CN102190638A - Biaryl alcohol diamine compound, its pharmaceutical composition, preparation method and application - Google Patents
Biaryl alcohol diamine compound, its pharmaceutical composition, preparation method and application Download PDFInfo
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- CN102190638A CN102190638A CN2010101256411A CN201010125641A CN102190638A CN 102190638 A CN102190638 A CN 102190638A CN 2010101256411 A CN2010101256411 A CN 2010101256411A CN 201010125641 A CN201010125641 A CN 201010125641A CN 102190638 A CN102190638 A CN 102190638A
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- 0 CC(C)C[N+]CC(C(Cc1ccc(-c2cc(C#N)ccc2)c(O*c(cc2)ccc2OC)c1)NC(OC1COCC1)=O)O Chemical compound CC(C)C[N+]CC(C(Cc1ccc(-c2cc(C#N)ccc2)c(O*c(cc2)ccc2OC)c1)NC(OC1COCC1)=O)O 0.000 description 1
- FRTYDUKFCSIDKE-UHFFFAOYSA-O CC(C)C[NH2+]CC(C(Cc1ccc(-c(cc2)ccc2N2CCOCC2)c(OSc(cc2)ccc2N)c1)NC(OC1COCC1)=O)O Chemical compound CC(C)C[NH2+]CC(C(Cc1ccc(-c(cc2)ccc2N2CCOCC2)c(OSc(cc2)ccc2N)c1)NC(OC1COCC1)=O)O FRTYDUKFCSIDKE-UHFFFAOYSA-O 0.000 description 1
- HVSRXRMYGFSJST-UHFFFAOYSA-O CC(C)C[NH2+]CC(C(Cc1ccc(-c2cccc(C(OC)=O)c2)c(OSc(cc2)ccc2OC)c1)NC(OC1COCC1)=O)O Chemical compound CC(C)C[NH2+]CC(C(Cc1ccc(-c2cccc(C(OC)=O)c2)c(OSc(cc2)ccc2OC)c1)NC(OC1COCC1)=O)O HVSRXRMYGFSJST-UHFFFAOYSA-O 0.000 description 1
- IVZOHAJUZGYHOH-UHFFFAOYSA-O CC(C[NH2+]CC(C(Cc(cc1)ccc1-c(cc1)ccc1C(C)=O)NC(OC1COCC1)=O)O)C[OH+][Os]c(cc1)ccc1OC Chemical compound CC(C[NH2+]CC(C(Cc(cc1)ccc1-c(cc1)ccc1C(C)=O)NC(OC1COCC1)=O)O)C[OH+][Os]c(cc1)ccc1OC IVZOHAJUZGYHOH-UHFFFAOYSA-O 0.000 description 1
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Abstract
The invention relates to a novel biaryl alcohol diamine compound represented by formula (I), a pharmaceutical composition containing the compound, a preparation method of the compound, and an application of the compound and its composition as a human immunodeficiency virus (HIV) protease inhibitor, especially an application of the compound and its composition in preparation of medicaments for treating acquired immune deficiency syndrome (AIDs).
Description
Technical field
The present invention relates to a kind of novel dibenzyl hydro diamine compounds, the pharmaceutical composition that comprises this compound, its preparation method and application.Particularly, the present invention relates to a kind of is skeleton with the dibenzyl hydro diamine, and the preparation method of synthetic novel cpd, the pharmaceutical composition that comprises this compounds, this compounds and this compounds are as the application of hiv protease inhibitor by designing different substituting groups.
Background technology
Acquired immune deficiency syndrome (AIDS) (acquired immunodeficiency syndrome, AIDS) be by human immunodeficiency virus (human immunodeficiency virus, HIV) infection causes human immunologic function's defective, and is easy to the clinical syndrome of generator opportunistic infections and tumour.Since the U.S. in 1981 reported the first acquired immune deficiency syndrome (AIDS) case, the scientist of countries in the world just endeavoured the research with anti-AIDS drug.Along with people to the going deep into of aspect researchs such as HIV virusology and molecular biology, hiv protease is confirmed as one of important target of antiviral design.The activity that suppresses hiv protease in vivo can be restrained virus replication.People have prepared a large amount of hiv protease inhibitor at present.These hiv protease inhibitor and reverse transcriptase inhibitors, viral fusion inhibitor can stop duplicating of virus together to a certain extent, improve acquired immune deficiency syndrome (AIDS) patient's quality of life, and patient's mortality ratio also obviously descends.Yet these proteinase inhibitor of life-time service produce obvious toxic and side effects and resistance, and therefore the research and development of new hiv protease inhibitor are imperative.
1998, people such as Salituro reported the Virahol diamine compounds that a class is novel, had good hiv protease in conjunction with activity.C2 symmetry according to the hiv protease crystalline structure, the inventor selects different substituting groups, design, synthesized the new alcamine compound of a class, found novel structure, the active well hiv protease inhibitor of in-vitro screening, hope can develop into easy, the active higher good medicine that is used for the treatment of acquired immune deficiency syndrome (AIDS) of preparation.
Summary of the invention
The present inventor organically combines the skeleton of fragment dibenzyl common in the medicine with the hydro diamine that is used as the hiv protease inhibitor, has obtained the new dibenzyl hydro diamine compounds of a class.This compounds can suppress hiv protease effectively, and after further optimization and screening, can research and develop becomes easy, the active higher medicine that is used for treating AIDS of preparation.
Therefore, one of purpose of the present invention provides a kind of novel dibenzyl hydro diamine compounds or its physiologically acceptable salt as the hiv protease inhibitor.
Another object of the present invention provides a kind of method for preparing above-mentioned novel dibenzyl hydro diamine compounds.
Another purpose of the present invention provides above-mentioned novel dibenzyl hydro diamine compounds or its physiologically acceptable salt purposes as the hiv protease inhibitor, and especially it is in the purposes that is used for preparing the medicine for the treatment of acquired immune deficiency syndrome (AIDS).
A further object of the present invention provides a kind of pharmaceutical composition as the hiv protease inhibitor.
An also purpose of the present invention provides a kind of method for the treatment of acquired immune deficiency syndrome (AIDS).
According to an aspect of the present invention, the invention provides the dibenzyl hydro diamine compounds shown in a kind of following general formula I or its physiologically acceptable salt:
Wherein,
R
1Be C1-C4 alkoxyl group, amino or nitro, and be preferably methoxyl group or amino;
R
2For replacing or the heterocyclic aromatic base of phenyl, replacement or the non-replacement of non-replacement or the condensed ring aromatic base of replacement or non-replacement, wherein, substituting group on the described phenyl is selected from one or more among C1-C4 alkoxyl group, C1-C4 alkylthio, C1-C4 alkyl and the heterocyclic radical that halogen, carboxyl, C1-C4 carbalkoxy, C1-C4 alkyl carbonyl, cyano group, hydroxyl, C1-C4 alkoxyl group, halogen replace, and the substituting group on heterocyclic aromatic base and the condensed ring aromatic base is selected from the C1-C4 alkyl;
Preferably, R
2For replace or the phenyl of non-replacement, thienyl, pyridyl, thiazolyl, pyrimidyl, pyrazolyl, oxazolyl, indyl, azaindolyl, naphthyl, quinolyl, isoquinolyl, benzimidazolyl-, benzothiazolyl, benzoxazolyl or
Deng, wherein, the substituting group on the described phenyl be selected from F, C1, carboxyl, C1-C2 carbalkoxy, C1-C2 alkyl carbonyl, cyano group, hydroxyl, C1-C2 alkoxyl group ,-OCF
3, C1-C2 alkylthio, C1-C2 alkyl and
Among one or more.
