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Definitions

• the present invention relates to novel compounds which are inhibitors of
• HDAC histone deacetylase
• HDACs are zinc metalloenzymes that catalyse the hydrolysis of acetylated lysine residues. In histones, this returns lysines to their protonated state and is a global mechanism of eukaryotic transcriptional control, resulting in 10 tight packaging of DNA in the nucleosome. Additionally, reversible lysine acetylation is an important regulatory process for non-histone proteins. Thus, compounds which are able to modulate HDAC have important therapeutic potential.
• WO2010/086646 discloses compounds which act as inhibitors of HDAC.
• heteroaryl capping groups and the zinc-binding groups are joined via an alkylene linker.
• the present invention is a compound of the formula
• R' is independently selected from H and QR ⁇
• each Q is independently selected from a bond, CO, CO 2 , NH, S, SO, SO 2 or O;
• each Ri is independently selected from H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, aryl, heteroaryl, C C 10 cycloalkyl, halogen, trifluoromethyl, C 1 -C 10 alkylaryl, C 1 -C 10 alkyl heteroaryl or Ci-Cio heterocycloalkyl;
• L is independently selected from an optionally substituted 6-membered nitrogen-containing heteroaryl;
• Y is independently selected from an optionally substituted 6-membered nitrogen-containing heteroaryl
• each M is selected from an optionally substituted 5- to 10-membered heteroaryl
• W is a zinc-binding group, which is not COOR 1 ;
• each R 2 is independently hydrogen or d to C 6 alkyi
• R 3 is an aryl or heteroaryl
• each aryl or heteroaryl may be substituted by up to three substituents selected from C C 6 alkyi, hydroxy, C C 3 hydroxyalkyl, C C 3 alkoxy, C C 3 haloalkoxy, amino, Ci-C 3 mono alkylamino, Ci-C 3 bis alkylamino, Ci-C 3 acylamino, Ci-C 3 aminoalkyi, mono (Ci-C 3 alkyi) amino Ci-C 3 alkyi, bis(Ci-C 3 alkyi) amino Ci-C 3 alkyi, Ci-C 3 -acylamino, Ci-C 3 alkyi sulfonylamino, halo, nitro, cyano, trifluoromethyl, carboxy, Ci-C 3 alkoxycarbonyl, aminocarbonyl, mono d- C 3 alkyi aminocarbonyl, bis Ci-C 3 alkyi aminocarbonyl, -S0 3 H, Ci-C 3 alkylsulfonyl, aminos
• each alkyi, alkenyl or alkynyl may be optionally substituted with C 1 -C 10 alkyi, C2-C10 alkenyl, C2-C10 alkynyl, aryl, cycloalkyl, heteroaryl, halogen, NH 2 , N0 2 or hydroxyl,
• the present invention is a compound represented by:
• M ! is a 5-6 membered monocyclic heteroaryl or a 8-10 membered bicyclic heteroaryl, preferably a 5-6-membered monocylic heteroaryl, optionally substituted by one, two or three substituents each independently selected from R M ;
• R M is selected for each occurrence from the group consisting of Ci -6 alkyl, C 2 . 6 alkenyl, C 2 - 6 alkynyl; d. 6 alkoxy, C 3 - 6 cycloalkyl, halogen, NR a R ; -NR a" C(0)-R a ; and - NR a S0 2 -R a (wherein Ci -6 alkyl, C ⁇ alkenyl, C ⁇ alkynyl, Ci. 6 alkoxy and C 3 . 6 cycloalkyl may be optionally substituted by one, two or three halogens);
• R 33 is selected from halogen and d. 6 alkyl (optionally substituted by one, two or three halogens);
• W is a zinc binding group
• _i_ is selected from the group consisting of H, CH 3 , and halogen
• Ryy is H, CH 3 , and halogen
• R a and R are each independently selected from H or Ci -4 alkyl; or R a and R taken together with the nitrogen to which they are attached form a 4-6 membered heterocycle.
• the present invention is a compound represented by:
• Mi is a 5-membered monocyclic heteroaryl or a 8-10 membered bicyclic heteroaryl, optionally substituted by one, two or three substituents each independently selected from R M ;
• R M is selected for each occurrence from the group consisting of Ci -6 alkyl, C 2 . 6 alkenyl, C 2 - 6 alkynyl; d. 6 alkoxy, C 3 - 6 cycloalkyl, halogen, NR a R ; -NR a" C(0)-R a ; and - NR a S0 2 -R a (wherein Ci -6 alkyl, C ⁇ alkenyl, C ⁇ alkynyl, Ci. 6 alkoxy and C 3 . 6 cycloalkyl may be optionally substituted by one, two or three halogens);
• R 33 is selected for each occurrence from the group consisting of H, halogen and Ci. 6 alkyl (optionally substituted by one, two or three halogens);
• W is a zinc binding group
• Ri_i_ is selected from the group consisting of H, CH 3 , and halogen
• Rw is H, CH 3 , and halogen
• R a and R are each independently selected from H or d. 4 alkyl; or R a and R taken together with the nitrogen to which they are attached form a 4-6 membered heterocycle.
