WO2009076206A1 - Procédés de synthèse d'inhibiteurs de l'histone désacétylase (hdaci) - Google Patents

Procédés de synthèse d'inhibiteurs de l'histone désacétylase (hdaci) Download PDF

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Publication number
WO2009076206A1
WO2009076206A1 PCT/US2008/085684 US2008085684W WO2009076206A1 WO 2009076206 A1 WO2009076206 A1 WO 2009076206A1 US 2008085684 W US2008085684 W US 2008085684W WO 2009076206 A1 WO2009076206 A1 WO 2009076206A1
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Prior art keywords
group
compound
aminomethyl
histone deacetylase
yield
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PCT/US2008/085684
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English (en)
Inventor
Vincent C. O. Njar
Lalji K. Gediya
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University Of Maryland, Baltimore
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Publication of WO2009076206A1 publication Critical patent/WO2009076206A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms

Definitions

  • PCA Prostate cancer
  • Histone Deacetylases are the catalytic subunits of multiprotein complexes responsible for deacetylation of histones and nonhistone proteins. Lysine acetylation, i.e., the transfer of an acetyl moiety from acetyl-coenzyme A to the ⁇ -amino group of a specific lysine residue, has emerged as the major form of posttranslational modification of histones, and other proteins have been correlated with transcription, chromatin assembly, DNA repair, and recombinatorial events (Marks et al., Histone deacetylases and cancer, causes and therapies.
  • Histone acetylation in vivo is a dynamic, reversible process governed by the opposite actions of histone acetyltransferases (HATs) and HDACs.
  • HATs histone acetyltransferases
  • Aberrant acetylation of histone tails, emerging from either HAT mutation or abnormal recruitment of HDACs, has been linked to carcinogenesis (Pandolfi, P. P. Transcription therapy for cancer. Oncogene, 20: 3116-3127, 2001).
  • HAT histone acetyltransferases
  • HDACs histone acetyltransferases
  • HDACl is up-regulated in prostate cancer compared to benign prostatic hyperplasia (BPH) (Patra et al., Histone deacetylase and DNA methyltransferase in human prostate cancer, Biochem Biophys Res Commun, 287: 705-713, 2001).
  • Histone deacetylase inhibitors have been found to be useful for the activation of genes responsive to hormone receptors.
  • HDACIs are potent inducers of growth arrest, differentiation and/or apoptosis of several cell lines, and they constitute a novel class of chemotherapeutic agents initially identified by their ability to reverse the malignant phenotype of transformed cells. They have been shown to activate differentiation programs, inhibit cell cycle, and induce apoptosis in a wide range of tumor-derived cell lines and to block angiogenesis and stimulate the immune system in vivo (Marks et al., Histone deacetylases and cancer, causes and therapies. Nat Rev Cancer, 1: 194-202, 2001 ; Johnstone, R. W.
  • Histone-deacetylase inhibitors novel drugs for the treatment of cancer, Nat Rev Drug Discov, 1: 287-299, 2002.). Whereas the mechanisms through which HDACIs exert these anti-tumor activities have not been fully delineated, induction of histone hyperacetylation and modulation of gene transcription through chromatin remodeling are thought to be primarily responsible, leading to the selective activation of genes associated with cell growth and survival.
  • Suberoylanilide hydroxamic acid (SAHA, Vorinostat ® or Zolinza ® ) was approved in 2006 for the treatment of patients with relapsed or refractory cutaneous T-cell lymphoma (Marks et al, Dimethyl sulfoxide to vorinostat. development of this histone deacetylase inhibitor as an anticancer drug. Nat Biotechnol, 25: 84-90, 2007.).
  • SAHA suberanilide hydroxamic acid
  • Histone acetyltransferase and histone deacetylase have opposing effect on transcription (Ito et al., Histone acetylation and histone deacetylation. MoI Biotechnol, 20: 99-106, 2002; Kuo et al., Roles of histone acetyltransferases and deacetylases in gene regulation. Bioessays, 20: 615-626, 1998. ).
  • D ⁇ A methylation and histone deacetylation of tumor suppressor genes occur in many human cancers, leading to suppression of function of these genes thereby conferring a growth advantage for the tumor cells (Macaluso et al., A.
  • HDACIs such as SAHA, and N-(2-aminophenyl)4-[N-(pyridine-3-yl-methoxy-carbonyl)aminomethyl] benzamide (MS-275) can directly interact with the HDAC enzymes at the catalytic site and inhibit their function (Bolden et al, Anticancer activities of histone deacetylase inhibitors.
  • MS-275 is now in phase I/II clinical trials for various solid tumors and hematological malignancies (Hess-Stumpp et al., MS-275. a potent orally available inhibitor of histone deacetylases-The development of an anticancer agent. Int J Biochem Cell Biol, 39: 1388-1405, 2007.).