Be defined as follows in the present invention, C1-C4 carbalkoxy, C1-C4 alkyl carbonyl and C1-C4 alkoxyl group etc., C1-C4 wherein are that the carbonatoms in the expression alkyl can be 1-4.
Dibenzyl hydro diamine compounds of the present invention most preferably is selected among the following dibenzyl hydro diamine compounds:
The physiologically acceptable salt of dibenzyl hydro diamine compounds of the present invention prepares by this compound being dissolved in reacting in the corresponding sour saturated alcoholic solution, for example: dibenzyl hydro diamine compounds of the present invention is dissolved in the saturated methanol solution of HCl, stirring at room 10 minutes, with the solvent evaporate to dryness, promptly make corresponding hydrochloride.
According to a further aspect in the invention, the invention provides a kind of method for preparing dibenzyl hydro diamine compounds, described method prepares dibenzyl hydro diamine compounds by the reaction path shown in following reaction formula 1, comprises the steps:
Wherein, R is C1-C4 alkoxyl group or nitro, and the definition of R2 is same as described above,
Step (1): after the compound of general formula 7 is sloughed tertbutyloxycarbonyl, obtain the compound of general formula 8 again through the triphosgene linked reaction with (s-) 3-hydroxyl tetrahydrofuran;
Step (2): the compound of general formula 8 and boric acid R
2-B (OH)
2Through Suzuki (Suzuki) linked reaction, obtain the compound of general formula 9;
Step (3): the R in the compound of general formula 9 is-NO
2The time, through nitro-reduction reaction, obtain the compound of general formula 10 of the present invention.
In the above-mentioned steps (1), the compound of described general formula 7 is sloughed the reaction of tertbutyloxycarbonyl and is selected for those skilled in the art's routine with the reaction conditions of the triphosgene linked reaction of (s-) 3-hydroxyl tetrahydrofuran.Generally speaking, the reaction of sloughing tertbutyloxycarbonyl can be carried out under strong acid condition.The triphosgene linked reaction can at room temperature be carried out in the presence of alkali, and described alkali is known in those skilled in the art, for example can be diisopropyl ethyl amine, triethylamine, diethylamine etc.
In the above-mentioned steps (2), the compound of described general formula 8 and and the corresponding boronic acid compounds (R of final product
2-B (OH)
2) the reaction conditions of Suzuki (Suzuki) linked reaction be that those skilled in the art's routine is selected.Generally speaking, this reaction can carried out under heating condition in the presence of alkali and the metal palladium catalyst.Described alkali is known in those skilled in the art, for example can be Na
2CO
3, NaHCO
3, K
2CO
3, KF, K
3PO
4Deng.Described metal palladium catalyst is known in those skilled in the art, for example can be the catalysis of palladium carbon, four (triphenyl) phosphine palladium etc.Described heating condition is known in those skilled in the art, for example can be heated to backflow or use microwave heating.
In the above-mentioned steps (3) ,-NO
2The reaction conditions of reduction reaction be that those skilled in the art's routine is selected.Generally speaking, can under heating condition, carry out with reductive agent.Described reductive agent is known in those skilled in the art, for example can be hydrazine hydrate, tindichloride, reduced iron powder, H2 etc.
Among the above-mentioned preparation method of the present invention, the compound of general formula 7 can be synthetic by the ordinary method in this area, for example, but is not limited to, and with the preparation of the reaction path shown in the following reaction formula 2, comprises the steps:
(1) the L-phenylalanine is made compound 1 through iodination reaction;
(2), make compound 2 with the tert-Butyl dicarbonate reaction again with after compound 1 and the methyl alcohol generation esterification;
(3) compound 2 and sodium chloroacetate reaction are made compound 3;
(4) reduction of compound 3 usefulness reductive agents is obtained compound 4;
(5) with compound 4 after elimination reaction, again with isobutylamine reaction, last and corresponding nitrobenzene sulfonyl chloride or the reaction of C1-C4 alkoxy benzene SULPHURYL CHLORIDE obtain the compound shown in the general formula 7.
Wherein, R is C1-C4 alkoxyl group or nitro.
Among the preparation method of the compound of above-mentioned general formula 7, the reaction conditions of described reaction is those skilled in the art's routine and selects.Wherein, the reductive agent described in the step (4) for example, but is not limited to sodium borohydride for well known to a person skilled in the art reductive agent.
According to the present invention, the present invention also is provided for preparing the intermediate of dibenzyl hydro diamine compounds of the present invention, i.e. hydro diamine compounds shown in the general formula 8.The physiologically acceptable salt of the hydro diamine compounds shown in the general formula 8 can be used the preparation method preparation identical with the physiologically acceptable salt of dibenzyl hydro diamine compounds of the present invention, for example, and with the HCl salify.
In accordance with a further aspect of the present invention, the present invention also provides a kind of pharmaceutical composition as the hiv protease inhibitor, and it contains hydro diamine compounds shown in the general formula I for the treatment of significant quantity and pharmaceutically acceptable carrier.
Above-mentioned pharmaceutically acceptable carrier is meant the pharmaceutical carrier of pharmaceutical field routine, for example: and thinner, as water etc.; Weighting agent is as starch, sucrose etc.; Tackiness agent is as derivatived cellulose, alginate, gelatin, polyvinylpyrrolidone; Wetting agent is as glycerine; Disintegrating agent is as agar, lime carbonate and sodium bicarbonate; Absorption enhancer is as quaternary ammonium compound; Tensio-active agent is as cetyl alcohol; Absorption carrier is as kaolin and soap clay; Lubricant is as talcum powder, calcium stearate and Magnesium Stearate and polyoxyethylene glycol etc.In addition, other assistant agent can also be added, as flavouring agent and sweeting agent etc. in composition.
Dibenzyl hydro diamine compounds of the present invention can be applied to the patient who needs this treatment in the form of the composition mode by oral, rectum or intestines external administration.Be used for when oral, can be made into conventional solid preparation,, or make liquid preparation, as water or oil-suspending agent, or other liquid preparation, as syrup etc. as tablet, pulvis, granula, capsule etc.; When being used for the intestines external administration, can be made into solution, water or oiliness suspension agent etc. that injection is used for.
