CN102675194B - Oximes-contained amino derivative, pharmaceutical composition of oximes-contained amino derivative, preparation method of oximes-contained amino derivative and application of oximes-contained amino derivative - Google Patents
Oximes-contained amino derivative, pharmaceutical composition of oximes-contained amino derivative, preparation method of oximes-contained amino derivative and application of oximes-contained amino derivative Download PDFInfo
- Publication number
- CN102675194B CN102675194B CN201110062879.9A CN201110062879A CN102675194B CN 102675194 B CN102675194 B CN 102675194B CN 201110062879 A CN201110062879 A CN 201110062879A CN 102675194 B CN102675194 B CN 102675194B
- Authority
- CN
- China
- Prior art keywords
- methyl
- fluoro
- amino
- tri
- benzaldoxime
- Prior art date
- Legal status (The legal status 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 status listed.)
- Active
Links
Classifications
-
- 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
- A61K31/13—Amines
- A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C223/00—Compounds containing amino and —CHO groups bound to the same carbon skeleton
- C07C223/06—Compounds containing amino and —CHO groups bound to the same carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/32—Oximes
- C07C251/50—Oximes having oxygen atoms of oxyimino groups bound to carbon atoms of substituted hydrocarbon radicals
- C07C251/54—Oximes having oxygen atoms of oxyimino groups bound to carbon atoms of substituted hydrocarbon radicals of hydrocarbon radicals substituted by singly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D401/02—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 two hetero rings
- C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention belongs to the field of pharmaceutical chemicals and relates to an olximes-contained amino derivative, a pharmaceutical composition of the oximes-contained amino derivative, a preparation method of the oximes-contained amino derivative and application of the oximes-contained amino derivative. Specifically, the olximes-contained amino derivative is represented as formula I or formula II, and all substituent groups are defined in the description. The olximes-contained amino derivative can effectively inhibit tumor cells.
Description
Technical field
The invention belongs to field of medicine and chemical technology, relate to a kind of aminoderivative, its pharmaceutical composition, Preparation Method And The Use containing oximes.
Background technology
Cancer is the disease of serious threat human health.From first cancer therapy drug forties in last century---since mustargen comes out, scientist's separation and Extraction from plant goes out some natural products with potential cytotoxic activity, by structural modification, obtained on this basis the compound of the clear and definite anti-tumor activity of multiple demonstration, wherein vinealeucoblastine(VLB), Etoposide, taxol etc. are approved for clinical anticancer in succession.Yet, the resource-constrained of these natural product medicines, its molecular structure is complicated, and chemosynthesis difficulty, is difficult for large-scale production.Therefore, need to find small molecules antitumor drug simple in structure.
Summary of the invention
The inventor, through performing creative labour and a large amount of tests, has obtained the new aminoderivative containing oximes of a class, and has been surprised to find, and should to kinds of tumor cells, have significant restraining effect containing the aminoderivative of oximes.Following invention is provided thus:
One aspect of the present invention relates to the compound shown in formula I or formula II, its pharmacologically acceptable salts, its solvate or its N-oxide compound,
Wherein:
R
1, R
2, R
3, R
4, R
5, R
7, R
8independently selected from hydrogen, hydroxyl, halogen, amino, nitro, itrile group, trifluoromethyl ,-OR
9,-C (O) R
10,-C (O) OR
9,-NR
10c (O) OR
9,-OC (O) R
9,-NR
10sO
2r
9,-SO
2nR
10r
9,-NR
10c (O) R
9, NR
10r
9, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl, C
3-C
10cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic radical and heterocyclic radical alkyl;
R
6independently selected from hydrogen, trifluoromethyl, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl, C
3-C
10cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic radical and heterocyclic radical alkyl;
R
9, R
10independently be selected from hydrogen, hydroxyl, halogen, trifluoromethyl, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl, C
3-C
10cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic radical and heterocyclic radical alkyl;
Be selected from-OR of W
9,-SO
2r
9, and-SOR
9;
X is C or N atom;
Wherein,
Alternatively, abovementioned alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic radical are replaced independently selected from following group by 1-5: hydroxyl, halogen, amino, nitro, trifluoromethyl ,-NR
9c (O) OR
10,-OC (O) R
3,-NR
9sO
2r
10,-SO
2nR
9r
10,-NR
9c (O) R
8,-C (O) NR
8r
9, NR
11c (O) NR
8r
9, NR
3r
4, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl, C
3-C
10cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic radical and heterocyclic radical alkyl;
In formula II,
show optional key, condition is two keys for there being and only having a nitrogen-atoms in ring.Be in formula II, R
6in the five-ring at place, two formed keys of nitrogen-atoms are singly-bound; Or when one of them nitrogen-atoms forms two key, the key that another one nitrogen-atoms forms is singly-bound (can not two nitrogen-atoms simultaneously form pair keys).When nitrogen-atoms forms two key, this nitrogen-atoms can not be connected with hydrogen atom again, and another does not form on the nitrogen-atoms of two keys and is connected with hydrogen atom.
In a specific embodiment, described solvate can be the solvate with DMSO formation.
According to compound recited above, its pharmacologically acceptable salts, its solvate or its N-oxide compound, wherein said compound is as shown in formula III or formula IV below:
Wherein, the definition of each substituted radical is the same.
Compound according to the present invention described in any one, its pharmacologically acceptable salts, its solvate or its N-oxide compound, wherein said compound is as shown in formula V or formula VI below:
Wherein, the definition of each substituted radical is the same.
Compound according to the present invention described in any one, its pharmacologically acceptable salts, its solvate or its N-oxide compound, wherein, R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8independently selected from hydrogen, halogen, nitro, itrile group, trifluoromethyl, C
1-C
6alkyl, C
3-C
6cycloalkyl, C
3-C
6cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic radical and heterocyclic radical alkyl.
Compound according to the present invention described in any one, its pharmacologically acceptable salts, its solvate or its N-oxide compound, wherein, W is-OR
9, R wherein
9definition as mentioned above.
Compound according to the present invention described in any one, its pharmacologically acceptable salts, its solvate or its N-oxide compound, wherein, described compound is selected from the compound shown in table 1 below.
Table 1: the title of particular compound and structural formula
A kind of pharmaceutical composition of another aspect of the present invention, it comprises compound, its pharmacologically acceptable salts, its solvate or its N-oxide compound described in any one above, and at least one pharmaceutically acceptable auxiliary material or carrier.
The method of preparing the compound described in any one above that also relates in one aspect to of the present invention,
Wherein, the preparation method of formula I compound is as shown in method (1) or (2) below:
Method (1)
Method (2)
The preparation method of formula II compound is as shown in method (3) below:
Method (3)
In method above (1)-(3), L represents leavings group independently, and described in the same any one above of various substituent definition.Particularly.Described L is halogen atom, for example F, Cl, Br or I.
Compound, its pharmacologically acceptable salts, its solvate or its N-oxide compound described in any one of the present invention or the pharmaceutical composition of the present invention of also relating in one aspect to of the present invention treats and/or prevents the purposes in the medicine of tumour in preparation; Particularly, described tumour is myelomatosis, large bowel cancer, melanoma, papilliferous thyroid carcinoma, colorectal carcinoma, carcinoma of the pancreas or non-small cell type lung cancer, etc.
Compound, its pharmacologically acceptable salts, its solvate or its N-oxide compound or the purposes of pharmaceutical composition of the present invention in preparing inhibiting tumour cells agent also relating in one aspect to described in any one of the present invention of the present invention; Particularly, described tumour cell is myelomatosis cell, Human Large Intestine Carcinoma Cells, melanoma cell, papilliferous thyroid carcinoma cell, colon cancer cell, pancreatic cancer cell or non-small cell type lung carcinoma cell, etc.。
Treatment and the method for prophylaxis of tumours of also relating in one aspect to of the present invention, comprises the step of compound, its pharmacologically acceptable salts, its solvate or its N-oxide compound or pharmaceutical composition of the present invention described in any one of the present invention that gives significant quantity.Particularly, described tumour is myelomatosis, large bowel cancer, melanoma, papilliferous thyroid carcinoma, colorectal carcinoma, carcinoma of the pancreas or non-small cell type lung cancer, etc.
In the present invention, term " C
1-C
10alkyl " refer to the straight or branched alkyl with 1-10 carbon atom, such as methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, amyl group, 2-amyl group, isopentyl, neo-pentyl, hexyl, 2-hexyl, 3-hexyl, 3-methyl amyl, heptyl, octyl group etc.; C
1-C
6alkyl and C
1-C
3alkyl also can be done similar understanding.Preferred alkyl is C
1-C
6alkyl, preferred alkyl is C
1-C
3alkyl.
