CN101479244A - New urea derivatives and the application thereof - Google Patents
New urea derivatives and the application thereof Download PDFInfo
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- CN101479244A CN101479244A CNA2007800237763A CN200780023776A CN101479244A CN 101479244 A CN101479244 A CN 101479244A CN A2007800237763 A CNA2007800237763 A CN A2007800237763A CN 200780023776 A CN200780023776 A CN 200780023776A CN 101479244 A CN101479244 A CN 101479244A
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Abstract
The invention relates to new urea derivatives suitable for the production of pharmaceutical compounds.
Description
The present invention relates to new urea derivatives, comprise the pharmaceutical composition of these compounds, these compounds are as active substance or as the purposes of prodrug, and the method that is used to prepare these compounds (active substance and prodrug).
Bioorganic ﹠amp according to people such as Porter; People's such as Medicinal Chemistry Letters11:1907-1910 (2001) and Bankston Organic Proces sResearch ﹠amp; Development, 6:777-781 documents such as (2002), various 1,3-biaryl ureas derivative is known in the art.
They are particularly useful for treating various disease, especially dissimilar cancers.
Be starved of new and improved active substance in principle, its can anticancer hyperplasia and therefore suppress the superfluous undue defense response of giving birth to tumor growth and suppressing health, as septic shock, allergy, autoimmune disease, the reaction of transplant rejection and acute and chronic inflammation only has very hypotoxicity even does not have cytotoxicity at all intact cell simultaneously.In addition, it should be able to suppress the growth and the new ill vessel growth in the retina (moving under water property of inhibition vision loss (AMD)) of unicellular organism.
For this reason, the present invention proposes compound according to formula I:
Formula I
Wherein X and Y can be identical or different, the expression key or-O-or-S-, wherein at least one radicals X or Y be-O-or-S-,
Wherein R1 is selected from down group: 2-or 3-pyrryl, 2-, 4-or 5-imidazolyl, 3-, 4-or 5-pyrazolyl, 2-, 3-or 4-pyridyl, 2-or 3-pyrazinyl, 2-or 4-pyrimidyl, 3-or 4-pyridazinyl, 3-, 4-or 5-isoxazolyl, 3-furazan base, 2-, 3-or 4-quinolyl, 1-, 3-or 4-isoquinolyl, 4-, 5-, 6-or 7-indyl (single polysubstituted or unsubstituted), 4-, 5-, 6-or 7-pseudoindoyl, 1,8-naphthyridines-2-or-3-or-the 4-base, and phenyl (single polysubstituted or unsubstituted)
Wherein R2 is 4-, 5-, 6-or 7-indyl (single polysubstituted or unsubstituted), 4-, 5-, 6-or 7-pseudoindoyl (single polysubstituted or unsubstituted), 4-, 5-, 6-or 7-benzoxazolyl (single polysubstituted or unsubstituted), or according to the residue of formula II
Formula II
Wherein Z is C or N,
Wherein V and W represent independently of each other key or-NH-,
Wherein R3 is any residue,
Left side ring among its Chinese style II can be used halogen atom, especially fluorine identical or differently, single, double, three or four replacements of chlorine or bromine,
The present invention also provides steric isomer, salt or the metabolite of these compounds of formula I.The glucuronide of above compound and N-pyridine-N-oxide especially belong to metabolite.
R1 can be by-F ,-Cl ,-Br ,-I, (C
1-C
8) alkyl, can be if feasible by-F ,-Cl ,-Br or-the single or many halogenations of I, or (C
1-C
8) single, double or three replacements of oxygen base alkyl, wherein substituting group can be identical or different.
R1 is phenyl preferably, quinolyl, or 1,8-naphthyridines-4-base is especially used-F ,-Cl ,-Br ,-I and/or (C
1-C
8) alkyl (if feasible, quilt-F ,-Cl ,-Br or-the single or many halogenations of I) replace.Further preferred R1 is 4-bromo-, 4-chloro-or 4-fluoro-3-(C
1-C
3) alkyl phenyl, wherein for (C
1-C
3) alkyl, quilt-F ,-Cl or-the single, double or three halogenated methyl of Br or ethyl are especially preferred.
At indyl, under the situation of pseudoindoyl or benzoxazolyl, R2 can be by-F ,-Cl ,-Br ,-I, (C
1-C
8) alkyl (if feasible, quilt-F ,-Cl ,-Br, or-the single or many halogenations of I), or (C
1-C
8) oxygen base alkyl list, two or three replacements, wherein said substituting group can be identical or different.It is the N-substituting group especially, for example the N-methyl.Under the situation of benzoxazolyl, it can be the 2-substituting group.
R3 can be-H-F ,-Cl ,-Br ,-I, (C
1-C
10) alkyl group or (C
1-C
6) oxygen base alkyl, (C
1-C
10If) alkyl group or the partially or completely halogenation of feasible quilt, especially fluorizated (C
1-C
10) alkyl group, (C
3-C
7) group of naphthene base, (C
2-C
10) kiki alkenyl group, (C
2-C
10) the alkynyl group group, (C
1-C
8) alkyl (C
3-C
7) group of naphthene base, (C
2-C
8) alkenyl (C
3-C
7) group of naphthene base, heterocyclic radical group, (C
1-C
8) the alkyl heterocyclic group, (C
2-C
8) alkenyl heterocyclic radical group, aromatic yl group, (C
1-C
8) kiki fang alkyl group, (C
2-C
8) the alkenyl aromatic yl group, or (C
2-C
8) the alkynyl group aromatic yl group, or optionally by 1-2 ketone groups, 1-2 (C
1-C
5) alkyl group, 1-2 (C
1-C
5) alkoxy base, 1-3 halogen atom, 1-2 outer methylene group list or bicyclic heteroaryl group that replace, that comprise 1-3 nitrogen-atoms and/or 1-2 Sauerstoffatom and/or 1-2 sulphur atom, (C
1-C
8) the miscellaneous alkyl aryl group, or (C
2-C
8) the alkenyl heteroaryl groups, (C
2-C
8) the alkynyl group heteroaryl groups, wherein these groups can be on any position is connected with formula II and can be if necessary in one or several on by hydration.
R3 can be especially-(CO)-the NH-alkyl, or-(CO)-the O-NH-alkyl, or-(CO)-NH-oxygen base alkyl.
The alkyl group of described residue can be straight or branched and can for example be methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl or n-pentyl, 2,2-dimethyl propyl, 2-methyl butyl or 3-methyl butyl group, and hexyl, heptyl, nonyl, decyl group and their derivative of branching at random.Methyl or ethyl group are preferred.Mentioned alkyl group can optionally be replaced by 1-5 halogen atom.For partially or completely halogenation, especially fluorizated C
1-C
3-alkyl group, fluorizated group partially or completely below for example can using: methyl fluoride, difluoromethyl, trifluoromethyl, fluoro ethyl, 1,1-two fluoro ethyls, 1,2-two fluoro ethyls, 1,1,1-trifluoroethyl, tetrafluoro ethyl, pentafluoroethyl group.Wherein preferably trifluoromethyl or pentafluoroethyl group group, wherein fluorinated groups is also referred to as perfluoro alkyl group fully.
Alkoxy base (=oxygen base alkyl) can be straight or branched and for example be methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy or n-pentyloxy, 2,2-dimethyl propoxy-, 2-methyl butoxy or 3-methyl butoxy radicals.C
1-C
5Alkoxy base is preferred.The methoxy or ethoxy group is especially preferred.
Group of naphthene base is optionally by one or more halogen atoms, (C
1-C
5) alkyl group, (C
1-C
5) alkoxy base, NR
10R
11-group, COOR
12-group, the saturated cyclic group that CHO, cyano group replace comprises 3 to 7 ring carbon atoms, cyclopropyl for example, methyl cyclopropyl, cyclobutyl, methyl cyclobutyl, cyclopentyl, methylcyclopentyl, cyclohexyl, methylcyclohexyl, suberyl, methyl suberyl.
(C
1-C
8) alkyl (C
3-C
7) group of naphthene base is by straight or branched (C
1-C
8) alkyl unit is bonded to the group of naphthene base on the member ring systems.