Dibenzyl hydro diamine compounds of the present invention or its physiologically acceptable salt and according to hydro diamine compounds or its physiologically acceptable salt of general formula 8 of the present invention, through the active Bioexperiment of the inhibition of hiv protease is shown, have very strong hiv protease and suppress active, can be used as the hiv protease inhibitor and be used to prepare the medicine for the treatment of acquired immune deficiency syndrome (AIDS).
The present invention also provides a kind of method for the treatment of acquired immune deficiency syndrome (AIDS), it comprise to AIDS patient's Combined Preparation treatment significant quantity according to dibenzyl hydro diamine compounds of the present invention and/or its physiologically acceptable salt, and conventional reverse transcriptase inhibitors; Perhaps, to hydro diamine compounds and/or its physiologically acceptable salt according to general formula 8 of the present invention of AIDS patient's Combined Preparation treatment significant quantity, and conventional reverse transcriptase inhibitors.
Described reverse transcriptase inhibitors and consumption are that those skilled in the art's routine is selected.For example can use zidovudine, lamivudine and non-nucleoside reverse transcriptase inhibitor Yi Feiweilun as reverse transcriptase inhibitors.
Embodiment
The following examples are used to specifically describe the preparation of The compounds of this invention, with and as the biologic activity of hiv protease inhibitor, but the present invention is not limited to these embodiment.
Proton nmr spectra BrukerAMX-400 type, Gemini-300 type or AMX-600 type nuclear magnetic resonance analyser record, the unit of chemical shift δ is ppm.Specific rotation is measured by the automatic polarimeter of Perkin-Elmer241 type, and used microwave is the CEM-discovery microwave reactor.All reaction solvents all carry out purifying according to ordinary method.Column chromatography is that Qingdao Haiyang chemical industry subsidiary factory produces with silica gel (200-300 order).Thin-layer chromatography uses the efficient plate of GF254, for the Yantai chemical institute is produced.Preparation type thin layer chromatography board is by oneself preparation, and stationary phase adopts GF254 (HG/T2354-92) silica gel and Xylo-Mucine (800-1200) preparation, is respectively Qingdao Marine Chemical Co., Ltd. and China Medicine (Group) Shanghai Chemical Reagent Co., and produces.All solvents are analytical reagent, and agents useful for same is all available from Chemical Reagent Co., Ltd., Sinopharm Group.Adopt method colour developings such as iodine, Ultraluminescence.Removing organic solvent under reduced pressure carries out in Rotary Evaporators.
The preparation of the compound of embodiment 1 general formula 7
Step 1: the preparation of compound 1
40.2 gram L-phenylalanines are dissolved in the mixing solutions of the 220ml Glacial acetic acid and the 29ml vitriol oil, add 24.6 gram elemental iodines and 10.2 gram sodium iodates while stirring, reacting by heating liquid to 70 degree centigrade reaction 24 hours, add 2.0 gram sodium periodates, solution becomes orange, revolve and boil off Glacial acetic acid, resistates dilutes with 400ml water, use each washed twice of ether and methylene dichloride respectively, transfer to neutrality with sodium hydroxide, leach solid, get crude product (m=62 gram) after the drying, the Glacial acetic acid recrystallization gets 4-iodo-L-phenylalanine (being compound 1) (m=50 gram, productive rate: 71%).
1H?NMR(300MHz，DMSO-d6)δppm?3.03(br.S.，2H)3.88(br.S.，1H)7.06(d，J＝7.62Hz，2H)7.65(d，J＝7.92Hz，2H)。
Step 2: the preparation of compound 2
22 gram 4-iodo-L-phenylalanines (compound 1), be dissolved in the 100ml anhydrous methanol, ice-water bath drips the 11ml thionyl chloride, room temperature reaction spends the night, revolve and boil off solvent, be dissolved in 100ml tetrahydrofuran (THF)-methyl alcohol (4: 1) mixed solvent, add 13 gram sodium bicarbonates (2 equivalent), 18.5 gram tert-Butyl dicarbonates (1.1 equivalent), room temperature reaction spends the night, revolve and boil off solvent, add water 200ml and methylene dichloride 200ml, separate organic phase, anhydrous magnesium sulfate drying, (ethyl acetate: sherwood oil=1: 10 gets target compound compound 2 (m=32 gram, quantitative yield) to column chromatography by volume).
1H NMR (300MHz, the δ ppm 1.41 of chloroform-d) (s, 9H) 3.04 (br.S., 2H) 3.71 (s, 3H) 4.55 (br.S., 1H) 4.98 (br.S., and 1H) 6.87 (m, J=7.70Hz, 2H) 7.61 (m, J=7.98Hz, 2H).
Step 3: the preparation of compound 3
Preparation diisopropyl amido magnesium bromide
In the dry reaction bottle, add 2.04g magnesium chips (84mmol), inject 60mlTHF (doing) after fully changing nitrogen, be added dropwise to 8.2ml (76.4mmol) bromination of n-butane, backflow 1.5h reduces to room temperature, drips 11.8ml diisopropylamine (84mmol), 40 ℃ are stirred 2h, promptly make.
Preparation target compound compound 3
5.14g (12.7mmol) compound 2,1.8g (19.1mmol) Magnesium Chloride Anhydrous, 2.2g (19.1mmol) sodium chloroacetate are added round-bottomed flask, change nitrogen, add 20ml THF, stirring at room 3h, 0 ℃ of diisopropylamine magnesium bromide that (3h) dropping in three batches makes, drip 16.5ml concentrated hydrochloric acid and 75ml water again, stir 30min, separate organic phase, wash with saturated sodium bicarbonate solution, wash with saturated nacl aqueous solution again, anhydrous sodium sulfate drying filters evaporate to dryness, cross silicagel column (PE: EA=10: 1) get compound 3 (m=4.01g, productive rate: 74.6%).
1H NMR (300MHz, the δ ppm 1.40 of chloroform-d) (s, 9H) 2.92 (s, 1H) 3.06 (s, 1H) 4.10 (s, 1H) 4.17 (s, 1H) 4.63 (s, 1H) 4.98 (br.S., and 1H) 6.91 (m, J=8.25Hz, 2H) 7.64 (m, J=8.25Hz, 2H).
Step 4: the preparation of compound 4
2.4 gram (5.7mmol) compound 3 is dissolved in the 100ml dehydrated alcohol, is chilled to-78 degrees centigrade, adds 0.43 gram (2 equivalent) sodium borohydride in batches ,-78 degrees centigrade were reacted 6 hours, rose to room temperature, reacted 1 hour; Then, add sodium bisulfate cancellation reaction, revolve to steam and remove ethanol, ethyl acetate extraction, anhydrous magnesium sulfate drying boils off solvent, and ethyl alcohol recrystallization gets compound 4 (2.0 grams, productive rate: 82.8%).
1H NMR (300MHz, the δ ppm 1.21-1.43 of chloroform-d) (m, 9H) 2.91 (br.S., 3H) 3.61 (s, 2H) 3.82 (br.S., 2H) 4.53 (br.S., and 1H) 6.97 (m, J=8.53Hz, 2H) 7.63 (m, 2H).
