CN102659785A - 2-amino-6-aminomethylpurine compound and preparation method and application thereof - Google Patents
2-amino-6-aminomethylpurine compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a 2-amino-6-aminomethylpurine compound and a preparation method and an application thereof. The compound has a structure shown in a general formula I. As proved by an activity screening experiment, the 2-amino-6-aminomethylpurine compound has suppressing activity on cyclin-dependent kinases and proliferation of a plurality of tumor cells, and can be possibly used for treating diseases caused by activity imbalance of cyclin-dependent kinases. The invention further relates to a pharmaceutical application of a composition containing the compound shown as the general formula I.
Description
Technical field
The present invention relates to 2-amino-6-aminomethyl purine compound, belong to technical field of chemistry.
Background technology
Malignant tumour is called cancer again, is the healthy disease of serious harm human life.According to " world cancer report " of the World Health Organization (WTO) in issue in 2008; Have 1,200 ten thousand people to be made a definite diagnosis in the worldwide in 2008 and suffer from cancer, and also have 7,600,000 people dead because of cancer, this death toll has accounted for 13% of whole world death toll; The number of estimating global range internal cause cancer mortality also can continue to increase; If cancer is not intervened, the year two thousand thirty will have 1,200 ten thousand people to die from cancer, this wherein 70% death be to occur in low income or middle-income country.Therefore, malignant tumour has become the significant problem of universe's common concern.Grasp the pathogenic factor of malignant tumour and the molecular mechanism of incidence and development, the selectivity cancer therapy drug of seeking high-efficiency low-toxicity has become the great task of medical field research.Malignant tumour is under environmental factors and inherited genetic factors acting in conjunction, causes one type of disease due to disorderly, the cell uncontrolled growth of cell cycle.Since the molecular mechanism of cell cycle regulation since early 1970s comes to light, cell cycle chechpoint just becomes the important target spot of antitumor drug research.Cell cycle protein dependent kinase (CDKs) is the main regulon of cell cycle, suppresses CDKs and can effectively block tumour cell cycle, suppresses the propagation and the differentiation of cell, for tumor treatment provides new thinking.
Cell cycle protein dependent kinase (CDKs) is the protein kinase of one type of cyclin dependent (Cyclin), belong to Serine and threonine kinase enzyme family (referring to Nurse, P., Nature, 1975,256,547-551.).To (comprising 200 to 400 amino acid) between the 45KD, the homology of the CDK of different subtype is about 40-75% to the relative molecular weight of CDKs at 35kD, all contains about 300 amino acid whose conservative property catalytic centers, and this protein kinase with other is the same.Up to now, in human genome, have been found that 13 CDK hypotypes (CDK1-13) and more than 25 kinds cyclins.CDKs need with regulate subunit cyclin and combine its activity of competence exertion afterwards, and different CDK/cyclin mixtures the not effect of phase simultaneously of cell cycle be different (referring to Wang, Q., et al., Curr Med.Chem., 2011,18,2025-2043).According to the cell cycle model of classics, participate in directly the cell cycle each the time phase transformation the CDKs/cyclin mixture be CDK4 (6)/cyclin D, CDK2/cyclin E, CDK2/cyclin A and CDK1/cyclin B.Cyclin D combines the back bringing into play important effect in the G1 phase with CDK4 and CDK6; CDK2/cyclin E can impel cell to get into the S phase from the G1 phase; Cyclin A can impel the cell cycle to accomplish the conversion of S phase respectively with after CDK2 and CDK1 combine, and prepares to get into the M phase; The entering of M phase and regulate then be under the control of CDK1/cyclinB completion (referring to van den Heuvel, S.; Et al., Science, 1993,262,2050-2054 and Hochegger, H., et al., Nat Rev Mol Cell Biol, 2008,9,910-916.).
The imbalance of cell cycle is the important symbol of human cancer, and the change of moity is relevant with the generation of most of human tumour in its setting device.Therefore, CDKs is considered to the potential target spot of new generation anti-cancer medicament.Developing some the specific C DKs suppressor factor that can block cancer cell cycle and cell death inducing should be very effective for treatment for cancer.In decades in the past, developed the CDKs suppressor factor of numerous structure types, and the kind scope of suppressor factor some natural products and verivate thereof have been comprised also in continuous expansion.Add developing rapidly of medicinal design; Carry out rational medicinal design through a large amount of CDKs and the formed X-ray crystal structure of suppressor factor; The competitive combination of suppressor factor not only is provided, can also have observed the active binding site of micromolecular inhibitor.Up to now, existing more than ten research that compound gets into clinical I phase or II phase.
The present invention is according to the Three Dimensions Structure of CDK2; Method based on the area of computer aided medicinal design; In taking into full account 2-amino-6-aminomethyl purine compound and CDK2 on the basis of the binding pattern of ATP-binding site; Designed a series of small molecules CDK suppressor factor, carried out chemosynthesis and screening active ingredients then, obtained having the lead compound that exploitation is worth.
Summary of the invention
The present invention is directed to the deficiency of prior art, a kind of 2-amino-6-aminomethyl purine compound and preparation method thereof is provided; The present invention also provides such application of compound.
Technical scheme of the present invention is following:
One, 2-amino of the present invention-6-aminomethyl purine compound
2-amino-6-aminomethyl purine compound or its pharmacy acceptable salt, steric isomer, solvate or prodrug have the structure shown in the formula I:
Wherein,
R1 is an aryl, heteroaryl, and assorted alkyl, naphthenic base, optional by one or more following groups replacements: hydroxyl, halogen, nitro, itrile group, carboxyl, alkyl, alkoxyl group, sulfoamido or methylsulfonic acid base;
R2 is an aryl, benzyl, and alkyl, heteroaryl, optional by one or more following groups replacements: hydroxyl, halogen, nitro, itrile group, carboxyl, alkyl, alkoxyl group, sulfoamido or methylsulfonic acid base;
R3 is hydrogen, carboxyl or hydroxymethyl;
R4 is hydrogen, methyl, ethyl, sec.-propyl, cyclopropyl or cyclopentyl;
Described aryl is meant the aromatic carbocyclic group, and aromatic ring contains 6-10 carbon atom;
Described heteroaryl is an aromatic heterocycle, is monocycle or bicyclic radicals; Comprise thienyl, furyl, pyrryl, pyridyl, pyrazinyl, thiazolyl, pyrimidyl, quinolyl, tetrazole base, benzothiazolyl, benzofuryl or indyl;
That described assorted alkyl refers to is saturated or unsaturated, carbon atoms and at least one heteroatomic chain, and wherein any heteroatoms is non-conterminous; Contain 2-15 carbon atom in the assorted alkyl, preferably contain 2-10 atom; Assorted alkyl is straight or branched, replacement or unsubstituted;
Described naphthenic base is replacement or unsubstituted, saturated or undersaturated cyclic group, and it contains carbon atom and/or one or more heteroatoms; This ring is monocycle or condensed ring, the ring system of bridged ring or volution; Monocycle has 3-9 atom, preferably has 4-7 atom, and many rings contain 7-17 atom, preferably contain 7-13 atom;
Described alkyl is meant the chain of saturated carbon atom, preferably contains 1-8 atom; Alkyl is a straight or branched;
Described halogen comprises fluorine, chlorine, bromine or iodine.
Preferably, R
1Be phenyl or cyclohexyl; R
2Be substituted-phenyl or hydroxyl substituted alkyl; R
3Be hydrogen, carboxyl or hydroxymethyl; R
4Be hydrogen or sec.-propyl.
Further preferred, above-mentioned formula I compound is one of following:
N
6-benzyl-N
2-(4-bromo phenyl)-9H-purine-2,6-diamines (4a),
N
6-benzyl-N
2-(4-p-methoxy-phenyl)-9H-purine-2,6-diamines (4b),
N
6-benzyl-N
2-p-methylphenyl-9H-purine-2,6-diamines (4c),
N
6-benzyl-N
2-(3-methoxyphenyl)-9H-purine-2,6-diamines (4d),
4-((6-benzylamine-9H-purine-2)-amido) phenol (4e),
N
6-benzyl-N
2-(4-fluorophenyl)-9H-purine-2,6-diamines (4f),
4-((6-benzylamine-9H-purine-2)-amido) benzsulfamide (4g),
N
6-benzyl-N
2-phenyl-9H-purine-2,6-diamines (4h),
N
6-benzyl-N
2-(4-first sulfo group phenyl)-9H-purine-2,6-diamines (4i),
4-((6-cyclohexyl methylamine-9H-purine-2)-amido) benzsulfamide (4j),
N
6-cyclohexyl methyl-N
2-phenyl-9H-purine-2,6-diamines (4k),
4-(6-cyclohexyl methylamine)-9H-purine-2-amido) phenol (4l),
N
6-cyclohexyl methyl-N
2-(4-fluorophenyl)-9H-purine-2,6-diamines (4m),
N
6-cyclohexyl methyl-N
2-(4-tolyl)-9H-purine-2,6-diamines (4n),
N
6-cyclohexyl methyl-N
2-(4-p-methoxy-phenyl)-9H-purine-2,6-diamines (4o),
N
6-cyclohexyl methyl-N
2-(4-bromophenyl)-9H-purine-2,6-diamines (4p),
N
6-cyclohexyl methyl-N
2-(4-first sulfo group phenyl)-9H-purine-2,6-diamines (4q),
2-(6-(cyclohexyl methylamine base)-9-sec.-propyl-9H-purine-2-amido)-1-butanols (10a),
2-(6-(cyclohexyl methylamine base)-9-sec.-propyl-9H-purine-2-amido) ethanol (10b),
2-(6-(cyclohexyl methylamine base)-9-sec.-propyl-9H-purine-2-amido)-3-hydroxy-propionic acid (10c),
2-(6-(cyclohexyl methylamine base)-9-sec.-propyl-9H-purine-2-amido)-3-hydroxybutyric acid (10d),
2-(6-(cyclohexyl methylamine base)-9-sec.-propyl-9H-purine-2-is amino) propane-1,3-glycol (10e),
2-(6-(cyclohexyl methylamine base)-9-sec.-propyl-9H-purine-2-amido)-4-methylpentane-1-alcohol (10f),
2-(6-(cyclohexyl methylamine base)-9-sec.-propyl-9H-purine-2-amido)-3-methyl isophthalic acid-butanols (10g),
2-(6-(cyclohexyl methylamine base)-9-sec.-propyl-9H-purine-2-amido) propane-1-alcohol (10h) or
2-(6-(cyclohexyl methylamine base)-9-sec.-propyl-9H-purine-2-amido) propionic acid (10i).
