIMK-1 catalyses the phosphorylation of its substrate cofilin thereby consuming ATP.
  • the second step involves the detection of the remaining ATP using the Luminescence ATP detection system, Kinase-Glo® (Promega).
  • the firefly luciferase enzyme produces light by its reaction with its substrate D-Luciferin and ATP. The light which is produced as a result of the reaction is proportional to the amount of ATP that is present in the initial kinase reaction.
  • LimK-1 and cofilin were supplied by Ora Bernard, St Vincent's Medical Institute. ATP (99% purity) supplied by Sigma Aldrich whilst the Kinase-Glo detection kit was obtained from Promega Corp (Cat #V6714).
  • Common assay buffer reagents such as HEPES, KCI, MgCI 2 , MnCI 2 , NaF, NaVO, and BSA were purchased from Sigma Aldrich. Library compounds were pre-prepared in Metrical 50 ⁇ , V-bottom polypropylene plates. The assay was carried out in PerkinElmer Lifesciences 384 well ProxiplatesTM (white, shallow well of 28 ⁇ total volume, inverted chimney design) with Matrical deep well plates
  • MiniTrak IX PerkinElmer Lifesciences
  • Thermo Corporation was used to perform all other additions and measurements were detected using the Envision 2103 (PerkinElmer Lifesciences).
  • a MultiDrop reagent dispenser added 4.9 pL of LIMK-1 in kinase buffer to all wells except negative control wells. Those were filled with the same volume of assay buffer.
  • the plates were de-lidded and 10 pL Kinase-Glo reagent per well were added with a MultiDrop. The plates were lidded again and incubated for further 10 min in the dark to allow for stabilization of the luminescence signal. Afterwards, the plates were read in the EnVision 2103 reader using the program "Ultrasensitive Luminescence". Each well was read for 0.1 sec. Because the Kinase-Glo reagents were sensitive to light, all handlings were done under modest light conditions. 2.2.3. Data Analysis
  • x signal in samples after compound treatment.
  • ⁇ * mean signal of the blanks (no LI K-1).
  • Label 1 Ultra sensitive Luminescence.
  • Plate filter 384 wells, 16 * 24.
  • the substrate solution was prepared according to the supplier's manual, e.g., bringing the solutions to room temperature and reconstituting the lyophilized substrate solution. This was carried out in the dark due to the reagent's sensitivity to light.
  • the reconstituted substrate solution contained a mutant of firefly luciferase and its substrate D-Luciferin which were necessary for the detection of ATP levels after the kinase reaction. 3.3. Automation Protocol
  • This protocol describes a method to quantify the effect of inhibitors of LIMK1.
  • the 384 well format assay is based on the Transcreener FP technology to measure ADP formed during the reaction.
  • Triton X-100 Stored at room temperature.
  • LIMK1 0.8 ng/5 pL will give a final concentration of 1.9 nM during the kinase reaction.
  • Cofilin 1.9 pg/5 pL will give 10 ⁇ final concentration during the kinase reaction.
  • ATP 40 pM in dilution to give 20 pM during the kinase reaction.
  • the concentration of the ADP antibody is dependent on the ATP concentration present due to a limited selectivity.
  • ADP-antibody 28.1 pg/mL in the mix.
  • Minitrak program for pin tool transfer is optimized to pick up the dilution out of 7.5 pL of DMSO, therefore 6 is usually 7.5 ul. Choose a to achieve any desired dilution factor of
  • Min/trak program 11_pt_titration_P30 the Min/trak program 11_pt_titration_P30.
  • MultiDrop prior to all additions flush the MultiDrop cassette with assay buffer containing ovalbumine to minimize loss of the enzyme/ substrate in the tubings.
  • excitation filter 620/40 nm the excitation filter 620/40 nm.
  • Plate layout 384 wells, 16 * 24.
  • Reading mode Fluorescence polarization.
  • 1X Kinase Buffer A 50 mM HEPES at pH 7.5, 10 mM gCI 2> 1 m EGTA, 0.01 % Brij-35.
  • the antibody tube was centrifuged at approximately 10,000 x g for 0 minutes and the desired volume aspirated from the top of the solution to eliminate spurious data points that can arise on occasion due to any particulates in the product.
  • a working solution of tracer 178 was prepared at 3x the final desired concentration in 1 X Buffer A.
  • 5 pL of kinase/antibody solution was added to all test compound wells and positive control wells.
  • An antibody solution containing no UMK2 kinase was added to the final two columns to give negative control wells.
  • 5 uL of Tracer 78 was added to all wells of the plate and then incubated at room temperature for 60 minutes. Following the incubation period the plate was read on a Tecan Ultra plate reader where two sequential measurements were measured: one at 620 nm for the antibody/donor emission, and the other at 665 nm for the acceptor/tracer emission. The emission ratio is calculated by the ratio of the two fluorescence intensities (acceptor/donor).
  • Measurement 1 Excitation Filter 337 nm, Emission Filter 620 nm, Mirror Dichroic2 (e.g., Fl 96), Lag time 100 ps, Integration time 200 ps, optimal Gain, optimal Z-position.
  • Mirror Dichroic2 e.g., Fl 96
  • Measurement 2 Excitation Filter 337 nm, Emission Filter 665 nm, Mirror Dichroic2 (e.g., Fl 96), Lag time 100 ps, Integration time 200 ps, optimal Gain, optimal Z-position.
  • Mirror Dichroic2 e.g., Fl 96
  • the following compounds were found to have
  • Biological Data - Assay 2 - LI K1 (Kinase Domain) Enzyme Binding Assay 2 The following compounds were examined using Assay 2: AA-001 , AA-002, AA-003, AA-005, AA-006, AA-007, AA-008, AA-009, AA-010, AA-0 1 , AA-012, AA-013, AA-014, AA-015, AA-016, AA-017, AA-0 8, AA-0 9, AA-020, AA-021 , AA-023, AA-028, AA-029, AA-032, AA-033, AA-036, AA-037, AA-038, AA-040, AB-001 , AB-002, AB-003, AB-004, AB-005, AB-006, AB-007, AB-009, AB-010, AB-011 , AB-012, AB-013, AB
  • the IC50 for AA-040 was 0.202 ⁇ .

