WO2009140164A1 - Dérivés de 6-aminonicotinamide formant des inhibiteurs puissants et sélectifs de l’histone désacétylase - Google Patents

Dérivés de 6-aminonicotinamide formant des inhibiteurs puissants et sélectifs de l’histone désacétylase Download PDF

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WO2009140164A1
WO2009140164A1 PCT/US2009/043302 US2009043302W WO2009140164A1 WO 2009140164 A1 WO2009140164 A1 WO 2009140164A1 US 2009043302 W US2009043302 W US 2009043302W WO 2009140164 A1 WO2009140164 A1 WO 2009140164A1
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mmol
compound
nicotinamide
ring
mixture
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Xian-Ping Lu
Zhi-bin LI
Zhi-Qiamg Ning
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Chipscreen Biosciences Ltd.
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Priority to EP09747249A priority Critical patent/EP2285376A4/fr
Priority to JP2011509573A priority patent/JP2011520891A/ja
Publication of WO2009140164A1 publication Critical patent/WO2009140164A1/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
    • C07D213/60—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to certain 6-aminonicotinamide derivatives which are capable of inhibiting histone deacetylases.
  • the compounds of this invention are therefore useful in treating diseases associated with abnormal histone deacetylase activities.
  • Pharmaceutical compositions comprising these compounds, methods of treating diseases utilizing pharmaceutical compositions comprising these compounds, and methods of preparing these compounds are also disclosed.
  • Histone deacetylase (HDAC) proteins play a critical role in regulating gene expression in vivo by altering the accessibility of genomic DNA to transcription factors. Specifically, HDAC proteins remove the acetyl group of acetyl-lysine residues on histones, which can result in nucleosomal remodelling (Grunstein, M., 1997, Nature, 389: 349-352). Due to their governing role in gene expression, HDAC proteins are associated with a variety of cellular events, including cell cycle regulation, cell proliferation, differentiation, reprogramming of gene expression, and cancer development (Ruijter, A-J-M., 2003, Biochem.
  • HDACs histone deacetylases
  • HDAC inhibition may induce the expression of anti-mitotic and anti-apoptotic genes, such as p21 and HSP-70, which facilitate survival.
  • HDAC inhibitors can act on other neural cell types in the central nervous system, such as reactive astrocytes and microglia, to reduce inflammation and secondary damage during neuronal injury or disease. HDAC inhibition is a promising therapeutic approach for the treatment of a range of central nervous system disorders (Langley B et al., 2005, Current Drug Targets - CNS & Neurological Disorders, 4: 41 -50).
  • Mammalian HDACs can be divided into three classes according to sequence homology.
  • Class I consists of the yeast Rpd3-like proteins (HDAC 1 , 2, 3, 8 and 11 ).
  • Class Il consists of the yeast HDA1-like proteins (HDAC 4, 5, 6, 7, 9 and 10).
  • Class III consists of the yeast SIR2-like proteins (SIRT 1 , 2, 3, 4, 5, 6 and 7).
  • the activity of HDAC1 has been linked to cell proliferation, a hallmark of cancer. Particularly, mammalian cells with knock down of HDAC1 expression using siRNA were antiproliferative (Glaser, K-B., 2003, Biochem. Biophys. Res. Comm., 310: 529-536).
  • HDAC1 While the knock out mouse of HDAC1 was embryonic lethal, the resulting stem cells displayed altered cell growth (Lagger, G., 2002, £M60 J., 21 : 2672-2681 ). Mouse cells overexpressing HDAC1 demonstrated a lengthening of G 2 and M phases and reduced growth rate (Bartl. S., 1997, MoI. Cell Biol., 17: 5033-5043). Therefore, the reported data implicate HDAC1 in cell cycle regulation and cell proliferation.
  • HDAC2 regulates expression of many fetal cardiac isoforms. HDAC2 deficiency or chemical inhibition of histone deacetylase prevented the re-expression of fetal genes and attenuated cardiac hypertrophy in hearts exposed to hypertrophic stimuli. Resistance to hypertrophy was associated with increased expression of the gene encoding inositol polyphosphate-5-phosphatase f (Inpp ⁇ f) resulting in constitutive activation of glycogen synthase kinase 3 ⁇ (Gsk3 ⁇ ) via inactivation of thymoma viral proto-oncogene (Akt) and 3-phosphoinositide-dependent protein kinase-1 (Pdk1 ).