Term and definition implication used among this paper is following:
" pharmacy acceptable salt " is meant that compound of Formula I has curative effect and nontoxic salt form.It can form anion salt by arbitrary acidic-group (like carboxyl), or forms cationic salts by arbitrary basic group (like amino).A lot of such salt known in the art.Go up the cationic salts that forms at any acidic-group (like carboxyl), or go up the anion salt that forms at any basic group (like amino).It is known in the art that these salt have many, comprises the salt and the organic salt (like ammonium salt) of basic metal (like sodium and potassium) and earth alkali metal (like magnesium and calcium) like cationic salts.Also can obtain anion salt easily through the I that uses corresponding s.t. alkaline form, such acid comprises mineral acid such as sulfuric acid, nitric acid, phosphoric acid etc.; Or organic acid such as acetate, propionic acid, oxyacetic acid, 2 hydroxy propanoic acid, 2-oxo propionic acid, oxalic acid, propanedioic acid, succsinic acid, toxilic acid, fumaric acid, oxysuccinic acid, tartrate, 2-hydroxyl-1; 2,3-the third three acid, methylsulfonic acid, ethyl sulfonic acid, benzene methanesulfonic acid, 4-toluene sulfonic acide, cyclohexyl-sulfinic acid, 2 hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid etc.These salt are that those of skill in the art know, and those skilled in the art can prepare any salt that this area knowledge is provided.In addition, those of skill in the art can get certain salt according to factors such as solubleness, stability, easy preparations and give up another kind of salt.The mensuration of these salt and optimization are in those of skill in the art's experience scope.
Used " steric isomer " of the present invention defined the form of The compounds of this invention or all possible steric isomer of its physiological verivate.Only if indication is arranged in addition; The chemical name of The compounds of this invention comprises the mixture of all possible stereochemical form, and affiliated mixture comprises all diastereomers and the enantiomorph of substruction molecule, and the single isomeric forms of the The compounds of this invention of substantially pure; Promptly wherein contain and be lower than 10%; Preferably be lower than 5%, particularly be lower than 2%, most preferably be lower than other isomer of 1%.The various stereoisomer forms of class peptide compounds of the present invention all obviously are contained in the scope of the present invention.
" solvate " is the title complex that solute (like cell cycle protein dependent kinase inhibitor) and solvent (like water) are combined to form.Referring to J.Honig etc., The Van Nostrand Chemist ' s Dictionary, p.650 (1953).The pharmaceutically acceptable solvent that the present invention adopts comprises not bioactive those solvents of interference cell cyclin-dependent kinase suppressor factor (for example water, ethanol, acetate, N, dinethylformamide, DMSO 99.8MIN. and the solvent that these those skilled in the art knew or confirm easily).
The form of all right other protected form of compound of Formula I or verivate exists, and these forms will be apparent to those skilled in the art, and all should be contained in the scope of the present invention.
Aforesaid substituting group self also can be replaced by one or more substituting groups.Such substituting group is included in C.Hansch and A.Leo, those substituting groups of listing among the Substituent Constants for Correlation Analysis in Chemistry and Biology (1979).Preferred substituted comprises alkyl, thiazolinyl, alkoxyl group, hydroxyl, oxygen base, nitro; Amino, aminoalkyl group (like aminomethyl etc.), cyanic acid, halogen, carboxyl, carbonylic alkoxy (like carbonyl oxyethyl group etc.); Sulfenyl, aryl, naphthenic base, heteroaryl, Heterocyclylalkyl (like piperidyl, morpholinyl; Pyrryl etc.), imino-, hydroxyalkyl, aryloxy, arylalkyl and combination thereof.
Two, the preparation method of 2-amino of the present invention-6-aminomethyl purine compound
The preparation method of 2-amino of the present invention-6-aminomethyl purine compound is one of following method:
Synthetic route one: with 2-amino-6-chloropurine is raw material, gets 2-amino-6-substituted purin with various substituted amine generation nucleophilic substitution reactions, then at HBF
4And NaNO
2Effect makes 2-fluoro-6-substituted purin through Ba Erci-Xi Man (Balz-Schiemann) reaction down, generates target compound 4a-4i with various substituted amine reactions more at last; Route one is following:
Wherein, the same general structure I of R1 and R2 is said;
Described various substituted amine is by phenyl, heteroaryl, the assorted substituted amine of alkyl or cycloalkyl, and can have hydroxyl in the organic amine structure, halogen, nitro, itrile group, carboxyl, alkyl, alkoxyl group, sulfoamido or methylsulfonic acid base.
Reagent and condition in said synthesis route one reaction formula: a. propyl carbinol, triethylamine, 130 ℃ of backflows; B.HBF
4, NaNO
2, H
2O ,-15 ℃; C. trifluoroacetic acid (TFA), propyl carbinol, 130 ℃ or trifluoroacetic acid (TFA), trifluoroethanol (TFE), 85 ℃.
The structural formula of the target compound of synthetic route one is as shown in table 1 below:
Table 1 compound 4a-4i structural formula
Synthetic route two: with 2, the 6-dichloropurine is a raw material, and obtains 2-chloro-6-substituted purin behind the various substituted amine generation nucleophilic substitution reactions, and then generates target compound 4j-4q with various substituted amine reactions; Route two is following:
Wherein, the same general structure I of R1 and R2 is said;
Described various substituted amine is by phenyl, heteroaryl, the assorted substituted amine of alkyl or cycloalkyl, and can have hydroxyl in the organic amine structure, halogen, nitro, itrile group, carboxyl, alkyl, alkoxyl group, sulfoamido or methylsulfonic acid base.
Reagent and condition in said synthesis route two reaction formula: d. propyl carbinol, triethylamine, 130 ℃ of backflows; E. trifluoroacetic acid, propyl carbinol, 130 ℃ or trifluoroacetic acid, trifluoroethanol, 85 ℃.
The structural formula of the target compound of synthetic route two is as shown in table 2 below:
Table 2 compound 4j-4q structural formula
Synthetic route three: with 2-fluoro-6-chloropurine is raw material, with various substituted amine generation nucleophilic substitution reactions, obtains 2-fluoro-6 substituted purins, then with the 9-H alkylation, last obtains target compound 10a-10i with each seed amino acid or amino alcohol reaction generation; Route three is following:
Wherein, the same general structure I of R1, R2, R3 and R4;
Described various substituted amine is by phenyl, heteroaryl, the assorted substituted amine of alkyl or cycloalkyl, and can have hydroxyl in the organic amine structure, halogen, nitro, itrile group, carboxyl, alkyl, alkoxyl group, sulfoamido or methylsulfonic acid base.
Described each seed amino acid or amino alcohol are common amino acids and corresponding amino alcohols thereof such as Serine, Threonine, L-Ala, Xie Ansuan, leucine.
Reagent and condition in said synthesis route three reaction formula: f. propyl carbinol, triethylamine, 130 ℃ of backflows; G. haloalkane, K
2CO
3, DMSO 99.8MIN.; H. amino acid, N-Methyl pyrrolidone, 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU), 160 ℃ or amino alcohol, DMSO 99.8MIN., diisopropylethylamine, 120-160 ℃.
The structural formula of the target compound of synthetic route three is as shown in table 3 below:
Table 3 compound 10a-10i structural formula
The concrete operations step of said compound will specify in an embodiment.
Three, the pharmaceutical composition that contains The compounds of this invention
A kind of mammiferous pharmaceutical composition of orally give that is suitable for, the arbitrary compound that comprises above-mentioned general formula I and one or more pharmaceutically acceptable vehicle.
A kind of parenteral that is suitable for gives mammiferous pharmaceutical composition, comprises arbitrary compound and one or more pharmaceutically acceptable vehicle of above-mentioned general formula I.
Part verivate of the present invention can free form or is existed with salt form.Pharmacy acceptable salt of the known chemical compound lot type of those skilled in the art and preparation method thereof.Pharmacy acceptable salt comprises conventional avirulent salt, comprises such compound alkali and quaternary ammonium salt inorganic or that organic acid forms.
