WO2005053609A2 - Methodes d'utilisation d'inhibiteurs de desacetylase nad+ dependante - Google Patents

Methodes d'utilisation d'inhibiteurs de desacetylase nad+ dependante Download PDF

Info

Publication number
WO2005053609A2
WO2005053609A2 PCT/US2004/039220 US2004039220W WO2005053609A2 WO 2005053609 A2 WO2005053609 A2 WO 2005053609A2 US 2004039220 W US2004039220 W US 2004039220W WO 2005053609 A2 WO2005053609 A2 WO 2005053609A2
Authority
WO
WIPO (PCT)
Prior art keywords
aryl
cancer
optionally substituted
compound
nad
Prior art date
Application number
PCT/US2004/039220
Other languages
English (en)
Other versions
WO2005053609A3 (fr
Inventor
Jie Zhang
Weizheng Xu
Original Assignee
Guilford Pharmaceuticals Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Guilford Pharmaceuticals Inc. filed Critical Guilford Pharmaceuticals Inc.
Publication of WO2005053609A2 publication Critical patent/WO2005053609A2/fr
Publication of WO2005053609A3 publication Critical patent/WO2005053609A3/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom

Definitions

  • the present invention relates to methods of treating cancer, cardiovascular disorders, and neurological disorders using NAD+-dependent deacetylase inhibitors.
  • the yeast SIR (silent information regulator) protein complex are responsible to establish, maintain and regulate gene silencing by modifying histones and thus changing chromatin into an transcriptionally inactive state.
  • SIR2 has recently been identified as a novel type of protein deacetylase.
  • the yeast SIR2 gene is a founding member of a broadly conserved family of deacetyalases found in organisms from bacteria to human.
  • the Sir2 family is categorized as a type III family of histone deacetylases (HDACs), which is insensitive to trichostatin A, a potent inhibitor to both type I and type II HDACs.
  • HDACs histone deacetylases
  • a unique feature of Sir2/type III HDACs is their dependence on NAD + for deacetylation activity. The deacetylation by Sir2 is strictly coupled with the consumption of NAD+ + to produce nicotinamide and a novel metabolite, O-acetyl-ADP-ribose.
  • S/r2 is essential for initiating and maintaining silencing at telomeres, mating type loci and ribosomal DNA.
  • the biochemical mechanism of how Sir2 functioned was only discovered recently. Sequence homology between yeast Sir2 and Salmonella typhimurium CobB provided a clue that Sir2 might be a ribosyltransferase, since CobB could rescue defect of CobT, a phosphoribosyltransferase gene for vitamin B12 synthesis.
  • Nicotinamide another major input molecule in the NAD + salvage pathway, is a feedback inhibitor of Sir2 with an IC 50 of less than 50 uM.
  • nicotinamide level has been reported between 11 - 400 uM, high enough to suppress Sir2.
  • Supplementary nicotinamide in growth media also abolishes the Sir2 mediated silencing at rDNA, telomeres and mating-type loci in yeast.
  • p53 the tumor suppressor.
  • p53 is known to be subject to multiple modifications including phosphorylation, acetylation and poly(ADP-ribosyl)ation, which all affect its activity in regulating cell cycle progression and apoptosis.
  • Immunoprecipitation result suggests association of p53 and human Sir2 in nuclei.
  • Antibody specific for acetylated p53 has revealed that Sir2 inhibition by nicotinamide enhances p53 acetylation level in mammalian cells.
  • the present invention relates to a method comprising administering an effective amount of a NAD+-dependent deacetylase inhibitor to treat cancer, cardiovascular disorders, and neurological disorders
  • the present invention also relates to a method comprising administering an effective amount of a NAD+-dependent deacetylase inhibitor and a Type I or Type II histone deacetylase inhibitor to treat cancer.
  • the present invention involves a method of an effective amount of a NAD+-dependent deacetylase inhibitor to treat cancer wherein said SIR2 inhibitor can be a compound of formula I:
  • A is a bond, H, CH2, CHR8, -CH2-NH-, -CHR8-NH-, -CH2-NR8-, -(CH2)2-, - CH2-CHR8-
  • B is C, N, S, C-A, N-A, S-A
  • Rl, R2, R3, R4, R5, R6, R7, R8, R9 is an optionally substituted H, F, Cl, Br, I, amino, hydroxy, -N-N, -CO-N-N, halogen-substituted amino, -O-alkyl, -O-aryl, or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -COR10, where RIO is H, -OH an optionally
  • Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO, Rl 1 and R12 can be optionally substituted H, F, Cl, Br, I, amino, hydroxy, -N-N, -CO-N-N, halogen-substituted amino, -O-alkyl, -O-aryl, or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -COR10, where RIO is H, and -OH.
  • the present invention involves a method of an effective amount of a NAD+-dependent deacetylase inhibitor to treat cancer wherein said SIR2 inhibitor can be a compound of formula II:
  • Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO, Rl 1 and R12 can be optionally substituted H, F, Cl, Br, I, amino, hydroxy, -N-N, -CO-N-N, halogen-substituted amino, -O-alkyl, -O-aryl, or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -COR10, where RIO is H, and -OH.
  • the compound can be
  • the present invention involves method of an effective amount of a NAD+-dependent deacetylase inhibitor to treat cancer wherein said NAD+-dependent deacetylase inhibitor can be a compound of formula III:
  • Rl, R2, R3, R4, R5, R6 is an optionally substituted H, F, Cl, Br, I, amino, hydroxy, -N-N, -CO-N-N, halogen-substituted amino, -O-alkyl, -O-aryl, or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -CORIO, where RIO is H, -OH an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, or-ORl l or-NHR12 where Rl 1 and R12 are each independently hydrogen or an optionally substituted alkyl, alkenyl, alkynyl, cycl
  • Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO, Rl 1 and R12 can be optionally substituted H, F, Cl, Br, I, amino, hydroxy, -N-N, -CO-N-N, halogen-substituted amino, -O-alkyl, -O-aryl, or an optionally substituted alkyl, RIO
  • methods of the present invention treat cancer such as bladder cancer, brain cancer, breast cancer, cervical cancer, head and neck cancer, Hodgkin's lymphoma, lung cancer (small and/or non-small cell), melanoma, non- Hodgkin's lymphoma, ovarian cancer, prostrate cancer, skin cancer, and mixtures thereof.
