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WO2010051664A1 - Dérivés de 7h-imidazo[1,20-a]pyrano[2,3-c]pyridine et leur utilisation - Google Patents

Dérivés de 7h-imidazo[1,20-a]pyrano[2,3-c]pyridine et leur utilisation Download PDF

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Publication number
WO2010051664A1
WO2010051664A1 PCT/CN2008/072962 CN2008072962W WO2010051664A1 WO 2010051664 A1 WO2010051664 A1 WO 2010051664A1 CN 2008072962 W CN2008072962 W CN 2008072962W WO 2010051664 A1 WO2010051664 A1 WO 2010051664A1
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Prior art keywords
amino
cyano
pyridine
imidazo
pyrano
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Chinese (zh)
Inventor
史秀兰
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Shenyang J & Health Pharamaceutical Co Ltd
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Shenyang J & Health Pharamaceutical Co Ltd
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Priority to CN200880131381.XA priority Critical patent/CN102171215B/zh
Priority to PCT/CN2008/072962 priority patent/WO2010051664A1/fr
Publication of WO2010051664A1 publication Critical patent/WO2010051664A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to novel 7H-imidazo[1,2-a]pyrano[2,3-c]pyridine derivatives, and optically active or racemic or pharmaceutically acceptable salts, hydrates thereof Or solvates, methods for their preparation, and pharmaceutical compositions containing the compounds.
  • the present invention also relates to 7H-imidazo[1,2-a]pyrano[2,3-c]pyridine derivatives for use in the preparation of therapeutic and
  • Malignant tumors are diseases that seriously endanger human life and health. With the changes of external factors such as environmental pollution, the number of cancers in the world is increasing year by year. According to the World Health Organization (WHO), about 10 million are diagnosed every year in the world. In cancer patients, 7 million people die from diseases caused by tumors, so malignant tumors have become the second largest killer of humans after cardiovascular disease.
  • WHO World Health Organization
  • antitumor drugs kill tumor cells by acting on different stages of the cell cycle, mainly in the S phase of DNA synthesis and the M phase of mitosis, such as cytarabine and 6-mercaptopurine.
  • Antitumor drugs, vincristine, and paclitaxel are M-phase specific anti-tumor drugs.
  • slow-growing tumors such as colon cancer
  • some rapidly proliferating tissues such as bone marrow, blood cells, hair, etc.
  • Targeted anti-tumor drugs have better selectivity and lower toxic side effects, and have become a hot research field for anti-tumor drugs.
  • Malignant carcinogenesis is generally thought to be caused by uncontrolled cell division and proliferation due to the loss of spontaneous apoptosis. Therefore, the most effective anti-tumor drug should be able to eliminate the need or seriousness by activating the cell death process in the body. Impaired cells, apoptosis will open up new avenues for cancer treatment.
  • Programmed cell death regulatory genes are present in all multicellular organisms that have evolved Highly conservative. Studies have shown that in addition to multicellular organisms, some bacteria maintain a stable internal cell environment through a similar process. In the process of apoptosis, the most important gene expression product is caspase.
  • the original form of the gene expression product of Caspases in cells is its zymogen form (Procaspase), including the N-terminal domain.
  • caspase Activation of caspase is mediated by two pathways, one is activated by the initiation of caspase (including caspase-8 and caspase-9) in response to apoptotic signals; the second is by effect caspase (including caspase-3 and caspase) -7, etc.) to enhance various apoptotic signal activities.
  • caspase activation a cascade reaction occurs, resulting in DNA fragmentation, cytoskeleton, actin, laminin and other degradation, which ultimately leads to apoptosis.
  • cancer cells contain caspase, the lack of a molecular mechanism that activates the caspase cascade makes cancer cells lose their ability to commit suicide, causing cells to die without malignant proliferation.
  • Some of the anticancer drugs currently being studied can trigger cancer cell death by activating the resting caspase cascade to achieve the purpose of clearing tumor cells.
  • Studies have shown that there are points in the process of apoptosis that control the activation of the caspase cascade. These control points include the CED-9-BCL and CED-3-ICE gene family products, which are the cell's own intrinsic proteins that regulate apoptosis. process.
  • WO 01/34591 discloses a series of substituted 4H-chromenes and analogs thereof which are capable of activating the activity of caspases and are capable of inducing apoptosis. These compounds inhibit the growth of malignant proliferating cells and block the spread of abnormal cells.
