WO2007015632A1 - Inhibiteur d’atm et d’atr - Google Patents

Inhibiteur d’atm et d’atr Download PDF

Info

Publication number
WO2007015632A1
WO2007015632A1 PCT/KR2006/003072 KR2006003072W WO2007015632A1 WO 2007015632 A1 WO2007015632 A1 WO 2007015632A1 KR 2006003072 W KR2006003072 W KR 2006003072W WO 2007015632 A1 WO2007015632 A1 WO 2007015632A1
Authority
WO
WIPO (PCT)
Prior art keywords
ethyl
phenyl
thioureido
trichloro
nitro
Prior art date
Application number
PCT/KR2006/003072
Other languages
English (en)
Inventor
Tae Kook Kim
Jae-Joon Won
Yong-Weon Yi
Original Assignee
Cgk Co., Ltd.
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 Cgk Co., Ltd. filed Critical Cgk Co., Ltd.
Publication of WO2007015632A1 publication Critical patent/WO2007015632A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/04—Derivatives of thiourea
    • C07C335/16—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
    • C07D249/14—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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
    • C07D307/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
    • C07D311/82—Xanthenes
    • C07D311/84—Xanthenes 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 in position 9

Definitions

  • the present invention relates to a urea compound of formula (1) having an inhibitory activity of ATM and ATR, its derivatives and pharmaceutically acceptable salts thereof.
  • a protein family called "PIKKs" phosphoinositide 3-kinase related kinases
  • ATM ataxia-telangiectasia mutated
  • ATR ATM and Rad 3-related protein
  • ATM is a gene product of ataxia telangiectasia mutated polypeptide having about
  • ATM and ATR protein are activated by DNA damage, but what proteins respond to any damages is not exactly known [Yang, J. et al. (2003) ATM, ATR and DNA-PK: initiators of the cellular genotoxic stress responses. Carcinogenesis 24, 1571- 1580]. It was just reported that ATM responds to double-strand breaks induced by ionic radiation, and ATR mainly responds to ultraviolet rays or stalled replication forks [See Lowndes, N. F. and Murguia, J. R. (2000) Sensing and responding to DNA damage. Curr. Opin. Genet. Dev. 10, 17-25; Abraham, R. T. (2001) Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev.
  • ATR protein also induces the phosphorylation of p53 protein resulted from damaging agents of DNA such as UV to increase the amount of p53 protein. [Tibbetts, R. S. et al. (1999) A role for ATR in the DNA damage-induced phosphorylation of p53. Genes Dev. 13, 152-157]. Therefore, inhibitors having low molecular weight that are specific for ATM/ ATR can be used for controlling the activity of p53 protein.
  • Caffeine and wortmannin that are non-specific inhibitors to ATM/ ATR can be used as addictives for increasing sensitivity in radiation therapy or chemotherapy of cancer which is performed by induction of DNA damage [Sarkaria, J. N. et al. (1998) Inhibition of phosphoinositide 3-kinase related kinases by the radiosensitizing agent wortmannin. Cancer Res. 58, 4375-4382; Nghiem, P. et al. (2001) ATR inhibition selectively sensitizes Gl checkpoint deficient cells to lethal premature chromatin condensation. Proc. Natl. Acad. Sci. 98, 9092-9097]. However, it is not clear whether - A -
  • ATM tissue-specific for ionizing radiation.
  • Atm-/- mouse in which the ATM gene is removed by homologous recombination, Atm-/- thymocyte has resistance against apoptosis induced by gamma radiation in comparison with thymocytes having normal ATM, whereas the other cells show sensitivity to gamma radiation.
  • Xu, Y. and Baltimore, D. (1996) Dual roles of ATM in the cellular response to radiation and in cell growth control. Genes Dev. 10, 2401-2410].
  • apoptosis induced by genotoxic stress did not occur. [Chong, M. J. et al.
  • Atm and Bax cooperate in ionizing radiation-induced apoptosis in central nervous system. Proc. Natl. Acad. Sci. 97, 889-894]. It was reported that ATM-dependent apoptosis induced by genotoxic stress at the nervous system in duration of development requires p53 protein and is varied according to the stage of cell differentiation [Lee, Y. et al. (2001) Ataxia telangiectasia mutated- dependent apoptosis after genotoxic stress in the developing nervous systems is determined by cellular differentiation status. J. Neurosci. 21, 6687-6693].
  • ATM/ATR-dependent DNA damage reaction occurs in degenerative brain diseases such as SBMA (spinobulbar muscular atrophy) caused by polyQ expansion, Huntington's disease, DRPLA (dentatorubral pallidolusian atrophy), and SCA (six spinocerebellar ataxias) [Giuliano, P. et al. (2003) DNA damage induced by polyglutamine-expanded proteins. Human MoI. Genet. 12, 2301-2309]. Therefore, ATM inhibitors can protect cells from genotoxicity and neurotoxicity at specific tissues or cells.
  • ATM/ ATR inhibitors can be used for controlling abnormal symptoms induced by the cellular senescence.
  • telomere is the terminal structure of a linear chromosome in a eukaryotic cell, and the essential structure for consistently maintaining the linear chromosome. In a normal cell, the telomere becomes shorter for every cell division. If the telomere becomes shorter to excess, cells no longer divide. It has been reported that the telomere becomes extremely shorter in various tissues of an Atm -/- mouse [Hande, M. P. et al.
  • ATM/ ATR inhibitors can be used as therapeutic agents for treating cellular proliferative diseases caused by the abnormal elongation of the telomere.
  • the ATM/ATR is related with a response to oxidative stress. It was reported that
  • ATR responds to hypoxia. It was also reported that the ATM responds to reoxygenation so as to show its activity [Watters, D. J. (2003) Oxidative stress in ataxia telangiectasia. Redox. Rep. 8, 23-29; Hammond, E. M. et al. (2003) Hypoxia links ATR and p53 through replication arrest. MoI. Cell. Biol. 22, 1834-1843; Hammond, E. M. (2003) ATR/ATM targets are phosphorylated by ATR in response to hypoxia and ATR in response to reoxygenation. J. Biol. Chem. 278, 12207-12213]. Therefore, ATM/ATR inhibitors can be potentially used for controlling the abnormality in cell function caused by any oxidative stress.
  • the stress occurred in the chronic inflammation is caused by free radicals such as NO.
  • the p53 protein is phosphorylated by the free radicals such as NO, wherein the ATM/ATR protein is concerned with the posttranslational modification of the p53 protein [Hofseth, L. J. et al. (2002) Nitric oxide-induced cellular stress and p53 activation in chronic inflammation. Proc. Natl. Acad. Sci. 100, 143-148].
  • the free radicals such as NO have been known to continually cause genetic damage.
  • ATM/ATR inhibitors can be used for controlling cytotoxicity derived from the free radicals.
  • the ATM protein was reported to contribute to the stabilization of p53 protein by heat shock [Wang, C. and Chen, J. (2003) Phosphorylation and hsp90 binding mediate heat shock stabilization of p53. J. Biol. Chem. 278, 2066-2071].
  • the stabilization of p53 protein by heat shock causes cell cycle arrest or apoptosis [Nitta, M. et al. (1997) Heat shock induces transient p53-dependent cell cycle arrest at Gl/S. Oncogene 15, 561-568; Ohnishi, T. et al. (1996) p53-dependent induction of WAFl by heat treatment in human glioblastoma cells. J. Biol. Chem. 271 , 14510- 14513] . Therefore, ATM/ATR inhibitors can be used for controlling the abnormality in cells induced by heat shock.
  • AT patients are characterized by hypoplasia of thymus and deficiency in immune mechanism.
  • An Atm-/- mouse was reported to show various immunodeficiencies similar to those as shown in AT patients [Xu, Y. and Baltimore, D. (1996) Dual roles of
  • ATM/ ATR inhibitors can be used for controlling immune function.
  • the ATM/ ATR plays a significant role in diseases caused by retroviruses. It was disclosed that the ATM/ ATR is required to stably introduce the DNA of a retrovirus into the genome of a host cell [Daniel, R. et al. (2001) Wortmannin potentiates integrase- mediated killing of lymphocytes and reduces the efficiency of stable transduction by retroviruses. MoI. Cell. Biol. 21, 1164-72; Daniel, R. et al. (2003) Evidence that the retroviral DNA integration process triggers an ATR-dependent DNA damage response. Proc. Natl. Acad. Sci. 100, 4778-4783; Roshal, M. et al.