Term " C
2-C
10thiazolinyl " refer to the thiazolinyl with the two keys of 2-10 carbon atom and at least one, and comprise vinyl, propenyl, 1-fourth-3-thiazolinyl, 1-penta-3-thiazolinyl, 1-oneself-5-thiazolinyl etc.; C
3-C
5thiazolinyl also can be done similar understanding.C preferably
3-C
5thiazolinyl.
Term " C
2-C
10alkynyl " refer to the alkyl with 2-10 carbon atom and at least one three key, and comprise ethynyl, proyl, butynyl, pentyne-2-base etc.; C
3-C
5alkynyl also can be done similar understanding.C preferably
3-C
5alkynyl.
Term " halogen " refers to fluorine, chlorine, bromine and iodine atom.
Term " aryl " refer to there is monocycle (as phenyl), many rings (as xenyl) or wherein at least one ring be that a plurality of fused rings of aromaticity are (as 1,2,3,4-tetralyl, naphthyl) aromatic carbocyclyl groups, it is optionally replaced by for example halogen, low alkyl group, lower alkoxy, trifluoromethyl, aryl, heteroaryl and hydroxyl list, two or three.
Term " heteroaryl " refers to five yuan, one or more aromatics ring systems of hexa-atomic or seven-membered ring, what it comprised 5-10 atom condenses ring system (wherein at least one ring is aromaticity), and described ring system contains at least one and maximum four heteroatomss that are selected from nitrogen, oxygen or sulphur.The example of heteroaryl is pyridyl, imidazolyl, pyrimidyl, pyrazolyl, triazolyl, pyrazinyl, tetrazyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrole ring, quinoline ring, isoquinoline 99.9 ring, indole ring, benzoglyoxaline, cumarone ring, thionaphthene ring, benzothiazole ring, pyridazine ring etc.It is optionally replaced by for example halogen, low alkyl group, lower alkoxy, trifluoromethyl, aryl, heteroaryl and hydroxyl list, two or three.
Term " C
3-C
10cycloalkyl " refer to the saturated carbon ring group with 3-10 carbon atom.This cycloalkyl can be that monocycle or many rings condense system, and can condense on aromatic ring.The example of these groups comprises cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.Ring a heatable brick bed base herein can be unsubstituted or as describe in detail, in one or more commutable positions, by various groups, replaced.For example, these cycloalkyl can optionally be replaced by following group: C
1-C
6alkyl, C
1-C
6alkoxyl group, itrile group, halogen, hydroxyl, amino, nitro, list (C
1-C
6) alkylamino, two (C
1-C
6) alkylamino, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
1-C
6haloalkyl, C
1-C
6halogenated alkoxy.
Term " heterocycle " or " heterocyclic radical " refer to five yuan, one or more carbocyclic ring ring system of hexa-atomic or seven-membered ring, it comprises the ring system that condenses of 4-10 atom, described ring system contains at least one and maximum four heteroatomss that are selected from nitrogen, oxygen or sulphur, and condition is that the ring of this group does not contain two adjacent O or S atom.Condensing ring system can be the heterocycle condensing on virtue group group.Preferred heterocycle includes but not limited to pyrrolidyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, piperidyl, morpholine ring, hexamethylene ring, piperazine ring etc., and they can be replaced by following group: C
1-C
6alkyl, C
1-C
6alkoxyl group, itrile group, halogen, hydroxyl, amino, nitro, list (C
1-C
6) alkylamino, two (C
1-C
6) alkylamino, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
1-C
6haloalkyl, C
1-C
6halogenated alkoxy.
Term " arylalkyl " refers to the alkyl (as defined above) being replaced by one or more aryl (as defined above).Preferred arylalkyl is aryl-C
1-C
3alkyl.Example comprises benzyl, phenylethyl etc.
Heteroarylalkyl refers to the alkyl (as defined above) being replaced by heteroaryl (as defined above).Preferred heteroarylalkyl is five yuan or six membered heteroaryl-C
1-C
3-alkyl.Example comprises pyridyl ethyl etc.
Heterocyclic radical alkyl refers to the alkyl (as defined above) being replaced by heterocyclic radical (as defined above).Preferred heterocyclic radical alkyl is five yuan or hexa-member heterocycle base-C
1-C
3-alkyl.Example comprises tetrahydropyrans ylmethyl.
Cycloalkylalkyl refers to the alkyl (as defined above) being replaced by cycloalkyl (as defined above).Preferred heterocyclic radical is five yuan or six-ring alkyl-C
1-C
3-alkyl.Example comprises cyclopropyl methyl.
The compounds of this invention also can be used with the form of its pharmacy acceptable salt or solvate.The pharmaceutically receivable salt of the compounds of this invention comprises the conventional salt that formed by pharmaceutically acceptable mineral acid or organic acid or mineral alkali or organic bases and the acid salt of quaternary ammonium.The example more specifically of suitable hydrochlorate comprises hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succsinic acid, oxyacetic acid, formic acid, lactic acid, toxilic acid, tartrate, citric acid, flutters the salt of acid, propanedioic acid, hydroxymaleic acid, toluylic acid, L-glutamic acid, phenylformic acid, Whitfield's ointment, fumaric acid, toluenesulphonic acids, methylsulfonic acid, naphthalene-2-sulfonic acid, Phenylsulfonic acid, hydroxynaphthoic acid, hydroiodic acid HI, oxysuccinic acid, steroic, tannic acid etc.Other acid, as oxalic acid, although itself is not pharmaceutically acceptable, can be for the preparation of the salt as intermediate, to obtain the compounds of this invention and pharmacy acceptable salt thereof.The example more specifically of suitable alkali salt comprises sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, N, N '-dibenzyl-ethylenediamin, chloro PROCAINE HCL, PHARMA GRADE, choline, diethanolamine, quadrol, N-METHYL-ALPHA-L-GLUCOSAMINE and procaine salt.
The present invention also comprises the prodrug of the compounds of this invention, and this prodrug, once administration, carries out chemical conversion by metabolic process, becomes afterwards the activated medicine of tool.Conventionally, this class prodrug is the functional derivatives of the compounds of this invention, and it is in vivo. easily change into required formula I or formula II compound.For example, at " Design Of Prodrugs ", H Bund Saard, Elsevier edits, and has described the ordinary method of selecting and prepare suitable prodrug derivant in 1985.
The present invention also comprises the active metabolite of the compounds of this invention.
Another aspect of the present invention relates to pharmaceutical composition, the raceme that it contains the compounds of this invention or optically active isomer and at least one pharmaceutically acceptable carrier, and it can be used for interior therapeutic and has biocompatibility.Described pharmaceutical composition can be prepared into various forms according to different way of administration.The mentioned compound of the present invention also can be prepared to various pharmacologically acceptable salts.
Pharmaceutical composition of the present invention comprises the compounds of this invention or its pharmacologically acceptable salt or hydrate and one or more suitable pharmaceutically acceptable carrier of effective dose.The pharmaceutical carrier here includes but not limited to: ion-exchanger, aluminum oxide, aluminum stearate, Yelkin TTS, serum protein is as human serum albumin, and buffer substance is as phosphoric acid salt, glycerine, Sorbic Acid, potassium sorbate, the partial glycerol ester mixture of saturated vegetable fatty acid, water, salt or ionogen, as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt, colloided silica, Magnesium Trisilicate, polyvinylpyrrolidone, cellulosic material, polyoxyethylene glycol, Xylo-Mucine, polyacrylic ester, beeswax, lanolin.
The pharmaceutical composition of the compounds of this invention can be used with any-mode below: oral, spraying sucks, rectal application, nasal cavity applied medicine, cheek medication, local application, non-enterally administer, as subcutaneous, vein, intramuscular, intraperitoneal, in sheath, in ventricle, in breastbone and intracranial injection or input, or by the medication of a kind of outer planting reservoir.Wherein preferred oral, intraperitoneal or intravenous administration mode.
When oral medication, the compounds of this invention can be made into oral acceptable dosage form arbitrarily, includes but not limited to tablet, capsule, the aqueous solution or aqeous suspension.Wherein, the carrier that tablet is used generally comprises lactose and W-Gum, also can add in addition lubricant as Magnesium Stearate.The thinner that capsule preparations is used generally comprises lactose and dried corn starch.Aqueous suspension preparation normally mixes use by activeconstituents with suitable emulsifying agent and suspension agent.If need, also can add some sweeting agents, perfume compound or tinting material in above oral preparations form.
When local application, particularly treat local external application easy to reach and suffer from face or organ, during as eyes, skin or lower intestinal tract nervous system disease, can the compounds of this invention be made to different local application's dosage forms according to different trouble faces or organ, be described as follows:
When eye topical application, the compounds of this invention can be mixed with the dosage form of a kind of micronization suspension or solution, the carrier that uses for waiting Sterile Saline of the certain pH ooze, wherein can add also not adding preservative agent as zephiran chloride alkoxide.For eye use, also compound can be made to paste form as vaseline paste.
