WO2008034579A1 - Derives de 2-heterocyclyl-5-phenoxymethylpyridine utilises en tant qu'agents anticancereux - Google Patents

Derives de 2-heterocyclyl-5-phenoxymethylpyridine utilises en tant qu'agents anticancereux Download PDF

Info

Publication number
WO2008034579A1
WO2008034579A1 PCT/EP2007/008094 EP2007008094W WO2008034579A1 WO 2008034579 A1 WO2008034579 A1 WO 2008034579A1 EP 2007008094 W EP2007008094 W EP 2007008094W WO 2008034579 A1 WO2008034579 A1 WO 2008034579A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
formula
triazol
trifluoromethyl
pyridine
Prior art date
Application number
PCT/EP2007/008094
Other languages
English (en)
Inventor
Edgar Voss
Original Assignee
F. Hoffmann-La Roche Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by F. Hoffmann-La Roche Ag filed Critical F. Hoffmann-La Roche Ag
Publication of WO2008034579A1 publication Critical patent/WO2008034579A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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 heterocyclic pyridine derivatives, to a process for their manufacture, pharmaceutical compositions containing them and their manufacture as well as the use of these compounds as pharmaceutically active agents.
  • tumor inhibitors are due to a very wide variety of mechanisms, only some of which are known. It is not unusual for known tumor drugs to be found to have new mechanisms of action. This is also to be expected in the case of the compounds according to the invention. Many tumor drugs act by way of mechanisms such as blockading the mechanism of cell division in the cell, preventing the tumor from being supplied with nutrients and oxygen (antiangiogenesis), preventing metastasis, preventing the reception and the onward transmission of growth signals to the tumor cell or forcing the tumor cell into programmed cell death (apoptosis).
  • the clinically relevant cytostatic agents are frequently administered in combination in order to achieve a synergistic therapeutic effect.
  • WO 98/03505 WO 01/77107, WO 03/031442 and WO 03/059907 relate to heterocyclic compounds as tyrosine kinase inhibitors which are useful as anticancer agents.
  • the present invention relates to compounds of the general formula I,
  • R 1 is hydrogen or alkyl
  • R 2 is hydrogen or alkyl
  • R 3 is hydrogen, fluorine, chlorine, bromine, methyl, methoxy, trifiuoromethyl or trifluoromethoxy;
  • X 1 , X 2 , X 3 , X 4 and X 5 independently represent N or (CH or C), with the proviso that at least one and not more than two of X 1 , X 2 , X 3 , X 4 and X 5 represent N and the remaining of X 1 , X 2 , X 3 , X 4 and X 5 represent (CH or C) wherein only one of X 1 , X 2 , X 3 , X 4 and X 5 is C;
  • the compounds of the present invention show anti-proliferative activity.
  • Objects of the present invention are the compounds of formula I and their pharmaceutically acceptable salts, enantiomeric forms, diastereoisomers and racemates, the preparation of the above-mentioned compounds, pharmaceutical compositions containing them and their manufacture as well as the use of the above-mentioned compounds in the control or prevention of illnesses, especially of illnesses and disorders as mentioned above like common human cancers (such as colorectal, breast, lung, prostate, pancreatic, gastric, bladder, ovarian, melanoma, neuroblastoma, cervical, kidney or renal cancers, leukemias or lymphomas) or in the manufacture of corresponding pharmaceutical compositions.
  • common human cancers such as colorectal, breast, lung, prostate, pancreatic, gastric, bladder, ovarian, melanoma, neuroblastoma, cervical, kidney or renal cancers, leukemias or lymphomas
  • alkyl as used herein means a saturated, straight-chain or branched-chain hydrocarbon containing from 1 to 5 carbon atoms, preferably from 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, t-butyl, n- pentyl, 3-methyl-butyl, 2-methyl-butyl, n-hexyl, 3-methyl-pentyl.
  • alkyl is selected from methyl, ethyl or isopropyl and more preferably alkyl is methyl.
