WO2013177983A1 - 吡咯[2,1-f][1,2,4]并三嗪类化合物,其制备方法及用途 - Google Patents
吡咯[2,1-f][1,2,4]并三嗪类化合物,其制备方法及用途 Download PDFInfo
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- HSGFMCUURBGHNS-UHFFFAOYSA-N CC(C)(C)NC(Nc(cc1)ccc1-c(nc1N2CCOCC2)n[n]2c1cc(CN(C)C)c2)=O Chemical compound CC(C)(C)NC(Nc(cc1)ccc1-c(nc1N2CCOCC2)n[n]2c1cc(CN(C)C)c2)=O HSGFMCUURBGHNS-UHFFFAOYSA-N 0.000 description 1
- 0 CC1OC(*)C(*)N(C)C1* Chemical compound CC1OC(*)C(*)N(C)C1* 0.000 description 1
- VDDZOFLILWFGHD-UHFFFAOYSA-N CCOC(Nc(cc1C(F)(F)F)ncc1-c(nc1N2CCOCC2)n[n]2c1cc(CN(CC1)CCN1S(C)(=O)=O)c2)=O Chemical compound CCOC(Nc(cc1C(F)(F)F)ncc1-c(nc1N2CCOCC2)n[n]2c1cc(CN(CC1)CCN1S(C)(=O)=O)c2)=O VDDZOFLILWFGHD-UHFFFAOYSA-N 0.000 description 1
- FOIDPPLSSVLNES-UHFFFAOYSA-N CN(C)C(CC1)CCN1C(c(cc1)ccc1NC(Nc(cc1)ccc1-c(nc1N2CCOCC2)n[n]2c1cc(CN(CC1)CCN1S(C)(=O)=O)c2)=O)=O Chemical compound CN(C)C(CC1)CCN1C(c(cc1)ccc1NC(Nc(cc1)ccc1-c(nc1N2CCOCC2)n[n]2c1cc(CN(CC1)CCN1S(C)(=O)=O)c2)=O)=O FOIDPPLSSVLNES-UHFFFAOYSA-N 0.000 description 1
- ZYFATRHDAAUULD-UHFFFAOYSA-N CN(C)Cc(cc12)c[n]1nc(-c(cc1)ccc1NC(NCc(cc1)ccc1F)=O)nc2N1CCOCC1 Chemical compound CN(C)Cc(cc12)c[n]1nc(-c(cc1)ccc1NC(NCc(cc1)ccc1F)=O)nc2N1CCOCC1 ZYFATRHDAAUULD-UHFFFAOYSA-N 0.000 description 1
- RKAZYMCDWJZSEK-UHFFFAOYSA-N CN(C)Cc(cc12)c[n]1nc(-c(cc1)ccc1NC(Nc(cc1)ccc1Cl)=O)nc2N1CCOCC1 Chemical compound CN(C)Cc(cc12)c[n]1nc(-c(cc1)ccc1NC(Nc(cc1)ccc1Cl)=O)nc2N1CCOCC1 RKAZYMCDWJZSEK-UHFFFAOYSA-N 0.000 description 1
- MHZCYDLNEXSOOY-UHFFFAOYSA-N CN(C)Cc(cc12)c[n]1nc(-c(cc1)ccc1NC(Nc1cc(Cl)ccc1)=O)nc2N1CCOCC1 Chemical compound CN(C)Cc(cc12)c[n]1nc(-c(cc1)ccc1NC(Nc1cc(Cl)ccc1)=O)nc2N1CCOCC1 MHZCYDLNEXSOOY-UHFFFAOYSA-N 0.000 description 1
- WVONEEHHJNIBEG-UHFFFAOYSA-N CN(C)Cc(cc12)c[n]1nc(-c1cccc(CO)c1)nc2N1CCOCC1 Chemical compound CN(C)Cc(cc12)c[n]1nc(-c1cccc(CO)c1)nc2N1CCOCC1 WVONEEHHJNIBEG-UHFFFAOYSA-N 0.000 description 1
- RKRBEIYGNSOYBF-UHFFFAOYSA-N CS(N(CC1)CCN1C(c(cc12)c[n]1nc(-c(c(C(F)(F)F)c1)cnc1N)nc2N1CCOCC1)=O)(=O)=O Chemical compound CS(N(CC1)CCN1C(c(cc12)c[n]1nc(-c(c(C(F)(F)F)c1)cnc1N)nc2N1CCOCC1)=O)(=O)=O RKRBEIYGNSOYBF-UHFFFAOYSA-N 0.000 description 1
- CDQYLEPGXQYJFJ-UHFFFAOYSA-N CS(N1CCN(Cc(cc23)c[n]2nc(-c(cc2)ccc2N)nc3N2CC(C3)OCC3C2)CC1)(=O)=O Chemical compound CS(N1CCN(Cc(cc23)c[n]2nc(-c(cc2)ccc2N)nc3N2CC(C3)OCC3C2)CC1)(=O)=O CDQYLEPGXQYJFJ-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Definitions
- the present invention relates to pyrrole [2, 1 - ][1 , 2, represented by the general formula I, and the like. 4] a triazine derivative, an isomer thereof or a pharmaceutically acceptable salt, ester or hydrate thereof, a process for the preparation thereof and use thereof.
