CN105503863A - Novel anti-tumor compound - Google Patents
Novel anti-tumor compound Download PDFInfo
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- CN105503863A CN105503863A CN201510919634.1A CN201510919634A CN105503863A CN 105503863 A CN105503863 A CN 105503863A CN 201510919634 A CN201510919634 A CN 201510919634A CN 105503863 A CN105503863 A CN 105503863A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The invention provides a pyrazolopyridine derivative anti-tumor compound with excellent anti-tumor activity. The anti-tumor compound is shown as a formula I, wherein X represents -NH2, -NHOH, -NHX<1>, amino acid residue and the like (shown as the accompanying diagram); Y represents hydrogen atoms, alkyl groups, naphthenic bases, benzyl groups, aryl groups, heteroaryl, alkyl amino groups, -COX2 or -CONHX3, wherein the aryl group, the heteroaryl and the alkyl group are respectively, independently and randomly substituted by one or a plurality of materials from halogen, trifluoromethyl, amino groups, alkyl amino groups, hydroxyl, hydroxyalkyl, alkoxy, cyanogroup, nitryl, aryl groups and heteroaryl; the definitions of R1, R2, X1 and X2 are identical to the definitions in the specifications. The invention also provides a preparation method of an anti-tumor agent and application of the anti-tumor agent to lung cancer, colon cancer and ovarian cancer anti-tumor medicine.
Description
Technical field
This area belongs to field of antineoplastic medicaments, is specifically related to a kind of new antitumoral compounds or its pharmaceutical salts and its production and use.
Background technology
Tumour is still common, the most serious a kind of disease that the world today directly jeopardizes human life, and its sickness rate is only second to cardiovascular disease.At present, chemotherapy of tumors makes some progress, and obviously extends the survival time of patient, but still does not obtain gratifying curative effect.In recent years, people to oncology and tumor focus position Molecular level study deeply and the discovery of many new therapy target, for the exploitation of new antitumoral medicine provides possibility.Along with deepening continuously of studying tumour cell signal transduction pathway, the design and research of new type antineoplastic medicine more and more receives publicity.Existing antitumor drug still cannot meet the needs of growing cancer patients far away, and antitumor drug is still the important directions of research and development.
Patent of invention CN103534254A discloses a kind of three rings as antineoplastic agent and Fourth Ring pyrazolo [3,4-b] pyridine compounds and pharmacy acceptable salt thereof, its tautomer, its steric isomer or with the mixture of the steric isomer of any ratio, as the mixture of enantiomer, especially racemic mixture, with and its production and use, especially as the purposes of antineoplastic agent.Its structure is as follows:
Patent of invention CN102131807A discloses a kind of compound being used as the following formula of kinases inhibitor, additionally provide the pharmaceutically acceptable composition comprising described compound and the method using described composition to treat various disease, illness or obstacle, its structure is as follows:
Patent of invention CN101544634A discloses a kind of medical compounds 2-phenyl-3-substituted pyrazolecarboxylic also [1,5-A] pyridine derivatives and its production and use with the disease such as treatment tumour and virus.Wherein R
1, R
2, R
3and R
4definition with the definition of its specification sheets.Also disclose the pharmaceutical composition of compound or its pharmacy acceptable salt and one or more pharmaceutically acceptable carrier, vehicle or the thinner composition comprised as antitumor and viral activeconstituents I.Its structure is as follows:
Also have and a series ofly there is bioactive pyrido pyrazole compound require study, develop the new pyridine base pyrazole compound with excellent anti-tumor activity and be significant at antitumor field of medicaments.
Summary of the invention
The object of the present invention is to provide a kind of Pyrazolopyridine anti-tumor compounds or its pharmaceutical salts and preparation method thereof.
Another the medical composition and its use being to provide antineoplastic compound described in contained I of the present invention.
Object of the present invention can be reached by following measures:
A compound shown in formula I, or its pharmacy acceptable salt, hydrate and isomer thereof,
Wherein,
X representative-NH
2,-NHOH ,-NHX
1, amino-acid residue,
Y represents hydrogen atom, alkyl, cycloalkyl, benzyl, aryl, heteroaryl, alkylamino ,-COX
2or-CONHX
3, wherein aryl, heteroaryl, alkyl independently of one another optionally by one or more be selected from halogen, trifluoromethyl, amino, alkylamino, hydroxyl, hydroxyalkyl, alkoxyl group, cyano group, nitro, aryl and heteroaryl replace;
X
1be selected from substituted or non-substituted aryl, heteroaryl, alkyl, cycloalkyl, amino, alkylamino, described substituting group is selected from one or more in halogen, trifluoromethyl, amino, alkylamino, hydroxyl, hydroxyalkyl, alkoxyl group, cyano group, nitro, aryl, ester group and heteroaryl;
Amino-acid residue in amino acid amino lack a hydrogen after the replacement residue that formed;
Q is 4 ~ 8 yuan of substituted or non-substituted Heterocyclylalkyls at least containing an atom N, wherein in 5 ~ 8 yuan of heterocycles containing one or more N, O, S atom, and on 4 ~ 8 yuan of heterocycles further by one or more be selected from the group of alkyl, aryl, heteroaryl or cyano group replace;
R
1, R
2separately be selected from alkyl;
X
2be selected from cycloalkyl, aryl, heteroaryl, alkylamino, wherein aryl, heteroaryl, alkyl independently of one another optionally by one or more be selected from the group of halogen, trifluoromethyl, amino, alkylamino, hydroxyl, hydroxyalkyl, alkoxyl group, cyano group, nitro, aryl and heteroaryl replace;
X
3be selected from substituted or non-substituted alkyl, cycloalkyl, aryl or heteroaryl, described substituting group is the one in halogen, nitro or alkyl.