Compound of the present invention can form hydrate or solvate.The one skilled in the art known with compound formed hydrate or form the method for solvate when in solution, concentrating during with the water freeze-drying with appropriate organic solvent.
The present invention comprises the medicine that contains the therapeutic dose The compounds of this invention and the pharmaceutical composition of one or more pharmaceutically acceptable carriers and/or vehicle.Carrier comprises like salt solution, BS, and glucose, water, glycerine, ethanol and their binding substances, hereinafter is discussed in more detail.If desired, said composition can also comprise wetting agent or emulsifying agent in a small amount, or the pH buffer reagent.Said composition can be liquid, suspension-s, emulsion, tablet, pill, capsule, extended release preparation or powder.Said composition can be mixed with suppository with traditional tamanori and carrier such as triglyceride.Oral prepns can comprise the mannitol of standard vector such as medicine grade, lactose, starch, Magnesium Stearate, soluble saccharin, Mierocrystalline cellulose and magnesiumcarbonate or the like.Preparation and deciding optionally, preparation can design mixing, granulation and compression or solvent components.In another approach, said composition can be mixed with nano particle.
The pharmaceutical carrier that uses can be solid or liquid.
The typical solid carrier comprises lactose, terra alba, sucrose, talcum, gel, agar, pectin, gum arabic, Magnesium Stearate, Triple Pressed Stearic Acid or the like.Solid carrier can comprise that one or more maybe be simultaneously as sweetener, lubricant, solubilizing agent, suspension agent, filler, glidant, compression aid, the material of tackiness agent or tablet-disintegrating agent; It can also be an encapsulating material.In powder, carrier is pulverizing solid, and it mixes with pulverizing activeconstituents.Activeconstituents and the carrier with necessary compression property are with suitable mixed, with the shape and the size compression of needs in tablet.Powder and tablet preferably comprise 99% activeconstituents at the most.Suitable solid carrier comprises, for example, and calcium phosphate, Magnesium Stearate, talcum, sugar, lactose, dextrin, starch, gel, Mierocrystalline cellulose, methylcellulose gum, sodium carboxymethyl-cellulose, Vinylpyrrolidone polymer alkane ketone, low melt wax and ion exchange resin.
Exemplary of liquid carriers comprises syrup, peanut oil, and sweet oil, water, or the like.Liquid vehicle is used to prepare solution, suspension-s, emulsion, syrup, the compsn of tincture and sealing.Activeconstituents can dissolve or be suspended in pharmaceutically acceptable liquid vehicle such as water, organic solvent, the mixture of the two or pharmaceutically acceptable oils or fat.Liquid vehicle can comprise other suitable medicated premix such as solubilizing agent, emulsifying agent, and buffer reagent, sanitas, sweetener, sweetener, suspension agent, thickening material, pigment, viscosity modifier is stablized shape or osmotic pressure-regulator.The suitable example that is used for the liquid vehicle of oral and administered parenterally comprises that water (partly comprises as above-mentioned additive; Derivatived cellulose for example; The preferably carboxymethyl cellulose sodium salt solution); Alcohol (comprising monohydroxy-alcohol and polyvalent alcohol, for example terepthaloyl moietie) and their verivate, and oils (for example fractionated coconut oil and peanut oil).The carrier that is used for administered parenterally can also be grease such as OE and sec.-propyl myristate.Aseptic liquid vehicle is used for the aseptic fluid composition of administered parenterally.The liquid vehicle that is used for pressurized compositions can be halohydrocarbon or other pharmaceutically acceptable propelling agents.Sterile solution or aaerosol solution composition of liquid medicine can be used for, for example, and intravenously, intramuscular, intraperitoneal or subcutaneous injection.But single pushes or injection gradually during injection, goes into 30 minutes the interior perfusion of passages through which vital energy circulates.This compound can also be with the form oral administration of liquid or solids compsn.
Carrier or vehicle can comprise time lag material known in the art, like glyceryl monostearate or distearin, also can comprise wax, TKK 021, Vltra tears, methyl methacrylate or the like.When preparation is used for when oral; Generally acknowledge PHOSALPG-50 (phospholipid and 1; The 2-Ucar 35 concentrates, A.Nattermann & Cie.GmbH) in 0.01% tween 80 be used for the preparation of the acceptable oral preparation of other compounds, can be adapted to the preparation of all cpds of the present invention.
Can use medicament forms miscellaneous when giving The compounds of this invention.If the use solid carrier, preparation can be tablet, is placed into powder or piller form or lozenge or lozenge form in the hard capsule.The amount of solid carrier changes to a great extent, but preferably from about 25mg to about 1.0g.If the use liquid vehicle, preparation can be syrup, emulsion, soft capsule, aseptic injectable solution or suspension-s in the liquid suspension of ampoule or bottle or non-water.
In order to obtain stable water miscible formulation, can compound or its pharmacy acceptable salt be dissolved in the organic or inorganic aqueous acid, 0.3M succsinic acid or citric acid solution.Optionally, the tart verivate can be dissolved in suitable basic soln.If can not get soluble form, can compound be dissolved in suitable cosolvent or their combination.The example of suitable cosolvent like this includes but are not limited to, and concentration range is from the ethanol of 0-60% TV, Ucar 35, Liquid Macrogol, polysorbate 80, glycerine, polyoxyethylene fatty acid ester, Fatty Alcohol(C12-C14 and C12-C18) or glycerine hydroxy fatty acid ester or the like.
Various release systems are known and can be used for the administration of compound or other various preparations, and these preparations comprise tablet, capsule, and injectable solution, the capsule in the liposome, particulate, microcapsule, or the like.The method of introducing includes, but are not limited to skin, intracutaneous, intramuscular, endoperitoneal, intravenous, subcutaneous, nasal cavity, lung, peridural, eyes with (preferred usually) oral route.Compound can through any easily or other suitable administration; For example through injecting or bolus injection; Through epithelium or the mucous membrane circuit (for example; Oral mucosa, rectum and intestines mucosa, or the like) absorb or the support through carrying medicament and can be in other biological promoting agent administration together.Can whole body or topical.Be used for nose, when the treatment of segmental bronchus or lung disease or prevention, preferred route of administration is oral, nasal administration or segmental bronchus smoke substance or atomizer.
Four, use
The application of compound of the present invention in the medicine for preparing prevention or the treatment mammalian diseases relevant with the active imbalance of cell cycle protein dependent kinase.The relevant mammalian diseases of the active imbalance of described and cell cycle protein dependent kinase comprises cancer, neurodegenerative disease, malaria and mellitus etc.
Embodiment
Below in conjunction with embodiment the present invention is further specified, but be not limited thereto.
The preparation of embodiment 1, compound 4a-4i
(1) N
6-benzyl-9H-purine-2,6-diamines (2)
With 2-amino-6-chloropurine (10.0g, 59.0mmol) and propyl carbinol (150mL) add in the eggplant-shape bottle, under agitation condition, add benzylamine (9.7mL then successively; 88.5mmol) and triethylamine (20mL 147.5mmol), finishes; Mixed solution places 130 ℃ of oil baths, prolong cooling for reflux.After TLC detection raw material total overall reaction finishes, stop to reflux the reaction solution cooling; Decompression and solvent recovery gets the off-white color solid, after solid is used the n-propyl alcohol thorough washing again; Suction filtration is collected solid, gets white powder 13.94g (58mmol after the vacuum-drying; 98.4%) mp 234-238 ℃ of .HRMS:m/z calcd for C,
12H
12N
6[M+1]
+241.1201Found:241.1218;
1H-NMR (600MHz, DMSO-d
6): δ ppm 4.64 (s, 2H); 5.75 (s, 2H); 7.20 (t, 2H); 7.28 (t, 2H); 7.34 (d, 2H); 7.68 (s, 1H); 12.15 (s, 1H)
(2) N-benzyl-2-fluoro-9H-purine-6-amine (3)
(2.4g 10mmol) uses HBF to compound 3
4(30mL) after the dissolving, reaction solution is cooled to-15 ℃.Under this temperature, in reaction solution, slowly drip NaNO with constant pressure funnel
2(after dropwising ,-15 ℃ are continued to stir 30min for 1.4g, aqueous solution 20mmol); Use 50%NaOH (w/v) to transfer pH to 7 then, separate out a large amount of solids, filter, filtrating discards; Solid adds in the ETHYLE ACETATE, behind the stirring 10min, filters once more; Solid with the ETHYLE ACETATE repetitive scrubbing after, combined ethyl acetate, anhydrous magnesium sulfate drying.The bullion that decompression and solvent recovery obtains gets white solid powder 0.83g (3.4mmol, 34%), mp 225-227 ℃ behind purification by silica gel column chromatography.HRMS:m/z?calcd?for?C
12H
10FN
5[M+1]
+244.0998Found:244.0997;
1H-NMR(600MHz,DMSO-d
6):δppm?4.64(d,2H);7.24(d,1H);7.31-7.36(m,4H);8.11(s,1H);8.80(s,1H);13.05(1H,s).