- Compound I represented by Formula I inhibits the phosphatidylinositol 3-kinase (PI3K) signaling pathway and is useful in the preparation of a medicament for the treatment of phosphatidylinositol 3-kinase-related diseases such as cancer.
- PI3K phosphatidylinositol 3-kinase
- PI3K is a lipid-protein dual kinase that phosphorylates the 3-position of the inositol ring in phosphatidylinositol to form phosphatidylinositol-3-phosphate (PIP), phosphatidylinositol-3,4- Diphosphate (PIP2) and phosphatidylinositol-3,4,5-triphosphate (PIP3).
- PIP phosphatidylinositol-3-phosphate
- PIP2 phosphatidylinositol-3,4- Diphosphate
- PIP3 phosphatidylinositol-3,4,5-triphosphate
- PIP, PIP2 and PIP3 serve as important second messengers, with a variety of pleckstrin homology domains, FYVE domains (the first to be found in the FfVE domain containing proteins Fablp, ⁇ , Vaclp and EEA1)
- the letters are named, see references Gaullier, J. ⁇ ; Simonsen, A.; D 'Arrigo, A.; Bremnes, B.; Stenmark, ⁇ , Chem. Phys.
- the PX domain (Phox homology domain) and other phospholipid-binding regions bind and activate proteins to form a signaling cascade that ultimately regulates cell proliferation, differentiation, survival, and migration (see literature Vanhaesebroeck, ⁇ ; Leevers , SJ; Ahmadi, K.; Timms, J.; Katso, .; Driscoll, P. C; Woscholski, .; Parker, PJ; Waterfield, MD, Annu. Rev. Biochem., 2001, 70: 535-602. ) o
- Type I PI3K superfamily is mainly divided into three types: type I, type II and type III PI3K.
- Type I ⁇ 3 ⁇ is by far the most widely studied category.
- the substrate of this class of ⁇ 3 ⁇ is phosphatidylinositol ( ⁇ ), phosphatidylinositol-4-phosphate ( ⁇ ( 4 ) ⁇ ), phosphatidylinositol 4,5-diphosphate ( ⁇ ( 4,5 ) ⁇ 2 ) . It is a heterodimer composed of a catalytic subunit and a regulatory subunit.
- type I ⁇ 3 ⁇ is further divided into two categories, ⁇ 3 ⁇ ⁇ and ⁇ 3 ⁇ IB.
- PI3K IA includes ⁇ 3 ⁇ , ⁇ and ⁇ 3 ⁇ , which are activated by receptor tyrosine kinase; ⁇ 3 ⁇ ⁇ consists only of ⁇ 3 ⁇ , which is activated by G protein-coupled receptor.
- ⁇ and ⁇ ( 4 ) ⁇ is the substrate of type II ⁇ 3 ⁇ .
- Type II ⁇ 3 ⁇ includes PI3KC2a, PI3KC2 and PI3KC2y. They are characterized by a C2 region at the carbon end, suggesting that their activity is regulated by calcium ions.
- the substrate for type III PI3K is only PI. Its activation mechanism is still unknown (see Engelman, JA; Luo, J.; Cantley, L. C, Nat. Rev. Genet, 2006, 7: 606-619).
- PI3K phosphatidylinositol 3-kinase/protein kinase B/mammalian rapamycin target protein (PI3K/Akt/mTOR) signaling pathway
- PTEN phosphatase and tensin homolog deleted on chromosome 10
- the mutation rate PI3K3CA encoding ⁇ ⁇ is more than 30%.
- PI3K protein kinase B kt
- mTOR rapamycin target protein
- TSC2 tumor suppressor gene 2
- the activated mTOR is mainly regulated by ribosome S6 kinase (S6K1, or P70S6K), eukaryotic translation initiation factor 4E (eIF-4E) binding protein 1 (4E-BP1), signal transduction and activator of transcription 3 ( Downstream signaling pathways, such as STAT3), are involved directly or indirectly in translation initiation, transcription, microfilament reorganization, membrane transport, protein degradation, protein kinase C (PKC) pathway, ribosomal protein synthesis, and tRNA synthesis. Regulation of proliferation and growth-related links. Therefore, mTOR is a central regulatory protein for cell growth and proliferation and has become a new anti-tumor drug target.