Step 5: the preparation of compound 7
2.1 gram (4.96mmol) compound 4 is dissolved in the 100ml anhydrous methanol, add 1.37 gram (9.9mmol) Anhydrous potassium carbonates while stirring, room temperature reaction spends the night, add the dilute hydrochloric acid neutralization, the elimination solid concentrates, add entry 50ml and ethyl acetate 50ml, separate organic phase, anhydrous magnesium sulfate drying, evaporate to dryness get the crude product (m=2.05 gram) of compound 5.
The crude product of above-claimed cpd 5 is dissolved in the 60ml dehydrated alcohol, stirs adding 1ml (2 equivalent) isobutylamine down, 60 degrees centigrade were reacted 6 hours, drained crude product 2.65 grams that obtain compound 6;
The crude product of above-claimed cpd 6 is dissolved in the 20ml methylene dichloride, the aqueous solution 10ml that adds 0.62 gram sodium bicarbonate (1.5 equivalent), ice bath drips the 10ml solution of 1.075 grams (1.05 equivalent) to the anisole SULPHURYL CHLORIDE down, stirred overnight at room temperature, separate organic phase, anhydrous magnesium sulfate drying, column chromatography get compound 7-1 (R is a methoxyl group) (m=2.114 gram, three step overall yields 67.6%).
1H NMR (300MHz, δ ppm 0.81-0.95 (m, 7H) 1.35 (s, 9H) 1.83 (br.S., 1H) 3.02 (br.S. of chloroform-d), 8H) 3.72 (br.S., 2H) 3.88 (s, 5H) 4.65 (br., s., 1H) 6.91-7.08 (m, 4H) 7.63 (s, 2H) 7.68 (s, 2H)
Perhaps except replacing the anisole SULPHURYL CHLORIDE, with identical with the aforesaid method compound 7-2 (three step overall yields 72.3%) that obtains with p-nitrophenyl SULPHURYL CHLORIDE (1.05 equivalent).
1H NMR (300MHz, δ ppm 0.81-0.95 (m, 7H) 1.35 (s, 9H) 1.83 (br.S. of chloroform-d), 1H) 3.02 (br.S., 8H) 3.72 (br.S., 2H) 3.88 (s, 5H) 4.65 (br., s., 1H) 5.14 (br.S., 1H) 6.99 (d, J=8.25Hz, 2H) 7.63 (d, J=8.25Hz, 2H) 7.95 (m, J=8.80Hz, 2H) 8.38 (m, J=8.80Hz, 2H)
The preparation of the compound of embodiment 2 general formulas 8
(1) preparation of compound 8-1
Be dissolved in the 9ml dioxane 1.81 digest compound 7-1, add the 3ml concentrated hydrochloric acid, room temperature reaction spends the night, and the evaporate to dryness reaction solution is dissolved in the exsiccant methylene dichloride, makes dichloromethane solution.
0.463 the gram triphosgene is dissolved in anhydrous methylene chloride, adds 0.29ml (s-) 3-hydroxyl tetrahydrofuran ,-40 degrees centigrade were stirred 30 minutes, drip 2.0ml triethylamine (5 equivalent), stirring at room 10 minutes drips the dichloromethane solution that back makes, stirring at room 3 hours, react completely, add the shrend reaction of going out, separate organic phase, anhydrous magnesium sulfate drying, column chromatography gets compound 8-1 (m=1.69 gram, productive rate: 90.2%).
1H NMR (300MHz, δ ppm 0.89 (dd, J=14.44, the 6.74Hz of chloroform-d), 6H) 1.81 (br.S., 2H) 1.91 (br.S., 1H) 2.84 (s, 4H) 2.95 (br.S., 5H) 3.67 (s, 2H) 3.81 (br.S., 5H) 3.88 (s, 5H) 4.88 (br.S., 1H) 5.13 (br.S., 1H) 6.99 (d, J=8.80Hz, 4H) 7.62 (d, J=8.25Hz, 2H) 7.68 (d, J=8.53Hz, 2H).
(2) preparation of compound 8-2
Except replace compound 7-1 with compound 7-2 (2.6g), adopt and the similar method synthetic compound of synthetic compound 8-1 8-2 (m=2.33g, productive rate: 87.7%).
1H NMR (300MHz, δ ppm 0.88 (dd, J=9.21, the 6.74Hz of chloroform-d), 6H) 1.84 (s, 2H) 2.12 (br.S., 1H) 2.96 (dd, J=11.42,7.56Hz, 4H) 3.04-3.25 (m, 2H) 3.58-3.75 (m, 2H) 3.75-3.97 (m, 5H) 4.88 (br.S., 1H) 5.14 (br.S., 1H) 6.99 (d, J=8.25Hz, 2H) 7.63 (d, J=8.25Hz, 2H) 7.95 (m, J=8.80Hz, 2H) 8.38 (m, J=8.80Hz, 2H).
The preparation of embodiment 3 compound YAN-PI01
Compound 8-1 (65mg), 4-fluorobenzoic boric acid (1.2 equivalent), 10% palladium carbon catalyst and 2 equivalent salt of wormwood are dissolved in the mixed solvent of own nitrile-water 20ml (volume ratio 1: 1); under nitrogen protection; reaction refluxes and spends the night; stopped reaction; with dichloromethane extraction (20ml x 2 times), merge organic phase, use anhydrous magnesium sulfate drying; column chromatography gets compound YAN-PI01 (45mg, productive rate 70%).
1H NMR (300MHz, δ ppm 0.89 (dd, J=13.89, the 6.46Hz of chloroform-d), 6H) 1.77-1.98 (m, 2H) 2.07-2.18 (m, 1H) 2.71-3.05 (m, 6H) 3.05-3.21 (m, 2H) 3.63 (d, J=10.18Hz, 1H) 3.69-3.95 (m, 8H) 4.99 (d, J=7.15Hz, 1H) 5.13 (br.S., 1H) 6.94 (m, J=8.80Hz, 2H) 7.11 (t, J=8.66Hz, 2H) 7.29 (d, J=8.25Hz, 2H) 7.42-7.59 (m, 4H) 7.69 (m, J=8.80Hz, 2H)
The preparation of embodiment 4 compound YAN-PI02
Except using the 3-fluorobenzoic boric acid to replace the 4-fluorobenzoic boric acid, prepare compound YAN-PI02 with the method identical with embodiment 3.
1H NMR (300MHz, δ ppm 0.89 (dd, J=14.85, the 6.33Hz of chloroform-d), 6H) 1.83 (br.S., 1H) 1.96 (br.S., 1H) 2.10 (br.S., 1H) 2.81 (d, J=6.60Hz, 2H) 2.97 (d, J=14.30Hz, 5H) 3.66 (br.S., 1H) 3.70-3.97 (m, 8H) 4.94 (br.S., 1H) 5.07-5.20 (m, 1H) 6.89-7.10 (m, 3H) 7.27-7.47 (m, 5H) 7.51 (d, J=7.43Hz, 2H) 7.70 (d, J=8.53Hz, 2H)
The preparation of embodiment 5 compound YAN-PI03
Except using the 2-fluorobenzoic boric acid to replace the 4-fluorobenzoic boric acid, prepare compound YAN-PI03 with the method identical with embodiment 3.