When topical application, the compounds of this invention can be made into suitable ointment, lotion or creme dosage form, wherein activeconstituents is suspended or is dissolved in one or more carriers.The spendable carrier of ointment formulation includes but not limited to: mineral oil, Albolene, white vaseline, propylene glycol, polyoxyethylene, polyoxytrimethylene, emulsifying wax and water; The spendable carrier of lotion or creme includes but not limited to: mineral oil, and sorbitan monostearate, polysorbate60, n-Hexadecane ester type waxes, cetene is fragrant and mellow, 2-Standamul G, benzyl alcohol and water.
The all right aseptic injection preparation form medication of the compounds of this invention, comprises aseptic injection water or oil suspension or aseptic injectable solution.Wherein, spendable carrier and solvent comprise water, Ringer's solution and isotonic sodium chlorrde solution.In addition, the fixed oil of sterilizing also can be used as solvent or suspension medium, as direactive glyceride or two glyceryl ester.
The dosage of compound of the present invention, its pharmacologically acceptable salts, its solvate or its N-oxide compound or pharmaceutical composition of the present invention depends on many factors, for example to treat or character and the severity of the tumour of assisting therapy, the sex of patient or animal, age, body weight and individual reaction, particular compound used, route of administration and administration number of times etc.Above-mentioned dosage can single dose form or be divided into several, for example two, three, four dosage form administrations.
The beneficial effect of the invention
Compound of the present invention, its pharmacologically acceptable salts, its solvate or its N-oxide compound or pharmaceutical composition of the present invention be inhibition tumor cell effectively, can be used for treatment or the assisting therapy of tumour.
Embodiment
Below in conjunction with embodiment, embodiment of the present invention are described in detail, but it will be understood to those of skill in the art that the following example is only for the present invention is described, and should not be considered as limiting scope of the present invention.Unreceipted actual conditions person in embodiment, carries out according to the condition of normal condition or manufacturers's suggestion.The unreceipted person of production firm of agents useful for same or instrument, being can be by the conventional products of commercial acquisition.
Melting point compound is measured by RY-1 type melting point apparatus, and temperature is not calibrated.
1h NMR spectrum is measured by Bruker ARX 400 type nuclear magnetic resonance spectrometers.
embodiment 1:3, the iodo-2-pyridyl of the fluoro-2[(3-methyl-5-of 4,5-tri-) amino] phenyl aldehyde
the preparation of (compound 1)
Step 1), the preparation of 2,3,4,5 tetra fluoro benzoic acid methyl esters: 2,3,4,5 tetra fluoro benzoic acid (48.5g, 0.25mol) is dissolved in 130mL anhydrous methanol, slowly drips trimethylchlorosilane (63mL, 0.50mol).Dropwise backflow 12h.Water pump removes solvent and excessive trimethylchlorosilane under reduced pressure, obtains weak yellow liquid, adds methylene dichloride 200mL, and washs by 10% aqueous sodium hydroxide washes, and the anti-water lift layer of methylene dichloride merges organic layer, and organic layer spends the night with anhydrous sodium sulfate drying.Filter next day, removes solvent under reduced pressure, obtains colourless liquid 2,3,4,5 tetra fluoro benzoic acid methyl esters (30.52g, 97.8%),
1h-NMR (400MHz, CDCl
3) δ ppm:7.65-7.60 (m, 1H), 3.97 (s, 1H).
Step 2), 2,3,4, the preparation of 5-tetra fluoro benzene methane amide: by 2,3,4,5 tetra fluoro benzoic acid methyl esters (29.5g, 0.147mol) and strong aqua (244mL, 3.24mol) join in eggplant-shape bottle, system is two-phase system, along with reaction is carried out, the appearance of adularescent insolubles, mechanical stirring is spent the night, filter to obtain white solid 2,3,4,5-tetra fluoro benzene methane amide (21.2g, 74.7%)
1h-NMR (400MHz, DMSO-D
6) δ ppm:7.93 (br s, 1H), 7.91 (br s, 1H), 7.63-7.61 (m, 1H), ESI-MS m/z:194.0[M+1]
+.
Step 3), the preparation of 2,3,4,5-tetrafluoro cyanophenyl: 2,3,4,5-tetra fluoro benzene methane amide (5g, 0.026mol) is joined in 20mL anhydrous acetonitrile, add phosphorus oxychloride (16.6g, 0.11mol), be warmed up to 70 ℃, reaction 1.5h.Reaction solution is slowly added drop-wise in 200mL mixture of ice and water, the strong heat release of this process, controls temperature not higher than 30 ℃ by controlling rate of addition, dropwises rear stirring at room 0.5h, ethyl acetate extraction, organic layer dried overnight, removes solvent next day under reduced pressure, obtains colourless liquid 2,3,4,5-tetrafluoro cyanophenyl (4.21g, 92.5%).
1H-NMR(400MHz，DMSO-D
6)δppm：10.01(br s，1H)，7.35-7.28(m，1H)，
19F-NMR(400MHz，CDCl
3)δppm：-130.04.～-130.06(m，1H)，-134.62～-134.66(m，1H)，-143.48～-143.60(m，1H)，-150.60～-150.62(m，1H)，ESI-MS m/z：176.0[M+1]
+。
Step 4), the preparation of 2-amino-3 methyl-5-iodine pyridine: by amino-3 picoline (5.5g of 2-, 0.05mol), iodine (5.1g, 0.02mol), Periodic acid dihydrate (2.28g, 0.01mol) join in reaction flask, add successively acetic acid (30mL), water (60mL) and the vitriol oil (0.9mL), system heat release, in system, temperature rises to 25 ℃ by room temperature, obtains dark-brown solution, be heated to 80 ℃, reaction 4h.System naturally cools to room temperature, adds wherein 10% Na
2s
2o
4in the aqueous solution (150mL), stir 30min, dichloromethane extraction water layer, washs organic layer by 10% aqueous sodium hydroxide washes, and organic layer spends the night with anhydrous sodium sulfate drying.Filter next day, removes solvent under reduced pressure, obtains faint yellow solid 2-amino-3 methyl-5-iodine pyridine (10.76g, 92.0%),
1h-NMR (400MHz, CDCl
3) δ ppm:8.11 (s, 1H), 7.53 (s, 1H), 4.85-4.80 (br s, 2H), 2.01 (s, 3H), ESI-MS m/z:235.8[M+1]
+.
Step 5); 3; 4; the iodo-2-pyridyl of the fluoro-2-[(3-methyl-5-of 5-tri-) amino] preparation of cyanobenzene: under nitrogen protection condition; 2-amino-3 methyl-5-iodine pyridine (23.10g, 0.0986mol) and Lithamide (7.89g, 0.343mol) are joined in 170mL dimethylbenzene; be heated to 100 ℃, stirring reaction 2h.Naturally cool to room temperature, add 2,3,4,5-tetrafluoro cyanophenyl (15g, 0.0857mol), be heated to 126 ℃, reaction 3.5h.The black solid that reaction process is obtained filters, and in black solid, double team has product, with ethyl acetate repeatedly washing on a small quantity, and uses ultrasonic echography 5min.The ethyl acetate layer and the reaction solution that with the washing of 1N aqueous hydrochloric acid, obtain, merge organic layer, and organic layer spends the night with anhydrous sodium sulfate drying.Filter next day, removes solvent under reduced pressure, and column chromatography obtains faint yellow solid 3,4, the iodo-2-pyridyl of the fluoro-2-[(3-methyl-5-of 5-tri-) amino] cyanobenzene (8.9g, 27%),
1h-NMR (400MHz, CDCl
3) δ ppm:8.24-8.23 (m, 1H), 7.76-7-75 (br s, 1H), 7.21-7.19 (m, 1H), 5.99 (s, 1H), 2.31 (s, 3H),
19f-NMR (400MHz, CDCl
3) δ ppm:-122.29 (s, 1H) ,-133.63～-133.72 (m, 1H) ,-135.71～-135.76 (m, 1H), ESI-MS m/z:390.0[M+1]
+.
Step 6), 3, the iodo-2-pyridyl of the fluoro-2-[(3-methyl-5-of 4,5-tri-) amino] benzoic preparation: by 3,4, the iodo-2-pyridyl of the fluoro-2-[(3-methyl-5-of 5-tri-) amino] cyanobenzene (8.90g, 0.023mol) be dissolved in dehydrated alcohol: distilled water: THF=150mL: 75mL: in the mixed solvent of 22.5mL, add potassium hydroxide (6.44g, 0.115mol), reflux, reaction 30h.Remove solvent under reduced pressure, obtain oily matter, with 10% aqueous hydrochloric acid, regulate pH value to 1, ethyl acetate extraction, organic layer spends the night with anhydrous sodium sulfate drying.Filter next day, removes solvent under reduced pressure, obtains faint yellow solid 3,4, the iodo-2-pyridyl of the fluoro-2-[(3-methyl-5-of 5-tri-) amino] phenylformic acid (8.72g, productive rate 92.9%), mp 103-105 ℃.
