WO2007095812A1 - Composés triazine [1,3,5] substitués, procédés de préparation et utilisations de ceux-ci - Google Patents

Composés triazine [1,3,5] substitués, procédés de préparation et utilisations de ceux-ci Download PDF

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Publication number
WO2007095812A1
WO2007095812A1 PCT/CN2006/003428 CN2006003428W WO2007095812A1 WO 2007095812 A1 WO2007095812 A1 WO 2007095812A1 CN 2006003428 W CN2006003428 W CN 2006003428W WO 2007095812 A1 WO2007095812 A1 WO 2007095812A1
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substituted
triazine
diamine
phenyl
piperazin
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PCT/CN2006/003428
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English (en)
Chinese (zh)
Inventor
Hong Liu
Hualiang Jiang
Xu Shen
Jian Ding
Xingzu Zhu
Liping Lin
Mingfang Zheng
Mingyue Zheng
Yu Zhou
Xinquan Ji
Haibin Luo
Xiaomin Luo
Jianhua Shen
Kaixian Chen
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Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences
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Priority claimed from CN 200610057786 external-priority patent/CN1970552A/zh
Application filed by Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences filed Critical Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences
Publication of WO2007095812A1 publication Critical patent/WO2007095812A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
    • C07D251/54—Three nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to the field of medicinal chemistry and pharmacotherapeutics, and in particular to substituted [1,3,5]triazine compounds and preparation methods thereof and Applications, and pharmaceutical compositions comprising the substituted [1,3,5]triazine compounds.
  • BACKGROUND OF THE INVENTION The pathogenesis of many diseases involves the involvement of inflammatory mediators, some inflammatory diseases (such as rheumatoid arthritis, rheumatic fever, osteoarthritis), asthma, chronic obstructive pulmonary disease, trauma, burns, endotoxin shock, Alzheimer's disease, even heart failure, has the involvement of inflammatory mediators.
  • AA acetylcholine
  • PGs prostaglandins
  • LTs leukotrienes
  • the first metabolic pathway includes the following series of reactions: Membrane phospholipids via phospholipase
  • a 2 (PLA 2 ) produces free arachidonic acid (AA), and AA is converted to prostaglandin G 2 (PG 2 ) by the action of cyclooxygenase (COX-1 and COX- 2 ), and its peroxidase activity proceeds.
  • the product is converted to prostaglandin H 2 (PGH 2 ), a tissue-specific isozyme that metabolizes PGH 2 to other forms of prostaglandins or thromboxane A 2 (TxA 2 ).
  • AA is metabolized to leukotrienes (LTs) by the action of 5-lipoxygenase.
  • glucocorticoid anti-inflammatory drugs are often used in the early stage, but long-term use of these drugs can cause complications such as adrenal cortical function decline.
  • phenylbutazone was used clinically, and the concept of non-steroidal anti-inflammatory drugs (SAID) was first proposed internationally.
  • NSAIDs with anti-inflammatory and analgesic effects emerged, such as indomethacin and ibuprofen, which are still widely used in clinical practice.
  • COX-2 is expressed in normal tissues and is a constituent protein of normal cells; and COX-2 is an induced form of enzymes, mainly in inflammatory cells, such as endothelial cells, macrophages, and synovial fibroblasts after tissue damage. Expression in dendritic cells, chondrocytes and osteoblasts.
  • COX-2 and COX-1 have similar active binding sites for AA or NSAID; COX-2 can be induced by various factors in inflammatory tissues, and its level will rise sharply at 8-10 times, causing inflammation sites. Increased levels of PGE 2 , PGI 2 , and PGEi promote inflammatory responses and tissue damage.
  • JR Vane et al. pointed out that the effective therapeutic effect of NSAID on inflammation stems from its inhibition of COX-2, which is attributed to inhibition of COX-1. Therefore, since the 1990s, the search for COX-2 selective inhibitors has become an important way to discover new anti-inflammatory drugs. However, COX-2 selective inhibitors have a cardiovascular safety hazard.
  • Classical NSAIDs such as aspirin, indomethacin, and diclofenac are COX selective inhibitors, generally do not contribute to 5-LOX metabolism, they not only affect the synthesis of PGs that have protective effects on the gastric mucosa, but also Single inhibition of COX-2 leads to increased metabolic activity of LOX, causing imbalance of AA metabolism, promoting the synthesis of LTs, thereby promoting leukocyte chemotaxis and increasing vascular permeability. Place In order to propose the need for a comprehensive anti-inflammatory drug with a toxic side effect, COX and 5-LOX should be simultaneously inhibited.
  • COX-2/5-LOX dual inhibitors to achieve synergistic anti-inflammatory purposes is the focus of research on anti-inflammatory drugs for medical workers at home and abroad in recent years.
  • NS AIDs especially selective COX-2 inhibitors (such as celecoxib), act synergistically with other chemotherapeutic drugs to treat rectal cancer.
  • selective 5-LOX inhibitors and COX-2/5-LOX dual inhibitors have been much less studied in rectal cancer.
  • COX-2 selective inhibitors or COX-2/5-LOX dual inhibitors as antitumor drugs and/or their auxiliary drugs will be more and more affected in the field of cancer treatment, especially the prevention and treatment of colorectal cancer.
  • Computer-Aided Drug Design has become an important method and tool for modern drug research and development, adding computer-aided drug design, especially computer-aided combination chemical library design, to the cycle of new drug research. It can shorten the cycle of new drug research, save research and development costs, and improve the hit rate of new drug screening.
  • Computer-Aided Drug Design is a new technology in medicinal chemistry and synthetic chemistry in recent years, which can rapidly generate a large number of molecular structures for high-throughput screening.
  • Structural biology also The original basic research entered the applied research stage.
  • Some substituted [1,3,5] triazine compounds have certain inhibitory activities on human intestinal cancer cells, HT-29 and HCT-116, and similar structures of morpholine triazines have been found to Intestinal cancer cell lines HT-29 and HCT-116 have strong inhibition Activity, a few compounds IC 5G up to nM grade; in addition, morpholine triazines also showed better epidermal growth factor receptor (EGFR) inhibitory activity; compounds that received cell chromosome teratogenicity test performed well, no teratogenicity Thus, the present invention has been completed.