(C
2-C
8) alkenyl (C
3-C
7) group of naphthene base is by straight or branched (C
2-C
8) the alkenyl unit is bonded to the group of naphthene base on the member ring systems.
The heterocyclic radical group is not aromatics and can for example is tetramethyleneimine, imidazolidine, pyrazolidine, piperidines.Perhydro quinoline and perhydro isoquinoline 99.9 also belong to these heterocyclic radical groups.
Aromatic yl group on the meaning of the present invention is aromatics or the partially aromatic carbon ring group with 6 to 14 carbon atoms, and it comprises a ring, as phenyl or phenylene, or a plurality of condensed ring such as naphthyl or anthryl.Example is a phenyl, naphthyl, tetralyl, anthryl, indanyl, and indenyl.
Aromatic yl group can be replaced by one or more residues that are selected from hydroxyl or halogen on the position of steric isomer is stablized in any suitable causing.
(C
1-C
8) kiki fang alkyl group is the (C by straight or branched as mentioned above
1-C
8) alkyl unit is bonded to the aromatic yl group on the member ring systems.
(C
2-C
8) the alkenyl aromatic yl group is the (C by straight or branched as mentioned above
2-C
8) the alkenyl unit is bonded to the aromatic yl group on the member ring systems.
(C
2-C
8) the alkynyl group aromatic yl group is the (C by straight or branched as mentioned above
2-C
8) the alkynyl group unit is bonded to the aromatic yl group on the member ring systems.
Monocycle shape heteroaryl groups can for example be a pyridine, pyrazine, pyrimidine, pyridazine, triazine, azepine indolizine, 2H-and 4H-pyrans, 2H-and 4H-sulfo-pyrans, furans, thiophene, 1H-and 4H-pyrazoles, 1H-and 2H-pyrroles oxazole, thiazole, furazan, 1H-and 4H-imidazoles isoxazole, isothiazole ， oxadiazole, triazole, tetrazolium, thiadiazoles.
The bicyclic heteroaryl group can for example be a phthalidyl, sulfo-phthalidyl, indyl, pseudoindoyl, indolinyl, dihydro-iso indolyl, indazolyl, benzothiazolyl, indoles ketone group, the indoline ketone group, isoindole ketone group, xylylenimine ketone group, benzofuryl, benzimidazolyl-, dihydro-isoquinoline base, the dihydroquinoline base, benzoxazine ketone group base, phthalazines ketone group, dihydro phthalazines ketone group, quinolyl, isoquinolyl, the quinoline ketone group, isoquinoline 99.9 ketone group, quinoline azoles base; quinoxalinyl, cinnolinyl, 2, the 3-phthalazinyl, dihydro 2 base, 1,7-or 1,8-naphthyridinyl, the tonka bean camphor base, isocoumarinyl, indolizine base, isobenzofuran-base, azaindolyl, azepine pseudoindoyl, furo pyridyl, the furo pyrimidyl, the furo pyrazinyl, furo pyridazinyl, dihydro benzo furyl, dihydrofuran and pyridyl, dihydrofuran and pyrimidyl, dihydrofuran and pyrazinyl, dihydrofuran and pyridazinyl, dihydro benzo furyl, chromenyl, heterochromatic thiazolinyl, chromene ketone group or heterochromatic ketenes base group.
(C
1-C
8) the miscellaneous alkyl aryl group is the (C by straight or branched as mentioned above
1-C
8) alkyl unit is bonded to the heteroaryl groups on the member ring systems.
(C
2-C
8) the alkenyl heteroaryl groups is the (C by straight or branched as mentioned above
2-C
8) the alkenyl unit is bonded to the heteroaryl groups on the member ring systems.
(C
2-C
8) the alkynyl group heteroaryl groups is the (C by straight or branched as mentioned above
2-C
8) the alkynyl group unit is bonded to the heteroaryl groups on the member ring systems.
(C
1-C
8) the alkyl heterocyclic group is the (C by straight or branched as mentioned above
1-C
8) alkyl unit is bonded to the heterocyclic radical group on the member ring systems.
(C
2-C
8) alkenyl heterocyclic radical group is the (C by straight or branched as mentioned above
2-C
8) the alkenyl unit is bonded to the heterocyclic radical group on the member ring systems.
Optionally be included in the structural unit of the formula II among the R2
Formula II
Can make V be in the neighbour of Y with the Y keyed jointing,, or contraposition.
Structural unit-the V-O-W-(referring to formula II) that optionally is included among the R2 can have following implication:
-O-，
-NH-O-，
-O-NH-, or
-NH-O-NH-。
Structural unit-V-O-W-preferably-O-,-NH-O-, or-O-NH-.More specifically preferred structure unit-V-O-W-is-O-.
The example of The compounds of this invention is:
N-[4-bromo-3-(trifluoromethyl) phenyl oxygen base]-(4-[2-(N-methylamino formyl radical) (4-pyridyl oxygen base)] and phenyl } amino)-methane amide,
N-[4-chloro-3-(trifluoromethyl) phenyl oxygen base]-(4-[2-(N-methylamino formyl radical) (4-pyridyl oxygen base)] and phenyl } amino)-methane amide,
N-[4-fluoro-3-(trifluoromethyl) phenyl oxygen base]-(4-[2-(N-methylamino formyl radical) (4-pyridyl oxygen base)] and phenyl } amino)-methane amide,
N-[4-chloro-3-(methyl) phenyl oxygen base]-(4-[2-(N-methylamino formyl radical) (4-pyridyl oxygen base)] and phenyl } amino)-methane amide,
N-[4-chloro-3-(perfluor ethyl) phenyl oxygen base]-(4-[2-(N-methylamino formyl radical) (4-pyridyl oxygen base)] and phenyl } amino)-methane amide,
N-[4-chloro-3-(trifluoromethyl) phenyl oxygen base]-(4-[2-(N-oxygen ylmethyl-formamyl) (4-pyridyl oxygen base)] and phenyl } amino) methane amide,
N-[4-chloro-3-(methyl) phenyl oxygen base]-(4-[2-(N-methylamino formyl radical) (4-pyridyl oxygen base)] and phenyl } amino)-methane amide,
N-[4-chloro-3-(ethyl) phenyl oxygen base]-(4-[2-(N-methylamino formyl radical) (4-pyridyl oxygen base)] and phenyl } amino)-methane amide,
N-[4-chloro-3-(trifluoromethyl) phenyl oxygen base]-(4-[2-(N-ethylamino formyl radical) (4-pyridyl oxygen base)] and phenyl } amino)-methane amide,
N-[4-chloro-3-(trifluoromethyl) phenyl oxygen base]-(4-[2-(N-trifluoromethyl-formamyl) (4-pyridyl oxygen base)] and phenyl } amino) methane amide,
N-[4-chloro-3-(methyl) phenyl oxygen base]-(4-[2-(N-trifluoromethyl formamyl) (4-pyridyl oxygen base)] and phenyl } amino)-methane amide,
4-[4-({ [4-chloro-3-(trifluoromethyl) phenoxy group] formamyl } amino)-3-fluorophenoxy]-N-picoline-2-methane amide,
4-[4-({ [4-chloro-3-(trifluoromethyl) phenoxy group] formamyl } amino)-2-fluorophenoxy]-N-picoline-2-methane amide,
4-[4-({ [4-chloro-3-(trifluoromethyl) phenoxy group] formamyl } amino)-3-chlorophenoxy]-N-picoline-2-methane amide,
4-[4-({ [4-chloro-3-(trifluoromethyl) phenoxy group] formamyl } amino)-2-chlorophenoxy]-N-picoline-2-methane amide.
Other The compounds of this invention can be in a similar way by the feedstock production of using residue R1 to R3 wherein to change according to definition.