(3) N
6-benzyl-N
2-(4-bromo phenyl)-9H-purine-2,6-diamines (4a)
(0.57g, 2.34mmol), (2.82g, 16.4mmol), (0.1mL 1.3mmol), adds in the propyl carbinol (10mL) trifluoroacetic acid para-bromoaniline compound 3., mixed solution places 130 ℃ of oil baths, prolong cooling for reflux.TLC monitoring, treat that compound 3 reactions finish after, stop to reflux, a large amount of solids are separated out in the reaction solution cooling.Suction filtration, solid be with methylene dichloride or methanol wash, drying, bullion behind purification by silica gel column chromatography pale brown look solid 0.5g (1.6mmol, 83%), mp 261-262 ℃ of .HRMS:m/z calcd for C
18H
16N
6[M+1]
+317.1514Found:317.1521;
1H-NMR (600MHz, DMSO-d
6): δ ppm4.74 (s, 2H); 6.88 (t, 1H); 7.20 (t, 2H); 7.25 (d, 1H); 7.33 (t, 2H); 7.39 (d, 2H); 7.70 (d, 2H); 8.11 (s, 1H); 8.32 (s, 1H); 9.10 (s, 1H); 12.81 (s, 1H).
(4) N
6-benzyl-N
2-(4-p-methoxy-phenyl)-9H-purine-2,6-diamines (4b)
The same 4a of method.Compound 3 (0.25g, 1mmol), P-nethoxyaniline (0.19g, 1.5mmol), trifluoroacetic acid (0.4mL, 5mmol), propyl carbinol (10mL).Purification by silica gel column chromatography obtains off-white color solid 0.11g (0.32mmol, 32%), mp 229-232 ℃ of .HRMS:m/z calcd for C
19H
18N
6O [M+1]
+347.1620Found:347.1610;
1H-NMR (600MHz, DMSO-d
6): δ ppm 3.69 (s, 3H); 4.69 (s, 2H); 6.77 (d, 2H); 7.20 (t, 1H); 7.30 (t, 2H); 7.37 (d, 2H); 7.61 (d, 2H); 7.78 (s, 1H); 7.96 (s, 1H); 8.60 (s, 1H); 12.37 (s, 1H).
(5) N
6-benzyl-N
2-p-methylphenyl-9H-purine-2,6-diamines (4c)
The same 4a of method.Compound 3 (0.61g, 2.5mmol), to monomethylaniline (1.88g, 17.6mmol), trifluoroacetic acid (0.1mL, 1.3mmol), propyl carbinol (20mL).Off-white color solid 0.39g (1.2mmol, 48%), mp 277-279 ℃ of .HRMS:m/z calcd for C
19H
18N
6[M+1]
+331.1671Found:331.1668;
1H-NMR (600MHz, DMSO-d
6): δ ppm 2.21 (s, 3H); 4.70 (s, 2H); 6.97 (d, 2H); 7.20 (t, 1H); 7.30 (t, 2H); 7.38 (d, 2H); 7.61 (d, 2H); 7.79 (s, 1H); 8.01 (s, 1H); 8.69 (s, 1H); 12.40 (s, 1H).
(6) N
6-benzyl-N
2-(3-methoxyphenyl)-9H-purine-2,6-diamines (4d)
The same 4a of method.Compound 3 (0.3g, 1.2mmol), m-anisidine (11g, 8.6mmol), trifluoroacetic acid (0.1mL, 1.3mmol), propyl carbinol (10mL).Purification by silica gel column chromatography obtains white solid 0.18g (0.5mmol, 42%), mp 236-238 ℃ of .HRMS:m/z calcd for C
19H
18N
6O [M+1]
+347.1620Found:347.1614;
1H-NMR (600MHz, DMSO-d
6): δ ppm 3.68 (d, 3H); 4.72 (s, 2H); 7.06 (t, 1H); 7.20 (t, 1H); 7.29 (t, 3H); 7.39 (d, 2H); 7.57 (t, 2H); 7.82 (s, 1H); 8.04 (s, 1H); 8.81 (s, 1H); 12.45 (s, 1H).
(7) 4-((6-benzylamine-9H-purine-2)-amido) phenol (4e)
The same 4a of method.Compound 3 (0.4g, 1.6mmol), PARA AMINOPHENOL (1.26g, 11.5mmol), trifluoroacetic acid (0.1mL, 1.3mmol), propyl carbinol (12mL).Purification by silica gel column chromatography obtains off-white color solid 0.22g (0.66mmol, 41%), mp258-260 ℃ of .HRMS:m/z calcd for C
18H
16N
6O [M+1]
+333.1464Found:333.1462;
1H-NMR (600MHz, DMSO-d
6): δ ppm 4.71 (t, 2H); 6.60 (d, 2H); 7.20 (t, 1H); 7.29 (t, 2H); 7.37 (d, 2H); 7.46 (t, 2H); 7.75 (s, 1H); 7.94 (s, 1H); 8.45 (s, 1H); 8.83 (s, 1H); 12.32 (s, 1H).
(8) N
6-benzyl-N
2-(4-fluorophenyl)-9H-purine-2,6-diamines (4f)
The same 4a of method.Compound 3 (0.46g, 1.9mmol), para-fluoroaniline (1.3mL, 13.2mmol), trifluoroacetic acid (0.1mL, 1.3mmol), propyl carbinol (10mL).White solid 0.13g (0.39mmol, 21%), mp 247-250 ℃ of .HRMS:m/z calcd for C
18H
15FN
6[M+1]
+335.1420Found:335.1350;
1H-NMR (600MHz, DMSO-d
6): δ ppm 4.71 (s, 2H ,-NC
H 2-); 7.04 (t, 2H); 7.24 (t, 1H); 7.33 (t, 2H); 7.38 (d, 2H); 7.68 (s, 2H); 8.14 (s, 1H); 8.32 (s, 1H); 9.16 (s, 1H); 12.93 (s, 1H)
(9) 4-((6-benzylamine-9H-purine-2)-amido) benzsulfamide (4g)
With compound 3 (0.6g 2.47mmol) adds in the 10mL trifluoroethanol (TFE), opens induction stirring, add then sulfanilamide (SN) (1.7g, 9.87mmol) and trifluoroacetic acid (1.83mL, 24.7mmol), mixed solution is as in 85 ℃ of the oil baths, the prolong cooling for reflux.TLC monitoring, treat that compound 3 reactions finish after, stop to reflux the reaction solution cooling; Concentrate, in resistates, behind the adding methyl alcohol, be stirred to abundant dissolving; Get white suspension, filter, collect filtrating; The bullion that obtains gets white solid 0.07g (0.18mmol, 8%) through purification by silica gel column chromatography, mp 215-218 ℃ of .HRMS:m/z calcd for C
18H
17N
7O
2S [M+1]
+396.1242Found:396.1238;
1H-NMR (600MHz, DMSO-d
6): δ ppm 4.72 (s, 2H); 7.10 (s, 2H); 7.22 (s, 1H); 7.32 (s, 2H); 7.39 (d, 2H); 7.60 (d, 2H); 7.86 (s, 2H); 7.90 (s, 1H); 8.19 (s, 1H); 9.32 (s, 1H); 12.55 (s, 1H)
(10) N
6-benzyl-N
2-phenyl-9H-purine-2,6-diamines (4h)
The same 4a of method.Compound 3 (0.47g, 1.9mmol), aniline (1.3ml, 13.2mmol), trifluoroacetic acid (0.1ml, 1.3mmol), n-butanol (10ml).Pale brown look solid 0.5g (1.6mmol, 83%), mp 261-262 ℃ of .HRMS:m/z calcd forC
18H
16N
6[M+1]
+317.1514Found:317.1521;
1H-NMR (600MHz, DMSO-d
6): δ ppm 4.74 (s, 2H); 6.88 (t, 1H); 7.20 (t, 2H); 7.25 (d, 1H); 7.33 (t, 2H); 7.39 (d, 2H); 7.70 (d, 2H); 8.11 (s, 1H); 8.32 (s, 1H); 9.10 (s, 1H); 12.81 (s, 1H)
(11) N
6-benzyl-N
2-(4-first sulfo group phenyl)-9H-purine-2,6-diamines (4i)
The same 4g of method.Compound 3 (0.6g, 2.47mmol), to methylsulphonic acid aniline (1.69g, 9.87mmol), trifluoroacetic acid (1.83mL, 24.7mmol), trifluoroethanol (10mL).Off-white color solid 0.04g (0.1mmol, 4%), mp 241-244 ℃ of .HRMS:m/z calcd for C
18H
17N
7O
2S [M+1]
+395.1290Found:395.1305;
1H-NMR (600MHz, DMSO-d
6): δ ppm 3.14 (s, 3H); 4.78 (s, 2H); 7.25 (s, 1H); 7.35 (s, 2H); 7.42 (s, 2H); 7.73 (d, 2H); 7.94 (s, 2H); 8.52 (s, 1H); 8.74 (s, 1H); 9.81 (s, 1H); 13.27 (s, 1H)
The preparation of embodiment 2, compound 4j-4q
(1) N-(cyclohexyl methyl)-2-chloro-9H-purine-6-amine (6)
With 2, the 6-dichloropurine (5.0g, 26.5mmol) and propyl carbinol (30mL) add in the eggplant-shape bottle; Under agitation condition, add successively then the aminomethyl hexanaphthene (4.2mL, 31.7mmol) and triethylamine (5.4mL, 40mmol); Finish, mixed solution places 130 ℃ of oil baths, prolong cooling for reflux.After TLC monitoring raw material total overall reaction finishes, stop to reflux, a large amount of white solids are separated out in the reaction solution cooling; Suction filtration, solid with the n-propyl alcohol thorough washing after, collect; Get white solid 6.41g (24.1mmol, 91%), mp 208-210 ℃ of .HRMS:m/z calcd for C after the vacuum-drying
12H
16ClN
5[M+1]
+266.1172Found:266.1177;
1H-NMR (400MHz, DMSO-d