1H-NMR(400MHz，DMSO-D
6)δppm：13.61(br s，1H)，8.38(s，1H)，8.11-8.09(d，1H)，7.85-7.84(d，1H)，7.56-7.52(m，1H)，2.49(s，3H).
19F-NMR(400MHz，DMSO-D
6)δppm：-12193～-121.99(m，1H)，-133.82～-133.88(m，1H)，-139.86～-139.97(m，1H)，ESI-MS m/z：409.1[M+1]
+。
Step 7), 3, the iodo-2-pyridyl of the fluoro-2-[(3-methyl-5-of 4,5-tri-) amino] preparation of phenylcarbinol: by 3,4, the iodo-2-pyridyl of the fluoro-2-[(3-methyl-5-of 5-tri-) amino] phenylformic acid (3.03g, 7.4mmol) be dissolved in 30mL THF, slowly drip wherein the borine THF solution (11.1mL, 11.1mmol) of 1M, in dropping process, there is γ-ray emission, stirring at room 16h.Add the borine THF solution (2mL, 2mmol) of 1M, stirring at room 21h.In system, add 2% aqueous hydrochloric acid 30mL, stir 1h, ethyl acetate extraction, machine layer spends the night with anhydrous sodium sulfate drying.Filter next day, removes solvent under reduced pressure, and column chromatography obtains yellow solid 3,4, the iodo-2-pyridyl of the fluoro-2-[(3-methyl-5-of 5-tri-) amino] phenylcarbinol (2.44g, 83.6%),
1h-NMR (400MHz, DMSO-D
6) δ ppm:8.38 (s, 1H), 7.85-7.84 (d, 1H), 7.40-7.37 (m, 1H), 6.60-6.58 (m, 1H), 4.65-4.63 (m, 2H), 3.65 (br s, 1H), 2.49 (s, 3H) .ESI-MS m/z:395.0[M+1]
+.
Step 8), 3, the iodo-2-pyridyl of the fluoro-2-[(3-methyl-5-of 4,5-tri-) amino] preparation of phenyl aldehyde: by 3,4, the iodo-2-pyridyl of the fluoro-2-[(3-methyl-5-of 5-tri-) amino] phenylcarbinol (0.86g, 2.19mmol) be dissolved in the methylene dichloride of 15mL, drip the methylene dichloride (20mL) of the PCC of new system, dropwise, reaction system becomes dark color, stirring at room reaction 2h.Decompression is the thick silica gel of 100-200 order for post, filters, and removes the black solid of generation, and ethyl acetate, as elutriant, obtains yellow solid (0.59g, 69.0%).
1H-NMR(400MHz，DMSO-D
6)δppm：9.93(s，1H)，8.50(s，1H)，7.81-7.76(m，1H)，7.40-7.37(m，1H)，6.60-6.58(m，1H)，2.27(s，3H).ESI-MS m/z：409.1[M+1]
+。
embodiment 2:(R, E)-3,4, iodo-2 pyridyl of the fluoro-2-[(3-methyl-5-of 5-tri-) ammonia
base] preparation of-O-(2,3-dihydroxypropyl) benzaldoxime (compound 2)
Step 1), (R, E)-3,4, iodo-2 pyridyl of the fluoro-2-[(3-methyl-5-of 5-tri-) amino]-O-[(2,2-methyl isophthalic acid, 3 dioxolane-4 bases) methyl] preparation of benzaldoxime: by 3,4, the iodo-2-pyridyl of the fluoro-2-[(3-methyl-5-of 5-tri-) amino] phenyl aldehyde (0.4g, 0.98mmol) and (R) the O-{3[(tertiary butyl-dimethyl-silicon) oxygen base] propyl group } azanol (0.30g, 2.05mmol) is dissolved in 10mL dehydrated alcohol, reflux, reaction 2h.Reaction system is directly used thick silica gel mixed sample, and column chromatography obtains yellow solid, is directly used in next step reaction, ESI-MS m/z:521.1[M+1]
+.
Step 2), (R, E)-3,4, iodo-2 pyridyl of the fluoro-2-[(3-methyl-5-of 5-tri-) amino]-O-(2,3-dihydroxypropyl) preparation of benzaldoxime: by (R, E)-3,4, iodo-2 pyridyl of the fluoro-2-[(3-methyl-5-of 5-tri-) amino]-O-[(2,2-methyl isophthalic acid, 3 dioxolane-4 bases) methyl] benzaldoxime (0.22g, 0.42mmol) joins in the mixed solvent of methyl alcohol (5mL) and water (0.5mL), adds tosic acid monohydrate (0.008g, 0.042mmol), stirring at room 18h.Add tosic acid monohydrate (0.008g, 0.042mmol) and water (0.5mL), stirring at room 24h.Concentration of reaction solution, adds water 10mL, ethyl acetate extraction, and with saturated sodium bicarbonate solution, saturated sodium-chloride water solution washing, organic layer spends the night with anhydrous sodium sulfate drying successively.Filter next day, removes solvent under reduced pressure, and column chromatography obtains deep yellow solid (0.11g, 60.1%).
1H-NMR(400MHz，DMSO-D
6)δppm：8.22(s，1H)，7.71(s，1H)，7.63-7.59(m，1H)，7.49-7.48(m，1H)，7.31-7.29(m，1H)，4.67(br s，2H)，4.18-4.16(m，1H)，4.03-3.99(m，1H，)，3.72-3.70(m，1H)，3.35-3.33(d，2H)，2.26(s，3H).ESI-MS m/z：410.1[M+1]
+。
embodiment 3:(E)-3,4, iodo-2 pyridyl of the fluoro-2-[(3-methyl-5-of 5-tri-) ammonia
base]--the preparation of O-(2,3-dihydroxypropyl) benzaldoxime (compound 3)
Method, with embodiment 2, obtains faint yellow solid.
1H-NMR(400MHz，DMSO-D
6)δppm：8.26-8.22(m，1H)，7.71(s，1H)，7.65-7.61(m，1H)，7.47-7.45(m，1H)，7.34-7.32(m，1H)，4.70(br s，2H)，4.18-4.15(m，1H，)，4.03-4.01(m，1H)，3.72-3.70(m，1H)，3.38-3.34(d，2H，J＝5.6Hz)，2.26(s，3H)。ES I-MS m/z：482.0[M+1]
+。
embodiment 4:(E)-3,4, iodo-2 pyridyl of 5 three fluoro-2-[(3-methyl-5-) ammonia
base] preparation of-O-(ring the third methyl) benzaldoxime (compound 4)
Method, with embodiment 2, obtains faint yellow solid.
1H-NMR(400MHz，DMSO-D
6)δppm：8.26-8.22(m，1H)，7.65-7.61(m，2H)，7.49-7.48(m，1H)，7.31-7.29(m，1H)，6.28-6.26(m，1H)，3.96-3.93(m，2H)，2.26(s，3H)，1.12-1.09(m，1H)，0.52-0.51(m，1H)，0.26-0.25(m，2H)，ESI-MS m/z：481.0[M+1]
+。
embodiment 5:(E)-3,4, iodo-2 pyridyl of 5 three fluoro-2-[(3-methyl-5-) ammonia
base] preparation of-O-(2-hydroxyethyl) benzaldoxime (compound 5)
Method is with embodiment 2,, obtain faint yellow solid.
1H-NMR(400MHz，DMSO-D
6)δppm：8.22(s，1H)，7.68(s，1H)，7.65-7.59(m，1H)，7.31-7.29(m，1H)，6.27-6.24(q，1H，J＝3.4Hz)，4.74-4.71(t，1H，J＝5.2Hz)，4.14-4.12(t，1H，J＝5.2Hz)，3.96-3.93(m，2H)，3.63-3.59(q，1H，J＝5.6Hz)，2.26(s，3H)，ESI-MS m/z：451.0[M+1]
+。
embodiment 6:(S, E) iodo-2 pyridyl of-3,4,5 three fluoro-2-[(3-methyl-5-) ammonia
base] preparation of-O-(2,3-dihydroxypropyl) benzaldoxime (compound 6)
Method, with embodiment 2, obtains faint yellow solid.