- Inhibitors of PI3K and the downstream signaling protein mTOR are a promising class of antitumor drugs.
- several PI3K pan-inhibitors have entered clinical research, such as GDC-0941, XL-147, PX-866, etc., but these clinical research drugs can not meet the needs of anti-tumor drug development in terms of species and quantity, but also There are various problems, such as PX-866 originating from Wortmannin, which is difficult to synthesize; the activity of GDC-0941 needs to be improved. Therefore, the discovery and development of a more active and safer target PI3K anti-tumor drug is one of the important areas of anti-tumor drug development in the world.
- the pyrrole [2, 1 - ][1 , 2, 4]-triazine structure is an advantageous structure in medicinal chemistry. Since the dominant structure has been reported as a purine analog (see literature: Hayashi, M.; Araki, A.; Maeba, I., Heterocycles, 1992, 34: 569-574. Patil, SA; Otter, BA; Klein, S., Tetrahedron Lett., 1994, 35: 5339 - 5342.), a growing number of compounds containing this predominant structure It is synthesized and shows a variety of biological activities, such as JAK2 inhibitors (see literature: Weinberg, L..; Albom, MS; Angeles, TS et al, Bioorg. Med. Chem. Lett.
- Pan-Aurora kinase inhibitor Abraham, S.; Hadd, MJ; Tran, L. et al, Bioorg. Med. Chem. Lett. 2011, 21: 5296-5300.
- ⁇ 38 ⁇ mitogen-activated protein kinase ( ⁇ 38 ⁇ ⁇ ) inhibitor Liu, C; Lin, J.; Wrobleski, ST et al, J. Med. Chem.,
- Lymphoma kinase ALK inhibitor (Mesaros, E. R; Thieu, TV; Wells, GJ et al, J. Med. Chem., 2012, 55: 115-125 ⁇ ), Dual inhibitors of VEGFR-2 and FGFR-1 (Cai, Z.-w.; Zhang, Y.; Borzilleri, . M. et al, J. Med. Chem., 2008, 5: 1976 - 1980.), VEGFR -2 inhibitor (Hunt, JT; Mitt, T.; Borzilleri, . et al, J. Med. Chem., 2004, 47: 4054 - 4059), EGFR 1/2 inhibitor (Gavai, AV; Fink, BE;
- 3 is -NH 2 , -NHC(O)NHR justify, -NHC(O)Oêt, -CH 2 OH, -CH 2 S(O) 2 R 12 , -CH 2 OS(O) 2 R 12 or - CH 2 NHS(O) 2 R 12 ;
- R 4 is H or CF 3 ;
- R 5 and R 6 are each independently a C1-C4 fluorenyl group, or a nitrogen atom to which they are bonded together form a saturated heterocyclic ring which is unsubstituted or substituted with a substituent, preferably a pyrrole ring, a piperidine ring or a piperazine ring. Most preferred is a piperazine ring; the substituent is -S(O) 2 R 12;
- R 7 , R 8 , R 9 and R 1() are each independently H or a C1-C3 fluorenyl group, or R 7 and or R 1 () together with the carbon atom to which they are attached form a 5-8 membered saturated ring.
- R 7 and or R 9 and R 1Q together with the carbon atom to which they are attached serve as a bridgehead carbon atom and a morpholine ring to form a bicyclic hybrid bridge ring;
- R 12 and R 15 are each independently a C1-C3 fluorenyl group.
- R 2 is morpholinyl, (5 3-methylmorpholinyl or 8-oxo-3-azabicyclo[3.2.1]octyl-3-yl;
- R 3 is -NH 2 , -NHC(O NHRu, -NHC(O)O n , -CH 2 OH, -CH 2 S(O) 2 Me or -CH 2 NHS(O) 2 Me ;
- R 4 is H or -CF 3
- Rrust is methyl, ethyl, propyl, cyclopropyl, tert-butyl, isobutyl, 4-fluorobenzyl, unsubstituted or substituted by one or more substituents, unsubstituted or by a Or a plurality of substituent-substituted isoxazoles, or a pyridine ring unsubstituted or substituted with one or more substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, methoxy, and B Oxycarbonyl, dimethylaminocarbonyl, 4-methylpiperazine-1-carbonyl, piperidin-1-carbonyl and 4-dimethylaminopiperidine-1-carbonyl.