• the compounds of the invention may be useful as an inhibitor of HDAC, i.e. in they may be used in a method of treating a disease associated with an over-expression of HDAC.
• alkyl means a C1-C10 alkyl group, which can be linear or branched. Preferably, it is a d-C 6 alkyl moiety. More preferably, it is a d-C 4 alkyl moiety. Examples include methyl, ethyl, n-propyl and t-butyl. It may be divalent, e.g. propylene.
• cycloalkyl contains from 3 to 10 carbon atoms. It may be monovalent or divalent.
• alkenyl means a C2-C10 alkenyl group. Preferably, it is a C 2 -C 6 alkenyl group. More preferably, it is a C 2 -C 4 alkenyl group.
• the alkenyl radicals may be mono- or di-saturated, more preferably monosaturated. Examples include vinyl, allyl, 1 -propenyl, isopropenyl and 1 -butenyl. It may be divalent, e.g. propenylene
• alkynyl is a C2-C10 alkynyl group which can be linear or branched. Preferably, it is a C 2 -C 4 alkynyl group or moiety. It may be divalent.
• Each of the C1-C10 alkyl, C 2 -Ci 0 alkenyl and C 2 -Ci 0 alkynyl groups may be optionally substituted with each other, i.e. C1-C10 alkyl optionally substituted with C 2 -Cio alkenyl. They may also be optionally substituted with aryl, cycloalkyl (preferably C 3 -C 10 ), aryl or heteroaryl. They may also be substituted with halogen (e.g. F, CI), NH 2 , N0 2 or hydroxyl. Preferably, they may be substituted with up to 10 halogen atoms or more preferably up to 5 halogens. For example, they may be substituted by 1 , 2, 3, 4 or 5 halogen atoms. Preferably, the halogen is fluorine.
• halogen e.g. F, CI
• aryl means a monocyclic, bicyclic, or tricyclic monovalent or divalent (as appropriate) aromatic radical, such as phenyl, biphenyl, naphthyl, anthracenyl, which can be optionally substituted with up to five substituents preferably selected from the group of Ci-C 6 alkyl, hydroxy, d- C 3 hydroxyalkyl, C C 3 alkoxy, C1-C3 haloalkoxy, amino, C C 3 mono alkylamino, Ci-C 3 bis alkylamino, Ci-C 3 acylamino, Ci-C 3 aminoalkyl, mono (Ci-C 3 alkyl) amino Ci-C 3 alkyl, bis(Ci-C 3 alkyl) amino Ci-C 3 alkyl, Ci-C 3 -acylamino, Ci-C 3 alkyl sulfonylamino, halo, nitro, cyano, trifluoromethyl, carboxy, C
• heteroaryl means a monocyclic, bicyclic or tricyclic monovalent or divalent (as appropriate) aromatic radical containing at least one and up to four heteroatoms selected from oxygen, nitrogen and sulfur, such as furanyl, pyrrolyl, thiazolyl, isothiazolyl, tetrazolyl, imidazolyl, oxazolyl, isoxazolyl, thienyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indolyl, azaindolyl, isoindolyl, quinolyl, isoquinolyl, triazolyl, thiadiazolyl, oxadiazolyl, said radical being optionally substituted with up to three substituents preferably selected from the group of C C 6 alkyl, hydroxy, Ci-C 3 hydroxyalkyl, Ci-C 3 alkoxy, C C 3 haloalkoxy, amino, C C 6 alky
• Preferred L groups are thiazolyl, imidazolyl, oxazolyl, pyrazolyl, thiadiazolyl and oxadiazolyl.
• heterocycle or “heterocycloalkyl” is a mono- or di-valent carbocyclic radical containing up to 4 heteroatoms selected from oxygen, nitrogen and sulfur. It may be monocyclic or bicyclic. It is preferably saturated.
• the word 'linker' has been used herein to mean di-valent. If the heterocycle is a di-valent linker, the heterocycle may be attached to neighbouring groups through a carbon atom, or through on of the heteroatoms, e.g. a N. Examples of heterocycles are piperazine or morpholine.
• the heterocyclic ring may be mono- or di-unsaturated.
• the radical may be optionally substituted with up to three substituents independently selected from Ci-C 6 alkyl, hydroxy, Ci-C 3 hydroxyalkyl, Ci-C 3 alkoxy, Ci-C 3 haloalkoxy, amino, Ci-C 3 mono alkylamino, C C 3 bis alkylamino, C C 3 acylamino, Ci-C 3 aminoalkyl, mono (Ci-C 3 alkyl) amino Ci-C 3 alkyl , bis (Ci-C 3 alkyl) amino Ci-C 3 alkyl, Ci-C 3 -acylamino, Ci-C 3 alkyl sulfonylamino, halo e.g.