1H-NMR(400MHz，DMSO-D
6)δppm：8.22(s，1H)，7.70s，1H)，7.63-7.59(m，1H)，7.49-748(m，1H)，7.31-7.29(m，1H)，6.27-6.24(q，1H，J＝3.6Hz)，4.81-4.79(d，1H，J＝5.3Hz)，4.61-4.58(t，1H，J＝5.9Hz)，4.18-4.14(q，1H，J＝4.2Hz)，4.03-3.99(q，1H，J＝6.7Hz)，3.72-3.68(m，1H)，2.26(s，3H)，ESI-MS m/z：481.1[M+1]
+。
embodiment 7:3, the fluoro-2-[(2-methyl-4-of 4,5-tri-iodophenyl) amino] phenyl aldehyde (change
compound 7) preparation
Step 1), 3,4, the fluoro-2[(2-methyl-4-of 5-tri-iodophenyl) amino] benzoic preparation: by 2,3,4,5--tetrafluorobenzoic aid (0.50g, 2.58mmol) be dissolved in the mixed solvent of anhydrous THF (7mL) and anhydrous acetonitrile (7mL) with 2-methyl-4-Iodoaniline (0.60g, 2.58mmol).Add Lithamide (0.21g, 9.03mmol) in batches, in this process, have insolubles to occur.Stirring at room 0.5h after adding, property adds Lithamide (0.03g, 0.25mmol) stirring at room 10min again, and property adds Lithamide (0.03g, 0.25mmol), stirring at room 10min again.TLC show reaction do not carry out.After add again Lithamide (0.21g, 9.03mmol), system becomes deep yellow system from khaki suspendible system, and heat release.Stirring at room 0.5h, TLC shows that raw material has reacted complete.With 1N aqueous hydrochloric acid adjust pH, between 4-5, anhydrous diethyl ether extracts water layer, and organic layer spends the night with anhydrous sodium sulfate drying.Filter next day, removes solvent under reduced pressure, and column chromatography obtains yellow solid 3,4, the fluoro-2[(2-methyl-4-of 5-tri-iodophenyl) amino] phenylformic acid (0.69g, 65.7%),
1h-NMR (400MHz, DMSO-D
6) δ ppm:13.92 (br s, 1H), 8.76 (s, 1H), 7.82-7.77 (m, 1H), 7.55-7.54 (m, 1H), 7.41-7.38 (m, 1H), 6.61-6.59 (m, 1H), 2.49 (s, 3H).
Step 2), 3, the fluoro-2-[(2-methyl-4-of 4,5-tri-iodophenyl) amino] preparation of phenylcarbinol: by 3,4, the fluoro-2[(2-methyl-4-of 5-tri-iodophenyl) amino] phenylformic acid (3.0g, 7.4mmol) be dissolved in 30mL THF, slowly drip wherein the borine THF solution (11.1mL, 11.1mmol) of 1M, in dropping process, there is γ-ray emission, stirring at room 16h.Add the borine THF solution (2mL, 2mmol) of 1M, stirring at room 21h.In system, add 2% aqueous hydrochloric acid 30mL, stir 1h, ethyl acetate extraction, machine layer spends the night with anhydrous sodium sulfate drying.Filter next day, removes solvent under reduced pressure, and column chromatography obtains the fluoro-2-[(2-methyl-4-of yellow solid three iodophenyl) amino] phenylcarbinol (2.74g, 94.5%), ESI-MS m/z:394.1[M+1]
+.
Step 3), 3, the fluoro-2-[(2-methyl-4-of 4,5-tri-iodophenyl) amino] preparation of phenyl aldehyde: by 3,4, the fluoro-2-[(2-methyl-4-of 5-tri-iodophenyl) phenylamino] phenylcarbinol (0.86g, 2.19mmol) be dissolved in the methylene dichloride of 15mL, drip the methylene dichloride (20mL) of the PCC of new system, dropwise, reaction system becomes dark color, stirring at room reaction 2h.Decompression is the thick silica gel of 100-200 order for post, filters, and removes the black solid of generation, and ethyl acetate, as elutriant, obtains yellow solid 3,4, the fluoro-2-[(2-methyl-4-of 5-tri-iodophenyl) amino] phenyl aldehyde (0.62g, 72.5%).
1H-NMR(400MHz，DMSO-D
6)δppm：9.93(s，1H)，8.50(s，1H)，7.81-7.76(m，1H)，7.55(s，1H)，7.40-7.37(m，1H)，6.60-6.58(m，1H)，2.27(s，3H).ESI-MS m/z：408.1[M+1]
+。
embodiment 8:(R, E)-3,4, the fluoro-2-[(2-methyl-4-of 5-tri-iodophenyl) ammonia
base] preparation of-O-(2,3-dihydroxypropyl) benzaldoxime (compound 8)
Step 1), (R, E)-3,4,5 three fluoro-2-[(2-methyl-4-iodophenyls) amino]-O-[(2,2-methyl isophthalic acid, 3 dioxolane-4 bases) methyl] preparation of benzaldoxime: by 3,4, the fluoro-2-[(2-methyl-4-of 5-tri-iodophenyl) amino] phenyl aldehyde (0.4g, 1.02mmmol) and (R) the O-{3[(tertiary butyl-dimethyl-silicon) oxygen base] propyl group } azanol (0.30g, 2.05mmol) is dissolved in 10mL dehydrated alcohol, reflux, reaction 2h.Reaction system is directly used thick silica gel mixed sample, and column chromatography obtains deep yellow solid, is directly used in next step reaction.
Step 2), (R, E)-3,4,5 three fluoro-2-[(2-methyl-4-iodophenyls) amino]-O-(2,3-dihydroxypropyl) preparation of benzaldoxime: by (R, E)-3,4,5 three fluoro-2-[(2-methyl-4-iodophenyls) amino]-O-[(2,2-methyl isophthalic acid, 3 dioxolane-4 bases) methyl] benzaldoxime (0.22g, 0.42mmol) joins in the mixed solvent of methyl alcohol (5mL) and water (0.5mL), adds tosic acid monohydrate (0.008g, 0.042mmol), stirring at room 18h.Add tosic acid monohydrate (0.008g, 0.042mmol) and water (0.5mL), stirring at room 24h.Concentration of reaction solution, adds water 10mL, ethyl acetate extraction, and with saturated sodium bicarbonate solution, saturated sodium-chloride water solution washing, organic layer spends the night with anhydrous sodium sulfate drying successively.Filter next day, removes solvent under reduced pressure, and column chromatography obtains deep yellow solid (R, E)-3,4,5 three fluoro-2-[(2-methyl-4-iodine) phenylamino]-O-(2,3-dihydroxypropyl) benzaldoxime (0.13g, 65.1%).
1H-NMR(400MHz，DMSO-D
6)δppm：8.22(s，1H)，7.71(s，1H)，7.63-7.59(m，1H)，7.49-7.48(m，1H)，7.31-7.29(m，1H)，6.60-6.58(m，1H)，4.67(br s，2H)，4.18-4.16(q，1H，J＝4.4Hz)，4.03-3.99(q，1H，J＝6.7Hz)，3.72-3.70(m，1H)，3.35-3.33(d，2H，J＝5.9Hz)，2.26(s，3H).ESI-MS m/z：409.1[M+1]
+。
embodiment 9:(E)-3,4, the fluoro-2-[(2-methyl-4-of 5-tri-iodophenyl) ammonia
base] preparation of-O-(2,3-dihydroxypropyl) benzaldoxime (compound 9)
Method, with embodiment 8, obtains brown solid.
1H-NMR(400MHz，DMSO-D
6)δppm：8.26-8.22(m，1H)，7.71(s，1H)，7.65-7.61(m，1H)，7.49-7.48(m，1H)，7.31-7.29(m，1H)，6.28-6.26(m，1H)，4.70(br s，2H)，4.18-4.15(q，1H，J＝4.2Hz)，4.03-4.01(q，1H，J＝6.7Hz)，3.72-3.70(m，1H)，3.38-3.34(d，2H，J＝5.6Hz)，2.26(s，3H)。ES I-MS m/z：481.0[M+1]
+。
embodiment 10:(E)-3,4,5 three fluoro-2-[(2-methyl-4-iodine) phenylamino]-O-(ring
the third methyl) preparation of benzaldoxime (compound 10)
Method, with embodiment 8, obtains faint yellow solid.
1H-NMR(400MHz，DMSO-D
6)δppm：8.26-8.22(m，1H)，7.65-7.61(m，2H)，7.49-7.48(m，1H)，7.31-7.29(m，1H)，6.28-6.26(m，1H)，3.96-3.93(m，2H)，2.26(s，3H)，1.12-1.09(m，1H)，0.52-0.51(m，1H)，0.26-0.25(m，2H)，ESI-MS m/z：481.0[M+1]
+。
embodiment 11:(E)-3,4,5 three fluoro-2-[(2-methyl-4-iodine) phenylamino]-O-(2-
hydroxyethyl) preparation of benzaldoxime (compound 11)
Method is with embodiment 8,, obtain faint yellow solid.