  • ATM/ATR inhibitors can be used for treating retrovirus-mediated diseases such as HIV infection and AIDS; and Human T-cell Lymphotropic Virus (HTLV) infection, HTLV associated Adult T-cell Leukemia/Lymphoma (ATLL), and Tropical Spastic Paraparesis/HTLV-1 Associated Myelopathy (TSP/HAM).
  • retrovirus-mediated diseases such as HIV infection and AIDS; and Human T-cell Lymphotropic Virus (HTLV) infection, HTLV associated Adult T-cell Leukemia/Lymphoma (ATLL), and Tropical Spastic Paraparesis/HTLV-1 Associated Myelopathy (TSP/HAM).
  • HTLV Human T-cell Lymphotropic Virus
  • ATLL HTLV associated Adult T-cell Leukemia/Lymphoma
  • TSP/HAM Tropical Spastic Paraparesis/HTLV-1 Associated Myelopathy
  • the present invention provides a urea compound of formula (1), its derivatives and pharmaceutically acceptable salts thereof that specifically inhibit the function of protein kinases of ATM and ATR by selectively binding to ATM and ATR.
  • the objective of the present invention is to provide a process for preparing a urea compound of formula (1), its derivatives and pharmaceutically acceptable salts thereof, and a pharmaceutical composition comprising them as an effective ingredient.
  • Urea compounds according to the present invention can be used for controlling cellular function and treating diseases, in connection with the abnormality in the function of ATM and ATR.
  • Fig. 1 is a western blot picture showing that phosphorylation of p53 protein by ATR protein is inhibited by the urea compounds.
  • Fig. 2 is a western blot picture showing that phosphorylation of p53 protein by ATM protein is inhibited by the urea compounds.
  • Fig. 3 is a western blot picture showing that phosphorylation of Serl5 of p53 protein by ATM protein is inhibited by the urea compounds in RKO cells and GM847 cells.
  • Fig. 4 is an electrophoresis picture showing that phosphorylation of p53 protein by ATM and ATR protein is inhibited by the urea compounds in vitro.
  • Fig. 5 is a graph showing that activity of ATM and ATR is inhibited by the urea compounds depending on the concentration thereof in vitro.
  • Fig. 6 is an electrophoresis picture showing that phosphorylation of p53 protein by other protein kinases is not inhibited by the urea compounds in vitro.
  • Fig. 7 is a graph showing that apoptosis of human cancer cells by chemotherapy is increased by addition of the urea compounds.
  • the numbers in the small squares represent the treatment concentration ( ⁇ M) of the compounds.
  • Fig. 8 is a graph showing that apoptosis of RKO cells by doxorubicin is inhibited by the urea compounds depending on the concentration thereof.
  • Fig. 9 shows the analysis result that the suppression of the cell cycle in the RKO cells by doxorubicin is inhibited by the urea compounds.
  • Fig. 10 is a growth graph showing that the urea compounds inhibit replicative senescence; BJ cells were continuously subcultured to reach replicative senescence (as indicated by asterisk); then treated by the urea compounds (as indicated by an inverted triangle) and continuously subcultured; thereafter subcultured again without the urea compounds (as indicated by a triangle); and subcultured by treating the cells again with the urea compounds.
  • Fig. 11 is a cell picture showing that SA- ⁇ -gal dyeing is inhibited by the urea compounds.
  • Fig. 12 is a cell picture showing that SA- ⁇ -gal dyeing formed as a result of premature senescence is inhibited by the urea compounds.
  • R 1 is any one of the following structures:
  • R 2 is any one of the following structures:
  • X is H, CH 3 , CF 3 , or CCl 3 ; and Y is O or S.
  • the above urea compounds of formula (1) may contain optical isomers, and may exist in free form or in the form of an acid or base addition salt thereof.
  • the preferable acid addition salt may be, without limitation, hydrochloric acid, sulphuric acid, acetic acid, trifluoracetic acid, phosphoric acid, fumaric acid, maleic acid, citric acid, or lactic acid.
  • R 2 is any one of the following structures:
  • X is CF 3 , or CCl 3 ;
  • Y is O, or S.
  • R 1 is any one of the following structures:
  • R 2 is any one of the following structures
  • X is CCl 3 ; and Y is S.
  • a urea compound(s) used herein means a compound(s) that can inhibit the activity of ATM or ATR protein, and, in more detail, contains a prodrug thereof and all compounds having unique inhibition activity, wherein the prodrug itself has a little activity or no unique inhibition activity.
  • the present invention provides a method of inhibiting the activity of ATM or ATR protein in cells, which comprises contacting the effective amount of the urea compounds, preferably in the form of a pharmaceutically acceptable composition, with cells.
  • cells e.g., tumor cells or normal cells
  • a medicine having the known therapeutic effect, and so increased therapeutic effect of the compounds on the cells is observed.
  • the present invention provides a method of inhibiting the activity of ATM or ATR protein in vivo or in vitro comprising contacting the effective amount of the urea compounds with cells, and also provides the urea compounds inhibiting the activity of ATM or ATR protein.
  • the present invention also provides a process of preparing the urea compound of formula (1).
  • the urea compound of the above formula (1) can be synthesized by the following reaction formula (1).
  • the compounds of the present invention may be in the form of optical isomers or diastereomers, and can be isolated and collected by the conventional technique.
  • reaction scheme (1) The compound of formula (1) according to the present invention is prepared by synthesis process of the following reaction scheme (1).
  • reaction scheme (1) after the acid compound of formula (2) is stirred together with BoC 2 O, ethyl chloroformate and isobutyl chloroformate in the presence of a suitable base such as triethylamine and pyridine, under nitrogen, NH 3 and NH 4 HCO 3 are added thereto, and then the compound of formula (3) is synthesized.
  • the reaction is completed when all of the compound of formula (2) has been consumed, which can be easily confirmed by thin-layer chromatography.
  • the reaction solvents are preferably dichloromethane, dioxane and so on.
  • the reaction temperature is O ° C to room temperature.
  • the reaction time is suitably 12 to 36 hours.
  • the amide compound of formula (3) is reacted with chloral hydrate, trifluoroacetaldehyde hemiacetal or acetaldehyde and with benzene or toluene to synthesize the compound of formula (4). If necessary, the addition of benzotriazole can promote the reaction.
  • the reaction temperature is room temperature under reflux condition.
  • the reaction time is suitably 12 to 36 hours.
  • the compound of formula (4) is reacted with SOCl 2 , PCl 5 or oxalylchloride and with benzene or toluene to synthesize the compound of formula (5).
  • the reaction temperature is room temperature under reflux condition.
  • the reaction time is suitably 1 to 24 hours.
  • the compound of formula (5) is reacted with KSCN or KOCN and with dichloromethane, dioxane or acetonitrile, and then suitable amine derivatives (R 2 NH 2 ) are added thereto, and thus the compound of formula (1) is synthesized.
  • the reaction temperature is room temperature under reflux condition.
  • the reaction time is suitably 1 to 24 hours.
  • Aqueous hydrogen peroxide is added to the compound of formula (1), wherein
  • the reaction temperature is room temperature under reflux condition.
  • the reaction time is suitably 1 to 24 hours.
  • the present invention comprises a pharmaceutical composition, for example, a composition useful for inhibiting the activity of ATM/ ATR, comprising a pharmaceutically acceptable carrier or a diluent and the effective amount of compounds of formula (1) or their derivatives or pharmaceutically acceptable acid addition salts thereof.
  • the present invention provides a method of inhibiting the activity of ATM/ ATR comprising administering therapeutically effective amount of compounds of formula (1) or their derivatives or pharmaceutically acceptable acid addition salts thereof, to a mammal that requires inhibition of ATM/ ATR.
  • the present invention provides a method for treating a certain disease, which includes administering therapeutically effective amount of compounds of formula (1) or their derivatives or pharmaceutically acceptable acid addition salts thereof, to a mammal that requires treatment of diseases mediated by ATM/ ATR.