1H NMR (300MHz, δ ppm 0.90 (dd, the J=15.13 of chloroform-d), 6.60Hz, 6H) 1.83 (br.S., 1H) 1.96 (br.S., 1H) 2.10 (br.S., 1H) 2.72-2.88 (m, 1H) 2.88-3.06 (m, 3H) 3.12 (d, J=6.33Hz, 1H) 3.613.72 (m, 1H) 3.72-3.97 (m, 8H) 4.92 (d, J=9.35Hz, 1H) 5.14 (br.S., 1H) 6.96 (d, J=8.80Hz, 2H) 7.09-7.24 (m, 2H) 7.27-7.38 (m, 4H) 7.43 (t, J=7.29Hz, 1H) 7.49 (d, J=7.43Hz, 2H) 7.71 (d, J=8.25Hz, 2H)
The preparation of embodiment 6 compound YAN-PI04
Except using 3 thienylboronic acid to replace the 4-fluorobenzoic boric acid, prepare compound YAN-PI04 with the method identical with embodiment 3.
1H NMR (300MHz, δ ppm 0.89 (dd, J=16.23, the 6.60Hz of chloroform-d), 7H) 1.77 (s, 1H) 1.94 (br.S., 1H) 2.09 (br, 1H) 2.74 (s, 1H) 2.94 (br, 5H) 3.57-3.94 (m, 10H) 4.93 (br, 1H) 5.13 (br, 1H) 6.92 (m, J=8.80Hz, 2H) 7.22-7.32 (m, 4H) 7.35-7.48 (m, 3H) 7.55 (m, J=8.25Hz, 2H) 7.67 (d, J=8.80Hz, 2H)
The preparation of embodiment 7 compound YAN-PI05
Except using 4-chlorobenzene boric acid (1.2 equivalent) to replace the 4-fluorobenzoic boric acid, prepare compound YAN-PI05 with the method identical with embodiment 3.
1H NMR (300MHz, δ ppm 0.89 (dd, J=14.17, the 6.46Hz of chloroform-d), 7H) 1.77 (s, 1H) 1.94 (br.S., 1H) 2.09 (br.S., 1H) 2.80 (br.S., 1H) 3.01 (br.S., 5H) 3.58-3.95 (m, 11H) 4.82-5.01 (m, 1H) 5.13 (br.S., 1H) 6.94 (d, J=7.98Hz, 2H) 7.31 (d, J=7.43Hz, 2H) 7.36-7.44 (m, 2H) 7.44-7.58 (m, 4H) 7.70 (d, J=8.25Hz, 2H)
The preparation of embodiment 8 compound YAN-PI06
Except using 3-methoxycarbonyl phenylo boric acid to replace the 4-fluorobenzoic boric acid, prepare compound YAN-PI06 with the method identical with embodiment 3.
1H NMR (300MHz, δ ppm 0.89 (dd, J=14.58,6.60Hz, 7H) 1.77 (s of chloroform-d), 1H) 1.94 (br, 1H) 2.09 (br.S., 1H) 2.80 (br, 1H) 2.80 (m, 1H) 2.96 (br, 5H) 3.59-3.91 (m, 11H) 3.95 (s, 3H) 4.97 (br.S., 1H) 5.11 (br.S., 1H) 6.94 (d, J=8.80Hz, 2H) 7.33 (d, J=8.25Hz, 2H) 7.45-7.63 (m, 3H) 7.70 (d, J=8.80Hz, 2H) 8.01 (d, J=7.70Hz, 1H) 8.27 (s, 1H)
The preparation of embodiment 9 compound YAN-PI07
Except using 4-acetylbenzene boric acid to replace the 4-fluorobenzoic boric acid, prepare compound YAN-PI07 with the method identical with embodiment 3.
1H NMR (300MHz, δ ppm 0.89 (dd, the J=12.65 of chloroform-d), 6.60Hz, 6H) 1.75 (s, 2H) 1.81 (br.S., 1H) 1.90 (br.S., 1H) 2.09 (br.S., 1H) 2.83 (d, J=6.88Hz, 1H) 2.93 (d, J=8.25Hz, 2H) 3.00-3.24 (m, 3H) 3.64 (s, 1H) 3.68-4.03 (m, 9H) 5.02 (br.S., 1H) 5.12 (br.S., 1H) 6.96 (m, J=8.53Hz, 2H) 7.31-7.43 (m, 3H) 7.52 (d, J=7.70Hz, 2H) 7.71 (m, J=8.80Hz, 2H) 7.86 (d, J=7.98Hz, 1H) 8.57 (d, J=4.95Hz, 1H)
The preparation of embodiment 10 compound YAN-PI08
Except using 3-methyl-4-methoxyphenylboronic acid to replace the 4-fluoroboric acid, prepare compound YAN-PI08 with the method identical with embodiment 3.
1H NMR (300MHz, chloroform d) δ ppm 0.89 (dd, J=15.13,6.60Hz, 7H) 1.80 (br.S., 1H) 1.93 (br.S., 1H) 2.09 (br.S., 1H) 2.52 (s, 3H) 2.71-2.87 (m, 1H) 2.87-3.21 (m, 5H) 3.67 (s, 1H) 3.71-3.93 (m, 10H) 4.95 (d, J=9.90Hz, 1H) 5.13 (br.S., 1H) 6.93 (m, J=8.80Hz, 2H) 7.26-7.35 (m, 4H) 7.51 (d, J=7.98Hz, 4H) 7.69 (m, J=8.80Hz, 2H)
The preparation of embodiment 11 compound YAN-PI09
Except using 3-pyridine boric acid to replace 4-fluoroboric acid and Potassium monofluoride (3 equivalent) to replace the salt of wormwood, prepare compound YAN-PI09 with the method identical with embodiment 3.
1H NMR (300MHz, δ ppm 0.89 (dd, the J=14.30 of chloroform-d), 6.60Hz, 7H) 1.75-1.88 (m, 1H) 1.95 (br.S., 1H) 2.02-2.16 (m, 1H) 2.71-2.87 (m, 1H) 2.87-3.05 (m, 4H) 3.09 (br.S., 2H) 3.65 (s, 1H) 3.69-3.95 (m, 10H) 4.95 (d, J=8.53Hz, 1H) 5.13 (br.S., 1H) 6.95 (m, J=8.80Hz, 2H) 7.26-7.36 (m, 4H) 7.50 (d, J=8.25Hz, 2H) 7.58 (m, J=8.53Hz, 2H) 7.70 (d, J=9.08Hz, 2H)
The preparation of embodiment 12 compound YAN-PI10
Except using 4-methylthio phenyl boric acid to replace the 4-fluoroboric acid, prepare compound YAN-PI10 with the method identical with embodiment 3.