  • alkoxy as used herein means an alkyl-O- group wherein the alkyl is defined as above.
  • a therapeutically effective amount of a compound means an amount of compound that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is within the skill in the art.
  • the therapeutically effective amount or dosage of a compound according to this invention can vary within wide limits and may be determined in a manner known in the art. Such dosage will be adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated. In general, in the case of oral or parenteral administration to adult humans weighing approximately 70 Kg, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded when indicated. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it may be given as continuous infusion.
  • a "pharmaceutically acceptable carrier” is intended to include any and all material compatible with pharmaceutical administration including solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and other materials and compounds compatible with pharmaceutical administration. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions of the invention are contemplated. Supplementary active compounds can also be incorporated into the compositions.
  • R 1 is hydrogen or alkyl; preferably alkyl.
  • R 2 is hydrogen or alkyl preferably alkyl.
  • R 3 is hydrogen, fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl or trifluoromethoxy; preferably fluorine, chlorine or trifluoromethyl; and more preferably chlorine or trifluoromethyl.
  • X 1 , X 2 , X 3 , X 4 and X 5 independently represent N or (CH or C), with the proviso that at least one and not more than two of X 1 , X 2 , X 3 , X 4 and X 5 represent N and the remaining of X 1 , X 2 , X 3 , X 4 and X 5 represent (CH or C) wherein only one of X 1 , X 2 , X 3 , X 4 and X 5 is C and the pyridyl residue of formula I is bound via said C.
  • X 1 , X 2 , X 3 , X 4 independently represent CH or C wherein only one of X 1 , X 2 , X 3 and X 4 is C and the pyridyl residue of formula I is bound via said C; and X 5 is N.
  • One embodiment of the invention are the compounds according to formula I, wherein
  • R 1 is hydrogen or alkyl; preferably alkyl
  • R 2 is alkyl
  • R 3 is fluorine, chlorine or trifluoromethyl; preferably chlorine or trifluoromethyl.
  • X ! , X 2 , X 3 , X 4 independently represent CH or C wherein only one of X 1 , X 2 , X 3 and X 4 is C;
  • X 5 is N.
  • R 1 is hydrogen or alkyl
  • R 2 is hydrogen or alkyl
  • R 3 is hydrogen, fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl or trifluoromethoxy;
  • R 1 is hydrogen or alkyl
  • R 2 is alkyl
  • R 3 is fluorine, chlorine or trifluoromethyl, preferably chlorine or trifluoromethyl.
  • R 1 is hydrogen or alkyl
  • R 2 is alkyl
  • R 3 is fluorine, chlorine or trifluoromethyl, preferably chlorine or trifluoromethyl
  • Such compounds may be selected from the group consisting of:
  • A is -CH(OCH 3 )-CH 2 -, -CH(OH)-CH 2 -, or -C(O)-CH 2 -, preferably
  • A is -CH(OCH 3 )-CH 2 -.
  • R 1 is hydrogen or alkyl
  • R 2 is alkyl
  • R 3 is fluorine, chlorine or trifiuoromethyl, preferably chlorine or trifluoromethyl; and A is -CH(OCH 3 )-CH 2 -.
  • Such compounds may be selected from the group consisting of:
  • A is -CH(OH)-CH 2 -.
  • Another embodiment are the compounds according to formula I or formula Ia, wherein
  • R 1 is hydrogen or alkyl
  • R 2 is alkyl
  • R 3 is fluorine, chlorine or trifluoromethyl, preferably chlorine or trifluoromethyl
  • A is -CH(OH)-CH 2 -.
  • Such compounds may be selected from the group consisting of:
  • A is -C(O)-CH 2 -.
  • R 1 is hydrogen or alkyl
  • R 2 is alkyl
  • R 3 is fluorine, chlorine or trifluoromethyl, preferably chlorine or trifluoromethyl; and A is -C(O)-CH 2 -.
  • Such compounds may be selected from the group consisting of:
  • A is -CH 2 -CH 2 -, -CH(OCH 3 )-CH 2 -, -CH(OH)-CH 2 -, or -C(O)-CH 2 -, preferably -CH 2 -CH 2 -, -CH(OCH 3 )-CH 2 - or -CH(OH)-CH 2 -.
  • A is -CH 2 -CH 2 - or -CH(OCH 3 )-CH 2 -.