6): δ ppm 0.92-1.00 (m, 2H); 1.57-1.21 (m, 3H); 1.61-1.73 (m, 6H); 3.23 (s, 2H); 7.94 (s, 1H); 8.08 (s, 1H); 12.85 (s, 1H)
(2) 4-((6-cyclohexyl methylamine-9H-purine-2)-amido) benzsulfamide (4j)
With compound (6,0.6g 2.26mmol) adds in the 15mL trifluoroethanol, opens induction stirring, add then sulfanilamide (SN) (1.56g, 9mmol) and trifluoroacetic acid (1.7mL, 22.6mmol), mixed solution is as in 90 ℃ of the oil baths, the prolong cooling for reflux.TLC monitoring, treat that compound 6 reactions finish after, stop to reflux, the reaction solution cooling, evaporated under reduced pressure solvent, residue behind purification by silica gel column chromatography white solid 0.1g (0.25mmol, 11%), 258 ℃ of decomposition of mp.HRMS:m/z?calcd?for?C
18H
23N
7O
2S[M+1]
+402.1712Found:402.1688;
1H-NMR(400MHz,DMSO-d
6):δppm?1.02(t,2H);1.19(t,3H);1.64(s,1H);1.70(s,3H);1.82(d,2H);3.39(s,2H);7.16(s,2H);7.70(d,2H);7.96(d,J＝8.4Hz,2H);8.22(s,1H);8.39(s,1H);9.65(s,1H);13.32(s,1H)
(3) N
6-cyclohexyl methyl-N
2-phenyl-9H-purine-2,6-diamines (4k)
(6,0.6g 2.25mmol) adds in the propyl carbinol (15mL), opens induction stirring, and (1.5mL, 15.8mmol) and behind the trifluoroacetic acid (0.1mL), mixed solution places 130 ℃ of oil baths, prolong cooling for reflux to add aniline then with compound.TLC monitoring, treat that compound 6 reactions finish after, stop to reflux, a large amount of solids are separated out in the reaction solution cooling.Suction filtration, solid get white solid 0.47g (1.5mmol, 65%), mp > with methylene dichloride or methanol wash after the drying; 290 ℃ of .HRMS:m/z calcd for C
18H
22N
6[M+1]
+323.1984Found:323.1987;
1H-NMR (400MHz, DMSO-d
6): δ ppm 0.95-1.03 (m, 2H); 1.13-1.21 (m, 3H); 1.63-1.80 (m, 6H); 3.36 (s, 2H); 6.94 (t, 1H); 7.26 (t, 2H); 7.75 (d, 2H); 8.20 (s, 2H); 9.27 (s, 1H); 13.13 (s, 1H).
(4) phenol (4l) 4-(6-cyclohexyl methylamine)-9H-purine-2-amido)
The same 4k of method.Compound (6,0.6g, 2.25mmol), PARA AMINOPHENOL (1.6g, 15.8mmol), trifluoroacetic acid (0.1mL), propyl carbinol (15mL).Off-white color solid 0.39g (1.2mmol, 51%), 285 ℃ of decomposition.HRMS:m/z?calcd?forC
18H
22N
6O[M+1]
+339.1933Found:339.1936;
1H-NMR(400MHz,DMSO-d
6):δppm?0.96(t,2H);1.17(t,3H);1.63-1.77(m,6H);3.31(s,2H);6.66(d,2H);7.52(d,2H);7.63(br?s,1H);7.84(s,1H);8.60(s,1H);8.90(s,1H);12.48(s,1H)
(5) N
6-cyclohexyl methyl-N
2-(4-fluorophenyl)-9H-purine-2,6-diamines (4m)
The same 4k of method.Compound (6,0.6g, 2.25mmol), para-fluoroaniline (1.5mL, 15.8mmol), trifluoroacetic acid (0.1mL), propyl carbinol (15mL).White solid 0.50g (1.5mmol, 65%), mp>300 ℃ of .HRMS:m/z calcd for C
18H
21FN
6[M+1]
+341.1890Found:341.1876;
1H-NMR (400MHz, DMSO-d
6): δ ppm 0.93-1.02 (m, 2H); 1.13-1.24 (m, 3H); 1.63-1.78 (m, 6H); 3.34 (s, 2H); 7.10 (t, 2H); 7.73-7.77 (m, 2H); 8.23 (s, 2H); 9.30 (s, 1H); 12.32 (s, 1H)
(6) N
6-cyclohexyl methyl-N
2-(4-tolyl)-9H-purine-2,6-diamines (4n)
The same 4k of method.Compound (6,0.6g, 2.25mmol), to monomethylaniline (1.69g, 15.8mmol), trifluoroacetic acid (0.1mL), propyl carbinol (15mL).White solid 0.45g (1.3mmol, 60%), mp>300 ℃ of .HRMS:m/z calcd for C
19H
24N
6[M+1]
+337.2140Found:337.2139;
1H-NMR (400MHz, DMSO-d
6): δ ppm 0.99 (t, 2H); 1.13-1.21 (m, 3H); 1.63-1.78 (m, 6H); 2.25 (s, 3H); 3.36 (s, 2H); 7.07 (d, 2H); 7.62 (d, 2H); 8.15 (s, 1H); 8.24 (s, 1H); 9.20 (s, 1H); 13.13 (s, 1H)
(7) N
6-cyclohexyl methyl-N
2-(4-p-methoxy-phenyl)-9H-purine-2,6-diamines (4o)
The same 4k of method.Compound (6,0.6g, 2.25mmol), P-nethoxyaniline (1.95g, 15.8mmol), trifluoroacetic acid (0.1mL), propyl carbinol (15mL).White solid 0.48g (1.4mmol, 61%), mp>300 ℃ of .HRMS:m/z calcd forC
19H
24N
6O [M+1]
+353.2090Found:353.2078;
1H-NMR (400MHz, DMSO-d
6): δ ppm 0.93-1.02 (m, 2H); 1.13-1.24 (m, 3H); 1.63-1.77 (m, 6H); 3.35 (s, 2H); 3.73 (s, 3H); 6.86 (d, 2H); 7.60 (d, 2H); 8.08 (s, 1H); 8.17 (s, 1H); 9.06 (s, 1H); 13.01 (s, 1H)
(8) N
6-cyclohexyl methyl-N
2-(4-bromophenyl)-9H-purine-2,6-diamines (4p)
The same 4k of method.Compound (6,0.6g, 2.25mmol), para-bromoaniline (2.72g, 15.8mmol), trifluoroacetic acid (0.1mL), propyl carbinol (15mL).White solid 0.53g (1.3mmol, 59%), mp>300 ℃ of .HRMS:m/z calcd for C
18H
21BrN
6[M+1]
+401.1089Found:401.1114;
1H-NMR (400MHz, DMSO-d
6): δ ppm 1.02 (d, 2H); 1.18 (t, 3H); 1.63-1.79 (m, 6H); 3.36 (s, 2H); 7.42 (d, 2H); 7.76 (d, 2H); 8.20 (s, 1H); 8.32 (s, 1H); 9.41 (s, 1H); 13.35 (s, 1H)
(9) N
6-cyclohexyl methyl-N
2-(4-first sulfo group phenyl)-9H-purine-2,6-diamines (4q)
The same 4j of method.Compound (6,0.6g, 2.26mmol), to methylsulphonic acid aniline (1.55g, 9mmol), trifluoroacetic acid (1.7mL, 22.6mmol), trifluoroethanol (12mL).White solid 0.05g (0.12mmol, 6%), mp 250-253 ℃ of .HRMS:m/zcalcd for C
19H
24N
6O
2S [M+1]
+401.1759Found:401.1762;
1H-NMR (400MHz, DMSO-d
6): δ ppm1.03 (d, 2H); 1.17-1.22 (m, 3H); 1.63-1.83 (m, 6H); 3.14 (s, 3H); 3.41 (s, 2H); 7.78 (d, 2H); 8.05 (d, 2H); 8.34 (s, 1H); 8.41 (s, 1H); 9.81 (s, 1H); 13.16 (s, 1H)
The preparation of embodiment 3, compound 10a-10i
(1) N-(cyclohexyl methyl)-2-fluoro-9H-purine-6-amine (8)
With 2-fluoro-6-chloropurine (5.0g 29mmol) is dissolved in the absolute ethyl alcohol (30mL), add successively then the aminomethyl hexanaphthene (4.5mL, 34.9mmol) and triethylamine (5.9mL 43.6mmol), finishes, and mixed solution places 80 ℃ of oil baths, prolong cooling for reflux.After TLC monitoring raw material total overall reaction finishes, stop to reflux cooling; After the reaction solution evaporated under reduced pressure, get light yellow solid, vacuum-drying is after get white solid powder 4.80g (19.3mmol behind the column chromatography purification; 66%) mp 164-168 ℃ of .ESI-MS:m/z 250.4 [M+1],
+;
1H-NMR (300MHz, DMSO-d
6): δ ppm 0.88-0.99 (m, 2H); 1.14-1.16 (t, 3H); 1.61-1.72 (m, 6H); 3.25 (s, 2H); 8.06 (s, 1H); 8.17 (s, 1H); 12.98 (s, 1H)
(2) N-(cyclohexyl methyl)-2-fluoro-9-sec.-propyl-9H-purine-6-amine (9)
With compound (8,4.80g 19.3mmol) is dissolved in the DMSO 99.8MIN. (15mL), add successively then bromo propane (4.5mL, 48.1mmol) and Anhydrous potassium carbonate (8.0g 57.8mmol), finishes, and mixed solution places 80 ℃ of reactions of oil bath.TLC monitoring, treat that the raw material total overall reaction finishes after, the reaction solution dilute with water is transferred in the separating funnel, use ethyl acetate extraction, merges organic layer, washs with saturated sodium-chloride again, obtains organic layer, anhydrous magnesium sulfate drying.Filter, decompression and solvent recovery, bullion get white solid powder 4.03g (13.8mmol, 72%), mp 112-115 ℃ .ESI-MS:m/z292.4 [M+1] behind purification by silica gel column chromatography