  • the compounds of the present invention can be used as additives in combination with radiation therapy and chemotherapy for increasing their sensitivity in treating ATM/ATR mediated diseases, for example, various solid cancers and hematologic malignancy.
  • the present invention provides a method of treating degenerative brain diseases in which apoptosis occurs by genotoxicity and neurotoxicity (e.g., Alzheimer's disease, Huntington's disease, hypoxia, Parkinson's disease, stroke, traumatic brain injury, ischemic insult and excitotoxic insult, spinobulbar muscular atrophy, DRPLA, SCA and so on), abnormal symptoms caused by cellular senescence such as replicative senescence or premature senescence, cellular proliferative diseases, abnormality in cellular function caused by oxidative stress, chronic inflammation, cellular abnormality induced by heat shock, and retrovirus-mediated diseases, and controlling immune function.
  • genotoxicity and neurotoxicity e.g., Alzheimer's disease, Huntington's disease, hypoxia, Parkinson's disease, stroke, traumatic brain injury, ischemic insult and excitotoxic insult, spinobulbar muscular atrophy, DRPLA, SCA and so on
  • abnormal symptoms caused by cellular senescence such as replicative senescence or premature
  • the present invention also relates to the use of the compounds of the present invention or their derivatives or pharmaceutically acceptable salts thereof, in preparing a medicine for preventing and treating diseases or disorders, for example, those related to increment of the amount of ATM/ATR.
  • Representative structure and NMR spectrum data of the urea compounds having formula (1) according to the present invention are shown in the following Table 1. Table 1. Structure and activity of urea compounds
  • urea compounds of formula (1) of the present invention show inhibitory activity of ATM/ATR, and thus the pharmaceutical composition comprising at least one of them as an effective ingredient(s) is useful as an agent for controlling the cellular function and treating diseases in connection with the abnormality in the function of ATM and ATR.
  • the present invention provides a pharmaceutical composition for controlling the cellular function and treating diseases in connection with the abnormality in the function of ATM and ATR, comprising at least one of the above urea compounds of formula (1), prodrugs, optical isomers, diastereomers, their derivatives or salts thereof, as an effective ingredient(s).
  • the pharmaceutical composition of the present invention can be provided in various oral dosage forms or parenteral dosage formulations.
  • the examples of oral dosage formulations are tablets, pills, hard and soft capsules, solutions, suspensions, emulsions, syrup, granules, elixirs, etc., wherein these formulations contain diluents (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine), or lubricants (e.g., silica, talc, stearic acid and magnesium or calcium salt thereof, and/or polyethylene glycol) as well as the effective ingredient(s).
  • diluents e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine
  • lubricants e.g., silica, talc, stearic acid and magnesium or calcium salt thereof, and
  • the tablets may contain a binding agent(s) such as magnesium aluminium silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and in some cases, may further contain disintegrant or boiling mixture such as starch, agar, arginic acid or sodium salt thereof, and/or absorbent, colorant, flavoring agent, and sweetening agent.
  • a binding agent(s) such as magnesium aluminium silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine
  • disintegrant or boiling mixture such as starch, agar, arginic acid or sodium salt thereof, and/or absorbent, colorant, flavoring agent, and sweetening agent.
  • the pharmaceutical composition comprising the above compound of formula (1) as an effective agent can be parenterally administered, wherein the parenteral administration is performed by subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection.
  • parenteral administration is performed by subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection.
  • the above compounds of formula (1) or their derivatives or pharmaceutically acceptable salts thereof are mixed with stabilizer or buffer in water to produce their solution or suspension, and then put into an ampule or vial in unit dosage form.
  • composition may be sterilized and/or contain preservatives, stabilizers, hydration agents or emulsification promoters, supporting agents such as salt for controlling osmotic pressure and/or buffers, and therapeutically useful substances, and can be formulated according to conventional methods such as mixing, granulation or coating.
  • the compound of formula (1) as an effective ingredient can be orally or parenterally administered to a mammal including a human at a dosage of 0.1 to 500 ing/ kg (on the basis of body weight), preferably, 0.5 to 100 mg/kg (on the basis of body weight), 1 time a day or with certain intervals.
  • Example 1 Synthesis of compound No. 1 of Table 1 (2,2-diphenyl-N- (2.2.2- trichloro-l-r3-(3-nitro-phenyl)-thioureidol-ethvU-acetamide) (Step 1) Synthesis of 2,2-diphenyl-acetamide
  • Example 2 Synthesis of compound No. 27 of Table 1 (2.2-diphenyl-N- (2.2,2- trichloro- 1 - [3 -(3 -hydroxy-phenyl )- thioureidol -ethyl ⁇ -acetamide)
  • Example 4 Synthesis of compound No. 29 of Table 1 (3-[3-(2,2.2-trichloro-l- diphenylacetylamino-ethyl)-thioureido]-benzamide) 100 mg (0.27 mmol) of 2,2-diphenyl-N-(l,2,2,2-tetrachloro-ethyl)-acetamide obtained in Example 1 was added and 7 ml of CH 3 CN was added thereto. Then, 28 mg (0.28 mmol, 1.1 eq) of KNCS was added thereto and stirred for 1 hr. After the reaction was completed, the reactant was filtered, and thus remaining KNCS was removed.
  • Example 7 Synthesis of compound No. 32 of Table 1 (2,2-diphenyl-N- (2,2,2- trichloro-l-[3-(4 -hvdroxy-3-nitro-phenyl)thioureidoi-ethvl ⁇ -acetamide)
  • Example 8 Synthesis of compound No. 33 of Table 1 (2,2-di ⁇ henyl-N- (2,2,2- trichloro- 1 - [3 -(4-fluoro-3-nitro-phenyl)- thioureido] -ethyl ⁇ -acetamide)
  • Example 9 Synthesis of compound No. 34 of Table 1 (2,2-diphenyl-N- (2,2,2- trifluoro-l-[3-(3-nitro-phenyl)-thioureido] -ethyl ⁇ -acetamide) (Step 1) Synthesis of 2,2-diphenyI-N-(2,2,2-trifluoro-l-hydroxy-ethyl)- acetamide
  • Step 2 Synthesis of N-(l-chloro-2,2,2-trifluoro-ethyl)-2,2-diphenyl- acetamide 1 g (3.23 mmol) of 2,2-diphenyl-N-(2,2,2-trifluoro-l-hydroxy-ethyl)-acetamide was added and 15 ml of benzene was added thereto. Then, 0.96 g (8.085mmol, 2.5 eq) of SOCl 2 was added thereto, and refluxed and stirred for about 6 hours. After the reaction was completed, the reactant was completely concentrated, and crystallized by adding hexane thereto, and then stirred for about 30 min. The solid materials were filtered to obtain 0.57 g (53.9 %) of N-(l-chloro-2,2,2-trifluoro-ethyl)-2,2-diphenyl- acetamide.
  • Example 10 Synthesis of compound No. 35 of Table 1 (N- (l-[3-(3-cyano- phenyl)-thioureido1-2,2,2-trifluoro-ethyll-2,2-diphenyl-acetamide)
  • Step 1 Synthesis of 9H-xanthen-9-carboxamide 10 g (44.2 mmol) of xanthen-9-carboxylic acid and 11.6 g (53.0 mmol, 1.2 eq) of (Boc) 2 O were added. Then, 2.1 g (26.5 mmol, 0.6 eq) of pyridine and 5.3 g (66.3 mmol, 1.5 eq) Of NH 4 HCO 3 were added thereto. Then, 100 ml of 1,4-dioxane was added thereto to dissolve them. Thereafter, the solution was stirred for 12 hours at room temperature.
  • Step 4 Synthesis of N-(2,2,2-trichIoro-l-(3-(3-nitrophenyl)thioureido)ethyI)- 9H-xanthen-9-carboxamide
  • 150 mg (0.38mmol) of N-(l,2,2,2-tetrachloroethyl)-9H-xanthen-9-carboxamide was added and 7 ml of CH 3 CN was added thereto. Then, 41 mg (0.42 mmol, 1.1 eq) of KNCS was added thereto, and stirred for 1 hr. After the reaction was completed, the reactant was filtered, and thus remaining KNCS was removed.
  • Example 13 Synthesis of compound No. 38 of Table 1 (2,2-diphenyl-N- (2,2,2- trichloro- 1 - [3 -(3-nitro-phenyl)-ureidol -ethyl ⁇ -acetamide)
  • composition of the present invention can be formulated in the following dosage forms, but the scope of the present invention is not limited thereby.
  • the above acid addition salt may be substituted with another salt according to the above examples.
