WO2010083649A1 - Dérivés de bisarylurée et leur utilisation - Google Patents

Dérivés de bisarylurée et leur utilisation Download PDF

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WO2010083649A1
WO2010083649A1 PCT/CN2009/070277 CN2009070277W WO2010083649A1 WO 2010083649 A1 WO2010083649 A1 WO 2010083649A1 CN 2009070277 W CN2009070277 W CN 2009070277W WO 2010083649 A1 WO2010083649 A1 WO 2010083649A1
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alkyl
phenyl
group
amino
piperazine
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PCT/CN2009/070277
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English (en)
Chinese (zh)
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宫平
赵燕芳
刘亚婧
翟鑫
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沈阳药科大学
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Priority to CN200980147890.6A priority Critical patent/CN102216280B/zh
Priority to PCT/CN2009/070277 priority patent/WO2010083649A1/fr
Publication of WO2010083649A1 publication Critical patent/WO2010083649A1/fr

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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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/66—Nitrogen atoms

Definitions

  • the present invention relates to a bisarylurea derivative, and a pharmaceutical composition comprising the same as an active ingredient, and a medicament thereof for preparing a receptor protein tyrosine kinase inhibitor and for treating and/or preventing various cancers Use in. Background technique
  • Cancer also known as malignant tumor, is a common type of disease that poses a serious threat to human health.
  • anti-tumor drugs is moving from traditional cytotoxic drugs to new aspects of multiple mechanisms in tumor development. Anti-tumor drug conversion.
  • RTKs selective protein tyrosine kinases
  • multi-target inhibitors are superior to single-target inhibitors in therapy, while drug molecules that inhibit multiple receptor tyrosine kinases simultaneously block multiple signal transductions in cancer cell growth.
  • the pathway can inhibit the growth of tumors more effectively.
  • the multi-target receptor protein tyrosine kinase inhibitor is a new development direction of tumor treatment and drug development.
  • Sorafenib is a bisaryl urea compound. It is an oral multi-target anti-tumor drug jointly developed by Bayer and ONYX in Germany. It was marketed in the US on December 20, 2005 and approved by the FDA for treatment. Advanced renal cell carcinoma, and was listed in China on November 29, 2006. Sorafenib has a dual anti-tumor effect, which directly inhibits tumor growth by blocking the RAF/MEK/ERK signaling pathway; on the other hand, it blocks tumor growth by inhibiting VEGF and platelet-derived growth factor (PDGF) receptors. The formation of blood vessels, indirectly inhibit the growth of tumor cells.
  • PDGF platelet-derived growth factor
  • the present inventors synthesized a series of bisarylurea derivatives, which were screened by in vitro receptor protein tyrosine kinase inhibitory activity and screened for antitumor activity in vitro, indicating strong inhibitory protein tyrosine kinase activity and antitumor activity. . Summary of the invention
  • the present invention relates to a derivative of the formula I or a pharmaceutically acceptable salt thereof, as defined below, among them,
  • ⁇ is phenyl, naphthyl or a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from 0, N and S, and optionally 3 substituents;
  • Ar 2 is phenyl, naphthyl or 5-10 membered heteroaryl, the heteroaryl contains 1-3 heteroatoms selected from 0, N and S, and Ar 2 optionally 1 - 3 R 2 is substituted ;
  • n is an integer between 0 and 4;
  • X is hydrogen, d-C 4 alkyl and d-C 4 alkoxy
  • R 2 is hydrogen, trifluoromethyl, trifluoromethoxy, amino, hydroxy, carboxy, cyano, (C-CJ alkyl, (d-C 4 ) alkoxy, N - (C" C 4 ) Alkyl J ⁇ , N, N-di(C "C 4 )alkyl J ⁇ , (d-C 4 ) alkane, (d-C 4 )alkylsulfinyl, (d-C 4 ) Alkylsulfonyl, (C-C 4 ) alkoxyfluorenyl, (d-C 4 )alkoxyethyl, (d-C 4 )alkyl acyl, aminodecanoyl, N-(d- C 4 Alkyl decanoyl, N, N-di(d-C 4 )alkyl decanoyl, ⁇ sulfonyl, N-(d-C 4 )alkylsulfonyl, N, N-di
  • the limit is: When Ar 2 is a phenyl group, ⁇ is not zero.
  • the present invention preferably relates to a derivative of the formula I, or a pharmaceutically acceptable salt thereof, wherein