  • EGFR epidermal growth factor receptor
  • the present invention provides a substituted [1,3,5]triazine compound which has a dual inhibitor action and an EGFR enzyme inhibitor action on COX-2/5-LOX.
  • a further object of the present invention is to provide a process for the preparation of the above compounds.
  • a further object of the invention is to provide the use of the above compounds.
  • a further object of the present invention is to provide a pharmaceutical composition comprising the above compound.
  • a further object of the invention is to provide the use of the above pharmaceutical compositions.
  • the present invention provides a substituted [1,3,5]triazine compound having a structure represented by the formula (I), a pharmaceutically acceptable salt thereof, and a solvate or hydrate thereof:
  • R 2 , R 3 and R 4 are each independently hydrogen, Q-C 8 linear or branched hydrocarbon, substituted or unsubstituted aryl, aralkyl, C r C 4 alkaryl, aroyl,
  • the aryl group is selected from the group consisting of phenyl, naphthyl and biphenyl, and the substituents are from 1 to 4 selected from the group consisting of halogen, d-linear or branched hydrocarbon, an aryl group, a nitro group, an amino group, a hydroxyl group, a hydroxy group, Group of trifluoromethyl, trifluoromethoxy, carboxy, C!-alkoxy, fluorenyl, C r C 4 alkylthio, C r C 4 alkane, C r C 4 alkoxycarbonyl, sulfonyl Group; and
  • Re and R 7 are each independently selected from the group consisting of hydrogen, halogen, d-linear or branched hydrocarbon, cyano, nitro, amino, hydroxy, hydroxydecyl, trifluoromethyl, trifluoromethoxy, carboxy, dC 4 alkoxy, mercapto, - C 4 alkylthio, -C 4 acyl, and sulfonyl groups group;
  • Y is CH 2, 0, S, or the RN, wherein R is hydrogen, - C a linear or branched hydrocarbon group, a hydroxyl group, an OC4 hydroxyalkyl group, a group, a C, a C 4 alkylcarbonyl group, a C!-alkoxycarbonyl group, a decanoyl group;
  • m, n are each independently 0, 1 , 2 Or 3, or R 5 is selected from the group consisting of a hydroxyl group, an amino group, a substituted amino group, a Ci-
  • R 8 is hydrogen, hydroxy, aryl, heteroaryl ring, heteroalicyclic or C 2 -C 6 alkenyl.
  • the compound according to the invention may be: ⁇ , ⁇ '-diphenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine;-Chloro-p-sulfonyl-p-phenyl-indole,-phenyl-[1,3,5]-triazine-2,4-diamine; ⁇ -p-sulfonylphenyl-indole, -phenyl-6- (piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; ⁇ -o-methylsulfonylphenyl-indole,-phenyl-6-(piperazin-1- Substituted)-[1,3,5]-triazine -2,4-diamine; N-m-methanesulfonylphenyl-N,-phenyl-6-(piperazin-1-substituted)
  • the present invention also provides a process for the preparation of the above compound, which comprises the steps of: (1) the compound of the formula (II) in an alkaline solvent at 0-50. Reacts with a substituted amine at C temperature, lsT, N
  • R x is hydrogen, halogen, hydroxy, decyl, -C 4 hydrocarbylamine, or C r C 4 aminoalkyl
  • R y and R z are respectively hydrogen, halogen, -C4 aminoalkyl, or dC 4 halogenated a hydrocarbon group to give a compound of the formula (III):
  • R 2 , R x and R y are the same as defined in the formulae (1) and (II);
  • the compound of the formula (III) is used in an alkaline solvent at 20-100.
  • the compound represented by the formula (IV) is obtained by reacting with a substituted amine, a substituted arylamine, a substituted arylalkylamine, an alcohol or a thiol at a C temperature:
  • a salt formation reaction or a solvate or a hydrate is formed by a conventional method in the art as needed.
  • the method according to the present invention wherein the alkaline solvent described in the step (1) and the step (2) is an alkali solution prepared by using an inert solvent selected from the group consisting of pyridine, triethylamine, 4-diamine.
  • the base is one or more selected from the group consisting of pyridine, triethylamine, 4-di
  • DMAP guanamine pyridine
  • the substituted [1,3,5]triazine compound or a pharmaceutically acceptable salt thereof or a solvate or hydrate thereof according to the present invention can be used as a cyclooxygenase inhibitor, a 5-lipoxygenase inhibitor, Double inhibitors of cyclooxygenase and 5-lipoxygenase, and EGFR enzyme inhibitors.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the formula (I) as an active ingredient, the pharmaceutical composition comprising a therapeutically effective amount of the substitution as shown in the formula (I) [1, 3, 5]
  • the pharmaceutically acceptable carrier includes an ion exchanger, aluminum oxide, aluminum stearate, lecithin, serum protein, a buffer substance such as phosphate, glycerin, sorbic acid, potassium sorbate, a partial glyceride of a saturated plant fatty acid.
  • the above pharmaceutical composition can be used for the prevention and/or treatment of inflammatory diseases, and for the prevention and/or treatment and/or adjuvant treatment of tumor diseases, particularly intestinal cancer.
  • composition of the compound of the present invention can be administered in any of the following ways: oral, spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration, such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal , intraventricular, intrasternal and intracranial injections or Enter, or use an explant reservoir.
  • oral or intramuscular injection, intraperitoneal or intravenous administration is preferred for the treatment of inflammation.
  • the dosage and method of use of the compounds of the invention depends on a number of factors, including the age, weight, sex, natural health, nutritional status of the compound, the strength of the compound, the time of administration, the rate of metabolism, the severity of the condition, and Subjective judgment of the doctor.
  • the recommended dose is 5 mg to 10 mg/kg daily, and the maintenance dose can be reduced to 3 mg/kg per day.
  • Gelling agent 0.25g / grain. Injection 0.25g/5ml.
  • Oral solution 5g / 50ml.