- the compound represented by the formula I has the following structure:
- Ri ⁇ R 2 and Ri []R 12 are the same as defined above.
- R 1S and Rn are the same or different and are each independently a C1-C4 fluorenyl group, or R 16 and R 17 are bonded to the nitrogen atom to which they are bonded to form 4-methylpiperazinyl, 4-dimethylaminopiperidinyl or piperidine. -1- base.
- the invention provides a compound as shown in Table 1:
- Another object of the present invention is to provide a process for the preparation of a compound of the formula I, which comprises the steps of:
- R 13 is nitro or -CH 2 OAc;
- R 14 is amino or -CH 2 OH;
- a pyrrole derivative 1 is obtained by subjecting an anhydrous N-N-dimethylformamide to a compound 2 obtained by N-amination of a chloramine in the presence of a base;
- the base may be sodium hydride, potassium carbonate or potassium t-butoxide
- the metal Lewis acid may be a monovalent or divalent copper reagent such as cuprous bromide, cuprous chloride, copper acetate monohydrate, copper bromide, anhydrous copper chloride, copper chloride dihydrate, etc., preferably Copper chloride dihydrate, because copper chloride dihydrate is more productive than other copper reagents, post-treatment is easier, the reaction solvent is dimethyl sulfoxide or N, N-dimethylformamide, N, N-dimethyl Acetamide, reaction temperature is 80-150 ° C;
- the chlorination reagent is phosphorus oxychloride or phosphorus pentachloride, and the base used is N,N-dimethylaniline or 4-dimethylaminopyridine (DMAP);
- the amine is dimethylamine or methanesulfonylpiperazine
- the reducing agent is borofluorene tetrahydrofuran or borofluorene dimethyl sulfide
- the compound represented by the formula Ia-If can be produced by the following steps:
- the pyrrole derivative 1 is subjected to N-amination reaction with chloramine in an anhydrous treatment of N,N-dimethylformamide in the presence of a base, and the base may be sodium hydride, potassium carbonate or potassium t-butoxide.
- Compound 2 was not purified, and was directly subjected to aminolysis in a sealed tube with a saturated ammonia methanol solution or a commercially available concentrated aqueous ammonia solution to obtain Compound 3.
- Compound 3 with the corresponding aromatic aldehyde e.g.
- the metal Lewis acid may be a monovalent or divalent copper reagent, such as cuprous bromide, cuprous chloride, copper acetate monohydrate, copper bromide, anhydrous copper chloride, copper chloride dihydrate, etc., dihydrate Compared with other copper reagents, copper chloride has higher yield and easier post-treatment.
- the reaction solvent is dimethyl sulfoxide or N,N-dimethylformamide, N,N-dimethylacetamide, and the reaction temperature is 80. -150 ° C.
- aldehyde 7 was synthesized in three steps. 2-Amino-4-trifluoromethylpyridine (4) is brominated with N-bromosuccinimide in chloroform to give compound 5. After the amino group of the compound 5 is protected with pivaloyl group, the compound 7 is obtained under the conditions of n-butyllithium / N,N-dimethylformamide / anhydrous tetrahydrofuran.
- Compound Ilia is chlorinated with phosphorus oxychloride or phosphorus pentachloride to give product 8, which is reacted with morpholine and an analog of morpholine in tetrahydrofuran to give compound 9.
- Compound 9 is reduced with 5% or 10% palladium on carbon to give compound 10, which is hydrolyzed by ester group under basic conditions to give acid 11.
- Compound 11 is condensed with an amine such as dimethylamine or methanesulfonylpiperazine to give 12.
- Compound 12 is reduced with a reducing agent to give compound 13, and the reducing agent used may be a solution of boron hydride tetrahydrofuran or boron arsenide.
- Compound 19 was subjected to microwave reaction with sodium decylsulfonate at 120 ° C for 30 minutes in N-methylpyrrolidone to obtain Compound Id.
- Compound 19 is first aminolyzed to give compound 20, 20 which is then reacted with decylsulfonyl chloride to give compound Ie.
- Ig Y NH or O
- compound IIIc is chlorinated, it is reacted with morpholine and an analog of morpholine in tetrahydrofuran at room temperature to give compound 22.
- the ester group of compound 22 is hydrolyzed to give product 23, 23 condensed with an amine or a substituted or unsubstituted saturated heterocyclic ring to give 24 .
- Compound 24 is reduced with a solution of borofluorene tetrahydrofuran or a solution of boron dimethyl sulfide to give If.
