CN102807514B - Substituted phenylenediamine derivative and preparation method and application thereof - Google Patents

Substituted phenylenediamine derivative and preparation method and application thereof Download PDF

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CN102807514B
CN102807514B CN201110149737.6A CN201110149737A CN102807514B CN 102807514 B CN102807514 B CN 102807514B CN 201110149737 A CN201110149737 A CN 201110149737A CN 102807514 B CN102807514 B CN 102807514B
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phenyl
compound
benzyloxy
methylsulfonyl
methylamino
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CN102807514A (en
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苏斌
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Abstract

The invention provides a substituted phenylenediamine derivative compound shown as a formula (I), a pharmaceutically-acceptable salt thereof and preparation methods thereof. The definition of each substituent is shown in the specifications. The compound provided by the invention has remarkable curative effects on cancers and a wide anti-tumor spectrum.

Description

Phenylenediamine derivative replaced and its production and use
Technical field
The invention belongs to medicinal chemistry art, more specifically to phenylenediamine derivative that a class replaces and its production and use.
Background technology
Epidemiology and all kinds of external and Research of Animal Model for Study show, the effect that NSAID (non-steroidal anti-inflammatory drug) (NSAIDs) has prophylaxis of tumours to generate and increase.These researchs are all based on a theory---the prostaglandin(PG) (PGE manufactured by cyclooxygenase (COX) 2) there is the effect promoting tumor propagation.NSAIDS can suppress the activity of COX, thus reduces PGE 2concentration, thus demonstrate anti-tumor activity.But a lot of evidence shows, the mechanism that NSAIDS also uses COX to have nothing to do is disinthibited the growth of tumour cell.
Nimesulide (Nimesulide) is a kind of NSAI drugs thing, and it belongs to Selective COX-2 inhibitor, and enters clinical application in 1985 in some Asia and European countries.Over closer year, a lot of research shows, nimesulide also has certain anti-tumor activity.Such as, Brueggemeier etc. describe about nimesulide derivative compound optionally regulates the expression of cell aromatizing enzyme in US Patent No. 7741520, thus suppress the breast cancer cell that hormone is relevant to increase.In addition, nimesulide can induce liver cancer and Increase Apoptosis of Lung Cancer Cells, the generation of the rat breast cancer that 2-amino-1-methyl-6-phenyl [4,5-b] pyridine (PhIP) also can be suppressed to induce.But, as the compound with anti-tumor activity, nimesulide and derivative anti-tumor activity lower, be difficult to use as clinical antitumor agents.
Summary of the invention
The invention provides a class new compound, overcome the low activity problem of existing compound, drastically increase the activity that inhibition tumor cell increases, such new compound anti tumor activity in vitro reaches 1nM50% tumour inhibiting rate, has exceeded the antitumor drug of a current clinical line.This compounds can suppress mammary cancer, colorectal carcinoma, central nerve neuroma, leukemia, melanoma, nonsmall-cell lung cancer, ovarian cancer, kidney, the growth of prostate cancer cell; And this compounds also can be applied to other and be similar to cell and to overrun the treatment of disease of propagation.Therefore, this type of new compound has more wide spectrum, more effective anticancer advantage.
The object of this invention is to provide a kind of phenylenediamine derivative of replacement.
Another object of the present invention there is provided the preparation method of said derivative.
3rd object of the present invention is to provide the medicinal use of said derivative.