  • Inpp ⁇ f inositol polyphosphate-5-phosphatase f
  • Gsk3 ⁇ glycogen synthase kinase 3 ⁇
  • Akt thymoma viral proto-oncogene
  • Pdk1 3-phosphoinositide-dependent protein
  • HDAC2 transgenic mice had augmented hypertrophy associated with inactivated Gsk3 ⁇ .
  • Chemical inhibition of activated Gsk3 ⁇ allowed HDAC2-deficient adults to become sensitive to hypertrophic stimulation.
  • HDAC3 is maximally expressed in proliferating crypt cells in the intestine. Silencing of HDAC3 expression in colon cancer cell lines resulted in growth inhibition, a decrease in cell survival, and increased apoptosis. Similar effects were observed for HDAC2 and, to a lesser extent, for HDAC1. HDAC3 gene silencing also selectively induced expression of alkaline phosphatase, a marker of colon cell maturation. Concurrent with its effect on cell growth, overexpression of HDAC3 inhibited basal and butyrate-induced p21 transcription in a Sp1/Sp3-dependent manner, whereas silencing of HDAC3 stimulated p21 promoter activity and expression.
  • HDAC3 as a gene deregulated in human colon cancer and as a novel regulator of colon cell maturation and p21 expression (Wilson, A-J., 2006, J. Biol. Chem., 281 : 13548-13558).
  • HDAC6 is a subtype of the HDAC family that deacetylates alpha-tubulin and increases cell motility.
  • OSCC oral squamous cell carcinoma
  • NOKs normal oral keratinocytes
  • HDAC6 mRNA and protein expression were commonly up-regulated in all cell lines compared with the NOKs.
  • Immunofluorescence analysis detected HDAC6 protein in the cytoplasm of OSCC cell lines. Similar to OSCC cell lines, high frequencies of HDAC6 up-regulation were evident in both mRNA (74%) and protein (51 %) levels of primary human OSCC tumors.
  • the clinical tumor stage was found to be associated with the HDAC6 expression states.
  • the analysis indicated a significant difference in the HDAC6 expression level between the early stage (stage I and II) and advanced -stage (stage III and IV) tumors (P O.014).
  • HDAC epigenetic silencing of functional chromosomes by HDAC is one of the major mechanisms that occurrs in pathological processes in which functionally critical genes are repressed or reprogrammed by HDAC activities leading to the loss of phenotypes in terminal differentiation, maturation and growth control, and the loss of functionality of tissues.
  • tumor suppressor genes are often silenced during development of cancer and chemical inhibitors of HDAC can derepress the expression of these tumor suppressor genes, leading to growth arrest and differentiation (Glaros S et al., 2007, Oncogene June 4 Epub ahead of print; Mai, A, et al., 2007, lnt J. Biochem Cell Bio., April 4, Epub ahead of print; Vincent A.
  • HDAC inhibitors include (1 ) short-chain fatty acids, e.g. butyrate and phenylbutyrate; (2) organic hydroxamic acids, e.g. suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA); (3) cyclic tetrapeptides containing a 2-amino-8-oxo 9,10-expoxydecanoyl (AOE) moiety, e.g. trapoxin and HC-toxin; (4) cyclic peptides without the AOE moiety, e.g. apicidin and FK228; and (5) benzamides, e.g.
  • SAHA suberoylanilide hydroxamic acid
  • TSA trichostatin A
  • AOE 2-amino-8-oxo 9,10-expoxydecanoyl
  • benzamides e.g.
  • HDAC represents a very promising drug target especially in the context of epigenic biology;; for example, in terms of preferential apoptosis-induction in malignant cells but not normal cells, differentiation of epithelia in cancer cells, anti-inflammatory and immunomodulation, and cell cycle arrest.
  • HDAC inhibitors can be considered as "neo-chemotherapy" having a much improved toxicity profile over existing chemotherapy options.