1H NMR (300MHz, δ ppm 0.89 (dd, J=15.13, the 6.60Hz of chloroform-d), 7H) 1.75-2.15 (m, 3H) 2.52 (s, 3H) 2.71-2.87 (m, 1H) 2.87-3.19 (m, 5H) 3.58-3.70 (m, 1H) 3.70-3.95 (m, 9H) 4.88-5.00 (m, 1H) 5.14 (br.S., 1H) 6.89-7.00 (m, 2H) 7.27-7.36 (m, 4H) 7.51 (d, J=7.98Hz, 4H) 7.69 (d, J=8.80Hz, 2H)
The preparation of embodiment 13 compound YAN-PI11
Except using 4-trifluoromethoxy phenylo boric acid to replace the 4-fluoroboric acid, prepare compound YAN-PI11 with the method identical with embodiment 3.
1H NMR (300MHz, δ ppm 0.89 (dd, J=14.30, the 6.60Hz of chloroform-d), 6H) 2.80 (s, 1H) 2.86-3.05 (m, 4H) 3.09 (br.S., 2H) 3.65 (s, 1H) 3.69-3.95 (m, 10H) 6.95 (m, J=8.80Hz, 2H) 7.26-7.35 (m, 4H) 7.50 (d, J=8.25Hz, 2H) 7.58 (m, J=8.53Hz, 2H) 7.70 (d, J=9.08Hz, 2H)
The preparation of embodiment 14 compound YAN-PI12
Except using the 3-cyanophenylboronic acid to replace the 4-fluoroboric acid, prepare compound YAN-PI12 with the method identical with embodiment 3.
1H NMR (300MHz, δ ppm 0.89 (dd, the J=12.10 of chloroform-d), 6.60Hz, 7H) 1.74-2.00 (m, 2H) 2.00-2.20 (m, 1H) 2.77-2.85 (m, 1H) 2.87-3.15 (m, 5H) 3.53-3.65 (m, 1H) 3.65-3.81 (m, 3H) 3.81-3.95 (m, 7H) 5.00 (d, J=9.08Hz, 1H) 5.11 (br.S., 1H) 6.96 (m, J=9.08Hz, 2H) 7.34 (m, J=8.25Hz, 2H) 7.49 (m, J=8.25Hz, 2H) 7.54 (d, J=7.70Hz, 1H) 7.57-7.64 (m, 1H) 7.71 (m, J=8.80Hz, 2H) 7.79 (d, J=7.98Hz, 1H) 7.84 (s, 1H)
The preparation of embodiment 15 compound YAN-PI13
Except using 3-hydroxybenzene boric acid to replace the 4-fluoroboric acid, prepare compound YAN-PI13 with the method identical with embodiment 3.
1H NMR (300MHz, δ ppm 0.87 (dd, the J=12.65 of chloroform-d), 6.60Hz, 6H) 1.74-1.95 (m, 2H) 2.06 (d, J=6.33Hz, 2H) 2.70-2.86 (m, 1H) 2.86-3.21 (m, 4H) 3.54-3.67 (m, 1H) 3.67-4.02 (m, 9H) 5.11 (br.S., 1H) 5.20 (d, J=8.80Hz, 1H) 6.77-6.84 (m, 1H) 6.87-6.99 (m, 3H) 7.02 (br.S., 1H) 7.08 (d, J=7.70Hz, 1H) 7.21-7.33 (m, 3H) 7.41-7.54 (m, 2H) 7.63-7.77 (m, 2H)
The preparation of embodiment 16 compound YAN-PI14
Except using 4-carboxyl phenylo boric acid to replace the 4-fluoroboric acid, prepare compound YAN-PI14 with the method identical with embodiment 3.
1H NMR (300MHz, δ ppm 0.89 (dd, the J=14.17 of chloroform-d), 6.46Hz, 7H) 2.80 (br.S., 1H) 3.01 (br.S., 5H) 3.58-3.95 (m, 11H) 4.82-5.01 (m, 1H) 5.13 (br.S., 1H) 6.94 (d, J=7.98Hz, 2H) 7.31 (d, J=7.43Hz, 2H) 7.36-7.44 (m, 2H) 7.44-7.58 (m, 4H) 7.70 (d, J=8.25Hz, 2H)
The preparation of embodiment 17 compound YAN-PI15
Except using 4-pyridine boric acid to replace the 3-pyridine boric acid, prepare compound YAN-PI15 with the method identical with embodiment 11.
1H NMR (300MHz, δ ppm 0.78-0.96 (m, 7H) 1.74-1.87 (m of chloroform-d), 1H) 1.94 (br.S., 1H) 1.99-2.19 (m, 2H) 2.81 (t, J=7.56Hz, 2H) 2.95 (br.S., 2H) 3.06 (d, J=19.53Hz, 3H) 3.53-3.68 (m, 2H) 3.75 (dd, J=10.59,4.26Hz, 3H) 3.84 (s, 6H) 4.94 (s, 1H) 5.11 (br.S., 1H) 6.96 (d, J=8.80Hz, 2H) 7.36 (d, J=7.98Hz, 2H) 7.50 (d, J=5.78Hz, 2H) 7.59 (d, J=8.25Hz, 2H) 7.71 (d, J=8.80Hz, 2H) 8.65 (d, J=5.50Hz, 2H)
The preparation of embodiment 18 compound YAN-PI16
Compound 8-2,3-pyridine boric acid (1.2 equivalent), tetrakis triphenylphosphine palladium (5%mol) are dissolved in toluene-alcohol mixed solvent, add 2 normal solution of potassium carbonate, change nitrogen, 110 degrees centigrade in microwave, reacted completely in 20 minutes, dichloromethane extraction, anhydrous magnesium sulfate drying, column chromatography obtains intermediate.
Above-mentioned intermediate is dissolved in dehydrated alcohol, adds 10% palladium carbon catalyst, 85% hydrazine hydrate is an amount of, reflux 1～2 hour, and reaction finishes, and adds the acetone backflow and removes the residue hydrazine hydrate, revolves to boil off solvent, and column chromatography obtains compound YAN-PI16.
1H NMR (300MHz, δ ppm 0.89 (dd, the J=14.03 of chloroform-d), 6.60Hz, 7H) 1.75-1.88 (m, 1H) 1.95 (br.S., 1H) 2.02-2.16 (m, 1H) 2.97 (d, J=14.30Hz, 3H) 3.10 (br.S., 2H) 3.63 (d, J=13.75Hz, 1H) 3.76 (dd, J=10.73,4.40Hz, 5H) 4.15 (br.S., 2H) 4.99 (br.S., 1H) 5.13 (br.S., 1H) 6.65 (d, J=8.80Hz, 2H) 7.31-7.43 (m, 3H) 7.46-7.58 (m, 4H) 7.87 (dd, J=5.91,1.79Hz, 1H) 8.58 (d, J=4.13Hz, 1H) 8.82 (s, 1H)
The preparation of embodiment 19 compound YAN-PI17
Except using 4-pyridine boric acid to replace the 3-pyridine boric acid, prepare compound YAN-PI17 with the method identical with embodiment 18.