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Abstract

La présente invention concerne généralement le domaine de composés thérapeutiques, et plus spécifiquement certains composés de triarylamine condensés de la formule suivante (par souci de commodité, collectivement appelés « composés FTA »), qui, entre autres, inhibent l'activité LIM kinase (LIMK). La présente invention concerne en outre des compositions pharmaceutiques comprenant de tels composés, et l'utilisation de tels composés et compositions, in vitro et in vivo, pour inhiber l'activité LIMK, et dans le traitement de maladies et affections qui sont médiées par LIMK, qui sont améliorées par l'inhibition de l'activité LIMK, etc., comprenant des affections prolifératives telles que le cancer (par exemple, le cancer du sein, le cancer de la prostate, le mélanome, le gliome, etc.), ainsi que la vasodilatation (comprenant, par exemple, l'hypertension, l'angor, un angiospasme cérébral, et une ischémie consécutive à une hémorragie méningée), des troubles neurodégénératifs, l'athérosclérose, la fibrose, et des maladies inflammatoires (comprenant, par exemple, la maladie de Crohn et la bronchopneumopathie chronique obstructive (BPCO)), et le glaucome (également appelé hypertension oculaire).
PCT/GB2012/000280 2011-03-28 2012-03-27 Dérivés de pyrido[3',2':4,5]thiéno[3,2-d]pyrimidin-4-ylamine et leur utilisation thérapeutique Ceased WO2012131297A1 (fr)

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US11376254B2 (en) 2017-12-05 2022-07-05 Vanderbilt University Positive allosteric modulators of the muscarinic acetylcholine receptor M4
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