WO2012094966A1 - 3-aryl-6-aryl-[1,2,4]triazolo[4,3-b]pyridazine comme agent inhibant la prolifération cellulaire et son utilisation - Google Patents

3-aryl-6-aryl-[1,2,4]triazolo[4,3-b]pyridazine comme agent inhibant la prolifération cellulaire et son utilisation Download PDF

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WO2012094966A1
WO2012094966A1 PCT/CN2012/070100 CN2012070100W WO2012094966A1 WO 2012094966 A1 WO2012094966 A1 WO 2012094966A1 CN 2012070100 W CN2012070100 W CN 2012070100W WO 2012094966 A1 WO2012094966 A1 WO 2012094966A1
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methoxyphenyl
group
pyridazine
triazole
cancer
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PCT/CN2012/070100
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English (en)
Chinese (zh)
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蔡遂雄
田野
董海军
余增辉
陈磊
吴利珍
刘丽军
殷峰
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南京英派药业有限公司
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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
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the invention belongs to the field of medicinal chemistry.
  • the invention particularly relates to 3-aryl-6-aryl-[1,2,4]triazolo[4,pyridazines, and their use as therapeutically effective anticancer drugs. Background technique
  • the cell division cycle refers to a series of steps in the cell proliferation process.
  • G When the cell is at rest, it is called G in the cell division cycle. stage.
  • the cell When the cell begins to proliferate, the cell begins to synthesize and replicate DNA, which is called the entry into the S phase.
  • the DNA When the DNA is copied and the corresponding preparations are ready, the cells divide into two, which is called mitosis or M phase.
  • Anticancer drugs such as vincristine, vinblastine, paclitaxel, etc., due to their interference with the formation and disassembly of microtubules, prevent cells from undergoing effective mitosis and remain in the M phase of the cell division cycle. Cancer cells do not effectively divide and proliferate, but enter apoptosis, thus achieving anti-cancer effects.
  • Caspases are usually present in cells in an inactive zymogen state. Caspases are cysteine-aspartate proteolytic enzymes. What they have in common is the peptide bond after specifically hydrolyzing the aspartic acid residue.
  • Caspase-3, _6 and _7 are key caspases that can cleave protein substrates in a variety of cells, leading to apoptosis. Intracellular caspase activity can be measured using a fluorescently labeled substrate.
  • WO2009089027 discloses the following triazolopyridazines, triazolothiadiazines, and related heterocycles as phosphodiesterase inhibitors.
  • each X is independently CH, CH 2 , or a hetero atom; each and independently is alkyl, haloalkyl, cycloalkyl, heterocyclylalkyl, or aryl; is substituted aryl.
  • W02008030744 discloses the preparation of heterocyclic compounds as C-MET inhibitors.
  • the present invention provides novel 3-aryl-6-aryl-[ 1, 2, 4]triazolo[4, 3-6] having anti-cell proliferative activity.
  • Pyridazine compounds As shown in Structural Formulas I and II, the present invention provides novel 3-aryl-6-aryl-[ 1, 2, 4]triazolo[4, 3-6] having anti-cell proliferative activity. Pyridazine compounds.
  • the invention also provides a pharmaceutical composition comprising an effective amount of a compound of formula I or II for use in treating or ameliorating a mammalian condition resulting from uncontrolled cell proliferation.
  • the pharmaceutical composition may also contain one or more pharmaceutically acceptable carriers or diluents.
  • the pharmaceutical composition may further comprise at least one known anticancer drug or a pharmaceutically acceptable salt of the anticancer drug.
  • the known anticancer drug may be selected from one or more of the following group of drugs: busulfan, cisplatin, mitomycin c, carboplatin, colchicum Alkali, vinblastine, yew drunk, docetaxel, camptothecin, topotecan, doxorubicin and metoprolol, 5-azapine, 5-fluorouridine, cysteine , 5-fluoro-2 '-deoxyuridine, ara-C, hydroxyurea, thioguanine, campath, Herceptin, Rituxan, melphalan, chlorambucil, cyclophosphamide, ifosfamide , vincristine, mitoguazone, epirubicin, aclaramycin, bleomycin, mitoxantrone, el liptinium, fludarabine, octreotide, retinoic acid, tamoxifen, arsenic
  • Ofatumumab Avastin , imatinib. gefitinib, erlotinib, lapatinib, sorafenib, sunitinib, Rotinib, dasatinib, pazopanib, bortezomib, vorinostat, romic psiiu, carbofuran, everolimus, salidolamine, lenalidomide and thioguanine, or A pharmaceutically acceptable salt of the anticancer drug.
  • the present invention also relates to a method of using the compound of formula I or II for the treatment, prevention or amelioration of mammalian diseases, particularly tumors and cancer, caused by uncontrolled cell proliferation.
  • the invention provides a method of treating a mammalian condition caused by uncontrolled cell proliferation, comprising administering to a mammal in need of such treatment an effective amount of a Formula I or ⁇ of the invention Compound.
  • the cancer is a drug resistant cancer.