  • the substituted [1,3,5]triazine compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof at the COX-2 and 5-LOX enzyme levels and the overall animal level (carrageenan-induced A series of models of mouse foot swelling, carrageenan-induced rat foot swelling, diterpene-induced mouse auricular inflammation model, rat adjuvant arthritis primary, secondary lesion model) In the study, both showed significant anti-inflammatory activity. It has good safety to Ames test and mouse micronucleus test, and has no toxic side effects on gastrointestinal tract. It is biocompatible for in vivo treatment.
  • the pharmaceutical composition of the present invention can be used for the prevention and/or treatment of inflammatory diseases and has a good therapeutic effect.
  • DRAWINGS Figure 1 is a graph showing the binding kinetics of substituted [1,3,5]triazine compounds with cyclooxygenase (COX-1 and COX-2).
  • Figures 1-1 and 1-2, Figures 1-3 and 1-4, Figures 1-5 and 1-6, Figures 1-7 and 1-8, and Figures 1-9 and 1-10 represent positive compound, compound B, compound B52, B58 compound, and K D values of compound 61 in combination with COX-2 and COX-1's.
  • Figure 1 shows the binding kinetics of the substituted [1,3,5]triazine compound to 5-lipoxygenase (5-LOX).
  • the instrument used is BIACORE3000 and the analysis software is Kinetic Analysis in the Application Wizard.
  • FIG. 2-1 and 2-2 show the K D of the positive compound ETYA and the compound B62 combined with 5-LOX, respectively.
  • Figure 3 is a photograph of the section of the gastrointestinal side effects test report of each group.
  • Figure 3-1 shows the negative control
  • Figure 3-2 shows indomethacin
  • Figure 3-3 shows the compound Celecoxib
  • Figure 3-4 shows compound B62
  • Figure 3-5 shows compound B68.
  • the solution is thoroughly mixed, then plated, dried, and activated at 100 ⁇ 110 oC for 1 ⁇ 2 hours, then stored in a desiccator for UV light ( ⁇ : 254 nm); column chromatography uses 200 mesh to 300 mesh column Analysis of silica gel (produced by Qingdao Ocean Chemical Plant).
  • Example 1 Synthesis of aniline monosubstituted tripolychloroazine (4,6-dichlorophenyl-[1,3,5]-triazin-2-amine) In a 50 ml eggplant-shaped flask, 4.726 g of tripolychloro The oxazine was dissolved in 20 ml of 1,4-dioxane, and an aqueous solution of 2.337 ml of aniline and 1.03 g of NaOH was slowly added dropwise with stirring, and the reaction was stirred for 6 hours; water was added thereto, and the mixture was filtered, washed with water, and evaporated. . Mp 136-138 0 C.
  • Example 2 Synthesis of aniline disubstituted tripolychloroazine (6-chloro-N,N,-diphenyl-[1,3,5]-triazine-2,4-diamine) in a 50 ml eggplant bottle 0.421 g of chloralazine was dissolved in 5 ml of 1,4-dioxane, and 0.42 ml of an aqueous solution of aniline and 0.2 g of NaOH was added thereto with stirring at room temperature; and the reaction was stirred at 20 to 100 ° C overnight. Filtration and washing with water to give a white solid (yield). Mp l97 °C.
  • LREI (m/z): 426 (M+), 384, 370, 358 (100), 299, 144, 119, 92, 77, 56.
  • HREI Calculated value (calculated as C 19 H 22 N 8 0 2 S) 426.1597; found 426.1584.
  • 6-chlorophenyl-N,-p-trifluoromethoxyphenyl-[1,3,5]-triazine-2,4-diamine instead of 6-chloro-N-p-sulfonylphenyl -N,-Phenyl-[1,3,5]-triazine-2,4-diamine, morpholine, m.p. Mp 178-180 0 C.
  • 6-chloro-p-fluorophenyl-N 6-chloro-p-fluorophenyl-N,-p-trifluoromethoxyphenyl-[1,3,5]-triazine-2,4-diamine instead of 6-chloro-p-sulfonylphenyl- N,-Phenyl-[1,3,5]-triazine-2,4-diamine, morpholine, m.p. Mp 198-199. C.
  • N,-dibenzyl-6-chloro-[1,3,5]-tri-2,4-diamine in place of 6-chloro-p-methylsulfonylphenyl-N,-phenyl-[1 3,5]-triazine-2,4-diamine, morpholine, m.p. Mp 134 ⁇ 136 0 C o ! HNMR (300Mz, CDCI3, TMS) ⁇ (ppm): 7.23-7.3 l(m, 10H); 5.17(Br-s, 2H); 4.57(d 5 J 5.7 Hz, 4H); 3.66-3.73 (m, 8H). LREI (m/z): 376 ( ⁇ ), 73 (100).
  • Example 69 Synthesis of 2-chloro-4,6-di(morpholine-4-substituted)-[1,3,5]-triazine (Compound C188) Operation was carried out as in Example 2 except that morpholine was used in place of aniline. , the title compound was obtained as a white solid. Mp 175. C. ! HNMR (300Mz, CDC1 3, TMS) ⁇ (ppm): 3.70 ⁇ 3.78 (m, 16H).
  • Example 76 2-[4-(4,6-Diphenylamino-[1,3,5]-triazine-2-substituted) piperazin-1-substituted]ethanol (Compound C193) was synthesized except 6- Chloro-N,N,-diphenyl-[1,3,5]-triazine-2,4-diamine instead of 6-chloro-N-p-methylsulfonylphenyl-N,-phenyl-[1 , 3,5]-triazine- 2,4-diamine, 2-(piperazin-1-substituted)ethanol, in place of piperazine.
  • Example 79 N-(3,4-Dimethoxy)phenyl-6-(morpholin-4-substituted)-N,-phenyl-[1,3,5-triazine-2,4-di synthesis of the amine (compound C73) except that 6-chloro -N- (3,4- two Yue yloxy) -N-phenyl, - phenyl - [1,3,5] - triazine - 2, 4 - two The amine was replaced by an amine instead of 6-chloro-N-p-sulfonylphenyl-N,-phenyl-[1,3,5]-triazine-2,4-diamine, morpholine instead of piperazine.
  • Example 81 N-p-Methylthiophenyl-6-(morpholin-4-substituted)-N,-p-p-phenyl-[1,3,5]-triazine-2,4-diamine (compound)
  • the synthesis of C19) is in addition to 6-chloro-N-p-methylthiophenyl-N,-p-phenylene-[1,3,5]-triazine-2,4-diamine instead of 6-chloro-N.