  • the B ring is selected from the group consisting of a benzene ring, a naphthalene ring, a quinoline ring and an isoquinoline ring.
  • the present invention relates to 7H-imidazo[1,2-a]pyrano[2,3-c]pyridine derivatives of the formula I, and optically active or racemic forms thereof, or pharmaceutically acceptable thereof Salt, hydrate or solvate,
  • R 1 is H, dC 6 alkyl
  • R 2 is H, dC 6 alkyl
  • A is aryl, aryl CC 4 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl CC 4 alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl dC a 4 alkyl group, a 5-10 membered saturated or partially saturated heterocyclic group, a 5-10 membered saturated or partially saturated heterocyclic group dC 4 alkyl group, said heteroaryl group and heterocyclic group having 1-3 selected from 0, N and S heteroatoms, and A optionally 1-3 R 3 substituted;
  • R 3 is halogen, hydroxy, trifluoromethyl, trifluoromethoxy, carboxy, amino, azido, nitro, cyano, fluorenyl, (C C4)alkyl, (C C4)alkenyl, (C C4) alkynyl, (C C4)alkoxy, (C C4)alkylthio, hydroxy (C C4) alkyl, amino (CC 4 ) alkyl, allyl, (2-methyl)allyl , (CC 4 )alkylamido, (CC 4 )alkyl Sulfonyl, (C C4)alkylsulfonyl, (d-C4)alkoxymethyl, (d-C4)alkyl acyl, carbamoyl, N-id-C) alkylcarbamoyl, N, N-di(CC 4 )decylcarbamoyl, aminosulfonyl, N-(CC 4 )nonylaminosulfony
  • R 3 is an NR 4 R 5 ;
  • R 4 and R 5 are the same or different, and each independently selects dC 6 alkyl group, C 3 -C 6 cycloalkyl group, which may be optionally substituted by 1-3 identical or different, or with R 5 and The linked nitrogen atoms together form a 5-10 membered saturated heterocyclic group which may contain from 1 to 3 heteroatoms selected from 0, N and S in addition to the nitrogen atom to which R 4 and R 5 are attached. , optionally substituted by 1 to 3 identical or different R 6 ;
  • R 6 is. . 4 ⁇ base.
  • the present invention preferably relates to a derivative of the formula I, and an optically active or racemic thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof,
  • R 1 is H, dC 4 alkyl
  • R 2 is H, dC 4 alkyl
  • A is an aryl group, an aryl CC 4 alkyl group, a 5-10 membered heteroaryl group, the heteroaryl group contains 1-3 hetero atoms selected from 0, N and S, and A optionally 1-3 R 3 substitution;
  • R 3 is halogen, hydroxy, trifluoromethyl, trifluoromethoxy, carboxy, amino, azido, nitro, cyano, fluorenyl, (d-Ca)alkyl, (Ci-Ca)alkenyl, (d-Ca)alkynyl, (d-Ca)alkoxy, (d-Ca)alkylthio, hydroxy(d-C4)alkyl, amino(dC 4 )alkyl, allyl, (2- Methyl)allyl, (dC 4 )alkylamido, (dC 4 )alkylsulfinyl, (C C4)alkylsulfonyl, (d-C4)alkoxymethyl, (d-C4 Alkyl acyl, carbamoyl, N-id-C) alkylcarbamoyl, N, N-di(CC 4 )nonylcarbamoyl, aminosulfonyl,
  • R 3 is an NR 4 R 5 ;
  • R 4 and R 5 are the same or different, and each independently selects dC 6 alkyl, C 3 -C 6 cycloalkyl, which may be optionally substituted by 1 to 3 identical or different R 6 , or R 4 and R 5 Together with the nitrogen atom to which they are attached, a 5-10 membered saturated heterocyclic group is formed, which may contain, in addition to the nitrogen atom to which R 4 and R 5 are attached, 1-3 selected from 0, N and a hetero atom of S, optionally substituted by 1 to 3 identical or different R 6 ;
  • R 6 is a C1-C4 alkyl group.