  • Formulation Example 2 Preparation of tablet A tablet containing 15 mg of the above effective ingredient was prepared by the following method. 25Og of HCl salt of 2,2-diphenyl-N- ⁇ 2,2,2-trichloro-l-[3-(3-nitro- phenyl)-thioureido] -ethyl ⁇ -acetamide (compound No. 1) was mixed with 175.9 g of lactose, 18O g of potato starch, and 32 g of colloidal silicic acid. To this mixture, 10% gelatin solution was added, triturated, and passed through a sieve of 14 mesh. Then, it was dried, and 16O g of potato starch, 50 g of talc and 5 g of magnesium stearate were added thereto to produce a tablet.
  • Formulation Example 3 Preparation of solution for injection A solution for injection containing 10 mg of the above effective ingredient was prepared by the following method.
  • Example 15 Acute toxicity test in a mouse
  • mice (5 mice/group) was moved into a cage, and the mice were raised at 22 ⁇ 2 ° C , at a
  • mice attached on the cage. The mice were allowed to have solid feed and drinking water
  • mice were selected from each group.
  • test group 1,000 mg/kg for the following tests. 50% DMSO was used as a solvent for administering the urea compound No. 1. The solution of the urea compound No. 1 was
  • mice orally administered to the mice in the following manner: for the medium-dose test group,
  • mice (5 mice/group) was moved into a cage, and the mice were raised at 22 ⁇ 2 ° C , at a
  • mice attached on the respective cage.
  • the mice were allowed to have solid feed and drinking water without limitation. 5 female mice and 5 male mice were selected from
  • mice On the next day of the administration (1 st day), the mice were not allowed to have feed. And then, the urea compound No. 33 in corn oil (Sigma, C8267) was administered orally to the mice from the test group, while only corn oil was administered orally to the urea compound No. 33 in corn oil (Sigma, C8267) was administered orally to the mice from the test group, while only corn oil was administered orally to the urea compound No. 33 in corn oil (Sigma, C8267) was administered orally to the mice from the test group, while only corn oil was administered orally to the
  • mice from the control group The general toxicity was monitored with the naked eye every 1 hour for 4 hours after the administration, and the mice were allowed to have
  • mice feed 4 hours later from the administration.
  • the general toxicity was monitored every 24 hours for 14 days after the oral administration.
  • the body weight of the mice was
  • Example 16 Results of oral acute toxicity test for the mice using urea compound
  • mice from the test groups and the control group survived. According to
  • Example 17 Results of oral acute toxicity test for the mice using the urea
  • mice subject to be tested survived at the end of the study period (6 days),
  • phosphorylation of p53 protein for Serl5 was analyzed by using an RKO cell (purchased from ATCC) and a GM847 cell (purchased from ATCC).
  • RKO cells derived from a human large intestine cancer cell
  • McCoy's 5 A medium purchased from Invitrogen
  • the cultured RKO cells were pre-incubated for 2 hours by adding a medium containing the urea compound and then were incubated for 20 hours by adding 1 ⁇ M of doxorubicin.
  • the cultured GM847 cells were pre-incubated for 2 hours by adding a medium containing the urea compound.
  • the pre-incubated GM847 cells were additionally incubated for 2 hours after adding 1 ⁇ M of doxorubicin to them, or irradiating them with 30 J/m 2 of UV. After the incubated cells were retrieved and their cell lysates were retrieved, proteins were developed by SDS-PAGE and western blot analysis was performed for the proteins.
  • the western blot was carried out by anti-actin antibody (C-Il; purchased from Santa Cruz Biotechnology), anti-p53 antibody DO-I (purchased from Santa Cruz Biotechnology), and anti-p53 Serl5 antibody (purchased from Cell Signaling Technology).
  • C-Il anti-actin antibody
  • DO-I anti-p53 antibody
  • anti-p53 Serl5 antibody purchased from Cell Signaling Technology
  • RNA activated protein kinase PKR physically associates with the tumor suppressor p53 protein and phosphorylates human p53 on serine 392 in vitro.
  • the platelet-derived growth factor ⁇ receptor triggers multiple cytoplasmic signaling cascades that arrive at the nucleus as distinguishable inputs. J. Biol. Chem. 272, 32670-32678].
  • protein kinases prepared by the above methods the enzymatic analysis of protein phosphorylation was carried out as follows: prepared protein kinases were added to a buffer (10 mM Hepes ( ⁇ H7.5), 50 mM glycerophosphate, 50 mM NaCl, 10 niM MgCl 2 , 10 mM MnCl 2 , 10 ⁇ M ATP, and 1 mM dithiothreitol) containing 10 ⁇ Ci [ ⁇ - 32 P]ATP and 1 ⁇ g GSTp53 protein (purchased from Santa Cruz Biotechnology), and allowed to be reacted for 30 mins at 30 ° C .
  • the protein kinases were reacted by adding the urea compound to the reactant so as to confirm its inhibition activity. After the reaction, proteins were developed by SDS-PAGE and the gel was dried and exposed to an X-ray film.
  • Example 20 Sensitivity analysis to chemotherapy in a cell HeLa cells (purchased from ATCC) of human cervical cancer cell line were incubated in a DMEM medium containing 10% bovine serum.
  • VA- 13 cells purchased from ATCC which were immortalized by transforming WI-38 cells of normal human lung fibroblasts with SV40 virus, and MCF-7 cells (purchased from ATCC) of breast cancer cell line were incubated in a DMEM medium containing 10% fetal bovine serum.
  • the agents used in the chemotherapy of human cancer are as follows: doxorubicin (purchased from Sigma), which is topoisomerase II inhibitor, was prepared at the concentration of 10 mM in DMSO (dimethyl sulfoxide); etopoxide (purchased from Calbiochem), which is topoisomerase II inhibitor, was prepared at the concentration of 40 mM in DMSO; and cisplatin (purchased from Calbiochem) of alkylating agent was prepared at the concentration of 30 mM in DMSO.
  • doxorubicin purchased from Sigma
  • etopoxide purchased from Calbiochem
  • cisplatin purchased from Calbiochem
  • HeLa cells (-3,000 cells), MCF-7 cells (-6,000 cells), and VA- 13 cells (-6,000 cells) were cultured per well of a 96-well plate.
  • the cells in a 96-well plate were cultured in a 37 ° C incubator which was provided with 5% CO 2 for 24 hours and then were cultured again in a 37 ° C incubator which was provided with 5% CO 2 for 2 hours by adding the urea compound.
  • the cells to which the urea compound was added were treated with chemotherapy and they were cultured again in a 37 °C incubator which was provided with 5% CO 2 for 24 to 72 hours.
  • As a negative control the cells were cultured in DMSO that did not contain the urea compound or chemotherapy agents.
  • Cytotoxicity was analyzed by using a CellTiter-Glo Luminescent Cell Viability Assay reagent (purchased from Promega) according to the manual of the company.
  • the luminescent intensity was calculated for luminescence generated by the reaction by using a luminescent detector (Wallac Victor V 2 Multi-reader).
  • the cell mortality resulted from cellular toxicity was determined by comparing the luminescent intensity with the measurement from cells as a negative control.
  • Example 21 Analysis of cell protection function induced by the urea compound
  • RKO cells of human large intestine cancer cells were cultured in McCoy's 5A medium containing 10% fetal bovine serum.
  • doxorubicin of topoisomerase II inhibitor was prepared at the concentration of 10 mM in DMSO.
  • the cultured cells were treated with trypsin and separated from the incubation vessel, the number of cells was counted and then the cells were cultured in a 96-well black plate having a transparent bottom wherein the number of cells is different in each well.
  • the cells were cultured in a 37 °C incubator which was provided with 5% CO 2 for 24 hours, they were cultured again by adding the urea compound in a 37 ° C incubator which was provided with 5% CO 2 for 2 hours.
  • the cells, to which the urea compound was added were treated with doxorubicin and they were cultured in a 37 ° C incubator which was provided with 5% CO 2 for 24 to 72 hours.
  • As a negative control the cells were cultured in DMSO that did not contain the urea compound or genotoxicity agents.
  • Cytotoxicity was analyzed by using CellTiter 96 ® AQ ueO us Non-Radioactive Cell Proliferation Assay reagent or MTT reagent (purchased from Promega) according to the manual of the company.