  • - sulfonylphenyl-N,-phenyl-[1,3,5]-triazine-2,4-diamine, morpholine in place of piperazine was operated as in Example 5 to give the title compound as white powder. Solid.
  • Example 82 6-(morpholine-4-substituted)-N-phenyl-N,-(pyridin-4-substituted)-[1,3,5]-triazine-2,4-di Synthesis of the amine (compound C20) except 6-chloro-N-phenyl-N,-(pyridin-4-substituted)-[1,3,5]-triazine-2,4-diamine instead of 6-chloro
  • the title compound was obtained as a powdery solid, m. m. m. m. . . .
  • Real horse method Binding experiments of compounds with cyclooxygenase (COX-1 and COX-2) were carried out at room temperature using BIACORE 3000 (BIACORE AB, Uppsala, Sweden) (Amersham).
  • the chip and buffer solution were as follows: CM5 chip, EDC, NHS, ethanolamine, HBS-EP (purchased from BIACORE AB (Uppsala, Sweden)) 0 Procedure: Dissolve the piperazine triazine compound in DMSO and dilute with HBS-EP To the corresponding concentrations (0.625, 1.25, 2.5, 5.0 and 10.0 ⁇ ), the DMSO content was 0.4%.
  • the purified protein is attached to the chip by amino coupling.
  • the dynamics of the BIACORE 3000 kinetic analysis Wizard was used for data collection and analysis.
  • Test compounds were prepared by the Shanghai Institute of Drug Research Center for Drug Discovery and Design (DDDC) synthesis laboratory.
  • P-day compounds Celecoxib and ETYA eicosa-5, 8, 11-tetraynoic acid
  • 5-LOX enzyme DDDC biological laboratory eukaryotic system expression preparation.
  • Test Example 2 Inhibition of neutrophil release of leukotriene B4 in isolated rat Experimental reagent: Type II glycogen (Sigma-Aldrich Co, 10K154), indomethacin
  • Test animals SD rats, clean grade, male or female, weighing 200 ⁇ 20 g (commercially available).
  • Experimental equipment Thermometer, Multiskan spectrum, constant temperature water bath, etc.
  • Experimental methods and data analysis :
  • the collected cells were adjusted to 5 X 10 6 /mL with Hanks balanced salt buffer, and dispensed in 0.5 mL, 37.
  • C was incubated for 10 min, and L-cysteine (10 mM), indomethacin (1 mg/L) and test compounds at various concentrations (50, 5, 0.5 ⁇ ), 37 were added in sequence. After incubating for 30 min, the calcium ionophore A23187 (5 ⁇ ), 37 was added. C continued to incubate for 30 min, immediately after 4.
  • C centrifuge at 14000 r/min for 5 minutes, and store the supernatant at -70. C spare.
  • the final concentration of the solvent in the reaction system is ⁇ 0.21%.
  • the cell extract was diluted with the buffer of the commercial EIA kit, and then added to the 96-well microtiter plate. Two replicate wells were set for each sample, and the test was repeated twice, and incubated at 4 ° C overnight. The force was applied to the developer, and the absorbance was measured at 412 nm after 90 minutes in the dark, and the content of LTB 4 in the sample was measured according to the standard curve established by the standard.
  • the concentration of LTB 4 in each treated sample is represented by mean SEM.
  • the formula for calculating the inhibition rate of neutrophils to 1 ⁇ 3 ⁇ 4 4 is:
  • Inhibition rate (solvent tube concentration - sample tube concentration) / solvent tube concentration xlOO%
  • the IC 5 G value of LTB 4 released from rat neutrophils (5 x 10 6 /ml) stimulated by calcium ionophore A23187 was further tested by the test method for compounds B62, B68, C72 and the positive control Zileuton. , 1.52 ⁇ , 31.12 ⁇ , 11.78 ⁇ and 0.86 ⁇ , respectively.
  • mice male healthy mice weighing 22-25 g.
  • mice Male healthy mice weighing 22-25 g were randomly divided into groups of 10 each. Negative (CMC sodium, sodium carboxymethylcellulose aqueous solution) and positive ( p -indomethacin, 5 mg/kg) control group were set. The test drug was dissolved in the CMC solution, and the amount of the drug was 50 mg/kg. Dosing (intraperitoneal injection or gavage) 30 minutes before the onset of inflammation. The mice were then fixed in a rat rack, the hind limbs were straightened, and 0.2% carrageenan (Can'ageenin) 20 ⁇ l was injected into the ankle of the mice with a 4 gauge syringe.
  • CMC sodium, sodium carboxymethylcellulose aqueous solution Positive (p -indomethacin, 5 mg/kg) control group were set.
  • the test drug was dissolved in the CMC solution, and the amount of the drug was 50 mg/kg. Dosing (intraperitoneal injection or gavage) 30 minutes before the onset of inflammation
  • mice were sacrificed 4 hours after the inflammation, and the left and right hind limbs were cut along the joints of the hind limbs.
  • the differences between the drug-administered group, the control group and the positive drug control group were compared.
  • the mean value, SD, P value and percent inhibition were determined by statistical analysis. (See Table 3).
  • Test Example 4 Anti-inflammatory drug screening pharmacodynamics experiment (II) Experimental animals: male Wister rats, weighing 150-180 g; male mice, weighing 26-30 g. Experimental methods and observation indicators: Experiment 1. Rat foot and carrageenan-induced swelling method. Male Wister rats weighing 150-180 g were randomly divided into groups of 10 rats each. A negative (CMC aqueous solution) and a positive (indomethacin 3.6 mg/kg) control group were set. The test drug was dissolved in the CMC solution, and the amount of each of the 15 compounds was 15 mg/kg. Administered by intragastric administration 60 minutes before the onset of inflammation.
  • mice Male SD rats weighing 180 ⁇ 20 g were randomly divided into groups of 10 rats each. A negative (CMC aqueous solution) and a positive (indomethacin 0.3 mg/kg) control group were set.