Further, Y and X in formula I
1aryl described in group is independently selected from 5 ~ 6 yuan of monocyclic aryl, and heteroaryl is independently selected from 5 ~ 6 yuan of bicyclic heteroaryls that are nitrogenous or sulphur.
Further, the alkyl described in formula I is independently selected from C
1-6alkyl; Cycloalkyl is independently selected from C
3-8cycloalkyl.
Further, the aryl described in formula I is independently selected from substituted or non-substituted phenyl.
Further, the heteroaryl described in formula I is independently selected from substituted or non-substituted pyridyl or thienyl.
In a kind of scheme, Q is substituted or non-substituted piperazinyl, and described substituting group is C
1-6alkyl, phenyl or pyridyl.
In a kind of scheme, described amino-acid residue for the amino in: carboxyl substituted or non-substituted L-Ala, phenylalanine, tyrosine, Isoleucine, aspartic acid or α-amino-isovaleric acid lack a hydrogen after the amino-acid residue that formed, described substituting group is C
1-4alkyl.
Shown below is the illustrative of compound of the present invention, nonrestrictive specific examples:
Further, the present invention also provides the preparation method of compound of Formula I, but is not limited only to method described below.All raw materials are all the group features of target molecule according to meeting general formula rule, and prepared by the method that the scheme in these routes, organic chemistry filed those of ordinary skill are known or directly to buy.The preparation method of the compound of formula I or its pharmacy acceptable salt, hydrate and isomer thereof is as shown in method one and method two:
Method one,
Step one:
Technician in technical field can, according to the constitutional features of formula I target molecule, select compound a as starting raw material, dissolves in organic solvent, is reduced into compound b under the effect of going back original reagent.
Step 2:
Compound b is dissolved in organic solvent, under the katalysis of organic bases, with methylsulfonyl chloride reacting generating compound c.
Step 3:
By compound c, d dissolve in organic solvent, under the katalysis of cesium carbonate, 90 ~ 120 DEG C react completely after add water washing, organic solvent extraction, after being spin-dried for, cross column separating purification obtain Verbindung.
Step 4:
By Verbindung through saponification reaction, obtain compound f.
Step 5:
According to the constitutional features of formula I target molecule, select and carry out through amidate action with compound f in a solvent containing aminated compounds X-H that is amino or imino-, compound g should be obtained.
Step 6:
Compound g is taken off BOC protecting group, obtains compound h.
Step 7:
According to the constitutional features of formula I target molecule, the carboxyl containing Y group counter structure feature, acyl chlorides, halohydrocarbon, halogenated aryl hydrocarbon, methylmesylate compound Z (such as: Isonicotinic acid, Benzoyl chloride, monobromethane, 4-bromo nitrobenzene, methylsulfonic acid ring pentyl ester etc.) is selected to carry out in a solvent being obtained by reacting Compound I as reaction raw materials and compound h.
As Y representative-CONHX
3time, the synthetic route of target compound is as follows:
Compound h and triphosgene are reacted, obtains compound h-1, then with compound H
2n-X
3reaction, obtains Compound I '
Method two
Step one:
Verbindung is taken off Boc protection, obtain compound j.
Step 2:
According to the constitutional features of formula I target molecule, the carboxyl containing Y group counter structure feature, acyl chlorides, halohydrocarbon, halogenated aryl hydrocarbon, methylmesylate compound Z (such as: Isonicotinic acid, Benzoyl chloride, monobromethane, 4-bromo nitrobenzene, methylsulfonic acid ring pentyl ester etc.) is selected to carry out in a solvent being obtained by reacting compound k as reaction raw materials and Verbindung.
Step 3:
Compound k is carried out saponification reaction, obtains compound i.
Step 4:
According to the constitutional features of formula I target molecule, select and carry out through amidate action with compound i in a solvent containing aminated compounds X-H that is amino or imino-, obtain target compound I.
In aforesaid method one and method two, radicals X, group Y and radicals X
3definition identical with the definition in specification sheets general formula I.
The amidate action related to is the amidate action of this area routine, can carry out under the effect of catalyzer, wherein catalyzer is selected from 1, 3-dicyclohexylcarbodiimide (DCC), N, N '-DIC (DIC), 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (EDC) and hydrochloride thereof, 1-(3-dimethyl aminopropyl)-3-ethylcarbonyl group diamines methiodide, N, N-diisopropylethylamine (DIEA), I-hydroxybenzotriazole (HoBt), 2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HATU), benzotriazole-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HBTU), 6-Chloro-Benzotriazole-1, 1, 3, 3-tetramethyl-urea phosphofluoric acid ester (HCTU), 2-(1H-benzo trisazo-L-1-yl)-1, 1, 3, 3-tetramethyl-urea Tetrafluoroboric acid ester (TBTU), 2-succinimido-1, 1, 3, 3-tetramethyl-urea Tetrafluoroboric acid ester (TSTU), 5-norbornylene-2, 3-dicarbapentaborane-N, N, N ', one or more combination in N '-tetramethyl-urea Tetrafluoroboric acid ester (TNTU).The ratio of condensing agent is greatly about 1 ~ 3 times.Also amidate action can be carried out under the katalysis of the condensation catalyst such as diethyl azodiformate/triphenyl phosphorus in addition.
Invention further provides the pharmaceutical composition of antineoplastic compound described in formula I, the described compound or pharmaceutically acceptable salt thereof wherein containing treatment significant quantity is as activeconstituents, and one or more pharmaceutically acceptable carriers.
This pharmaceutical composition preferably containing weight ratio be the antineoplastic compound of the present invention of 0.1%-99.5% or its pharmaceutical salts as activeconstituents, be more preferably the activeconstituents of 0.5%-99.5% containing weight ratio.