  • the luminescent intensity was calculated for luminescence generated by the reaction by using a luminescent detector (Wallac Victor V 2 Multi-reader).
  • the cell mortality resulted from cellular toxicity was determined by comparing the luminescent intensity with the measurement from cells as a negative control.
  • the change of cell cycle occurred during cell death by doxorubicin was analyzed using FACS (fluorescence activated cell sorter).
  • the cells, which were treated with the compounds and doxorubicin, were isolated by applying trypsin from the incubation vessel and then were dyed with PI (propium iodide) solution (0.1 % sodium citrate, 0.1 % Triton X-IOO, 50 ⁇ g/ml propidium iodide and 1 mg/ml RNase A), and then the cell cycle was analyzed by FACSCalibur (purchased from Becton-Dickinson).
  • Example 22 Analysis of inhibition of replicative senescence in a cell BJ cells (purchased from ATCC) of human prepuce cells were cultured in a DMEM medium containing 10% fetal bovine serum. BJ cells were subcultured in a ratio of 1 :4, and the number of cell population doubling (PD) was calculated with the cumulative number of cells obtained from the number of cells per subculture. The cells in replicative senescence were treated with 1 ⁇ M of the urea compound, and then the effect of the urea compound on the cells in senescence was analyzed by counting the number of cell population doubling in the same method as above.
  • SA- ⁇ -galactosidase SA- ⁇ - gal
  • the incubated BJ cells were washed with PBS and then were fixed with PBS containing 2% formaldehyde and 0.2% glutaraldehyde for 5 mins.
  • the cells fixed with PBS were washed, and then they were dyed for 12 hours by adding buffer containing 1 mg/ml of X-gal (5-bromo-4-chloro-3-indolyl ⁇ -D-galactoside) [150 niM NaCl, 2 mM MgCl 2 , 5 mM K 3 Fe(CN) 6 , 5 mM K 4 Fe(CN) 6 , 40 mM citric acid and
  • Example 23 Analysis of inhibition of premature senescence in a cell
  • BJ cells (purchased from ATCC) of human prepuce cells were cultured in a DMEM medium containing 10% fetal bovine serum. BJ cells were subcultured in a ratio of 1 :4, and the number of cell population doubling (PD) was calculated with the cumulative number of cells obtained from the number of cells per subculture.
  • the premature senescence in cells was induced with treatment of 100 ⁇ M of hydrogen peroxide (H 2 O 2 ) to BJ cells in which the number of cell population doubling was 30 (PD30).
  • the cells in premature senescence were treated with 1 ⁇ M of the urea compound, and then the effect of the urea compound on the cells in senescence was analyzed by counting the number of cell population doubling in the same method as above.
  • the incubated BJ cells were washed with PBS and then were fixed with PBS containing 2% formaldehyde and 0.2% glutaraldehyde for 5 mins.
  • the fixed cells were washed with PBS and then were fixed with PBS containing 2% formaldehyde and 0.2% glutaraldehyde for 5 mins.
  • the fixed cells were washed with PBS and then were fixed with PBS containing 2% formaldehyde and 0.2% glutaraldehyde for 5 mins.
  • the fixed cells with
  • PBS were washed, and then they were dyed for 12 hours by adding buffer containing 1 mg/ml of X-gal (5-bromo-4-chloro-3-indolyl ⁇ -D-galactoside) [150 niM NaCl, 2 niM MgCl 2 , 5 mM K 3 Fe(CN) 6 , 5 mM K 4 Fe(CN) 6 , 40 mM citric acid and Na 2 HPO 4 (pH 6.0)].
  • X-gal 5-bromo-4-chloro-3-indolyl ⁇ -D-galactoside
  • GM847 cells The inhibition of ATR activity by the urea compound in a cell was confirmed by using GM847 cells as mentioned in the part of "materials and methods".
  • GM847 cells under incubation were pretreated with the urea compound for 2 hours and then were irradiated with 30 J/m 2 of UV.
  • the cells were cultured again for 2 hours, and then phosphorylation of Serl5 of p53 protein in the cells was determined by performing western blot analysis. As shown in Fig. 1, it was observed that when GM847 cells were irradiated with UV, Serl5 of p53 protein was phosphorylated.
  • the inhibition of ATM activity by the urea compound in a cell was also determined by using GM847 cells. After the GM847 cells in incubation were treated with the urea compounds for 2 hours, they were treated with 1 ⁇ M of doxorubicin. They were cultured again for 2 hours, and then the phosphorylation of Ser 15 of p53 protein was determined by performing western blot analysis. It was confirmed that Serl5 of p53 protein was specifically phosphorylated in the cells by doxorubicin, and the phosphorylation of Ser 15 was inhibited depending on the concentration of the urea compounds when GM847 cells were pretreated at the different concentration of the urea compound Nos. 28 and 34 (Fig. 2).
  • the inhibition of phosphorylation of Serl5 of p53 protein in a cell by the urea compound was determined by using GM847 cells and RKO cells. It was confirmed that when RKO cells were treated with 1 ⁇ M of doxorubicin in the same manner as GM847 cells, Serl5 of p53 protein was specifically phosphorylated in the RKO cells. It was confirmed that the compound Nos. 1, 27, 28, 29 and 31 inhibited the phosphorylation of Ser 15 of p53 protein induced by doxorubicin, depending on the concentration of the compounds. Specially, the compound Nos. 1, 27 and 28 inhibited the phosphorylation of Serl5 in both GM847 cells and RKO cells (Fig. 3). As shown in Fig. 3, the phosphorylation of Serl5 of p53 protein was changed in its intensity in RKO cells by treatment of the urea compounds.
  • the inhibition of ATM and ATR activity by the compounds was carried out in vitro and determined by using protein kinases prepared as mentioned in the above part of "materials and methods". As shown in Fig. 4, GST-p53 protein was specifically phosphorylated by wild type ATM and ATR proteins, while GST-p53 protein was not phosphorylated by mutant ATM and ATR proteins in which their protein kinase activity is eliminated. When the compound Nos. 28 and 33 were added to the reaction solution, the phosphorylation of GST-p53 protein by ATM and ATR was inhibited depending on the concentration of the compounds. LY294002(LY) compound (purchased from Calbiochem) used as a positive control also inhibited the phosphorylation of GST-p53 protein by ATM and ATR. The LY and the compound Nos. 28 and 33 could not inhibit the phosphorylation of GST-p53 protein by JNK and p38 protein kinases.
  • the inhibitory activity of the urea compound was confirmed in vitro by using protein kinases known to phosphorylate p53 protein (Fig. 6). It was confirmed that the compound No. 33 did not inhibit the phosphorylation of GST-p53 protein by protein kinases other than ATM and ATR.
  • VA- 13 cell is a cell immortalized by transforming WI-38 cell of normal human lung fibroblast with SV40 virus.
  • VA- 13 cells were treated with cisplatin, etoposide, and doxorubicin used in cancer chemotherapy, the cell growth was inhibited depending on the concentration. It was confirmed that when the cells were treated with the compound No. 28 in combination with the chemotherapy agents, the cell growth was more strongly inhibited than when each of the chemotherapy agents was used alone (Fig. 7).
  • Doxorubicin is an inhibitor of topoisomerase II, and causes genotoxic stress to induce apoptosis of cells.
  • the apoptosis induced by doxorubicin Dox
  • Fig. 8 concentration of the compound No. 28
  • the cell cycle was inhibited at the G2/M phase (see left- lower side in Fig. 9).
  • RKO cells were treated only with the compound No. 28, they showed the cell cycle that was similar to that as shown in the cells treated with DMSO as a negative control (see right-upper side in Fig. 9).
  • RKO cells was treated with doxorubicin after being treated with the compound No. 28, it was confirmed that the inhibition of the G2/M phase caused by doxorubicin was suppressed (see right-lower side in Fig. 9).
  • a urea compound of formula (1) or a pharmaceutically acceptable salt thereof according to the present invention selectively binds to ATM and ATR so as to specifically suppress the function of ATM and ATR as protein kinase. Therefore, the urea compound and the pharmaceutical composition comprising it as an effective ingredient are very useful for controlling cell function and treating diseases, in connection with function abnormality in ATM and ATR.