1H-NMR(400MHz，DMSO-D
6)δppm：8.22(s，1H)，7.68(s，1H)，7.65-7.59(m，1H)，7.31-7.29(m，1H)，6.27-6.24(q，1H，J＝3.4Hz)，4.74-4.71(t，1H，J＝5.2Hz)，4.14-4.12(t，1H，J＝5.2Hz)，3.96-3.93(m，2H)，3.63-3.59(q，1H，J＝5.6Hz)，2.26(s，3H)，ESI-MS m/z：451.0[M+1]
+。
embodiment 12:(S, E)-3,4,5 three fluoro-2-[(2-methyl-4-iodine) phenylamino
base] preparation of-O-(2,3-dihydroxypropyl) benzaldoxime (compound 12)
Method, with embodiment 8, obtains faint yellow solid.
1H-NMR(400MHz，DMSO-D
6)δppm：8.22(s，1H)，7.70s，1H)，7.63-7.59(m，1H)，7.49-748(m，1H)，7.31-7.29(m，1H)，6.27-6.24(q，1H，J＝3.6Hz)，4.81-4.79(d，1H，J＝5.3Hz)，4.61-4.58(t，1H，J＝5.9Hz)，4.18-4.14(q，1H，J＝4.2Hz)，4.03-3.99(q，1H，J＝6.7Hz)，3.72-3.68(m，1H)，2.26(s，3H)，ESI-MS m/z：481.1[M+1]
+。
the iodo-3-methyl of embodiment 13:5-[(5-2-pyridyl) amino] the fluoro-1H-benzoglyoxaline of-4-
the preparation of-6-formaldehyde (compound 13)
Step 1), 5-nitro-2,3, the preparation of 4-trifluoro-benzoic acid: will slowly be added drop-wise under nitrosonitric acid (37mL, 0.78mol) condition of ice bath in the vitriol oil (200mL), in another one reaction system, add 2,3,4-trifluoro-benzoic acid (109.4g, 0.62mol) and vitriol oil 330mL.Under condition of ice bath, the concentrated sulfuric acid solution of nitrosonitric acid is slowly added drop-wise in the concentrated sulfuric acid solution of reaction raw materials.Remove ice bath, be naturally warming up to room temperature, stirring reaction 5h.Under agitation condition, reaction soln is slowly added drop-wise in the frozen water solution of 2000mL, stirring at room 2h, standing over night, filters and obtains white solid 5-nitro-2,3,4-trifluoro-benzoic acid (123.7g, 90.3%), ESI-MS m/z:222.0[M+1]
+.
Step 2); 5-nitro-3; the iodo-3-methyl of the fluoro-2-[(5-of 4-bis-2-pyridyl) amino]-benzoic preparation: under nitrogen protection condition; by 2-amino-3-methyl-5-iodine pyridine (10.61g; 0.045mol); be dissolved in 70mL anhydrous tetrahydro furan (THF), cool to-70 ℃.The THF solution of the lithium diisopropylamine of 2M (LDA) is dripped to (34mL, 0.068mol) and be added in reaction system, under-70 ℃ of conditions, react 1h.In reaction system, drip 5-nitro-2, the THF solution of 3,4-trifluoro-benzoic acid (5.01g, 0.023mol), dropwises ,-70 ℃ of reaction 1h.Naturally be warmed up to room temperature, stirred overnight at room temperature.Saturated aqueous ammonium chloride, saturated sodium-chloride water solution washing successively, ethyl acetate is extracted water layer, organic layer dried overnight, column chromatography obtains yellow solid 5-nitro-3, the iodo-3-methyl of the fluoro-2-[(5-of 4-bis-2-pyridyl) amino]-phenylformic acid (4.78g, 47.8%)
1h-NMR (400MHz, CDCl
3) δ ppm:8.26-8.25 (m, 1H), 7.76-7-75 (br s, 1H), 7.21-7.19 (m, 1H), 5.99 (s, 1H), 2.31 (s, 3H), ESI-MS m/z:436.0[M+1]
+.
Step 3), the iodo-3-methyl of the fluoro-2-[(5-of 5-nitro-4-amino-3-2-pyridyl) amino]-benzoic preparation: by 5-nitro-3, the iodo-3-methyl of the fluoro-2-[(5-of 4-bis-2-pyridyl) amino]-phenylformic acid (2.30g, 5.29mmol) join in 100mL distilled water, cool to 0 ℃.In reaction system, dropwise add strong aqua (2.21mL, 29.6mmol), 0 ℃ of reaction 1h.Naturally return to room temperature, reaction 4h, filters to obtain the iodo-3-methyl of the fluoro-2-[(5-of yellow solid 5-nitro-4-amino-3-2-pyridyl) amino]-phenylformic acid (1.82g, 79.5%),
1h-NMR (400MHz, CDCl
3) δ ppm:8.26-8.25 (m, 1H), 7.76-7-75 (br s, 1H), 7.21-7.19 (m, 1H), 6.27 (s, 2H), 5.99 (s, 1H), 2.31 (s, 3H), ESI-MS m/z:433.1[M+1]
+.
Step 4), the iodo-3-methyl of the fluoro-2-[(5-of 5-nitro-4-amino-3-2-pyridyl) amino] preparation of-methyl benzoate: by the iodo-3-methyl of the fluoro-2-[(5-of 5-nitro-4-amino-3-2-pyridyl) amino]-phenylformic acid (1.82g, 4.21mmol) be dissolved in 20mL anhydrous methanol, slowly drip trimethylchlorosilane (1.06mL, 8.42mmol).Dropwise backflow 12h.Water pump removes solvent and excessive trimethylchlorosilane under reduced pressure, obtains weak yellow liquid, adds methylene dichloride 20mL, and washs by 10% aqueous sodium hydroxide washes, and the anti-water lift layer of methylene dichloride merges organic layer, and organic layer spends the night with anhydrous sodium sulfate drying.Filter next day, removes solvent under reduced pressure, obtains the iodo-3-methyl of the fluoro-2-[(5-of yellow solid 5-nitro-4-amino-3-2-pyridyl) amino]-methyl benzoate (1.84g, 97.9%),
1h-NMR (400MHz, CDCl
3) δ ppm:8.26-8.25 (m, 1H), 7.76-7-75 (br s, 1H), 7.21-7.19 (m, 1H), 6.27 (s, 2H), 5.99 (s, 1H), 3.97 (s, 3H), 2.31 (s, 3H), ESI-MS m/z:447.1[M+1]
+.
Step 5), the iodo-3-methyl of 5-[(5-2-pyridyl) amino] preparation of the fluoro-1H-benzoglyoxaline-6-of-4-methyl-formiate: by the iodo-3-methyl of the fluoro-2-[(5-of 5-nitro-4-amino-3-2-pyridyl) amino]-methyl benzoate (1.84g, 4.12mmol), formic acid (25mL) and 20%Pd (OH)/C (1.57g, 2.95mrnol) are heated to 95 ℃ in 25mL ethanol.After 16 hours, reaction mixture is cooled to room temperature, and adds 0.5g 20%Pd (OH) 2/C and 10mL formic acid.Reaction mixture is heated to 95 ℃.After 16 hours, reaction mixture is cooled to room temperature, and by diatomite filtration, uses washing with alcohol.Concentrating under reduced pressure filtrate, has solid to separate out, and filters and obtains the iodo-3-methyl of deep yellow solid 5-[(5-2-pyridyl) amino] the fluoro-1H-benzoglyoxaline-6-of-4-methyl-formiate (1.35g, 76.7%),
1h-NMR (400MHz, CDCl
3) δ ppm:8.41-8.39 (m, 1H), 8.19 ((s, 1H), 7.76-7-75 (br s, 1H), 7.21-7.19 (m, 1H), 6.21 (s, 1H), 5.99 (s, 1H), 3.97 (s, 3H), 2.31 (s, 3H), ES I-MS m/z:427.1[M+1]
+.
Step 6), the iodo-3-methyl of 5-[(5-2-pyridyl) amino] preparation of the fluoro-1H-benzoglyoxaline-6-of-4-formic acid: by the iodo-3-methyl of 5-[(5-2-pyridyl) amino] the fluoro-1H-benzoglyoxaline-6-of-4-methyl-formiate (1.35g 3.17mmol) is suspended in methyl alcohol in (30mL), add 20%NaOH (8mL), after 16h, reaction mixture is cooled to 0 ℃, and drip 1NHCl solution, until pH is 2-3.By ethyl acetate and water dilution for reaction mixture, and separated each layer.With saturated sodium-chloride water solution, wash organic layer, organic layer spends the night with anhydrous sodium sulfate drying.Filter next day, removes solvent under reduced pressure, and column chromatography obtains the iodo-3-methyl of deep yellow solid 5-[(5-2-pyridyl) amino] the fluoro-1H-benzoglyoxaline-6-of-4-formic acid (0.68g, 52.3%),
1h-NMR (400MHz, CDCl
3) δ ppm:8.41-8.39 (m, 1H), 8.19 ((s, 1H), 7.76-7-75 (br s, 1H), 7.21-7.19 (m, 1H), 6.21 (s, 1H), 5.99 (s, 1H), 2.31 (s, 3H), ES I-MS m/z:413.1[M+1]
+.