  • a method of an effective amount of a NAD+-dependent deacetylase inhibitor and an anti-cancer agent treat cancer wherein said NAD+-dependent deacetylase inhibitor can be a compound as described herein.
  • the anti-cancer agent can be chemotherapy, radiosensitizers, and mixtures thereof.
  • a method of an effective amount of a NAD+-dependent deacetylase inhibitor to treat a cardiovascular disorder wherein said NAD+-dependent deacetylase inhibitor can be a compound as described herein.
  • methods of the present invention treat cardiovascular disorder such as cardiovascular tissue damage, coronary artery disease, myocardial infarction, angina pectoris, cardiogenic shock, coronary artery bypass surgery, cardiac arrest, cardio-pulmonary resuscitation, and mixtures thereof.
  • a method of an effective amount of a NAD+-dependent deacetylase inhibitor and a Type I or Type II histone deacetylase inhibitor to treat cancer wherein said NAD+-dependent deacetylase inhibitor can be a compound as described herein.
  • a method of an effective amount of a NAD+-dependent deacetylase inhibitor and a Type I or Type II histone deacetylase inhibitor to treat cancer or a cardiovascular disorder wherein said NAD+-dependent deacetylase inhibitor can be a compound described herein.
  • the Type I or Type II histone deacetylase inhibitor can be tricostatin A, SAHA, oxamflatin, trapoxin A, FR901228, apicidin, MS-27-275, and mixtures thereof.
  • a method of an effective amount of a NAD+-dependent deacetylase inhibitor to treat a neurological disorder wherein said NAD+-dependent deacetylase inhibitor can be a compound as described herein.
  • the neurological disorder can be peripheral neuropathy caused by physical injury or disease state, traumatic brain injury, physical damage to the spinal cord, stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease, and mixtures thereof.
  • Alkyl refers to a branched or unbranched saturated hydrocarbon chain comprising a designated number of carbon atoms. For example, Cj .
  • -C alkyl is a straight or branched hydrocarbon chain containing 1 to 9 carbon atoms, and includes but is not limited to substituents such as methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert- butyl, n-pentyl, n-hexyl, and the like, unless otherwise indicated.
  • Alkenyl refers to a branched or unbranched unsaturated hydrocarbon chain comprising a designated number of carbon atoms.
  • C 2 -C alkenyl is a straight or branched hydrocarbon chain containing 2 to 9 carbon atoms having at least one double bond, and includes but is not limited to substituents such as ethenyl, propenyl, iso-propenyl, butenyl, iso-butenyl, tert-butenyl, n-pentenyl, n-hexenyl, and the like, unless otherwise indicated.
  • Alkoxy refers to the group -OR wherein R is alkyl as herein defined.
  • R is a branched or unbranched saturated hydrocarbon chain containing 1 to 9 carbon atoms.
  • Carbocycle refers to a hydrocarbon, cyclic moiety having one or more closed ring(s) that is/are alicyclic, aromatic, fused and/or bridged. Examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, cycloheptene, cycloctene, benzyl, naphthene, anthracene, phenanthracene, biphenyl and pyrene.
  • Aryl refers to an aromatic, hydrocarbon cyclic moiety having one or more closed ring(s).
  • Heterocycle refers to a cyclic moiety having one or more closed ring(s) that is/are alicyclic, aromatic, fused and/or bridged, with one or more heteroatom(s) (for example, sulfur, nitrogen or oxygen) in at least one of the rings.
  • heteroatom(s) for example, sulfur, nitrogen or oxygen
  • examples include, without limitation, pyrrolidine, pyrrole, thiazole, thiophene, piperidine, pyridine, isoxazolidine and isoxazole.
  • Heteroaryl refers to an aromatic, cyclic moiety having one or more closed ring(s) with one or more heteroatom(s) (for example, sulfur, nitrogen or oxygen) in at least one of the rings. Examples include, without limitation, pyrrole, thiophene, pyridine and isoxazole.
  • Derivative refers to a substance produced from another substance either directly or by modification or partial substitution.
  • Effective amount refers to the amount required to produce the desired effect.
  • “Therapeutically effective amount” refers to the amount required to treat glaucoma in an animal or a mammal.
  • “Pharmaceutically acceptable carrier” refers to any carrier, diluent, excipient, wetting agent, buffering agent, suspending agent, lubricating agent, adjuvant, vehicle, delivery system, emulsifier, disintegrant, absorbent, preservative, surfactant, colorant, flavorant, or sweetener, 1 preferably non-toxic, that would be suitable for use in a pharmaceutical composition.
  • “Pharmaceutically acceptable equivalent” includes, without limitation, pharmaceutically acceptable salts, hydrates, metabolites, prodrugs, and isosteres. Many pharmaceutically acceptable equivalents are expected to have the same or similar in vitro or in vivo activity as the inventive compounds.
  • “Pharmaceutically acceptable salt” refers to a salt of the inventive compounds that possesses the desired pharmacological activity and that is neither biologically nor otherwise undesirable.
  • the salt can be formed with acids that include without limitation acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycero-phosphate, hemisulfate, heptanoate, hexanoate, hydrochloride hydrobromide, hydroiodide, 2- hydroxyethane-sulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, thio
  • Examples of a base salt include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine and lysine.
  • the basic nitrogen-containing groups can be quarternized with agents including lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aralkyl halides such as benzyl and phenethyl bromides.
  • “Prodrug” refers to a derivative of the inventive compounds that undergoes biotransformation, such as metabolism, before exhibiting its pharmacological effect(s).