  • the success of SAHA from Merck is currently only limited to the treatment of cutaneous T cell lymphoma. No reports exist indicating that SAHA treatment is effective against major solid tumors or for any other indications. Therefore, there is still a need to discover new compounds with improved profiles, such as stronger HDAC inhibitory activity and anti-cancer activity, more selective inhibition on different HDAC subtypes, and lower toxicity; There is a continuing need to identify novel HDAC inhibitors that can be used to treat potential new indications such as neurological and neurodegenerative disorders, cardiovascular disease, metabolic disease, and inflammatory and immunological diseases.
  • the present invention is directed to certain 6-aminonicotinamide derivatives which exhibit selective histone deacetylase inhibition activity and are therefore useful in treating diseases associated with aberrant histone deacetylase activities, such as Rubinstein-Taybi syndrome, fragile X syndrome, leukemia, cardiac hypertrophy, metabolic disease, cancer and various neurological and neurodegenerative disorders.
  • diseases associated with aberrant histone deacetylase activities such as Rubinstein-Taybi syndrome, fragile X syndrome, leukemia, cardiac hypertrophy, metabolic disease, cancer and various neurological and neurodegenerative disorders.
  • the present invention provides a compound having the structure represented by formula (I), or its stereoisomer, enantiomer, diastereomer, hydrate, or pharmaceutically acceptable salts thereof:
  • R 1 , R 2 , R 3 and R 4 are independently hydrogen, halo, alkyl, alkoxy or trifluoromethyl;
  • R is pyridyl, which optionally substituted with one or more halogen, alkyl, alkoxy or trifluoromethyl; or R 5 is
  • Ring A and ring B, fused to the ring containing X, independently of each other represents a benzene ring, which optionally substituted with one or more halogen, nitro, alkyl or alkoxy; n is an integer ranging from 2 to 6.
  • halo as used herein means fluorine, chlorine, bromine or iodine.
  • alkyl as used herein includes methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl and the like.
  • alkoxy as used herein includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and the like.
  • R 1 , R 2 , R 3 and R 4 are independently hydrogen, halo, alkyl, alkoxy or trifluoromethyl;
  • R 5 is pyridyl, which optionally substituted with one or more halogen, alkyl, alkoxy or trifluoromethyl; and
  • n is an integer ranging from 2 to 4.
  • R 1 , R 2 , R 3 and R 4 are independently H or F; R 5 is pyridyl; and n is an integer ranging from 2 to 4.
  • R 1 , R 2 , R 3 and R 4 are independently
  • R 1 , R 2 , R 3 and R 4 are independently H
  • R 5 is , wherein X is a bond; Ring A and ring B, fused to the ring containing X, independently of each other represents a benzene ring; n is an integer ranging from 2 to 4.
  • Condensation reactions (a) and (c) are conducted by using a peptide condensing agent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), dicyclohexylcarbodiimide (DCC), N,N'-carbonyldiimidazole (CDI), etc.
  • EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
  • DCC dicyclohexylcarbodiimide
  • CDI N,N'-carbonyldiimidazole
  • the reaction may be conducted at 0 to 80 0 C for 4 to 72 hours.
  • Solvents which may be used are normal solvents such as benzene, toluene, tetrahydrofuran, dioxane, dichloromethane, chloroform, N, N-dimethylformamide, etc.
  • a base such as sodium hydroxide, trie
  • Condensation reaction (b) is conducted at 40 to 120 0 C for 1 to 24 hours.
  • Solvents which may be used are normal solvents such as benzene, toluene, tetrahydrofuran, dioxane, dichloromethane, chloroform, N, N-dimethylformamide, etc. If necessary, a base such as sodium hydroxide, triethylamine and pyridine may be added to the reaction system.
  • the compounds represented by formula (I) and the intermediate (2) and (4) may be purified or isolated by the conventional separation method such as extraction, recrystallization, column chromatography and the like.
  • the compounds represented by formula (I) are capable of inhibiting histone deacetylases and are therefore useful in treating diseases associated with abnormal histone deacetylase activities, such as Rubinstein-Taybi syndrome, fragile X syndrome, leukemia, cardiac hypertrophy, metabolic disease, cancer and various neurological and neurodegenerative disorders.