  • the test drug is dissolved in CMC solution, B62 large dose 30mg/kg, medium dose lOmg/kg, low dose 3mg/kg, B68 large dose 100mg/kg, medium dose 50mg/kg, low dose 25mg/kg. It was administered by intragastric administration 60 minutes before the onset of inflammation.
  • FCA Freund's complete adjuvant
  • Negative control 10 7.30 ⁇ 2.18 Positive control 10 3.90 ⁇ 1.02 46.58% Small dose (lmg/kg) 10 7.70 ⁇ 1.27 -5.48% Small dose (3mg/kg) 10 4.80 ⁇ 2.26* 34.25% Medium dose 4.05 ⁇ 2.72** 44.52 %
  • mice male SD rats
  • Test drugs indomethacin, Celecoxib, B62, B68
  • Experimental methods and observation indicators Male Sprague-Dawley rats weighing 200-220 g were randomly selected, with 10 rats in each group. Negative and positive control groups were set. Administered by gavage, once a day for 4 consecutive days, during which no control was given to food or water. The animals were sacrificed 24 hours after the last administration, and the stomach and small intestine were taken out. The mouth was made in the longitudinal direction of the small bend. The stomach and small intestine were washed with running water, and the stomach was opened with the index finger to check the stomach damage and record. One or more lesions (bleeding point, erosion, ulceration, or perforation) are considered positive.
  • Test Example 6 Compound B and B62 bacterial back mutation test
  • TA97 9-aminoacridine TA98 manufactured by Sigma Chemical Company lnc: 2-Nitroflucrene TA100 manufactured by Aldrich Chemical Company lnc: Methyl methanesulfonate TA102 manufactured by Sigma Chemical Company lnc: Mitomycin C TA1535 manufactured by KYOWAHAKKO KOGYO CO.LTD.: Sodium azide by Merck produce
  • TA97, TA98, TA100 2-aminofluorene produced by Sigma Chemical Company lnc
  • TA1535 Cyclophosphamide for injection is produced by Shanghai Hualian Pharmaceutical Co., Ltd.: Salmonella typhimurium histidine auxotrophic mutant.
  • the identification includes: histidine auxotrophy, lipopolysaccharide barrier defect (rfa), UV repair defect O uvrB, except TA102), and R-factor.
  • TA97 TA98, and TA100 have a ⁇ plasmid with ampicillin resistance, TA102 with ⁇ and pAQl plasmids, and ampicillin and tetracycline. Those who have passed the above-mentioned identification, the spontaneous mutation number meets the required strain, and the bacteria are added as a mutagenized experimental strain.
  • Toxicity prediction of 5 strains Toxicity evaluation criteria: First, it was observed that the bacterial growth background was toxic if it became thinner or disappeared than the negative control group. Second, the average number of regressions per count compared to the negative control is toxic if the return variable is significantly reduced or dose dependent.
  • Aroclor 1254-induced rat liver S 9 was prepared with about 200 grams of body weight Sprague -Dawley rats, intraperitoneal injection of Aroclor 1254 (Dainippon Pharmaceutical Co., Ltd.) 500 mg / kg, the fifth day of sacrifice, the liver was removed and rinsed under sterile conditions Immediately irrigate with 4 C 0.15M KCl, then add 0.15M KC1 4 C homogenate at a ratio of 3 ml/g wet weight, centrifuge at 9000 xg, and take the supernatant as s 9 and store in liquid nitrogen. The frozen s 9 was slowly melted before the experiment, using the newly prepared S 9 Mix each time.
  • Pre-culture is used to measure the mutagenic effect of drug metabolism activation.
  • the composition of the test top layer is:
  • the measured drug solution, bacterial solution, and S 9 mixture were subjected to 25 minutes and 35 minutes. After shaking and incubating, the experiment was carried out according to the standard plate infiltration method. Each dose group was set to 3 i, and each strain was counted in the absence of drug metabolism or by the drug-based activation system (-S 9 or +S 9 ). The number of colonies was X-SD. Effective experiment acceptance criteria:
  • a positive (negative) control must fall within or close to the historical background data of the laboratory or be consistent with the literature.
  • Results evaluation criteria 1. The return mutation value of all test groups was 2 times lower than that of the negative control group and was negative. The recovery mutation value of any test group was 4 times greater than that of the negative control group, and the pretest and the conclusion of the main test were consistent, and it was judged as positive.
  • test compounds B and B62 meet the guidelines.
  • the negative and positive recovery mutation rates are consistent with the background data of the laboratory, and there is no pollution in the experiment. This experiment is valid for evaluation.
  • Compound B is - S 9 test system a concentration of 50 ( ⁇ g / i, of the TA97, TA98, TA102 strain inhibitory effect when a dose of 50, 5, 0.5, when 0.05 ⁇ ⁇ / dish without suppression. There was no mutagenic effect and the results are shown in Table 13.
  • the compound ⁇ has a bacteriostatic effect on TA97, TA98, TA100, TA102, TA1535 and 5 strains in 5000 and 1000 g/Jni in the +S 9 experimental system.
  • the dose is 500 ⁇ ⁇ /, it has a bacteriostatic effect on ⁇ 97, ⁇ 98, ⁇ 102, and 3 strains. 50, 5 ⁇ no bacteriostatic or mutagenic effect.
  • Compound B62 has a bacteriostatic effect on TA97, TA98, TA 100, TA102, and 4 strains in the -S 9 and + S 9 experimental systems at a concentration of 500 ( ⁇ g / dish).
  • 500 ⁇ g / dish
  • TA1535 strain dose 5000, 1000, 500, 50, 5 g / no inhibition of the growth of bacterial colonies, no mutagenic effects. See Table 15 and Table 16 .
  • B and B62 have no mutagenicity and no mutagenicity under the conditions of this experiment.