  • R 1 is hydrogen or alkyl
  • R 2 is alkyl
  • R 3 is fluorine, chlorine or trifluoromethyl, preferably chlorine or trifluoromethyl
  • A is -CH 2 -CH 2 -, -CH(OCH 3 )-CH 2 -, -CH(OH)-CH 2 -, or -C(O)-CH 2 -, preferably -CH 2 -CH 2 -, -CH(OCH 3 )-CH 2 - or -CH(OH)-CH 2 -, more preferably -CH 2 -CH 2 - or -CH(OCH 3 )-CH 2 -.
  • Another embodiment of the invention is a process for the manufacture of the compounds of formula I in claim 1, wherein
  • R 1 and A have the significance given in formula I above, to give the respective compound of formula I;
  • the compounds of formula I or a pharmaceutically acceptable salt thereof, which are subject of the present invention, may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Such processes, when used to prepare a compound of the formula I or a pharmaceutically-acceptable salt thereof, are illustrated by the following representative schemes 1 to 3 and examples in which, unless otherwise stated, R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , X 4 , X 5 , and A have the significance given herein before.
  • Necessary starting materials are either commercially available or they may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is e.g. described within the accompanying examples or in the literature cited below with respect to scheme 1 to 3. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist. Scheme 1;
  • R > 1 , T R) 2 , ⁇ R>3 , X vl , X v 2 , X v3 , v X 4 , X v 5 , and A have the significance as given above for formula I.
  • the derivatives of formula I can be obtained by reactions well known to someone skilled in the art, e.g. by alkylation of compounds of formula III with compounds of formula II according to step 1 scheme 1.
  • the alkylation can be carried out in the presence of potassium iodide or sodium iodide in solvents like N,N- dimethylformamide (DMF), methanol, ethanol, isopropanol and 2-butanone.
  • Typical bases for this reaction are sodium methylate, sodium hydride, lithium diisopropyl amide or cesium carbonate.
  • the reaction temperatures may vary from 0 0 C to 150 0 C.
  • the phenolic intermediates of formula III, wherein W is -CH 2 -CH 2 - can be prepared e.g. according to US 6,743,924 or US 6,716,863.
  • the phenolic intermediates of formula III, wherein A is -C(O)-CH 2 - or -CH(OH)- CH 2 - can be prepared e.g. by methods described in WO 2006/032453.
  • the chloromethyl-pyridinyl-heterocycles of formula II can be prepared by two general methods, the first one shown in scheme 2 involving a Suzuki-Miyaura- Coupling, which allows a general access to this compound class.
  • the second method that is shown in scheme 3, gives access to compounds of formula I in cases where the ketones represented by formula VIII are easily accessible.
  • R 2 , R 3 , X 1 , X 2 , X 3 , X 4 , and X 5 have the significance as given above for formula I and X is iodine or bromine.
  • step 1 the compounds of formula IV and formula V are reacted in a coupling reaction (Suzuki-coupling, step 1) which can be performed under different reaction conditions well known in the literature.
  • Preferred reaction conditions are described in Meier, P., et al., Synthesis 4 (2003) 551-554, and WO 2005/040100, including a mixture of 1,2-dimethoxyethane and aqueous sodium carbonate solution, the latter also working as the required base, together with the use of palladium tetrakis- triphenylphospine as catalyst.
  • Transformation of the obtained pyridine derivatives of VI in step 2, scheme 2, to the corresponding alcohols VII is achieved by complex hydrides, most conveniently with diisobutylaluminiumhydrid (DIBAL) or lithium aluminum hydride in tetrahydrofuran (THF).
  • DIBAL diisobutylaluminiumhydrid
  • THF tetrahydrofuran
  • step 3 scheme 2, the obtained alcohols of formula VII are reacted with thionyl chloride in dichloromethane to yield the chlorides of formula II.
  • R 2 , R 3 , X 1 , X 2 , X 3 , X 4 , and X 5 have the significance as given above for formula I.
  • Heterocycles of formula II can be prepared by an alternative route shown in scheme 3.
  • a Mannich-type synthesis a mixture of ketones of formula VIII with para-formaldehyde and dimethylamine hydrochloride in a solvent like ethanol in the presence of an acid like 37% HCl is heated to reflux for 2 to 10 hours to give aminoketones of formula IX (scheme 3, step 1).
  • Reaction of compounds of formula IX with 3-aminocrotonic acid esters of formula X in acetic acid at reflux for 2 to 8 hours gives esters of formula VIII (scheme 3, step 2) (see e.g.
  • R 2 , R 3 , X 1 , X 2 , X 3 , X 4 , and X 5 have the significance as given above for formula I.
  • the compounds of formula I or formula can contain one or several chiral centers and can then be present in a racemic, enantiomeric or diastereomeric form.
  • the racemates can be separated according to known methods into the enantiomers. For instance, diastereomeric salts which can be separated by crystallization are formed from the racemic mixtures by reaction with an optically active acid such as e.g. D- or L- camphorsulfonic acid. Alternatively separation of the enantiomers can also be achieved by using chromatography on chiral HPLC-phases which are commercially available.
  • the compounds of formula I or formula Ia and their pharmaceutically acceptable salts possess valuable pharmacological properties. It has been found that said show anti-proliferative activity. Consequently the compounds of the present invention are useful in the therapy and/or prevention of proliferative disorders such as cancer.
  • the activity of the present compounds as antiproliferative inhibitors is demonstrated by the following biological assay:
  • the CellTiter-GloTM Luminescent Cell Viability Assay is a homogeneous method of determining the number of viable cells in culture based on quantitation of the ATP present, which signals the presence of metabolically active cells.
  • HEK293 cells human embryonic kidney cell line transformed by Adenovirus 5 fragments, ATCC-No. CRL 15763
  • DMEM Dulbecco's Modified Eagle Medium
  • GlutamaxTM Invitrogen, 31966-021
  • the cell-plate was equilibrated to room temperature for approximately 30 minutes and than the CellTiter-GloTM reagent was added. The contents were carefully mixed for 15 minutes to induce cell lysis. After 45 minutes the luminescent signal was measured in Victor 2, (scanning multiwell spectrophotometer, Wallac). Details: 1. day:
  • DMEM Dulbecco's Modified Eagle Medium
  • GlutamaxTM Invitrogen, 31966-021
  • 5 % Fetal Calf Serum FCS, Sigma Cat-No. F4135 (FBS)
  • Pen/Strep Invitrogen Cat. No. 15140.
  • the dilution steps are 1:3 a) Add 8 ⁇ l of 10 mM stock solution of compound to 72 ⁇ l DMSO b) dilute 9x 1:3 (always 30 ⁇ l to 60 ⁇ l DMSO) in this DMSO dilution row (results in 10 wells with concentrations from 1000 ⁇ M to 0.06 ⁇ M) c) dilute each concentration 1: 4.8 (10 ⁇ l compound dilution to 38 ⁇ l medium) d) dilute each concentration 1: 10 (10 ⁇ l compound dilution to 90 ⁇ l medium) e) add 10 ⁇ l of every concentration to 60 ⁇ l medium in the cell plate
  • the compounds according to this invention and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions.
  • the pharmaceutical compositions can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions.
  • the administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
  • compositions can be obtained by processing the compounds according to this invention with pharmaceutically acceptable, inorganic or organic carriers.
  • Lactose, corn starch or derivatives thereof, talc, stearic acids or it's salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules.
  • Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules.
  • Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like.
  • Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
  • compositions can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • compositions comprise e.g. the following: a) Tablet Formulation (Wet Granulation):
  • Medicaments or pharmaceutical compositions containing a compound of the present invention or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers are also an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of the present invention and/or pharmaceutically acceptable salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more pharmaceutically acceptable carriers.
  • the compounds of the present invention as well as their pharmaceutically acceptable salts are useful in the control or prevention of illnesses. Based on their antiproliferative activity, said compounds are useful for the treatment of diseases such as cancer in humans or animals and for the production of corresponding medicaments.
  • the dosage depends on various factors such as manner of administration, species, age and/or individual state of health.
  • Another embodiment of the invention is pharmaceutical composition, containing one or more compounds of formula I or formula Ia together with one or more pharmaceutically acceptable carriers.
  • composition comprising a therapeutically effective amount of one or more compounds of formula I or formula Ia together with one or more pharmaceutically acceptable carriers. Still another embodiment of the invention is said pharmaceutical composition for the inhibition of tumor growth.
  • Another embodiment of the invention is a pharmaceutical composition, containing one or more compounds according to formula I or formula Ia, for the treatment of cancer.
  • Another embodiment of the invention is a pharmaceutical composition, containing one or more compounds of formula I or formula Ia as active ingredients together with pharmaceutically acceptable carriers for the treatment of colorectal, breast, lung, prostate, pancreatic, gastric, bladder, ovarian, melanoma, neuroblastoma, cervical, kidney or renal cancers, leukemias or lymphomas.
  • Still another embodiment of the invention is the use of a compound of formula I or formula Ia for the manufacture of corresponding pharmaceutical compositions for the inhibition of tumor growth.
  • Another embodiment of the invention is the use of a compound according to formula I or formula Ia, for the manufacture of corresponding pharmaceutical compositions for the treatment of cancer.
  • Another embodiment of the invention is the use of the compounds of formula I or formula Ia as anti-proliferating agents.
  • Still another embodiment of the invention is the use of a compound of formula I or formula Ia for the treatment of cancer.
  • Lithium aluminium hydride 1.41 g (37.18 mmol) was suspended in 55 ml tetrahydrofuran and it was stirred for 20 min. Under cooling 6'-Chloro-6-methyl- [2,3']bipyridinyl-5-carboxylic acid ethyl ester 5.30 g (18.58 mmol) dissolved in 55 ml tetrahydrofuran were added dropwise and the reaction mixture was stirred for 2 hours at 0 0 C. 68 ml brine was added and it was stirred at 0 0 C for 1 hour. The solution was carefully adjusted to pH 5 by adding cone, hydrochloric acid.
  • reaction mixture was adjusted to pH 6-7 by adding ammonium chloride solution and stirring for 1 hour.
  • the organic solvent was removed and the aqueous layer was extracted three times with ethyl acetate.
  • the combined organic layers were dried over sodium sulphate and evaporated.
  • the residue was purified by chromatography on silica gel (ethyl acetate/n-heptane 5:1) to yield 227 mg (76%) of the title compound as a white powder.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés de formule I, leurs sels, formes énantiomères, diastéréoisomères et racémates pharmaceutiquement acceptables, la préparation desdits composés, des médicaments les contenant, la fabrication de ces médicaments, ainsi que l'utilisation de ces composés dans le traitement ou la prévention de maladies telles que le cancer.
PCT/EP2007/008094 2006-09-20 2007-09-18 Derives de 2-heterocyclyl-5-phenoxymethylpyridine utilises en tant qu'agents anticancereux WO2008034579A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP06019627.6 2006-09-20
EP06019627 2006-09-20