  • the invention also provides a method for treating diseases associated with abnormal deacetylase activitites to a mammal, including man and mammmals, comprising administering a compound of formula (I) or apharmaceutically acceptable salt thereof to a mammal in need of such treatment.
  • the compounds represented by formula (I) useful as a drug may be used in the form of a general pharmaceutical composition.
  • the pharmaceutical compositions may be in forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions, aerosols, and the like, may contain flavorants, sweeteners etc. in suitable solids or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions.
  • Such composition typically contains from 0.5 to 70%, preferably 1 to 20% by weight of active compound, the remainder of the composition being pharmaceutically acceptable carriers, diluents or solvents or salt solutions.
  • the compounds represented by formula (I) are clinically administered to mammals, including man and animals, via oral, nasal, transdermal, pulmonary, or parenteral routes. Administration by the oral route is preferred, being more convenient and avoiding the possible pain and irritation of injection. By either route, the dosage is in the range of about 0.0001 to 200 mg/kg body weight per day administered singly or as a divided dose. However, the optimal dosage for the individual subject being treated will be determined by the person responsible for treatment, generally smaller dose being administered initially and thereafter increments made to determine the most suitable dosage.
  • Example 1 Representative compounds of the present invention are shown in Table 1 below.
  • the compound numbers correspond to the "Example numbers” in the Examples section. That is, the synthesis of the compound 3 as shown in the Table 1 is described in “Example 3” and the synthesis of the compound 51 as shown in the Table 1 is described in “Example 51 ".
  • the compounds presented in the Table 1 are exemplary only and are not to be construed as limiting the scope of this invention in any manner.
  • 6-Chloronicotinic acid 158 mg, 1 mmol
  • 8 ml of DMF 8 ml
  • 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride 384 mg, 2 mmol
  • hydroxybenzotriazole 162 mg, 1 .2 mmol
  • triethylamine 404 mg, 4 mmol
  • o-phenylenediamine 216 mg, 2 mmol
  • N-(2-Aminophenyl)-6-chloronicotinamide (248 mg, 1 mmol) and 5 ml of ethylenediamine were heated to 8O 0 C for 3 hours. The excess ethylenediamine was removed under vacuum. To the residue was added 5 ml of 0.20 M NaOH. The mixture was extracted with 100 ml of ethyl acetate. The ethyl acetate was removed under vacuum to give the title compound (150 mg, 55% yield) as a brown solid. LC-MS (m/z) 272 (M+1 ).
  • Nicotinic acid (123 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (384 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1 .2 mmol), triethylamine (404 mg, 4 mmol) and N-(2-aminophenyl)-6-(2-aminoethylamino)nicotinamide (284 mg, 1.05 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 400 ml of brine and extracted with 200 ml of ethyl acetate.
  • N-(2-Aminophenyl)-6-chloronicotinamide (248 mg, 1 mmol) and 6 ml of 1 ,3-propanediamine were heated to 8O 0 C for 3 hours. The excess 1 ,3-propanediamine was removed under vacuum. To the residue was added 5 ml of 0.20 M NaOH. The mixture was extracted with 100 ml of ethyl acetate. The ethyl acetate was removed under vacuum to give the title compound (168 mg, 59% yield) as a brown solid. LC-MS (m/z) 286 (M+1 ).
  • Nicotinic acid (123 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (384 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1 .2 mmol), triethylamine (404 mg, 4 mmol) and N-(2-aminophenyl)-6-(3-aminopropylamino)nicotinamide (299 mg, 1.05 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 400 ml of brine and extracted with 200 ml of ethyl acetate.
  • N-(2-Aminophenyl)-6-chloronicotinamide (248 mg, 1 mmol) and 7 ml of 1 ,4-butanediamine were heated to 8O 0 C for 3 hours. The excess 1 ,4-butanediamine was removed under vacuum. To the residue was added 5 ml of 0.20 M NaOH. The mixture was extracted with 100 ml of ethyl acetate. The ethyl acetate was removed under vacuum to give the title compound (158 mg, 53% yield) as a brown solid. LC-MS (m/z) 300 (M+1 ).