Specifically, the invention provides a kind of such as formula the phenylenediamine derivative shown in (I), or its pharmacy acceptable salt:
Wherein, R 10, R 11, R 12, R 13and R 14be selected from hydrogen, the alkyl of alkyl or replacement, the alkoxyl group of alkoxyl group or replacement or halogen independently of one another, and specify R 10to R 14be asynchronously hydrogen; Preferably, be selected from hydrogen, the C1-C6 alkyl of C1-C6 alkyl or replacement, the C1-C6 alkoxyl group of C1-C6 alkoxyl group or replacement or halogen, and be asynchronously hydrogen; Here, (alkyl such as replaced or the alkoxyl group of replacement) of described replacement refers to by replacements such as halogen, nitro, hydroxyls;
Rb is selected from hydrogen, alkyl (be such as the alkyl of C1-C6, such as methyl, ethyl, propyl group, or sec.-propyl etc.), and the combination of alkane chain and vitamin H (Biotin);
X is selected from sulphur or carbon atom, and specifies, when X is sulphur, n equals 1 or 2; When X is carbon, n equals 1;
Rf is selected from alkyl, such as, be the alkyl of C1-C6, such as methyl, ethyl and propyl group; With
R 3be selected from naphthenic hydrocarbon (such as pentamethylene, hexanaphthene etc.), straight-chain paraffin (such as normal hexane etc.), monosubstituted phenyl, tri-substituted phenyl, heterocycle structure, and following structure,
Wherein Rc can be that single condensed ring merges, and two condensed ring merges, and any condensed ring merges;
And specify, formula (I) compound does not comprise following compounds:
Work as R 10and R 13be respectively methyl, R 11, R 12and R 14for hydrogen;
Or, R 10and R 13be respectively chlorine, R 11, R 12and R 14for hydrogen;
Or, R 10and R 14be respectively methyl, R 11, R 12and R 13for hydrogen;
Or, R 10for methyl, R 11, R 12, R 13and R 14for hydrogen;
Or, R 11for methyl, R 10, R 12, R 13and R 14for hydrogen;
Or, R 12for sec.-propyl, R 10, R 11, R 13and R 14for hydrogen;
Or, R 10, R 12and R 14be respectively methyl, R 11and R 13during for hydrogen; Meanwhile,
Rb is methyl;
X is sulphur, and n equals 2;
Rf is methyl; With
R 3for methyl, cyclohexyl, phenyl, 3-pyridyl, 4-pyridyl or methyl substituted pyridyl (picolinyl).
In formula provided by the invention (I) compound, preferably, wherein, R 10, R 11, R 12, R 13and R 14, wherein two be dialkoxy independently of one another, all the other are hydrogen; R 10, R 11, R 12, R 13and R 14, one of them is alkyl, another is alkoxyl group, all the other are hydrogen; R 10, R 11, R 12, R 13and R 14, wherein two independently of one another for for dialkyl group, all the other are hydrogen; R 10, R 11, R 12, R 13and R 14, wherein three be alkoxyl group independently of one another, all the other are hydrogen; R 10, R 11, R 12, R 13and R 14, wherein two be alkoxyl group independently of one another, another is alkyl, all the other are hydrogen; R 10, R 11, R 12, R 13and R 14, wherein two be alkyl independently of one another, another is alkoxyl group, all the other are hydrogen; R 10, R 11, R 12, R 13and R 14, wherein three be alkyl independently of one another, all the other are hydrogen; Or R 10, R 11, R 12, R 13and R 14, wherein two be halogen independently of one another, all the other are hydrogen;
More preferably, wherein, R 10, R 11, R 12, R 13and R 14, wherein two be methoxy or ethoxy (namely these two for dimethoxy, diethoxy or methoxyethoxy) independently of one another, all the other are hydrogen; R 10, R 11, R 12, R 13and R 14, one of them is methyl or ethyl, another is methoxy or ethoxy (namely these two is methyl methoxy base, methyl ethoxy, ethyl methoxyl group, and ethyl oxyethyl group), all the other are hydrogen; R 10, R 11, R 12, R 13and R 14, wherein two be methyl or ethyl (namely these two is dimethyl, diethyl, and the first and second bases) independently of one another, all the other are hydrogen; R 10, R 11, R 12, R 13and R 14, wherein three be methoxy or ethoxy (namely these three for trimethoxy, triethoxy, methoxy diethoxy and dimethoxy oxyethyl group) independently of one another, all the other are hydrogen; R 10, R 11, R 12, R 13and R 14, wherein two be methoxy or ethoxy independently of one another, for methyl or ethyl, (namely these three is methyl dimethoxy oxygen base, methyl methoxy base oxethyl for another, methyl diethoxy, ethyl dimethoxy, ethyl methoxyethoxy, and ethyl diethoxy), all the other are hydrogen; R 10, R 11, R 12, R 13and R 14, wherein two independent is separately methyl or ethyl, for methoxy or ethoxy, (namely these three is methoxyl group dimethyl, methoxy methyl ethyl for another, morpholine, oxyethyl group dimethyl, (ethoxymethyl) ethyl, and oxyethyl group diethyl), all the other are hydrogen; R 10, R 11, R 12, R 13and R 14, wherein three be methyl or ethyl (namely these three is trimethylammonium, methyl diethyl, dimethyl ethyl, triethyl) independently of one another, all the other are hydrogen; Or R 10, R 11, R 12, R 13and R 14, wherein two be chlorine, all the other are hydrogen;
Here, particularly preferably, R 10, R 11, R 12, R 13and R 14, wherein R 10and R 13in or R 10and R 14in two be dialkoxy independently of one another, all the other are hydrogen; R 10, R 11, R 12, R 13and R 14, wherein R 10and R 13in or R 10and R 14in one be alkyl, another is alkoxyl group, all the other are hydrogen; R 10, R 11, R 12, R 13and R 14, wherein R 10and R 13in or R 10and R 14in two independently of one another for for dialkyl group, all the other are hydrogen; R 10, R 11, R 12, R 13and R 14, wherein R 10, R 12and R 14in three be alkoxyl group independently of one another, all the other are hydrogen; R 10, R 11, R 12, R 13and R 14, wherein R 10, R 12and R 14in two be alkoxyl group independently of one another, another is alkyl, all the other are hydrogen; R 10, R 11, R 12, R 13and R 14, wherein R 10, R 12and R 14in two be alkyl independently of one another, another is alkoxyl group, all the other are hydrogen; R 10, R 11, R 12, R 13and R 14, wherein R 10, R 12and R 14in three be alkyl independently of one another, all the other are hydrogen; Or R 10, R 11, R 12, R 13and R 14, wherein R 10and R 13in or R 10and R 14in two be halogen independently of one another, all the other are hydrogen;
In formula provided by the invention (I) compound, the R in formula (I) compound 3can be selected from naphthenic hydrocarbon as hexanaphthene, straight-chain paraffin is as normal hexane, and the substituted-phenyl that structure is following,
Here, R 4be be selected from hydrogen, halogen is as fluorine, chlorine, bromine and iodine, or aromatic base (as phenyl or substituted-phenyl), and the combination of alkoxyl group (as methoxyl group, oxyethyl group and propoxy-);
Here, R 5and R 6separate alkoxyl group, as methoxyl group, oxyethyl group, propoxy-and arbitrary combination thereof; And
Here, Rc can be that single condensed ring merges, and two condensed ring merges, and any condensed ring merges.It is methyl that representative compound in this compounds includes, but are not limited to those Rb, and Rf is methyl, R 10methoxyl group, R 13it is methoxyl group.
In formula provided by the invention (I) compound, wherein the combination of substituent R b and Rf and other structure branches is as follows: Rb is methyl, and Rf is methyl, R 10for methoxyl group, R 13for methoxyl group, R 3be selected from:
Wherein, R 4be selected from bromine, iodine, OCH 3, phenyl and phenyl replace; Or
Wherein, R 5and R 6be all OCH 3; Or
(i.e. 3,4-(methylene-dioxy) phenyl);
Or (as 2-naphthyl).
The invention provides a class such as formula the phenylenediamine derivative shown in (II), or its pharmacy acceptable salt:
Wherein, R 10and R 13be selected from the alkyl of alkyl or replacement, the alkoxyl group of alkoxyl group or replacement or halogen independently of one another; Preferably, the C1-C6 alkyl of C1-C6 alkyl or replacement, the C1-C6 alkoxyl group of C1-C6 alkoxyl group or replacement or halogen is selected from; Here, (alkyl such as replaced or the alkoxyl group of replacement) of described replacement refers to by replacements such as halogen, nitro, hydroxyls; More preferably, R 10and R 13be methyl, methoxyl group or chlorine simultaneously, or R 10for methyl, and R 13for trifluoromethyl;
R 3definition such as formula (I);
And specify, formula (II) compound does not comprise following compounds:
Work as R 10and R 13be respectively methyl;
Or, R 10and R 13be respectively chlorine;
And, R 3for methyl, cyclohexyl, phenyl, 3-pyridyl, 4-pyridyl or methyl substituted pyridyl (picolinyl).
More particularly, the invention provides the phenylenediamine derivative as shown in table 1 to 5, or its pharmacy acceptable salt:
Table 1
Table 2
Table 3
Table 4
Table 5
Second aspect, the invention provides the pharmaceutical composition containing above-mentioned phenylenediamine derivative or its pharmacy acceptable salt, also contains any preparation way of this compounds (there is I structure), and their salt quasi-mode, with any array configuration of all kinds of carrier auxiliary material.Present invention encompasses the formulation ingredients of this compounds as pharmaceutical carrier and/or thinner.These compositions also may comprise other chemotherapeutics or immunostimulant or other antitumor drugs.The medicine carrier of this compounds or thinner comprise any physiological buffer medium, as pH value 7.0 to 7.4 water-soluble organic carrier.These organic carriers include but not limited to Semen Maydis oil, dimethyl sulfoxide (DMSO), the cyclodextrin of modified and other similar carriers.
Phenylenediamine derivative provided by the present invention, wherein its pharmacy acceptable salt refers to " conventional alkaline metal salt form, and the salt formed with free acid or alkali.The form of which kind of salt is unimportant, as long as it is acceptable on technology of pharmaceutics.The pharmacy acceptable salt of this compounds can use mineral acid or organic acid to prepare.Mineral acid example hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, nitric acid, carbonic acid, sulfuric acid and phosphoric acid.Organic acid comprises lipid acid and aromatic acid, such as formic acid, acetic acid, propionic acid, succsinic acid, glycolic acid, glucose, lactic acid, oxysuccinic acid, tartrate, citric acid, aliphatics, alicyclic, aromatic series, heterocyclic, carboxyl and sulfo group acid, xitix, toxilic acid, fumaric acid, aspartic acid, L-glutamic acid, Whitfield's ointment, p-hydroxyphenylaceticacid, stearic acid etc.
Phenylenediamine derivative pharmacy acceptable salt provided by the present invention, its neutral and alkali " pharmacy acceptable salt " comprises aluminium, calcium, lithium, magnesium, potassium, sodium, the metallic salt that zinc is made.In addition, also comprise by N, N '-double benzyl ethylenediamine, chloroprocaine, choline, thanomin, quadrol, the compound alkali salt that the compound in methylglucamine and PROCAINE HCL, PHARMA GRADE and this invention is formed.All these salt can be prepared by this compounds and suitable alkali reaction.
The third aspect, present invention also offers the pharmaceutically acceptable preparation of phenylenediamine derivative as antitumor application.And antineoplastic application comprises the tumour that treatment is easily subject to the interference of Ca2+ oscillations transduction.
The present invention further comprises any preparation way of this compounds (having I structure), and their salt quasi-mode, with the application of any array configuration in the mankind and cancers of mammal treatment of all kinds of carrier auxiliary material.
In embodiments of the invention, cancer involved in the present invention includes but not limited to mammary cancer, colorectal carcinoma, central nerve neuroma, leukemia, melanoma, nonsmall-cell lung cancer, ovarian cancer, kidney, prostate cancer.Such as, (I) structural compounds used may be:
Present invention also offers the compound (I) to (VI) of a class Therapeutic cancer and pharmaceutically acceptable all kinds of preparation thereof and the combined utilization with other antitumor drugs, and medicable cancer includes but not limited to the tumour of the Ca2+ oscillations transduction interference be easily subject in cell.
The cancer that phenylenediamine derivative of the present invention is treated includes but not limited to mammary cancer, colorectal carcinoma, central nerve neuroma, leukemia, melanoma, nonsmall-cell lung cancer, ovarian cancer, kidney, prostate cancer.
Phenylenediamine derivative provided by the present invention the experiment proved that, has the activity of very effective anticancer growth, and, there is broad spectrum, thus provide a class effective antitumour medicine.So-called " derivative " comprises all analogues of structure (I) to (VI).As an example, this compound may include but not limited to their ester class product, meta-bolites, and prodrug pattern.What this kind of product had can be formed, in vivo as active metabolite.In addition, compound #10 (benzo [1 provided by the invention, 3] dioxolane-5-carboxylic acid [3-(2, 5-Dimethyl-benzyloxy)-4-(methylsulfonyl-Methyl-amino)-phenyl]-acid amides), compound #40 (N-[3-(2, 5-Dimethyl-benzyloxy)-4-(methylsulfonyl-Methyl-amino)-phenyl]-4-iodo-benzamide), compound #41 (N-[3-(2, 5-Methoxy-benzyloxy)-4-(methylsulfonyl-Methyl-amino)-phenyl]-4-methoxy-benzamide) Therapeutic cancer, include but not limited to, prostate cancer, mammary cancer, leukemia, nonsmall-cell lung cancer, colorectal carcinoma, central nerve neuroma, melanoma, ovarian cancer, kidney, bladder cancer and lymphatic cancer.These three compound structures are as follows:
compound 40,
compound 41, and
compound 10.
The compound in the present invention with formula (I) can be used for blocking cell proliferation, also can increase fast by T suppression cell, can be used for Therapeutic cancer but be not limited to cancer.This compounds can prevention and therapy Mammals, and the disease of propagation of particularly overrunning at the cell of the mankind, includes but not limited to cancer.This compounds comprises prostate cancer to lower class cancer, mammary cancer, leukemia, nonsmall-cell lung cancer, colorectal carcinoma, central nerve neuroma, melanoma, ovarian cancer, kidney, bladder cancer, lymphoma, and mammary cancer is more effective, but is not limited to the treatment of this kind of cancer.The compound with (I) structure can be used for the prevention and therapy of human cancer.