  • Table 13 B without the action of the S 9 metabolic system i show change test for Salmonella typhimurium
  • TA97, TA98, TA100 2-aminofluorene (50 g/i)
  • TA102 1 ,8-dihydroxyanthraquinone (50 g/ ⁇ 111 )
  • TA 1535 cyclophosphamide 200 ⁇ g/ m ⁇ Table 14.B via the S 9 metabolic system
  • the dosage of colonies and reverting colonies of Salmonella typhimurium is ⁇ ⁇ / ⁇ ⁇ 97 ⁇ 98 TA100 TA102 TA1535
  • TA102 Muitomycin C (0.5 g/ ⁇ )
  • TA100 2-aminofluorene (50 ⁇ )
  • TA102 1 ,8-dihydroxyanthraquinone (50 g/dish)
  • TA1535 Cyclophosphamide 200
  • Solvent control 0.5% sodium carboxymethyl cellulose.
  • mice 90 ICR mice (?45, $45) were provided by the Shanghai Real-face Animal Center of the Chinese Academy of Sciences, and the certificate of conformity: Laboratory Animal Quality Certificate No. SCXK (Shanghai) 2002-0010.
  • the mice were adaptively reared in the animal room of Shanghai Institute of Materia Medica, Chinese Academy of Sciences for three days.
  • the body weight was 18 ⁇ 22 grams, and they were randomly divided into groups according to their body weight. 14 samples (?7, ⁇ 7) were used as one dose group.
  • the control group consisted of 10 rats (? 5, $ 5).
  • the feed was purchased from Sino-British joint venture Sipper - Bikai Experimental Animals Co., Ltd. Free water intake, feeding temperature is 23 ⁇ 2.
  • C humidity is 60 ⁇ 10%.
  • the selected doses are 2000, 1000, 500, 250, 125 mg/kg 5 dose groups, each group Fourteen, male and female, were administered intragastrically once a day for two consecutive days, and the death of the animals was recorded. As a result, the mice did not die after administration of the high dose of 2000 mg/kg (Table 1).
  • the mouse LD50 is greater than 2000 mg/kg.
  • the selected doses are 2000, 1000, 500, 250, 125 mg/kg 5 dose groups, each group
  • the mouse LD50 is approximately 1000 mg/kg.
  • the highest dose of B62 was selected as 2000 mg/kg, and another 1000, 500 mg/kg dose group, one solvent control group and one positive control group.
  • the highest dose of B68 was selected as 500 mg/kg, and another 250 doses of 250 and 125 mg/kg were administered.
  • Agent distance 0.5 times the highest dose.
  • Dosing volume 0.2 ml/10 g. .
  • the test substance can be sampled two or more times at a time point between 12 and 24 hours after the last administration.
  • Mice were intragastrically administered B62: 2000, 1000, 500 mg/kg/day and the negative control group for 2 days; B68: 500, 250, 125 mg/kg/day and the negative control group were administered continuously for 2 days.
  • the positive control group was intraperitoneally injected (60 mg/kg) and sampled 24 hours after the last administration.
  • the bilateral femurs were removed, washed with inactivated calf serum, centrifuged, dispersed cell smears, air-dried and fixed by Giemsa staining and microscopic examination.
  • mice must meet the criteria in accordance with the guidelines.
  • the highest dose must be greater than 1/2 LD 50 if there is no serious physical illness or severe bone marrow toxicity.
  • micronucleus rate of mouse bone marrow polychromatic erythrocytes caused by positive and negative controls must fall within or close to the historical background data of this laboratory or be consistent with the literature.
  • the PCE/NCE ratio in the drug-administered group was in the appropriate range and there was no obvious bone marrow cytotoxicity.
  • the nuclear rate of the test substance in all dose groups is similar to the micronucleus rate of the negative control group, or not more than 2 times, it can be judged as negative. 2. Any increase in the nucleus rate of the nucleus induced by the test substance was 4 times higher than that of the negative control group.
  • the statistical difference is significant, it should be compared with the historical negative control data 95% upper limit, if it is less than still can be judged as negative. When it is greater than the dose relationship, the micronucleus rate increases with the dose, and the statistical difference is judged to be positive.
  • mice were intragastrically administered with B62 for 2 consecutive days.
  • the micronucleus rate of the 2000, 1000, and 500 mg/kg/day dose groups was similar to the negative control group at 24 h after the last administration. There was no significant difference.
  • Table 17 The mice were intragastrically administered with B62 for 2 consecutive days.
  • the micronucleus rate of the 2000, 1000, and 500 mg/kg/day dose groups was similar to the negative control group at 24 h after the last administration. There was no significant difference.
  • Table 17 The mice were intragastrically administered with B62 for 2 consecutive days.
  • the micronucleus rate of the 2000, 1000, and 500 mg/kg/day dose groups was similar to the negative control group at 24 h after the last administration. There was no significant difference.
  • mice were intragastrically administered B68 twice, at the time point of 24 h after the last administration.
  • the micronucleus rate of the three dose groups of 125, 250, and 500 mg/kg/day was similar to that of the negative control group, and there was no significant difference.
  • the results are shown in Table 18.
  • Test Example 8 Compound ⁇ Inducing Chromosomal Aberration in Cultured Mammalian Cells The purpose of the experiment was to observe the chromosomal aberration and to observe whether the compound ⁇ caused damage to the chromosome of CHL cells in vitro. Preparation method:
  • Cyclophosphamide (Shanghai Twelfth Pharmaceutical Product) as a metabolic activation system
  • CHL cells serve as sputum cells for the effect of B on chromosomes.
  • CHL cells were introduced by the Shanghai Institute of Drug Control and the mycoplasma test was negative.
  • RPMI1640 (GIBCO product) cells plus 15% calf serum were placed at 37. C, 5% C0 2 incubator for monolayer cell culture.
  • the IC 5Q value was measured to be 1.82 ⁇ ⁇ / ⁇ , which was diluted as the highest dose, and the final concentration was 1.82, 0.91, 0.455 g/ml.
  • the metabolic activation experiment was continued for 6 h after changing to fresh medium for 24 h.
  • the non-metabolic activation group and the metabolic activation group were harvested for 24 hours to prepare specimens.
  • Inoculate CHL cells each containing approximately 1xlO 5 37 cells.
  • the test substance solution was added so that the final concentration in the culture solution was 1.82, 0.91, and 0.455 g/ml.
  • Each of the three dose groups and the negative control group the positive control group.
  • Non-metabolic activation was performed at 24 h to collect cells.
  • 0.1 ml of S 9 mixture was added, and three dose groups and a negative and positive control group were also measured. After 6 hours of culture, the fresh medium was changed, and the cells were further cultured until 24 hours to collect the cells.