• the group W is a zinc-chelating residue, i.e. a metallophile capable of binding with zinc in the active site of HDAC. Suitable metallophiles are known to those skilled in the art.
• W may be selected from:
• Pr 2 is H or a thiol protecting group
• Z is selected from O, S or NH
• T is N or CH.
• Ri is not halogen.
• Ri is H or C 1 -C 10 alkyl.
• W is -COOH, COOMe, -CONHOH, -CONHS0 2 CH 3 , - CONHNHSO 2 CH 3 , -CONHNH 2 , -CONH(2-pyridyl), -NHCONHOH, tetrazole, hydroxypyridin-2-thione or hydroxypyridin-2-one.
• W is not COOR 1 .
• W is COOMe, -CONHOH, CONHS0 2 CH 3 , -CONHNHS0 2 CH 3 , - CONHNH 2 , -CONH(2-pyridyl) -NHCONHOH, tetrazole, hydroxypyridin-2-thione or hydroxypyridin-2-one. Even more preferably, W is -CONHOH, tetrazole, hydroxypyridin-2-thione or hydroxypyridin-2-one.
• W is -CONHOH.
• L is selected from pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl. More preferably, L is pyrazinyl.
• L is optionally substituted with H, C 1 -C 1 0 alkyl or O-(Ci-Ci 0 alkyl), halogen, C 1 -C 10 heterocycloalkyl, aryl, trifluoromethyl or heteroaryl, more preferably H.
• Y is selected from pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl. More preferably, Y is pyridyl.
• M is selected from furanyl, pyrrolyl, thiazolyl, isothiazolyl, tetrazolyl, imidazolyl, oxazolyl, isoxazolyl, thienyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indolyl, azaindolyl, isoindolyl, quinolyl, isoquinolyl, triazolyl, thiadiazolyl and oxadiazolyl.
• M is selected from pyrimidinyl, indolyl, pyrazolyl, furanyl, isoxazolyl, pyridyl, azaindolyl. Most preferably, M is pyridyl.
• M is optionally substituted with H, C 1 -C 1 0 alkyl or O-(Ci-Ci 0 alkyl), halogen, NH 2 , C 1 -C 1 0 heterocycloalkyl, aryl, trifluoromethyl, NHC(0)Me, NHS0 2 Me or heteroaryl, more preferably H, halogen, NH 2 , C 1 -C 1 0 alkyl, NHC(0)Me, NHS0 2 Me or trifluoromethyl.
• the atom that is directly bonded to X is a carbon, and at least one nitrogen atom is directly bonded to said carbon.
• R 3 is phenylene or phenylene substituted with a halogen.
• the halogen is fluorine.
• At least one, preferably both, R 2 is/are H.
• R' is hydrogen or halogen, more preferably hydrogen or fluorine.
• M is:
• Mi may be represented by:
• R may be selected for each occurrence from the group consisting of F,-CH 3 , NH 2 , -NH-C(0)-CH 3 ; and -NH-S0 2 -CH 3 .
• a pharmaceutical composition of the invention comprises a compound as defined above, and a pharmaceutically acceptable carrier or diluent.
• a pharmaceutical composition of the invention typically contains up to 85 wt% of a compound of the invention. More typically, it contains up to 50 wt% of a compound of the invention.
• Preferred pharmaceutical compositions are sterile and pyrogen-free.
• the pharmaceutical compositions provided by the invention typically contain a compound of the invention which is a substantially pure optical isomer.
• the pharmaceutical composition comprises a pharmaceutically acceptable salt form of a compound of the invention.
• contemplated herein is a pharmaceutically acceptable composition comprising a disclosed compound and a pharmaceutically acceptable excipient.
• a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base.
• Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulfonic, ethanesulfonic, ethanedisulfonic, salicylic, stearic, benzenesulfonic or p- toluenesulfonic acid.
• Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines, aryl amines or heterocyclic amines.
• the present invention also embraces prodrugs which react in vivo to give a compound of the present invention.
• the compounds of the present invention are found to be inhibitors of HDAC.
• the compounds of the present invention are therefore therapeutically useful in the treatment of conditions affected by HDAC activity.
• the compounds of the invention may be prepared by synthetic routes that will be apparent to those skilled in the art, e.g. based on the Examples.
• the compounds of the present invention are found to be inhibitors of HDAC.
• the compounds of the present invention are therefore therapeutically useful.
• a pharmaceutical composition comprising a compound of the invention may be formulated in a format suitable for oral, rectal, parenteral, intranasal or transdermal administration or administration by inhalation or by suppository. Typical routes of administration are parenteral, intranasal or transdermal administration or administration by inhalation.
• the compounds of the invention can be administered orally, for example as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules.
• Preferred pharmaceutical compositions of the invention are compositions suitable for oral administration, for example tablets and capsules.
• the compounds of the invention may also be administered parenterally, whether subcutaneously, intravenously, intramuscularly, intrasternally, transdermal ⁇ or by infusion techniques.