So-called " treatment " is defined as in the invention: suppress bad cell proliferation, but minimum to Normocellular injury.
" prevention " in the present invention, comprises and prevents any clinical complete unwanted cells propagation, or prevents manifesting of in high risk population unwanted cells fast breeding preclinical feature.Also the prevention of Nasopharyngeal neoplasms and malignant progression is comprised.This type of prevention relates to be suffered from cancer and has the high risk crowd of cancer to the use of the compound in this invention.
Medication colony in the present invention refers to the Clinical symptoms with cell generation disorders or has the colony developing into this type of Clinical symptoms, comprises any mankind or animal.These diseases include but not limited to symptom before cancer and cancer.In the present invention, administrated method is the cell proliferation symptom having or have excessive risk to develop to overrun for any mankind or animal, as cancer.The disease of this kind of patient can be caused by heredity, or may touch carcinogenic substance and caused.Except effective to the mankind, compound of the present invention is also used for the treatment of other Mammals, comprises companion pet and farm-animals, such as but not limited to dog, and cat, horse, ox, sheep and pig.
Term " cell proliferation ", " cell fast breeding ", " cell overrun propagation ", " cell is without control propagation ", " cell useless but fast breeding " and so on, refers to tumour cell, the abnormal cell divided fast such as preneoplastic cell.
Compound provided by the present invention also can be used for assisting therapy." assisting therapy " (or " CMT "), be defined as the coupling of a kind of compound of the present invention and one or more other medicaments, these medicines can use pari passu simultaneously, also can have and necessarily sequentially use, and object is to obtain best curative effect.
Phenylenediamine formula (I) compound provided by the invention can use any preparation and known dosage regimen when being used for the mankind and other mammiferous treatments.In intravenous injection, intramuscular injection, subcutaneous injection, or during abdominal injection, compound of the present invention can mix with aseptic aqueous solution, also can mix with the blood etc. of patient.Here, the described aqueous solution can containing the physiologically active substance be dissolved in water and the material increasing medicine water-soluble degree, as sodium-chlor, and glycine, the material of cyclodextrin of modification and so on, or make the aqueous solution have the material of buffered pH value feature.Such preparation can single dose or multiple doses sealed storage, as being stored in ampoule conventional at present.
When as oral preparations, compound provided by the present invention can make tablet according to effective dose, capsule, suspension or liquid dosage form.One or more traditional additive can be selected, as lactose, N.F,USP MANNITOL, W-Gum or yam starch; Capsule material containing as crystalline cellulose, derivatived cellulose, corn starch adhesive agent or gelatin; Disintegrating agent as W-Gum, yam starch, carboxymethyl cellulose; Lubricant is as talcum powder or Magnesium Stearate lubricating oil.Effective constituent wherein also by drug administration by injection, such as, can use physiological saline, and glucose or water are as a suitable carrier.
" effectively treatment " and " pharmacology is effective " object are in the present invention the consumptions limiting medicine, and to reach prevention, the best effect of improvement and disease therapy, lowers the generation of side effect simultaneously.
The optimal dose of this compounds can be determined with reference to completed clinical trial.Optimal dose is subject to various factors, the situation of disease, patient age, body weight, sex and healthy state, organ residing for disease, adopt specific compound, the position of proliferative cell, propagation severity, and the pharmacokinetic properties of individuality, therefore may be very different.If this compound is locally used, be that dosage is generally lower as prevention instead for the treatment of.Doctor in charge also can need adjustment dosage to obtain optimal effectiveness according to treatment.The possible dosage of such medicine can be 0.1 to 2000 milligram in the patient group had, and can be 0.5 to 500 milligram in the patient group had.
Accompanying drawing explanation
Fig. 1-9 represent be exemplifying compound #10 to leukemia, nonsmall-cell lung cancer, colorectal carcinoma, central nerve neuroma, melanoma, ovarian cancer, kidney, the growth-inhibiting curve of prostate cancer and breast cancer cell.This compound has parent nucleus (I) structure;
What Figure 10 represented is exemplifying compound and the two phenyl ester (2-APB) of the amino ethoxy of Calcium Signal channel inhibitor boric acid 2-combine the restraining effect that grows breast cancer cell SKBR-3 and this compound is used alone inhibiting contrast.