Abstract

La présente invention concerne un composé d’urée de formule (1) et un sel pharmaceutiquement acceptable de celui-ci ayant une activité inhibitrice de l’ATM et de l’ATR. Selon la présente invention, le composé d’urée de formule (1) se lie de manière sélective à l’ATM et l’ATR, et ainsi supprime spécifiquement la fonction de l’ATM et de l’ATR en tant que protéine kinase. Ainsi, le composé d’urée selon la présente invention peut être utilisé afin de contrôler la fonction cellulaire et de traiter des maladies, en rapport avec une anomalie de fonction de l’ATM et de l’ATR.
PCT/KR2006/003072 2005-08-04 2006-08-04 Inhibiteur d’atm et d’atr WO2007015632A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR20050071360 2005-08-04
KR10-2005-0071360 2005-08-04

Publications (1)

Publication Number Publication Date
WO2007015632A1 true WO2007015632A1 (fr) 2007-02-08

Family

ID=37708893

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2006/003072 WO2007015632A1 (fr) 2005-08-04 2006-08-04 Inhibiteur d’atm et d’atr

Country Status (1)

Country Link
WO (1) WO2007015632A1 (fr)

Cited By (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010071837A1 (fr) * 2008-12-19 2010-06-24 Vertex Pharmaceuticals Incorporated Dérivés pyrazines utiles en tant qu'inhibiteurs d'atr kinase
WO2011143399A1 (fr) * 2010-05-12 2011-11-17 Vertex Pharmaceuticals Incorporated Composés utiles en tant qu'inhibiteurs de l'atr kinase
US8410112B2 (en) 2008-11-10 2013-04-02 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
JP2013530939A (ja) * 2010-05-14 2013-08-01 チャイニーズ・ピーエルエイ・ゼネラル・ホスピタル 尿素化合物及びアポトーシスを阻害するためのその使用
US8623869B2 (en) 2010-06-23 2014-01-07 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US8765751B2 (en) 2011-09-30 2014-07-01 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US8822469B2 (en) 2011-06-22 2014-09-02 Vertex Pharmaceuticals Incorporated Pyrrolo[2,3-B]pyrazines useful as inhibitors of ATR kinase
US8841337B2 (en) 2011-11-09 2014-09-23 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US8841450B2 (en) 2011-11-09 2014-09-23 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US8841449B2 (en) 2011-11-09 2014-09-23 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US8846686B2 (en) 2011-09-30 2014-09-30 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US8846918B2 (en) 2011-11-09 2014-09-30 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US8846917B2 (en) 2011-11-09 2014-09-30 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US8853217B2 (en) 2011-09-30 2014-10-07 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US8877759B2 (en) 2011-04-05 2014-11-04 Vertex Pharnaceuticals Incorporated Aminopyrazines as ATR kinase inhibitors
US8912198B2 (en) 2012-10-16 2014-12-16 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US8962631B2 (en) 2010-05-12 2015-02-24 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9035053B2 (en) 2011-09-30 2015-05-19 Vertex Pharmaceuticals Incorporated Processes for making compounds useful as inhibitors of ATR kinase
US9062008B2 (en) 2010-05-12 2015-06-23 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
WO2015090209A1 (fr) * 2013-12-20 2015-06-25 中国人民解放军军事医学科学院毒物药物研究所 Nouveau composé d'urée, son procédé de production et son application
WO2015108303A1 (fr) * 2014-01-15 2015-07-23 주식회사 노바셀테크놀로지 Composition pharmaceutique destinée au traitement du diabète
US9096602B2 (en) 2011-06-22 2015-08-04 Vertex Pharmaceuticals Incorporated Substituted pyrrolo[2,3-B]pyrazines as ATR kinase inhibitors
US9096584B2 (en) 2010-05-12 2015-08-04 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9309250B2 (en) 2011-06-22 2016-04-12 Vertex Pharmaceuticals Incorporated Substituted pyrrolo[2,3-b]pyrazines as ATR kinase inhibitors
US9334244B2 (en) 2010-05-12 2016-05-10 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9340546B2 (en) 2012-12-07 2016-05-17 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9630956B2 (en) 2010-05-12 2017-04-25 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
WO2017014480A3 (fr) * 2015-07-17 2017-05-11 (주)티앤케이바이오이노베이션 Composition pour atténuer les rides de la peau et pour traiter les maladies inflammatoires endommageant la peau, contenant comme principe actif un inhibiteur de la sénescence cellulaire
KR101737051B1 (ko) 2015-07-22 2017-05-22 (주)노바셀테크놀로지 당뇨병 치료용 약학적 조성물
US9663519B2 (en) 2013-03-15 2017-05-30 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9670215B2 (en) 2014-06-05 2017-06-06 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
WO2017157825A1 (fr) 2016-03-15 2017-09-21 F. Hoffmann-La Roche Ag Combinaisons d'inhibiteurs de lsd1 pour leur utilisation dans le traitement des tumeurs solides
US9791456B2 (en) 2012-10-04 2017-10-17 Vertex Pharmaceuticals Incorporated Method for measuring ATR inhibition mediated increases in DNA damage
WO2018232317A1 (fr) * 2017-06-16 2018-12-20 University Of Utah Research Foundation Méthodes et compositions pour le traitement ou la prévention de symptômes de galactosémie classique
US10160760B2 (en) 2013-12-06 2018-12-25 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US10478430B2 (en) 2012-04-05 2019-11-19 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase and combination therapies thereof
US10813929B2 (en) 2011-09-30 2020-10-27 Vertex Pharmaceuticals Incorporated Treating cancer with ATR inhibitors
US11028076B2 (en) 2016-01-11 2021-06-08 Celator Pharmaceuticals, Inc. Inhibiting ataxia telangiectasia and Rad3-related protein (ATR)
US11179394B2 (en) 2014-06-17 2021-11-23 Vertex Pharmaceuticals Incorporated Method for treating cancer using a combination of Chk1 and ATR inhibitors
WO2022078480A1 (fr) 2020-10-16 2022-04-21 上海迪诺医药科技有限公司 Dérivé trihétérocyclique, ainsi que composition pharmaceutique et application de celui-ci
US11464774B2 (en) 2015-09-30 2022-10-11 Vertex Pharmaceuticals Incorporated Method for treating cancer using a combination of DNA damaging agents and ATR inhibitors