  • the present invention preferably relates to a derivative of the formula I, and an optically active or racemic thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof,
  • A is phenyl, pyridyl, thienyl, furyl, pyrrolyl, naphthyl, quinolyl, isoquinolinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, trinitrogen Azolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzyl, phenethyl, and optionally 1-3 R 3 substituted;
  • R 3 is halogen, hydroxy, trifluoromethyl, trifluoromethoxy, carboxy, amino, azido, nitro, cyano, fluorenyl, (d-Ca)alkyl, (Ci-C 4 )alkenyl , (Ci-C 4 ) alkynyl, (d-Ca)alkoxy, (d-Ca)alkylthio, hydroxy(Ci-Ca)alkyl, amino(dC 4 )alkyl, allyl, ( 2-methyl)allyl, (dC 4 )alkylamido, (dC 4 )alkylsulfinyl, (C C4)alkylsulfonyl, (d-C4)alkoxymethyl, (d -C4)alkyl acyl, carbamoyl, N-id-C) alkylcarbamoyl, N,N-di(CC 4 )nonylcarbamoyl, aminosulf
  • the present invention also preferably relates to a derivative of the formula I, and an optically active or racemic thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof,
  • R 1 is H, Ci-. 4 burning base 5
  • R 2 is H
  • A is phenyl, pyridyl, thienyl, furyl, pyrrolyl, naphthyl, quinolyl, isoquinolinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, trinitrogen Azolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzyl, phenethyl, and optionally 1-3 R 3 substituted;
  • R 3 is halogen, hydroxy, trifluoromethyl, trifluoromethoxy, carboxy, amino, azido, nitro, cyano, fluorenyl, (C C4)alkyl, (C C4)alkenyl, (C C4) alkynyl, (C C4)alkoxy, (C C4)alkylthio, hydroxy (C C4) Alkyl, amino (CC 4 ) alkyl, allyl, (2-methyl)allyl, (CC 4 )alkylamido, (CC 4 )alkylsulfinyl, (C C4)alkyl Sulfonyl, (d-C4) alkoxymethyl, (d-C4)alkyl acyl, carbamoyl, N-id-C) alkylcarbamoyl, N, N-di(dC 4 ) fluorenyl Carboyl, sulfamoyl, N-(dC 4 )nonylaminosulfony
  • R 3 is an NR 4 R 5 ;
  • R 4 and R 5 are the same or different, and each independently is selected from a C 6 alkyl group, a C 3 -C 6 cycloalkyl group, which may be optionally substituted by 1 to 3 identical or different R 6 or R 4 and R 5 Together with the nitrogen atom to which they are attached, morpholinyl, pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, piperidinyl, imidazolidinyl and pyrazolidinyl;
  • the present invention particularly preferably defines a compound of formula I, and an optically active or racemic thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof,
  • R 1 is H, -CH 3 ;
  • R 2 is H;
  • A is phenyl, pyridyl, thienyl, furyl, pyrrolyl, naphthyl, quinolyl, isoquinolinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, trinitrogen Azolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzyl, phenethyl, and optionally 1-3 R 3 substituted;
  • R 3 is halogen, hydroxy, trifluoromethyl, trifluoromethoxy, carboxy, amino, azido, nitro, cyano, fluorenyl, (d-Ca)alkyl, (Ci-Ca)alkenyl, (d-Ca)alkynyl, (d-Ca)alkoxy, (d-Ca)alkylthio, hydroxy(d-C4)alkyl, amino(CC 4 )alkyl, allyl, (2- Methyl)allyl, (CC 4 )alkylamido, (CC 4 )alkylsulfinyl, (C C4)alkylsulfonyl, (d-C4)alkoxymethyl, (d-C4 Alkyl acyl, carbamoyl, N-id-C) alkylcarbamoyl, N, N-di(CC 4 )nonylcarbamoyl, aminosulfonyl, N-(
  • R 3 is an NR 4 R 5 ;
  • R 4 and R 5 are the same or different, and each independently selects dC 6 alkyl, C 3 -C 6 cycloalkyl, which may be optionally substituted by 1 to 3 identical or different R 6 or R 4 and R 5 Forming morpholinyl, pyrrolidine together with the nitrogen atom to which they are attached Base, piperazinyl, 4-methylpiperazinyl, piperidinyl, imidazolidinyl and pyrazolidinyl;
  • R 1 is H, -CH 3 ;
  • R 2 is H;
  • A is phenyl, and A is optionally substituted with 1-3 R 3 ;
  • R 3 is halogen, hydroxy, trifluoromethyl, trifluoromethoxy, carboxy, amino, azido, nitro, cyano, fluorenyl, (C C4)alkyl, (C C4)alkenyl, (C C4) alkynyl, (C C4)alkoxy, (C C4)alkylthio, hydroxy (C C4) alkyl, amino (dC 4 )alkyl, allyl, (2-methyl)allyl , (dC 4 )alkylamido, (dC 4 )alkylsulfinyl, (dC 4 )alkylsulfonyl, (d-C4)alkoxymethyl, (dC 4 )alkylacyl,aminocarbyl Acyl, N-id-C) alkylcarbamoyl, N, N-di(dC 4 )nonylcarbamoyl, aminosulfonyl, N-(dC 4
  • R 3 is an NR 4 R 5 ;
  • the compound of the formula I of the present invention and its optically active or racemic form or a pharmaceutically acceptable salt, hydrate or solvate thereof are preferably the following compounds, but these compounds are not meant to limit the invention:
  • the 7H-imidazo[1,2-a]pyrano[2,3-c]pyridine derivatives of the above formula I of the present invention can be used in the formation of pharmaceutically active acids. Acceptable salt.