Can be applicable to oral form containing the pharmaceutical composition of compound activity composition described in formula I, such as tablet, dragee, lozenge, water or oil suspension, dispersible powder or particle, emulsion, hard or soft capsule, or syrup.Can prepare oral compositions according to any known method preparing medicinal compositions in this area, such composition can be selected from following composition containing one or more: sweeting agent, correctives, tinting material and sanitas, to provide pleasing and good to eat medicinal preparations.Tablet contains activeconstituents and the suitable nontoxic pharmaceutically useful vehicle preparing tablet for mixing.These vehicle can be inert excipients, as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; Granulating agent and disintegrating agent, such as Microcrystalline Cellulose, croscarmellose sodium, W-Gum or alginic acid; Tackiness agent, such as starch, gelatin, polyvinylpyrrolidone or gum arabic and lubricant, such as Magnesium Stearate, stearic acid or talcum powder.These tablets can not dressing or by the taste of covering medicine or postpone disintegration and absorption in the gastrointestinal tract, thus provides the known technology of slow releasing function by its dressing in a long time.Such as, water soluble taste can be used to shelter material, such as Vltra tears or hydroxypropylcellulose, or time expand material such as ethyl cellulose, cellulose acetate butyrate.
The hard gelatin capsule that also can mix with wherein activeconstituents and inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or the soft gelatin capsule of wherein activeconstituents and water-soluble carrier such as polyoxyethylene glycol or oily solvent such as peanut oil, whiteruss or mixed with olive oil provides oral preparations.
Aqeous suspension contains active substance and the suitable vehicle preparing aqeous suspension for mixing.This type of vehicle is suspension agent, such as sodium carboxy methyl cellulose, methylcellulose gum, Vltra tears, sodiun alginate, polyvinylpyrrolidone and gum arabic, dispersion agent or wetting agent can be the phosphatide such as Yelkin TTS of natural generation, or the condensation product of alkylene oxide and lipid acid such as polyoxyethylene stearic acid ester, or the condensation product of oxyethane and long chain aliphatic alcohol, such as 17 carbon ethyleneoxy group hexadecanols (heptadecaethyleneoxycetanol), or oxyethane and the condensation product of part ester that derived by lipid acid and hexitol, such as polyoxyethylene sorbitol monoleate, or oxyethane and the condensation product of partial ester that derived by lipid acid and hexitan, such as polyethylene oxide polyoxyethylene-sorbitan mono-oleate.Aqueous suspension also can contain one or more sanitass such as ethyl p-hydroxybenzoate or Tegosept E n-propyl, one or more tinting materials, one or more correctivess and one or more sweeting agents, such as sucrose, asccharin or aspartame.
Oil suspension is suspended in vegetables oil as peanut oil, sweet oil, sesame oil or Oleum Cocois by making activeconstituents, or formulated in mineral oil such as whiteruss.Oil suspension can contain thickening material, such as beeswax, paraffinum durum or hexadecanol.Above-mentioned sweeting agent and correctives can be added, to provide good to eat preparation.These compositions are preserved by adding antioxidant such as Butylated Hydroxyanisole or alpha-tocopherol.
Can make to be applicable to prepare water suspendible dispersible powder and particle also provide activeconstituents and for the dispersion agent that mixes or wetting agent, suspension agent or one or more sanitass by adding water.Suitable dispersion agent or wetting agent and suspension agent can illustrate above-mentioned example.Also other excipients can be added as sweeting agent, correctives and tinting material.These compositions are preserved by adding antioxidant such as xitix.
Pharmaceutical composition of the present invention also can be the form of oil-in-water emulsion.Oil phase can be vegetable oil as sweet oil or peanut oil, or mineral oil such as whiteruss or its mixture.Suitable emulsifying agent can be the phosphatide of natural generation, such as soybean lecithin and the ester derived by lipid acid and hexitan or partial ester such as sorbitan monooleate, with the condensation product of described partial ester and oxyethane, such as polyoxyethylene sorbitol monoleate.Emulsion also can contain sweeting agent, correctives, sanitas and oxidation inhibitor.Available Sweetening agents is as glycerine, propylene glycol, sorbyl alcohol or sucrose obtain syrup and elixir.This type of preparation also can contain negative catalyst, sanitas, tinting material and oxidation inhibitor.
Pharmaceutical composition can be sterile injectable aqueous form.Water, ringer's solution and isotonic sodium chlorrde solution can be had in the acceptable solvent used and solvent.Aseptic injection preparation can be that wherein activeconstituents is dissolved in the aseptic injection oil-in-water microemulsion of oil phase.Such as activeconstituents is dissolved in the mixture of soybean oil and Yelkin TTS.Then oil solution is added process in the mixture of water and glycerine and form micro emulsion.By a large amount of injection in local, injection liquid or micro emulsion are injected the blood flow of patient.Or, preferably by the mode of the compounds of this invention constant circulating concentration can be kept to give solution and micro emulsion.For keeping this constant density, continuous intravenous delivery device can be used.The example of this device is DeltecCADD-PLUS.TM.5400 type Iv pump.
Pharmaceutical composition can be for intramuscular and the aseptic injection water of subcutaneous administration or the form of oil suspension.Aseptic injection preparation also can be the aseptic injectable solution or suspension prepared in the acceptable thinner of nontoxic parenteral or solvent, the solution such as, prepared in 1,3 butylene glycol.In addition, can easily with aseptic fixing oil as solvent or suspension medium.For this purpose, the fixing oil of any mediation comprising synthetic glycerine list or diester can be used.In addition, fatty acids such as oleic acid also can prepare injection.