+;
1H-NMR (400MHz, DMSO-d
6): δ ppm 0.94 (m, 2H); 1.14-1.16 (m, 3H); 1.49 (d, 6H); 1.64-1.67 (m, 6H); 3.26 (t, 2H); 4.59-4.65 (m, 1H); 8.20 (s, 1H); 8.29 (s, 1H)
(3) 2-(6-(cyclohexyl methylamine base)-9-sec.-propyl-9H-purine-2-amido)-1-butanols (10a)
With compound (9,0.6g, 2.1mmol), (1.2mL 13.4mmol) adds in the DMSO 99.8MIN. (10mL) 2-amino-1-butanols, and after the extracting vacuum, mixed solution places 130 ℃ of reactions of oil bath under the nitrogen protection.TLC monitoring, treat that compound 9 reactions finish after, stopped reaction behind the reaction solution thin up, use ethyl acetate extraction, the combined ethyl acetate layer washs anhydrous magnesium sulfate drying with saturated sodium-chloride.Filter, decompression and solvent recovery, bullion gets .mp 116-118 ℃ of .HRMS:m/z calcd for of white solid 0.23g (0.6mmol, 32.3%) C through column chromatography purification
19H
32N
6O [M+1]
+361.2716Found:361.2711;
1H-NMR (600MHz, CDCl
3): 0.97-1.01 (m, 2H); 1.03 (t, 3H); 1.13-1.26 (m, 3H); 1.53 (d, 6H); 1.56-1.60 (m, 2H); 1.61-1.67 (m, 2H); 1.71-1.73 (m, 2H); 1.82 (d, 2H); 3.38 (s, 2H); 3.62-3.65 (dd, 1H); 3.82-3.89 (m, 2H); 4.57-4.61 (m, 1H); 4.88 (s, 1H); 5.45-5.67 (d, 2H); 7.49 (s, 1H).
(4) 2-(6-(cyclohexyl methylamine base)-9-sec.-propyl-9H-purine-2-amido) ethanol (10b)
The same 10a of method.Compound (9,0.5g, 1.7mmol), thanomin (1mL, 11.2mmol), DMSO (10mL)..mp 95-98 ℃ of .HRMS:m/z calcd for of off-white color solid 0.18g (0.5mmol, 31.6%) C
17H
28N
6O [M+1]
+333.2401Found:333.2418;
1H-NMR (600MHz, CDCl
3): 0.94-1.03 (m, 2H); 1.18-1.27 (m, and 3H) 1.53 (d, 6H); 1.55-1.61 (m, 1H); 1.63 (t, 1H), 1.72 (t, 2H); 1.81 (d, 2H); 3.38 (s, 2H); 3.55-3.58 (m, 2H); 3.83 (t, 2H); 4.57-4.64 (m, 1H); 5.02 (br s, 1H), 5.37 (t, 1H); 5.87 (s, 1H); 7.50 (s, 1H)
(5) 2-(6-(cyclohexyl methylamine base)-9-sec.-propyl-9H-purine-2-amido)-3-hydroxy-propionic acid (10c)
With compound (9,0.5g, 1.7mmol); The L-Serine (3.6g, 34mmol) with 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU) (5.3mL; 34mmol) add in the N-Methyl pyrrolidone (10mL), after the extracting vacuum, mixed solution places 160 ℃ of reactions of oil bath under the nitrogen protection.TLC monitoring, treat that compound 9 reactions finish after, stopped reaction, reaction solution dilutes with 10% Hydrocerol A, dichloromethane extraction, the combined dichloromethane layer washs anhydrous magnesium sulfate drying with saturated sodium-chloride.Filter, decompression and solvent recovery, bullion get .mp 158-160 ℃ of .HRMS:m/zcalcd for C of off-white color solid 0.11g (0.3mmol, 17%) behind column chromatography purification
18H
28N
6O
3[M+1]
+377.2301Found:377.2319;
1H-NMR (300MHz, CD
3OD): 0.98-1.12 (m, 2H); 1.29-1.40 (m, 3H); 1.58 (d, 6H); 1.65-1.73 (m, 2H); 1.78-1.89 (m, 4H); 3.38 (s, 2H); 4.03 (d, 2H); 4.61 (t, 1H); 4.66-4.72 (m, 1H); 7.86 (s, 1H).
(6) 2-(6-(cyclohexyl methylamine base)-9-sec.-propyl-9H-purine-2-amido)-3-hydroxybutyric acid (10d)
The same 10c of method.Compound (9,0.6g, 2.1mmol), the L-Threonine (5.0g, 41.2mmol), DBU (6.3mL, 41.2mmol), N-Methyl pyrrolidone (10mL)..mp 138-142 ℃ of .HRMS:m/zcalcd for C of off-white color solid 0.15g (0.38mmol, 18.8%)
19H
30N
6O
3[M+1]
+391.2457Found:391.2469;
1H-NMR (300MHz, CD
3OD): 0.95-1.07 (m, 2H); 1.17-1.27 (m, 3H); 1.30 (d, 3H); 1.53 (d, 6H); 1.58-1.83 (m, 6H); 3.34 (s, 2H); 4.22-4.37 (m, 1H); 4.51-4.57 (m, 1H); 4.58-4.68 (m, 1H); 7.81 (s, 1H)
(7) 2-(6-(cyclohexyl methylamine base)-9-sec.-propyl-9H-purine-2-is amino) propane-1,3-glycol (10e)
The same 10a of method.Compound (9,0.3g, 1mmol), the L-serinol (0.61g, 6.7mmol), DMSO 99.8MIN. (4mL)..mp 166-168 ℃ of .HRMS:m/z calcd for of white solid 0.15g (0.4mmol, 40.5%) C
18H
30N
6O
2[M+1]
+363.2508Found:363.2536;
1H-NMR (600MHz, CDCl
3): 0.93-0.99 (m, 2H); 1.09-1.27 (m, 3H); 1.50 (d, 6H); 1.53-1.60 (m, 1H); 1.63 (d, 1H), 1.69 (d, 2H); 1.78 (d, 2H); 3.32 (s, 2H); 3.82-3.90 (m, 4H); 4.08 (t, 1H); 4.53-4.59 (hept., 1H); 5.12 (s, 2H); 5.70 (d, 1H); 5.96 (s, 1H); 7.50 (s, 1H)
(8) 2-(6-(cyclohexyl methylamine base)-9-sec.-propyl-9H-purine-2-amido)-4-methylpentane-1-alcohol (10f)
The same 10a of method.Compound (9,0.3g, 1mmol), the L-leucinol (0.86g, 6.7mmol), diisopropylethylamine (1.7mL, 10mmol), DMSO 99.8MIN. (4mL).Faint yellow gluey liquid, with behind the saturated ETHYLE ACETATE salify of hydrogenchloride .mp 145-149 ℃ of .HRMS:m/z calcd for of white solid 0.08g (0.19mmol, 18.2%) C
21H
36N
6O [M+1]
+389.3029Found:389.3007;
1H-NMR (400MHz, CD
3OD): 1.02 (t, 6H); 1.07-1.15 (m, 2H); 1.25-1.36 (m, 3H); 1.51-1.59 (m, 2H); 1.62 (t, 6H); 1.73-1.81 (m, 4H); 1.92 (d, 2H); 3.43-3.47 (m, 2H); 3.64-3.72 (m, 2H); 4.24-4.27 (m, 1H); 4.74-4.80 (m, 1H); 8.51 (s, 1H)
(9) 2-(6-(cyclohexyl methylamine base)-9-sec.-propyl-9H-purine-2-amido)-3-methyl isophthalic acid-butanols (10g)
The same 10a of method.Compound (9,0.6g, 2.1mmol), the L-valerian ammonia alcohol (1.5mL, 13.4mmol), diisopropylethylamine (3.4mL, 20.6mmol), DMSO 99.8MIN. (6mL).Faint yellow gluey liquid, with behind the saturated ETHYLE ACETATE salify of hydrogenchloride 75-79 ℃ of .HRMS:m/z calcd of off-white color solid 0.15g (0.3mmol.17.6%) .mp for C
20H
34N
6O [M+1]
+375.2872Found:375.2884;
1H-NMR (400MHz, CD
3OD): 1.03-1.07 (m, 6H); 1.13 (d, 2H); 1.24-1.35 (m, 3H); 1.58-1.61 (dd, 6H); 1.72-1.81 (m, 4H); 1.89 (d, 2H); 2.07 (t, 1H); 3.41 (s, 2H); 3.75 (d, 2H); 4.02 (s, 1H); 4.67-4.73 (m, 1H); 8.04 (s, 1H)
(10) 2-(6-(cyclohexyl methylamine base)-9-sec.-propyl-9H-purine-2-amido) propane-1-alcohol (10h)
The same 10a of method.Compound (9,0.6g, 2.1mmol), the L-aminopropanol (1.0g, 13.4mmol), diisopropylethylamine (3.4mL, 20.6mmol), DMSO 99.8MIN. (8mL).Faint yellow gluey liquid, with behind the saturated ETHYLE ACETATE salify of hydrogenchloride .mp 184-188 ℃ of .HRMS:m/z calcd for of white solid 0.55g (1.4mmol, 70.5%) C
18H
30N
6O [M+1]
+347.2559Found:347.2556;
1H-NMR (400MHz, CD
3OD): 1.09-1.17 (m, 2H); 1.24-1.30 (m, 3H); 1.34 (d, 3H); 1.67 (d, 6H); 1.74 (d, 2H); 1.81 (d, 2H); 1.95 (d, 2H); 3.52 (d, 2H); 3.63-3.74 (m, 2H); 4.20-4.24 (m, 1H); 4.84-4.90 (m, 1H); 9.00 (s, 1H)
(11) 2-(6-(cyclohexyl methylamine base)-9-sec.-propyl-9H-purine-2-amido) propionic acid (10i)
The same 10c of method.Compound (9,0.6g, 2.1mmol), the L-L-Ala (3.7g, 41.2mmol), DBU (6.3mL, 41.2mmol), N-Methyl pyrrolidone (4mL)..mp 84-90 ℃ of .HRMS:m/z calcd for of off-white color solid 0.21g (0.6mmol, 28.4%) C
18H