  • Suberoylanilide hydroxamic acid is a modest HDACI and has been used extensively in vitro and in vivo in cancer models (Butler et al., Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase. suppresses the growth of prostate cancer cells in vitro and in vivo. Cancer Res, 60: 5165-5170, 2000.) and it is the only HDACI currently approved for clinical use (Marks et al, Dimethyl sulfoxide to vorinostat.
  • FIG. 1 shows structures of SAHA, MS-275 and CI-994 HDACIs and their IC50 values.
  • Suzuki et al (Suzuki et al Synthesis and histone deacetylase inhibitory activity of new benzamide derivatives, J Med Chem 1999, 42, (15), 3001-3) discloses benzamide derivatives having histone deacetylase inhibitory activity and methods of making benzamide derivatives having histone deacetylase inhibitory activity. Suzuki et al is hereby incorporated herein by reference in its entirety.
  • Ri, R 2 , R 3 , and R 4 are each independently selected from the group consisting of H, -NHAc, -OH, alkyl, alkoxy, halogen, an amino group, a nitro group, a cyano group, an aminoalkyl group, an alkylamino group, an acyl group, an acylamino group, a thiol, thiolurea, an alkylthio group, a perfluoroalkyl group, a perfluoroalkyloxy group, a carboxyl group and an alkoxycarbonyl group.
  • the alkyl group, the alkoxy group, the aminoalkyl group, the alkylamino group, the acyl group, the acylamino group, the alkylthio group, the perfluoroalkyl group, and the perfluoroalkyloxy group substituents may contain a lower alkyl group (C 1-4).
  • the alkyl groups may be linear or branched and substituted or unsubstituted.
  • the alkyl may -CH 3 .
  • the alkoxy may be -OCH 3 .
  • the halogen may be F or Cl.
  • Ri is H, an amino group, -NHAc, or -OH. More preferably Ri is an amino group.
  • R 2 -R 4 are H, an amino group, alkyl, alkoxy, or halogen. More preferably
  • R 2 -R 4 are each H.
  • Table 1 shows some examples of benzamide derivatives of Formula M-I
  • M- 1 is of structural formula MS-275
  • Rj, R 2 , R 3 , and R 4 are each independently selected from the group consisting of H, -NHAc, -OH, alkyl, alkoxy, halogen, an amino group, a nitro group, a cyano group, an aminoalkyl group, an alkylamino group, an acyl group, an acylamino group, a thiol, thiolurea, an alkylthio group, a perfluoroalkyl group, a perfluoroalkyloxy group, a carboxyl group and an alkoxycarbonyl group.
  • Compound 7A may be converted into acyimidazole using CDI in THF at room temperature and then condensed in situ with 4-(aminomethyl)benzoic acid in the presence of DBU and triethylamine in THF at room temperature afforded Compound 8A.
  • Compound 8A may be treated with CDI in THF at elevated temperature, for example, about 55-60 0 C, to form imidazolide, which may be cooled and further reacted in situ with Compound 9A in the presence of TFA to yield Compound M-I.
  • THF tetrahydrofuran
  • aprotic solvents such as aprotic solvents, electron donating solvents, such as aceonitrile (ACN) and dimethylformaide (DMF) solvents.
  • ACN aceonitrile
  • DMF dimethylformaide
  • the compounds of structural formula MS-275 may be synthesized using two transformations such as those described in Scheme 4a above.
  • Conventional column chromatography for purification may be used.
  • Applicants have also developed a simpler process for large scale purification of crude benzamide derivatives having histone deacetylase inhibitory activity of structural formula M- 1.
  • work up procedures well known in the art may be employed. For example, the solvent may be evaporated and a mixture of solvent and water added to the concentrate while stirring, for about one hour. The resulting precipitate may be filtered, washed with solvent and dried.
  • the crude product may be further stirred twice in dichloromethane to remove excess of 1,2-phenylenediamine, filtered and washed with solvent to yield purified benzamide derivatives having histone deacetylase inhibitory activity of structural formula M-I .
  • the solvents may be short-chain hydrocarbons.
  • the solvent may be pentane, hexane or ether, including pet ether, and the volume ratio of solvent to water of about 1 : 1, 1 :2, 1 :3, 1 :4, 1:5, 1 :6, 1 :7, 1 :8, 1 :9, 1 : 10, 2:1, 2:2, 2:3, 2:4, 2:5, 2:6, 2:7, 2:8, 2:9, 2: 10 or the like.
  • the yield was about 80.0% yield (>99% as determined by HPLC).
  • the overall yield for the simple and efficient production of MS-275 (4) was 72.8%.
  • the compound may be used in a pharmaceutical composition.
  • the pharmaceutical composition may be formulated for oral administration, parentral administration or for injectable administration.
  • the compound in making compositions with the compounds of the present invention, can be mixed with a pharmaceutically acceptable carrier or an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container.