  • ⁇ is phenyl or a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from the group consisting of 0, ⁇ and S, and ⁇ ⁇ optionally 1-1-3 ⁇ ;
  • Ar 2 is a phenyl group or a 5- to 10-membered heteroaryl group, the heteroaryl group contains 1-3 hetero atoms selected from 0, N and S, and Ar 2 is optionally substituted with 1 to 3 R 2 ;
  • n is an integer between 0 and 4; X is hydrogen;
  • R 2 is hydrogen, trifluoromethyl, trifluoromethoxy, amino, hydroxy, carboxy, cyano, (C-CJ alkyl, (d-C 4 ) alkane! L &, N- (d- C 4 Alkyl ⁇ 1 ⁇ 2, N,N-di(d-C 4 )alkyl J ⁇ , (d-C 4 ) alkane, (d-C 4 )alkylsulfinyl, (d-C 4 Alkylsulfonyl, (C-C 4 ) alkoxyfluorenyl, (d-C 4 )alkoxyethyl, (d-C 4 )alkyl acyl, aminodecanoyl, N- (d- C 4 ) alkyl decanoyl, N, N-di(d-C 4 )alkyl decanoyl, ⁇ sulfonyl, N-(d-C 4 )alkylsulfonyl, N, N-
  • the limit is: When Ar 2 is a phenyl group, ⁇ is not zero.
  • the present invention preferably further relates to a derivative of the formula I, or a pharmaceutically acceptable salt thereof, wherein
  • ⁇ is phenyl, and ⁇ ⁇ is optionally substituted with 1 - 3 ⁇ ;
  • Ar 2 is a 5-6 membered heteroaryl group, the heteroaryl group contains 1-3 hetero atoms selected from 0, N and S, and Ar 2 is optionally substituted with 1 to 3 R 2 ;
  • n is an integer between 0 and 4;
  • X is hydrogen
  • R 2 is hydrogen, trifluoromethyl, trifluoromethoxy, amino, hydroxy, carboxy, cyano, (C-CJ alkyl, (d-C 4 ) alkane! L &, N- (d- C 4 Alkyl ⁇ 1 ⁇ 2, N, N-di(d-C 4 )alkyl J ⁇ , (C“C 4 ) alkane, (C “C 4 ) alkylsulfinyl, (d- C 4 ) Alkylsulfonyl, (C-C 4 ) alkoxyfluorenyl, (d-C 4 )alkoxyethyl, (d-C 4 )alkyl acyl, aminodecanoyl, N- (d- C 4 ) alkyl decanoyl, N, N-di(d-C 4 )alkyl decanoyl, sulfonate Acyl, N-(d-C 4 )alkylsulfonyl, N
  • the invention particularly preferably relates to derivatives of the formula I defined below,
  • ⁇ is phenyl, and ⁇ ⁇ is optionally substituted with 1 - 3 ⁇ ;
  • Ar 2 is a pyrimidinyl group, and the pyrimidinyl group is optionally substituted with 1-3 R 2 ;
  • n is an integer between 0 and 4;
  • X is hydrogen
  • R 2 is hydrogen, trifluoromethyl, trifluoromethoxy, amino, hydroxy, carboxy, cyano, (C-CJ alkyl, (d-C 4 ) alkane! L &, N- (d- C 4 Alkyl ⁇ 1 ⁇ 2, N, N-di(d-C 4 )alkyl J ⁇ , (C“C 4 ) alkane, (C “C 4 ) alkylsulfinyl, (d- C 4 ) Alkylsulfonyl, (C-C 4 ) alkoxyfluorenyl, (d-C 4 )alkoxyethyl, (d-C 4 )alkyl acyl, aminodecanoyl, N- (d- C 4 ) alkyl decanoyl, N, N-di(d-C 4 )alkyl decanoyl, ⁇ sulfonyl, N-(C "C 4 )alkylsulfonyl, N,
  • the present invention particularly preferably relates to a derivative of the formula I, or a pharmaceutically acceptable salt thereof, wherein
  • ⁇ is phenyl, and ⁇ ⁇ is optionally substituted with 1 - 3 ⁇ ;
  • Ar 2 is a pyrimidinyl group, and the pyrimidinyl group is optionally substituted with 1-3 R 2 ;
  • n 1;
  • X is hydrogen
  • R 2 is hydrogen, trifluoromethyl, trifluoromethoxy, amino, hydroxy, carboxy, cyano, (C-CJ Alkyl, (d-C 4 ) alkane! L &, N-(d-C 4 )alkyl ⁇ 1 ⁇ 2, N,N-di(d-C 4 )alkyl J ⁇ , (C"C 4 ) alkane, (d-C 4 ) alkane a sulfinyl group, a (d-C 4 )alkylsulfonyl group, a (C-C 4 ) alkoxyfluorenyl group, a (d-C 4 ) alkoxyethyl group, a (d-C 4 )alkyl acyl group, Aminodecanoyl, N-(d-C 4 )alkyl decanoyl, N,N-di(d-C 4 )alkyl decanoyl, ⁇ sulfonyl, N
  • the invention particularly preferably relates to derivatives of the formula I defined below,
  • ⁇ is phenyl, and ⁇ ⁇ is optionally substituted with 1 - 3 ⁇ ;
  • Ar 2 is 2- 3-trifluoromethyl-6-pyrimidine
  • n 1;
  • X is hydrogen
  • the bisarylurea derivative of the formula I of the present invention can form a pharmaceutically acceptable salt thereof with an acid according to some usual methods in the art to which the present invention pertains.
  • the acid may include a mineral acid or an organic acid, and a salt formed with the following acids is particularly preferred: hydrochloric acid, oxalic acid, maleic acid, fumaric acid, citric acid, tartaric acid, malic acid, isethionic acid, tartaric acid, hydrazine Sulfonic acid, ethanesulfonic acid, hydrobromic acid, sulfuric acid, phosphoric acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, benzoic acid or p-toluenesulfonic acid.
  • the invention also includes prodrugs of the derivatives of the invention.
  • the prodrugs are derivatives of the 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 as used herein, unless otherwise indicated, means fluoro, chloro, bromo or substituted; "alkyl” means a straight or branched alkyl group; “alkylene” means straight or branched.
  • the present invention includes a pharmaceutical composition
  • a pharmaceutical composition comprising a bisarylurea derivative of the formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient, and a pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient refers to any diluent, adjuvant and/or carrier that can be used in the pharmaceutical arts.
  • 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 an allergic reaction.
  • compositions of the present invention may be formulated in a number of dosage forms containing some of the excipients commonly used in the pharmaceutical arts; for example, oral preparations (e.g., tablets, capsules, solutions or suspensions); injectable preparations (for example, an injectable solution or suspension, or an injectable dry powder, can be used immediately after the injection of water for injection; a topical preparation (such as an ointment or solution).
  • oral preparations e.g., tablets, capsules, solutions or suspensions
  • injectable preparations for example, an injectable solution or suspension, or an injectable dry powder, can be used immediately after the injection of water for injection
  • a topical preparation such as an ointment or solution.
  • the carrier used in the pharmaceutical composition of the present invention is a common type available in the pharmaceutical field, including: a binder for an oral preparation, a lubricant, a disintegrant, a solubilizer, a diluent, and a stable Preservatives, suspending agents, non-pigmenting, flavoring agents, etc.; preservatives, solubilizers, stabilizers, etc. for injectable preparations; bases, diluents, lubricants, preservatives, etc. for topical preparations.
  • 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 compounds of the invention may be used in the treatment of a disease or condition in which a protein tyrosine kinase receptor inhibitor is administered alone or in part, i.e., the compound may be used to produce protein tyrosine kinase receptor inhibition in a mammal in need of such treatment. effect.
  • the compounds of the present invention are useful in the treatment of cancers which provide anti-proliferative effects, particularly in the treatment of cancers susceptible to protein tyrosine kinase receptors such as breast, lung, colon, rectum, stomach, prostate, bladder, pancreas and ovary.
  • the compounds of the invention are also expected to be useful in the treatment of other cell proliferative disorders such as psoriasis, benign prostatic hypertrophy, atherosclerosis and restenosis.
  • the bisarylurea derivatives of the present invention will have activity against leukemia, lymphoid malignant and solid tumors such as cancer and sarcoma in tissues such as liver, kidney, prostate and pancreas.
  • the compounds of the invention are also contemplated for use in the treatment of diseases in which other cells proliferate, including by receptor protein tyrosine kinases, including those of the receptor protein tyrosine kinase that have not yet been identified.
  • diseases include, for example, inflammation, angiogenesis, restenosis, immunological diseases, pancreatic diseases, kidney disease, and embryo maturation and transplantation.
  • the in vitro antitumor activity test indicates that the bisarylurea derivative of the formula I of the present invention has an anticancer effect, and therefore, it can be used as a medicament for the preparation of a medicament for treating and/or preventing cancer.
  • the derivative according to the present invention can be used as an active ingredient for the preparation of a medicament for treating and/or preventing various cancers, and the present invention also provides a method for treating or preventing the above-mentioned diseases, comprising administering a therapeutically effective amount to a patient suffering from or susceptible to the disease.
  • the clinical dose of the bisarylurea derivative of formula I for use in a patient must depend on the subject being treated, the particular route of administration, the severity of the condition being treated, and the optimal dosage will be determined by the physician treating the particular patient. .
  • the active compounds of the invention may be used as the sole anticancer drug or may be used in combination with one or more other antineoplastic agents. Combination therapy is achieved by administering the individual therapeutic components simultaneously, sequentially or separately.
  • the nuclear magnetic resonance spectrum of the derivative was determined by Bruker ARX-300, and the mass spectrum was determined by Agilent 1100 LC/MSD; the reagents used were either analytically pure or chemically pure.
  • the metal sodium 4. 6 g (0. 20 mol) was gradually added to n-butanol 80 mL, heated until the sodium was completely dissolved, and then added to the ruthenium nitrate 11.6 g (0. 10 mol), refluxed for 15 min, gradually dripped Add 27. 6 g (0.15 mol) of ethyl trifluoroacetoacetate, reflux for about 6 h, after the reaction is completed, cool to room temperature, adjust the pH to 4-5 with 10% hydrochloric acid, precipitate a large amount of solid, suction filtration, cold water The washing cake was washed with a vacuum to give a white powdery solid, 14.9 g, yield: 83. 4%, MS: 180. 2 (M+l).
  • Step D Preparation of 2-amino-4-[4-(4-nitrophenylhydrazino)piperazine-1-yl]-6-trifluorodecylpyrimidine
  • 2-Amino-4-[4-(4-nitrophenylhydrazino)piperazine-1-yl-6-trifluoromethylpyrimidine 8.2 g (0.021 mol) was added to 40 mL of absolute ethanol and stirred. Add DMF 20 mL, polyethylene glycol 400 5 mL, and 0.1 g (0. Oil mol) activated carbon to the reaction solution, stir for 80 min for 5 min, then add 1.7 g (0.006 mol) of ferric chloride hexahydrate to the reaction solution. ), stirring. To the reaction solution, 13.4 g (0.21 mol) of hydrazine hydrate having a content of 80% was added dropwise, and the reaction was carried out for 12 hours.
  • Step G 1-[4-[[4-(2- 6-Trifluoromethylpyrimidin-4-yl)piperazine-1-yl]nonylphenyl]-3-(3-chlorophenyl) Preparation of urea hydrochloride
  • the bisarylurea derivative of the above formula I according to the present invention was subjected to in vitro protein tyrosine kinase inhibitory activity screening and in vitro antitumor activity screening.
  • kinase reaction solution 50 uL was added to each well of a 96-well plate.
  • the test sample lOuL (concentration: 9 ⁇ g/mL) was added to the 2-11 column of the 96-well plate, and the kinase reaction solution 10 uL was added to the columns 1 and 12 by a row of guns.
  • 50 uL of rat brain tissue tyrosine extract [protein content of about 0.4 mg/mL] was added to each well of a 96-well plate, incubated by shaking, incubated for 1 hour, and washed three times with 200 uL of eluate.
  • Inhibition rate % (Control 0D - Sample 0D) I (Control 0D - Blank 0D) X 100%
  • the iiJ ⁇ product is a Sorafenib as an oral multi-kinase inhibitor developed by Bayer and ONYX in Germany.
  • the structural formula is as follows.
  • in vitro anti-tumor activity test (1) Resuscitate MDA-MB-231 (human breast cancer cells), Beb 7402 (human liver cancer cells) and A549 (human non-small cell lung cancer) cells and pass them for 2-3 times to stabilize with trypsin solution (0.25 %) digested from the bottom of the flask.
  • the cell digest is poured into a centrifuge tube and the culture is added to terminate the digestion. Centrifuge the tube at 1300 r/min for 3 min, gently discard the supernatant, add 5 mL of the culture solution, mix and mix the cells, and pipette the lO uL 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 uL of cell suspension. The 96-well plate was placed in an incubator for 24 h.
  • Example compounds in vitro antitumor activity are shown in Table 3.
  • Example compounds in vitro antitumor activity are shown in Table 3.
  • Example 6 0.42 1 Example 7 0. 66 1. 1 Example 8 0. 53 0. 3 Example 9 1. 22 1. 5 Example 10 0. 91 1 Example 11 0. 83 1 Example 12 1. 6 0. 90 Example 13 0. 98 1. 1 Example 15 0. 93 0. 88 Example 16 0. 46 1 Example 17 0. 94 0. 86 Example 19 0. 83 1. 1 Example 20 1. 0 1 Example 22 0. 92 1 Example 26 1. 1 1 Sorafenib 1. 1 1. 6 Note: / indicates untested activity.
  • the compound of the formula I to be protected by the present invention has excellent receptor protein tyrosine kinase inhibitory activity and anticancer activity. Therefore, the compounds of the present invention have a good industrial application prospect.