  • the prodrug is formulated with the objective(s) of improved chemical stability, improved patient acceptance and compliance, improved bioavailability, prolonged duration of action, improved organ selectivity, improved formulation (e.g., increased hydrosolubility), and/or decreased side effects (e.g., toxicity).
  • the prodrug can be readily prepared from the inventive compounds using methods known in the art, such as those described by Burger's Medicinal Chemistry and Drug Chemistry, Fifth Ed., Vol. 1, pp. 172-178, 949-982 (1995).
  • Treating refers to: (i) preventing a disease, disorder or condition from occurring in an animal that maybe predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it; (ii) inhibiting the disease, disorder or condition, i.e., arresting its development; and/or (iii) relieving the disease, disorder or condition, i.e., causing regression of the disease, disorder and/or condition.
  • Histone deacetylase and "HDAC” are intended to refer to any one of a family of enzymes that remove acetyl groups from the epsilon-amino groups of lysine residues at the N-terminus of a histone.
  • histone is meant to refer to any histone protein, including HI, H2A, H2B, H3, H4, and H5, from any species.
  • Other histone deacetylases include class I and class II enzymes such as the histone deacetylase is a human HDAC, including, but not limited to, HDAC-1, HDAC-2, HDAC-3, HDAC-4, HDAC-5, HDAC-6, HDAC-7, and HDAC-8.
  • Histone deacetylase inhibitor or “inhibitor of histone deacetylase” is used to identify a compound having a structure as defined herein, which is capable of interacting with a histone deacetylase and inhibiting its enzymatic activity.
  • Inhibiting histone deacetylase enzymatic activity means reducing the ability of a histone deacetylase to remove an acetyl group from a histone.
  • NAD+-dependent deacetylase refers to a protein that removes the acetyl groups from a lysine residue of another protein, wherein the deacetylation is coupled to NAD+' (nicotinamide adenosine dinucleotide) cleavage.
  • p53-dependent apoptosis refers to the genetically determined death of a cell that is dependent on, or stimulated by, the p53 gene, a gene that typically inhibits non- natural cell growth, such as that observed in tumors.
  • “Silence”, “silencing” and “silenced” refers to a mechanism by which gene expression in particular regions of the genome are expressed.
  • “Cancer” or “neoplasms” include malignancies of the various organ systems, such as affecting lung, breast, thyroid, lymphoid, gastrointestinal, and genito-urinary tract, as well as adenocarcinomas which include malignancies such as most colon cancers, renal-cell carcinoma, prostate cancer and/or testicular tumors, non-small cell carcinoma of the lung, cancer of the small intestine and cancer of the esophagus.
  • the term “cancer” is interpreted broadly.
  • the compounds of the present invention can be "anti-cancer agents", which term also encompasses "anti-tumor cell growth agents” and "anti-neoplastic agents".
  • the methods of the invention are useful for treating cancers and radiosensitizing tumor cells in cancers such as ACTH-producing tumors, acute lymphocytic leukemia, acute nonlymphocytic leukemia, cancer of the adrenal cortex, bladder cancer, brain cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia, chronic myelocytic leukemia, colorectal cancer, cutaneous T- cell lymphoma, endometrial cancer, esophageal cancer, Ewing's sarcoma, gallbladder cancer, hairy cell leukemia, head & neck cancer, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, liver cancer, lung cancer (small and/or non-small cell), malignant peritoneal effusion, malignant pleural effusion, melanoma
  • Carcinoma is art recognized and refers to malignancies of epithelial or endocrine tissues including respiratory system carcinomas, gastrointestinal system carcinomas, genitourinary system carcinomas, testicular carcinomas, breast carcinomas, prostatic carcinomas, endocrine system carcinomas, and melanomas. Exemplary carcinomas include those forming from tissue of the cervix, lung, prostate, breast, head and neck, colon and ovary. The term also includes carcinosarcomas, e.g., which include malignant tumors composed of carcinomatous and sarcomatous tissues. An “adenocarcinoma” refers to a carcinoma derived from glandular tissue or in which the tumor cells form recognizable glandular structures. "Sarcoma” is art recognized and refers to malignant tumors of mesenchymal derivation.
  • Sir2 Assay A cDNA encoding the human Sirturin2 was amplified by polymerase chain reaction from human spleen cDNA (Clontech, Palo Alto, California) using a pair of primers with the sequences of 5'- GCGAATTCTCACTGGGGTTTCTCCCTCTC-3' and 5*- GCGGATCCGCAGAGCAGACCGACTCAGATTC -3'. These primers contained the restriction enzyme sites for Bam HI and Eco RL The PCR amplified Sirturin2 DNA was digested with Eco Rl and Bam HI, and then ligated to the same restriction sites in the pET28a expression vector (Novagen) to create pET28a- Sirturin2, using standard molecular biology procedures.
  • the pET28a-Sirturin2 was transformed into E. coli strain Rosetta (LysS) (Novagen) for expression of the recombinant protein with a penta-His tag at the amino terminus.
  • LysS E. coli strain Rosetta
  • the Sir2 assay is carried out in a 50 ⁇ L volume.
  • reaction is carried out at 37°C for 45 minutes and then terminated by adding 50 ⁇ L of Fluor de LysTM deleveloper (Biomol) with 1 mM nicotinamide. Following a 5-10 minute incubation at room temperature, sample fluorescence is read with a fluorimeter (Spectra MAX Gemini XS, Molecular Devices) using an excitation wavelength of 365 nm and an emission wavelength of 450 nm. A typical dose response curve is illustrated in Figure 1 using nicotinamide as an example.
  • Phenoxazine, phenothiazine and phenoxazinone derivatives of Example 1-10 can be prepared fromphenoxazine, phenothiazine or anthrannilic acid as illustrated in Scheme 1.
  • 1 -Phenoxazine carboxylic acid or 1 -phenothiazine carboxylic acid can be prepared by lithiation at the 1 -position of phenoxazine and phenothiazine, followed by quenching with carbon dioxide.
  • 1 -phenoxazine carboxylic acid was prepared as follows.