- the compounds of the invention are effective in inhibiting PI3K kinase activity. These compounds can therefore be used to treat diseases associated with the PI3K pathway, particularly for the treatment of tumors. Accordingly, it is still another object of the present invention to provide a compound represented by Formula I or a physiologically acceptable salt thereof for the preparation of phosphatidyl Use of a drug for inositol 3-kinase and a target protein inhibitor of rapamycin, that is, a drug for treating a phosphatidylinositol 3-kinase-related disease.
- the phosphatidylinositol 3-kinase related diseases include tumors.
- the tumor includes human rhabdomyosarcoma, non-small cell lung cancer, human glioma, prostate cancer, ovarian cancer, liver cancer, colon cancer, breast cancer and the like.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by the general formula I, which may further comprise other ingredients such as a carrier, an excipient and the like.
- the present invention provides a method of treating a phosphatidylinositol 3-kinase associated disease comprising administering a therapeutically effective amount of a compound of formula I.
- BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the effect of 1-33 on the PI3K signaling pathway in human rhabdomyosarcoma Rh30 cells and human glioma U87MG cells.
- Figure 2 shows the growth inhibitory effects of compounds 1-30, 1-33 on subcutaneous xenografts of human glioma U87-MG nude mice.
- BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be further illustrated by the following examples, but these examples are not intended to limit the invention in any way.
- 1H NMR was recorded by Brucher AM-400 and GEMINI-300 NMR, chemical shifts were expressed in ⁇ (ppm); mass spectra were recorded by MAT-95 mass spectrometer; and silica gel was separated from 200-300 mesh.
- the compound pyrrole-1,3-dicarboxylate 1 (5 g, 25.4 mmol, prepared by reference Kamijo, S., Kanazawa, C., and Yamamoto YJ AM. CHEM. SOC. 2005, 127, 9260-9266
- the starting material methyl propiolate, ethyl isocyanate ethyl acetate was purchased from Dari Chemical) dissolved in 25 mL of anhydrous N, N-dimethylformamide, cooled to 0 ° C in an ice bath.
- Dimethylamine hydrochloride (686 mg, 8.4 mmol) was added to 30 mL of anhydrous N,N-dimethylformamide, and potassium carbonate (3.48 g, 25.2 mmol). Then add compound 11a (4.2 mmol), benzotriazole-N, N, N, N,-tetramethylurea hexafluorophosphate (4.77 g, 12.6 mmol), triethylamine (2.9 mL, 21 mmol) ), reacted at room temperature overnight under nitrogen atmosphere. Pour into the water and filter. The filtrate was extracted once with ethyl acetate, dried over anhydrous sodium sulfate, filtered and evaporated.
- the starting material was 4-(dimethylcarbamoyl)benzoic acid according to the general procedure of 13 and the obtained 4-(dimethylcarbamoyl)benzoyl azide was reacted with 13a to give a pale yellow solid. 14 mg, 25.8%) c mp 240 ° C.
- the starting material was 4-(4-methylpiperazinyl-1-carbonyl)benzoic acid according to the general procedure described in 13 to give 4-(4-methylpiperazinyl-1-carbonyl)benzoyl azide.
- the compound was reacted with Compound 13a to give a white solid (9 mg, 15.1%).
- the starting material is 4-(piperidinyl-1-carbonyl)benzoic acid according to the general procedure of 13 and the obtained 4-(piperidinyl-1-carbonyl)benzoyl azide is reacted with compound 13a to give yellow. Solid (11 mg, 18.9%). Mp 184-186 ° C.
- Methyl chloroformate (28.85 mmol) was added to a solution of 1-34 (880 mg, 1.44 mmol) and triethylamine (1.5 g, 14.4 mmol) in chloroform at -40 ° C.
- the crude product was purified by column chromatography using methylene chloride / methanol (60:1). White solid (44.2%). Mp 150-152 ° C.
- the Kinase-Glo® Plus Kinase Luminescence Assay detects the activity of purified kinase quantitatively by detecting the amount of ATP remaining in the solution following the kinase reaction.
- the kinase reaction was performed in a 384-well white plate (Greiner) with 1 test compound or control DMSO and 5 ⁇ L of reaction buffer per well [10 mM Tris-HCl pH 7.5, 50 mM NaCl, 3 mM MgCl 2 , 1 mM DTT (dithiothreitol), 0.05% CHAPS (3-[(3-Cholamidopropyl) dimethylammonio]-l-propanesulfonate, 3-(3-cholaminopropyl)dimethylamino-1-propanesulfonic acid), the reaction The buffer was supplemented with 12 ⁇ M substrate D-mjo-Phosphatidylinositol-4, 5-bisphosphate (phospho
- the kinase reaction was then initiated by the addition of 4 ⁇ L of reaction buffer containing 62.5 ⁇ ⁇ 3 ⁇ or a control without ⁇ . After 1 hour at room temperature, the reaction was stopped by adding 10 Kinase Glo-Plus mixture for 1 hour. Chemiluminescence values were measured using an EnVision 2104 multi-function microplate reader (Perkinelmer).