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001016357A2 (fr) * 1999-08-30 2001-03-08 K.U. Leuven Research & Development Nouvelle cible pour des agents antiparasitaires et inhibiteurs de ladite cible
WO2002095361A2 (fr) * 2001-05-22 2002-11-28 President And Fellows Of Harvard College Identification d'agents anti-protozoaires
US6555561B2 (en) * 1998-12-09 2003-04-29 Wyeth Diaminopyridine-containing thiourea inhibitors of herpes viruses
US6645968B2 (en) * 1999-08-03 2003-11-11 Abbott Laboratories Potassium channel openers

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6555561B2 (en) * 1998-12-09 2003-04-29 Wyeth Diaminopyridine-containing thiourea inhibitors of herpes viruses
US6645968B2 (en) * 1999-08-03 2003-11-11 Abbott Laboratories Potassium channel openers
WO2001016357A2 (fr) * 1999-08-30 2001-03-08 K.U. Leuven Research & Development Nouvelle cible pour des agents antiparasitaires et inhibiteurs de ladite cible
WO2002095361A2 (fr) * 2001-05-22 2002-11-28 President And Fellows Of Harvard College Identification d'agents anti-protozoaires

Cited By (82)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8410112B2 (en) 2008-11-10 2013-04-02 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
CN106496210B (zh) * 2008-12-19 2020-06-09 沃泰克斯药物股份有限公司 用作atr激酶抑制剂的化合物
AU2016222396B2 (en) * 2008-12-19 2018-04-05 Vertex Pharmaceuticals Incorporated Pyrazine derivatives useful as inhibitors of ATR kinase
CN106496209B (zh) * 2008-12-19 2020-06-30 沃泰克斯药物股份有限公司 用作atr激酶抑制剂的化合物
EP3354650A1 (fr) * 2008-12-19 2018-08-01 Vertex Pharmaceuticals Incorporated Composés utiles en tant qu'inhibiteurs de kinase d'atr
US10961232B2 (en) 2008-12-19 2021-03-30 Vertex Pharmaceuticals Incorporated Substituted pyrazines as ATR kinase inhibitors
KR101958632B1 (ko) 2008-12-19 2019-03-15 버텍스 파마슈티칼스 인코포레이티드 Ａｔｒ 키나제의 억제제로서 유용한 피라진 유도체
WO2010071837A1 (fr) * 2008-12-19 2010-06-24 Vertex Pharmaceuticals Incorporated Dérivés pyrazines utiles en tant qu'inhibiteurs d'atr kinase
US10479784B2 (en) 2008-12-19 2019-11-19 Vertex Pharmaceuticals Incorporated Substituted pyrazin-2-amines as inhibitors of ATR kinase
US8841308B2 (en) 2008-12-19 2014-09-23 Vertex Pharmaceuticals Incorporated Pyrazin-2-amines useful as inhibitors of ATR kinase
KR20170081739A (ko) * 2008-12-19 2017-07-12 버텍스 파마슈티칼스 인코포레이티드 Ａｔｒ 키나제의 억제제로서 유용한 피라진 유도체
US9701674B2 (en) 2008-12-19 2017-07-11 Vertex Pharmaceuticals Incorporated Substituted pyrazines as ATR kinase inhibitors
CN106518856A (zh) * 2008-12-19 2017-03-22 沃泰克斯药物股份有限公司 用作atr激酶抑制剂的化合物
CN106518856B (zh) * 2008-12-19 2020-04-28 沃泰克斯药物股份有限公司 用作atr激酶抑制剂的化合物
US9365557B2 (en) 2008-12-19 2016-06-14 Vertex Pharmaceuticals Incorporated Substituted pyrazin-2-amines as inhibitors of ATR kinase
AU2009327357B2 (en) * 2008-12-19 2016-06-16 Vertex Pharmaceuticals Incorporated Pyrazine derivatives useful as inhibitors of ATR kinase
JP2012512906A (ja) * 2008-12-19 2012-06-07 バーテックス ファーマシューティカルズ インコーポレイテッド Ａｔｒキナーゼのインヒビターとして有用なピラジン誘導体
KR101755216B1 (ko) 2008-12-19 2017-07-07 버텍스 파마슈티칼스 인코포레이티드 Ａｔｒ 키나제의 억제제로서 유용한 피라진 유도체
RU2604066C2 (ru) * 2008-12-19 2016-12-10 Вертекс Фармасьютикалз Инкорпорейтед Производные пиразина, используемые в качестве ингибиторов киназы atr
AU2009327357C1 (en) * 2008-12-19 2017-02-02 Vertex Pharmaceuticals Incorporated Pyrazine derivatives useful as inhibitors of ATR kinase
CN106496209A (zh) * 2008-12-19 2017-03-15 沃泰克斯药物股份有限公司 用作atr激酶抑制剂的化合物
CN106496210A (zh) * 2008-12-19 2017-03-15 沃泰克斯药物股份有限公司 用作atr激酶抑制剂的化合物
EP4059932A1 (fr) * 2008-12-19 2022-09-21 Vertex Pharmaceuticals Incorporated Composés utiles en tant qu'inhibiteurs de kinase d'atr
US9062008B2 (en) 2010-05-12 2015-06-23 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US8969356B2 (en) 2010-05-12 2015-03-03 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9096584B2 (en) 2010-05-12 2015-08-04 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US8962631B2 (en) 2010-05-12 2015-02-24 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
WO2011143399A1 (fr) * 2010-05-12 2011-11-17 Vertex Pharmaceuticals Incorporated Composés utiles en tant qu'inhibiteurs de l'atr kinase
US9334244B2 (en) 2010-05-12 2016-05-10 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9630956B2 (en) 2010-05-12 2017-04-25 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9260384B2 (en) 2010-05-14 2016-02-16 Chinese Pla General Hospital Urea compounds and use thereof for inhibiting apoptosis
JP2013530939A (ja) * 2010-05-14 2013-08-01 チャイニーズ・ピーエルエイ・ゼネラル・ホスピタル 尿素化合物及びアポトーシスを阻害するためのその使用
US8623869B2 (en) 2010-06-23 2014-01-07 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US8877759B2 (en) 2011-04-05 2014-11-04 Vertex Pharnaceuticals Incorporated Aminopyrazines as ATR kinase inhibitors
US9096602B2 (en) 2011-06-22 2015-08-04 Vertex Pharmaceuticals Incorporated Substituted pyrrolo[2,3-B]pyrazines as ATR kinase inhibitors
US8822469B2 (en) 2011-06-22 2014-09-02 Vertex Pharmaceuticals Incorporated Pyrrolo[2,3-B]pyrazines useful as inhibitors of ATR kinase
US9309250B2 (en) 2011-06-22 2016-04-12 Vertex Pharmaceuticals Incorporated Substituted pyrrolo[2,3-b]pyrazines as ATR kinase inhibitors
US9035053B2 (en) 2011-09-30 2015-05-19 Vertex Pharmaceuticals Incorporated Processes for making compounds useful as inhibitors of ATR kinase
US10208027B2 (en) 2011-09-30 2019-02-19 Vertex Pharmaceuticals Incorporated Processes for preparing ATR inhibitors
US10822331B2 (en) 2011-09-30 2020-11-03 Vertex Pharmaceuticals Incorporated Processes for preparing ATR inhibitors
US10813929B2 (en) 2011-09-30 2020-10-27 Vertex Pharmaceuticals Incorporated Treating cancer with ATR inhibitors
US8853217B2 (en) 2011-09-30 2014-10-07 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9862709B2 (en) 2011-09-30 2018-01-09 Vertex Pharmaceuticals Incorporated Processes for making compounds useful as inhibitors of ATR kinase
US8765751B2 (en) 2011-09-30 2014-07-01 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US8846686B2 (en) 2011-09-30 2014-09-30 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US8846917B2 (en) 2011-11-09 2014-09-30 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US8841450B2 (en) 2011-11-09 2014-09-23 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US8841337B2 (en) 2011-11-09 2014-09-23 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US8841449B2 (en) 2011-11-09 2014-09-23 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US8846918B2 (en) 2011-11-09 2014-09-30 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US10478430B2 (en) 2012-04-05 2019-11-19 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase and combination therapies thereof
US11110086B2 (en) 2012-04-05 2021-09-07 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase and combination therapies thereof
US9791456B2 (en) 2012-10-04 2017-10-17 Vertex Pharmaceuticals Incorporated Method for measuring ATR inhibition mediated increases in DNA damage
US8912198B2 (en) 2012-10-16 2014-12-16 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US10392391B2 (en) 2012-12-07 2019-08-27 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9340546B2 (en) 2012-12-07 2016-05-17 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US10787452B2 (en) 2012-12-07 2020-09-29 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9650381B2 (en) 2012-12-07 2017-05-16 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US11117900B2 (en) 2012-12-07 2021-09-14 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US11370798B2 (en) 2012-12-07 2022-06-28 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9718827B2 (en) 2012-12-07 2017-08-01 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9663519B2 (en) 2013-03-15 2017-05-30 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US10815239B2 (en) 2013-12-06 2020-10-27 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US11485739B2 (en) 2013-12-06 2022-11-01 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US10160760B2 (en) 2013-12-06 2018-12-25 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9718770B2 (en) 2013-12-20 2017-08-01 Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China Substituted thioureas as heat shock protein 70 inhibitors
WO2015090209A1 (fr) * 2013-12-20 2015-06-25 中国人民解放军军事医学科学院毒物药物研究所 Nouveau composé d'urée, son procédé de production et son application
CN105814018A (zh) * 2013-12-20 2016-07-27 中国人民解放军军事医学科学院毒物药物研究所 新型脲类化合物、制备方法及其用途
WO2015108303A1 (fr) * 2014-01-15 2015-07-23 주식회사 노바셀테크놀로지 Composition pharmaceutique destinée au traitement du diabète
US10800781B2 (en) 2014-06-05 2020-10-13 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US10093676B2 (en) 2014-06-05 2018-10-09 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9670215B2 (en) 2014-06-05 2017-06-06 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US11179394B2 (en) 2014-06-17 2021-11-23 Vertex Pharmaceuticals Incorporated Method for treating cancer using a combination of Chk1 and ATR inhibitors
WO2017014480A3 (fr) * 2015-07-17 2017-05-11 (주)티앤케이바이오이노베이션 Composition pour atténuer les rides de la peau et pour traiter les maladies inflammatoires endommageant la peau, contenant comme principe actif un inhibiteur de la sénescence cellulaire
KR101737051B1 (ko) 2015-07-22 2017-05-22 (주)노바셀테크놀로지 당뇨병 치료용 약학적 조성물
US11464774B2 (en) 2015-09-30 2022-10-11 Vertex Pharmaceuticals Incorporated Method for treating cancer using a combination of DNA damaging agents and ATR inhibitors
US11028076B2 (en) 2016-01-11 2021-06-08 Celator Pharmaceuticals, Inc. Inhibiting ataxia telangiectasia and Rad3-related protein (ATR)
US11787781B2 (en) 2016-01-11 2023-10-17 Celator Pharmaceuticals, Inc. Inhibiting ataxia telangiectasia and RAD3-related protein (ATR)
US10265279B2 (en) 2016-03-15 2019-04-23 Oryzon Genomics, S.A. Combinations of LSD1 inhibitors for use in the treatment of solid tumors
WO2017157825A1 (fr) 2016-03-15 2017-09-21 F. Hoffmann-La Roche Ag Combinaisons d'inhibiteurs de lsd1 pour leur utilisation dans le traitement des tumeurs solides
WO2018232317A1 (fr) * 2017-06-16 2018-12-20 University Of Utah Research Foundation Méthodes et compositions pour le traitement ou la prévention de symptômes de galactosémie classique
WO2022078480A1 (fr) 2020-10-16 2022-04-21 上海迪诺医药科技有限公司 Dérivé trihétérocyclique, ainsi que composition pharmaceutique et application de celui-ci