• the compounds may also be administered as suppositories.
• the compounds of the invention may also be administered by inhalation.
• a further advantage may be to treat diseases of the pulmonary system, such that delivering drugs by inhalation delivers them to the proximity of the cells which are required to be treated.
• the present invention also provides an inhalation device containing such a pharmaceutical composition.
• said device is a metered dose inhaler (MDI), which contains a pharmaceutically acceptable chemical propellant to push the medication out of the inhaler.
• MDI metered dose inhaler
• the compounds of the invention may also be administered by intranasal administration.
• the nasal cavity's highly permeable tissue is very receptive to medication and absorbs it quickly and efficiently, more so than drugs in tablet form.
• Nasal drug delivery is less painful and invasive than injections, generating less anxiety among patients. By this method absorption is very rapid and first pass metabolism is usually bypassed, thus reducing inter-patient variability.
• the present invention also provides an intranasal device containing such a pharmaceutical composition.
• the compounds of the invention may also be administered by transdermal administration.
• the present invention therefore also provides a transdermal patch containing a compound of the invention.
• the compounds of the invention may also be administered by sublingual administration.
• the present invention therefore also provides a sub-lingual tablet comprising a compound of the invention.
• a compound of the invention may also be formulated with an agent which reduces degradation of the substance by processes other than the normal metabolism of the patient, such as anti-bacterial agents, or inhibitors of protease enzymes which might be the present in the patient or in commensural or parasite organisms living on or within the patient, and which are capable of degrading the compound.
• an agent which reduces degradation of the substance by processes other than the normal metabolism of the patient such as anti-bacterial agents, or inhibitors of protease enzymes which might be the present in the patient or in commensural or parasite organisms living on or within the patient, and which are capable of degrading the compound.
• Liquid dispersions for oral administration may be syrups, emulsions and suspensions.
• Suspensions and emulsions may contain as carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
• the suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.
• Solutions for injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.
• the compounds of the present invention may be used in combination with another known inhibitor of HDAC, such as SAHA.
• the combination product may be formulated such that it comprises each of the medicaments for simultaneous, separate or sequential use.
• the compounds of the present invention can be used in both the treatment and prevention of cancer and can be used in a monotherapy or in a combination therapy.
• the compounds of the present invention are typically used together with small chemical compounds such as platinum complexes, anti-metabolites, DNA topoisomerase inhibitors, radiation, antibody-based therapies (for example herceptin and rituximab), anticancer vaccination, gene therapy, cellular therapies, hormone therapies or cytokine therapy.
• a compound of the invention is used in combination with another chemotherapeutic or antineoplastic agent in the treatment of a cancer.
• chemotherapeutic or antineoplastic agents include platinum complexes including cisplatin and carboplatin, mitoxantrone, vinca alkaloids for example vincristine and vinblastine, anthracycline antibiotics for example daunorubicin and doxorubicin, alkylating agents for example chlorambucil and melphalan, taxanes for example paclitaxel, antifolates for example methotrexate and tomudex, epipodophyllotoxins for example etoposide, camptothecins for example irinotecan and its active metabolite SN38 and DNA methylation inhibitors for example the DNA methylation inhibitors disclosed in WO02/085400.
• products which contain a compound of the invention and another chemotherapeutic or antineoplastic agent as a combined preparation for simultaneous, separate or sequential use in alleviating a cancer.
• a compound of the invention in the manufacture of a medicament for use in the alleviation of cancer by co-administration with another chemotherapeutic or antineoplastic agent.
• the compound of the invention and the said other agent may be administrated in any order. In both these cases the compound of the invention and the other agent may be administered together or, if separately, in any order as determined by a physician.
• HDAC is believed to contribute to the pathology and/or symptomology of several different diseases such that reduction of the activity of HDAC in a subject through inhibition of HDAC may be used to therapeutically address these disease states. Examples of various diseases that may be treated using the HDAC inhibitors of the present invention are described herein.
• HDAC inhibitors of the present invention may be used to treat is those involving undesirable or uncontrolled cell proliferation.
• indications include benign tumours, various types of cancers such as primary tumours and tumour metastasis, restenosis (e.g. coronary, carotid, and cerebral lesions), abnormal stimulation of endothelial cells (atherosclerosis), insults to body tissue due to surgery, abnormal wound healing, abnormal angiogenesis, diseases that produce fibrosis of tissue, repetitive motion disorders, disorders of tissues that are not highly vascularized, and proliferative responses associated with organ transplants.
• More specific indications for HDAC inhibitors include, but are not limited to prostate cancer, lung cancer, acute leukaemia, multiple myeloma, bladder carcinoma, renal carcinoma, breast carcinoma, colorectal carcinoma, neuroblastoma and melanoma.
• a method for treating diseases associated with undesired and uncontrolled cell proliferation.
• the method comprises administering to a subject suffering from uncontrolled cell proliferation a therapeutically effective amount of a HDAC inhibitor according to the present invention, such that said uncontrolled cell proliferation is reduced.