- Rh30 cells were seeded at 3000 cells/well in a 96-well plate. After adherence, the test compounds were added at a concentration of 10, 3, 1, 0.3, 0.1 ⁇ for 72 hours, then the culture solution was discarded and three were added. Fix with chloroacetic acid, wash with distilled water for five times, dry, add sulforhodamine stain, wash with 5% glacial acetic acid five times, dry, add trishydroxymethylcarbamate buffer, measure OD at 560 nm wavelength Value, calculate the inhibition rate. The experimental results are shown in Table 3. The above experimental results show that the compound of the present invention has a good proliferation inhibitory activity against Rh30 cells, wherein IC- 5 of 1-24, 1-25, 1-28. Even reaching the tens of nanomolar level.
- H30 and U87MG cells were seeded into 12-well plates at 2 ⁇ 10 5 cells/well. After adhering overnight, fresh serum-free medium was added to starve for 24 hours. Different concentrations of the active compounds 1-33 were added for 1 hour. IGF-1 ⁇ After 10 minutes of stimulation, the lysed cells were collected and added to 4xSDS loading buffer [200 mM Tris.Cl (pH 6.8), 400 mM DTT, 8% SDS (sodium dodecyl sulfonate), 0.4% bromophenol blue, 40 % glycerol] boiled for 10 minutes after mixing.
- 4xSDS loading buffer 200 mM Tris.Cl (pH 6.8), 400 mM DTT, 8% SDS (sodium dodecyl sulfonate), 0.4% bromophenol blue, 40 % glycerol
- Tris-glycine running buffer 25 mM Tris, 250 mM glycine, 0.1% SDS
- the protein was transferred from the gel to a nitrocellulose filter by semi-dry method.
- the filter was blocked with a blocking solution containing 5% skim milk powder [5% skim milk powder, 20 mM Tris-HCl (pH 7.2-7.4), 150 mM NaCk 0.1% (v/v) Tween 20] for 2 hours at room temperature in a shaker. Then, a specific primary antibody was added to hybridize overnight at 4 °C.
- Fig. 1 The experimental results (Fig. 1) indicate that 1-33 significantly inhibits the transduction of PI3K signaling pathway in human rhabdomyosarcoma Rh30 cells and human glioma U87MG cells.
- Compounds 1-30 and 1-33 are in a plurality of cell lines such as colon cancer cells C-HCT-116, colon cancer cells C-LOVO, endometrial cancer cells E-RL95-2, Gastric cancer cells G-MKN-45, liver cancer cells L-BEL-7402, and rhabdomyosarcoma cells S-RH30 were equivalent to the positive control GDC0941 (purchased from Shanghai Musk Fragrance Co., Ltd., which was dimethanesulfonate). One order of magnitude, but significantly better on the B-BT474 cell line than the positive control.
- the tumor tissue in the vigorous growth period was cut into 1.5 mm 3 and inoculated subcutaneously in the right axilla of the nude mice under aseptic conditions.
- the diameter of the transplanted tumor was measured with a vernier caliper in a nude mouse subcutaneous xenograft, and the animals were randomly divided into groups after the tumor was grown to 100-200 mm 3 .
- 1-33 mesylate salt was orally administered in 50 mg/kg group and 25 mg/kg group; 1-30 mesylate salt was orally administered in 50 mg/kg group; GDC0941 mesylate salt was orally administered in 50 mg/kg group.
- the solvent control group was given an equal amount of blank solvent and administered orally once a day for three consecutive weeks.
- the diameter of the transplanted tumor was measured twice a week during the entire experiment, and the body weight of the mice was weighed.
- V Q is the tumor volume measured at the time of sub-cage administration (i.e., d Q )
- V t is the tumor volume at each measurement.
- T/C (%) (T RTV / C RTV ) l00 %, T RTV : treatment group RTV; C RTV : negative Control group RTV.