  • Color body preparation
  • Colchicine 0.2 g/ml was added 3 h before the cells were collected, then trypsinized, centrifuged, and the supernatant was decanted. After being treated with 0.075M KC1 hypotonic solution, it was fixed in sterol: water acetic acid (3:1) fixative. Take a few drops of the drop on the clean glass, Giemsa staining, microscopic examination.
  • the highest concentration should meet the requirements of China's guiding principles. This will achieve the highest concentration allowed by solubility or toxicity.
  • the negative control value should be within the 99% confidence limit of the previous negative control background data in this laboratory.
  • Negative Negative if all the test groups have a distortion rate below 4.9%. Positive: If the test group has at least one group that meets the positive criteria and is dose dependent or repeatable, it can be judged as a positive result. If the result is not certain, the test should be repeated. Experimental result
  • (+S 9 ) group The final concentration of compound B was 1.82, 0.91, 0.455 g/ml and the chromosome aberration rates of the negative control group were: 2%, 4% and 3%, respectively. In the experiment, the chromosomal aberration rate of the high, medium and low dose groups was ⁇ 5%, which was negative. The positive drug cyclophosphamide 24h induced distortion rate was 13% positive (see Table 19). Table 19 Chromosomal aberration rate of Compound B in CHL cells (+S 9 group)
  • Distortion type b-fracture; p-polyploid; t-triple body; q-four-body; a-deficient; e-exchange; f-fragmentation; d-double centromere; g-crack; r- Ring; 1-lost; tr-translocation
  • a cell chromosome aberration occurs in the n-type, and the distortion rate is calculated as 1 time.
  • test substance was formulated into a corresponding concentration with 0.5% CMC-Na, so that the dose groups of each dose group were equal in volume and were ready for use.
  • mice 60 Kunming mice ($30, ⁇ 30) were provided by the Shanghai Experimental Animal Center of the Chinese Academy of Sciences, and the certificate of compliance was: No. 005 of the Chinese Medicine. Adapted to feeding in a week. Feed purchase free Shanghai Shilin Technology Co., Ltd. Free water intake, feeding temperature 23 soil 2 . C. Body weight: The body weight is 18-22 grams when administered. Gender: Male and female. Number of animals per group: Randomly grouped by body weight, one dose per 10 groups during the experiment. Dosage
  • Dose setting According to the preliminary experimental results, the highest dose was determined to be 4082 mg/kg, which was decreased by 0.7, which was 6 dose groups of 686, 980, 1400, 2000, 2857, 4082 mg/kg; 0.7; each animal receives volume: gavage volume: 0.2 ml / g body weight,
  • mice were administered intragastrically.
  • mice were randomly divided into 6 groups according to body weight, with 10 mice in each group. The body weight distribution of each group was similar. After the administration, all aspects of the animal's reaction were observed, and the dead animals were dissected. Check the internal organs and record the number of deaths per day.
  • Toxic reaction Observe the appearance, behavior, eating, feces, etc. of the mice, and the dead animals are subjected to autopsy. At the end of the experiment on the 15th day, the surviving mice were dissected, and the lesions of the heart, lung, liver, spleen, kidney and other organs were examined visually.
  • mice After 30 minutes of oral administration, the mice showed decreased activity, paroxysmal tremor, gait, and began to die about 1 hour after the drug. Most deaths occur within 4 hours. The toxicity is proportional to the dose. There was no obvious abnormality in the visual examination of the organs of the mice. Surviving mice were dissected on the 15th day, and no obvious lesions were seen in the internal organs. The deaths are listed in the table below.
  • Test object logarithm animal death animal mortality probability single LD50 and dose number rate 95% confidence limit (mg/kg) (x) (only) (only) (%) (Y) (mg/kg)
  • the LD 5Q is calculated by the Bliss method as follows:
  • mice After 30 minutes of oral administration, the mice showed decreased activity, paroxysmal tremor, gait, and began to die about 1 hour after the drug. Most deaths occur within 4 hours.
  • the toxicity is proportional to the dose.
  • the survivors were all dissected on the 15th day, and no obvious lesions were seen in the viscera. Mortality was determined by Bliss method to obtain LD 5 Q: 2315 mg/kg;
  • the 95% confidence limit is 1790 ⁇ 2993 mg/kg.
  • Test Example 10 Cell level test compound EGFR inhibitory activity
  • Cells SPCA1 human lung cancer cells; stimulating factor: hEGF: human epidermal growth factor (R and D Catalog: 236-EG); medium: DMEM F12 1 : l (GIBCO); calf serum (Hangzhou Sijiqing); DMSO; MTT ( 5g / l ) Real ⁇ r method: MTT
  • the inhibition rate of proliferation in the negative control group was 0, and the other concentrations were compared with it, and the inhibition rate was calculated as follows: (Control group OD value - experimental group OD value) / control group OD value X 100% III.
  • this experiment established a hEGF stimulation group for the crude screening drug. Fine screening was performed to identify new and strong tyrosine kinase inhibitors that inhibited cell proliferation and had the lowest concentration.
  • the cells were seeded in a 96-well plate with DMEM/F12 medium containing 10% serum, and the cell density was 1 10 4 /well;
  • the drug was diluted as above with serum-free DMEM/F 12 containing 10 ng/ml hEGF as a solvent, and the negative control was serum-free DMEM/F12 containing 10 ng/ml hEGF.
  • the preparation method of the substituted [1,3,5]triazine compound of the present invention has the advantages of mild reaction conditions, abundant raw materials, easy handling and post-treatment.
  • Substituted [1,3,5]triazine compounds of the present invention in computer virtual screening and binding experiments of cyclooxygenase and 5-lipoxygenase (COX-1, COX-2 and 5-LOX) and pharmacological tests in animals These compounds were confirmed to be dual inhibitors of cyclooxygenase and 5-lipoxygenase (COX-2 and 5-LOX), which have good preventive and therapeutic effects on experimental inflammation, and Ames experiments and mice.
  • the micronucleus test has better safety and the side effects on the gastrointestinal tract are significantly weakened.