  • Nicotinic acid (123 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (384 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1 .2 mmol), triethylamine (404 mg, 4 mmol) and N-(2-aminophenyl)-6-(4-aminobutylamino)nicotinamide (314 mg, 1.05 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 400 ml of brine and extracted with 200 ml of ethyl acetate.
  • 6-Chloronicotinic acid (157.5 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (384 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 4-fluoro-o-phenylenediamine (151 mg, 1.2 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 400 ml. of brine and extracted with 200 ml of ethyl acetate. The ethyl acetate was removed under vacuum.
  • N-(2-Amino-4-fluorophenyl)-6-chloronicotinamide (266 mg, 1 mmol) and 5 ml of ethylenediamine were heated to 8O 0 C for 3 hours. The excess ethylenediamine was removed under vacuum. To the residue was added 5 ml of 0.20 M NaOH. The mixture was extracted with 100 ml of ethyl acetate. The ethyl acetate was removed under vacuum to give the title compound (176 mg, 61 % yield) as a brown solid. LC-MS (m/z) 290 (M+1 ).
  • Nicotinic acid (123 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (384 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1 .2 mmol), triethylamine (404 mg, 4 mmol) and N-(2-amino-4-fluorophenyl)-6-(2-aminoethylamino)nicotinamide (303 mg, 1.05 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 400 ml of brine and extracted with 200 ml of ethyl acetate.
  • N-(2-Amino-4-fluorophenyl)-6-chloronicotinamide (266 mg, 1 mmol) and 6 ml of 1 ,3-propanediamine were heated to 8O 0 C for 3 hours. The excess 1 ,3-propanediamine was removed under vacuum. To the residue was added 5 ml of 0.20 M NaOH. The mixture was extracted with 100 ml of ethyl acetate. The ethyl acetate was removed under vacuum to give the title compound (158 mg, 52% yield) as a brown solid. LC-MS (m/z) 304 (M+1 ).
  • Nicotinic acid (123 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (384 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1 .2 mmol), triethylamine (404 mg, 4 mmol) and N-(2-amino-4-fluorophenyl)-6-(3-aminopropylamino)nicotinamide (318 mg, 1.05 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 400 ml of brine and extracted with 200 ml of ethyl acetate.
  • N-(2-Amino-4-fluorophenyl)-6-chloronicotinamide (266 mg, 1 mmol) and 7 ml of 1 ,4-butanediamine were heated to 8O 0 C for 3 hours. The excess 1 ,4-butanediamine was removed under vacuum. To the residue was added 5 ml of 0.20 M NaOH. The mixture was extracted with 100 ml of ethyl acetate. The ethyl acetate was removed under vacuum to give the title compound (149 mg, 47% yield) as a brown solid. LC-MS (m/z) 318 (M+1 ).
  • Nicotinic acid (123 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (384 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1 .2 mmol), triethylamine (404 mg, 4 mmol) and N-(2-amino-4-fluorophenyl)-6-(4-aminobutylamino)nicotinamide (333 mg, 1.05 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 400 ml of brine and extracted with 200 ml of ethyl acetate.
  • 6-Chloronicotinic acid (157.5 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (384 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 4-chloro-o-phenylenediamine (171 mg, 1.2 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 400 ml. of brine and extracted with 200 ml of ethyl acetate. The ethyl acetate was removed under vacuum.
  • N-(2-Amino-4-chlorophenyl)-6-chloronicotinamide (282 mg, 1 mmol) and 5 ml of ethylenediamine were heated to 8O 0 C for 3 hours. The excess ethylenediamine was removed under vacuum. To the residue was added 5 ml of 0.20 M NaOH. The mixture was extracted with 100 ml of ethyl acetate. The ethyl acetate was removed under vacuum to give the title compound (180 mg, 59% yield) as a brown solid. LC-MS (m/z) 306 (M+1 ).