Step 7), the iodo-3-methyl of 5-[(5-2-pyridyl) amino] preparation of the fluoro-1H-benzoglyoxaline-6-of-4-methyl alcohol: by the iodo-3-methyl of 5-[(5-2-pyridyl) amino] the fluoro-1H-benzoglyoxaline-6-of-4-formic acid (3.05g, 7.4mmol) be dissolved in 30mL THF, slowly drip wherein the borine THF solution (11.1mL of 1M, 11.1mmol), in dropping process, there is γ-ray emission, stirring at room 16h.Add the borine THF solution (2mL, 2mmol) of 1M, stirring at room 21h.In system, add 2% aqueous hydrochloric acid 30mL, stir 1h, ethyl acetate extraction, organic layer spends the night with anhydrous sodium sulfate drying.Filter next day, removes solvent under reduced pressure, and column chromatography obtains yellow solid (2.56g, 87.1%),
1h-NMR (400MHz, CDCl
3) δ ppm:8.43-8.41 (m, 1H), 8.19 ((s, 1H), 7.76-7-75 (br s, 1H), 7.21-7.19 (m, 1H), 6.21 (s, 1H), 5.99 (s, 1H), 4.63-4.61 (m, 2H) 2.31 (s, 3H), ESI-MS m/z:399.1[M+1]
+.
Step 8), the iodo-3-methyl of 5-[(5-2-pyridyl) amino] preparation of the fluoro-1H-benzoglyoxaline-6-of-4-formaldehyde: by the iodo-3-methyl of 5-[(5-2-pyridyl) amino] the fluoro-1H-benzoglyoxaline-6-of-4-methyl alcohol (2.56g, 6.41mmol) be dissolved in the methylene dichloride of 35mL, drip the methylene dichloride (40mL) of the PCC of new system, dropwise, reaction system becomes dark color, stirring at room reaction 2h.Decompression is the thick silica gel of 100-200 order for post, filters, and removes the black solid of generation, and ethyl acetate, as elutriant, obtains dark solid (1.98g, 80.0%).
1H-NMR(400MHz，DMSO-D
6)δppm：9.93(s，1H)，8.43-8.41(m，1H)，8.19((s，1H)，7.76-7-75(br s，1H)，7.21-7.19(m，1H)，6.21(s，1H)，5.99(s，1H)，2.31(s，3H)，ES I-MS m/z：397.1[M+1]
+。
embodiment 14:(E) the iodo-3-methyl of-5-[(5-2-pyridyl) amino] the fluoro-1H-benzo of-4-
the preparation of imidazoles-O-(ring the third methyl)-6-formoxime (compound 14)
Utilize the iodo-3-methyl of the 5-[(5-making in embodiment 13 2-pyridyl) amino] the fluoro-1H-benzoglyoxaline-6-of-4-formaldehyde, method, with embodiment 8, obtains deep yellow solid,
1h-NMR (400MHz, DMSO-D
6) δ ppm:9.93 (s, 1H), 8.65-8.63 (m, 1H), 8.42-8.41 (m, 1H), 8.21 ((s, 1H), 7.75-7-73 (br s, 1H), 7.21-7.19 (m, 1H), 6.21 (s, 1H), 5.99 (s, 1H), 4.67 (s, 2H), 4.35-4.33 (m, 2H), 4.14-4.12 (m, 1H), 3.82-380 (m, 1H), 3.37-3.35 (m, 2H), 2.26 (s, 3H), ESI-MS m/z:470.1[M+1]
+.
embodiment 15: biological activity test
Part of compounds (as table 3) has been carried out to active testing, evaluated these compounds and pressed down in vitro the activity of myelomatosis cell (K562) and Human Large Intestine Carcinoma Cells (HT-29) tumor cell proliferation.Use the positive contrast of PD198306.PD198306 is the conventional instrument medicine in this area (can be purchased or synthesize according to prior art), and its structural formula is as follows:
The growth of tumour cell of cultivating is to suitable density, 0.25% tryptic digestion 2-5min for attached cell, suspension cell centrifugal (1000rpm/min), with the corresponding nutrient solution of cell, prepare single cell suspension, adjust cell concn to corresponding density (table 2), be inoculated in 96 well culture plates, 100 μ L/ holes, 37 ℃ of 5%CO
2the full substratum that first adds the 80 corresponding cells in μ L/ hole after lower cultivation 24h, the test-compound 20 μ L/ holes that add again different concns, 3 repetitions are established in every kind of processing, under 37 ℃ of 5%CO2, continue to cultivate after 72h, every hole sucking-off supernatant 100 μ L, then add tetrazolium bromide (MTT) the solution 10 μ L of 5mg/mL, 37 ℃ are continued to hatch 4h, last every hole adds the SDS of 100 μ L 10%, 37 ℃ of 5%CO
2under hatch 24h, MTT crystallization is dissolved completely.Enzyme-linked immunosorbent assay instrument 570nm wavelength is measured every hole absorbancy.
Table 2: cell culture medium and inoculum density
| Cell title | Substratum | Plant plate density |
| K562 | 1640+10％FBS | 1×10 5Individual/mL |
| HT-29 | DMEM (Hg)+F12+5% import FBS | 1×10 5Individual/mL |
Press formula:
Inhibiting rate (%)=(1-is subject to the average OD value in prospect hole OD value/solvent control hole) * 100%
Calculate inhibiting rate, and to take the logarithm of test-compound concentration be X-coordinate, cell inhibitory rate mean value is that ordinate zou is drawn dose effect curve, and asks half cytostatics value (IC with Origin analysis software
50).Result represents with SD.
Before test, with DMSO (Sigma), medicine is assigned to mother liquid concentration, with the full substratum that does not contain the factor, is diluted to required application concentration.Preliminary assessment compound is done the used time for the growth-inhibiting of tumour cell, selects tri-dosage groups of 3,30,300 μ M, blank group, solvent control group; Further ask its half cytostatics value (IC
50) time, according to primary dcreening operation result, select six dosage groups, blank group, the solvent control group in 1,3,10,30,100,200,300 μ M.
Result is as shown in table 3.
Table 3: part of compounds is active to the inhibition of K562 and HT-29
Result demonstration, compound of the present invention has significant inhibition to tumour cell.
Although the specific embodiment of the present invention has obtained detailed description, it will be understood to those of skill in the art that.According to disclosed all instructions, can carry out various modifications and replacement to those details, these change all within protection scope of the present invention.Four corner of the present invention is provided by claims and any equivalent thereof.
Claims (8)
1. compound or its pharmacologically acceptable salts shown in formula V or formula VI:
Wherein,
R
1, R
2, R
3independently selected from halogen, hydroxyl, amino, nitro, itrile group and trifluoromethyl;
R
4and R
6for hydrogen;
R
5be selected from halogen, hydroxyl, amino, nitro, itrile group and trifluoromethyl;
R
7be selected from halogen, hydroxyl, amino, nitro, itrile group and trifluoromethyl;
R
8be selected from C
1-C
6alkyl;
X is C or N;
W is-OR
9;
R wherein
9be selected from C
1-C
10alkyl, C
3-C
10cycloalkyl, C
3-C
10cycloalkylalkyl, and replaced by 1-5 hydroxyl.