The compounds of this invention can be given by the suppository form for rectal administration.By by medicine be solid at normal temperatures but be liquid in the rectum, thus can dissolve in the rectum and the suitable nonirritant excipient that discharges medicine mixes and prepares these pharmaceutical compositions.This type of material comprises the mixture of theobroma oil, glycogelatin, hydrogenated vegetable oil, the polyoxyethylene glycol of various molecular weight and the fatty acid ester of polyoxyethylene glycol.
Well-known to those skilled in the art, the dosage of medicine depends on many factors, comprise but and non-limiting following factor: the body weight of the activity of specific compound used, the age of patient, patient, the healthy state of patient, the diet of patient, administration time, administering mode, the speed of excretion, the combination etc. of medicine; In addition, pattern, the daily dosage portion of general formula compound I or the kind of pharmaceutically useful salt of best therapeutic modality as treated can be verified according to traditional treatment plan.
Except as otherwise noted, the following term be used in claims and specification sheets has following implication:
" alkyl " represents the saturated aliphatic radical of 1-20 carbon atom, comprise straight chain and the branched group (digital scope mentioned in the application's book, such as " 1-20 ", refer to this group, it is now alkyl, can 1 carbon atom, 2 carbon atoms, 3 carbon atoms etc. be contained, until comprise 20 carbon atoms).Alkyl in the present invention comprises " alkylidene group ".Alkyl containing 1-6 carbon atom is called low alkyl group.When low alkyl group does not have substituting group, be called unsubstituted low alkyl group.It is further preferred that alkyl is the medium sized alkyl having 1-10 carbon atom, such as methyl, ethyl, ethylidene, propyl group, propylidene, 2-propyl group, normal-butyl, isobutyl-, butylidene, the tertiary butyl, amyl group etc.Preferably, alkyl is the low alkyl group having 1-4 carbon atom, such as methyl, ethyl, propyl group, 2-propyl group, normal-butyl, butylidene, isobutyl-or the tertiary butyl etc.Alkyl can be replacement or unsubstituted.
" cycloalkyl " represents saturated or the unsaturated monocycle of part or many rings cyclic hydrocarbon substituent, it comprises 3 to 20 carbon atoms, preferably includes 3 to 12 carbon atoms, and more preferably cycloalkyl ring comprises 3 to 10 carbon atoms, most preferably cycloalkyl ring comprises 3 to 6 carbon atoms, and the best is cyclopropyl.The non-limiting example of monocyclic cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, suberyl, cycloheptatriene base, ring octyl group etc., preferred cyclopropyl, cyclohexenyl.Polycyclic naphthene base comprises the cycloalkyl of volution, condensed ring and bridged ring.Cycloalkyl can be optional replacement or unsubstituted, when substituted, substituting group is preferably one or more following group, independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, sulfydryl, hydroxyl, nitro, cyano group, cycloalkyl, heterocyclic radical, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio, oxo base, amino, haloalkyl, hydroxyalkyl, carboxylic acid group, carboxylic acid ester groups ,-OR
11,-C (O) OR
11,-OC (O) R
11,-NHS (O)
mr
11,-C (O) R
11,-NHC (O) R
11,-NHC (O) OR
11,-NR
9r
10,-OC (O) NR
9r
10or-C (O) NR
9r
10.
" halogen " represents fluorine, chlorine, bromine or iodine, is preferably fluorine, chlorine or bromine.
" nitro " expression-NO
2group.
" alkoxyl group " represents-O-(unsubstituted alkyl) and-O-(unsubstituted cycloalkyl).Representative example includes but not limited to methoxyl group, oxyethyl group, propoxy-, butoxy, ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc.
" hydroxyalkyl " refers to the alkyl be optionally substituted by a hydroxyl group, and wherein the definition of alkyl is described above.
" aryl " represents full carbon monocycle or the fused polycycle group of 6 to 12 carbon atoms, has the π-electron system of total conjugated.The limiting examples of aryl has phenyl, naphthyl and anthryl.Described aryl rings can condense on heteroaryl, heterocyclic radical or cycloalkyl ring, and the ring wherein linked together with precursor structure is aryl rings.Aryl can be replacement or unsubstituted.When substituted; substituting group is preferably one or more; be more preferably one, two or three; and then be more preferably one or two, independently selected from by low alkyl group, three alkylhalide groups, halogen, hydroxyl, lower alkoxy, sulfydryl, (low alkyl group) sulfenyl, cyano group, acyl group, Thioacyl, O-formamyl, N-formamyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, nitro, N-sulfonamido, S-sulfonamido.Preferably, aryl is 5 yuan of monocyclic aryl, 6 yuan of monocyclic aryl.
" heteroaryl " represents monocycle or the fused ring group of 5 to 12 annular atomses, and be selected from the ring hetero atom of N, O or S containing one, two, three or four, all the other annular atomses are C, has the π-electron system of total conjugated in addition.Described heteroaryl ring can condense on aryl, heterocyclic radical or cycloalkyl ring, and the ring wherein linked together with precursor structure is heteroaryl ring.Heteroaryl can be replacement or unsubstituted.When substituted, substituting group is preferably one or more, be more preferably one, two or three, and then more preferred one or two.Unsubstituted heteroaryl ground limiting examples has pyrroles, furans, thiophene, imidazoles, oxazole, thiazole, pyrazoles, pyrimidine, quinoline, isoquinoline 99.9, purine, tetrazolium, triazine and carbazole; Preferably, heteroaryl is sulfur-bearing 5 yuan of bicyclic heteroaryls, nitrogenous 6 yuan of bicyclic heteroaryls.