  • Nicotinic acid (123 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (384 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1 .2 mmol), triethylamine (404 mg, 4 mmol) and N-(2-amino-4-chlorophenyl)-6-(2-aminoethylamino)nicotinamide (321 mg, 1.05 mmol)were added. The mixture was stirred for 20 hours at room temperature.
  • 6-Chloronicotinic acid (157.5 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (384 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 4-methyl-o-phenylenediamine (146 mg, 1.2 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 400 imL of brine and extracted with 200 ml of ethyl acetate. The ethyl acetate was removed under vacuum.
  • N-(2-Amino-4-methyl-phenyl)-6-chloronicotinamide (261 mg, 1 mmol) and 5 ml of ethylenediamine were heated to 8O 0 C for 3 hours. The excess ethylenediamine was removed under vacuum. To the residue was added 5 ml of 0.20 M NaOH. The mixture was extracted with 100 ml of ethyl acetate. The ethyl acetate was removed under vacuum to give the title compound (145 mg, 51 % yield) as a brown solid. LC-MS (m/z) 286 (M+1 ).
  • Nicotinic acid (123 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (384 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1 .2 mmol), triethylamine (404 mg, 4 mmol) and N-(2-amino-4-methylphenyl)-6-(2-aminoethylamino)nicotinamide (299 mg, 1 .05 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 400 ml of brine and extracted with 200 ml of ethyl acetate.
  • 6-Chloronicotinic acid (157.5 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (384 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 4-methoxy-o-phenylenediamine (166 mg, 1.2 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 400 ml. of brine and extracted with 200 ml of ethyl acetate. The ethyl acetate was removed under vacuum.
  • N-(2-Amino-4-methoxyphenyl)-6-chloronicotinamide (277 mg, 1 mmol) and 5 ml of ethylenediamine were heated to 8O 0 C for 3 hours. The excess ethylenediamine was removed under vacuum. To the residue was added 5 ml of 0.20 M NaOH. The mixture was extracted with 100 ml of ethyl acetate. The ethyl acetate was removed under vacuum to give the title compound (144 mg, 48% yield) as a brown solid. LC-MS (m/z) 302 (M+1 ).
  • Nicotinic acid 123 mg, 1 mmol
  • 8 ml of DMF were stirred at room temperature while 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (384 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1 .2 mmol), triethylamine (404 mg, 4 mmol) and N-(2-amino-4-methoxyphenyl)-6-(2-aminoethylamino)nicotinamide (316 mg, 1.05 mmol) were added.
  • the mixture was stirred for 20 hours at room temperature.
  • the mixture was diluted with 400 ml of brine and extracted with 200 ml of ethyl acetate.
  • the ethyl acetate was removed under vacuum to give the title compound (244 mg, 60%) as a brown solid.
  • 6-Chloronicotinic acid (157.5 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (384 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 4-trifluoromethyl-o-phenylenediamine (211 mg, 1.2 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 400 imL of brine and extracted with 200 ml of ethyl acetate. The ethyl acetate was removed under vacuum.
  • N-(2-Amino-4-trifluoromethylphenyl)-6-chloronicotinamide (316 mg, 1 mmol) and 5 ml of ethylenediamine were heated to 8O 0 C for 3 hours. The excess ethylenediamine was removed under vacuum. To the residue was added 5 ml of 0.20 M NaOH. The mixture was extracted with 100 ml of ethyl acetate. The ethyl acetate was removed under vacuum to give the title compound (159 mg, 47% yield) as a brown solid. LC-MS (m/z) 340 (M+1 ).
  • Nicotinic acid (123 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (384 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and N-(2-amino-4-trifluoromethylphenyl)-6-(2-aminoethylamino)nicotinamide (356 mg, 1.05 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 400 ml of brine and extracted with 200 ml of ethyl acetate. The ethyl acetate was removed under vacuum to give the title compound (275 mg, 62%) as a brown solid.
  • LC-MS (m/z) 445 (M+1 ).