• a therapeutically effective amount of a HDAC inhibitor according to the present invention is administered to a subject suffering from uncontrolled cell proliferation a therapeutically effective amount of a HDAC inhibitor according to the present invention, such that said uncontrolled cell proliferation is reduced.
• the particular dosage of the inhibitor to be used will depend on the severity of the disease state, the route of administration, and related factors that can be determined by the attending physician. Generally, acceptable and effective daily doses are amounts sufficient to effectively slow or eliminate uncontrolled cell proliferation.
• HDAC inhibitors according to the present invention may also be used in conjunction with other agents to inhibit undesirable and uncontrolled cell proliferation.
• anti-cell proliferation agents include, but are not limited to, retinoid acid and derivatives thereof, 2-methoxyestradiol, AngiostatinTM protein, EndostatinTM protein, suramin, squalamine, tissue inhibitor of metalloproteinase-l, tissue inhibitor of metalloproteinase-2, plasminogen activator inhibitor-1 , plasminogen activator inhibitor-2, cartilage-derived inhibitor, paclitaxel, platelet factor 4, protamine sulfate (clupeine), sulfated chitin derivatives (prepared from queen crab shells), sulfated polysaccharide peptidoglycan complex (sp-pg), staurosporine, modulators of matrix metabolism, including for example, proline analogs ((1 -azetidine-2-carboxylic acid (L)
• anti-angiogenesis agents include antibodies, preferably monoclonal antibodies against these angiogenic growth factors: bFGF, aFGF, FGF-5, VEGF isoforms, VEGF-C, HGF/SF and Ang-1/Ang-2.
• bFGF vascular endothelial growth factor
• FGF-5 vascular endothelial growth factor
• VEGF isoforms VEGF-C
• HGF/SF Ang-1/Ang-2.
• Ferrara N. and Alitalo, K. “Clinical application of angiogenic growth factors and their inhibitors" (1999) Nature Medicine 5:1359- 1364.
• a benign tumour is usually localized and nonmetastatic.
• Specific types of benign tumours that can be treated using HDAC inhibitors of the present invention include hemangiomas, hepatocellular adenoma, cavernous haemangioma, focal nodular hyperplasia, acoustic neuromas, neurofibroma, bile duct adenoma, bile duct cystanoma, fibroma, lipomas, leiomyomas, mesotheliomas, teratomas, myxomas, nodular regenerative hyperplasia, trachomas and pyogenic granulomas.
• Malignant tumors In the case of malignant tumors, cells become undifferentiated, do not respond to the body's growth control signals, and multiply in an uncontrolled manner. Malignant tumors are invasive and capable of spreading to distant sites (metastasizing). Malignant tumors are generally divided into two categories: primary and secondary. Primary tumors arise directly from the tissue in which they are found. Secondary tumours, or metastases, are tumours that originated elsewhere in the body but have now spread to distant organs. Common routes for metastasis are direct growth into adjacent structures, spread through the vascular or lymphatic systems, and tracking along tissue planes and body spaces (peritoneal fluid, cerebrospinal fluid, etc.).
• cancers or malignant tumours include, but are not limited to, leukaemia, breast cancer, skin cancer, bone cancer, prostate cancer, liver cancer, lung cancer, brain cancer, cancer of the larynx, gallbladder, pancreas, rectum, parathyroid, thyroid, adrenal, neural tissue, head and neck, colon, stomach, bronchi, kidneys, basal cell carcinoma, squamous cell carcinoma of both ulcerating and papillary type, metastatic skin carcinoma, osteo sarcoma, Ewing's sarcoma, veticulum cell sarcoma, myeloma, giant cell tumour, small-cell lung tumour, gallstones, islet cell tumour, primary brain tumour, acute and chronic lymphocytic and granulocytic tumours, hairy-cell tumour, adenoma, hyperplasia, medullary carcinoma, pheochromocytoma, mucosal neuromas, intestinal
• the HDAC inhibitors of the present invention may also be used to treat abnormal cell proliferation due to insults to body tissue during surgery. These insults may arise as a result of a variety of surgical procedures such as joint surgery, bowel surgery, and cheloid scarring.
• Diseases that produce fibrotic tissue that may be treated using the HDAC inhibitors of the present invention include emphysema.
• Repetitive motion disorders that may be treated using the present invention include carpal tunnel syndrome.
• An example of a cell proliferative disorder that may be treated using the invention is a bone tumour.
• Proliferative responses associated with organ transplantation that may be treated using HDAC inhibitors of the invention include proliferative responses contributing to potential organ rejections or associated complications. Specifically, these proliferative responses may occur during transplantation of the heart, lung, liver, kidney, and other body organs or organ systems.