  • a pharmaceutically acceptable carrier or an excipient When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier, or medium for the novel compound.
  • the compositions can be in the form of tablets, pills, powers, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, soft and hard gelatin capsules, and other orally ingestible formulations.
  • compositions may be in the form of a solution, suspension, tablet, capsule or the like, prepared according to methods well known in the art. It is also contemplated that administration of such compositions may be by the oral, injectable and/or parenteral routes depending upon the needs of the artisan.
  • the novel compound can be administered by nasal or oral inhalation, oral ingestion, injection (intramuscular, intravenous, and intraperitoneal), transdermal Iy, or other forms of administration.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propyl-hydroxybenzoates, sweetening agents; and flavoring agents.
  • the compositions of the present invention can also be formulated so as to provide quick, sustained or delayed release of the novel compound after administration to the patient by employing procedures known in the art.
  • pharmaceutically acceptable carrier refers to those components in the particular dosage form employed which are considered inert and are typically employed in the pharmaceutical arts to formulate a dosage form containing a particular active compound. This may include without limitation solids, liquids and gases, used to formulate the particular pharmaceutical product.
  • carriers include diluents, flavoring agents, solubilizers, suspending agents, binders or tablet disintegrating agents, encapsulating materials, penetration enhancers, solvents, emolients, thickeners, dispersants, sustained release forms, such as matrices, transdermal delivery components, buffers, stabilizers, and the like. Each of these terms is understood by those of ordinary skill.
  • Aerosol formulations for use in this invention typically include propellants, such as a fluorinated alkane, surfactants and co-solvents and may be filled into aluminum or other conventional aerosol containers which are then closed by a suitable metering valve and pressurized with propellant, producing a metered dose inhaler. Aerosol preparations are typically suitable for nasal or oral inhalation, and may be in powder or solution form, in combination with a compressed gas, typically compressed air. Additionally, aerosols may be useful topically.
  • propellants such as a fluorinated alkane, surfactants and co-solvents
  • Aerosol preparations are typically suitable for nasal or oral inhalation, and may be in powder or solution form, in combination with a compressed gas, typically compressed air. Additionally, aerosols may be useful topically.
  • the amount of the novel compound used in the treatment methods is that amount which effectively achieves the desired therapeutic result in animals.
  • the dosages of the various novel compounds will vary somewhat depending upon the parent compound, rate of in vivo hydrolysis, etc. Those skilled in the art can determine the optimal dosing of the novel compound selected based on clinical experience and the treatment indication.
  • the amount of the novel compound is 0.1 to 100 mg/kg of body weight, more preferably, 5 to 40 mg/kg.
  • Suitable solid carriers are known, e.g., magnesium carbonate, magnesium stearate, talc, lactose and the like. These carriers are typically used in oral tablets and capsules.
  • Suitable carriers for oral liquids include, e.g., water, ethanol, propylene glycol and others.
  • Topical preparations useful herein include creams, ointments, solutions, suspensions and the like. These may be formulated to enable one to apply the appropriate dosage topically to the affected area once daily, up to 3-4 times daily as appropriate. Topical sprays may be included herein as well.
  • transdermal delivery may be an option, providing a relatively steady state delivery of the medication which is preferred in some circumstances. Transdermal delivery typically involves the use of a compound in solution, with an alcoholic vehicle, optionally a penetration enhancer, such as a surfactant and other optional ingredients. Matrix and reservoir type transdermal delivery systems are examples of suitable transdermal systems. Transdermal delivery differs from conventional topical treatment in that the dosage form delivers a systemic dose of medication to the patient.
  • the compounds can also be converted into a pharmaceutically acceptable salt or pharmaceutically acceptable solvate or other physical forms (e.g., polymorphs by way of example only and not limitation) via known in the art field methods.
  • Figure 1 shows structures of SAHA, MS-275 and CI-994 HDACIs and their IC50 values.
  • CDI 1 , 1 '-Carbonyldiimidazole (C 3 H 3 N 2 )2CO)
  • TFA Trifluoroacetic acid (CF 3 CO 2 H)