  • the compound of the present invention has low toxicity. It has good safety to Ames test and mouse micronucleus test, and has no toxic side effect on gastrointestinal tract.
  • the substituted [1,3,5]triazine of the present invention The compound showed good inhibitory activity in an in vitro screening test of anti-tumor cell line HCT-116 human intestinal cancer and HT-29 human intestinal cancer, and many compounds appeared as potent inhibitors.
  • the compound of the present invention is in EGFR cells. ⁇ -level inhibition was also shown in the test. Activity t due to jtb, the present invention. J m
  • the compounds of the invention are also useful in the prevention and/or treatment and/or adjuvant treatment of neoplastic diseases.

Abstract

L'invention concerne des composés triazine [1,3,5] substitués de formule suivante (I), leurs sels et solvates ou hydrates acceptables sur le plan pharmaceutique, des compositions pharmaceutiques les contenant et leurs utilisations. Les compositions de l'invention peuvent être utilisées pour la prévention et/ou le traitement de maladies inflammatoires, et produisent un effet bénéfique. Lesdits composés triazine [1,3,5] substitués ou leurs sels acceptables sur le plan pharmaceutique ont présenté une activité inhibitrice de l'enzyme EGFR et une activité antitumorale remarquables lors d'une série de tests sélectifs du niveau de l'enzyme EGFR et du niveau de cellule tumorale (HT-29 et HCT-116 humaines). Les compositions de l'invention peuvent ainsi être utilisées pour la prévention et/ou le traitement et/ou le traitement d'appoint de maladies tumorales.
PCT/CN2006/003428 2006-02-27 2006-12-15 Composés triazine [1,3,5] substitués, procédés de préparation et utilisations de ceux-ci WO2007095812A1 (fr)

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CN 200610057786 CN1970552A (zh) 2005-11-25 2006-02-27 取代[1,3,5]三嗪类化合物及其制备方法和应用
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009008371A1 (fr) 2007-07-06 2009-01-15 Astellas Pharma Inc. Composé de di(arylamino)aryle
US20160159771A1 (en) * 2013-07-11 2016-06-09 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US10028961B2 (en) 2013-07-11 2018-07-24 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
JP2019087533A (ja) * 2017-11-03 2019-06-06 長興材料工業股▲ふん▼有限公司Ｅｔｅｒｎａｌ Ｍａｔｅｒｉａｌｓ Ｃｏ．，Ｌｔｄ． 電解質組成物及びその応用
US10376510B2 (en) 2013-07-11 2019-08-13 Agios Pharmaceuticals, Inc. 2,4- or 4,6-diaminopyrimidine compounds as IDH2 mutants inhibitors for the treatment of cancer
US11230535B2 (en) 2015-12-24 2022-01-25 The Regents Of The University Of California CFTR regulators and methods of use thereof
US11839616B2 (en) 2017-08-24 2023-12-12 The Regents Of The University Of California Ocular pharmaceutical compositions
US11844758B2 (en) 2013-07-11 2023-12-19 Servier Pharmaceuticals Llc Therapeutically active compounds and their methods of use

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4269832A (en) * 1978-04-12 1981-05-26 American Cyanamid Company Method of treating arthritic disease
EP0263213A1 (fr) * 1986-10-09 1988-04-13 The Upjohn Company Stéroides aminés en C20 à C26
CN1625410A (zh) * 2002-02-05 2005-06-08 山之内制药株式会社 2,4,6－三氨基－1,3,5－三嗪衍生物
WO2005058875A1 (fr) * 2003-12-19 2005-06-30 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences Composes de piperazine triazine, leur obtention, et preparations pharmaceutiques les contenant

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4269832A (en) * 1978-04-12 1981-05-26 American Cyanamid Company Method of treating arthritic disease
EP0263213A1 (fr) * 1986-10-09 1988-04-13 The Upjohn Company Stéroides aminés en C20 à C26
CN1625410A (zh) * 2002-02-05 2005-06-08 山之内制药株式会社 2,4,6－三氨基－1,3,5－三嗪衍生物
WO2005058875A1 (fr) * 2003-12-19 2005-06-30 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences Composes de piperazine triazine, leur obtention, et preparations pharmaceutiques les contenant

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DHAINAUT A. ET AL.: "New triazine derivatives as potent modulators of multidrug resistance", JOURNAL OF MEDICINAL CHEMISTRY, vol. 35, no. 13, 1992, pages 2481 - 2496 *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009008371A1 (fr) 2007-07-06 2009-01-15 Astellas Pharma Inc. Composé de di(arylamino)aryle
US8318702B2 (en) 2007-07-06 2012-11-27 Astellas Pharma Inc. Di(arylamino)aryl compounds
JP5233996B2 (ja) * 2007-07-06 2013-07-10 アステラス製薬株式会社 ジ（アリールアミノ）アリール化合物
US10172864B2 (en) 2013-07-11 2019-01-08 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US10017495B2 (en) * 2013-07-11 2018-07-10 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US10028961B2 (en) 2013-07-11 2018-07-24 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US20160159771A1 (en) * 2013-07-11 2016-06-09 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US10376510B2 (en) 2013-07-11 2019-08-13 Agios Pharmaceuticals, Inc. 2,4- or 4,6-diaminopyrimidine compounds as IDH2 mutants inhibitors for the treatment of cancer
US10946023B2 (en) 2013-07-11 2021-03-16 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US11844758B2 (en) 2013-07-11 2023-12-19 Servier Pharmaceuticals Llc Therapeutically active compounds and their methods of use
US11230535B2 (en) 2015-12-24 2022-01-25 The Regents Of The University Of California CFTR regulators and methods of use thereof
US11839616B2 (en) 2017-08-24 2023-12-12 The Regents Of The University Of California Ocular pharmaceutical compositions
JP2019087533A (ja) * 2017-11-03 2019-06-06 長興材料工業股▲ふん▼有限公司Ｅｔｅｒｎａｌ Ｍａｔｅｒｉａｌｓ Ｃｏ．，Ｌｔｄ． 電解質組成物及びその応用
US11011780B2 (en) 2017-11-03 2021-05-18 Eternal Materials Co., Ltd. Electrolyte composition and application thereof

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