  • 6-Chloronicotinic acid 158 mg, 1 mmol
  • 8 ml of DMF 8 ml
  • 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride 384 mg, 2 mmol
  • hydroxybenzotriazole 162 mg, 1 .2 mmol
  • triethylamine 404 mg, 4 mmol
  • N-(2-aminophenyl)-6-(2-aminoethylamino)nicotinamide 284 mg, 1.05 mmol
  • 6-Methylnicotinic acid 137 mg, 1 mmol
  • 8 ml of DMF 8 ml
  • 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride 384 mg, 2 mmol
  • hydroxybenzotriazole 162 mg, 1 .2 mmol
  • triethylamine 404 mg, 4 mmol
  • N-(2-aminophenyl)-6-(2-aminoethylamino)nicotinamide 284 mg, 1.05 mmol
  • 6-(Trifluoromethyl)nicotinic acid (162 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (384 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and N-(2-aminophenyl)-6-(2-aminoethylamino)nicotinamide (284 mg, 1.05 mmol) were added. The mixture was stirred for 20 hours at room temperature.
  • N-(2-Aminophenyl)-6-chloronicotinamide (248 mg, 1 mmol) and 1 ,6-diaminohexane (5.80 g, 50 mmol) were heated to 8O 0 C for 3 hours. The excessi ,6-diaminohexane was removed under vacuum. To the residue was added 5 ml of 0.20 M NaOH. The mixture was extracted with 100 ml of ethyl acetate. The ethyl acetate was removed under vacuum to give the title compound (219 mg, 67% yield) as a brown solid. LC-MS (m/z) 328 (M+1 ).
  • Nicotinic acid (123 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (384 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1 .2 mmol), triethylamine (404 mg, 4 mmol) and N-(2-aminophenyl)-6-(6-aminohexylamino)nicotinamide (343 mg, 1 .05 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 400 ml of brine and extracted with 200 ml of ethyl acetate. The ethyl acetate was removed under vacuum to give the title compound (311 mg, 72%) as a brown solid. LC-MS (m/z) 433 (M+1 ).
  • CS055 Chidamide is a HDACi currently in clinical development with good efficacy and toxicity profile in oncology indication from Chipscreen Biosciences
  • HDAC Fluorimetric Assay/Drug Discovery Kit (BIOMOL) according to manufacture's instruction. 1. Add Assay buffer, diluted trichostatin A or test inhibitor to appropriate wells of the microtiter plate. Following table lists examples of various assay types and the additions required for each test.
  • HDAC subtype selectivity inhibition assay of tested compounds was carried out by several reporter gene assays experiments. Briefly, HeLa cells were seeded in 96-well plates the day before transfection to give a confluence of 50-80%. Cells were transfected with one of reporter gene plasmid containing a promoter sequence or response element upstream of a luciferase gene construct using FuGene ⁇ transfection reagent according to the manufacturer's instruction (Roche). The promoters or response elements including p21-promoter, gdf11 -promoter, MEF-binding element (MEF2), Nur77-promoter were fused upstream to the luciferase gene reporter construct.
  • MEF-binding element MEF-binding element
  • a GFP expression plasmid was cotransfected.
  • Cells were allowed to express protein for 24 hours followed by addition of individual compounds or the vehicle (DMSO). 24 hours later the cells were harvested, and the luciferase assay and GFP assay were performed using corresponding assay kits according to the manufacturer's instructions (Promega).
  • Chidamide is a HDAC inhibitor currently in clinical development against cancers with preference against class I HDAC enzyme; Suten and Sorafinib are two marketed RTK and Ser/Thr kinase inhibitors with broad activity against many different receptor tyrosine or ser/thr kinases
  • Tumor cells were trypsinized and plated into 96-well plates at 3,000 per well and incubated in complete medium with 10% FBS for 24 hours. Compounds were added over a final concentration range of 100 ⁇ mol/L to 100 nmol/L in 0.1 % DMSO and incubated for 72 hours in complete medium. The effects on proliferation were determined by addition of MTS reagent (Promega) according to the instruction, incubation for 2 hours at 37 0 C in CO 2 incubator, and record the absorbance at 490nm using an ELISA plate reader.