• Abnormal angiogenesis that may be treated using this invention include those abnormal angiogenesis accompanying rheumatoid arthritis, ischemic- reperfusion related brain edema and injury, cortical ischemia, ovarian hyperplasia and hypervascularity, polycystic ovary syndrome, endometriosis, psoriasis, diabetic retinopathy, and other ocular angiogenic diseases such as retinopathy of prematurity (retrolental fibroplastic), macular degeneration, corneal graft rejection, neuroscular glaucoma and Oster Webber syndrome.
• abnormal angiogenesis accompanying rheumatoid arthritis, ischemic- reperfusion related brain edema and injury, cortical ischemia, ovarian hyperplasia and hypervascularity, polycystic ovary syndrome, endometriosis, psoriasis, diabetic retinopathy, and other ocular angiogenic diseases such as retinopathy
• diseases associated with uncontrolled angiogenesis include, but are not limited to retinal/choroidal neovascularization and corneal neovascularization.
• diseases which include some component of retinal/choroidal neovascularization include, but are not limited to, Best's diseases, myopia, optic pits, Stargart's diseases, Paget's disease, vein occlusion, artery occlusion, sickle cell anemia, sarcoid, syphilis, pseudoxanthoma elasticum carotid apo structive diseases, chronic uveitis/vitritis, mycobacterial infections, Lyme's disease, systemic lupus erythematosus, retinopathy of prematurity, Eale's disease, diabetic retinopathy, macular degeneration, Bechet's diseases, infections causing a retinitis or chroiditis, presumed ocular histoplasmosis, pars planitis
• corneal neovascularization examples include, but are not limited to, epidemic keratoconjunctivitis, Vitamin A deficiency, contact lens overwear, atopic keratitis, superior limbic keratitis, pterygium keratitis sicca, sjogrens, acne rosacea, phylectenulosis, diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, Mooren ulcer, Terrien's marginal degeneration, marginal keratolysis, polyarteritis, Wegener sarcoidosis, Scleritis, periphigoid radial keratotomy, neovascular glaucoma and retrolental fibroplasia, syphilis, Mycobacteria infections, lipid degeneration, chemical burns, bacterial ulcers, fungal ulcers, Herpes simplex infections, Herpes zoster infections, protozoan infections and Kaposi sarcoma
• Chronic inflammatory diseases associated with uncontrolled angiogenesis may also be treated using HDAC inhibitors of the present invention.
• Chronic inflammation depends on continuous formation of capillary sprouts to maintain an influx of inflammatory cells. The influx and presence of the inflammatory cells produce granulomas and thus maintains the chronic inflammatory state. Inhibition of angiogenesis using a HDAC inhibitor alone or in conjunction with other anti-inflammatory agents may prevent the formation of the granulosmas and thus alleviate the disease.
• Examples of chronic inflammatory diseases include, but are not limited to, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, psoriasis, sarcoidosis, and rheumatoid arthritis.
• Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis are characterized by chronic inflammation and angiogenesis at various sites in the gastrointestinal tract.
• Crohn's disease occurs as a chronic transmural inflammatory disease that most commonly affects the distal ileum and colon but may also occur in any part of the gastrointestinal tract from the mouth to the anus and perianal area.
• Patients with Crohn's disease generally have chronic diarrhoea associated with abdominal pain, fever, anorexia, weight loss and abdominal swelling.
• Ulcerative colitis is also a chronic, nonspecific, inflammatory and ulcerative disease arising in the colonic mucosa and is characterized by the presence of bloody diarrhoea.
• inflammatory bowel diseases are generally caused by chronic granulomatous inflammation throughout the gastrointestinal tract, involving new capillary sprouts surrounded by a cylinder of inflammatory cells. Inhibition of angiogenesis by these inhibitors should inhibit the formation of the sprouts and prevent the formation of granulomas. Inflammatory bowel diseases also exhibit extra intestinal manifestations, such as skin lesions. Such lesions are characterized by inflammation and angiogenesis and can occur at many sites other the gastrointestinal tract. Inhibition of angiogenesis by HDAC inhibitors according to the present invention can reduce the influx of inflammatory cells and prevent lesion formation.
• Sarcoidosis another chronic inflammatory disease, is characterized as a multisystem granulomatous disorder.
• the granulomas of this disease can form anywhere in the body. Thus, the symptoms depend on the site of the granulomas and whether the disease is active.
• the granulomas are created by the angiogenic capillary sprouts providing a constant supply of inflammatory cells.
• HDAC inhibitors according to the present invention to inhibit angiogenesis, such granulomas formation can be inhibited.
• Psoriasis also a chronic and recurrent inflammatory disease, is characterized by papules and plaques of various sizes. Treatment using these inhibitors alone or in conjunction with other anti-inflammatory agents should prevent the formation of new blood vessels necessary to maintain the characteristic lesions and provide the patient relief from the symptoms.
• Rheumatoid arthritis is also a chronic inflammatory disease characterized by non-specific inflammation of the peripheral joints. It is believed that the blood vessels in the synovial lining of the joints undergo angiogenesis. In addition to forming new vascular networks, the endothelial cells release factors and reactive oxygen species that lead to pannus growth and cartilage destruction. The factors involved in angiogenesis may actively contribute to, and help maintain, the chronically inflamed state of rheumatoid arthritis. Treatment using HDAC inhibitors according to the present invention alone or in conjunction with other anti-RA agents may prevent the formation of new blood vessels necessary to maintain the chronic inflammation.