- GDC0941 50 mg/kg 100.00 75.12 79.34 74.75 56.86 53.57 51.40
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Abstract
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Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
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RU2014147863/04A RU2589053C1 (ru) | 2012-05-31 | 2013-04-23 | ПИРРОЛО[2,1-f][1,2,4]ТРИАЗИНОВОЕ СОЕДИНЕНИЕ, СПОСОБ ЕГО ПОЛУЧЕНИЯ И ПРИМЕНЕНИЯ |
US14/403,014 US9447101B2 (en) | 2012-05-31 | 2013-04-23 | Pyrrolo[2,1-f][1,2,4]triazine compound, and preparation method and application thereof |
SG11201407752YA SG11201407752YA (en) | 2012-05-31 | 2013-04-23 | Pyrrolo[2,1-f][1,2,4]triazine compound, and preparation method and application thereof |
KR1020147033824A KR101824299B1 (ko) | 2012-05-31 | 2013-04-23 | 피롤로[2, 1-f][1, 2, 4]트리아진계 화합물, 그 제조방법 및 용도 |
BR112014029708-8A BR112014029708B1 (pt) | 2012-05-31 | 2013-04-23 | Composto de pirrolo[2,1-f][1,2,4]triazina e método de preparação de compostos de pirrolo[2,1-f][1,2,4]triazina |
EP13798006.6A EP2857403B1 (en) | 2012-05-31 | 2013-04-23 | Pyrrolo[2,1-f][1,2,4]triazine compound, and preparation method and application thereof |
AU2013270326A AU2013270326B2 (en) | 2012-05-31 | 2013-04-23 | Pyrrolo[2,1-f][1,2,4]triazine compound, and preparation method and application thereof |
CA2874062A CA2874062C (en) | 2012-05-31 | 2013-04-23 | Pyrrolo[2,1-f][1,2,4]triazine compound, and preparation method and application thereof |
MX2014014622A MX359207B (es) | 2012-05-31 | 2013-04-23 | Compuesto de pirrolo [2,1-f] [1,2,4]triazina, y método de preparación y aplicación del mismo. |
ES13798006T ES2703934T3 (es) | 2012-05-31 | 2013-04-23 | Compuesto de pirrolo[2,1-f][1,2,4]triazina y procedimiento de preparación y aplicación del mismo |
JP2015514329A JP6067107B2 (ja) | 2012-05-31 | 2013-04-23 | ピロロ[2,1−f][1,2,4]トリアジン系化合物、その製造方法および用途 |
HK15104065.5A HK1203499A1 (zh) | 2012-05-31 | 2015-04-27 | 吡咯 並三嗪類化合物,其製備方法及用途 |
US15/269,069 US9724352B2 (en) | 2012-05-31 | 2016-09-19 | Pyrrolo[2,1-F[1,2,4]triazine compounds, preparation methods and applications thereof |
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CN201210177980.3 | 2012-05-31 | ||
CN201210177980.3A CN103450204B (zh) | 2012-05-31 | 2012-05-31 | 吡咯[2,1-f][1,2,4]并三嗪类化合物,其制备方法及用途 |
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US14/403,014 A-371-Of-International US9447101B2 (en) | 2012-05-31 | 2013-04-23 | Pyrrolo[2,1-f][1,2,4]triazine compound, and preparation method and application thereof |
US15/269,069 Continuation-In-Part US9724352B2 (en) | 2012-05-31 | 2016-09-19 | Pyrrolo[2,1-F[1,2,4]triazine compounds, preparation methods and applications thereof |
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WO2013177983A1 true WO2013177983A1 (zh) | 2013-12-05 |
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PCT/CN2013/074559 WO2013177983A1 (zh) | 2012-05-31 | 2013-04-23 | 吡咯[2,1-f][1,2,4]并三嗪类化合物,其制备方法及用途 |
Country Status (14)
Country | Link |
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US (1) | US9447101B2 (zh) |
EP (1) | EP2857403B1 (zh) |
JP (1) | JP6067107B2 (zh) |
KR (1) | KR101824299B1 (zh) |
CN (1) | CN103450204B (zh) |
AU (1) | AU2013270326B2 (zh) |
BR (1) | BR112014029708B1 (zh) |
CA (1) | CA2874062C (zh) |
ES (1) | ES2703934T3 (zh) |
HK (1) | HK1203499A1 (zh) |
MX (1) | MX359207B (zh) |
RU (1) | RU2589053C1 (zh) |
SG (1) | SG11201407752YA (zh) |