Similar Documents

Publication Publication Date Title
WO2007015632A1 (fr) Inhibiteur d’atm et d’atr
CA2656202C (fr) Traitement de maladies neurodegeneratives par l'inhibition de hsp90
AU2007245625B2 (en) N- ( 2-thiazolyl) -amide derivatives as GSK-3 inhibitors
US8518968B2 (en) Hydrazone and diacyl hydrazine compounds and methods of use
US7531320B2 (en) Modulation of β-catenin/TCF-activated transcription
US7514406B2 (en) Methods for inhibiting deacetylase activity
Long et al. Structure–activity relationship studies of salubrinal lead to its active biotinylated derivative
US20080269144A1 (en) Synthesis of Inhibitors of P90Rsk
Song et al. Discovery of bazedoxifene analogues targeting glycoprotein 130
US10308663B2 (en) Inhibitors of PTP4A3 for the treatment of cancer
US11306100B2 (en) Spirooxindole compounds as GSK3B inhibitors and process for preparation thereof
KR100792587B1 (ko) 유레아 화합물을 유효성분으로 함유하는 포유동물세포의노화방지제
US7049468B2 (en) Modulators of Rho C activity
US11512073B2 (en) Benzimidazole derivatives, pharmaceutical composition comprising the same, and use thereof
US20210353631A1 (en) 1,4-Benzoxazines for the Treatment of Cancers and Other Neurodegenerative Diseases
KR20230116005A (ko) Cdc7 억제제로 사용되는 염 형태 및 이의 결정 형태
US6800634B2 (en) Modulators of Rho C activity
KR100792583B1 (ko) 유레아 화합물을 유효성분으로 함유하는 화학적 암치료제의 감작제
KR101373912B1 (ko) Ｓｈｐ－2의 활성을 특이적으로 저해하는 조성물 및 이의 제조방법
KR100392468B1 (ko) 사이클린 의존 키나아제의 저해제로서 유용한3-히드록시크로멘-4-온 유도체
KR100396739B1 (ko) 2' 또는 3' 위치가 치환된 신남알데하이드계 화합물, 이의 제조 방법 및 이를 포함하는 약학 조성물
Debnath et al. Synthesis, biological evaluation, in silico docking and virtual ADME studies of novel isatin analogs as promising antimicrobial agents
AU2017200078B2 (en) Treatment of neurodegenerative diseases through inhibition of Hsp90
US20090247520A1 (en) INHIBITORS OF ANTIGEN RECEPTOR-INDUCED NF-kappa B ACTIVATION
US20190382392A1 (en) Novel furazan-3-carboxylic acid derivatives and use thereof in treatment of cancer

Legal Events

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

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 06769326

Country of ref document: EP

Kind code of ref document: A1