  • the cancer is liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, Breast cancer, ovarian cancer, lung cancer, Wilms' tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic leukemia, primary brain cancer, malignant melanin Tumor, small cell lung cancer, gastric cancer, colon cancer, malignant pancreatic islet tumor, malignant carcinoid cancer, choriocarcinoma, mycosis fungoides, head or neck cancer, osteogenic sarcoma, pancreatic cancer, acute myeloid leukemia, hair Cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary tumor, thyroid cancer, es
  • the method further comprises administering at least one known anticancer drug or a pharmaceutically acceptable salt of the anticancer drug.
  • the known anticancer drug is selected from the group consisting of: busulfan, cisplatin, mitomycin c, carboplatin, colchicine, vinblastine, yew drunk, Docetaxel, camptothecin, topotecan, doxorubicin and metoprolol, 5-azapine, 5-fluorouridine, cysteine, 5-fluoro-2' - go Oxyuridine, ara-C, hydroxyurea, thioguanine, campath, Herceptin, Rituxan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, vincristine, mitoguazone, epidermis , aclarithromycin, bleomycin, mitoxantrone, ell iptin
  • the method further comprises performing radiation therapy on the mammal.
  • the compounds of the invention may be administered after the mammal has undergone cancer surgery.
  • the invention also relates to a process for the preparation of novel compounds of structural formula I and I I. Detailed ways
  • the present inventors have found that 3-aryl-6-aryl-[1,2,4]triazolo[4-b]pyridazine can be used as a cell proliferation inhibitor.
  • the compounds of formula I and formula II are useful in the treatment of diseases caused by abnormal cell growth.
  • a compound useful in the present invention is a compound of formula I or a pharmaceutically acceptable salt or prodrug thereof:
  • ⁇ ⁇ and Ar 2 are independently an aryl group which may be substituted or a heteroaryl group which may be substituted;
  • a and Ar 2 are optionally substituted phenyl or pyridyl. More preferably, A and Ar 2 are phenyl groups. Preferred compounds of formula I are neutralized by hydrogen.
  • 1 and independently are hydrogen, halogen, amino group which may be substituted, an anthracene group which may be substituted, a fluorenyl group which may be substituted, a 3,4 decyl group, an alkenyl group, an alkynyl group, a hydroxyalkyl group, an amine fluorenyl group a carboxyalkyl group, a nitro group, a cyano group, an amide group, a hydroxyl group, a decyl group, an acyloxy group, an azide group, a carboxyl group, a hydroxyamido group or a sulfonium sulphide which may be substituted;
  • R 3 -R 12 are independently hydrogen, halogen, amino, alkoxy, ( ⁇ . fluorenyl, haloalkyl, aryl, carbocyclyl, heterocyclyl, heteroaryl, alkenyl, alkynyl, aryl Base, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, hydroxy hydrazine Oxyl, amino fluorenyl, amino methoxy, carboxy fluorenyl, carboxy fluorenyl, nitro, cyano, amide, hydroxy, decyl, acyloxy, azide, carboxy, hydroxyamido, alkane A sulfamoyl group, an aminosulfonyl group, a disubstituted nonylaminosulfonyl group, a de
  • a preferred group of compounds of formula II is neutralized as hydrogen.
  • Another preferred group of compounds of formula II are d- 3 alkoxy, d- 3 haloalkoxy, d- 3 alkyl, amino or amine;
  • Ru is hydrogen, halogen, C M methoxy, d- 3 alkyl, nitro or cyano.
  • Another preferred group of compounds of formula II are amino, amine, C M alkoxy, ( -3 alkyl or C M halo); and are hydrogen, amino, amine, d- 3 , ( 3- haloalkyl, halogen, hydroxy or nitro.
  • R 6 are independently hydrogen, decyl, halogen, hydroxy, amino, nitro or haloalkyl.
  • R 12 are independently selected from the group consisting of d- 3 methoxy and d- 3 halooxy. It is selected from the group consisting of hydrogen, decyloxy, nitro, halogen, and d- 3 fluorenyl, and 1 ⁇ is independently selected from the group consisting of hydrogen, halogen, d- 3 methoxy, and d- 3 alkyl.
  • the sum is hydrogen, and independently is d- 3 fluorenyl, halogen, hydroxy, amino and nitro, C 3 decyloxy, d- 3 halodecyl and d- 3- alkyl .
  • R 12 are independently selected from the group consisting of d- 3 methoxy and d- 3 haloalkoxy. Selected from hydrogen, alkoxy, nitro, halogen and d- 3 fluorenyl, and 1 ⁇ independently selected from the group consisting of hydrogen, halogen, d- 3 methoxy and d- 3 fluorene
  • the base, and R 7 are hydrogen, and independently hydrogen, CM alkyl, halogen, hydroxy, amino and nitro, are decyloxy. 3
  • the compound does not include the following compound: 3-(2-methoxyphenyl)-6-(3,4-dimethoxyphenyl)-[1, 2, 4] triazole [4, 3-]pyridazine; and 3-(4-chlorophenyl)_6_(3,4,5-trimethoxyphenyl)-[1, 2,4]triazole [4, 3-6] pyridazine.
  • Preferred compounds of Formula I and Formula II include, but are not limited to:
  • mercapto refers to an alkyl group itself or a group having up to ten carbon atoms in a straight or branched chain.
  • Useful sulfhydryl groups include straight chains or branched chains.