  • the lactam ring formation from the amide 3 can be carried out by heating the amide with a single carbon source reagents, such as trimethoxy methane and triethoxymethyl acetate in co-solvent of ether/toluene or DMF.
  • a single carbon source reagents such as trimethoxy methane and triethoxymethyl acetate in co-solvent of ether/toluene or DMF.
  • Nitration of compound Example 1 provides 3-oxo-2,3-dihydro-lH-7-thia- 2,l lb-diaza-benzo[ ⁇ fe]anthracene-9-sulfonic acid (example 5).
  • Several nitration methods can also be used by those skilled in the art, include fuming nitric acid or sodium nitrate.
  • Acidic solvents can be sulfuric acid, acetic acid or trifluoroacetic acid.
  • Temperature of the reaction is general between 0 and 200 °C.
  • Example 2 and 7 can be made by reaction of compound Example 1 with fuming sulfuric acid or a mixture of fuming sulfuric acid and concentrate sulfuric acid at temperature between 0 and 50 °C.
  • the sulfonic acid compounds can be converted to sulfonyl chloride derivatives as intermediates.
  • Common reagents used for the chloration are sulfonyl chloride, phosphorus trichloride and phosphorus oxychloride.
  • Amidation of the intermediates using primary or secondary amines affords target compounds (Example 3 and 4).
  • Formation of the final sulfonamides using sulfonylchloride with amino derivatives can be carried out by a variety of conditions known to those skilled in the art, including reaction with first or secondary amines using pyridine or triethyl amine as base.
  • Typical solvents include chlorinated solvents, various ethers, and dipolar aprotic solvents like DMF.
  • the compounds Example 3 and 4 can be prepared by reaction of the acid Example 2 with sulfonyl chloride to give a substituted sulfonyl chloride intermediate, which was amidated with either 2-morpholin-4-yl-ethylamine or 2-piperidin-l-yl-ethylamine to give desired products.
  • Example 1 Prepared from the Example 1 (0.12 g) and the fuming sulfuric acid at 0 ° C. Precipitation was formed upon adding ice-cold water to the mixture. The solid was collected by filtration and titrated with 2 N NaOH to give the sodium salt, mp > 300 ° C (dec).
  • Example 2 The acid form of Example 2 in DMF was mixed with sulfonyl chloride to give a substituted sulfonyl chloride intermediate. The solvent was removed and the residue was dissolved in a mixture of solvents methylene chloride/ 1,4-dioxane. To the solution was added triethyl amine and 2-morpholin-4-yl-ethylamine at 0 °C. The mixture was allowed to warm to room temperature and continued for 2 hr. The solvent was removed and the residue was purified by silica gel chromatography to give desired products, mp 227 - 228 °C.
  • Example 2 The acid form of Example 2 in DMF was mixed with sulfonyl chloride to give a substituted sulfonyl chloride intermediate. The solvent was removed and the residue was dissolved in a mixture of solvents methylene chloride/ 1,4-dioxane. To the solution was added triethyl amine and 2-piperidin-l-yl-ethylamine at 0 °C. The mixture was allowed to warm to room temperature and continued for 2 hr. The solvent was removed and the residue was purified by silica gel chromatography to give desired products, mp 170 - 172 °C. !
  • Example 6 Prepared from the Example 6 and the fuming sulfuric acid at 0 °C. Precipitation was formed upon adding ice-cold water to the mixture. The solid was collected by filtration and titrated with 2 N NaOH to give the sodium salt, mp 300 (dec) °C.
  • DMSO dimethyl sulfoxide
  • the rats then can be anesthetized with halothane (4% for induction and 0.8%-1.2% for the surgical procedure) in a mixture of 70% nitrous oxide and 30% oxygen.
  • the body temperature can be monitored by a rectal probe and maintained at 37.5.+- .0.5.degree. C. with a heating blanket regulated by a homeothermic blanket control unit (Harvard Apparatus Limited, Kent, U.K.).
  • a catheter (PE-50) can be placed into the tail artery, and arterial pressure can be continuously monitored and recorded on a Grass polygraph recorder (Model 7D, Grass Instruments, Quincy, Mass.): Samples for blood gas analysis (arterial pH, PaO.sub.2 and PaCO.sub.2) can also be taken from the tail artery catheter and measured with a blood gas analyzer (ABL 30, Radiometer, Copenhagen, Denmark). Arterial blood samples can be obtained 30 minutes after MCA occlusion.
  • the head of the animal can be positioned in a stereo taxic frame, and a right parietal incision between the right lateral canthus and the external auditory meatus can be made.
  • a dental drill constantly cooled with saline, a 3 mm burr hole can be prepared over the cortex supplied by the right MCA, 4 mm lateral to the sagittal suture and 5 mm caudal to the coronal suture.
  • the dura mater and a thin inner bone layer can be kept, care being taken to position the probe over a tissue area devoid of large blood vessels.
  • the flow probe (tip diameter of 1 mm, fiber separation of 0.25 mm) can be lowered to the bottom of the cranial burr hole using a micromanipulator.
  • the probe can be held stationary by a probe holder secured to the skull with dental cement.
  • the microvascular blood flow in the right parietal cortex can be continuously monitored with a laser Doppler flowmeter (FloLab, Moor, Devon, U.K., and Periflux 4001, Perimed, Sweden).
  • Focal cerebral ischemia can be produced by cauterization of the distal portion of the right MCA with bilateral temporary common carotid artery (CCA) occlusion by the procedure of Chen et al., "A Model of Focal Ischemic Stroke in the Rat: Reproducible Extensive Cortical Infarction", Stroke 17:738-43 (1986) and/or Liu et al., "Polyethylene Glycol-conjugated Superoxide Dismutase and Catalase Reduce Ischemic Brain Injury", Am. J. Physiol. 256:H589-93 (1989), both of which are hereby incorporated by reference.
  • CCA common carotid artery
  • bilateral CCA's can be isolated, and loops made from polyethylene (PE- 10) catheter can be carefully passed around the CCA's for later remote occlusion.
  • the incision made previously for placement of the laser doppler probe can be extended to allow observation of the rostral end of the zygomatic arch at the fusion point using a dental drill, and the dura mater overlying the MCA can be cut.