Described amino-acid residue in amino acid amino lack a hydrogen after the replacement residue that formed, amino acid can be L-Ala (Ala), α-amino-isovaleric acid (Val), leucine (Leu), Isoleucine (Ile), proline(Pro) (Pro), phenylalanine (Phe), tryptophane (Trp), methionine(Met) (Met), glycine (Gly), tyrosine (Tyr), Serine (Ser), Threonine (Thr), halfcystine (Cys), l-asparagine (Asn), glutamine (Gln), Methionin (Lys), arginine (Arg), Histidine (His), aspartic acid (Asp), one in L-glutamic acid (Glu), can be that hydrogen atom on its carboxyl is by C
1 ~ 6the replacement residue formed after amino lacks a hydrogen in amino acid after alkyl replaces.
" pharmacy acceptable salt " represents the reservation biological effectiveness of parent compound and those salt of character.This kind of salt comprises:
(1) with sour salify, react by the free alkali of parent compound and mineral acid or organic acid and obtain, mineral acid is (but being not limited to) hydrochloric acid such as, Hydrogen bromide, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid and perchloric acid etc., organic acids is as (but being not limited to) acetic acid, propionic acid, vinylformic acid, oxalic acid, or (L) oxysuccinic acid (D), fumaric acid, toxilic acid, hydroxy-benzoic acid, gamma-hydroxybutyric acid, methoxybenzoic acid, phthalic acid, methylsulfonic acid, ethyl sulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, tosic acid, Whitfield's ointment, tartrate, citric acid, lactic acid, amygdalic acid, succsinic acid or propanedioic acid etc.
" medicinal compositions " refers to one or more compounds described here or their pharmacy acceptable salt and prodrug and other chemical composition, the such as mixture of pharmaceutically acceptable carrier and vehicle.The object of medicinal compositions is the administration promoting compound on organism body.
" pharmaceutically acceptable carrier " refers to and does not cause obvious pungency to organism and do not disturb the biological activity of given compound and the carrier of character or thinner.
" vehicle " refers to and joins in medicinal compositions with the convenient inert substance giving compound further.The example of vehicle comprises (being not limited to) calcium carbonate, calcium phosphate, various saccharides and polytype starch, derivatived cellulose, gelatin, vegetables oil and polyoxyethylene glycol.
Present invention also offers the application at anti-tumor aspect of described compound or pharmaceutically acceptable salt thereof, hydrate and isomer, research shows it and has significant anti-tumor activity.Preliminary pharmaceutical activity result of study shows: this compounds is to lung cancer, colorectal carcinoma and ovarian cancer tumor cell have good restraining effect, simultaneously with SD rat for animal subject, application LC/MS/MS method determines the drug level that rat oral gavage to give after the compounds of this invention not in blood plasma in the same time, study the pharmacokinetics behavior of compound of the present invention in rat body, result shows that the compounds of this invention has significant medicine for assimilation effect, in field of antineoplastic medicaments, especially lung cancer, colorectal carcinoma and ovarian cancer field of antineoplastic medicaments have good application prospect.
Embodiment
Following examples further describe the present invention, but these embodiments are only for illustration of the present invention, instead of limitation of the scope of the invention.
The preparation of embodiment 1 Compound I-1
Throw T-160g, it is clearly molten to add 250ml methyl alcohol, more slowly adds NaBH
4, maintain the temperature at less than 10 DEG C, it is complete that TLC monitors raw material reaction, obtains about 60.5g, yield 99.8%.
Throw T-260g, it is clearly molten to add methylene dichloride, then adds triethylamine, is placed in less than 0 DEG C, and dripping MeSO2Cl, TLC, to monitor raw material reaction complete.About 80g is obtained, yield 96% through aftertreatment.
Throw 13.6gT-3, dissolves with the DMF of 100ml, then add the cesium carbonate of compound T-4 and 1.5eq of 1.0eq, be warming up to 100 DEG C of reactions, HPLC monitoring raw material reaction is complete.Column chromatography for separation obtains about 8gT-5, yield 42.37%.
Throw 4gT-5, use 40ml dissolve with ethanol, add the sodium hydroxide of 40ml water and 2eq, stirring at room temperature 12h, TLC detection reaction is complete, adds 400ml water, adjust pH=5 ~ 6, has a large amount of white solid to separate out to filter, dry 3.2g white solid, yield 84%
Throw 0.31g compound T-6, add 20mlDMF and dissolve, add the bicarbonate of ammonia of 2.0eq, it is complete that 100 DEG C of reactions 4h, TLC monitor raw material reactions, pours in the water of 200ml, separate out white solid, filter, dryly obtains about 0.25g, yield 80% by reaction.
Throw 0.25g compound T-7, use 5ml dissolve with methanol, add 2ml concentrated hydrochloric acid, stirring at room temperature 3h, it is complete that TLC detects raw material reaction, is spin-dried for, is dissolved in water, adjust pH=8 ~ 9, extraction into ethyl acetate, anhydrous sodium sulfate drying, filtration are spin-dried for obtain white solid 0.17g, yield 94%.
1HNMR(DMSO-d6)δ:9.03(d,J＝2Hz,1H),8.78(d,J＝2Hz,1H),5.73～5.65(br,2H),5.19～5.11(m,1H),4.87～4.82(m,2H),4.41～4.35(m,2H),3.22～3.06(m,2H),2.55(s,3H)1.95～1.90(m,2H)。
m/z＝259(M+H
+).