• the compounds of the present invention can further be used in the treatment of cardiac/vasculature diseases such as hypertrophy, hypertension, myocardial infarction, reperfusion, ischaemic heart disease, angina, arrhythmias, hypercholesterolemia, atherosclerosis and stroke.
• cardiac/vasculature diseases such as hypertrophy, hypertension, myocardial infarction, reperfusion, ischaemic heart disease, angina, arrhythmias, hypercholesterolemia, atherosclerosis and stroke.
• the compounds can further be used to treat neurodegenerative disorders/CNS disorders such as acute and chronic neurological diseases, including stroke, Huntington's disease, Amyotrophic Lateral Sclerosis and Alzheimer's disease.
• the compounds of the present invention can also be used as antimicrobial agents, for example antibacterial agents.
• the invention therefore also provides a compound for use in the treatment of a bacterial infection.
• the compounds of the present invention can be used as anti-infectious compounds against viral, bacterial, fungal and parasitic infections. Examples of infections include protozoal parasitic infections (including Plasmodium, Cryptosporidium parvum, toxoplasma gondii, sarcocystis neurona and Eimeria sp.)
• the compounds of the present invention are particularly suitable for the treatment of undesirable or uncontrolled cell proliferation, preferably for the treatment of benign tumours/hyperplasias and malignant tumours, more preferably for the treatment of malignant tumours and most preferably for the treatment of chronic lymphocytic leukaemia (CLL), breast cancer, prostate cancer, ovarian cancer, mesothelioma, T-cell lymphoma.
• CLL chronic lymphocytic leukaemia
• the compounds of the invention are used to alleviate cancer, cardiac hypertrophy, chronic heart failure, an inflammatory condition, a cardiovascular disease, a haemoglobinopathy, a thalassemia, a sickle cell disease, a CNS disorder, an autoimmune disease, organ transplant rejection, diabetes, osteoporosis, MDS, benign prostatic hyperplasia, oral leukoplakia, a genentically related metabolic disorder, an infection, Rubens-Taybi, fragile X syndrome, or alpha-1 antitrypsin deficiency, or to accelerate wound healing, to protect hair follicles or as an immunosuppressant.
• said inflammatory condition is a skin inflammatory condition (for example psoriasis, acne and eczema), asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis (RA), inflammatory bowel disease (IBD), Crohn's disease or colitis.
• COPD chronic obstructive pulmonary disease
• RA rheumatoid arthritis
• IBD inflammatory bowel disease
• Crohn's disease or colitis a skin inflammatory condition
• said cancer is chronic lymphocytic leukaemia, breast cancer, prostate cancer, ovarian cancer, mesothelioma or T-cell lymphoma.
• said cardiovascular disease is hypertension, myocardial infarction (Ml), ischemic heart disease (IHD) (reperfusion), angina pectoris, arrhythmia, hypercholesterolemia, hyperlipidaemia, atherosclerosis, stroke, myocarditis, congestive heart failure, primary and secondary i.e. dilated (congestive) cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, peripheral vascular disease, tachycardia, high blood pressure or thrombosis.
• Ml myocardial infarction
• IHD ischemic heart disease
• said genetically related metabolic disorder is cystic fibrosis (CF), peroxisome biogenesis disorder or adrenoleukodystrophy.
• the compounds of the invention are used as an immunosuppressant following organ transplant.
• said infection is a viral, bacterial, fungal or parasitic infection, in particular an infection by S aureus, P acne, Candida or aspergillus.
• said CNS disorder is Huntingdon's disease, Alzheimer's disease, multiple sclerosis or amyotrophic lateral sclerosis.
• the compounds of the invention may be used to alleviate cancer, cardiac hypertrophy, chronic heart failure, an inflammatory condition, a cardiovascular disease, a haemoglobinopathy, a thalassemia, a sickle cell disease, a CNS disorder, an autoimmune disease, diabetes or osteoporosis, or are used as an immunosuppressant.
• the compounds of the invention may also be used to alleviate chronic lymphocytic leukaemia (CLL), breast cancer, prostate cancer, ovarian cancer, mesothelioma, T-cell lymphoma, cardiac hypertrophy, chronic heart failure or a skin inflammatory condition, in particular psoriasis, acne or eczema.
• CLL chronic lymphocytic leukaemia
• breast cancer prostate cancer
• ovarian cancer mesothelioma
• T-cell lymphoma T-cell lymphoma
• cardiac hypertrophy chronic heart failure
• chronic heart failure or a skin inflammatory condition, in particular psoriasis, acne or eczema.
• the compounds of the present invention can be used in the treatment of animals, preferably in the treatment of mammals and more preferably in the treatment of humans.
• the compounds of the invention may, where appropriate, be used prophylactically to reduce the incidence of such conditions.
• a therapeutically effective amount of a compound of the invention is administered to a patient.
• a typical dose is from about 0.001 to 50 mg per kg of body weight, according to the activity of the specific compound, the age, weight and conditions of the subject to be treated, the type and severity of the disease and the frequency and route of administration.
• Compounds of the invention may be tested for HDAC inhibitory activity by any suitable assay, e.g. the assay described in WO2008/062201.
• Example A illustrates the invention.
• reaction mixture was flushed with N 2 (g) and heated up to 90°C for another 1 h. Once cooled down, it was partitioned between H 2 0 (15ml_) and IPA/CHCI 3 (1 :2, 3 x 30ml_). The combined organic extracts were dried over MgS0 4 , filtered and concentrated in vacuo. Purification by prep HPLC yielded (5) (85mg, 39%).
• reaction mixture was flushed with N 2 (g) and heated up to 90°C for another 1 h. Once cooled down, it was partitioned between H 2 0 (15ml_) and IPA/CHCI 3 (1 :2, 3 x 30ml_). The combined organic extracts were dried over MgS0 4 , filtered and concentrated in vacuo. Purification by flash column chromatography with CH 2 CI 2 /MeOH (1 :0-9: 1) yielded (5) (168mg, 65%) as an orange solid.
• Example P (280mg, 85%) as an off-white solid.
• Example Q (191mg, 59%) as an off-white solid.
• Example R Purification by prep HPLC yielded Example R (22mg, 55%) as a white solid.
• Example T (36mg, 20%).
• HDAC4 acetylated AMC-labeled peptide substrate
• RHKKAc acetylated AMC-labeled peptide substrate
• HDAC8 the substrate used was RHKAcKAc.
• Activity against the class lla HDACs was determined using a class I la- specific substrate, Acetyl-Lys(trifluoroacetyl)-AMC (Lahm et al, 2007, PNAS, 104, 17335-17340). All assays were based on the AMC-labeled substrate and developer combination.
• the protocol involved a two-step reaction: first, the substrate with the acetylated lysine side chain is incubated with a sample containing HDAC activity, to produce the deacetylated products, which are then digested in the second step by the addition of developer to produce the fluorescent signal proportional to the amount of deacetylated substrates.
• Enzymes ii. Enzymes
• Assay Buffer 50mM Tris-HCI, pH8.0, 137 mM NaCI, 2.7 mM KCI, 1 mM MgCI 2 . Before use, 1 mg/ml_ BSA and DMSO are added.
• HDAC1 2.68 nM HDAC1 and 50m M HDAC substrate are in the reaction buffer with 1 % DMSO final. Incubate for 2 hours at 30°C.
• HDAC2 3.33 nM HDAC2 and 50mM HDAC substrate are in the reaction buffer with 1 % DMSO final. Incubate for 2 hours at 30°C.
• HDAC3 1.13 nM HDAC3 and 50mM HDAC substrate are in the reaction buffer with 1 % DMSO final. Incubate for 2 hours at 30°C.
• HDAC6 0.56 nM HDAC6 and 50mM HDAC substrate are in the reaction buffer with 1 % DMSO final. Incubate for 2 hours at 30°C.
• HDAC8 46.4 nM HDAC8 and 50mM HDAC8 substrate are in the reaction buffer with 1 % DMSO final. Incubate for 2 hours at 30°C.
• HDAC 10 96.15 nM HDAC10 and 50mM HDAC substrate are in the reaction buffer with 1 % DMSO final. Incubate for 2 hours at 30°C.
• HDAC1 1 227.27 nM HDAC1 1 and 50mMHDAC substrate are in the reaction buffer with 1 % DMSO final. Incubate for 2 hours at 30°C.
• assay buffer is the same.
• HDAC4 0.03 nM HDAC4 and 50mM Class lla HDAC substrate are in the reaction buffer with 1 % DMSO final. Incubate for 30 minutes at room temperature.
• HDAC5 0.67 nM HDAC5 and 50mM Class lla HDAC substrate are in the reaction buffer with 1 % DMSO final. Incubate for 30 minutes at room temperature.
• HDAC7 0.26 nM HDAC7 and 50mM Class lla HDAC substrate are in the reaction buffer with 1 % DMSO final. Incubate for 30 minutes at room temperature.
• HDAC9 2.37 nM HDAC9 and 50mM Class lla HDAC substrate are in the reaction buffer with 1 % DMSO final. Incubate for 30 minutes at room temperature.
• TSA Trichostatin A
• compound is added at assay concentrations to 50 mM HDAC substrate; 10 doses in 6 uL.
• Fluorescence background signal is then subtracted from compound data signal. % Conversion must be between 5% and 15% to obtain optimum result,
• Stage 2 Development by addition of Developer to digest the deacetylated substrate, and generate the fluorescent colour; Detection: 360/460 Ex/Em

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