28N
6O
2[M+1]
+361.2352Found:361.2354;
1H-NMR (400MHz, CD
3OD): 0.98-1.07 (m, 2H); 1.19-1.33 (m, 3H); 1.51 (d, 3H); 1.55-1.57 (dd, 6H); 1.69 (d, 2H); 1.77 (d, 2H); 1.85 (d, 2H); 3.38 (s, 2H); 4.43-4.48 (m, 1H); 4.61-4.68 (m, 1H); 7.82 (s, 1H)
Embodiment 4, target compound suppress the preliminary activity experiment (In vitro) of cell cycle protein dependent kinase
1) material: CDK1/cyclin B Kinase (CDK1/cyclin B kinases); Kinase-Glo Plus reagent (Kinase-
Plus reagent); ATP (Triphosaden);
Substrate (substrate): Histone H derived peptide (Histone H derived peptide, Histidine H derived peptide): H09-19T;
Assay Buffer:25mM HEPES (4-HEPES), 10mM MgCl
2, 0.01%Triton X-100,100 μ g/mL BSA, 2.5mM DTT (WR 34678), pH7.4.
Roscovitine: the cell cycle protein dependent kinase inhibitor series antineoplastic medicament, just carrying out the clinical II phase and studying at present.
2) method: the solution that compound is mixed with 10 μ g/mL.The every hole of experimental port adds 1 μ L to measure concentration is the testing compound of 10 μ M in 384 orifice plates, blank well (ZPE) and negative control hole (HPE) adding 1 μ L 10%DMSO solution.The every hole of testing compound experimental port and ZPE adds 4 μ L, 2.5 * CDK1/cyclin B kinases then, adds 4 μ L assaybuffer in the HPE hole.Every hole adds 5 μ L, 2 * ATP-substrate mixtures (ATP and substrate mixed solution) behind the mixed solution mixing, and the mixed solution mixing was hatched 1 hour under 30 ℃ of conditions.Every hole adds 10 μ L Kinase Glo Plus reagent, hatches 20min under 27 ℃ of conditions of mixed solution mixing.On EnVision, read luminous intensity at last, calculate inhibiting rate.Experimental result is seen table 4, table 5.
The external enzyme experimental result that presses down of table 4. target compound 4a-4q
The external enzyme experimental result that presses down of table 5. target compound 10a-10i
Find through CDK1/cyclin B kinases tentatively being suppressed activity experiment; Compound 4g, 4j, 4l, 4m, 4q, 10a are superior to positive control drug Roscovitine in the inhibition activity of 10 μ M concentration levels, and compound 4e, 4i, 4o, 10g and 10h are more approaching with the inhibition specific activity of Roscovitine on 10 μ M concentration levels simultaneously.
Embodiment 5, target compound suppress the activity test (In vitro) of cell proliferation
Target compound is carried out the activity experiment of vitro inhibition cancer cell multiplication, and the result sees table 6, table 7.
1) material: MD-MBA-231 cell strain, the blue MTT of tetramethyl-azo azoles, 10% foetal calf serum, 96 orifice plates.
2) method:
Cell cultures: the MD-MBA-231 tumor cell line all adopts conventional the cultivation.All use the logarithmic phase cell during experiment.
The cell growth detects (mtt assay): the MD-MBA-231 cell suspension all is adjusted to 5 * 10
4/ mL is inoculated in 96 orifice plates (100 μ L/ hole) respectively, 5000 cells/well.Behind the bed board 4h; Add the substratum that 100 μ L contain the different concns compound in every hole; Make that the compound final concentration is respectively in the hole: 100,50,25,12.5,6.25 μ g/mL, each concentration is established four multiple holes, makes blank well when not adding the hole reading of cell; Add the hole that cell do not add compound and make negative control hole, Roscovitine makes the compound positive control.In 37 ℃, 5%CO
2In hatch 48h, every hole adds the MTT staining fluid of 10 μ L0.5%, after continuing to hatch 4h, 2500rpm, centrifugal 12min abandons substratum in the plate hole then, adds DMSO solution, 100 μ L/ holes.Measure the absorbancy OD value in every hole on the ELIASA in the 570nm place, inhibitory rate of cell growth is calculated as follows:
The antiproliferative experimental result of table 6. target compound 4a-4q
aNumerical value is the MV of three tests in the table, the numeric representation standard deviation after " ± ".
The antiproliferative experimental result of table 7. target compound 10a-10i
aNumerical value is the MV of three tests in the table, the numeric representation standard deviation after " ± ".
Last table test data shows that compound 4a, 4e, 4g, 4h, 4i, 4j, 4k, 4l, 4m, 4o, 4p, 4q, 10a, 10f, 10g and 10h will get well MD-MBA-231 cell inhibitory effect specific activity positive control Roscovitine external.
Claims (9)
1.2-amino-6-aminomethyl purine compound or its pharmacy acceptable salt, steric isomer, solvate or prodrug have the structure shown in the formula I:
Wherein,
R1 is an aryl, heteroaryl, and assorted alkyl, naphthenic base, optional by one or more following groups replacements: hydroxyl, halogen, nitro, itrile group, carboxyl, alkyl, alkoxyl group, sulfoamido or methylsulfonic acid base;
R2 is an aryl, benzyl, and alkyl, heteroaryl, optional by one or more following groups replacements: hydroxyl, halogen, nitro, itrile group, carboxyl, alkyl, alkoxyl group, sulfoamido or methylsulfonic acid base;
R3 is hydrogen, carboxyl or hydroxymethyl;
R4 is hydrogen, methyl, ethyl, sec.-propyl, cyclopropyl or cyclopentyl;
Described aryl is meant the aromatic carbocyclic group, and aromatic ring contains 6-10 carbon atom;
Described heteroaryl is an aromatic heterocycle, is monocycle or bicyclic radicals; Comprise thienyl, furyl, pyrryl, pyridyl, pyrazinyl, thiazolyl, pyrimidyl, quinolyl, tetrazole base, benzothiazolyl, benzofuryl or indyl;
That described assorted alkyl refers to is saturated or unsaturated, carbon atoms and at least one heteroatomic chain, and wherein any heteroatoms is non-conterminous; Contain 2-15 carbon atom in the assorted alkyl, preferably contain 2-10 atom; Assorted alkyl is straight or branched, replacement or unsubstituted;
Described naphthenic base is replacement or unsubstituted, saturated or undersaturated cyclic group, and it contains carbon atom and/or one or more heteroatoms; This ring is monocycle or condensed ring, the ring system of bridged ring or volution; Monocycle has 3-9 atom, preferably has 4-7 atom, and many rings contain 7-17 atom, preferably contain 7-13 atom;
Described alkyl is meant the chain of saturated carbon atom, preferably contains 1-8 atom; Alkyl is a straight or branched;
Described halogen comprises fluorine, chlorine, bromine or iodine.
2. compound as claimed in claim 1 is characterized in that R
1Be phenyl or cyclohexyl; R
2Be substituted-phenyl or hydroxyl substituted alkyl; R
3Be hydrogen, carboxyl or hydroxymethyl; R
4Be hydrogen or sec.-propyl.