The preparation of embodiment 2 Compound I-2
Throw 0.31gT-6, add 20mlDMF to dissolve, the methylamine hydrochloride of 1.5eq, the triethylamine of 3eq and the HBTU of 1.5eq, stirred at ambient temperature reaction 24h, TLC detection reaction is complete, reaction is poured in the water of 200ml, extraction into ethyl acetate, anhydrous sodium sulfate drying, filter, be spin-dried for, cross post and obtain white solid 0.21g, yield 71%
Throw 0.21gT-7, use 5ml dissolve with methanol, add 2ml concentrated hydrochloric acid, stirring at room temperature 3h, it is complete that TLC detects raw material reaction, is spin-dried for, is dissolved in water, adjust pH=8 ~ 9, extraction into ethyl acetate, anhydrous sodium sulfate drying, filtration are spin-dried for obtain white solid 0.12g, yield 80%.
1HNMR(DMSO-d6)δ:9.04(d,J＝2Hz,1H),8.75(d,J＝2Hz,1H),5.80～5.63(br,2H),5.16～5.07(m,1H),4.33～4.24(m,2H),3.48(s,3H),3.16～3.10(m,2H),2.69(s,3H),2.47～2.32(m,2H),2.13～2.05(m,2H)。
m/z＝274(M+H
+).
The preparation of embodiment 3 Compound I-3
Throw compound T-58g, add 40ml dehydrated alcohol, add 16ml concentrated hydrochloric acid, stirring at room temperature 6h, it is complete that TLC detects raw material reaction, is spin-dried for, is dissolved in water, adjust pH=8 ~ 9, extraction into ethyl acetate, anhydrous sodium sulfate drying, filtration are spin-dried for obtain white solid 5.4g, yield 85%.
Throw C-12.9g, dissolve, add the Tetrabutyl amonium bromide of the salt of wormwood of 1.5eq, the potassiumiodide of 0.1eq, the monobromethane of 1.2eq and 0.1eq with the DMSO of 30ml, stirring reaction at 60 DEG C, obtains about 1.9g through aftertreatment, yield 60.1%.
Throw 1.5gC-2, use 20ml dissolve with ethanol, add the sodium hydroxide of 20ml water and 2eq, stirring at room temperature 12h, TLC detection reaction is complete, adds 200ml water, adjust pH=5 ~ 6, has a large amount of white solid to separate out to filter, dry 0.9g white solid.Drop into 0.4gC-3, add 10mlDMF and dissolve, add the bicarbonate of ammonia of 2.0eq, 100 DEG C of reaction 4h, pour in the water of 200ml by reaction, separate out white solid, filter, dryly obtain about 0.25g, yield 62%.
1HNMR(DMSO-d6)δ:9.04(d,J＝2Hz,1H),8.75(d,J＝2Hz,1H),5.55～5.39(br,2H),5.07(m,1H),3.18～3.11(m,2H),2.62～2.55(m,4H),2.35～2.19(m,5H),1.97～1.92(m,2H),1.14～1.06(m,3H).
m/z＝288(M+H
+).
The preparation of embodiment 4 Compound I-4
Throw 0.4gC-3, add 10mlDCM and dissolve, under room temperature, add 0.3ml oxalyl chloride, add 1 DMF again, back flow reaction 1h, concentrated, residue 10mlTHF dissolves, add the THF solution of the azanol of 1.0eq, room temperature reaction 2h, pours in the water of 200ml by reaction, extraction into ethyl acetate, anhydrous sodium sulfate drying, filter, be spin-dried for, cross post obtain about 0.21g, yield 50%.
1HNMR(DMSO-d6)δ:9.03(d,J＝2Hz,1H),8.74(d,J＝2Hz,1H),5.55(br,1H),5.39(br,1H),5.01(m,1H),3.18～3.11(m,2H),2.62～2.56(m,4H),2.35～2.19(m,5H),1.97～1.92(m,2H),1.14～1.06(m,3H)。
m/z＝304(M+H
+).
The preparation of embodiment 5 Compound I-5
Throw I-50.29g, dissolve with 10mlDMF, add the HBTU of the triethylamine of 1.5eq, the phenylformic acid of 1.0eq and 1.5eq, it is complete that stirred at ambient temperature reaction 12h, TLC detect raw material reaction, is poured into water by reaction solution, extraction into ethyl acetate, anhydrous sodium sulfate drying, mixes sample and crosses post and obtain 0.21g off-white color solid, yield 52%.
1HNMR(DMSO-d6)δ:9.02(d,J＝2Hz,1H),8.75(d,J＝2Hz,1H),7.68～7.66(m,2H),7.40～7.36(m,2H),5.83(br,1H),5.61(br,1H),5.16～5.07(m,1H),4.33～4.24(m,2H),3.40～3.28(s,3H),3.16～3.10(m,2H),2.79(s,3H),2.77～2.32(m,2H),2.13～2.05(m,2H)。
m/z＝378(M+H
+).
The preparation of embodiment 6 ~ 50 with reference to specification sheets operational path above, the preparation process of compound and the method for above-described embodiment similar.Following table gives the test data of the object of experiment product of each embodiment.
Table 1 embodiment 6 ~ 51 list
The preparation of embodiment 51 Compound I-51
Drop into raw material I-60.29g, add 10mlDCM, at being placed in 0 DEG C, stir 10min, instill the triphosgene of the 1.5eq that DCM dissolves again, low temperature 3h, TLC detection reaction is complete, washing organic phase 2 times, anhydrous sodium sulfate drying organic phase, filters, is spin-dried for and obtains 0.25g off-white color solid.
Drop into 0.25ga 10ml dioxane to dissolve and add the aniline of 1.0eq and the triethylamine of 1.5eq again, be placed in stirred at ambient temperature 36h, TLC detection reaction is complete, directly mixes sample and crosses post and obtain 0.15g faint yellow solid.