2. be selected from following compound or its pharmacologically acceptable salts:
(R, E)-3,4, the iodo-2-pyridyl of the fluoro-2-[(3-methyl-5-of 5-tri-) amino]-O-(2,3-dihydroxypropyl) benzaldoxime
(E)-3,4, the iodo-2-pyridyl of the fluoro-2-[(3-methyl-5-of 5-tri-) amino]-O-(2,3-dihydroxypropyl) benzaldoxime
(E)-3,4, the iodo-2-pyridyl of the fluoro-2-[(3-methyl-5-of 5-tri-) amino]-O-(ring the third methyl) benzaldoxime
(E)-3,4, the iodo-2-pyridyl of the fluoro-2-[(3-methyl-5-of 5-tri-) amino]-O-(2-hydroxyethyl) benzaldoxime
(S, E)-3,4, the iodo-2-pyridyl of the fluoro-2-[(3-methyl-5-of 5-tri-) amino]-O-(2,3-dihydroxypropyl) benzaldoxime
(R, E)-3,4, the fluoro-2-[(2-methyl-4-of 5-tri-iodophenyl) amino]-O-(2,3-dihydroxypropyl) benzaldoxime
(E)-3,4, the fluoro-2-[(2-methyl-4-of 5-tri-iodophenyl) amino]-O-(2,3-dihydroxypropyl) benzaldoxime
(E)-3,4, the fluoro-2-[(2-methyl-4-of 5-tri-iodine) phenylamino]-O-(ring the third methyl) benzaldoxime
(E)-3,4, the fluoro-2-[(2-methyl-4-of 5-tri-iodine) phenylamino]-O-(2-hydroxyethyl) benzaldoxime
(S, E)-3,4, the fluoro-2-[(2-methyl-4-of 5-tri-iodine) phenylamino]-O-(2,3-dihydroxypropyl) benzaldoxime, and
(E) the iodo-3-methyl-2-of-5-[(5-pyridyl) amino] the fluoro-1H-benzoglyoxaline-O-of-4-(ring the third methyl)-6-formoxime.
3. be selected from following compound or its pharmacologically acceptable salts:
The fluoro-2-[(2-methyl-4-of 3,4,5-tri-iodophenyl) amino] phenyl aldehyde.
4. a pharmaceutical composition, it comprises the compound described in any one or its pharmacologically acceptable salts in claims 1 to 3, and at least one pharmaceutically acceptable auxiliary material.
5. in claims 1 to 3, the compound described in any one, its pharmacologically acceptable salts or pharmaceutical composition claimed in claim 4 treat and/or prevent the purposes in the medicine of tumour in preparation.
6. purposes according to claim 5, wherein, described tumour is myelomatosis, large bowel cancer, melanoma, papilliferous thyroid carcinoma, colorectal carcinoma, carcinoma of the pancreas or non-small cell type lung cancer.
7. the compound described in any one, its pharmacologically acceptable salts or the purposes of pharmaceutical composition claimed in claim 4 in preparing inhibiting tumour cells agent in claims 1 to 3.
8. purposes according to claim 7, wherein, described tumour cell is myelomatosis cell, Human Large Intestine Carcinoma Cells, melanoma cell, papilliferous thyroid carcinoma cell, colon cancer cell, pancreatic cancer cell or non-small cell type lung carcinoma cell.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110062879.9A CN102675194B (en) | 2011-03-16 | 2011-03-16 | Oximes-contained amino derivative, pharmaceutical composition of oximes-contained amino derivative, preparation method of oximes-contained amino derivative and application of oximes-contained amino derivative |
| PCT/CN2012/071706 WO2012122891A1 (en) | 2011-03-16 | 2012-02-28 | Oxime-containing amino derivative, pharmaceutical composition, preparation method and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110062879.9A CN102675194B (en) | 2011-03-16 | 2011-03-16 | Oximes-contained amino derivative, pharmaceutical composition of oximes-contained amino derivative, preparation method of oximes-contained amino derivative and application of oximes-contained amino derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102675194A CN102675194A (en) | 2012-09-19 |
| CN102675194B true CN102675194B (en) | 2014-10-01 |
Family
ID=46807816
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110062879.9A Active CN102675194B (en) | 2011-03-16 | 2011-03-16 | Oximes-contained amino derivative, pharmaceutical composition of oximes-contained amino derivative, preparation method of oximes-contained amino derivative and application of oximes-contained amino derivative |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN102675194B (en) |
| WO (1) | WO2012122891A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101831553B1 (en) | 2017-01-23 | 2018-02-22 | 계명대학교 산학협력단 | Novel compounds for treatment of metastatic blast cancer and medical use thereof |
| WO2023283425A1 (en) | 2021-07-09 | 2023-01-12 | Plexium, Inc. | Aryl compounds and pharmaceutical compositions that modulate ikzf2 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4981865A (en) * | 1989-05-26 | 1991-01-01 | Warner-Lambert Co. | N-hydroxyamide, N-hydroxythioamide, hydroxyurea, and N-hydroxythiourea derivatives of selected nsaids as antiinflammatory agents |
| US5840758A (en) * | 1996-06-06 | 1998-11-24 | Abbott Laboratories | Oxime derivatives of fenamates as inhibitors of prostaglandin biosynthesis |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4931419B2 (en) * | 2003-09-19 | 2012-05-16 | 中外製薬株式会社 | Novel 4-phenylamino-benzaldoxime derivatives and their use as MEK inhibitors |
-
2011
- 2011-03-16 CN CN201110062879.9A patent/CN102675194B/en active Active
-
2012
- 2012-02-28 WO PCT/CN2012/071706 patent/WO2012122891A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4981865A (en) * | 1989-05-26 | 1991-01-01 | Warner-Lambert Co. | N-hydroxyamide, N-hydroxythioamide, hydroxyurea, and N-hydroxythiourea derivatives of selected nsaids as antiinflammatory agents |
| US5840758A (en) * | 1996-06-06 | 1998-11-24 | Abbott Laboratories | Oxime derivatives of fenamates as inhibitors of prostaglandin biosynthesis |
Non-Patent Citations (4)
| Title |
|---|
| Gas-phase cyclisation reactions of 1-(2-arylaminophenyl)alkaniminyl radicals;Rino Leardini et al.,;《J. Chem. Soc., Perkin Trans. 1》;19981231;第1833页化合物9 * |
| Gianluca Calestani et al.,.Thermal decomposition of tert-butyl o-(phenoxy)- and o-(anilino)-phenyliminoxyperacetates.《J. Chem. Soc., Perkin Trans. 1》.1998, |
| Rino Leardini et al.,.Gas-phase cyclisation reactions of 1-(2-arylaminophenyl)alkaniminyl radicals.《J. Chem. Soc., Perkin Trans. 1》.1998, |
| Thermal decomposition of tert-butyl o-(phenoxy)- and o-(anilino)-phenyliminoxyperacetates;Gianluca Calestani et al.,;《J. Chem. Soc., Perkin Trans. 1》;19981231;第1818页左栏第24行 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2012122891A1 (en) | 2012-09-20 |
| CN102675194A (en) | 2012-09-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP7017523B2 (en) | A novel mitochondrial uncoupler for the treatment of metabolic diseases and cancer | |
| CN105153122A (en) | [(indole-3-yl)pyrimidine-2-yl]aminophenylpropyl-2-eneamide derivative and its salt, preparation method of derivative, and application of derivative and salt | |
| CN104812761B (en) | Double B-carboline alkaloid compounds, its preparation method and its pharmaceutical composition and purposes | |
| CN102675194B (en) | Oximes-contained amino derivative, pharmaceutical composition of oximes-contained amino derivative, preparation method of oximes-contained amino derivative and application of oximes-contained amino derivative | |
| CN107522657A (en) | A kind of compound with the multiple agonist activities of PPAR and its preparation method and application | |
| ES2963054T3 (en) | Guanidine derivative | |
| CN101230045B (en) | Aromatic triazin derivatives and uses thereof | |
| CN110922415B (en) | Synthesis and application of novel anti-tumor active compound | |
| CN110938109B (en) | O-quinone compound, preparation method and medical application thereof | |
| CN101429183B (en) | 2H-1-benzopyran-2-ketone compounds with alpha-glucosidase inhibit activity, its composition and preparation method thereof | |
| CN101974016A (en) | Amide compound and preparation method and applications thereof | |
| CN102718702B (en) | Aminopyridine derivatives and application thereof | |
| CN102746212B (en) | Beta-elemene indole derivative, preparation and application thereof | |
| CN103864765A (en) | Benzoazepine derivative containing five-membered heterocycle as well as preparation method and application of derivative | |
| CN102718750B (en) | Aminopyridine derivatives containing acridine ring and application thereof | |
| CN108864082A (en) | One kind has the indolizine class compound and its derivative of anticancer activity | |
| EP2570403B1 (en) | Urea compounds and use thereof for inhibiting apoptosis | |
| CN102408395B (en) | Novel piperazine and homopiperazine derivative and preparation method and use thereof | |
| CN106349257B (en) | The double B-carboline alkaloid compounds and its pharmaceutical applications that 3 piperazine bridgings connect | |
| CN108164476B (en) | Isophthalonitrile compound, application thereof and medicine containing compound | |
| CN115703736A (en) | Multi-target inhibitors targeting HDAC and NAD synthesis and uses thereof | |
| CN102241673A (en) | Acrylamide compounds and medicinal uses thereof | |
| CN102241627B (en) | Carbamide compound and its medicinal usage | |
| CN102241646B (en) | Hexenone compound, and medical purpose thereof | |
| CN110746392A (en) | Application of furan compound in preparation of antitumor drugs |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |