CN102718750B - Aminopyridine derivatives containing acridine ring and application thereof - Google Patents
Aminopyridine derivatives containing acridine ring and application thereof Download PDFInfo
- Publication number
- CN102718750B CN102718750B CN201110079345.7A CN201110079345A CN102718750B CN 102718750 B CN102718750 B CN 102718750B CN 201110079345 A CN201110079345 A CN 201110079345A CN 102718750 B CN102718750 B CN 102718750B
- Authority
- CN
- China
- Prior art keywords
- amino
- methyl
- acridine
- fluoro
- pyridyl
- 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
- 0 CN(*)c(c(*)c(c(C(N(C1)CC1C(N)=O)=O)c1*)Nc2ncc(*)cc2*)c1N Chemical compound CN(*)c(c(*)c(c(C(N(C1)CC1C(N)=O)=O)c1*)Nc2ncc(*)cc2*)c1N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
The present invention relates to aminopyridine derivatives containing acridine ring, in particular to compounds as shown in the formula I or II, their preparation methods and an application of the derivatives in the preparation of drugs for inhibiting cell over-proliferation. The invention also relates to a pharmaceutical composition containing the compounds. The compounds provided by the invention can be used to treat over-proliferative diseases such as cancer, neuropathic pain, inflammation and the like.
Description
Technical field
The present invention relates to the aminopyridine analog derivative containing acridine ring, be specifically related to such as formula the compound shown in I or formula II, its preparation method and its purposes for the preparation of the medicine of T suppression cell hyper-proliferative.
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, obtained the compound of the clear and definite anti-tumor activity of multiple display on this basis by structural modification, wherein vinealeucoblastine(VLB), Etoposide, taxol etc. are approved for clinical anticancer in succession.But the resource-constrained of these natural product medicament, its molecular structure is complicated, chemosynthesis difficulty, not easily large-scale production.Therefore, need to find the simple small molecule, anti-tumor drug of structure.
Summary of the invention
The present invention aims to provide a kind of aminopyridine analog derivative containing acridine ring with T suppression cell hyperproliferative activity.
The invention provides the compound shown in formula I, II or its pharmaceutically useful salt, solvate or N-oxide compound.
Wherein:
In formula II,---represent optional key, condition is have in ring and only have a nitrogen-atoms to be double bond;
R
1, R
2, R
3, R
4, R
5, R
7or R
8be selected from hydrogen, hydroxyl, halogen, amino, nitro, itrile group, trifluoromethyl ,-OR independently of one another
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 cycloheteroalkylalkyl;
R
6be 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 cycloheteroalkylalkyl;
W is selected from-OR
9,-NR
10oR
9,-NR
10sO
2r
9,-NR
10r
9;
R
9, R
10be selected from hydrogen, hydroxyl, halogen, trifluoromethyl, C independently of one another
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 cycloheteroalkylalkyl;
Wherein each alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl ground is replaced independently selected from following group by 1-5: hydroxyl, halogen, amino, nitro and trifluoromethyl;
Preferred compound has the structure of formula III, IV:
Wherein, each substituted radical as defined above;
The compound be more preferably has the structure of formula V, VI:
Wherein, each substituted radical as defined above;
Preferred compound is R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8for hydrogen, halogen, nitro, itrile group, trifluoromethyl;
Preferred compound is W is-NR
10oR
9,-NR
10r
9.
In embodiments of the invention, described compound is selected from following compound:
The fluoro-2-of 1-{3,4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-carboxylic acid acridine;
The fluoro-2-of N-(cyclohexyl methyl)-1-{3,4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-Carboxylamide acridine;
N-(2-morpholine ethyl) the fluoro-2-of-1-{3,4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-Carboxylamide acridine;
The fluoro-2-of N-(benzyloxy)-1-{3,4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-Carboxylamide acridine;
N-[(2,2-methyl isophthalic acid, 3 dioxolane-4 bases) methoxyl group] the fluoro-2-of-1-{3,4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-Carboxylamide acridine;
(R)-N-[(2,2-methyl isophthalic acid, 3 dioxolane-4 bases) methoxyl group] the fluoro-2-of-1-{3,4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-Carboxylamide acridine;
N-(2,3-dihydroxyl propoxy-) the fluoro-2-of-1-{3,4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-Carboxylamide acridine;
The fluoro-2-of 1-{3,4,5-tri-[(3-methyl-5-bromo-2-pyridyl base) is amino] benzoyl }-3-carboxylic acid acridine;
The fluoro-2-of N-(cyclohexyl methyl)-1-{3,4,5-tri-[(3-methyl-5-bromo-2-pyridyl base) is amino] benzoyl }-3-Carboxylamide acridine;
N-(2-morpholine ethyl) the fluoro-2-of-1-{3,4,5-tri-[(3-methyl-5-bromo-2-pyridyl base) is amino] benzoyl }-3-Carboxylamide acridine;
The fluoro-2-of N-(benzyloxy)-1-{3,4,5-tri-[(3-methyl-5-bromo-2-pyridyl base) is amino] benzoyl }-3-Carboxylamide acridine;
(R)-N-(2,3-dihydroxyl propoxy-) the fluoro-2-of-1-{3,4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-Carboxylamide acridine;
N-[2-(piperidin-1-yl) ethyl] the fluoro-2-of-1-{3,4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-Carboxylamide acridine;
N-(ring third methoxyl group) the fluoro-2-of-1-{3,4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-Carboxylamide acridine;
(S)-N-(2,3-dihydroxyl propoxy-) the fluoro-2-of-1-{3,4,5-tri-[(3-methyl-5-bromo-2-pyridyl base) is amino] benzoyl }-3-Carboxylamide acridine;
1-{5-[(5-iodo-3-methyl 2-pyridyl) is amino] the fluoro-1H-benzoglyoxaline of-4--6-formyl }-3-carboxylic acid acridine;
N-[2-(thiophene-2-base) ethyl]-1{5-[(5-iodo-3-methyl 2-pyridyl) is amino] the fluoro-1H-benzoglyoxaline of-4--6-methane amide }-3-Carboxylamide acridine;
N-[2-(piperidin-1-yl) ethyl]-1{5-[(5-iodo-3-methyl 2-pyridyl) is amino] the fluoro-1H-benzoglyoxaline of-4--6-methane amide }-3-Carboxylamide acridine.
On the other hand, the invention still further relates to formula I, II compound or its pharmaceutically useful salt, solvate or N-oxide synthesis.
Its compounds of formula I synthetic schemes is as follows:
With the phenylformic acid containing leaving group L replaced for starting raw material, through reacting, by carboxymethyl group with methylating reagent; Again by reacting with ammoniacal liquor, methyl esters is converted into amide group; At POCl
3slough the water of an one's share of expenses for a joint undertaking under effect, amido linkage is converted into cyano group; The benzene first cyanogen containing leaving group L replaced is under alkali (such as Lithamide) effect, and leaving group is left away and carried out condensation reaction with the aminopyridines replaced; Cyan-hydrolysis is being obtained carboxyl.React with 3-carboxyl acridine ring, the carboxyl on acridine ring and corresponding side chain react, and obtain formula I again;
L represents leaving group, can be halogen;
Formula II compou nd synthesis scheme is as follows; :
With the phenylformic acid containing leaving group L replaced for starting raw material, through nitration reaction, phenyl ring introduces nitro; Under alkali (such as Lithamide) effect, leaving group is left away and is carried out condensation reaction with the aminopyridines replaced; Under ammoniacal liquor effect, phenyl ring is introduced amino; Through reacting, by carboxymethyl group with methylating reagent; Be, after amino, carry out annulation by nitroreduction, piptonychia ester obtains carboxylic key intermediate, then reacts with 3-carboxyl acridine ring, and the carboxyl on acridine ring and corresponding side chain react, and obtain formula II compound;
L represents leaving group, can be halogen.
The present invention also provides the pharmaceutical composition containing formula I of the present invention, II compound or its pharmaceutically useful salt, solvate or N-oxide compound and pharmaceutically acceptable carrier.
The invention still further relates to compound of the present invention or its pharmaceutically useful salt, solvate or the N-oxide compound purposes for the preparation of the medicine of T suppression cell hyper-proliferative.
Described cell hyperproliferation comprises the diseases such as leukemia, glioblastoma, lymphoma, melanoma, cancer, neuropathic pain, inflammation.In one embodiment of the invention, described T suppression cell hyper-proliferative refers to that inhibition tumor cell is bred.
The invention still further relates to compound of the present invention or its pharmaceutically useful salt, solvate or the N-oxide compound purposes for the preparation of antitumor drug.
C in the present invention
1-C
10alkyl, alkyl refer to the straight or branched a heatable brick bed base 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.Preferred alkyl is C
1-C
6alkyl.Preferred alkyl is C
1-C
3alkyl;
C
2-C
10thiazolinyl refers to the thiazolinyl with 2-10 carbon atom and at least one double bond, and comprises vinyl, propenyl, 1-fourth-3-thiazolinyl, 1-penta-3-thiazolinyl, oneself-5-thiazolinyl of 1-etc.More preferably there is the low-grade alkenyl of 3-5 carbon atom;
C
2-C
10alkynyl refers to the alkyl with 2-10 carbon atom and at least one three key, such as, comprise ethynyl, proyl, butynyl, pentyne-2-base etc.More preferably there is the alkynyl of 3-5 carbon atom;
Halogen refers to fluorine, chlorine, bromine and atomic iodine;
Aryl refer to have monocycle (as phenyl), many rings (as xenyl) or wherein at least one ring be that multiple fused rings of aromaticity are (as 1,2,3,4-tetralyl, naphthyl) aromatic carbocyclyl groups, its optionally by such as halogen, low alkyl group, lower alkoxy, trifluoromethyl, aryl, heteroaryl and hydroxyl list, two or three replace.
Heteroaryl refers to one or more aromatics ring systems of 5,6 or 7 rings, and 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 being 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 such as halogen, low alkyl group, lower alkoxy, trifluoromethyl, aryl, heteroaryl and hydroxyl list, two or three.
Carbocyclic ring, carbocylic radical, cycloalkyl, C
3-C
10cycloalkyl refers to the saturated carbon ring group with 3-10 carbon atom.This cycloalkyl can be monocycle or many rings fused system, and can condense on aromatic ring.The example of these groups comprises cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.Cycloalkyl herein can be unsubstituted or as described in detail, is replaced by various group in one or more commutable position.Such as, 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;
Heterocycle or heterocyclic radical refer to one or more carbocyclic ring system of 5,6 or 7 rings, what it comprised 4-10 atom condenses ring system, described ring system contains at least one and maximum four heteroatomss being selected from nitrogen, oxygen or sulphur, and condition is that the ring of this group does not conform to two adjacent O or S atoms.Condensing ring system can be condense the heterocycle 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 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;
Arylalkyl refers to (as defined above) alkyl replaced by one or more (as defined above) aryl.Preferred arylalkyl is aryl-C
1-C
3alkyl.Example comprises benzyl, phenylethyl etc.;
Heteroarylalkyl refers to (as defined above) alkyl replaced by (as defined above) heteroaryl.Preferred heteroarylalkyl is 5-or 6-unit heteroaryl-C
1-C
3-alkyl.Example comprises pyridyl-ethyl group etc.;
Cycloheteroalkylalkyl refers to (as defined above) alkyl replaced by (as defined above) heterocyclic radical.Preferred cycloheteroalkylalkyl is 5 or 6 yuan of heterocyclic radical-C
1-C
3-alkyl.Example comprises tetrahydropyrans ylmethyl;
Cycloalkylalkyl refers to by (as defined above) alkyl of (as defined above) cycloalkyl substituted.Preferred heterocyclic radical is 5 or 6 yuan of cycloalkyl-C
1-C
3-alkyl.Example comprises Cvclopropvlmethvl;
The compounds of this invention also can use with the form of its pharmacy acceptable salt or solvate.On the physiology of formula I or formula II compound, receivable salt comprises the salt of routine and the acid salt of quaternary ammonium that are formed by pharmaceutically acceptable mineral acid or organic acid or mineral alkali or organic bases.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, may be used for preparing the salt being used 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, chloroprocaine, choline, diethanolamine, quadrol, N-METHYL-ALPHA-L-GLUCOSAMINE and procaine salt.
Some compound in the present invention with water or various organic solvent crystallization or recrystallization, in this case, may may form all kinds of SOLVENTS compound.The present invention includes those stoichiometric solvate, such as hydrates, be also included within the compound comprising variable water gaging formed when preparing with lyophylization.
Therefore, when relating to compound of the present invention, formula I or formula II compound and pharmacy acceptable salt thereof and solvate is comprised.
The present invention also comprises the prodrug of the compounds of this invention, and this prodrug, once administration, namely carries out chemical conversion by metabolic process, becomes the activated medicine of tool afterwards.Usually, this kind of 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.Such as, at " Design Of Prodrugs ", H Bund Saard, Elsevier edits, and describes the ordinary method selecting and prepare suitable prodrug derivatives 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, and it contains the raceme of the compounds of this invention or optically active isomer and the pharmaceutically acceptable carrier of at least one, 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.Compound mentioned by the present invention also can be prepared to various pharmacologically acceptable salts.
Pharmaceutical composition of the present invention comprises the formula formula I of effective dose or formula II compound or pharmaceutically acceptable salt thereof or hydrate and one or more suitable pharmaceutically acceptable carrier.Here pharmaceutical carrier 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 glyceride mixtures 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, and spraying sucks, rectal application, nasal cavity applied medicine, cheek medication, local application, non-bowel medication, as subcutaneous, vein, intramuscular, intraperitoneal, in sheath, in ventricle, with intracranial injection or input in breastbone, 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 any oral acceptable dosage form, includes but not limited to tablet, capsule, the aqueous solution or aqeous suspension.Wherein, the carrier that tablet uses generally comprises lactose and W-Gum, also can add lubricant in addition as Magnesium Stearate.The thinner that capsule preparations uses generally comprises lactose and dried corn starch.Aqueous suspension preparation then normally by activeconstituents and suitable emulsifying agent and suspension agent used in combination.If needed, in above oral dosage form, also some sweeting agents, perfume compound or tinting material can be added.
When local application, particularly treat Local out dressing easy to reach and suffer from face or organ, during as eyes, skin or lower intestinal tract nervous system disease, according to different trouble faces or organ, the compounds of this invention can be made different using topical preparations forms, be described as follows:
When eye topical application, the compounds of this invention can be mixed with the dosage form of a kind of micronized suspension or solution, use carrier to be the Sterile Saline of isotonic certain pH, wherein can add also can not adding preservative agent as zephiran chloride alkoxide.For eye use, also compound can be made ointment as vaseline paste.
When topical application, the compounds of this invention can be made into suitable ointment, lotion or cream formulation form, is wherein suspended by activeconstituents 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; Lotion or the spendable carrier of creme include but not limited to: mineral oil, sorbitan monostearate, polysorbate60, cetyl ester wax, and cetene is fragrant and mellow, 2-Standamul G, benzyl alcohol and water.
The compounds of this invention can also the medication of aseptic injection preparation form, 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 beneficial effect of the invention
Compound of the present invention can the hyper-proliferative of effective T suppression cell, can be used for excess proliferative disease in treatment Mammals, as cancer, neuropathic pain, inflammation etc.
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 only for illustration of the present invention, and should not be considered as limiting scope of the present invention.Unreceipted actual conditions person in embodiment, the condition of conveniently conditioned disjunction manufacturers suggestion is carried out.Agents useful for same or the unreceipted production firm person of instrument, being can 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 spectrometer.
The fluoro-2-of embodiment 1 1-{3,4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-carboxylic acid acridine
Step 1,2,3,4,5 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 with the aqueous sodium hydroxide solution of 10%, the anti-water lift layer of methylene dichloride, and merge organic layer, organic over anhydrous dried over sodium sulfate is spent the night.Next day filters, and 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 2,2,3,4,5-tetrafluorobenzamide
By 2,3,4,5-methyl 4-fluorobenzene (29.5g, 0.147mol) and strong aqua (244mL, 3.24mol) join in eggplant-shape bottle, system is two-phase system, and along with reaction is carried out, adularescent insolubles occurs, mechanical stirring is spent the night, and filters to obtain white solid 2,3,4,5-tetrafluorobenzamide (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 3,2,3,4,5-tetrafluoro cyanophenyls
2,3,4,5-tetrafluorobenzamide (5g, 0.026mol) is joined in 20mL anhydrous acetonitrile, adds phosphorus oxychloride (16.6g, 0.11mol), be warmed up to 70 DEG C, reaction 1.5h.Reaction solution is slowly added drop-wise in 200mL mixture of ice and water, this process very exothermic, carrying out control temperature not higher than 30 DEG C by controlling rate of addition, dropwising rear stirring at room temperature 0.5h, extraction into ethyl acetate, organic layer dried overnight, next day removes solvent 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(brs，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]
+。
Amino-3 methyl-5-iodine pyridines of step 4,2-
By amino for 2--3 picoline (5.5g, 0.05mol), iodine (5.1g, 0.02mol), Periodic acid dihydrate (2.28g, 0.01mol) join in reaction flask, add acetic acid (30mL), water (60mL) and the vitriol oil (0.9mL) successively, system heat release, in system, temperature from ambient rises to 25 DEG C, obtain dark brown solution, be heated to 80 DEG C, reaction 4h.System naturally cools to room temperature, adds the Na of 10% wherein
2s
2o
4in the aqueous solution (150mL), stir 30min, dichloromethane extraction water layer, with the aqueous sodium hydroxide solution washing organic layer of 10%, organic over anhydrous dried over sodium sulfate is spent the night.Next day filters, and removes solvent under reduced pressure, obtains amino-3 methyl-5-iodine pyridines (10.76g, 92.0%) of faint yellow solid 2-,
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-MSm/z:235.8 [M+1]
+.
Step 5,3,4,5-tri-fluoro-2-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] cyanobenzene
Under nitrogen protection condition, amino for 2--3 methyl-5-iodine pyridine (23.10g, 0.0986mol) and Lithamide (7.89g, 0.343mol) are joined in 170mL dimethylbenzene, is heated to 100 DEG C, stirring reaction 2h.Temperature fall, to room temperature, adds 2,3,4,5-tetrafluoro cyanophenyl (15g, 0.0857mol), is heated to 126 DEG C, reaction 3.5h.Black solid reaction process obtained filters, and sandwiching in black solid has product, repeatedly washs on a small quantity, and use ultrasonic echography 5min by ethyl acetate.Wash the ethyl acetate layer and reaction solution that obtain with 1N aqueous hydrochloric acid, merge organic layer, organic over anhydrous dried over sodium sulfate is spent the night.Next day filters, and removes solvent under reduced pressure, and column chromatography obtains the fluoro-2-of faint yellow solid 3,4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is 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 6,3,4,5-tri-fluoro-2-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] phenylformic acid
By 3,4, the fluoro-2-of 5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] cyanobenzene (8.90g, 0.023mol) be dissolved in dehydrated alcohol: distilled water: in the mixed solvent of THF=150mL: 75mL: 22.5mL, add potassium hydroxide (6.44g, 0.115mol), reflux, reaction 30h.Remove solvent under reduced pressure, obtain oily matter, by 10% aqueous hydrochloric acid adjust ph to 1, extraction into ethyl acetate, organic over anhydrous dried over sodium sulfate is spent the night.Next day filters, and removes solvent under reduced pressure, obtains the fluoro-2-of faint yellow solid 3,4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] phenylformic acid (8.72g, productive rate 92.9%), mp 103-105 DEG C.
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 7,1-{3, the fluoro-2-of 4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-carboxylic acid acridine
By 3,4, the fluoro-2-of 5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] phenylformic acid (0.20g, 0.49mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) (0.14g, 0.73mmol), 1-hydroxyl-benzo-triazole (HOBT) (0.07g, 0.49mmol) join in DMF (5mL), stirring at room temperature 30min, add 3-carboxylic acid acridine (0.07g, 0.73mmol), stirring at room temperature 2h.Add ethyl acetate 30mL, successively with water, saturated sodium-chloride water solution washing, organic over anhydrous dried over sodium sulfate is spent the night.Next day filters, and remove solvent under reduced pressure, column chromatography obtains faint yellow solid 1-{3, the fluoro-2-of 4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-carboxylic acid acridine (0.19g, 79.2%)
1h-NMR (400MHz, DMSO-D
6) δ ppm: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), 4.22-4.02 (m, 4H), 2.95-2.92 (m, 1H), 2.49 (s, 3H) .ESI-MS m/z:492.0 [M+1]
+.
The fluoro-2-of embodiment 2N-(cyclohexyl methyl)-1-{3,4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-Carboxylamide acridine
By 1-{3 obtained in embodiment 1,4, the fluoro-2-of 5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-carboxylic acid acridine (0.23g, 0.47mmol) be dissolved in DMF (5mL), add benzotriazole-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HBTU) (0.54g, 1.41mmol), stirring at room temperature 30min, benzene methanamine (0.11g is added in system, 0.94mmol) with N-methylmorpholine (0.52mL, 4.7mmol), stirring at room temperature reaction 3d.Add methylene dichloride 30mL in reaction system, wash organic phase with water, the anti-water lift phase of aqueous phase methylene dichloride, merge organic phase.Organic over anhydrous dried over sodium sulfate is spent the night.Next day filters, remove solvent under reduced pressure, column chromatography obtains yellow particle shape solid N-(cyclohexyl methyl)-1-{3, and 4, the fluoro-2-of 5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-Carboxylamide acridine (0.12g, 43.7%).
1H-NMR(400MHz，DMSO-D
6)δppm：8.23(s，1H)，8.08-8.07(m，1H)，8.00-7.97(m，1H)，7.82-7.81(m，1H)，7.31-7.30(m，1H)，4.22-4.02(m，4H)，2.95-2.92(m，2H)，2.69(s，1H)，2.25(s，3H)，1.66-1.63(m，5H)，1.38-1.12(m，6H).ESI-MS m/z：587.2[M+1]
+。
Embodiment 3N-(2-morpholine ethyl) the fluoro-2-of-1-{3,4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-Carboxylamide acridine
Method, with embodiment 2, obtains faint yellow look solid N-(2-morpholine ethyl) the fluoro-2-of-1-{3,4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-Carboxylamide acridine.
1H-NMR(400MHz，DMSO-D
6)δppm：10.97(br s，1H)，8.51-8.50(m，1H)，8.26(s，1H)，8.08-8.07(m，1H)，7.82-7.81(m，1H)，7.31-7.30(m，1H)，4.25-4.08(m，4H)，3.96-3.80(m，4H)，3.51-3.38(m，3H)，3.19-3.03(m，4H)，2.89(s，1H)，2.73(s，1H)，2.25(s，3H)，ESI-MS m/z：604.2[M+1]
+。
The fluoro-2-of embodiment 4N-(benzyloxy)-1-{3,4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-Carboxylamide acridine
Method, with embodiment 2, obtains faint yellow solid N-(benzyloxy)-1-{3, the fluoro-2-of 4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-Carboxylamide acridine.
1H-NMR(400MHz，DMSO-D
6)δppm：11.54-11.52(br s，0.21H)，11.26-11.24(br s，0.87H)，8.25(s，1H)，8.08-8.07(m，1H)，7.82-7.81(m，1H)，7.40-7.36(m，7H)，4.82(s，2H)，4.22-4.11(m，4H)，3.28-3.25(m，1H)，2.25(s，3H)，ESI-MS m/z：597.2[M+1]
+。
Embodiment 5 N-[(2,2-methyl isophthalic acid, 3 dioxolane-4 bases) methoxyl group] the fluoro-2-of-1-{3,4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-Carboxylamide acridine
Method, with embodiment 2, obtains dark yellow solid N-[(2,2-methyl isophthalic acid, 3 dioxolane-4 bases) methoxyl group] the fluoro-2-of-1-{3,4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-Carboxylamide acridine.
1H-NMR(400MHz，DMSO-D
6)δppm：11.34(br s，1H)，8.26(s，1H)，8.08(s，1H)，7.96(m，1H)，7.82(m，1H)，7.35-7.32(m，1H)，4.26-4.15(m，4H)，3.82-3.80(m，2H)，3.71-3.68(m，1H)，3.28-3.25(m，1H)，2.89(s，1H)，2.73(s，1H)，2.25(s，3H)，1.34-1.23(m，6H)，ESI-MS m/z：621.3[M+1]
+。
Embodiment 6 (R)-N-[(2,2-methyl isophthalic acid, 3 dioxolane-4 bases) methoxyl group] the fluoro-2-of-1-{3,4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-Carboxylamide acridine
Method is with embodiment 2, obtain dark yellow solid (R)-N-[(2,2-methyl isophthalic acid, 3 dioxolane-4 bases) methoxyl group]-1-{3, the fluoro-2-of 4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-Carboxylamide acridine.
1H-NMR(400MHz，DMSO-D
6)δppm：11.34(br s，1H)，8.26(s，1H)，8.08(s，1H)，7.96(m，1H)，7.82(m，1H)，7.35-7.32(m，1H)，4.26-4.15(m，4H)，3.82-3.80(m，2H)，3.71-3.68(m，1H)，3.28-3.25(m，1H)，2.89(s，1H)，2.73(s，1H)，2.25(s，3H)，1.32-1.26(m，6H).ESI-MS m/z：621.4[M+1]
+。
Embodiment 7, N-(2,3-dihydroxyl propoxy-) the fluoro-2-of-1-{3,4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-Carboxylamide acridine
By N-[(2 obtained for embodiment 5,2-methyl isophthalic acid, 3 dioxolane-4 bases) methoxyl group]-1-{3,4, the fluoro-2-of 5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) amino] benzoyl }-3-Carboxylamide acridine (0.27g, 0.45mmol) is dissolved in the mixed solvent of methyl alcohol (5mL) and water (0.5mL), adds tosic acid monohydrate (0.008g, 0.042mmol), stirring at room temperature 18h.Concentration of reaction solution, adds water 10mL, extraction into ethyl acetate, and successively with saturated sodium bicarbonate solution, saturated sodium-chloride water solution washing, organic over anhydrous dried over sodium sulfate is spent the night.Next day filters, remove solvent under reduced pressure, column chromatography obtains faint yellow solid N-(2,3-dihydroxyl propoxy-)-1-{3,4, the fluoro-2-of 5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-Carboxylamide acridine (0.16g, 56.3%), mp110-112 DEG C.
1H-NMR(400MHz，DMSO-D
6)δppm：11.34(br s，1H)，8.26(s，1H)，8.08(s，1H)，7.82(m，1H)，7.35-7.32(m，1H)，4.24-4.15(m，4H)，3.85-3.83(m，1H)，3.68-3，66(m，1H)，3.36-3.34(m，2H)，2.89(s，1H)，2.73(s，1H)，2.25(s，3H)，ESI-MS m/z：581.3[M+1]
+。
The fluoro-2-of embodiment 8 1-{3,4,5-tri-[(3-methyl-5-bromo-2-pyridyl base) is amino] benzoyl }-3-carboxylic acid acridine
The chloro-5-bromopyridine of step 1,2-amino-3-
By 2-amino-5-bromopyridine (3.0g, 17.34mmol), be dissolved in DMF (10mL), obtain deep yellow solution.Ice bath is cooled to 0 DEG C, adds NCS (2.40g, 18.03mmol), 0 DEG C of reaction 1h.In reaction system, add 30mL water, with anhydrous diethyl ether extraction, organic over anhydrous dried over sodium sulfate is spent the night.Next day filters, and removes solvent under reduced pressure, obtains black solid (2.72g, 75.6%), ESI-MS m/z:207.9 [M+1]
+.
Step 2,3,4,5-tri-fluoro-2-[(3-chloro-5-bromo-2-pyridyl base) is amino] cyanobenzene
Under nitrogen protection condition, chloro-for 2-amino-3-5-bromopyridine (10.30g, 0.050mol) and Lithamide (4.58g, 0.20mol) are joined in 150mL dimethylbenzene, is heated to 100 DEG C, stirring reaction 2h.Temperature fall, to room temperature, adds 2,3,4,5-tetrafluoro cyanophenyl (7.33g, 0.042mol), is heated to 126 DEG C, reaction 3.5h.Reaction solution is joined in 100mL ethyl acetate, stir 10min, produce a large amount of black solids, filter.Sandwich in black solid and have product, repeatedly wash on a small quantity by ethyl acetate, and use ultrasonic echography 5min.The ethyl acetate layer and reaction solution that obtain is washed with 1N aqueous hydrochloric acid, merge organic layer, organic layer dried overnight, next day removes solvent under reduced pressure, column chromatography obtains the fluoro-2-of faint yellow solid 3,4,5-tri-[(3-chloro-5-bromo-2-pyridyl base) is amino] cyanobenzene (4.5g, 29.6%)
1h-NMR (400MHz, CDCl
3) δ ppm:8.16-8.13 (m, 1H), 7.82-7.81 (m, 1H), 7.24-7.23 (m, 1H), 6.57 (br s, 1H), 19F-NMR (400MHz, CDCl
3) δ ppm:-123.65 ~-123.71 (m, 1H) ,-136.9
1～-136.50(m，1H)，-138.60～-138.74(m，1H)，ESI-MS m/z：363.9[M+1]
+。
Step 3,3,4,5-tri-fluoro-2-[(3-chloro-5-bromo-2-pyridyl base) is amino] phenylformic acid
By 3,4, the fluoro-2-of 5-tri-[(3-chloro-5-bromo-2-pyridyl base) is amino] cyanobenzene (4.50g, 12.4mmmol) be dissolved in dehydrated alcohol: distilled water: in the mixed solvent of THF=100mL: 50mL: 15mL, add potassium hydroxide (3.48g), reflux, reaction 30h.Remove solvent under reduced pressure, obtain oily matter, by 10% aqueous hydrochloric acid adjust ph to 1, extraction into ethyl acetate, organic layer dried overnight, next day removes solvent under reduced pressure, obtain faint yellow solid 3, the fluoro-2-of 4,5-tri-[(3-chloro-5-bromo-2-pyridyl base) is amino] phenylformic acid (4.27g, 90.2%).
Step 4,1-{3, the fluoro-2-of 4,5-tri-[(3-methyl-5-bromo-2-pyridyl base) is amino] benzoyl }-3-carboxylic acid acridine
By 3,4, the fluoro-2-of 5-tri-[(3-chloro-5-bromo-2-pyridyl base) is amino] phenylformic acid (3.0g, 8.31mmol), EDCI (2.39g, 12.46mmol), HOBT (1.16g, 8.31mmol) join in DMF (5mL), stirring at room temperature 30min, add 3-carboxylic acid acridine (1.26g, 12.46mmol), stirring at room temperature 2h.Add ethyl acetate 30mL, successively with water, saturated sodium-chloride water solution washing, organic over anhydrous dried over sodium sulfate is spent the night.Next day filters, and remove solvent under reduced pressure, column chromatography obtains faint yellow solid 1-{3, the fluoro-2-of 4,5-tri-[(3-methyl-5-bromo-2-pyridyl base) is amino] benzoyl }-3-carboxylic acid acridine (3.02g, 82.1%)
1h-NMR (400MHz, DMSO-D
6) δ ppm:13.67 (br s, 1H), 8.26 (s, 1H), 8.06-8.04 (d, 1H), 7.83-7.81 (d, 1H), 7.56-7.52 (m, 1H), 4.16-4.02 (m, 4H), 2.95-2.92 (m, 1H), 2.49 (s, 3H) .ESI-MS m/z:444.1 [M+1]
+.
Embodiment 9, the fluoro-2-of N-(cyclohexyl methyl)-1-{3,4,5-tri-[(3-methyl-5-bromo-2-pyridyl base) is amino] benzoyl }-3-Carboxylamide acridine
By 1-{3,4, the fluoro-2-of 5-tri-[(3-methyl-5-bromo-2-pyridyl base) amino] benzoyl }-3-carboxylic acid acridine (0.25g, 0.56mmol) is dissolved in DMF (5mL), adds HBTU (0.64g, 1.68mmol), stirring at room temperature 30min, adds cyclohexylmethylamine (0.13g, 1.13mmol) and N-methylmorpholine (0.61mL in system, 5.6mmol), stirring at room temperature reaction 3d.Add methylene dichloride 30mL in reaction system, wash organic phase with water, the anti-water lift phase of aqueous phase methylene dichloride, merge organic phase.Organic over anhydrous dried over sodium sulfate is spent the night.Next day filters, remove solvent under reduced pressure, column chromatography obtains faint yellow solid N-(cyclohexyl methyl)-1-{3, and 4, the fluoro-2-of 5-tri-[(3-methyl-5-bromo-2-pyridyl base) is amino] benzoyl }-3-Carboxylamide acridine (0.17g, 57.3%).
1H-NMR(400MHz，DMSO-D
6)δppm：8.28(s，1H)，8.02-7.99(m，2H)，7.73-7.72(m，1H)，7.32-7.31(m，1H)，4.23-4.01(m，4H)，2.93-2.89(m，2H)，2.28(s，3H)，2.73-2.70(m，1H)，1.66-1.63(m，6H)，1.19-1.12(m，4H)，ESI-MS m/z：541.3[M+1]
+
Embodiment 10, N-(2-morpholine ethyl) the fluoro-2-of-1-{3,4,5-tri-[(3-methyl-5-bromo-2-pyridyl base) is amino] benzoyl }-3-Carboxylamide acridine
Method, with embodiment 9, obtains faint yellow solid N-(2-morpholine ethyl) the fluoro-2-of-1-{3,4,5-tri-[(3-methyl-5-bromo-2-pyridyl base) is amino] benzoyl }-3-Carboxylamide acridine.
1H-NMR(400MHz，DMSO-D
6)δppm：8.42(m，1H)，8.27(s，1H)，7.96(m，1H)，7.72(m，1H)，7.35-7.32(m，1H)，3.59-3.57(m，4H)，3.40-3.37(m，2H)，2.49-2.42(m，6H)，2.28(s，3H)，ESI-MS m/z：557.3[M+1]
+
Embodiment 11, the fluoro-2-of N-(benzyloxy)-1-{3,4,5-tri-[(3-methyl-5-bromo-2-pyridyl base) is amino] benzoyl }-3-Carboxylamide acridine
Method, with embodiment 9, obtains faint yellow solid N-(benzyloxy)-1-{3, the fluoro-2-of 4,5-tri-[(3-methyl-5-bromo-2-pyridyl base) is amino] benzoyl }-3-Carboxylamide acridine.
1H-NMR(400MHz，DMSO-D
6)δppm：11.29(m，1H)，8.73(br s，1H)，8.31(s，1H)，8.00-7.99(m，1H)，7.74-7.73(m，1H)，7.40-7.38(m，6H)，4.82(s，2H)，4.23-4.11(m，4H)，3.28-3.25(m，1H)，2.28(s，3H)，ESI-MS m/z：549.3[M+1]
+。
Embodiment 12, (R)-N-(2,3-dihydroxyl propoxy-) the fluoro-2-of-1-{3,4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-Carboxylamide acridine
Method, with embodiment 2, obtains faint yellow solid (R)-N-(2,3-dihydroxyl propoxy-) the fluoro-2-of-1-{3,4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-Carboxylamide acridine.
1H-NMR(400MHz，DMSO-D
6)δppm：8.42(m，1H)，8.27(s，1H)，7.96(m，1H)，7.72(m，1H)，7.35-7.32(m，1H)，3.59-3.57(m，4H)，3.40-3.37(m，2H)，2.49-2.42(m，6H)，2.28(s，3H)。ESI-MS m/z：534.3[M+1]
+。
Embodiment 13, N-[2-(piperidin-1-yl) ethyl] the fluoro-2-of-1-{3,4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-Carboxylamide acridine
Method, with embodiment 2, obtains dark yellow solid N-[2-(piperidin-1-yl) ethyl] the fluoro-2-of-1-{3,4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-Carboxylamide acridine,
1h-NMR (400MHz, DMSO-D
6) δ ppm:10.22 (br s, 1H), 8.56 (s, 1H), 8.29 (s, 1H), 8.09 (m, 1H), 7.83 (m, 1H), 7.35-7.32 (m, 1H), 4.25-4.08 (m, 4H), 3.10-3.09 (m, 3H), 2.90-2.80 (m, 4H), 273 (s, 2H), 2.25 (s, 3H), 1.84-1.67 (m, 6H), ESI-MS m/z:602.3 [M+1]
+.
Embodiment 14, N-(ring third methoxyl group) the fluoro-2-of-1-{3,4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-Carboxylamide acridine
Method, with embodiment 9, obtains white solid N-(ring third methoxyl group) the fluoro-2-of-1-{3,4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-Carboxylamide acridine.
1H-NMR(400MHz，DMSO-D
6)δppm：11.21(br s，1H)，8.31(s，1H)，7.99-7.98(m，1H)，7.74-7.73(m，1H)，7.35-7.32(m，1H)，4.24-4.02(m，4H)，3.60-3.59(m，2H)，3.27-3.26(m，1H)，2.28(s，3H)，1.05-1.03(m，1H)，0.52-0.51(m，1H)，0.23-0.21(m，2H)，ESI-MS m/z：513.2[M+1]
+
Embodiment 15, (S)-N-(2,3-dihydroxyl propoxy-) the fluoro-2-of-1-{3,4,5-tri-[(3-methyl-5-bromo-2-pyridyl base) is amino] benzoyl }-3-Carboxylamide acridine
Method with embodiment 9, obtain white solid (S)-N-(2,3-dihydroxyl propoxy-) the fluoro-2-of-1-{3,4,5-tri-[(3-methyl-5-bromo-2-pyridyl base) amino] benzoyl }-3-Carboxylamide acridine.
1H-NMR(400MHz，DMSO-D
6)δppm：8.27(s，1H)，7.99-7.98(m，1H)，7.73(m，1H)，7.35-7.32(m，1H)，4.24-4.02(m，5H)，3.60-3.58(m，5H)，2.28(s，3H)，ESI-MS m/z：513.2[M+1]
+
Embodiment 16,1-{5-[(5-iodo-3-methyl 2-pyridyl) is amino] the fluoro-1H-benzoglyoxaline of-4--6-formyl }-3-carboxylic acid acridine
Step 1,5-nitro-2,3,4-trifluoro-benzoic acid
By being slowly added drop-wise in the vitriol oil (200mL) under nitrosonitric acid (37mL, 0.78mol) condition of ice bath, 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 ice water solution of 2000mL, stirring at room temperature 2h, hold over night, filters and obtain white solid 5-nitro-2,3,4-trifluoro-benzoic acid (123.7g, 90.3%), ESI-MS m/z:222.0 [M+1]
+
Step 2, the fluoro-2-of 5-nitro-3,4-bis-[(5-iodo-3-methyl 2-pyridyl) is amino]-phenylformic acid
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 DEG C.The THF solution of the lithium diisopropylamine (LDA) of 2M is dripped (34mL, 0.068mol) to be added in reaction system, reacts 1h under-70 DEG C of conditions.In reaction system, drip the THF solution of 5-nitro-2,3,4-trifluoro-benzoic acid (5.01g, 0.023mol), dropwise ,-70 DEG C of reaction 1h.Naturally room temperature is warmed up to, stirred overnight at room temperature.Saturated aqueous ammonium chloride, saturated sodium-chloride water solution washing successively, ethyl acetate extracts water layer, organic layer dried overnight, column chromatography obtains yellow solid 5-nitro-3, the fluoro-2-of 4-bis-[(5-iodo-3-methyl 2-pyridyl) is 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 fluoro-2-of 5-nitro-4-amino-3-[(5-iodo-3-methyl 2-pyridyl) is amino]-phenylformic acid
The fluoro-2-of 5-nitro-3,4-bis-[(5-iodo-3-methyl 2-pyridyl) is amino]-phenylformic acid (2.30g, 5.29mmol) is joined in 100mL distilled water, cools to 0 DEG C.Strong aqua (2.21mL, 29.6mmol) is dropwise added, 0 DEG C of reaction 1h in reaction system.Clear-cutting forestland is to room temperature, and reaction 4h, filters to obtain the fluoro-2-of yellow solid 5-nitro-4-amino-3-[(5-iodo-3-methyl 2-pyridyl) is 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 fluoro-2-of 5-nitro-4-amino-3-[(5-iodo-3-methyl 2-pyridyl) is amino]-methyl benzoate
By the fluoro-2-of 5-nitro-4-amino-3-[(5-iodo-3-methyl 2-pyridyl) is amino]-phenylformic acid (1.82g, 4.21mmol) be dissolved in 20mL anhydrous methanol, slow dropping 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 with the aqueous sodium hydroxide solution of 10%, the anti-water lift layer of methylene dichloride, and merge organic layer, organic over anhydrous dried over sodium sulfate is spent the night.Next day filters, and removes solvent under reduced pressure, obtains the fluoro-2-of yellow solid 5-nitro-4-amino-3-[(5-iodo-3-methyl 2-pyridyl) is 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 5,5-[(5-iodo-3-methyl 2-pyridyl) is amino] the fluoro-1H-benzoglyoxaline of-4--6-methyl-formiate
By the fluoro-2-of 5-nitro-4-amino-3-[(5-iodo-3-methyl 2-pyridyl) is amino]-methyl benzoate (1.84g, 4.12mmol), formic acid (25mL) and 20%Pd (OH)/C (1.57g, 2.95mrnol) are heated to 95 DEG C 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 DEG C.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 dark yellow solid 5-[(5-iodo-3-methyl 2-pyridyl) is amino] the fluoro-1H-benzoglyoxaline of-4--6-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), ESI-MS m/z:427.1 [M+1]
+.
Step 6,5-[(5-iodo-3-methyl 2-pyridyl) is amino] the fluoro-1H-benzoglyoxaline of-4--6-formic acid
5-[(5-iodo-3-methyl 2-pyridyl) amino] the fluoro-1H-benzoglyoxaline of-4--6-methyl-formiate (1.35g 3.17mmol) to be suspended in methyl alcohol in (30mL), add 20%NaOH (8mL), after 16h, reaction mixture is cooled to O DEG C, and drip 1NHCl solution, until pH is 2-3.By reaction mixture ethyl acetate and water dilution, and be separated each layer.Wash organic layer with saturated sodium-chloride water solution, organic over anhydrous dried over sodium sulfate is spent the night.Next day filters, and removes solvent under reduced pressure, and column chromatography obtains dark yellow solid 5-[(5-iodo-3-methyl 2-pyridyl) is amino] the fluoro-1H-benzoglyoxaline of-4--6-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), ESI-MS m/z:413.1 [M+1]
+.
Step 7,1-{5-[(5-iodo-3-methyl 2-pyridyl) is amino] the fluoro-1H-benzoglyoxaline of-4--6-formyl }-3-carboxylic acid acridine
By 5-[(5-iodo-3-methyl 2-pyridyl) is amino] the fluoro-1H-benzoglyoxaline of-4--6-formic acid (0.68g, 1.65mmol), EDCI (2.39g, 12.46mmol), HOBT (1.16g, 8.31mmol) join in DMF (5mL), stirring at room temperature 30min, add 3-carboxylic acid acridine (1.26g, 12.46mmol), stirring at room temperature 2h.Add ethyl acetate 30mL, successively with water, saturated sodium-chloride water solution washing, organic over anhydrous dried over sodium sulfate is spent the night.Next day filters, and removes solvent under reduced pressure, and column chromatography obtains faint yellow solid 1-{5-[(5-iodo-3-methyl 2-pyridyl) is amino] the fluoro-1H-benzoglyoxaline of-4--6-formyl }-3-carboxylic acid acridine (0.57g, 70.3%),
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), 4.16-4.02 (m, 4H), 2.95-2.92 (m, 1H), 2.49 (s, 3H) .ESI-MS m/z:496.0 [M+1]
+.
Embodiment 17, N-[2-(thiophene-2-base) ethyl]-1{5-[(5-iodo-3-methyl 2-pyridyl) is amino] the fluoro-1H-benzoglyoxaline of-4--6-methane amide }-3-Carboxylamide acridine
1-{5-[(5-iodo-3-methyl 2-pyridyl) is amino] the fluoro-1H-benzoglyoxaline of-4--6-formyl by obtained in embodiment 16 }-3-carboxylic acid acridine (0.28g, 0.57mmol), 2-(thiophene-2-base) ethamine (0.13g, 1.03mmol), DIEA (0.12mL, 0.68mmol) be dissolved in 20mL methylene dichloride, add PyBOP (0.34g, 0.65mmol) stirred overnight at room temperature.In reaction system, add anhydrous diethyl ether 40mL, respectively by water, saturated sodium-chloride water solution washing organic phase, organic over anhydrous dried over sodium sulfate is spent the night.Next day filters, remove solvent under reduced pressure, column chromatography obtains faint yellow solid N-[2-(thiophene-2-base) ethyl]-1{5-[(5-iodo-3-methyl 2-pyridyl) is amino] the fluoro-1H-benzoglyoxaline of-4--6-methane amide }-3-Carboxylamide acridine (0.15g, 44.1%)
1h-NMR (400MHz, CDCl
3) δ ppm:8.41-8.39 (m, 1H), 8.19 ((s, 1H), 7.76-7-75 (brs, 1H), 7.21-7.19 (m, 1H), 6.98-6.96 (m, 2H), 6.89-6.88 (m, 1H), 6.21 (s, 1H), 5.99 (s, 1H), 6.75-6.78 (m, 1H), 4.16-4.02 (m, 4H), 3.78-3.75 (m, 2H), 3.18-3.15 (t, 2H, J=6.7Hz), 2.95-2.92 (m, 1H), 2.31 (s, 3H), ESI-MS m/z:605.1.0 [M+1]
+.
Embodiment 18, N-[2-(piperidin-1-yl) ethyl]-1{5-[(5-iodo-3-methyl 2-pyridyl) is amino] the fluoro-1H-benzoglyoxaline of-4--6-methane amide }-3-Carboxylamide acridine
Method, with embodiment 17, obtains yellow solid N-[2-(piperidin-1-yl) ethyl]-5-[(5-iodo-3-methyl 2-pyridyl) is amino] the fluoro-1H-benzoglyoxaline of-4--6-methane amide,
1h-NMR (400MHz, DMSO-D
6) δ ppm:8.41-8.39 (m, 1H), 8.19 ((s, 1H), 7.76-7-75 (brs, 1H), 6.89-6.88 (m, 1H), 6.21 (s, 1H), 5.99 (s, 1H), 6.75-6.78 (m, 1H), 4.16-4.02 (m, 4H), 3.36-3.34 (m, 2H), 2.95-2.92 (m, 1H), 2.43-2.38 (m, 6H), 2.31 (s, 3H), 1.51-1.49 (m, 6H), ESI-MS m/z:606.1 [M+1]
+.
Embodiment 19, active testing
Preliminary activation test is carried out to the part of compounds of embodiment 1-18, have rated the activity that compound presses down myelogenous leukemia cells (K562) and Human Large Intestine Carcinoma Cells (HT-29) tumor cell proliferation in vitro.
After cultured tumor cells grows to certain density, attached cell 0.25% tryptic digestion 2-5min, suspension cell centrifugal (1000rpm/min), prepares single cell suspension with the corresponding nutrient solution of cell, and adjustment cell concn is to corresponding density (1 × 10
5individual/mL), be inoculated in 96 well culture plates, 100 μ L/ holes, 37 DEG C, 5%CO
2the full substratum of the 80 corresponding cells in μ L/ hole is first added after lower cultivation 24h, add the test-compound 20 μ L/ hole of different concns again, 3 repetitions are established in often kind of process, 37 DEG C, continue to cultivate 72h under 5%CO2 after, every hole sucking-off supernatant 100 μ L, then tetrazolium bromide (MTT) the solution 10 μ L adding 5mg/mL, 37 DEG C are continued to hatch 4h, last every hole adds the SDS of 100 μ L 10%, 37 DEG C of 5%CO
2under hatch 24h, MTT crystallization is dissolved completely.Enzyme-linked immunosorbent assay instrument 570nm wavelength measures every hole absorbancy.By formula:
Inhibiting rate (%)=(1-is by prospect hole OD value/solvent control hole mean OD value) × 100%
Calculate inhibiting rate, and with the logarithm of Test compound concentrations for X-coordinate, cell inhibitory rate mean value is that ordinate zou draws dose effect curve, and asks half Carbazole alkaloid dose value (IC with Origin analysis software
50).
Wherein the substratum of K562 cell is the substratum of 1640+10%FBS, HT-29 is DMEM (Hg)+F12+5%FBS.
Test front DMSO (Sigma) and medicine is assigned to mother liquid concentration, be diluted to required application concentration with the full substratum not conforming to the factor.During the growth-inhibiting effect of preliminary assessment compound for tumour cell, compound concentration is selected to be 3,30,300 μMs of three dosage groups, blank group (do not add tumour cell and test-compound, only add nutrient solution), solvent control group (solubilizing agent does not add test-compound); Ask its half Carbazole alkaloid dose value (IC further
50) time, select compound concentration to be six dosage groups, blank group (ditto), the solvent control group (ditto) of 1,3,10,30,100,200,300 μM according to primary dcreening operation result.Concrete outcome is in table 1.
Table 1 part of compounds is to the inhibit activities of K562 and HT-29
Wherein Pd198306 is positive control, and its structural formula is as follows:
Experimental result shows, compound on tumor cell of the present invention has significant inhibition.
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 amendment 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 (7)
1. the compound shown in formula V, VI, or its pharmacologically acceptable salts,
Wherein:
R
1, R
2, R
3, R
5or R
7be selected from halogen independently of one another;
R
4, R
6for hydrogen;
R
8be selected from C
1-C
6alkyl;
W is independently selected from-OR
9,-NR
10oR
9with-NR
10r
9;
R
9be selected from hydrogen, C
1-C
10alkyl, C
3-C
l0cycloalkyl, C
3-C
10cycloalkyl-C
1-C
3alkyl, aryl, aryl-C
1-C
3alkyl, heteroaryl, heteroaryl-C
1-C
3alkyl, heterocyclic radical and heterocyclic radical-C
1-C
3alkyl, wherein said aryl is phenyl, and described heteroaryl is thienyl, and described heterocyclic radical is piperidyl or morpholinyl;
Wherein each alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl ground is replaced independently selected from following group by 1-5: hydroxyl, halogen, amino, nitro and trifluoromethyl;
R
10for hydrogen.
2. compound according to claim 1, it is selected from:
The fluoro-2-of 1-{3,4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-carboxylic acid acridine;
The fluoro-2-of N-(cyclohexyl methyl)-1-{3,4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-Carboxylamide acridine;
N-(2-morpholine ethyl) the fluoro-2-of-1-{3,4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-Carboxylamide acridine;
The fluoro-2-of N-(benzyloxy)-1-{3,4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-Carboxylamide acridine;
N-[(2,2-methyl isophthalic acid, 3 dioxolane-4 bases) methoxyl group] the fluoro-2-of-1-{3,4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-Carboxylamide acridine;
(R)-N-[(2,2-methyl isophthalic acid, 3 dioxolane-4 bases) methoxyl group] the fluoro-2-of-1-{3,4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-Carboxylamide acridine;
N-(2,3-dihydroxyl propoxy-) the fluoro-2-of-1-{3,4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-Carboxylamide acridine;
The fluoro-2-of 1-{3,4,5-tri-[(3-methyl-5-bromo-2-pyridyl base) is amino] benzoyl }-3-carboxylic acid acridine;
The fluoro-2-of N-(cyclohexyl methyl)-1-{3,4,5-tri-[(3-methyl-5-bromo-2-pyridyl base) is amino] benzoyl }-3-Carboxylamide acridine;
N-(2-morpholine ethyl) the fluoro-2-of-1-{3,4,5-tri-[(3-methyl-5-bromo-2-pyridyl base) is amino] benzoyl }-3-Carboxylamide acridine;
The fluoro-2-of N-(benzyloxy)-1-{3,4,5-tri-[(3-methyl-5-bromo-2-pyridyl base) is amino] benzoyl }-3-Carboxylamide acridine;
(R)-N-(2,3-dihydroxyl propoxy-) the fluoro-2-of-1-{3,4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-Carboxylamide acridine;
N-[2-(piperidin-1-yl) ethyl] the fluoro-2-of-1-{3,4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-Carboxylamide acridine;
N-(ring third methoxyl group) the fluoro-2-of-1-{3,4,5-tri-[(the iodo-2-pyridyl of 3-methyl-5-) is amino] benzoyl }-3-Carboxylamide acridine;
(S)-N-(2,3-dihydroxyl propoxy-) the fluoro-2-of-1-{3,4,5-tri-[(3-methyl-5-bromo-2-pyridyl base) is amino] benzoyl }-3-Carboxylamide acridine;
1-{5-[(5-iodo-3-methyl-2-pyridyl) is amino] the fluoro-1H-benzoglyoxaline of-4--6-formyl }-3-carboxylic acid acridine;
N-[2-(thiophene-2-base) ethyl]-1{5-[(5-iodo-3-methyl-2-pyridyl) is amino] the fluoro-1H-benzoglyoxaline of-4--6-methane amide }-3-Carboxylamide acridine;
N-[2-(piperidin-1-yl) ethyl]-1{5-[(5-iodo-3-methyl-2-pyridyl) is amino] the fluoro-1H-benzoglyoxaline of-4--6-methane amide }-3-Carboxylamide acridine.
3. the method for compound described in preparation formula I or formula II,
Its compounds of formula I synthetic schemes is as follows:
With the phenylformic acid containing leavings group L replaced for starting raw material, through reacting, by carboxymethyl group with methylating reagent; Again by reacting with ammoniacal liquor, methyl esters is converted into amide group; At POCl
3slough the water of an one's share of expenses for a joint undertaking under effect, amido linkage is converted into cyano group; Replace containing the benzene first cyanogen of leavings group L under alkali effect, leavings group is left away and is carried out condensation reaction with the aminopyridines replaced; Cyan-hydrolysis is being obtained carboxyl.React with 3-carboxyl acridine ring, the carboxyl on acridine ring and corresponding side chain react, and obtain formula I again;
Leavings group L is halogen;
Its Chinese style II compou nd synthesis scheme is as follows:
With the phenylformic acid containing leavings group L replaced for starting raw material, through nitration reaction, phenyl ring introduces nitro; Under alkali effect, leavings group is left away and is carried out condensation reaction with the aminopyridines replaced; Under ammoniacal liquor effect, phenyl ring is introduced amino; Through reacting, by carboxymethyl group with methylating reagent; Be, after amino, carry out annulation by nitroreduction, piptonychia ester obtains carboxylic key intermediate, then reacts with 3-carboxyl acridine ring, and the carboxyl on acridine ring and corresponding side chain react, and obtain formula II compound;
Leavings group L is halogen;
Wherein:
In formula II,---represent optional key, condition is have in ring and only have a nitrogen-atoms to be double bond;
R
1, R
2, R
3, R
4, R
5, R
7or R
8be selected from hydrogen, hydroxyl, halogen, amino, nitro, itrile group, trifluoromethyl ,-OR independently of one another
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
l0thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl, C
3-C
10cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic radical and cycloheteroalkylalkyl;
R
6independently selected from hydrogen, trifluoromethyl, C
1-C
10alkyl, C
2-C
l0thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl, C
3-C
10cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic radical and cycloheteroalkylalkyl;
W is independently selected from-OR
9,-NR
10oR
9,-NR
10sO
2r
9with-NR
10r
9;
R
9, R
10be selected from hydrogen, hydroxyl, halogen, trifluoromethyl, C independently of one another
1-C
10alkyl, C
2-C
l0thiazolinyl, C
2-C
l0alkynyl, C
3-C
l0cycloalkyl, C
3-C
10cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic radical and cycloheteroalkylalkyl;
Wherein each alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl ground is replaced independently selected from following group by 1-5: hydroxyl, halogen, amino, nitro and trifluoromethyl.
4. the method for claim 3, wherein said alkali is Lithamide.
5. a pharmaceutical composition, it comprises compound described in claim 1 or 2 or its pharmacologically acceptable salts, and pharmaceutically acceptable carrier.
6. the compound of claim 1 or 2 or its pharmaceutically useful salt are for the preparation of the purposes of the medicine of T suppression cell hyper-proliferative.
7. the compound of claim 1 or 2 or its pharmaceutically useful salt are for the preparation of the purposes of antitumor drug.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110079345.7A CN102718750B (en) | 2011-03-31 | 2011-03-31 | Aminopyridine derivatives containing acridine ring and application thereof |
| PCT/CN2012/073303 WO2012130160A1 (en) | 2011-03-31 | 2012-03-30 | Aminopyridine derivatives containing acridine ring and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110079345.7A CN102718750B (en) | 2011-03-31 | 2011-03-31 | Aminopyridine derivatives containing acridine ring and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102718750A CN102718750A (en) | 2012-10-10 |
| CN102718750B true CN102718750B (en) | 2015-03-11 |
Family
ID=46929479
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110079345.7A Active CN102718750B (en) | 2011-03-31 | 2011-03-31 | Aminopyridine derivatives containing acridine ring and application thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN102718750B (en) |
| WO (1) | WO2012130160A1 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101365676A (en) * | 2005-10-07 | 2009-02-11 | 埃克塞利希斯股份有限公司 | Azetidines as mek inhibitors for the treatment of proliferative diseases |
| CN101528231A (en) * | 2006-08-16 | 2009-09-09 | 埃克塞利希斯股份有限公司 | Methods of using pi3k and mek modulators |
| CN101605540A (en) * | 2006-12-14 | 2009-12-16 | 埃克塞利希斯股份有限公司 | Use the method for mek inhibitor |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008124085A2 (en) * | 2007-04-03 | 2008-10-16 | Exelixis, Inc. | Methods of using combinations of mek and jak-2 inhibitors |
-
2011
- 2011-03-31 CN CN201110079345.7A patent/CN102718750B/en active Active
-
2012
- 2012-03-30 WO PCT/CN2012/073303 patent/WO2012130160A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101365676A (en) * | 2005-10-07 | 2009-02-11 | 埃克塞利希斯股份有限公司 | Azetidines as mek inhibitors for the treatment of proliferative diseases |
| CN101528231A (en) * | 2006-08-16 | 2009-09-09 | 埃克塞利希斯股份有限公司 | Methods of using pi3k and mek modulators |
| CN101605540A (en) * | 2006-12-14 | 2009-12-16 | 埃克塞利希斯股份有限公司 | Use the method for mek inhibitor |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2012130160A1 (en) | 2012-10-04 |
| CN102718750A (en) | 2012-10-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6078640B2 (en) | Benzamide derivatives for inhibiting the activity of ABL1, ABL2 and BCR-ABL1 | |
| JP7017523B2 (en) | A novel mitochondrial uncoupler for the treatment of metabolic diseases and cancer | |
| MX2014013376A (en) | Benzamide derivatives for inhibiting the activity of abl1, abl2 and bcr-abl1. | |
| CN103044395B (en) | Desloratadine-containing amino acid derivative as well as preparation method and application thereof | |
| JP6511450B2 (en) | Maleimide Derivatives as Modulators of the WNT Pathway | |
| JP2022107730A (en) | 2-SUBSTITUTED AMINO-NAPHTH[1,2-d]IMIDAZOL-5-ONE COMPOUNDS OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF | |
| BR112018067922B1 (en) | ANTIBACTERIAL COMPOUNDS, USES THEREOF AND PHARMACEUTICAL COMPOSITIONS | |
| CN107163044A (en) | Naphthylethylenedione compound with protease modification activity and derivative thereof | |
| US20150232439A1 (en) | Process for the preparation of c-fms kinase inhibitors | |
| CN111499591A (en) | ROR gamma modulators | |
| ES2651015T3 (en) | Quinolinone derivatives and use to treat diseases caused by poor osteoblast function | |
| CN107162982A (en) | Imidazole compounds with anticancer activity and derivatives thereof | |
| 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 | |
| CN102718750B (en) | Aminopyridine derivatives containing acridine ring and application thereof | |
| CN102718702B (en) | Aminopyridine derivatives and application thereof | |
| CN103864765B (en) | Benzazepine analog derivative containing five-membered ring, Preparation Method And The Use | |
| CN102746212B (en) | Beta-elemene indole derivative, preparation and application thereof | |
| CN101974016A (en) | Amide compound and preparation method and applications thereof | |
| CN110305123B (en) | Adamantane-containing compound and application thereof in treating cancer | |
| CN104370885A (en) | Aminopyridine derivatives and use thereof | |
| CN102408395B (en) | Novel piperazine and homopiperazine derivative and preparation method and use thereof | |
| JP2023506119A (en) | Use of phenylquinolinone derivatives and flavonoid derivatives in the treatment of neuropathic pain | |
| CN102241627B (en) | Carbamide compound and its medicinal usage | |
| CN105814018B (en) | New carbamide compounds, preparation method and its usage | |
| EP2570408B1 (en) | Hexaketide compound and medicinal use thereof |
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 |