1HNMR(DMSO-d6)δ:9.57(br,1H),9.46(br,1H),9.04(d,J＝2Hz,1H),8.69(d,J＝2Hz,1H),8.21～7.85(m,4H),7.55～7.08(m,5H),5.06(m,1H),3.37～3.26(m,2H),2.82～2.73(m,2H),2.59(s,3H),2.41～2.27(m,2H),2.12～1.99(m,2H).
m/z＝500(M+H
+).
Pharmacologically active is tested:
Pharmacological testing proves, compound of the present invention all has excellent anti-tumor activity.Therefore the compounds of this invention can be used for the medicine preparing treatment tumor disease.Here is pharmacodynamics test and the result of part of compounds of the present invention.The structural formula of compound is shown in embodiment.
Compound is to the growth-inhibiting effect of many strains human tumor cells
Application CCK-8 (CellCountingKit) detection kit detects compound in specification sheets of the present invention to 6 tumor cell line (A549, NCI-H1299, NCI-H460, HCT-116, HT-29 & SK-OV-3) cytotoxicity test.
1. cell strain:
A549 Non-small cell lung carcinoma cell strain (ordering in cellular resources center, Chinese Academy of Sciences Shanghai, Cat#TCHu150)
NCI-H1299 Non-small cell lung carcinoma cell strain (ordering in cellular resources center, Chinese Academy of Sciences Shanghai, Cat#TCHu160)
NCI-H460 National People's Congress sclc cell line (ordering in cellular resources center, Chinese Academy of Sciences Shanghai, Cat#TCHu205)
HCT-116 human colon cancer cell strain (ordering in cellular resources center, Chinese Academy of Sciences Shanghai, Cat#TCHu99)
HT-29 human colon cancer cell strain (ordering in cellular resources center, Chinese Academy of Sciences Shanghai, Cat#TCHu103)
SK-OV-3 human oophoroma cell line (ordering in cellular resources center, Chinese Academy of Sciences Shanghai, Cat#TCHu185)
2. reagent and consumptive material:
CellCountingKit-8(Cat#CK04-13，Dojindo)
96 well culture plates (Cat#3599, CorningCostar)
Substratum and foetal calf serum (GIBCO)
Desk-top microplate reader: SpectraMaxM5MicroplateReader (MolecularDevices)
Each compound of test-compound: embodiment 1-32.
3. the preparation of substratum
Table 2
| Clone | Substratum |
| A549 | RPMI 1640+10％FBS |
| NCI-H1299 | RPMI 1640+10％FBS |
| NCI-H460 | RPMI1640+10％FBS |
| HCT-116 | DMEM+10％FBS |
| HT-29 | Mccoy’s 5A+10％FBS |
| SK-OV-3 | Mccoy’s 5A+10％FBS |
4.IC50 tests (CCK-8 detection)
A) collect logarithmic phase cell, counting, with perfect medium Eddy diffusion cell, adjustment cell concn is to suitable concn (determining according to cell density optimization Test result), and inoculate 96 orifice plates, every hole adds 100 μ l cell suspensions.Cell at 37 DEG C, 100% relative humidity, 5%CO
224 hours are hatched in incubator.
B) with substratum, testing compound is diluted to set respective action concentration, adds cell by 25 μ l/ holes.Experimentally desired concn is dissolved in dimethyl sulfoxide (DMSO), be made into Compound D MSO solution, the effect final concentration of compound is 100 μMs, 25 μMs, 6.25 μMs, 1.5625 μMs, 0.390625 μM, 0.097656 μM, 0.024414 μM, 0.006104 μM, 0.001526 μM;
C) cell is placed in 37 DEG C, 100% relative humidity, 5%CO
272 hours are hatched in incubator.
D) inhale and abandon substratum, the perfect medium added containing 10%CCK-8 is placed in 37 DEG C of incubators and hatches 1-4 hour.
E) on SpectraMaxM5MicroplateReader, measure the absorbancy at 450nm wavelength place after shaking gently, using 650nm place absorbancy as reference, calculate inhibiting rate.
5. data processing
Be calculated as follows the inhibiting rate of drug on tumor Growth of Cells: growth of tumour cell inhibiting rate %=[(A
c-A
s)/(A
c-A
b)] × 100%
A
s: the OA (cell+CCK-8+ testing compound) of sample
A
c: the OA (cell+CCK-8+DMSO) of negative control
A
b: the OA (substratum+CCK-8+DMSO) of positive control
Use software GraphpadPrism5 and adopt calculation formula log (inhibitor) vs.normalizedresponse carry out IC50 fitting of a curve and calculate IC50 value, as shown in the table:
Table 3 compound is to the IC of various human tumor cell line
50value
Result: the compounds of this invention all has obvious restraining effect to the growth of various human tumor cell line.
Pharmacokinetic Evaluation
With SD rat for animal subject, application LC/MS/MS method determines the drug level that rat oral gavage to give after Compound I-2, Compound I-22, Compound I-36, Compound I-50 not in blood plasma in the same time, study the pharmacokinetics behavior of compound of the present invention in rat body, evaluate its Pharmacokinetic Characteristics.
Experimental program:
1. dosage choice
Dosage is 5mg/kg.
2. animal subject
The environmental adaptation phase of 2 days is given before tested rat experiment.
Get SD rat 24, male and female half and half, body weight is about 200g.According to mean body weight, female/great and mighty or powerful mouse group is divided into 4 tested group (often organizing 6, male and female half and half) at random.
3. plasma sample process
Get rat plasma 50 μ l, add 200 μ l protein precipitants, vibration 3min protein precipitation, after 20000rcf*10min is centrifugal, shift 80 μ l supernatant liquors to sample injection bottle, 2 μ l sample introductions are analyzed.