  • the thiol group is more preferably a d- 3 alkyl group. typical.
  • the fluorenyl group includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, 3-pentyl, hexyl and octyl groups.
  • alkenyl refers to a radical having from 1 to 10 carbon atoms in a straight or branched chain wherein at least one of the two carbon atoms in the chain contains a double bond.
  • Typical alkenyl groups include ethenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl.
  • alkynyl means a straight or branched chain containing from 2 to 10 carbon atoms, wherein at least one of the two carbon atoms in the chain contains a hydrazone bond.
  • Typical alkynyl groups include ethynyl, 1-propynyl, 1-methyl-2-propynyl, 2-propynyl, 1-butynyl and 2-butynyl.
  • Useful alkoxy groups include those substituted with any of the above alkyl groups.
  • Useful sulfonylthio groups include any of the above.
  • Useful amino groups include -NH 2 , - Legs 1 - 15 and - 15 6 , wherein R 15 and R 16 are.
  • the alkyl group can be substituted.
  • the alkyl group, the decyloxy group, the alkylthio group, the alkenyl group, the alkynyl group, the cycloalkyl group, the carbocyclic ring and the heterocyclic ring may be one or more (for example 1, 2, 3 or 4) selected from the group consisting of Substituent substituent substitution: halogen, hydroxy, carboxy, amino, amine, nitro, cyano, amido, d- 6 acyloxy, d- 6 alkoxy, aryloxy, alkylthio, C 6 -C 1() aryl, C 4 —C 7 cycloalkyl, C 2 -C 6 alkenyl, Cs-Ci.
  • the decyloxy group may be substituted by one or more (eg, 1 to 4 or 1 to 3 unequal) substituents selected from the group consisting of: halogen, morpholinyl, ammonia including decylamine And dinonylamine and carboxy ester.
  • An aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl and heteroaryl fluorenyl group may be selected from one or more (eg 1, 2, 3 or 4) Substituents for the following groups are substituted: halogen, methylenedioxy, dC 6th generation, CC 10 aryl, CrC? ring, Cf Ci; chain fluorenyl, C "C 6 block, C 6 _C 10 aryl (C "C 6 ) group, Cs-. aryl (C 2 - C 6 ) alkenyl, Cs-G.
  • aryl refers to a aryl group or as part of another group, and refers to a monocyclic, bicyclic or tricyclic aromatic group containing from 6 to 14 carbon atoms.
  • Useful aryl groups include C 6 - 14 aryl group, more preferably Yes.
  • Aryl Typical (6 - 14 aryl groups include phenyl, naphthyl, phenanthryl, anthryl, indenyl, biphenyl, biphenylene, and Fuji.
  • Carbocycle as used herein includes cycloalkyl and partially saturated carbocyclic groups.
  • a useful cyclic fluorenyl group is a C 3 -8 cyclodecyl group.
  • Typical cyclodecyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Useful saturated or partially saturated carbocyclic groups are the cycloalkyl and cycloalkenyl groups described above, such as cyclopentenyl, cycloheptenyl and cyclooctenyl.
  • Useful halogen or halogen groups include fluorine, chlorine, bromine and iodine.
  • aryl alkyl with includes any of a C 6 _ 14 aryl unsubstituted. alkyl.
  • Preferred arylalkyl groups are benzyl, phenethyl or naphthylmethyl.
  • arylalkenyl includes any of the above C 6 _ 14 aryl-substituted alkenyl group.
  • arylalkynyl includes any of the above C 6 _ 14 aryl unsubstituted. Alkynyl.
  • aryloxy includes any of the above groups are C 6 _ 14 aryl group substituted aryl group which may be substituted with.
  • Useful aryloxy groups include phenoxy and 4-methylphenoxy.
  • aryloxy is substituted by any of the above aryl groups.
  • An alkoxy group the aryl group of which may be substituted.
  • Useful arylalkoxy groups include benzyloxy and phenylethoxy.
  • Useful haloalkyl groups include those substituted by one or more fluorine, chlorine, bromine or iodine atoms, such as fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1 , 1-difluoroethyl, chloromethyl, chlorofluoromethyl and trichloromethyl.
  • Useful acylamino (amido) is any acyl (decanoyl) attached to an amine nitrogen, such as acetamido, chloroacetamido, propionamido, butyramido, pentanoamide, and An amide group, and an aryl-substituted d- 6 amide group such as a benzamide group.
  • acyloxy groups are any d- 6 acyl (decanoyl) attached to oxygen (-0-), such as formyloxy, acetoxy, propionyloxy, butyryloxy, pentyl Acyloxy and acyloxy.
  • a heterocyclic ring refers to a saturated or partially saturated 3-7 membered monocyclic ring, or a 7-10 membered bicyclic ring system, which is composed of a carbon atom and optionally from 1 to 4 heteroatoms from 0, N, and S.
  • Useful saturated or partially saturated heterocyclic groups include tetrahydrofuranyl, pyranyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolium, imidazolinyl, indanyl, iso-dihydro Mercapto, quinuclidinyl, morpholinyl, heterochromyl, chromanyl, pyrazolyl and pyrazolinyl.
  • heteromatic ring means having 5 to 14 ring atoms and having 6, 10 or 14 ⁇ electrons are shared on the ring system. Further, the ring atoms contained are carbon atoms and optionally 1-3 hetero atoms from oxygen, nitrogen and sulfur.
  • Useful heteroaryl groups include thienyl, benzo[ZJ thienyl, benzo[2,3-6]thienyl, thioxyl, furyl, pyranyl, isobenzopyranyl, color Alkenyl, anthranilyl, phenoxanthi inyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, including but not limited to 2-pyridyl, 3-pyridyl and 4-pyridyl, pyridyl Azinyl, pyrimidinyl, pyridazinyl, fluorenyl, isodecyl, 3H-indenyl, fluorenyl, oxazolyl, fluorenyl, 4H-quinolizinyl, isoquinolinyl, quinolinyl , pyridazinyl, naphthyridinyl, acridinyl, naphthyldiazo(
  • heteroaryloxy includes oxy substituted with any of the above heteroaryl groups, wherein the heteroaryl group may have a substituent.
  • Useful heteroaryloxy groups include pyridyloxy, pyrazinyloxy, pyrrolyloxy, pyrazolyloxy, imidazolyloxy and phenylthiooxy.
  • heteroaryloxy refers to being substituted with any of the above heteroaryl groups.
  • stereoisomers including optical isomers.
  • the present invention includes all stereoisomers and racemic mixtures of such stereoisomers, as well as the individual enantiomers which can be separated according to methods well known to those skilled in the art.
  • Examples of pharmaceutically acceptable salts include inorganic and organic acid salts such as hydrochlorides, hydrobromides, sulfates, citrates, lactates, tartrates, maleates, fumarates, Mandelic acid salts and oxalates; and inorganic and organic base salts formed with bases such as sodium hydroxy, tris(hydroxymethyl)aminocarboxamidine (TRIS, tromethamine) and N-methylglucamine.
  • inorganic and organic acid salts such as hydrochlorides, hydrobromides, sulfates, citrates, lactates, tartrates, maleates, fumarates, Mandelic acid salts and oxalates
  • inorganic and organic base salts formed with bases such as sodium hydroxy, tris(hydroxymethyl)aminocarboxamidine (TRIS, tromethamine) and N-methylglucamine.
  • prodrugs of the compounds of the invention include simple esters of carboxylic acid containing compounds (e.g., esters obtained by condensation with d- 4 alcohols according to methods known in the art); esters of hydroxyl containing compounds (e.g. An ester obtained by condensation with a C 4 carboxylic acid, a C 3 -6 diacid or an anhydride thereof such as succinic anhydride and fumaric anhydride according to methods known in the art); an imine of an amino group-containing compound (for example, according to the art) The method is an imine obtained by condensation with a CH aldehyde or a ketone; a carbamate of an amino group-containing compound, such as Leu et al.
  • esters of hydroxyl containing compounds e.g. An ester obtained by condensation with a C 4 carboxylic acid, a C 3 -6 diacid or an anhydride thereof such as succinic anhydride and fumaric anhydride according to methods known in the art
  • the compounds of the invention can be prepared using methods known to those skilled in the art or by the novel methods of the invention. Specifically, the compound of the present invention having the formula I or the formula ⁇ can be produced as shown in the reaction examples in Reaction Scheme 1.
  • 3,6-dihalopyridazines such as 3,6-dichloropyridazine and benzoacylhydrazines such as 2-methoxybenzohydrazide are reacted in n-butanol to give 6-chloro-3-(2- Methoxyphenyl)-[1,2,4]triazole[4,3-6]pyridazine.
  • a palladium catalyst such as tetrakistriphenyl palladium
  • a base such as cesium carbonate
  • the compound of the present invention can be produced as shown in the reaction examples in Reaction Scheme 2.
  • a 3,6-dihalopyrazine such as 3,6-dichloropyridazine
  • phenylboronic acid such as 4-methoxybenzeneboronic acid
  • a palladium catalyst such as tetrakistriphenylphosphorus palladium
  • a base such as cesium carbonate.
  • 3-Chloro-6-(4-methoxyphenyl)pyridazine is reacted with hydrazine hydrate to give 3-hydrazinyl-6-(4-methoxyphenyl)pyridazine.
  • a condensate B0P, benzotriazole-l-yl-oxy-tris-(dimethylamino)-phosphoniumhexaf luorophosphate
  • a base such as N-methylmorpholine
  • 3-hydrazide-6-(4-methoxyl) Reaction of phenyl)pyridazine with substituted benzoic acid such as 2-trifluoromethoxybenzoic acid to give N'-(6-(4-methoxyphenyl)pyridazin-3-position)-2-(trifluoromethyl) Oxyphenyl) phenylhydrazine.
  • Another important aspect of the present invention is the discovery that the compounds of Formula I and Formula II have potent anti-cell proliferative activity against drug-resistant cancer cells such as breast cancer cells, and are effective in killing these drug-resistant cancer cells. In contrast, many standard anticancer drugs do not effectively kill cancer cells that are resistant under the same conditions. Thus, the compounds of the invention are useful in the treatment of drug resistant cancers, such as breast cancer in mammals.
  • the invention also encompasses methods of treating an animal with an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt or prodrug thereof.
  • the method of treatment is for the treatment of cancer - a disease caused by uncontrolled cell growth or abnormal cell spread.
  • Such diseases include, but are not limited to, liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer , Wilms tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic leukemia, primary brain cancer, malignant melanoma, small cell lung cancer, stomach cancer, Colon cancer, malignant pancreatic islet tumor, malignant carcinoid cancer, choriocarcinoma, mycosis fungoides, head or neck cancer, osteogenic sarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, neuroblastoma, Rhabdomyosarcoma, Kaposi's sarcoma, genitourinary tumor, thyroid cancer, esophage
  • an effective amount of a pharmaceutical formulation is administered to a patient having one or more of these conditions.
  • the pharmaceutical preparations contain a therapeutically effective concentration of a compound of formula I or formula, formulated for oral, intravenous, topical or topical administration for the treatment of cancer and other diseases.
  • the amount administered is the amount effective to ameliorate or eliminate one or more conditions.
  • an effective amount is a dose sufficient to ameliorate or in some way reduce the symptoms associated with the disease.
  • Such a dose can be administered as a single dose or can be administered according to an effective therapeutic regimen.
  • the amount administered may cure the disease, but administration is usually to improve the symptoms of the disease. Repeated administration is generally required to achieve the desired improvement in symptoms.
  • the invention also relates to the use of a compound of formula I or I I according to the invention for the manufacture of a medicament for the treatment or prevention of a disease caused by uncontrolled cell growth and abnormal cell spread.
  • the diseases caused by the uncontrolled cell growth and abnormal cell spread include cancer.
  • the disease is selected from the diseases described above.
  • the disease is selected from the group consisting of liver cancer, melanoma, lung cancer, and breast cancer.
  • the medicament may also contain other known anticancer agents including, but not limited to, the various known anticancer agents described herein.
  • a pharmaceutical composition comprising a compound of Formula I or Formula II, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier, which comprises an anti-malignant cell proliferating drug.
  • Another embodiment of the present invention relates to a pharmaceutical composition effective for treating cancer, comprising a compound of Formula I or Formula II, or a pharmaceutically acceptable salt or prodrug thereof, and at least one compound comprising an anti-malignant cell proliferation agent
  • a pharmaceutical composition effective for treating cancer comprising a compound of Formula I or Formula II, or a pharmaceutically acceptable salt or prodrug thereof, and at least one compound comprising an anti-malignant cell proliferation agent
  • a known anticancer drug or a pharmaceutically acceptable salt of an anticancer drug is used in combination.
  • Known anticancer drugs that can be used in combination therapy for cancer include, but are not limited to, alkylating agents such as busulfan, cisplatin, mitomycin c, and carboplatin; antimitotic agents such as colchicine, vinblastine, and yew drunk And docetaxel; topoisomerase I preparations such as camptothecin and topotecan; topoisomerase II inhibitors such as doxorubicin and metoprolol; RNA/DNA antimetabolites such as 5-aza Cytosine, 5-fluorouridine and cysteine; DNA antimetabolites such as 5-fluoro-2'-deoxyuridine, ara-C, hydroxyurea and thioguanine; antibodies such as campath, Hersey Ting and Ritu X an.
  • alkylating agents such as busulfan, cisplatin, mitomycin c, and carboplatin
  • antimitotic agents such as colchicine, vinblastine, and yew
  • anticancer drugs for anticancer combination therapy include melphalan, chlorambucil, cyclophosphamide, ifosfamide, vincristine, mitoguazone, epirubicin, aclarithromycin, breez , mitoxantrone, ell iptinium, fludarabine, octreotide, retinoic acid, tamoxifen, arsenic, ji Cicitabine, letrozole, fulvestrant, bendamustine, pralatrexate, pemetrexed, nelarabine, temozolomide, zoledronic acid, irinotecan, ixabepilone, cabaz itaxel, vinorelbine , Panitumuma Ofatumumab, Avastin, imatinib, gefitinib, ⁇ rotorinib, lapatinib, sorafenib, sunitin
  • the compounds of the invention may be administered as a single pharmaceutical composition with at least one known anti-cancer drug.
  • the compounds of the invention may be administered separately from at least one known anticancer drug.
  • the compound of the invention is administered at about the same time as at least one of the known anticancer agents, i.e., all drugs are administered simultaneously or sequentially, as long as the compound achieves a therapeutic concentration in the blood simultaneously.
  • the compound of the invention and at least one known anticancer drug are administered according to a respective dosage regimen as long as the compound reaches a therapeutic concentration in the blood.
  • Another embodiment of the present invention is a bioconjugate of the compound which is effective for inhibiting tumors.
  • the bioconjugant capable of inhibiting tumors consists of the compound with a medically active antibody, such as Herceptin or Rituxan, or an auxin, such as DGF or NGF, or a cytokine, such as interleukin 2 or 4, or any A molecular composition that binds to the cell surface.
  • the antibody and other molecules are capable of delivering the compound to its target, making it an effective anticancer drug.
  • This bioconjugate can also increase the anticancer effect of medically active antibodies such as Herceptin or Rituxan.