The present invention has further proposed a kind of pharmaceutical composition that comprises The compounds of this invention.Optionally can be with one or more physiological tolerance auxiliary substances and/or carrier substance and this compound, with this mixture is used for part or system administration in the galenic mode, especially oral, parenteral, be used for perfusion or immerse Target organ, be used for injecting (as i.v., i.m., in the capsule or in the waist marrow), be used for using and/or being used for inhalation of tooth bag (space between root of the tooth and the gum).Selected form of medication is depended in selection to additional and/or auxiliary substance.Galenic administration according to pharmaceutical composition of the present invention can be carried out in a conventional manner.As the counter ion of ionic compound, can use for example Ca
++, CaCl
+, Na
+, K
+, Li
+Or cyclohexyl ammonium or Cl
-, Br
-, acetate moiety, trifluoroacetic acid root, propionate, lactate, oxalate, malonate, maleate, citrate, benzoate anion, salicylate, 4-toluene sulfonic acide root etc.Suitable solid or liquid galenical form for example are granulas, pulvis, drageeing, tablet, (little) capsule, suppository, syrup, juice, suspension, emulsion, drops or injection solution (i.v., i.p., i.m., s.c.) or sprays (aerosol), be used for the dosage form that dry powder sucks, transdermal system and have the preparation of the active substance that postpone to discharge uses conventional auxiliary substance during production, as carrier substance, disintegrating agent, tackiness agent, dressing, soak the agent of rising, slide or lubricant, seasonings, sweetener and solubilising.Also active substance can be encapsulated in the preferably biodegradable Nano capsule, for example be used for producing the suction preparation.As auxiliary substance, for example mention magnesiumcarbonate, titanium dioxide at this, lactose, mannitol and other sugar, talcum, milk-protein, gelatin, starch, Mierocrystalline cellulose and its derivative, animal and plant is oily as Oils,glyceridic,cod-liver, sunflower oil, peanut oil or sesame oil, polyoxyethylene glycol and solvent are as sterilized water and list or polyvalent alcohol, for example glycerine.Can make like this according to pharmaceutical composition of the present invention: with at least a combinations of substances used according to the present invention with the medicine of dosage and the prescribed dose of regulation suitable with carrier physiological tolerance and suitable other suitable actives matter, add or auxiliary substance mixes and is made into required form of medication.
As thinner, can use polyglycol, ethanol, water and buffering solution.Suitable buffer substance is N for example, N '-dibenzyl ethylene diamine, diethanolamine, quadrol, N-methylglucosamine, N-benzyl-1-phenylethylamine, diethylamine, phosphoric acid salt, sodium bicarbonate, or yellow soda ash.But also may not use any thinner.
Physiological tolerance salt is and inorganic or organic acid, as lactic acid, hydrochloric acid, sulfuric acid, acetate, citric acid, tosic acid, or with inorganic or organic bases, as NaOH, KOH, Mg (OH)
2, diethanolamine, ethylene diamine, or and amino acid, as arginine, Methionin, L-glutamic acid etc., or and inorganic salt, as CaCl
2, NaCl or its dissociated ion are as Ca
2+, Na
+, Cl
-, SO
4 2-Or the salt of its combination.They are made by using standard method.
The present invention is based on such discovery: by with at least one-O-introduces one of radicals X or Y, the active function that is improved is because have
Compound on the one hand competitively in conjunction with native ligand, on the other hand can not be by metabolism.Therefore the inhibition effect significantly increases.
Further act on or suppress two kinds of kinases kinds according to material of the present invention.This comprises the signal transduction (angiogenesis inhibitor) that suppresses on the one hand to vascular cell, wherein relates to receptor tyrosine kinase such as VEGFR, PDGFR, KIT and FLT-3.On the other hand, this comprises the inhibition tumor proliferative, wherein relates to serine/threonine kinase, as the RAF/MEK/ERK signal path, and for example c-Raf, B-Raf or A-Raf.
The present invention has further proposed the purposes that compound according to the present invention is used for pharmaceutical compositions, said composition be used for the treatment of one or more be selected from down the group in disease: cancer, as lung cancer (NSCLC), head/neck cancer (HNSCC), and kidney (RCC, NPC), leukemia, ovarian cancer, liver cancer, sarcoma, meningioma, intestinal cancer, the lymphoglandula cancer, cerebral tumor, mammary cancer, carcinoma of the pancreas, prostate cancer, skin carcinoma, thyroid carcinoma, chronic inflammatory diseases, asthma, transformation reactions, rhinitis, uveitis, urticaria, sacroiliitis, osteoarthritis, chronic polyarthritis, rheumatic arthritis, inflammatory bowel disease, degenerative joint disease, the rheumatism of cartilage breaks, septicemia, autoimmune disease, type i diabetes, Hashimoto thyroiditis, autoimmunization thrombocytopenia, multiple sclerosis, myasthenia gravis, the chronic inflammatory diseases intestinal disease, Crohn's disease, uveitis, psoriasis, atypical dermatitis, whole body property lupus erythematosus (Kollagenosen), Gourde(G) Paasche syndromes, entanglement white cell adhesivity disease, emaciation is owing to the disease that the TNF-α concentration that increases produces, diabetes, fat, infectation of bacteria is especially infected by antibiotic-resistant bacteria, and heart function is not enough and chronic heart failure (CCF).The term treatment also comprises prevention.
For the present invention, various further embodiments are possible.For example, can comprise multiple different falling into according to pharmaceutical composition of the present invention with the compound in the following formula I.In addition, can comprise the active substance that is different from formula I compound in addition according to pharmaceutical composition of the present invention.At this moment it is a kind of combination preparation.Different used active substances can be made into the single medicament shape of giving, and promptly active substance mixes in form of administration.But the form of administration administration different activities material that separates on also can space with identical or different kind.
The invention still further relates to a kind of method that is used to produce pharmaceutical composition, wherein at least a The compounds of this invention and medicine are suitable to also have other suitable actives matter with carrier substance physiological tolerance and suitable words, additional or auxiliary substance mixes, and makes suitable form of medication.
Preferred pharmaceutical compositions is made into dosage device and with the dosage device administration, and wherein each unit comprises the The compounds of this invention as the formula I of the prescribed dose of active ingredient.For solid dosage unit such as tablet, capsule, drageeing or suppository, this dosage can be 0.1 to 1000mg, and preferred 1 to 300mg, for the injection solution of bottle form, are 0.01 to 1000mg, and preferred 1 to 100mg.
In order to treat 50 to 100kg heavy adult patients of 70kg for example, for example per daily dose is designated as 0.1 to 1000mg active substance, and preferred 1 to 500mg.But in some cases, higher or lower dosage every day is also passable.The administration of per daily dose can be once a day with single dosage unit form or with a plurality of smaller doses unit and by divided dose multiple dosing in certain interval is carried out.
One or more are according to active substance of the present invention and amino oxygen guanidine-acetic acid thing (AOA, NH2-O-CH2-COOH or its salt or ester, for example C
1-C
10Alkyl or hydroxyalkyl acrylate) combination also be possible.AOA at little tumour (＜0.1 to 1cm3) especially effectively or suppress its generation especially shift diffusion, and The compounds of this invention is effective especially to big tumour.Its reason is different metabolism little and big tumour.More than the explanation of combination is suitable in a similar manner.In addition, can comprise the active substance that is different from The compounds of this invention in addition, especially be selected from down the active substance in the group: rIL-2, amifostine according to pharmaceutical composition of the present invention, atrasentan, rhuMAb-VEGF, bud salol fourth, Velcade, capecitabine, carboplatin, Chlorambucil, cis-platinum, CldAdo, endoxan, Saite acid amides (cytamide), Dacarbazine, Docetaxel, droloxifene, Edrecolomab, esperamicin, Tarceva, Etoposide, Exemestane, husband's degree of evening up, fludarabine is fluoridized uridylic, formestane, fulvestrant, Gefitinib, gemcitabine, idarubicin, irinotecan, ipsapirone, Luo Nafani, miltefosine, mitomycin, Neovastat, oxaliplatin, pemetrexed, porphines nurse, Mabthera, Tegafur, Temozolomide, for pyrrole method Buddhist nun and U.S. new, trimetrexate, vorozole, the mixture of vinealeucoblastine(VLB) and two or more these active substances.
The synthetic embodiment and the biological activity of The compounds of this invention are below described.At first provide basic synthetic schemes.
Embodiment 1: synthetic 4-chloropyridine-2-carbonyl villaumite hydrochlorate (1377.3)
Reaction:
Batch of material 1377.3-2:
Thionyl chloride (89ml, 5 equivalents) is heated to 40 ℃ and mix with dried DMF (3ml) in argon atmospher.(30g 243.7mmol) adds (making each reacting away) with aliquot to pyridine carboxylic acid.In adition process, at first produce green color, when dissolving, become scarlet.After 40 ℃ were down stirred 1 hour, temperature rose to 72 ℃ and stirring spend the night (gas generates, and color becomes intense violet color).The gained orange suspension is mixed with dried toluene (250ml) and is concentrated into about 100ml in a vacuum.This step repeats twice and finally is concentrated into drying.Obtain the dark-brown liquid that a kind of crystallization gradually goes out.Be used for next step 1377.3-2 need not to be further purified.
Synthetic (4-chloro-(2-pyridyl))-N-methylformamide (1377.4)
Reaction:
Batch of material 1377.4-3:
Methylamine (2M is in THF) and dried methyl alcohol are cooled to 0 ℃ in ice bath under argon atmospher.Slowly drip 1377.3 subsequently (14g, 65.9mmol).After 0 ℃ is stirred 3h down, concentrate in a vacuum, resistates receives with the 200ml ethyl acetate, uses the saturated NaCl solution washing of 200ml respectively, drying and vacuum concentration on sodium sulfate.Go up purification and in high vacuum, after the drying, obtain 1377.4-3 (10.45g, 93%) at flash distillation silica gel (PE/EE 2:1) as light brown liquid.
Synthetic [4-(4-amino-benzene oxygen (2-pyridyl))-N-methylformamide (1377.14) reaction:
Batch of material 1377.14-1:
(2.62g 24mmol) is dissolved in 50ml and does among the DMF 4-hydroxyanilines under argon atmospher, be cooled to 0 ℃ and adding potassium tert.-butoxide (2.78g, 24.8mmol) (solution becomes dark-brown).Stir at ambient temperature after the 2h, add 1377.4 (4.09g, 24mmol) and salt of wormwood (1.79g 13mmol), is heated to 80 ℃ and spends the night with stirring.Reaction soln is placed on the 400ml ethyl acetate and with the saturated NaCl solution washing of 400ml.Water extracts with the 400ml ethyl acetate again, and the organic phase that merges is used the saturated NaCl solution washing of 200ml four times, drying and vacuum concentration on sodium sulfate at every turn.Dry back obtains the 1377.14-1 as brown solid material (5g, 85%) under high vacuum.
Synthetic 4-bromo-(3-trifluoromethyl) phenoxy group acetohydroxamic acid ethyl ester (1377.13)
Reaction:
Batch of material 1377.13-1:
(EH-671.2-2,3.85g 37.3mmol) are dissolved in the 40ml dry DMF and adding K under 0 ℃ the acetohydroxamic acid ethyl ester
tOBu (EH-671.2-2,4.61g, 41.1mmol).After stirring at ambient temperature 30 minutes, (10g 41.2mmol), and continues to stir other 2h down at 80 ℃ subsequently to add 2-bromo-5-fluoro trifluoromethyl benzene.Mixing with 300ml water down with ice-cooled, using 200ml ethyl acetate (EH-86.7-28) to extract twice at every turn,, going up drying and vacuum concentration at sodium sulfate (EH-93.8-10) with the saturated NaCl washing of 200ml.After flash distillation silica gel (Tol/PE 2:1) is gone up purification, obtain 1377.13-1 (12.08g, 90%).
Synthetic 4-bromo-(3-trifluoromethyl) Atenolol (1377.15)
Reaction:
Batch of material 1377.15-1:
(1377.13,12.08g 37mmol) is dissolved in diox (60ml) neutralization and is cooled to 0 ℃ with ice bath 4-bromo-(3-trifluoromethyl) phenoxy group acetohydroxamic acid ethyl ester.Utilize syringe, slowly add 60% perchloric acid (15ml).Ice bath is removed and at room temperature stirred after the 1h, reaction mixture is placed on the 1200ml frozen water and with 40% sodium hydroxide solution neutralizes.Water is used 1000ml ethyl acetate extraction twice at every turn, with the saturated NaCl solution washing of 800ml, drying and vacuum concentration on sodium sulfate.Acquisition is as the 1377.13-1 (8.7g, 92%) of dark-brown liquid.
Synthetic N-[4-bromo-3-(trifluoromethyl) phenyl oxygen base]-(4[2-(N-methyl-formamyl) (4-pyridyl oxygen base)] and phenyl } amino) methane amide (1377.0)
Reaction:
Batch of material 1377.0-2:
(1377.15,2.1g is 8.20mmol) with [4-(4-amino-benzene oxygen (2-pyridyl))-(1377.14,2g 8.22mmol) is dissolved in the 80ml pyridine under argon atmospher the N-methylformamide 4-bromo-(3-trifluoromethyl) Atenolol together.Utilize subsequently syringe slowly drip phosgene (20%, in toluene, 4.3ml) and with mixture at room temperature stir 2h.Reaction mixture is placed on the silica gel and at flash distillation silica gel (EE) and goes up chromatography by vacuum concentration.Again carry out chromatogram (PE/EE 1:1) and handle, Cong diox Deep-Frozen dry and under 65 ℃ in high vacuum dry 48h, final product is amorphous powder (0.9g, 21%).
Analytical data is as follows:
1HNMR (uses Bruker Avance 400 to measure 400MHz, dmso-d
6, TMS is as interior mark): d (ppm)=2,78 (d, 3H, J=4,9Hz, Me), 7,14 (dd, 1H, J=2,6Hz, J=5,6Hz, 5-H
Pyridyl), 7,17 (d, 2H, J=8,9Hz, AA '/BB '), 7,37 (d, 1H, J=2,6Hz, 3-H
Pyridyl), 7,42 (dd, 1H, J=8,9Hz, J=3,0Hz, 6-H), 7,59 (d, 1H, J=3,0Hz, 2-H), 7,66 (d, 2H, J=9,0Hz, AA '/BB '), 7,87 (d, 1H, J=8,9Hz, 5-H), 8,50 (d, 1H, J=5,6Hz, 6-H
Pyridyl), 8,76 (q, 1H, J=4,8Hz, N
HMe),, 42 (s, 1H, NH), 10,55 (s, 1H, NH).
13C NMR (measure with Bruker Avance 400,100,6MHz, dmso-d
6, TMS is as interior mark): d (ppm)=20,66 (s, 1C, Me), 108,63 (s, 1C, 3-C
Pyridyl), 110,45 (d, 1C, 4-C), 113,59 (d, 1C, 2-C), 113,95 (s, 1C, 5-C
Pyridyl), 119,24 (s, 1C, 6-C), 121,14 (s, 2C, AA '/BB '), 122,56 (q, 1C, J=273,4Hz,
CF
3), 121,74 (s, 2C, AA '/BB '), 128,93 (q, 1C, J=31,0Hz,
CCF
3), 136,07 (s, 1C), 136,19 (s, 1C), 148,37 (s, 1C), 150,30 (s, 1C, 6-C
Pyridyl), 152,38 (s, 1C), 156,56 (s, 1C), 159,21 (s, 1C), 163,67 (s, 1C), 165,77 (s, 1C).
Fusing point uses Electrothermal IA 9200 to measure, 2 ℃ of heating rate/min:91-99 ℃.
Embodiment 2: synthetic N-[4-chloro-3-(trifluoromethyl) phenyl oxygen base]-(4-[2-(N-methyl-formamyl) (4-pyridyl oxygen base)] and phenyl } amino)-methane amide
Step is as follows:
(5g 48.5mmol) is dissolved in the 50ml dry DMF and adding KO under 0 ℃ the acetohydroxamic acid ethyl ester
tBu (6g, 53.5mmol).After 20 ℃ are stirred 30 minutes down, add 2, (10g 53.73mmol), and continues to stir 2h down at 80 ℃ to the 4-dinitrofluorobenzene subsequently.Adding 300ml water down, use 200ml ethyl acetate extraction twice, with the saturated NaCl solution washing of 200ml, drying and vacuum concentration on sodium sulfate with ice-cooled at every turn.After flash distillation silica gel (Tol/PE 2:1) is gone up purification, obtain product (6.67g, 46%).
Synthetic O-(2, the 4-dinitrophenyl) azanol
2, (3g 11.14mmol) is dissolved in diox (12ml) neutralization and is cooled to 0 ℃ with ice bath 4-2,4-dinitrophenoxy base acetohydroxamic acid ethyl ester.Utilize syringe, slowly add 60% perchloric acid (9ml).Remove ice bath and after 20 ℃ are stirred 2h down, reaction mixture is placed on the 240ml frozen water and with 50% sodium hydroxide solution neutralizes.Water is used 240ml ethyl acetate extraction twice at every turn, uses the 240mlNaCl solution washing, drying and vacuum concentration on sodium sulfate.Obtain a kind of dark brown solid material as product (2g, 91%).
Synthetic 4-chloro-(3-trifluoromethyl) Atenolol
(3.9g 19.84mmol) is dissolved in 86ml and does among the DMF 4-chloro-(3-trifluoromethyl) phenol under argon, be cooled to 0 ℃ and mix with 351mg NaH.30min subsequently stirs the mixture under this temperature.(2g 10.04mmol) is dissolved in 27ml and does among the DMF O-(2, the 4-dinitrophenyl) azanol, adds molecular sieve and utilizes syringe slowly to drop to reaction soln in 2h under 20 ℃.After another 2h stirs, add 0.8ml TFA, pour the saturated NaHCO of 390ml into
3In the solution and each with 390ml ether extraction four times.With the organic phase that merges at every turn with 390ml0.5M NaOH solution and with the saturated NaCl solution washing of 390ml four times and on sodium sulfate drying.Reaction mixture is placed on the silica gel and at flash distillation silica gel (Tol/PE 1:2) and goes up chromatography by vacuum concentration.After the drying, product obtains as crystal (1.46g, 35%) in high vacuum.
Synthetic N-[4-chloro-3-(trifluoromethyl } phenyl oxygen base]-(4-[2-(N-methyl-formamyl } (and 4-pyridyl oxygen base }] phenyl } amino)-methane amide
The synthetic of final product carries out according to embodiment 1 subsequently, and wherein above synthetic 4-chloro-(3-trifluoromethyl) Atenolol is used for substituting 4-bromo-(3-trifluoromethyl) Atenolol.
The analytical data of final product is as follows:
1HNMR (measures 400MHz, dmso-d with Bruker Avance 400
6, TMS is as interior mark): d (ppm)=2,78 (d, 3H, J=4,9Hz, Me), 7,13 (dd, 1H, J=2,6Hz, J=5,6Hz, 5-H
Pyridyl), 7,17 (d, 2H, J=8,9Hz, AA '/BB '), 7,38 (d, 1H, J=2,6Hz, 3-H
Pyridyl), 7,50 (dd, 1H, J=9,0Hz, J=3,2Hz, 6-H), 7,59 (d, 1H, J=2,9Hz, 2-H), 7,66 (d, 2H, J=9,0Hz, AA '/BB '), 7,71 (d, 1H, J=8,9Hz, 5-H), 8,50 (d, 1H, J=5,6Hz, 6-H
Pyridyl), 8,73 (q, 1H, J=5,1Hz, N
HMe), 9,39 (s, 1H, NH), 10,53 (s, 1H, NH).
Fusing point uses Electrothermal IA 9200 to measure, 1 ℃ of heating rate/min:88-100 ℃.
The analytical data of the tosylate of final product is as follows:
1H NMR (measures 400MHz, dmso-d with Bruker Avance400
6, TMS is as interior mark): d (ppm)=2,29 (s, 3H, MeTos), 2,79 (d, 3H, J=4,8Hz, Me), 7,16 (dd, 1H, J=2,6Hz, J=5,7Hz, 5-H
Pyridyl), 7,11 (d, 2H, J=7,9Hz, AA '/BB '), 7,41 (d, 1H, J=2,5Hz, 3-H
Pyridyl), 7,52 (dd, 1H, J=8,9Hz, J=2,9Hz, 6-H), 7,59 (d, 1H, J=2,9Hz, 2-H), 7,48 (d, 2H, J=8,1Hz, AA '/BB '), 7,66 (d, 2H, J=9,0Hz, AA '/BB '), 7,72 (d, 1H, J=8,9Hz, 5-H), 8,51 (d, 1H, J=5,7Hz, 6-H
Pyridyl), 8,80 (q, 1H, J=4,7Hz, N
HMe), 9,43 (s, 1H, NH), 10,55 (s, 1H, NH).
13C NMR (measure with Bruker Avance 400,100,6MHz, dmso-d
6, TMS is as interior mark): d (ppm)=20,66 (1C, Me), 25,92 (1C, Me) 108,78 (1C), 113,12 (1C), 113,19 (1C), 114,00 (1C), 119,09 (1C), 121,12 (1C), 121,71 (1C), 123,11 (1C), 123,80 (1C), 125,39 (1C), 126,94 (1C), 127,24 (1C), 127,93 (1C), 132,70 (1C), 136,25 (1C), 137,46 (1C), 145,66 (1C), 148,28 (1C), 150,01 (1C), 151,97 (1C), 156,54 (1C), 158,67 (1C), 163,38 (1C), 166,03 (1C).
Alternative is synthetic
Synthetic N-[4-chloro-3-(trifluoromethyl) phenyl oxygen base]-another synthesis mode of ({ 4-[2-(N-methyl-formamyl) (4-pyridyl oxygen base)] phenyl } amino) methane amide is, uses equally that known 2-chloro-5-fluorobenzene and trifluoride substitute 2-bromo-5-fluorobenzene and trifluoride as starting raw material from document.Therefore other technology mode is corresponding to the method (embodiment 1) of the bromine compounds of above detailed explanation.In addition 2-chloro-5-fluorobenzene and trifluoride can 2-nitro-5-fluorobenzene and trifluoride (as deriving from Aldrich, Acros) be initiator, of file US 4,469,893, use the vapor-phase reaction device and make.
Retrosynthesis:
In addition:
The preparation of 2-chloro-5-fluorobenzene and trifluoride is described in following file:
A?novel，base-induced?fragmentation?of?Hantzsch-type?4-aryl-1，4-dihydropyridines.McInally，Thomas；Tinker，AlanC.Dep.Med.Chem.，Fisons?plc，Res.Dev.Lab.，Loughborough/Leicestershire，UK.Journal?of?the?ChemicalSociety，Perkin?Transactions1：Organic?and?Bio-OrganicChemistry(1972-1999)(1988)，(7)，1837-44.CODEN：JCPRB4ISSN：0300-922X.Journal?written?in?English.CAN109：230744?AN?1988：630744?CAPLUS
Tang，David?Y.；Cotter，Byron?R.；Goetz，Frederick?J.Nitrodiphenyl?ethers.Eur.Pat.Appl.(1986)，21?pp.CODEN：EPXXDW?EP?173349?A1?19860305?CAN?105：42472?AN1986：442472?CAPLUS
Tang，David?Y.；Cotter，Byron?R.；Goetz，Frederick?J.Nitrodiphenyl?ethers.U.S.(1984)，5pp.CODEN：USXXAM?US?4469893?A?19840904?CAN?101：210733?AN1984：610733?CAPLUS
Tang，David?Y.；Cotter，Byron?R.；Goetz，Frederick?J.Nuclear?chlorinated?aromatic?compounds.U.S.(1984)，7?pp.CODEN：USXXAM?US?4470930?A?19840911?CAN101：210711?AN?1984：610711?CAPLUS
Tang，David?Y.；Cotter，Byron?R.；Goetz，Frederick?J.Nuclear?chlorinated?compounds.Eur.Pat.Appl.(1985)，26?pp.CODEN：EPXXDW?EP?159388?A2?19851030?CAN104：168090?AN?1986：168090?CAPLUS
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Embodiment 3: synthetic 4-[4-({ [4-chloro-3-(trifluoromethyl) phenoxy group] formamyl } amino)-3-fluorophenoxy]-N-picoline-2-methane amide
Similar fashion according to embodiment 2 is synthesized, but does not use the 4-hydroxyanilines, and mole 4-amino-3-fluorophenol such as is to use.As a supplement, [4-(the iodine phenoxy group-(use in a similar manner by the reaction scheme of 2-pyridyl-N-methylformamide (1377.14) with reference to being used to synthesize.