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  • Dermatology (AREA)

Abstract

L'invention porte sur des dérivés de bisarylurée de la formule I ou sur leurs sels de qualité pharmaceutique. Les composés de la formule I sont utilisés pour la fabrication d'inhibiteurs de récepteurs à activité de protéine-tyrosine kinase et d'un médicament pour le traitement et/ou la prévention d'une tumeur.
PCT/CN2009/070277 2009-01-22 2009-01-22 Dérivés de bisarylurée et leur utilisation WO2010083649A1 (fr)

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CN200980147890.6A CN102216280B (zh) 2009-01-22 2009-01-22 双芳基脲类衍生物及用途
PCT/CN2009/070277 WO2010083649A1 (fr) 2009-01-22 2009-01-22 Dérivés de bisarylurée et leur utilisation

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CN102887860A (zh) * 2012-09-29 2013-01-23 上海泰坦科技有限公司 4-氯-6-三氟甲基嘧啶类化合物的制备方法
CN103435553A (zh) * 2013-09-16 2013-12-11 中国药科大学 基于哌嗪结构的芳甲酰胺类Raf激酶抑制剂及其制备方法和用途

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CN108102087B (zh) * 2017-12-25 2021-01-05 湖南华腾制药有限公司 一种peg化敌草隆合成及其在除草中的应用

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CN1341098A (zh) * 1999-01-13 2002-03-20 拜尔有限公司 用ω－羧基芳基取代的二苯脲作为raf激酶抑制剂
WO2003068228A1 (fr) * 2002-02-11 2003-08-21 Bayer Pharmaceuticals Corporation Urees aryliques a activite inhibitrice d'angiogenese
WO2006040056A1 (fr) * 2004-10-13 2006-04-20 Merck Patent Gmbh Derives de bisaryluree substitues, heterocycliques, utilises en tant qu'inhibiteurs de kinases
WO2006062982A2 (fr) * 2004-12-07 2006-06-15 Locus Pharmaceuticals, Inc. Inhibiteurs urée de map kinases

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CN101039932A (zh) * 2004-10-13 2007-09-19 默克专利有限公司 作为激酶抑制剂的杂环取代的二芳基脲衍生物

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CN1341098A (zh) * 1999-01-13 2002-03-20 拜尔有限公司 用ω－羧基芳基取代的二苯脲作为raf激酶抑制剂
WO2003068228A1 (fr) * 2002-02-11 2003-08-21 Bayer Pharmaceuticals Corporation Urees aryliques a activite inhibitrice d'angiogenese
WO2006040056A1 (fr) * 2004-10-13 2006-04-20 Merck Patent Gmbh Derives de bisaryluree substitues, heterocycliques, utilises en tant qu'inhibiteurs de kinases
WO2006062982A2 (fr) * 2004-12-07 2006-06-15 Locus Pharmaceuticals, Inc. Inhibiteurs urée de map kinases

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102887860A (zh) * 2012-09-29 2013-01-23 上海泰坦科技有限公司 4-氯-6-三氟甲基嘧啶类化合物的制备方法
CN102887860B (zh) * 2012-09-29 2015-07-01 上海泰坦科技有限公司 4-氯-6-三氟甲基嘧啶类化合物的制备方法
CN103435553A (zh) * 2013-09-16 2013-12-11 中国药科大学 基于哌嗪结构的芳甲酰胺类Raf激酶抑制剂及其制备方法和用途

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