  • Another embodiment of the present invention relates to a pharmaceutical composition which is effective for inhibiting tumors, comprising a compound of formula I or I I which is resistant to cytoplasmic proliferation, or a usable pharmaceutically acceptable salt or prodrug thereof, in combination with radiation therapy.
  • the compounds of the invention may be administered at the same time or at different times as the radiation therapy.
  • Another embodiment of the present invention relates to a pharmaceutical composition which is effective for post-operative treatment of cancer, comprising a compound of formula I or I I which is resistant to cell proliferation, or a usable pharmaceutically acceptable salt or prodrug thereof.
  • the present invention also relates to a method of treating a cancer in a mammal by surgically removing the tumor and then using the pharmaceutical composition of the present invention.
  • Stent implantation has become the new standard angioplasty.
  • in-stent restenosis remains a major limitation of intracoronary stenting.
  • New approaches have been developed for topical administration of local vascular biological pharmacological modulation. This approach allows for precise and timely application of the drug at the site of vascular injury.
  • Many anti-cell proliferative agents are currently undergoing clinical studies, including actinomycin D, rapamycin or paclitaxel-coated stents (Regar E., et al., Br. Med. Bull. 59: 227-248 (2001) Therefore, the anti-cell proliferative agent of the present invention can also be used to prevent in-stent restenosis.
  • the pharmaceutical composition of the present invention includes all of the pharmaceutical preparations of the present invention in an amount effective to achieve their intended purpose. While the needs of each individual are different, one skilled in the art can determine the optimal dosage for each portion of the pharmaceutical formulation.
  • the compound, or a pharmaceutically acceptable salt thereof is administered orally to a mammal daily, in an amount of from about 0.0025 to 50 mg/kg body weight. 01 ⁇ Preferably, it is about 0.01 to 10 mg per kilogram of oral administration. If a known anticancer drug is also administered, the dose should be effective to achieve its intended purpose.
  • the optimal dosage of these known anticancer drugs is well known to those skilled in the art.
  • the unit oral dose may comprise from about 0.01 to 50 mg, preferably from about 0.1 to 10 mg of the compound of the invention.
  • the unit dose may be administered one or more times per day in one or more tablets, each tablet containing from about 0.1 to 50 milligrams, conveniently about 0.5 to 10 milligrams of a compound of the invention or a solvate thereof.
  • the concentration of the compound of the present invention may be about 0.01 to 100 mg per gram of the carrier.
  • the compounds of the invention can be administered as unprocessed pharmaceutical products.
  • the compounds of the invention may also be administered as part of a suitable pharmaceutical formulation containing a pharmaceutically acceptable carrier (including adjuvants, adjuvants).
  • a pharmaceutically acceptable carrier including adjuvants, adjuvants.
  • These pharmaceutically acceptable carriers facilitate the processing of the compounds into pharmaceutically acceptable pharmaceutical preparations.
  • the preferred pharmaceutical preparations especially those of the oral and preferred modes of administration, such as tablets, troches and capsules, and solutions suitable for injection or oral administration, containing from about 0.01% to about 99%, preferably from about 0. 25% to 75% of active compound and excipients.
  • non-toxic pharmaceutically acceptable salts of the compounds of the invention are non-toxic pharmaceutically acceptable salts of the compounds of the invention.
  • the acid addition salt is formed by mixing a non-toxic pharmaceutically acceptable acid solution and a solution of the compound of the present invention.
  • the acid is, for example, hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid or the like.
  • the base addition salt is formed by mixing a non-toxic pharmaceutically acceptable base solution and a solution of the compound of the present invention.
  • the base is, for example, sodium hydroxide, potassium hydroxide, hydrogen choline, sodium carbonate, Tri s, N-methyl-glucosamine or the like.
  • the pharmaceutical preparation of the present invention can be administered to any mammal as long as they can obtain the therapeutic effect of the compound of the present invention.
  • the most important of these mammals are human and veterinary animals, although the invention is not intended to be so limited.
  • the pharmaceutical preparation of the present invention can be administered by any route to achieve its intended purpose.
  • it can be administered parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, transdermally, intranasally, intrathecally, intracranically, nasally or externally.
  • it can be administered orally.
  • the dosage of the drug will be determined by the age of the patient, the health and weight, the type of concurrent treatment, the frequency of treatment, and the desired therapeutic benefit.
  • the pharmaceutical preparation of the present invention can be produced in a known manner. For example, it is manufactured by conventional mixing, granulating, tableting, dissolving, or freeze drying processes. When preparing oral preparations, it can be combined with solid adjuvants and active compounds. Selectively grind the mixture. If necessary or necessary, after adding appropriate amounts of auxiliaries, the granule mixture is processed to obtain a tablet or lozenge core.
  • Suitable excipients are, in particular, fillers, such as sugars such as lactose or sucrose, mannitol or sorbitol; cellulose preparations or calcium phosphates, such as tricalcium phosphate or calcium hydrogen phosphate; and binders, such as starch pastes, These include corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone.
  • fillers such as sugars such as lactose or sucrose, mannitol or sorbitol
  • cellulose preparations or calcium phosphates such as tricalcium phosphate or calcium hydrogen phosphate
  • binders such as starch pastes, These include corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, or polyvinylpyrroli
  • disintegrants such as the starch mentioned above, as well as carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salts, such as sodium alginate.
  • Adjuvants especially flow regulation Agents and lubricants, for example, silica, talc, stearates, such as calcium magnesium stearate, stearic acid or polyethylene glycol.
  • the tablet core can be provided with a suitable coating that is resistant to gastric juice. For this purpose, a concentrated sugar solution can be applied.
  • This solution may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, a lacquer solution and a suitable organic solvent or solvent mixture.
  • a suitable cellulose solution such as cellulose acetate phthalic acid or hydroxypropyl methylcellulose phthalic acid can be used.
  • a dye or pigment can be added to the coating of the tablet or tablet core. For example, a combination for identifying or for characterizing the dose of an active ingredient.
  • Other orally administrable pharmaceutical preparations include pressure-bonded capsules made of gelatin, and sealed soft capsules made of gelatin and a plasticizer such as glycerin or sorbitol.
  • the pressure-bonded capsules may contain the active compound in the form of granules mixed with a filler such as lactose, a binder such as a starch, a lubricant such as talc or magnesium stearate, and a stabilizer.
  • the active compound is preferably dissolved or suspended in a suitable liquid such as a fat or liquid paraffin, to which a stabilizer may be added.
  • Formulations suitable for parenteral administration include aqueous solutions of the active compounds, such as solutions of water-soluble salts and basic solutions.
  • an oily injection suspension of the appropriate active compound may be employed.
  • Suitable lipophilic solvents or vehicles include oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate, triglycerides or polyethylene glycol 400, cremophor, or cyclodextrin.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Suspension stabilizers may also be included.
  • topical and parenteral formulations made of the compounds of the invention are useful in the treatment of skin cancer.
  • the external preparation of the present invention can be formulated into an oil, a cream, an emulsion, an ointment or the like by a preferably suitable carrier.
  • suitable carriers include vegetable or mineral oils, white mineral oil (white soft paraffin), branched chain fats or fats, animal fats and high molecular alcohols (greater than c 12 ).
  • Preferred carriers are those in which the active ingredient is soluble.
  • Emulsifiers, stabilizers, humectants and antioxidants, as well as agents which impart color or aroma, if desired, may also be included.
  • these external preparations may contain a transdermal penetration enhancer. Examples of such enhancers can be found in U.S. Patent Nos. 3,989,816 and 4,444,762.
  • the cream is preferably prepared by mixing a mixture of mineral oil, self-emulsifying beeswax and water with an active ingredient dissolved in a small amount of oil such as almond oil.
  • a typical example of a cream includes about 40 parts water, 20 parts beeswax, 40 parts mineral oil and 1 part almond oil.
  • the ointment may be formulated by mixing a vegetable oil containing an active ingredient such as almond oil and warm soft paraffin, and then cooling the mixture.
  • a typical ointment example includes about 30% by weight of almond oil and 70% by weight of white soft paraffin.
  • Example 2 The following compounds were prepared using a synthetic procedure analogous to that described in Example lb.
  • the starting material was 6-chloro-3-(2-methoxyphenyl)-[1, 2, 4]triazole [4, 3 -6] pyridazine and the corresponding phenylboronic acid.
  • Example 2 6-chloro-3-(2-methoxyphenyl)-[1, 2, 4]triazole [4, 3 -6] pyridazine and the corresponding phenylboronic acid.
  • 6-(4-Methoxyphenyl)-3-(2-trifluoromethoxyphenyl)-[1 2 4]triazole[4 3-6]pyridazine a) 3-chloro-6- ( 4-methoxyphenyl)pyridazine.
  • 3 6-dichloropyridazine (10 g 67 ol 4-methoxyphenylboronic acid (12.2 g, 80 ol), tetratriphenylphosphine palladium (1.5 g, 1.34 mmol) and 300 mL of toluene and 100 mL of water.
  • Barium carbonate (43.6 g 134 mmol). The mixture was stirred under argon atmosphere for 16 hours at 100 ° C.
  • 6_(4-Methoxyphenyl)-3-(2-trifluoromethoxyphenyl)-[1,2,4]triazolo[4,3-]pyridazine Mix-(6-(4-methoxyphenyl)pyridazin-3-position)-2-(trifluoromethoxy)phenyl hydrazide with 10 mL of phosphorus oxychloride and stir at 100 X overnight. After the reaction solution was cooled to room temperature, it was concentrated under vacuum. The remaining residue was mixed with 20 mL of dichloromethane and 20 mL of ice water, and the pH was adjusted to greater than 10 with a saturated sodium carbonate solution.
  • Example 14 The following compound was obtained by a synthetic method similar to that described in Example 13c-d, starting from 2- hydrazinyl-5-(4-methoxyphenyl)pyridazine and the corresponding substituted benzoic acid.
  • Example 14 The following compound was obtained by a synthetic method similar to that described in Example 13c-d, starting from 2- hydrazinyl-5-(4-methoxyphenyl)pyridazine and the corresponding substituted benzoic acid.
  • the medium was supplemented with the corresponding cell culture medium recommended by the American Cell Culture Preservation Center (ATCC), and penicillin (100 U/ml), streptomycin (100 lg/ml) and 10% fetal bovine serum (Hangzhou Sijiqing Bio) were added. Engineering Materials (China) Co., Ltd.).
  • the cells were harvested by trypsinization at about 80% confluence, cell counted, centrifuged and resuspended in fresh medium for passage.
  • a certain number of cells (3000 cells/well of pG2 T-47D and A549 cells, 5000 cells/well of SMMC-7721 cells, 2000 cells/well of B16F10 cells) were seeded into 96-well cell culture plates at 100 ⁇ per well. 1. The cells were cultured overnight in a 5% C0 2 37 °C incubator. On the next day, 100 ⁇ M of the culture medium containing the test compound (concentration from 10 ⁇ to 1 ⁇ ) and the positive compound was added, and the blank control group was added with 100 ⁇ l of the culture solution. Three parallel holes are provided for each concentration to ensure data accuracy.
  • the relative absorption is 550 minus 660 nm.
  • the compound concentration is plotted on the abscissa and the relative absorbance is plotted on the ordinate.
  • the data fit is processed by Prism software (GraphPad Software, Inc) using the lg (IC 5 .) formula.
  • the absorbance value at the time of inhibition, the highest 0D value is the absorbance value of the blank control group.
  • the calculated IC 5 value refers to the cytotoxic effect of the specific compound.
  • Human breast cancer cell line T47D was grown in DMEM/F12 + 10% FBS medium. Before the experiment, 20,000 cells/well were seeded in a 96-well cell culture plate and returned to a 5% C0 2 cell incubator for 18-24 hours at 37 °C. After aspirating the original culture solution, 180 ⁇ l of fresh culture solution was added to each well, and then 20 ⁇ l of a culture solution containing 10% DMS0 and a 10-fold gradient dilution of the compound (reference compound or test compound) was added to each well. Shake well and mix in a 5% C0 2 incubator at 37 ° C. After 24 h, the plate was centrifuged at 1000 g for 5 minutes, and the supernatant was decanted.
  • cell lysis buffer (10 mM Tris, ⁇ 7 ⁇ 5, 0.1 ⁇ NaCl, 1 Mm EDTA, 0.01%
  • Triton X-100 oscillates at 4 ° C for 30 minutes. It was then centrifuged at 1000 g for 10 minutes at 4 ° C. Then, 20 ⁇ l of the supernatant was pipetted into each well and transferred to the corresponding 384-well blackboard. Then add 20 ⁇ l of caspase-3 assay buffer (20 mM PIPES, pH 7.4, 4Mm) containing 20 ⁇ ⁇ caspase-3 fluorogenic substrate ((Ac-DEVD) 2 -R110, AnaSpec Cat #60304-5) per well.
  • T47D compound induces apoptosis EC 5.
  • the values are summarized in Table III.
  • 6-(3-hydroxy-4-methoxyphenyl)-3-(2-methoxyphenyl)-[1,2,4]triazole [4,3-/ J-pyridazine (Example 12) and its analogs are potent inducers of apoptosis in human breast cell T-47D.

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Abstract

L'invention porte sur une nouvelle 3-aryl-6-aryl-[1,2,4]triazolo[4,3-b]pyridazine représentée par la formule I, dans laquelle formule Ar1, Ar2 et R1-R2 sont tels que définis dans la description. Le composé de formule I est un agent inhibant la prolifération cellulaire. Par conséquent, le composé de la présente invention est utile pour le traitement de maladies provoquées par une croissance cellulaire et une propagation de cellules anormales et incontrôlées.
PCT/CN2012/070100 2011-01-14 2012-01-06 3-aryl-6-aryl-[1,2,4]triazolo[4,3-b]pyridazine comme agent inhibant la prolifération cellulaire et son utilisation WO2012094966A1 (fr)

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CN106188069B (zh) * 2016-07-26 2018-05-08 沈阳药科大学 3,6-二芳基-1H-吡唑并[5,1-c][1,2,4]三氮唑类化合物作为肿瘤细胞增殖抑制剂的用途
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CN116969955B (zh) * 2023-09-25 2023-12-19 中国药科大学 一种[1,2,4]三唑[4,3-b]哒嗪类化合物及其制法与应用

Citations (3)

* Cited by examiner, † Cited by third party
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WO2008030744A2 (fr) * 2006-09-05 2008-03-13 Board Of Regents, The University Of Texas System Inhibiteurs de c-met et leurs utilisations
WO2008069500A1 (fr) * 2006-12-07 2008-06-12 Amorepacific Corporation Dérivés de triazolopyridazine présentant une activité inhibitrice contre l'acétyl-coa carboxylase
WO2009089027A1 (fr) * 2008-01-09 2009-07-16 Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Service, National Institutes Of Health Inhibiteurs de phosphodiestérase

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008030744A2 (fr) * 2006-09-05 2008-03-13 Board Of Regents, The University Of Texas System Inhibiteurs de c-met et leurs utilisations
WO2008069500A1 (fr) * 2006-12-07 2008-06-12 Amorepacific Corporation Dérivés de triazolopyridazine présentant une activité inhibitrice contre l'acétyl-coa carboxylase
WO2009089027A1 (fr) * 2008-01-09 2009-07-16 Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Service, National Institutes Of Health Inhibiteurs de phosphodiestérase

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