3. according to claim 1 or claim 2 compound is characterized in that it being one of following compound:
N
6-benzyl-N
2-(4-bromo phenyl)-9H-purine-2,6-diamines (4a),
N
6-benzyl-N
2-(4-p-methoxy-phenyl)-9H-purine-2,6-diamines (4b),
N
6-benzyl-N
2-p-methylphenyl-9H-purine-2,6-diamines (4c),
N
6-benzyl-N
2-(3-methoxyphenyl)-9H-purine-2,6-diamines (4d),
4-((6-benzylamine-9H-purine-2)-amido) phenol (4e),
N
6-benzyl-N
2-(4-fluorophenyl)-9H-purine-2,6-diamines (4f),
4-((6-benzylamine-9H-purine-2)-amido) benzsulfamide (4g),
N
6-benzyl-N
2-phenyl-9H-purine-2,6-diamines (4h),
N
6-benzyl-N
2-(4-first sulfo group phenyl)-9H-purine-2,6-diamines (4i),
4-((6-cyclohexyl methylamine-9H-purine-2)-amido) benzsulfamide (4j),
N
6-cyclohexyl methyl-N
2-phenyl-9H-purine-2,6-diamines (4k),
4-(6-cyclohexyl methylamine)-9H-purine-2-amido) phenol (4l),
N
6-cyclohexyl methyl-N
2-(4-fluorophenyl)-9H-purine-2,6-diamines (4m),
N
6-cyclohexyl methyl-N
2-(4-tolyl)-9H-purine-2,6-diamines (4n),
N
6-cyclohexyl methyl-N
2-(4-p-methoxy-phenyl)-9H-purine-2,6-diamines (4o),
N
6-cyclohexyl methyl-N
2-(4-bromophenyl)-9H-purine-2,6-diamines (4p),
N
6-cyclohexyl methyl-N
2-(4-first sulfo group phenyl)-9H-purine-2,6-diamines (4q),
2-(6-(cyclohexyl methylamine base)-9-sec.-propyl-9H-purine-2-amido)-1-butanols (10a),
2-(6-(cyclohexyl methylamine base)-9-sec.-propyl-9H-purine-2-amido) ethanol (10b),
2-(6-(cyclohexyl methylamine base)-9-sec.-propyl-9H-purine-2-amido)-3-hydroxy-propionic acid (10c),
2-(6-(cyclohexyl methylamine base)-9-sec.-propyl-9H-purine-2-amido)-3-hydroxybutyric acid (10d),
2-(6-(cyclohexyl methylamine base)-9-sec.-propyl-9H-purine-2-is amino) propane-1,3-glycol (10e),
2-(6-(cyclohexyl methylamine base)-9-sec.-propyl-9H-purine-2-amido)-4-methylpentane-1-alcohol (10f),
2-(6-(cyclohexyl methylamine base)-9-sec.-propyl-9H-purine-2-amido)-3-methyl isophthalic acid-butanols (10g),
2-(6-(cyclohexyl methylamine base)-9-sec.-propyl-9H-purine-2-amido) propane-1-alcohol (10h) or
2-(6-(cyclohexyl methylamine base)-9-sec.-propyl-9H-purine-2-amido) propionic acid (10i).
4. the preparation method of claim 1 or 2 said compounds is characterized in that step is following:
With 2-amino-6-chloropurine is raw material, gets 2-amino-6-substituted purin with various substituted amine generation nucleophilic substitution reactions, then at HBF
4And NaNO
2Effect makes 2-fluoro-6-substituted purin through Ba Erci-Xi Man (Balz-Schiemann) reaction down, generates target compound 4a-4i with various substituted amine reactions more at last; Synthetic route one is following:
Wherein, R
1And R
2The same general structure I is said;
Described various substituted amine is by phenyl, heteroaryl, the assorted substituted amine of alkyl or cycloalkyl, and can have hydroxyl in the organic amine structure, halogen, nitro, itrile group, carboxyl, alkyl, alkoxyl group, sulfoamido or methylsulfonic acid base;
Reagent and condition in said synthesis route one reaction formula: a. propyl carbinol, triethylamine, 130 ℃ of backflows; B.HBF
4, NaNO
2, H
2O ,-15 ℃; C. trifluoroacetic acid (TFA), propyl carbinol, 130 ℃ or trifluoroacetic acid (TFA), trifluoroethanol (TFE), 85 ℃.
5. the preparation method of claim 1 or 2 said compounds is characterized in that step is following:
With 2, the 6-dichloropurine is a raw material, and obtains 2-chloro-6-substituted purin behind the various substituted amine generation nucleophilic substitution reactions, and then generates target compound 4j-4q with various substituted amine reactions; Synthetic route two is following:
Wherein, R
1And R
2The same general structure I is said;
Described various substituted amine is by phenyl, heteroaryl, the assorted substituted amine of alkyl or cycloalkyl, and can have hydroxyl in the organic amine structure, halogen, nitro, itrile group, carboxyl, alkyl, alkoxyl group, sulfoamido or methylsulfonic acid base;
Reagent and condition in said synthesis route two reaction formula: d. propyl carbinol, triethylamine, 130 ℃ of backflows; E. trifluoroacetic acid, propyl carbinol, 130 ℃ or trifluoroacetic acid, trifluoroethanol, 85 ℃.
6. the preparation method of claim 1 or 2 said compounds is characterized in that step is following:
With 2-fluoro-6-chloropurine is raw material, with various substituted amine generation nucleophilic substitution reactions, obtains 2-fluoro-6 substituted purins, then with the 9-H alkylation, last obtains target compound 10a-10i with each seed amino acid or amino alcohol reaction generation; Synthetic route three is following:
Wherein, R
1, R
2, R
3And R
4The same general structure I;
Described various substituted amine is by phenyl, heteroaryl, the assorted substituted amine of alkyl or cycloalkyl, and can have hydroxyl in the organic amine structure, halogen, nitro, itrile group, carboxyl, alkyl, alkoxyl group, sulfoamido or methylsulfonic acid base;
Described each seed amino acid or amino alcohol are common amino acids and corresponding amino alcohols thereof such as Serine, Threonine, L-Ala, Xie Ansuan, leucine;
Reagent and condition in said synthesis route three reaction formula: f. propyl carbinol, triethylamine, 130 ℃ of backflows; G. haloalkane, K
2CO
3, DMSO 99.8MIN.; H. amino acid, N-Methyl pyrrolidone, 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU), 160 ℃ or amino alcohol, DMSO 99.8MIN., diisopropylethylamine, 120-160 ℃.
7. claim 1 and the 2 described compounds application in the medicine for preparing prevention or the treatment mammalian diseases relevant with the imbalance of cell cycle protein dependent kinase activity; Described related mammalian disease with the active unconventionality expression of cell cycle protein dependent kinase comprises cancer, neurodegenerative disease, malaria and mellitus.
8. one kind is suitable for the mammiferous pharmaceutical composition of orally give, comprises claim 1 and 2 described compounds and one or more pharmaceutically acceptable carriers or vehicle.
9. one kind is suitable for parenteral and gives mammiferous pharmaceutical composition, comprises claim 1 and 2 described compounds and one or more pharmaceutically acceptable carriers or vehicle.
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| CN114685507A (en) * | 2022-04-06 | 2022-07-01 | 山东大学 | Purine amine derivative CDK2 inhibitor and preparation method and application thereof |
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| WO2015039292A1 (en) * | 2013-09-18 | 2015-03-26 | 华安医学股份有限公司 | Ampk-activating compound, and use thereof |
| CN105153163A (en) * | 2015-08-24 | 2015-12-16 | 山东大学 | 2,9-disubstituted purine-6-amino hydroxamic acid HDAC (histone deacetylase) inhibitor, preparation method and application |
| CN105418616A (en) * | 2015-12-26 | 2016-03-23 | 山东大学 | JAK kinase inhibitor containing 4-aminopyrazole structure, preparation method and application thereof |
| CN105418616B (en) * | 2015-12-26 | 2018-01-12 | 山东大学 | A kind of JAK kinase inhibitors containing 4 amino-pyrazol structures and its preparation method and application |
| CN108371662A (en) * | 2018-02-06 | 2018-08-07 | 中国药科大学 | A kind of application of five-ring heterocycles miazines compound |
| CN108371662B (en) * | 2018-02-06 | 2023-03-03 | 中国药科大学 | Application of five-membered heterocyclic pyrimidine compound |
| CN114105887A (en) * | 2021-09-16 | 2022-03-01 | 沈阳药科大学 | Aminopyrimidine derivative and preparation method and application thereof |
| WO2023040537A1 (en) * | 2021-09-16 | 2023-03-23 | 沈阳药科大学 | Aminopyrimidine derivative, preparation method therefor and use thereof |
| CN114105887B (en) * | 2021-09-16 | 2023-12-01 | 沈阳药科大学 | Aminopyrimidine derivative and preparation method and application thereof |
| CN114685507A (en) * | 2022-04-06 | 2022-07-01 | 山东大学 | Purine amine derivative CDK2 inhibitor and preparation method and application thereof |
| CN114685507B (en) * | 2022-04-06 | 2024-01-12 | 山东大学 | Purine amine derivative CDK2 inhibitor and preparation method and application thereof |
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