1H NMR (300MHz, δ ppm 0.70-0.97 (m, 6H) 1.77-1.90 (m, 1H) 1.94 (br.S. of chloroform-d), 1H) 2.02-2.20 (m, 1H) 2.78 (dd, J=12.38,7.70Hz, 2H) 2.86-3.24 (m, 5H) 3.62 (br.S., 3H) 3.87 (br.S., 5H) 4.14 (br.S., 2H) 4.87-5.05 (m, 1H) 5.12 (br.S., 1H) 6.65 (d, J=8.25Hz, 2H) 7.36 (d, J=7.43Hz, 2H) 7.43-7.70 (m, 6H) 8.52-8.71 (m, 2H)
The preparation of embodiment 20 compound YAN-PI18
Except using phenylo boric acid to replace the 3-pyridine boric acid, prepare compound YAN-PI18 with the method identical with embodiment 18.
1H NMR (300MHz, δ ppm 0.89 (dd, J=14.99, the 6.74Hz of chloroform-d), 6H) 1.76-1.87 (m, 1H) 1.95 (br.S., 1H) 2.00-2.21 (m, 1H) 2.68-2.81 (m, 1H) 2.94 (d, J=13.48Hz, 3H) 3.08 (br.S., 2H) 3.64 (s, 1H) 3.78 (dd, J=10.45,4.68Hz, 3H) 3.88 (br.S., 3H) 4.10 (s, 2H) 6.62 (d, J=8.53Hz, 2H) 7.27-7.38 (m, 3H) 7.38-7.48 (m, 2H) 7.48-7.62 (m, 6H)
The preparation of embodiment 21 compound YAN-PI19
Except using the 3-cyanophenylboronic acid to replace the 3-pyridine boric acid, prepare compound YAN-PI19 with the method identical with embodiment 18.
1H NMR (300MHz, δ ppm 0.90 (dd, the J=13.75 of chloroform-d), 6.60Hz, 6H) 1.76-1.87 (m, 1H) 1.95 (br.S., 1H) 2.00-2.21 (m, 1H) 2.77 (dd, J=13.20,6.60Hz, 1H) 2.86-3.20 (m, 5H) 3.60 (d, J=10.73Hz, 2H) 3.67-3.97 (m, 6H) 4.17 (s, 2H) 4.97 (d, J=8.53Hz, 1H) 5.12 (br.S., 1H) 6.66 (d, J=8.80Hz, 2H) 7.34 (d, J=8.25Hz, 2H) 7.45-7.51 (m, 2H) 7.55 (d, J=8.53Hz, 3H) 7.58-7.65 (m, 1H) 7.80 (d, J=7.70Hz, and 1H) 7.84 (s, 1H)
The preparation of embodiment 22 compound YAN-PI20
Except using 1-ethyl pyrazoles [2,3-b] pyridine-5-boric acid to replace beyond the 3-pyridine boric acid, prepare compound YAN-PI20 with the method identical with embodiment 18.
1H NMR (300MHz, δ ppm 0.89 (dd, J=15.13, the 6.60Hz of chloroform-d), 6H) 1.51 (t, J=7.29Hz, 3H) 1.80 (br.S., 1H) 1.96 (br.S., 1H) 2.09 (br.S., 1H) 2.75 (dd, J=13.20,6.60Hz, 2H) 2.94 (d, J=13.75Hz, 3H) 3.00-3.25 (m, 2H) 3.60-3.71 (m, 1H) 3.78 (dd, J=10.59,4.54Hz, 3H) 3.89 (d, J=9.08Hz, 3H) 4.13 (br.S., 2H) 4.37 (q, J=7.15Hz, 2H) 4.99 (br.S., 1H) 5.14 (br.S., 1H) 6.50 (d, J=3.58Hz, 1H) 6.62 (d, J=8.53Hz, 2H) 7.27 (d, J=3.58Hz, 1H) 7.33 (d, J=8.25Hz, 2H) 7.53 (t, J=7.70Hz, 4H) 8.06 (d, J=1.93Hz, 1H) 8.53 (d, J=2.20Hz, 1H)
The preparation of embodiment 23 compound YAN-PI21
Except using the luxuriant and rich with fragrance quinoline phenylo boric acid of 4-to replace the 3-pyridine boric acid, prepare compound YAN-PI21 with the method identical with embodiment 18.
1H NMR (300MHz, δ ppm 0.89 (dd, J=15.13, the 6.60Hz of chloroform-d), 6H) 1.51 (t, J=7.29Hz, 3H) 1.80 (br.S., 1H) 1.96 (br.S., 1H) 2.09 (br.S., 1H) 2.75 (dd, J=13.20,6.60Hz, 2H) 2.94 (d, J=13.75Hz, 3H) 3.00-3.25 (m, 6H) 3.60-3.71 (m, 5H) 3.78 (dd, J=10.59,4.54Hz, 3H) 3.89 (d, J=9.08Hz, 3H) 4.13 (br.S., 2H) 4.37 (q, J=7.15Hz, 2H) 4.99 (br.S., 1H) 5.14 (br.S., 1H) 6.68 (m, 4H) 7.27 (d, J=7.66Hz, 2H) 7.41 (t, J=7.70Hz, 4H) 7.54 (d, J=7.76Hz, 2H)
EXPERIMENTAL EXAMPLE 1 dibenzyl hydro diamine compounds of the present invention is to the inhibition activity of hiv protease:
Institute's synthetic compound has at first been carried out external anti-HIV-1 proteolytic enzyme (HIV-PR) screening active ingredients.
Test philosophy: HIV-1 proteolytic enzyme can cut the fluorescent mark substrate in optimum reaction condition and reaction system, and fluorescence intensity reflects the activity of enzyme in the measurement of enzymatic reaction products.In reaction system, add the inhibitor that sample can be used for screening this enzyme.
Test material and method:
HIV-1PR: available from Invitrogen ,-85 ℃ of preservations.
Sample preparation: sample faces with before being dissolved in DMSO or distilled water is made into proper concn, 5 times of dilutions, each 5 extent of dilution.
Positive control drug: indinavir (indinavir), Ge Lansu company provides.
Substrate: Invitrogen company provides.
Testing method: add behind the diluted sample and contain in the reaction buffer of fluorescent mark substrate, and add genetically engineered target enzyme, under optimum reaction condition, hatch, measure fluorescent value with FLUO star Galaxy luminoscope.The DCO method is referring to Dong Biao, Zhang Tian, Tao Peizhen, the foundation [J] of high throughput fluorescence substrate HIV-1 proteolytic enzyme model, China's AIDS venereal disease, 2006,12[5], 402-405, whole disclosures of the document are incorporated this paper into by reference at this.