  • the MCA distal to its crossing with the inferior cerebral vein can be lifted by a fine stainless steel hook attached to a micromanipulator and, following bilateral CCA occlusion, the MCA can be cauterized with an electrocoagulator.
  • the burr hole can be covered with a small piece of Gelform, and the wound can be sutured to maintain the brain temperature within the normal or near-normal range.
  • the carotid loops can be released, the tail arterial catheter can be removed, and all of the wounds can be sutured.
  • Gentamicin sulfate (10 mg/ml) can be topically applied to the wounds to prevent infection.
  • the anesthetic can be discontinued, and the animal can be returned to his cage after awakening. Water and food can be allowed ad libitum.
  • the animals can be given the same doses of the compound as in the pretreatment.
  • the brain can be carefully removed from the skull and cooled in ice-cold artificial CSF for five minutes.
  • the cooled brain can then be sectioned in the coronal plane at 2 mm intervals using a rodent brain matrix (RBM-4000C, ASI Instruments, Warren, Michigan).
  • the brain slices can be incubated in phosphate-buffered saline containing 2% 2,3,5-triphenyltetrazolium chloride (TTC) at 37. degree. C. for ten minutes.
  • TTC 2,3,5-triphenyltetrazolium chloride
  • the damaged area can be calculated by subtracting the area of the normal tissue in the hemisphere ipsilateral to the stroke from the area of the hemisphere contralateral to the stroke, by the method of Swanson et al., "A Semiautomated Method for Measuring Brain Infarct Volume", J. Cereb. Blood Flow Metabol. 10:290-93 (1990), the disclosure of which is hereby incorporated by reference.
  • the total volume of infarction can be calculated by summation of the damaged volume of the brain slices.
  • the cauterization of the distal portion of the right MCA with bilateral temporary CCA occlusion can consistently produce a well-recognized cortical infarct in the right MCA territory of each test animal. There can be an apparent uniformity in the distribution of the damaged area as measured by TTC staining in each group.
  • a patient just diagnosed with acute retinal ischemia is immediately administered parenterally, either by intermittent or continuous intravenous administration, a compound as disclosed herein, either as a single dose or a series of divided doses of the compound.
  • the patient optionally may receive the same or a different compound of the invention in the form of another parenteral dose. It is expected by the inventors that significant prevention of neural tissue damage would ensue and that the patient's neurological symptoms would considerably lessen due to the administration of the compound, leaving fewer residual neurological effects post- stroke. In addition, it is expected that the re-occurrence of retinal ischemia would be prevented or reduced.
  • a patient has just been diagnosed with acute retinal ischemia.
  • a physician or a nurse parenterally administers a compound as disclosed herein, either as a single dose or as a series of divided doses.
  • the patient also receives the same or a different compound by intermittent or continuous administration via implantation of a biocompatible, biodegradable polymeric matrix delivery system comprising a compound as disclosed herein, or via a subdural pump inserted to administer the compound directly to the infarct area of the brain. It is expected by the inventors that the patient would awaken from the coma more quickly than if the compound of the invention were not administered.
  • the treatment is also expected to reduce the severity of the patient's residual neurological symptoms. In addition, it is expected that reoccurrence of retinal ischemia would be reduced.
  • Focal cerebral ischemia experiments can be performed using male Wistar rats weighing 250-300 g, which can be anesthetized with 4% halothane. Anesthesia can be maintained with 1.0-1.5% halothane until the end of surgery. The animals can be installed in a warm environment to avoid a decrease in body temperature during surgery.
  • An anterior midline cervical incision can be made.
  • the right common carotid artery (CCA) can be exposed and isolated from the vagus nerve.
  • a silk suture can be placed and tied around the CCA in proximity to the heart.
  • the external carotid artery (ECA) can then be exposed and ligated with a silk suture.
  • a puncture can be made in the CCA and a small catheter (PE 10, Ulrich & Co., St-Gallen, Switzerland) can be gently advanced to the lumen of the internal carotid artery (ICA).
  • ICA internal carotid artery
  • the pterygopalatine artery may not be occluded.
  • the catheter can be tied in place with a silk suture.
  • a 4-0 nylon suture (Braun Medical, Crissier, Switzerland) can be introduced into the catheter lumen and can be pushed until the tip blocks the anterior cerebral artery.
  • the length of catheter into the ICA can be approximately 19 mm from the origin of the ECA.
  • the suture can be maintained in this position by occlusion of the catheter with heat.
  • One cm of catheter and nylon suture can be left protruding so that the suture can be withdrawn to allow reperfusion.
  • the skin incision can be closed with wound clips.
  • the animals can be maintained in a warm environment during recovery from anesthesia. Two hours later, the animals can be re-anesthetized, the clips can be discarded, and the wound can be re-opened.
  • the catheter can be cut, and the suture can be pulled out. The catheter can then be obturated again by heat, and wound clips can be placed on the wound.
  • the animals can be allowed to survive for 24 hours with free access to food and water.
  • the rats can be sacrificed with CO.sub.2 and decapitated.
  • the brains can be immediately removed, frozen on dry ice and stored at -80.degree. C.
  • the brains can be cut in 0.02 mm-thick sections in a cryocut at -19. degree. C, selecting one of every 20 sections for further examination.