Embodiment 4: biological study
Use as above synthetic according to material N-[4-bromo-3-of the present invention (trifluoromethyl) phenyl oxygen base]-({ 4-[2-(N-methyl-formamyl) (4-pyridyl oxygen base)] phenyl } amino) methane amide, carry out the XTT test at the mitochondria activity of viable cell.At this, yellow tetrazolium salts XTT (3 ＂-[1-(phenyl amino carbonyl)-3,4-tetrazolium]-two (methoxyl group-6-nitro) benzene sulfonic acid sodium salt) is converted to orange Jia Za (decomposition of the tetrazole ring of XTT) by the metabolic activity cell.The biological reducing of XTT increases by adding PMS (electron coupling azophenlyene metilsulfate).Colour intensity number active with mitochondrial dehydrogenase and viable cell is relevant.It is quantitative that colour intensity utilizes ELISA Reader to carry out spectrophotometric.
When establishment method, the best initiator cell counting/well of determining each clone is to measure optical density (OD) ideally.In addition, at each clone determine OD and as the basis cell counting between correlation curve.In addition, for each clone, determine optimisation substance joining day and incubation time.
According to clone, 500 to 5000 cells go down to posterity in 100 μ l nutrient media/wells of 96 well plates when time t0.Add 50 μ l materials or in contrast, add 50 μ l solvents.In brooder 4 (NK, MCF-7, BxPC-3, WI-38) or 6 (MDA-MB-453, HT29, KB-V1) cultivate day after, add XTT solution (1mg/ml XTT, the 0.383mg/ml PMS: ratio 1: 50) of 75 μ l prepared fresh.In brooder, after 37 ℃ are cultivated 3h down, in ELISA Reader, measure OD down at wavelength 450nm (reference wavelength 620nm).For measuring method, reference paper Scudiero, people such as D.: Cancer Res. (1988), 48:4827-4833.The result shows in Fig. 1 and 2.Two kinds of clones are MCF-7.
Embodiment 6: the contrast biological study of synthesizing the material of embodiment 1 and 2.
All 3 kinds of materials are tested its hyperplasia restraining effect for different clones in nutrient media under the situation that has and do not exist pyruvic acid.For this reason, substance dissolves is tested with eight kinds of concentration at interval in the DMSO neutralization.The calculating of IC50 value (having the concentration of 50% of hyperplasia when suppressing) each concentration during based on eight independent pH-value determination pHs.
The result provides in Fig. 3.SO 779 is synthetic products of embodiment 1, and SO 779I is the synthetic product of embodiment 2, and SO 779I (S) is the tosylate of the synthetic product of embodiment 2.MCF-7 and MDA-MB-453 are MCF-7, HT 29 is CCL188, and BxPC-3 is human pancreas's tumor cell line, and Novikoff is a rat hepatocytes oncocyte system, KB-V1 is the multiple medicines thing tolerance offspring of HELA cell, and WI 38 is a tire poultry lung fibroblast clone.
As can be seen, for pancreatic cell system, there are special activity in breast cancer cell line and KB V1 clone, because produce low-down IC50 value this moment.Further as can be seen, pyruvic acid in nutrient medium existence or do not exist and do not have substantial effect.
At Fig. 4 as can be seen, all three kinds of materials have very similar activity usually, and wherein IC50 value maximum difference only is 2.5 times.
Embodiment 7: cluster analysis.
The synthetic product of embodiment 2 (free form) is test in bacterium colony is analyzed.Wherein, the tumor stem cell of different people tumour body is cultivated in soft agar, and tumour group counts under the situation that has and do not exist substances.Test is 25 different tumor models altogether.Comprising colon, pancreas and cancer of the stomach, minicell and non-small cell lung tumor, mammary cancer, ovarian cancer and kidney and melanoma.The use of these different tumor types can be assessed tested material and whether only optionally act on some tumour body or act on multiple or even numerous tumour body.
Fig. 5 and 6 shows effect.For all 25 models, the dose-dependent inhibition that these materials cause the tumour group to form.(under this material concentration, compare contrast, cell counting has 50% minimizing to the IC50 value, Fig. 5) is 26 μ M; (70% reduces the IC70 value, Fig. 6) is 49 μ M.
In Fig. 5 and 6, post is represented the relation of the mean value of IC50/IC70 concentration and all IC50/IC70.For the post towards a left side, the IC50/IC70 value is lower than the mean value of all IC50/IC70 values, and promptly these models mean value of comparing all models is responsive more.Represent that towards the post on the right side IC50/IC70 value is higher than mean value and so susceptibility subaverage of model.Hereinafter to be referred as being used for tumor model.CXF: colorectal carcinoma, GXF: cancer of the stomach, LXFA: the non-small cell gland cancer of lung, LXFE: the squamous cell carcinoma of lung, FXFL: maxicell lung cancer, LXFS: small cell lung cancer, MAXF: chest tumour, MEXF: melanoma, OVXF: ovarian cancer, PAXF: carcinoma of the pancreas, RXF: kidney.
In a word, can be observed wide especially efficiency spectrum, promptly in 25 models, only a model is not suppressed when 100 μ M.Almost for all models, IC50 is relative with the IC70 value approaching.The non-small cell lung tumor model, small cell lung tumor model and chest tumor model be tested makes extra high susceptibility.At this, IC50 is 60 μ M, and IC70 is 100 μ M.The highest IC50 or IC70 value be respectively 240 μ M or 400 μ M, is found to be the tumor of kidney model.
For the structure of embodiment 6.2,6.3 and 6.4, being similar to above research, to obtain average IC50 value in cell culture test be 80 μ M, 340 μ M and 180 μ M.
Claims (15)
1. according to the compound of formula I and steric isomer, salt or the metabolite of these compounds:
Formula I
Wherein X and Y can be identical or different, the expression key or-O-or-S-, wherein at least one radicals X or Y be-O-or-S-,
Wherein R1 is selected from down group: 2-or 3-pyrryl, 2-, 4-or 5-imidazolyl, 3-, 4-or 5-pyrazolyl, 2-, 3-or 4-pyridyl, 2-or 3-pyrazinyl, 2-or 4-pyrimidyl, 3-or 4-pyridazinyl, 3-, 4-or 5-isoxazolyl, 3-furazan base, 2-, 3-or 4-quinolyl, 1-, 3-or 4-isoquinolyl, 4-, 5-, 6-or 7-indyl, it is single polysubstituted or unsubstituted, 4-, 5-, 6-or 7-pseudoindoyl, 1,8-naphthyridines-2-or-3-or-the 4-base, and phenyl, it is single polysubstituted or unsubstituted
Wherein R2 is single polysubstituted or unsubstituted 4-, 5-, 6-or 7-indyl, single polysubstituted or unsubstituted 4-, 5-, 6-or 7-pseudoindoyl, single polysubstituted or unsubstituted 4-, 5-, 6-or 7-benzoxazolyl, or according to the residue of formula II
Formula II
Wherein Z is C or N,
Wherein V and W represent independently of each other key or-NH-,
Wherein R3 is any residue,
Left side among its Chinese style II ring can be identical or differently by halogen atom, especially single, double by fluorine, chlorine or bromine, three or four replace.
2. according to the compound of claim 1, wherein R1 quilt-F ,-Cl ,-Br ,-I, (C
1-C
8) alkyl, if possible its quilt-F ,-Cl ,-Br or-the single or many halogenations of I, or (C
1-C
8) single, double or three replacements of oxygen base alkyl, wherein said substituting group can be identical or different.
3. according to the compound of claim 1 or 2, wherein R1 is phenyl, quinolyl or 1,8-naphthyridines-4-base, especially have-F ,-Cl ,-Br ,-I and/or (C
1-C
8) alkyl, if possible by-F ,-Cl ,-Br or-the single or many halogenations of I.
4. according to the compound of one of claim 1 to 3, wherein R1 is 4-bromo-, 4-chloro-or 4-fluoro-3-(C
1-C
3) alkyl phenyl, wherein for (C
1-C
3) alkyl, quilt-F ,-Cl or-the single, double or three halogenated methyl of Br or ethyl are preferred.