WO (1) | WO2013177983A1 (zh) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2014115171A1 (en) | 2013-01-24 | 2014-07-31 | Council Of Scientific & Industrial Research | Triazine compounds and a process for preparation thereof |
WO2018233684A1 (zh) * | 2017-06-23 | 2018-12-27 | 中国科学院上海药物研究所 | 7-位取代吡咯并三嗪类化合物或其药学上可用的盐,及其制备方法和用途 |
US10292985B2 (en) * | 2015-08-31 | 2019-05-21 | Bristol-Myers Squibb Company | TGF beta receptor antagonists |
US11484597B2 (en) | 2019-09-19 | 2022-11-01 | Totus Medicines Inc. | Therapeutic conjugates |
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US9724352B2 (en) * | 2012-05-31 | 2017-08-08 | Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences | Pyrrolo[2,1-F[1,2,4]triazine compounds, preparation methods and applications thereof |
ES2749679T3 (es) | 2014-10-22 | 2020-03-23 | Bristol Myers Squibb Co | Compuestos de pirrolotriazina amina sustituidos como inhibidores de PI3k |
US10214537B2 (en) | 2014-10-22 | 2019-02-26 | Bristol-Myers Squibb Company | Bicyclic heteroaryl amine compounds |
WO2017004134A1 (en) * | 2015-06-29 | 2017-01-05 | Nimbus Iris, Inc. | Irak inhibitors and uses thereof |
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CN112851563A (zh) * | 2020-12-30 | 2021-05-28 | 安徽金鼎医药股份有限公司 | N-氨基-3-氮杂双环[3,3,0]辛烷盐酸盐的合成工艺 |
CN118119383A (zh) * | 2021-09-10 | 2024-05-31 | 上海海和药物研究开发股份有限公司 | 包含PI3Kα抑制剂的药物组合 |
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Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014115171A1 (en) | 2013-01-24 | 2014-07-31 | Council Of Scientific & Industrial Research | Triazine compounds and a process for preparation thereof |
US10292985B2 (en) * | 2015-08-31 | 2019-05-21 | Bristol-Myers Squibb Company | TGF beta receptor antagonists |
WO2018233684A1 (zh) * | 2017-06-23 | 2018-12-27 | 中国科学院上海药物研究所 | 7-位取代吡咯并三嗪类化合物或其药学上可用的盐,及其制备方法和用途 |
KR20200015786A (ko) * | 2017-06-23 | 2020-02-12 | 상하이 인스티튜트 오브 마테리아 메디카 차이니즈 아카데미 오브 싸이언시즈 | 7-부위 치환된 피롤로트라이아진 화합물 또는 이의 약학적으로 허용되는 염, 및 이의 제조 방법 및 용도 |
US11214572B2 (en) | 2017-06-23 | 2022-01-04 | Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences | 7-site substituted pyrrole triazine compounds or pharmaceutically acceptable salts thereof, and preparation method thereof and uses thereof |
KR102413943B1 (ko) | 2017-06-23 | 2022-06-27 | 상하이 인스티튜트 오브 마테리아 메디카 차이니즈 아카데미 오브 싸이언시즈 | 7-부위 치환된 피롤로트라이아진 화합물 또는 이의 약학적으로 허용되는 염, 및 이의 제조 방법 및 용도 |
US11484597B2 (en) | 2019-09-19 | 2022-11-01 | Totus Medicines Inc. | Therapeutic conjugates |
US12029791B2 (en) | 2019-09-19 | 2024-07-09 | Totus Medicines Inc. | Therapeutic conjugates |
Also Published As
Publication number | Publication date |
---|---|
EP2857403B1 (en) | 2018-10-10 |
MX2014014622A (es) | 2015-08-10 |
BR112014029708A2 (pt) | 2017-06-27 |
US20150141644A1 (en) | 2015-05-21 |
HK1203499A1 (zh) | 2015-10-30 |
EP2857403A4 (en) | 2015-10-21 |
JP6067107B2 (ja) | 2017-01-25 |
BR112014029708A8 (pt) | 2021-09-08 |
MX359207B (es) | 2018-09-19 |
US9447101B2 (en) | 2016-09-20 |
SG11201407752YA (en) | 2015-01-29 |
CA2874062A1 (en) | 2013-12-05 |
CA2874062C (en) | 2015-09-22 |
KR20150009565A (ko) | 2015-01-26 |
AU2013270326B2 (en) | 2016-07-14 |
EP2857403A1 (en) | 2015-04-08 |
ES2703934T3 (es) | 2019-03-13 |
RU2589053C1 (ru) | 2016-07-10 |
KR101824299B1 (ko) | 2018-03-14 |
AU2013270326A1 (en) | 2014-12-18 |
JP2015518010A (ja) | 2015-06-25 |
CN103450204A (zh) | 2013-12-18 |
BR112014029708B1 (pt) | 2023-05-02 |
CN103450204B (zh) | 2016-08-17 |
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