With the mathematical principle of Probit backspace data probability point, in Excel,, return on the Growth function with gained probability and drug dose then and calculate IC50 with Probit function calculation probability.
Dibenzyl hydro diamine compounds of the present invention is listed in the table 1 the active test result of the inhibition of hiv protease.
The active result of inhibition of table 1:HIV proteolytic enzyme
Test-results shows that compound of the present invention has stronger hiv protease and suppresses active.
Compound according to the present invention has good hiv protease inhibitor activity.Can be used to prepare the good medicine for the treatment of acquired immune deficiency syndrome (AIDS) according to compound of the present invention.
Claims (13)
1. dibenzyl hydro diamine compounds or its physiologically acceptable salt shown in following general formula I:
Wherein,
R
1Be C1-C4 alkoxyl group, amino or nitro;
R
2For replacing or the heterocyclic aromatic base of phenyl, replacement or the non-replacement of non-replacement or the condensed ring aromatic base of replacement or non-replacement, wherein, substituting group on the described phenyl is selected from one or more among C1-C4 alkoxyl group, C1-C4 alkylthio, C1-C4 alkyl and the heterocyclic radical that halogen, carboxyl, C1-C4 carbalkoxy, C1-C4 alkyl carbonyl, cyano group, hydroxyl, C1-C4 alkoxyl group, halogen replace, and the substituting group on heterocyclic aromatic base and the condensed ring aromatic base is selected from the C1-C4 alkyl.
2. dibenzyl hydro diamine compounds according to claim 1 or its physiologically acceptable salt, wherein, R
1Be methoxyl group or amino.
3. dibenzyl hydro diamine compounds according to claim 1 and 2 or its physiologically acceptable salt, wherein, R
2Be selected from replace or the phenyl of non-replacement, thienyl, pyridyl, pyrimidyl, thiazolyl, pyrazolyl, oxazolyl, indyl, azaindolyl, naphthyl, quinolyl, isoquinolyl, benzimidazolyl-, benzothiazolyl, benzoxazolyl and
In, wherein, the substituting group on the described phenyl be selected from F, Cl, carboxyl, C1-C2 carbalkoxy, C1-C2 alkyl carbonyl, cyano group, hydroxyl, C1-C2 alkoxyl group ,-OCF3, C1-C2 alkylthio, C1-C2 alkyl and
Among one or more.
4. dibenzyl hydro diamine compounds according to claim 1 or its physiologically acceptable salt, wherein, described dibenzyl hydro diamine compounds is one of following compounds:
5. hydro diamine compounds or its physiologically acceptable salt of general formula 8 expression below one kind:
Wherein, R is C1-C4 alkoxyl group or nitro.
6. method for preparing the described dibenzyl hydro diamine of claim 1 compounds, described method is undertaken by the reaction path shown in following reaction formula 1,
Wherein, R is C1-C4 alkoxyl group or nitro, and the definition of R2 is identical with the definition in the claim 1,
This method comprises the steps:
Step (1): after the compound of general formula 7 is sloughed tertbutyloxycarbonyl, obtain the compound of general formula 8 again through the triphosgene linked reaction with (s-) 3-hydroxyl tetrahydrofuran;
Step (2): the compound of general formula 8 and boric acid R
2-B (OH)
2Through the Suzuki linked reaction, obtain the compound of general formula 9;
Step (3): the R in the compound of general formula 9 is-NO
2The time, through nitro-reduction reaction, obtain the compound of general formula 10.
7. preparation method according to claim 6, the compound of wherein said general formula 7 prepares with the reaction path shown in the following reaction formula 2,
Wherein, R is C1-C4 alkoxyl group or nitro
Comprise the steps:
(1) the L-phenylalanine is made compound 1 through iodination reaction;
(2), make compound 2 with the tert-Butyl dicarbonate reaction again with after compound 1 and the methyl alcohol generation esterification;
(3) compound 2 and sodium chloroacetate reaction are made compound 3;
(4) reduction of compound 3 usefulness reductive agents is obtained compound 4;
(5) with compound 4 after elimination reaction, again with isobutylamine reaction, last and corresponding nitrobenzene sulfonyl chloride or the reaction of C1-C4 alkoxy benzene SULPHURYL CHLORIDE obtain the compound shown in the general formula 7.
8. pharmaceutical composition as the hiv protease inhibitor, its comprise the treatment significant quantity according to each described dibenzyl hydro diamine compounds or its physiologically acceptable salt and pharmaceutically acceptable carrier among the claim 1-4.
9. pharmaceutical composition as the hiv protease inhibitor, it comprises hydro diamine compounds according to claim 5 or its physiologically acceptable salt and the pharmaceutically acceptable carrier for the treatment of significant quantity.
10. according to each described dibenzyl hydro diamine compounds of claim 1-4 or its physiologically acceptable salt purposes in preparation hiv protease inhibitor.
11. the purposes in the medicine of preparation treatment acquired immune deficiency syndrome (AIDS) according to each described dibenzyl hydro diamine compounds of claim 1-4 or its physiologically acceptable salt.
12. hydro diamine compounds according to claim 5 or its physiologically acceptable salt purposes in the medicine of preparation treatment acquired immune deficiency syndrome (AIDS).
13. a method for the treatment of acquired immune deficiency syndrome (AIDS), it comprises to the dibenzyl hydro diamine compounds according to claim 1 of AIDS patient's Combined Preparation treatment significant quantity and/or its physiologically acceptable salt and conventional reverse transcriptase inhibitors; Perhaps, to hydro diamine compounds according to claim 5 and/or its physiologically acceptable salt of AIDS patient's Combined Preparation treatment significant quantity, and conventional reverse transcriptase inhibitors.
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| US20170253607A1 (en) * | 2014-09-11 | 2017-09-07 | Shionogi & Co., Ltd. | Long-acting hiv protease inhibitor |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1087347A (en) * | 1992-09-08 | 1994-06-01 | 沃泰克斯药物股份有限公司 | The new sulfonamide inhibitors of aspartyl protease |
| WO2005042772A1 (en) * | 2003-10-24 | 2005-05-12 | Gilead Sciences, Inc. | Methods and compositions for identifying therapeutic compounds |
| CN101448838A (en) * | 2006-03-29 | 2009-06-03 | 吉里德科学公司 | Process for preparation of HIV protease inhibitors |
-
2010
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1087347A (en) * | 1992-09-08 | 1994-06-01 | 沃泰克斯药物股份有限公司 | The new sulfonamide inhibitors of aspartyl protease |
| WO2005042772A1 (en) * | 2003-10-24 | 2005-05-12 | Gilead Sciences, Inc. | Methods and compositions for identifying therapeutic compounds |
| CN101448838A (en) * | 2006-03-29 | 2009-06-03 | 吉里德科学公司 | Process for preparation of HIV protease inhibitors |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20170253607A1 (en) * | 2014-09-11 | 2017-09-07 | Shionogi & Co., Ltd. | Long-acting hiv protease inhibitor |
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Application publication date: 20110921 |