5. according to the compound of one of claim 1 to 4, wherein under the situation of indyl, pseudoindoyl or benzoxazolyl, R2 quilt-F ,-Cl ,-Br ,-I, (C
1-C
8) alkyl, if possible by-F ,-Cl ,-Br or-I is single or polyhalogenated, or (C
1-C
8) single, double or three replacements of oxygen base alkyl, wherein said substituting group can be identical or different.
6. according to the compound of one of claim 1 to 5, wherein R3 be-H ,-F ,-Cl ,-Br ,-I, (C
1-C
10) alkyl or (C
1-C
6) oxygen base alkyl, (C
1-C
10) alkyl or if possible by partially or completely halogenation, especially fluorizated (C
1-C
10) alkyl, (C
3-C
7) cycloalkyl, (C
2-C
10) alkenyl, (C
2-C
10) alkynyl group, (C
1-C
8) alkyl (C
3-C
7) group of naphthene base, (C
2-C
8) alkenyl (C
3-C
7) group of naphthene base, heterocyclic radical group, (C
1-C
8) the alkyl heterocyclic group, (C
2-C
8) alkenyl heterocyclic radical group, aromatic yl group, (C
1-C
8) kiki fang alkyl group, (C
2-C
8) the alkenyl aromatic yl group, or (C
2-C
8) the alkynyl group aromatic yl group, or if possible by 1-2 ketone groups, 1-2 (C
1-C
5) alkyl group, 1-2 (C
1-C
5) alkoxy base, 1-3 halogen atom, 1-2 the monocycle or the bicyclic heteroaryl group that comprise 1-3 nitrogen-atoms and/or 1-2 Sauerstoffatom and/or 1-2 sulphur atom that outer methylene group replaces, (C
1-C
8) the miscellaneous alkyl aryl group, or (C
2-C
8) the alkenyl heteroaryl groups, (C
2-C
8) the alkynyl group heteroaryl groups, wherein these groups can be on any position is connected with formula II and if possible on one or more by hydration.
7. according to the compound of one of claim 1 to 6, wherein R3 be-(CO)-the NH-alkyl or-(CO)-the O-NH-alkyl or-(CO)-NH-oxygen base alkyl.
8. according to the compound of one of claim 1 to 7, wherein R1 is phenyl, quinolyl or 1,8-naphthyridines-4-base, especially have-F ,-Cl ,-B ,-I and/or (C
1-C
8) alkyl, if possible by-F ,-Cl ,-Br or-the single or many halogenations of I, or 4-bromo-, 4-chloro-or 4-fluoro-3-(C
1-C
3) alkyl phenyl, wherein R2 is single polysubstituted or unsubstituted 5-indyl, single polysubstituted or unsubstituted 6-benzoxazolyl, or according to the residue of formula II, wherein Z is N, R3 is-(CO)-the NH-alkyl or-(CO)-the O-NH-alkyl or-(CO)-NH-oxygen base alkyl.
9. according to the compound of one of claim 1 to 8, that is:
N-[4-bromo-3-(trifluoromethyl) phenyl oxygen base]-(4-[2-(N-methylamino formyl radical) (4-pyridyl oxygen base)] and phenyl } amino)-methane amide,
N-[4-chloro-3-(trifluoromethyl) phenyl oxygen base]-(4-[2-(N-methylamino formyl radical) (4-pyridyl oxygen base)] and phenyl } amino)-methane amide,
N-[4-fluoro-3-(trifluoromethyl) phenyl oxygen base]-(4-[2-(N-methylamino formyl radical) (4-pyridyl oxygen base)] and phenyl } amino)-methane amide,
N-[4-chloro-3-(methyl) phenyl oxygen base]-(4-[2-(N-methylamino formyl radical) (4-pyridyl oxygen base)] and phenyl } amino)-methane amide,
N-[4-chloro-3-(perfluor ethyl) phenyl oxygen base]-(4-[2-(N-methylamino formyl radical) (4-pyridyl oxygen base)] and phenyl } amino)-methane amide,
N-[4-chloro-3-(trifluoromethyl) phenyl oxygen base]-(4-[2-(N-oxygen ylmethyl-formamyl) (4-pyridyl oxygen base)] and phenyl } amino) methane amide,
N-[4-chloro-3-(methyl) phenyl oxygen base]-(4-[2-(N-methylamino formyl radical) (4-pyridyl oxygen base)] and phenyl } amino)-methane amide,
N-[4-chloro-3-(ethyl) phenyl oxygen base]-(4-[2-(N-methylamino formyl radical) (4-pyridyl oxygen base)] and phenyl } amino)-methane amide,
N-[4-chloro-3-(trifluoromethyl) phenyl oxygen base]-(4-[2-(N-ethylamino formyl radical) (4-pyridyl oxygen base)] and phenyl } amino)-methane amide,
N-[4-chloro-3-(trifluoromethyl) phenyl oxygen base]-(4-[2-(N-trifluoromethyl-formamyl) (4-pyridyl oxygen base)] and phenyl } amino) methane amide,
N-[4-chloro-3-(methyl) phenyl oxygen base]-(4-[2-(N-trifluoromethyl formamyl) (4-pyridyl oxygen base)] and phenyl } amino)-methane amide,
4-[4-({ [4-chloro-3-(trifluoromethyl) phenoxy group] formamyl } amino)-3-fluorophenoxy]-N-picoline-2-methane amide,
4-[4-({ [4-chloro-3-(trifluoromethyl) phenoxy group] formamyl } amino)-2-fluorophenoxy]-N-picoline-2-methane amide,
4-[4-({ [4-chloro-3-(trifluoromethyl) phenoxy group] formamyl } amino)-3-chlorophenoxy]-N-picoline-2-methane amide,
4-[4-({ [4-chloro-3-(trifluoromethyl) phenoxy group] formamyl } amino)-2-chlorophenoxy]-N-picoline-2-methane amide.
10. pharmaceutical composition, its comprise the physiology effective dose according to the compound of one of claim 1 to 9 and the auxiliary and/or carrier substance of physiological tolerance of optional.
11. according to the pharmaceutical composition of claim 10, comprise the active substance that is different from described compound in addition, this active substance especially is selected from down group: rIL-2, amifostine, atrasentan, rhuMAb-VEGF, bud salol fourth, Velcade, capecitabine, carboplatin, Chlorambucil, cis-platinum, CldAdo, endoxan is filled in special acid amides, Dacarbazine, Docetaxel, droloxifene, Edrecolomab, esperamicin, Tarceva, Etoposide, Exemestane, husband's degree of evening up, fludarabine is fluoridized uridylic, formestane, fulvestrant, Gefitinib, gemcitabine, idarubicin, irinotecan, ipsapirone, Luo Nafani, miltefosine, mitomycin, Neovastat, oxaliplatin, pemetrexed, porphines nurse, Mabthera, Tegafur, Temozolomide, for pyrrole method Buddhist nun and U.S. new, trimetrexate, vorozole, the mixture of vinealeucoblastine(VLB) and two or more these active substances.
12. be used for the purposes of pharmaceutical compositions according to the compound of one of claim 1 to 9, described composition is used for prevention or treatment hyperplasia or inflammatory disease or is used to suppress the new ill vessel growth of retina (moving under water property of inhibition vision loss (AMD)).
13. according to the purposes of claim 12, wherein said disease is selected from down group: cancer, as lung cancer (non-small cell gland cancer, squamous cell carcinoma, maxicell lung cancer, small cell lung cancer), bronchogenic carcinoma, especially non-small cell bronchogenic carcinoma, hepatocellular carcinoma (HCC), primary hepatocarcinoma, primary skin cancer, leukemia, ovarian cancer, sarcoma, meningioma, intestinal cancer, lymphoglandula cancer, cerebral tumor, mammary cancer, carcinoma of the pancreas, prostate cancer, kidney, malignant melanoma, chronic inflammatory diseases, asthma, transformation reactions, rhinitis, uveitis, urticaria, sacroiliitis, osteoarthritis, chronic polyarthritis, rheumatoid arthritis, inflammatory bowel disease, degenerative joint disease, the rheumatism of cartilage breaks, septicemia, autoimmune disease, type i diabetes, Hashimoto thyroiditis, autoimmunization thrombocytopenia, multiple sclerosis, myasthenia gravis, the chronic inflammatory diseases intestinal disease, Crohn's disease, uveitis, psoriasis, atypical dermatitis, whole body property lupus erythematosus, Gourde(G) Paasche syndromes, entanglement white cell adhesivity disease, emaciation is owing to the disease that the TNF-α concentration that increases produces, diabetes, fat, infectation of bacteria is especially infected by antibiotic-resistant bacteria, and heart function is not enough and chronic heart failure (CCF).