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)

Abstract

La présente invention a pour objet des protocoles simples et efficaces pour la synthèse d'inhibiteurs de l'histone désacétylase. Le protocole peut fournir le MS-275 avec des rendements globaux de 72 %.
PCT/US2008/085684 2007-12-07 2008-12-05 Procédés de synthèse d'inhibiteurs de l'histone désacétylase (hdaci) WO2009076206A1 (fr)

Applications Claiming Priority (4)

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US1226907P 2007-12-07 2007-12-07
US61/012,269 2007-12-07
US1270907P 2007-12-10 2007-12-10
US61/012,709 2007-12-10

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104610133A (zh) * 2015-01-26 2015-05-13 亿腾药业（泰州）有限公司 一种抗癌新药恩替诺特的合成方法
CN104876857A (zh) * 2015-05-12 2015-09-02 亿腾药业（泰州）有限公司 具有分化和抗增殖活性的苯甲酰胺类组蛋白去乙酰化酶抑制剂的制备
EP3168210A1 (fr) 2015-11-13 2017-05-17 Sandoz Ag Formes crystallines de l'entinostat

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0847992B1 (fr) * 1996-09-30 2004-06-23 Schering Aktiengesellschaft Dérivés de benzamide, utiles comme inducteurs de différentiation cellulaire
US7244751B2 (en) * 2003-02-14 2007-07-17 Shenzhen Chipscreen Biosciences Ltd. Histone deacetylase inhibitors of novel benzamide derivatives with potent differentiation and anti-proliferation activity

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0847992B1 (fr) * 1996-09-30 2004-06-23 Schering Aktiengesellschaft Dérivés de benzamide, utiles comme inducteurs de différentiation cellulaire
US7244751B2 (en) * 2003-02-14 2007-07-17 Shenzhen Chipscreen Biosciences Ltd. Histone deacetylase inhibitors of novel benzamide derivatives with potent differentiation and anti-proliferation activity

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MAI A: "Histone deacetylation in epigenetics: an attractive target for anticancer therapy", MED RES REV., vol. 25, no. 3, May 2005 (2005-05-01), pages 261 - 309 *
SUZUKI T ET AL.: "Synthesis and histone deacetylase inhibitory activity of new benzamide derivatives", J MED CHEM., vol. 42, no. 15, 29 July 1999 (1999-07-29), pages 3001 - 3003 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104610133A (zh) * 2015-01-26 2015-05-13 亿腾药业（泰州）有限公司 一种抗癌新药恩替诺特的合成方法
CN104876857A (zh) * 2015-05-12 2015-09-02 亿腾药业（泰州）有限公司 具有分化和抗增殖活性的苯甲酰胺类组蛋白去乙酰化酶抑制剂的制备
EP3168210A1 (fr) 2015-11-13 2017-05-17 Sandoz Ag Formes crystallines de l'entinostat
WO2017081278A1 (fr) 2015-11-13 2017-05-18 Sandoz Ag Formes cristallines d'entinostat

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