Publications (1)

Publication Number Publication Date
WO2008034579A1 true WO2008034579A1 (fr) 2008-03-27

Family

ID=37651323

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2007/008094 WO2008034579A1 (fr) 2006-09-20 2007-09-18 Derives de 2-heterocyclyl-5-phenoxymethylpyridine utilises en tant qu'agents anticancereux

Country Status (1)

Country Link
WO (1) WO2008034579A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103159740A (zh) * 2011-12-19 2013-06-19 天津市国际生物医药联合研究院 1,5-二取代-1,2,3-三氮唑三氟甲基类化合物的制备及其应用
EP3868749A1 (fr) 2016-03-23 2021-08-25 Syngenta Participations Ag Composés herbicides

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998003505A2 (fr) * 1996-07-19 1998-01-29 Takeda Chemical Industries, Ltd. Composes heterocycliques, leur production et leur utilisation
WO2001077107A1 (fr) * 2000-04-07 2001-10-18 Takeda Chemical Industries, Ltd. Production et utilisation de composes heterocycliques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998003505A2 (fr) * 1996-07-19 1998-01-29 Takeda Chemical Industries, Ltd. Composes heterocycliques, leur production et leur utilisation
WO2001077107A1 (fr) * 2000-04-07 2001-10-18 Takeda Chemical Industries, Ltd. Production et utilisation de composes heterocycliques

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103159740A (zh) * 2011-12-19 2013-06-19 天津市国际生物医药联合研究院 1,5-二取代-1,2,3-三氮唑三氟甲基类化合物的制备及其应用
CN103159740B (zh) * 2011-12-19 2016-08-03 天津市国际生物医药联合研究院 1,5-二取代-1,2,3-三氮唑三氟甲基类化合物的制备及其应用
EP3868749A1 (fr) 2016-03-23 2021-08-25 Syngenta Participations Ag Composés herbicides

Similar Documents

Publication Publication Date Title
US7005432B2 (en) Substituted imidazol-pyridazine derivatives
AU2020340299B2 (en) Crystalline forms of a CD73 inhibitor
JP5026633B2 (ja) 細胞増殖の阻害のための置換ビスインドリルマレイミド類
WO2009138338A1 (fr) Nouveaux n-(2-amino-phényl)-acrylamides
WO2008034579A1 (fr) Derives de 2-heterocyclyl-5-phenoxymethylpyridine utilises en tant qu'agents anticancereux
US7208526B2 (en) Styrylsulfonamides
US7429605B2 (en) Phenylpyridine derivatives
KR100843533B1 (ko) 신규한 디아진 유도체, 이의 제조 및 약학적 제제로서의용도
KR100763293B1 (ko) 신규 아닐린 유도체, 그의 제조 및 약학 제제로서의 용도
EP1904471B1 (fr) Derives d'heteroarylethenyle, fabrication et utilisation comme agents pharmaceutiques
US7939532B2 (en) Heterocyclyl pyridyl sulfonamide derivatives, their manufacture and use as pharmaceutical agents
JP2008513402A (ja) 受容体チロシンキナーゼ阻害剤としての１，２，３−トリアゾール誘導体
JP2009509998A (ja) ジアジンアゾール誘導体、それらの製造及び薬剤としての使用
JP2008514566A (ja) チロシンキナーゼ阻害剤としてのオキサゾール誘導体
US7879884B2 (en) Aryl pyridyl sulfonamide derivatives, their manufacture and use as pharmaceutical agents
WO2023057371A1 (fr) Dérivés de 1,2,4-oxadiazol-5-one pour traiter le cancer
JP2009504586A (ja) ピラゾール誘導体、それらの製造及び医薬品としての使用
BR112018001209B1 (pt) Composto de pirimidina de anel fundido, intermediário, e método de preparação, composição e uso do mesmo

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07818200

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07818200

Country of ref document: EP

Kind code of ref document: A1