  • MTS reagent Promega
  • HL-60 Acute promyelocytic leukemia
  • Hut-78 Cutaneous T cell lymphoma
  • A549 Non small cell lung carcinoma
  • HeLa Cervix adenocarcinoma
  • MCF-7 Mammary gland adenocarcinoma
  • MDA-MB-231 Mammary gland adenocarcinoma
  • HCT-8 Ileocecal colorectal adenocarcinoma

Abstract

La présente invention concerne certains dérivés de 6-aminonicotinamide qui sont capables d’inhiber les histone désacétylases. Les composés de cette invention sont en conséquence utiles dans le traitement de maladies associées à des activités anormales de l’histone désacétylase. Des compositions pharmaceutiques comprenant ces composés, des procédés de traitement de maladies à l’aide des compositions pharmaceutiques comprenant ces composés et des procédés de préparation de ces composés sont également décrits.
PCT/US2009/043302 2008-05-16 2009-05-08 Dérivés de 6-aminonicotinamide formant des inhibiteurs puissants et sélectifs de l’histone désacétylase WO2009140164A1 (fr)

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EP09747249A EP2285376A4 (fr) 2008-05-16 2009-05-08 Dérivés de 6-aminonicotinamide formant des inhibiteurs puissants et sélectifs de l histone désacétylase
JP2011509573A JP2011520891A (ja) 2008-05-16 2009-05-08 強力かつ選択的なヒストン脱アセチル化酵素阻害剤としての６−アミノニコチンアミド誘導体

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WO2020076951A1 (fr) * 2018-10-10 2020-04-16 Regenacy Pharmaceuticals, Llc Inhibiteurs de pyrimidine et de pyrazine hdac 1, 2

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US4108859A (en) * 1977-06-06 1978-08-22 The Dow Chemical Company Microbicidal (pyridinylamino) alkyl guanidines
WO2001018045A1 (fr) * 1999-09-08 2001-03-15 Sloan-Kettering Institute For Cancer Research Structure cristalline d'une deacetylase et ses inhibiteurs
US6362351B2 (en) * 1997-12-22 2002-03-26 Eli Lilly And Company Catalyst and method for amide formation
WO2004071400A2 (fr) * 2003-02-14 2004-08-26 Shenzhen Chipscreen Biosciences Ltd. Inhibiteurs d'histone desacetylase de nouveaux derives de benzamide a differenciation puissante et a activite inhibant la proliferation
WO2005030704A1 (fr) * 2003-09-24 2005-04-07 Methylgene, Inc. Inhibiteurs d'histone deacetylase
WO2006123121A1 (fr) * 2005-05-19 2006-11-23 Chroma Therapeutics Ltd Inhibiteurs de l’histone desacetylase

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JP2001081031A (ja) * 1999-08-30 2001-03-27 Schering Ag 溶解性および経口吸収性を改善したベンズアミド誘導体含有製剤
JP2009514859A (ja) * 2005-11-03 2009-04-09 メルク エンド カムパニー インコーポレーテッド 置換ニコチンアミド化合物

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US4108859A (en) * 1977-06-06 1978-08-22 The Dow Chemical Company Microbicidal (pyridinylamino) alkyl guanidines
US6362351B2 (en) * 1997-12-22 2002-03-26 Eli Lilly And Company Catalyst and method for amide formation
WO2001018045A1 (fr) * 1999-09-08 2001-03-15 Sloan-Kettering Institute For Cancer Research Structure cristalline d'une deacetylase et ses inhibiteurs
WO2004071400A2 (fr) * 2003-02-14 2004-08-26 Shenzhen Chipscreen Biosciences Ltd. Inhibiteurs d'histone desacetylase de nouveaux derives de benzamide a differenciation puissante et a activite inhibant la proliferation
WO2005030704A1 (fr) * 2003-09-24 2005-04-07 Methylgene, Inc. Inhibiteurs d'histone deacetylase
WO2006123121A1 (fr) * 2005-05-19 2006-11-23 Chroma Therapeutics Ltd Inhibiteurs de l’histone desacetylase

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Publication number Priority date Publication date Assignee Title
WO2020076951A1 (fr) * 2018-10-10 2020-04-16 Regenacy Pharmaceuticals, Llc Inhibiteurs de pyrimidine et de pyrazine hdac 1, 2

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