  • the pharmaceutically acceptable addition salts include inorganic acids and organic acid addition salts, and salts with the following acids are particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid , benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, and the like.
  • the invention also includes prodrugs of the derivatives of the invention.
  • Prodrugs of the derivatives of the invention are derivatives of formula I which may themselves have weak or even no activity, but after administration, under physiological conditions (for example by metabolism, solvolysis or otherwise) Converted to the corresponding biologically active form.
  • halogen means fluorine, chlorine, bromine or iodo
  • alkyl means a straight or branched alkyl group
  • alkylene means a straight or branched alkylene group
  • Cycloalkyl means a substituted or unsubstituted cycloalkyl group
  • aryl means a phenyl group having no substituent or a substituent
  • heteroaryl means having one or more selected from N, 0 a monocyclic or polycyclic ring system of S heteroatoms, the cyclic system being aromatic, such as imidazolyl, pyridyl, pyrazolyl, (1,2,3)- and (1,2,4) - triazolyl, furyl, thienyl, pyrrolyl, thiazolyl, benzothiazolyl, oxazolyl, isoxazolyl, naphthyl, quinolyl, isoquinolinyl,
  • the present invention may contain a 7H-imidazo[1,2-a]pyrano[2,3-c]pyridine derivative of the above formula I, and a pharmaceutically acceptable salt, hydrate or solvate thereof as an activity
  • the composition is prepared into a composition by mixing with a pharmaceutically acceptable carrier or excipient, and is prepared into a clinically acceptable dosage form, and the above pharmaceutically acceptable excipient means any diluent and auxiliary which can be used in the pharmaceutical field. And/or carrier.
  • the derivatives of the present invention can be used in combination with other active ingredients as long as they do not cause other adverse effects such as allergic reactions.
  • the pharmaceutical composition of the present invention can be formulated into several dosage forms, which contain some commonly used forms in the field of medicine.
  • Agent A plurality of dosage forms as described above may be administered as a medicament such as an injection, a tablet, a capsule, an aerosol, a suppository, a film, a pill, a tanning agent, an ointment or the like.
  • Carriers for use in the pharmaceutical compositions of the present invention are common types available in the pharmaceutical arts, including: binders, lubricants, disintegrants, solubilizers, diluents, stabilizers, suspending agents, non-pigmenting, flavoring agents , preservatives, solubilizers and matrices.
  • the pharmaceutical preparations can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically), and if certain drugs are unstable under gastric conditions, they can be formulated into enteric coated tablets.
  • the compound of the present invention has antitumor activity, and thus the compound of the present invention can be used for the preparation of a medicament for treating and/or preventing various cancers such as breast, lung, liver, kidney, colon, rectum, stomach. , prostate, bladder, uterus, pancreas, bone marrow, testis, ovary, lymph, soft tissue, head and neck, thyroid, esophageal cancer and leukemia, neuroblastoma, etc. It is especially useful for the preparation of a medicament for the treatment and/or prevention of lung cancer and liver cancer.
  • various cancers such as breast, lung, liver, kidney, colon, rectum, stomach. , prostate, bladder, uterus, pancreas, bone marrow, testis, ovary, lymph, soft tissue, head and neck, thyroid, esophageal cancer and leukemia, neuroblastoma, etc. It is especially useful for the preparation of a medicament for the treatment and/or prevention of lung cancer and liver cancer.
  • the active compound of the present invention or a pharmaceutically acceptable salt thereof and a solvate thereof can be used alone as the sole antitumor drug, or can be combined with an antitumor drug which has been marketed (for example, the platinum drug cisplatin, the camptothecin drug irinotene). Kang, vinca alkaloids noviben, deoxycytidine drugs gemcitabine, etoposide, paclitaxel, etc.). Combination therapy is achieved by administering the individual therapeutic components simultaneously, sequentially or separately.
  • Derivatives of formula I according to the invention may be prepared by condensation of compounds IV and II according to the method of Scheme 1; wherein 2-amino-3-hydroxypyridine is cyclized with a compound of formula V to give compound IV, Dimerization of dinitrile to give compound II;
  • the examples are intended to illustrate and not to limit the scope of the invention.
  • the nuclear magnetic resonance spectrum of the derivative was measured by Bruker ARX-600, and the mass spectrum was measured by Agilent 1100 LC/MSD; the reagents used were either analytically pure or chemically pure.
  • Step B Preparation of 2-[(3,4,5-trimethoxy)phenyl]methylenemalononitrile 3,4,5-trimethoxybenzaldehyde 10 g (51 mmol) and malononitrile 3.4 g (51 mmol) were added to 50 mL of ethanol, 1 drop of piperidine was added dropwise, and stirred at room temperature for 3 hours to precipitate a solid. The filter cake was filtered, washed with ethanol and dried to give 9.7 g (yield: 78%).
  • the 8-hydroxyimidazo[1,2-a]pyridine derivative was prepared by first reacting 2-amino-3-light pyridine with a suitable ⁇ -chloroaldehyde (ketone); Further, a suitable aldehyde is reacted with malononitrile to prepare a 2-substituted methylenemalononitrile; an 8-hydroxyimidazo[1,2-a]pyridine derivative obtained by the above method and a 2-substituted sub Methylmalononitrile was subjected to a condensation reaction to obtain the compounds of Examples 2-26:
  • Example 12 9-Amino-8-cyano-7-(3-bromo-4,5-dimethoxyphenyl)-7H-imidazo[1,2-a]pyrano[2,3 -c] pyridine step D
  • 3-bromo-4-hydroxy-5-methoxybenzaldehyde 5 g (33 mmol) 4-light 3-methoxybenzaldehyde was dissolved in 50 mL of glacial acetic acid at room temperature 2.5 ml (36 mmol) of liquid bromine was added dropwise, and the mixture was added dropwise, and the mixture was reacted at room temperature for 18 hours.
  • Example 16 9-Amino-8-cyano-7-(3-dallow-4-hydroxy-5-methoxyphenyl)-7H-imidazo[1,2-a]pyrano[
  • 2,3-c]pyridine step F 3-methoxy-4-(dipropoxy)benzaldehyde 3 g (20 mmol) 4-hydroxy-3-methoxybenzaldehyde, 3.29 g (24 Methyl carbonate and 2.4 g (16 mmol) of sodium iodide were dissolved in 30 mL of DMF. 3 mL (23.6 mmol) of 3-bromopropene was added dropwise at room temperature, and the reaction was completed at room temperature for 6 hours.
  • Example 16 was obtained according to the procedure of Example 1.
  • Example 17 The compound of Example 17 was obtained according to the method of Example 16.
  • the allyloxybenzaldehyde derivative is prepared by reacting with a suitable hydroxybenzaldehyde and 3-bromopropene, and then subjected to a rearrangement reaction to obtain a hydroxyl group-containing and allyl-substituted group.
  • the benzaldehyde derivative was finally methylated with dimethyl sulfate to prepare the appropriate aldehyde for use in the synthesis of the compound of Example 18-21.
  • Example 19 The compound of Example 19 was obtained according to the procedure of Example 1.
  • the cells were digested from the bottom of the culture flask with trypsin solution (0.25%). After the cell digest is poured into a centrifuge tube, the culture solution is then added to terminate the digestion. Centrifuge the tube at 800r/min for 10min, discard the supernatant, add 5mL of the culture solution, mix and mix the cells, and pipette 10 ⁇ L of the cell suspension into the cell counting plate to adjust the cell concentration to 10 4 / hole. In the 96-well plate, except for the A1 well, which was blank, no cells were added, and the rest were added with 100 ⁇ : cell suspension. The 96-well plate was placed in an incubator for 24 h.
  • test sample Dissolve the test sample with 50 ⁇ : dimethyl sulfoxide, then add the appropriate amount of the culture solution to dissolve the sample into 2 mg/mL solution, and then dilute the sample to 20, 4, 0.8 in a 24-well plate. , 0.16, 0.032 g/mL.
  • the 96-well plate was placed in an incubator for 72 h.
  • Example 1 2.3 0.2 0.4 0.5
  • Example 2 5 1.3 2.9 1.5
  • Example 3 44 0.1 0.3 0.4
  • Example 4 6.4 49 - -
  • Example 5 11 2 1.5 5.3
  • Example 6 66 7.8 15.2 23.1
  • Example 7 10 1.2 1.8 0.9 Implementation
  • Example 9 6 1.2 2.8 4.6
  • Example 12 6 0.00001 0.00001 0.00001
  • Example 16 6 0.00001 0.00001 0.0005
  • Example 17 16 5.2 6.7 6.3
  • Example 20 30 0.009 0.8 0.5
  • Example 21 15 3.5 288 - Example 23 5.8 19 25 16
  • Example 27 86 4.8 - - Compound C 4.1 5.3 7.2 6.1 It is clear from the above test results that the compound of the formula I to be protected by the present invention has good antitumor activity in vitro, and some compounds and the compound c reported in the literature. The activity is comparable or superior to compound c.
  • the compounds of formula I in the present invention may be administered alone, but are usually administered as a mixture of pharmaceutically acceptable carriers which are selected according to the desired route of administration and standard pharmaceutical practice.
  • the preparation of dosage forms such as tablets, capsules, injections, aerosols, suppositories, films, pills, topical tinctures and ointments, illustrates their new applications in the pharmaceutical field.
  • Example 30 Tablet 10 g of the compound containing the compound of claim 1 (exemplified by the compound of Example 12) was mixed according to the general tableting method and 20 g of the adjuvant, and then compressed into 100 tablets each weighing 300 mg.
  • Example 37 Topical tincture Using a compound containing the compound of claim 1 (exemplified by the compound of Example 21) 10 g, it is prepared by mixing and grinding with 2.5 g of an auxiliary agent such as an emulsifier according to a conventional pharmaceutical method, and adding distilled water to 200 mL.
  • an auxiliary agent such as an emulsifier according to a conventional pharmaceutical method

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Abstract

L'invention porte sur des dérivés de 7H-imidazo[1,20-a]pyrano[2,3-c]pyridine de formule I et des sels, hydrates et solvates de ceux-ci, dans laquelle formule R1, R2 et A sont des groupes tels que définis dans la description. L'invention porte en outre sur l'utilisation de composés de formule I dans la préparation d'un médicament ayant pour effet de traiter ou prévenir un cancer ou d'autres maladies prolifératives.
PCT/CN2008/072962 2008-11-05 2008-11-05 Dérivés de 7h-imidazo[1,20-a]pyrano[2,3-c]pyridine et leur utilisation Ceased WO2010051664A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN200880131381.XA CN102171215B (zh) 2008-11-05 2008-11-05 7H-咪唑并[1,2-a]吡喃并[2,3-c]吡啶类衍生物及其应用
PCT/CN2008/072962 WO2010051664A1 (fr) 2008-11-05 2008-11-05 Dérivés de 7h-imidazo[1,20-a]pyrano[2,3-c]pyridine et leur utilisation

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1257505A (zh) * 1997-05-28 2000-06-21 比克·古尔顿·劳姆贝尔格化学公司 稠合的二氢吡喃类化合物
CN1325303A (zh) * 1998-09-23 2001-12-05 研究发展基金会 生良酚、生育三烯酚、其它苯并二氢吡喃和侧链衍生物,及其用途

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT1230232E (pt) * 1999-11-05 2004-07-30 Cytovia Inc 4h-cromeno substituido e seus analogos como activadores de caspases e indutores de apoptose e sua utilizacao

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1257505A (zh) * 1997-05-28 2000-06-21 比克·古尔顿·劳姆贝尔格化学公司 稠合的二氢吡喃类化合物
CN1325303A (zh) * 1998-09-23 2001-12-05 研究发展基金会 生良酚、生育三烯酚、其它苯并二氢吡喃和侧链衍生物,及其用途

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