14., wherein the compound of one of claim 1 to 9 is mixed with at least a carrier and/or auxiliary substance with the physiology effective dose and makes the galenic form of medication according to the purposes of claim 12 or 13.
15. be used to prevent or treat the method for disease, described disease is followed hyperplasia or inflammatory disease, especially is selected from following: cancer, as lung cancer (NSCLC), head/neck cancer (HNSCC), kidney (RCC, NPC), leukemia, ovarian cancer, liver cancer, sarcoma, meningioma, intestinal cancer, lymphoglandula cancer, cerebral tumor, mammary cancer, carcinoma of the pancreas, prostate cancer, skin carcinoma, thyroid carcinoma, chronic inflammatory diseases, asthma, transformation reactions, rhinitis, uveitis, urticaria, sacroiliitis, osteoarthritis, chronic polyarthritis, rheumatic arthritis, inflammatory bowel disease, degenerative joint disease, the rheumatism of cartilage breaks, septicemia, autoimmune disease, type i diabetes, Hashimoto thyroiditis, the autoimmunization thrombocytopenia, multiple sclerosis, myasthenia gravis, the chronic inflammatory diseases intestinal disease, Crohn's disease, uveitis, psoriasis, atypical dermatitis, whole body property lupus erythematosus, Gourde(G) Paasche syndromes, entanglement white cell adhesivity disease, emaciation, owing to the disease that the TNF-α concentration that increases produces, diabetes, obesity, infectation of bacteria, especially infected by antibiotic-resistant bacteria, heart function is not enough and chronic heart failure (CCF), wherein supplies with the compound of one of claim 1 to 9 of physiology effective dose or the pharmaceutical composition of claim 10 or 11 to the people of described prevention of needs or treatment.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102006029795A DE102006029795A1 (en) | 2006-06-27 | 2006-06-27 | New urea derivatives and their uses |
| DE102006029795.4 | 2006-06-27 |
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| Publication Number | Publication Date |
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| CN101479244A true CN101479244A (en) | 2009-07-08 |
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ID=38573071
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007800237763A Pending CN101479244A (en) | 2006-06-27 | 2007-06-27 | New urea derivatives and the application thereof |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP2032537A1 (en) |
| JP (1) | JP2009541370A (en) |
| CN (1) | CN101479244A (en) |
| DE (1) | DE102006029795A1 (en) |
| WO (1) | WO2008000252A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103476756A (en) * | 2011-03-29 | 2013-12-25 | 埃科特莱茵药品有限公司 | 3-ureidoisoquinolin-8-yl derivatives |
| CN104496896A (en) * | 2014-05-21 | 2015-04-08 | 江西科技师范大学 | Preparation and application of sorafenib derivative containing sulfonylurea structure |
| EP2492701B1 (en) | 2011-02-28 | 2018-09-05 | Siemens Aktiengesellschaft | Method and device for testing a wind turbine assembly |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102008021699A1 (en) | 2008-04-25 | 2009-10-29 | Schebo Biotech Ag | New pyrrolopyrimidine compounds are epidermal growth factor receptor tyrosine kinase inhibitors useful for preventing or treating proliferative or inflammatory disease, where the disease is e.g. cancer, asthma, allergy and psoriasis |
| DE102009019852A1 (en) | 2009-05-06 | 2010-11-11 | Schebo Biotech Ag | New polymer compound comprising amine structural elements, useful as synthetic resins, coatings, foams, liquid crystals, adhesives, paints, varnishes, composite materials, in cosmetics, and in polymer electronics |
Family Cites Families (16)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO1999032111A1 (en) * | 1997-12-22 | 1999-07-01 | Bayer Corporation | INHIBITION OF p38 KINASE ACTIVITY USING SUBSTITUTED HETEROCYCLIC UREAS |
| AU2198999A (en) * | 1997-12-22 | 1999-07-12 | Bayer Corporation | Inhibition of raf kinase using substituted heterocyclic ureas |
| AU2006201959B2 (en) * | 1997-12-22 | 2008-09-04 | Bayer Healthcare Llc | Inhibition of Raf Kinase using Substituted Heterocyclic Ureas |
| US7928239B2 (en) * | 1999-01-13 | 2011-04-19 | Bayer Healthcare Llc | Inhibition of RAF kinase using quinolyl, isoquinolyl or pyridyl ureas |
| WO2002085857A2 (en) * | 2001-04-20 | 2002-10-31 | Bayer Corporation | Inhibition of raf kinase using quinolyl, isoquinolyl or pyridyl ureas |
| US20030207914A1 (en) * | 2001-04-20 | 2003-11-06 | Bayer Corporation | Inhibition of raf kinase using quinolyl, isoquinolyl or pyridyl ureas |
| EA006243B1 (en) * | 2001-10-22 | 2005-10-27 | Пфайзер Продактс Инк. | Piperazine derivatives with ccr1 receptor antagonist activity |
| EP1576150A4 (en) * | 2002-10-16 | 2006-05-03 | Univ Texas | Methods and compositions for increasing the efficacy of biologically-active ingredients |
| MXPA05009104A (en) * | 2003-02-28 | 2006-05-31 | Bayer Pharmaceuticals Corp | Novel bicyclic urea derivatives useful in the treatment of cancer and other disorders. |
| JP4927533B2 (en) * | 2003-02-28 | 2012-05-09 | ニッポネックス インコーポレイテッド | Substituted pyridine derivatives useful for the treatment of cancer and other diseases |
| UY28213A1 (en) * | 2003-02-28 | 2004-09-30 | Bayer Pharmaceuticals Corp | NEW CYANOPIRIDINE DERIVATIVES USEFUL IN THE TREATMENT OF CANCER AND OTHER DISORDERS. |
| MXPA06012394A (en) * | 2004-04-30 | 2007-01-31 | Bayer Pharmaceuticals Corp | Substituted pyrazolyl urea derivatives useful in the treatment of cancer. |
| AU2005325676A1 (en) * | 2004-12-23 | 2006-08-03 | Deciphera Pharmaceuticals, Llc | Anti-inflammatory medicaments |
| WO2007059202A2 (en) * | 2005-11-15 | 2007-05-24 | Bayer Healthcare Ag | Pyrazolyl urea derivatives useful in the treatment of cancer |
| WO2007064872A2 (en) * | 2005-12-01 | 2007-06-07 | Bayer Healthcare Llc | Urea compounds useful in the treatment of cancer |
| CN101007801A (en) * | 2006-01-27 | 2007-08-01 | 上海恒瑞医药有限公司 | Pyrrole substituted 2-dihydromolindone derivative, its preparation method and medical uses |
-
2006
- 2006-06-27 DE DE102006029795A patent/DE102006029795A1/en not_active Ceased
-
2007
- 2007-06-27 EP EP07764419A patent/EP2032537A1/en not_active Withdrawn
- 2007-06-27 CN CNA2007800237763A patent/CN101479244A/en active Pending
- 2007-06-27 JP JP2009516893A patent/JP2009541370A/en active Pending
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2492701B1 (en) | 2011-02-28 | 2018-09-05 | Siemens Aktiengesellschaft | Method and device for testing a wind turbine assembly |
| CN103476756A (en) * | 2011-03-29 | 2013-12-25 | 埃科特莱茵药品有限公司 | 3-ureidoisoquinolin-8-yl derivatives |
| CN104496896A (en) * | 2014-05-21 | 2015-04-08 | 江西科技师范大学 | Preparation and application of sorafenib derivative containing sulfonylurea structure |
| CN104496896B (en) * | 2014-05-21 | 2017-07-14 | 江西科技师范大学 | The preparation and application of the Sorafenib derivative of the urea structure containing sulphonyl |
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| JP2009541370A (en) | 2009-11-26 |
| DE102006029795A1 (en) | 2008-01-03 |
| EP2032537A1 (en) | 2009-03-11 |
| WO2008000252A1 (en) | 2008-01-03 |
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