4. experimentation
Rat Fast 12h, gavage (i.g.) gives 5mg/kg Compound I-1, Compound I-11, Compound I-12, Compound I-20 and Aura handkerchief Buddhist nun successively respectively.After rat administration, 15min, 30min, 45min, 1h, 2h, 4h, 6h, 8h, 12h and 24h rat vein blood about 200 μ l is gathered before administration behind (0) and administration in heparin tube (heparin tube uses 0.5% heparin sodium anti-freezing in advance) from orbital venous plexus, to shift upper plasma after the centrifugal 5min of 4000rpm, plasma sample is analyzed after protein precipitation pre-treatment, measure compound in blood plasma through time concentration.
5. pharmacokinetic parameter result
After SD rat single oral gavage administration 5mg/kg compound of the present invention, in body actual measurement medicine through time Plasma Concentration use DAS software to ask to calculate its pharmacokinetic parameter in SD rat body, result lists in table 3 ~ 7 respectively.
The pharmacokinetic parameters of table 4 Compound I-2 in rat body (fasting)
The pharmacokinetic parameters of table 5 Compound I-22 in rat body (fasting)
The pharmacokinetic parameters of table 6 Compound I-36 in rat body (fasting)
The pharmacokinetic parameters of table 7 Compound I-50 in rat body (fasting)
Conclusion: the medicine generation of the compounds of this invention absorbs good, has obvious medicine for assimilation effect.
Claims (10)
1. the compound shown in formula I structure and pharmacy acceptable salt, hydrate, isomer:
Wherein,
X representative-NH
2,-NHOH ,-NHX
1, amino-acid residue,
Y represents hydrogen atom, alkyl, cycloalkyl, benzyl, aryl, heteroaryl, alkylamino ,-COX
2or-CONHX
3, wherein aryl, heteroaryl, alkyl arbitrarily independently by one or more be selected from halogen, trifluoromethyl, amino, alkylamino, hydroxyl, hydroxyalkyl, alkoxyl group, cyano group, nitro, aryl and heteroaryl replace;
X
1be selected from substituted or non-substituted aryl, heteroaryl, alkyl, cycloalkyl, amino, alkylamino, one or more in described substituting group independent selected from halo, trifluoromethyl, amino, alkylamino, hydroxyl, hydroxyalkyl, alkoxyl group, cyano group, nitro, aryl, ester group and heteroaryl;
Amino-acid residue in amino acid amino lack a hydrogen after the replacement residue that formed;
Q is 4 ~ 8 yuan of substituted or non-substituted Heterocyclylalkyls at least containing an atom N, wherein in 5 ~ 8 yuan of heterocycles containing one or more N, O, S atom, and on 4 ~ 8 yuan of heterocycles further by one or more be selected from the group of alkyl, aryl, heteroaryl or cyano group replace;
R
1, R
2separately be selected from alkyl;
X
2be selected from cycloalkyl, aryl, heteroaryl, alkylamino, wherein aryl, heteroaryl, alkyl arbitrarily independently by one or more be selected from the group of halogen, trifluoromethyl, amino, alkylamino, hydroxyl, hydroxyalkyl, alkoxyl group, cyano group, nitro, aryl and heteroaryl replace;
X
3be selected from substituted or non-substituted alkyl, cycloalkyl, aryl or heteroaryl, described substituting group is the one in halogen, nitro or alkyl.
2. compound as claimed in claim 1 and pharmacy acceptable salt, hydrate, isomer, is characterized in that described Y and X
1aryl described in group is independently selected from 5 ~ 6 yuan of monocyclic aryl, and heteroaryl is selected from 5 ~ 6 yuan of bicyclic heteroaryls that are nitrogenous or S.
3. compound as claimed in claim 1 and pharmacy acceptable salt, hydrate, isomer, is characterized in that described alkyl is independently selected from C
1-6alkyl; Cycloalkyl is independently selected from C
3-8cycloalkyl.
4. compound as claimed in claim 1 and pharmacy acceptable salt, hydrate, isomer, is characterized in that described aryl is independently selected from substituted or non-substituted phenyl.
5. compound as claimed in claim 1 and pharmacy acceptable salt, hydrate, isomer, is characterized in that described heteroaryl is independently selected from substituted or non-substituted pyridyl or thienyl.
6. compound as claimed in claim 1 and pharmacy acceptable salt, hydrate, isomer, it is characterized in that Q is substituted or non-substituted piperazinyl, described substituting group is C
1-6alkyl, phenyl or pyridyl.
7. compound as claimed in claim 1 and pharmacy acceptable salt, hydrate, isomer, it is characterized in that described amino-acid residue for the amino in: carboxyl substituted or non-substituted L-Ala, phenylalanine, tyrosine, Isoleucine, aspartic acid or α-amino-isovaleric acid lack a hydrogen after the amino-acid residue that formed, described substituting group is C
1-4alkyl.
8. the compound according to claim 1 ~ 7 any one and pharmacy acceptable salt, hydrate, isomer, is characterized in that compound is selected from:
9. a pharmaceutical composition, this pharmaceutical composition to comprise in the treatment free form of significant quantity or the claim 1 to 8 of pharmaceutical acceptable salt the compound that defines of any one as activeconstituents; One or more medicinal carrier substances and/or thinner.
10. the pharmaceutical composition containing compound according to claim 1, the application in lung cancer, colorectal carcinoma and ovarian cancer antitumor drug.
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| WO2020263967A1 (en) * | 2019-06-27 | 2020-12-30 | Biogen Ma Inc. | 2h-indazole derivatives and their use in the treatment of disease |
| CN113943227A (en) * | 2021-11-29 | 2022-01-18 | 中南大学湘雅医院 | Compound, pharmaceutical composition containing compound and application of compound |
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