  • the selected sections can be stained with cresyl violet according to the Nissl procedure. Each stained section can be examined under a light microscope, and the regional infarct area can be determined according to the presence of cells with morphological changes.
  • Various doses of the compounds of the invention can be tested in this model.
  • the compounds can be administered in either a single dose or a series of multiple doses, i.p. or i.v., at different times, both before or after the onset of ischemia.
  • Compounds of the invention can be found to provide protection from ischemia in the range of about 20 to 80%.
  • mice Female Sprague-Dawley rats, each weighing about 300-350 g can be anesthetized with intraperitoneal ketamine at a dose of 150 mg/kg.
  • the rats can be endotracheally intubated and ventilated with oxygen-enriched room air using a Harvard rodent ventilator.
  • Polyethylene catheters inserted into the carotid artery and the femoral vein are used for artery blood pressure monitoring and fluid administration respectively.
  • Arterial pCO.sub.2 can be maintained between 35 and 45 mm Hg by adjusting the respirator rate.
  • the rat chests can be opened by median sternotomy, the pericardium can be incised, and the hearts can be cradled with a latex membrane tent.
  • Hemodynamic data can be obtained at baseline after at least a 15-minute stabilization period following the end of the surgical operation.
  • the LAD (left anterior descending) coronary artery can be ligated for 40 minutes, and then re-perfused for 120 minutes. After 120 minutes' reperfusion, the LAD artery can be re-occluded, and a 0.1 ml bolus of monastral blue dye can be injected into the left atrium to determine the ischemic risk region.
  • the hearts can be arrested with potassium chloride and cut into five 2-3 mm thick transverse slices. Each slice can be weighed and incubated in a 1% solution of trimethyltetrazolium chloride to visualize the infarcted myocardium located within the risk region. Infarct size can be calculated by summing the values for each left ventricular slice and can be further expressed as a fraction of the risk region of the left ventricle.
  • the compounds of the invention can be tested in this model.
  • the compounds can be given either in a single dose or a series of multiple doses, i.p. or i.v., at different times, both before or after the onset of ischemia.
  • the compounds of the invention can be found to have ischemia/reperfusion injury. Therefore, they can protect against ischemia-induced degeneration of rat hippocampal neurons in vitro.
  • a patient just diagnosed with acute vascular stroke is immediately administered parenterally, either by intermittent or continuous intravenous administration, a compound as disclosed herein, either as a single dose or a series of divided doses of the compound.
  • the patient optionally may receive the same or a different compound of the invention in the form of another parenteral dose. It is expected by the inventors that significant prevention of neural tissue damage would ensue and that the patient's neurological symptoms would considerably lessen due to the administration of the compound, leaving fewer residual neurological effects post- stroke. In addition, it is expected that the re-occurrence of vascular stroke would be prevented or reduced.
  • a patient has just been diagnosed with acute multiple vascular strokes and is comatose.
  • a physician or a nurse parenterally administers a compound as disclosed herejn, either as a single dose or as a series of divided doses.
  • the patient also receives the same or a different compound by intermittent or continuous administration via implantation of a biocompatible, biodegradable polymeric matrix delivery system comprising a compound as disclosed herein, or via a subdural pump inserted to administer the compound directly to the infarct area of the brain. It is expected by the inventors that the patient would awaken from the coma more quickly than if the compound of the invention were not administered.
  • the treatment is also expected to reduce the severity of the patient's residual neurological symptoms. In addition, it is expected that reoccurrence of vascular stroke would be reduced.
  • a patient is diagnosed with life-threatening cardiomyopathy and requires a heart transplant. Until a donor heart is found, the patient is maintained on Extra Corporeal Oxygenation Monitoring (ECMO). A donor heart is then located, and the patient undergoes a surgical transplant procedure, during which the patient is placed on a heart-lung pump. The patient receives a compound as disclosed herein intracardiac within a specified period of time prior to re-routing his or her circulation from the heart-lung pump to his or her new heart, thus preventing cardiac reperfusion injury as the new heart begins to beat independently of the external heart-lung pump.
  • ECMO Extra Corporeal Oxygenation Monitoring
  • the human prostate cancer cell line, PC-3s can be plated in 6 well dishes and grown at monolayer cultures in RPMI1640 supplemented with 10% FCS.
  • the cells are maintained at 37. degree. C. in 5% CO.sub.2 and 95% air.
  • the cells were exposed to a dose response (0.1 mM to 0.1 uM) of 3 different compounds as disclosed herein prior to irradiation at one sublethal dose level.
  • the six well plates can be exposed at room temperature in a Seifert 250 kV/15 mA irradiator with a 0.5 mm Cu/1 mm. Cell viability can be examined by exclusion of 0.4% trypan blue.
  • Dye exclusion can be assessed visually by microscopy and viable cell number can be calculated by subtracting the number of cells from the viable cell number and dividing by the total number of cells.
  • Cell proliferation rates can be calculated by the amount of .sup.3H-thymidine incorporation post-irradiation.
  • a patient Before undergoing radiation therapy to treat cancer, a patient is administered an effective amount of a compound or a pharmaceutical composition of the present invention.
  • the compound or pharmaceutical composition acts as a radiosensitizer and making the tumor more susceptible to radiation therapy.

Abstract

La présente invention concerne des méthodes de traitement du cancer, de troubles cardiovasculaires et de troubles neurologiques à l'aide d'inhibiteurs de désacétylase NAD+ dépendante.
PCT/US2004/039220 2003-11-26 2004-11-23 Methodes d'utilisation d'inhibiteurs de desacetylase nad+ dependante WO2005053609A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US52530303P 2003-11-26 2003-11-26
US60/525,303 2003-11-26

Publications (2)

Publication Number Publication Date
WO2005053609A2 true WO2005053609A2 (fr) 2005-06-16
WO2005053609A3 WO2005053609A3 (fr) 2005-09-01

Family

ID=34652323

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2004/039220 WO2005053609A2 (fr) 2003-11-26 2004-11-23 Methodes d'utilisation d'inhibiteurs de desacetylase nad+ dependante

Country Status (1)

Country Link
WO (1) WO2005053609A2 (fr)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010026592A1 (fr) * 2008-09-05 2010-03-11 Ramot At Tel Aviv University Ltd. Dérivés de naphtoquinone utiles pour la prévention de dépôts amyloïdes et pour le traitement de maladies mettant en jeu l'amyloïdogenèse
US7732475B2 (en) 2005-07-14 2010-06-08 Takeda San Diego, Inc. Histone deacetylase inhibitors
US8168658B2 (en) 2006-02-28 2012-05-01 Merck Sharp & Dohme Corp. Inhibitors of histone deacetylase
US8242171B2 (en) 2003-12-29 2012-08-14 President And Fellows Of Harvard College Method for reducing the weight of a subject or inhibiting weight gain in a subject
JP2013532733A (ja) * 2010-08-04 2013-08-19 ペルフィキュア ファーマシューティカルズ，インコーポレイテッド 前立腺癌を処置するための併用療法
WO2014074976A1 (fr) * 2012-11-09 2014-05-15 Musc Foundation For Research Development Compositions et méthodes de traitement de maladies ou de lésions neurologiques
US8846724B2 (en) 2003-12-29 2014-09-30 President And Fellows Of Harvard College Compositions for treating obesity and insulin resistance disorders
US8980825B2 (en) 2010-07-12 2015-03-17 Celgene Corporation Romidepsin solid forms and uses thereof
US9241916B2 (en) 2005-06-14 2016-01-26 President And Fellows Of Harvard College Cognitive performance with sirtuin activators
US9518032B2 (en) 2010-04-30 2016-12-13 Dana-Farber Cancer Institute, Inc. Small molecule inhibitors of USP1 deubiquitinating enzyme activity
US9725425B1 (en) 2014-02-25 2017-08-08 Dana-Farber Cancer Institute, Inc. Compounds and methods for treating cancer
US9782451B2 (en) 2013-12-27 2017-10-10 Celgene Corporation Romidepsin formulations and uses thereof
KR101876750B1 (ko) * 2016-07-26 2018-07-11 한밭대학교 산학협력단 신규한 2-아민 치환 1,4-나프토퀴논 화합물 및 이를 포함하는 암의 예방 또는 치료용 약제학적 조성물
CN112770735A (zh) * 2018-07-29 2021-05-07 Musc研究发展基金会 用于治疗神经或线粒体疾病的化合物
CN113368087A (zh) * 2020-03-10 2021-09-10 复旦大学附属华山医院 胡桃醌其衍生物及其在制备化疗脑肿瘤的药物中的用途

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7977049B2 (en) 2002-08-09 2011-07-12 President And Fellows Of Harvard College Methods and compositions for extending the life span and increasing the stress resistance of cells and organisms
US20100137239A1 (en) 2006-04-24 2010-06-03 Gloucester Pharmaceuticals Gemcitabine combination therapy
WO2007146730A2 (fr) 2006-06-08 2007-12-21 Gloucester Pharmaceuticals Thérapie à base d'inhibiteurs de désacétylase (dac)
US8691534B2 (en) 2006-12-29 2014-04-08 Celgene Corporation Preparation of romidepsin
US8859502B2 (en) 2010-09-13 2014-10-14 Celgene Corporation Therapy for MLL-rearranged leukemia
AU2013202506B2 (en) 2012-09-07 2015-06-18 Celgene Corporation Resistance biomarkers for hdac inhibitors
AU2013202507B9 (en) 2012-11-14 2015-08-13 Celgene Corporation Inhibition of drug resistant cancer cells

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6511990B1 (en) * 1999-09-08 2003-01-28 Sloan-Kettering Institute For Cancer Research Class of cytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof
WO2003007933A1 (fr) * 2001-07-16 2003-01-30 The University Court Of The University Of Aberdeen Derives de napthoquinone en tant qu'inhibiteurs de l'agregation des tau pour le traitement de la maladie d'alzheimer et des troubles de neurodegenerescence associes

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6511990B1 (en) * 1999-09-08 2003-01-28 Sloan-Kettering Institute For Cancer Research Class of cytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof
WO2003007933A1 (fr) * 2001-07-16 2003-01-30 The University Court Of The University Of Aberdeen Derives de napthoquinone en tant qu'inhibiteurs de l'agregation des tau pour le traitement de la maladie d'alzheimer et des troubles de neurodegenerescence associes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HODNETT E. ET AL: 'Subtituted 1,4-Naphthoquinones vs. the Ascitic Sarcoma 180 of Mice.' J.MED.CHEM. vol. 23, no. 4, 1983, pages 570 - 574, XP002988938 *

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8846724B2 (en) 2003-12-29 2014-09-30 President And Fellows Of Harvard College Compositions for treating obesity and insulin resistance disorders
US8242171B2 (en) 2003-12-29 2012-08-14 President And Fellows Of Harvard College Method for reducing the weight of a subject or inhibiting weight gain in a subject
US9597347B2 (en) 2003-12-29 2017-03-21 President And Fellows Of Harvard College Compositions for treating obesity and insulin resistance disorders
US9241916B2 (en) 2005-06-14 2016-01-26 President And Fellows Of Harvard College Cognitive performance with sirtuin activators
US7732475B2 (en) 2005-07-14 2010-06-08 Takeda San Diego, Inc. Histone deacetylase inhibitors
US7741494B2 (en) 2005-07-14 2010-06-22 Takeda San Diego, Inc. Histone deacetylase inhibitors
US8168658B2 (en) 2006-02-28 2012-05-01 Merck Sharp & Dohme Corp. Inhibitors of histone deacetylase
US8697680B2 (en) 2008-09-05 2014-04-15 Ramot At Tel Aviv University Ltd. Naphthoquinone derivatives useful for prevention of amyloid deposits and treatment of diseases involving amyloidogenesis
WO2010026592A1 (fr) * 2008-09-05 2010-03-11 Ramot At Tel Aviv University Ltd. Dérivés de naphtoquinone utiles pour la prévention de dépôts amyloïdes et pour le traitement de maladies mettant en jeu l'amyloïdogenèse
US9272993B2 (en) 2008-09-05 2016-03-01 Ramot At Tel Aviv University Ltd. Naphthoquinone derivatives useful for prevention of amyloid deposits and treatment of diseases involving amyloidogenesis
US20170202810A1 (en) * 2010-04-30 2017-07-20 Dana-Farber Cancer Institute, Inc. Small molecule inhibitors of usp1 deubiquitinating enzyme activity
US9518032B2 (en) 2010-04-30 2016-12-13 Dana-Farber Cancer Institute, Inc. Small molecule inhibitors of USP1 deubiquitinating enzyme activity
US10653676B2 (en) 2010-04-30 2020-05-19 Dana-Farber Cancer Institute, Inc. Small molecule inhibitors of USP1 deubiquitinating enzyme activity
US8980825B2 (en) 2010-07-12 2015-03-17 Celgene Corporation Romidepsin solid forms and uses thereof
US9624271B2 (en) 2010-07-12 2017-04-18 Celgene Corporation Romidepsin solid forms and uses thereof
US9877932B2 (en) 2010-08-04 2018-01-30 Pellficure Pharmaceuticals, Inc. Treatment of prostate carcinoma
JP2013532733A (ja) * 2010-08-04 2013-08-19 ペルフィキュア ファーマシューティカルズ，インコーポレイテッド 前立腺癌を処置するための併用療法
US9655868B2 (en) 2010-08-04 2017-05-23 Pellficure Pharmaceuticals, Inc. Treatment of prostate carcinoma
US10245240B2 (en) 2010-08-04 2019-04-02 Pellficure Pharmaceuticals, Inc. Treatment of prostate carcinoma
US10391070B2 (en) 2012-11-09 2019-08-27 Musc Foundation For Research Development Compositions and methods for treating neurological diseases or injury
US9861596B2 (en) 2012-11-09 2018-01-09 Musc Foundation For Research Development Compositions and methods for treating neurological diseases or injury
WO2014074976A1 (fr) * 2012-11-09 2014-05-15 Musc Foundation For Research Development Compositions et méthodes de traitement de maladies ou de lésions neurologiques
US9782451B2 (en) 2013-12-27 2017-10-10 Celgene Corporation Romidepsin formulations and uses thereof
US9795650B2 (en) 2013-12-27 2017-10-24 Celgene Corporation Romidepsin formulations and uses thereof
US10450281B1 (en) 2014-02-25 2019-10-22 Dana-Farber Cancer Institute, Inc. Compounds and methods for treating cancer
US9725425B1 (en) 2014-02-25 2017-08-08 Dana-Farber Cancer Institute, Inc. Compounds and methods for treating cancer
KR101876750B1 (ko) * 2016-07-26 2018-07-11 한밭대학교 산학협력단 신규한 2-아민 치환 1,4-나프토퀴논 화합물 및 이를 포함하는 암의 예방 또는 치료용 약제학적 조성물
CN112770735A (zh) * 2018-07-29 2021-05-07 Musc研究发展基金会 用于治疗神经或线粒体疾病的化合物
EP3829560A4 (fr) * 2018-07-29 2022-08-03 Musc Foundation for Research Development Composés pour le traitement de maladies neurologiques ou mitochondriales
US11771685B2 (en) 2018-07-29 2023-10-03 Musc Foundation For Research Development Compounds for the treatment of neurological or mitochondrial diseases
CN113368087A (zh) * 2020-03-10 2021-09-10 复旦大学附属华山医院 胡桃醌其衍生物及其在制备化疗脑肿瘤的药物中的用途

Also Published As

Publication number Publication date
WO2005053609A3 (fr) 2005-09-01

Similar Documents

Publication Publication Date Title
WO2005053609A2 (fr) Methodes d'utilisation d'inhibiteurs de desacetylase nad+ dependante
JP4002067B2 (ja) シクロアルキル置換されたベンズイミダゾールおよびｐａｒｐ阻害剤としてのその使用
CA3030510C (fr) Composes d'azole-dione presentant une activite anti-cancer
ES2630062T3 (es) Inhibidores de la histona desacetilasa (HDAC)
KR100655808B1 (ko) 혈관 손상제로서 콜치놀 유도체, 그것의 용도 및 제조 방법
CA2935317C (fr) Derive a base de 1,2-naphtoquinone et methode de preparation associee
JP2016511237A (ja) 選択的ｈｄａｃ３阻害剤
AU2008203305A1 (en) New benzimidazole derivatives
MXPA04001583A (es) Agentes quimioterapeuticos.
BRPI0517274A2 (pt) 4-feniltetrahidroisoquinolinas substituÍdas, mÉtodo para sua preparaÇço, seu uso como um medicamento, e um medicamento contendo-as
MX2007005857A (es) Inhibidores de cinasa.
CA3063111A1 (fr) Inhibiteurs des histone desacetylases (hdac)
WO2007036131A1 (fr) Dérivés de carzole sulfamide et leur procédé de préparation
BRPI0618806A2 (pt) 5-fenil-3,6-diidro-2-oxo-6h-[1,3,4]-tiadiazinas substituìdas
CN115304583B (zh) 靶向抑制clk2的5-吡啶-1h-吲唑类化合物及其应用
JP2000143635A (ja) 血管新生阻害剤
BR112020000564A2 (pt) novos derivados de heteroarilamida como inibidores seletivos das histonas desacetilases 1 e/ou 2 (hdac1-2)
FR3066761A1 (fr) Nouveaux composes inhibiteurs des canaux ioniques
KR20180094880A (ko) 5원 헤테로시클릭 아미드계 wnt 경로 억제제
AU2002333626B2 (en) 1-glyoxlylamide indolizines for treating cancer
EA010392B1 (ru) Производные имидазолов, способ их получения и их применение в качестве лекарственного средства
JP2011519966A (ja) 新規なｎ−（２−アミノ−フェニル）−アクリルアミド
CN107311933B (zh) 一类苯并咪唑衍生物，及其制备方法和用途
KR100820173B1 (ko) 4-메틸이미다졸-5-카보닐구아니딘 유도체, 이의 약학적으로허용가능한 염, 이의 제조방법 및 이를 유효성분으로함유하는 허혈성 심장질환의 예방 및 치료용 약학적 조성물
CN114401935B (zh) 离子通道拮抗剂/阻断剂及其用途

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase in:

Ref country code: DE

WWW Wipo information: withdrawn in national office

Country of ref document: DE

122 Ep: pct application non-entry in european phase