What Figure 11 represented is the growth-inhibiting (20 day) of exemplifying compound to HT29 Transplanted Colon Cancer in Nude Mice.
What Figure 12 represented is the single dose growth-inhibiting effect of compound #41 to 60 cancer cell strains.Wherein tumor type comprises leukemia (leukemia), Non-Small cell lung cancer (nonsmall-cell lung cancer), colon cancer (colorectal carcinoma), CNS cancer (central nerve neuroma), Melanoma (melanoma), Ovarian cancer (ovarian cancer), Renal cancer (kidney), prostate cancer (prostate cancer), breast cancer (mammary cancer).
What Figure 13 represented is the single dose growth-inhibiting effect of compound #40 to 60 cancer cell strains.Wherein, tumor type comprises leukemia (leukemia), Non-Small cell lung cancer (nonsmall-cell lung cancer), colon cancer (colorectal carcinoma), CNS cancer (central nerve neuroma), Melanoma (melanoma), Ovarian cancer (ovarian cancer), Renal cancer (kidney), prostate cancer (prostate cancer), breast cancer (mammary cancer).
embodiment
In this example, chemical reagent used is commercial chemicals, does not usually need further purification, except as otherwise noted.The protection of dry glass vessel and dry argon gas can be used to the reaction of humidity sensitive.Tlc silica gel plate F254 is from Hitman company.Silica gel column chromatography silica gel is 60A (Merck, 230-400 order).NMR (Nuclear Magnetic Resonance) spectrum employs Varian 400 MHz instrument, with dimethyl sulfoxide (DMSO)-D6 or CDCl3 for reagent.
Embodiment 1: the general preparation method of amine intermediate (N-[4-amino-2-(the two replacement-benzyloxy of 2,5-)-phenyl]-N-methyl-methanesulfonamide)
Bromine (chlorine) benzyl of starting raw material 2-amino-5-nitro and replacement and salt of wormwood are that solvent reaction obtains ether intermediate with DMF.And then sulfonylation and hydrolysis generate single sulfonylated intermediate.The nitrogen of sulfonylated intermediate methylates in DMF again and methyl-iodide reaction generates oil of mirbane intermediate.
Subsequently, DMF and water mixed solvent (6: 1,7mL) add in an iron(ic) chloride (4mmol, 4eq) and oil of mirbane intermediate (1mmol, 1eq) mixture.Stir 30 minutes, then slowly add zinc powder (10mmol, 10eq).After having reacted (TLC monitoring), reaction mixture has passed through diatomite filtration.Filtrate thin up, and add saturated aqueous sodium carbonate alkalization.Collect solid precipitation after filtration, dry, then make it be dissolved in acetone.Filter out the residue of insolubility, utilize underpressure distillation to remove recover acetone target compound.
Embodiment 2:R 3general procedure prepared by substitution compound
Salt of wormwood (for 5mmol, 5eq) and replacement acyl chlorides (1.2mmol, 1.2 equivalents) successively join amine intermediate (being 1.0mmol, 1.0 equivalents) in the solution of Isosorbide-5-Nitrae dioxane, stirred overnight at room temperature.After cooling, add 10 ml waters and 3 milliliters of saturated aqueous sodium carbonates in mixture, room temperature for overnight.Filtering solids precipitates, and uses cold diethyl ether/hexane mixture (1: 1 volume ratio) to rinse product.
Embodiment 3:N-[3-2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-4-nitrobenzamide (compound #1)
4-nitrobenzoyl chloride is raw material, according to as above program room temperature for overnight.Product is light yellow solid, output 88%: nucleus magnetic resonance 1h-NMR (400MHz, DMSO-d 6) δ 10.68 (1H, s), 8.41 (2H, d, J=8.0Hz), 8.21 (2H, d, J=8.2Hz), 7.75 (1H, s), 7.44 (1H, d, J=8.4Hz), 7.33 (2H, m), 7.15 (1H, d, J=7.8Hz), 7.09 (1H, d, J=7.8Hz), 5.11 (2H, s), 3.12 (3H, s), 2.88 (3H, s), 2.32 (3H, s), 2.28 (3H, s); HRMS calculated for C 24h 26n 2naO 4s (M+Na) +461.1511, found 461.1511.
Embodiment 4:N-[3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-3-nitrobenzamide (compound #2)
3-nitrobenzoyl chloride is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 86%: nucleus magnetic resonance 1h-NMR (400MHz, DMSO-d 6) δ 10.70 (1H, s), 8.80 (1H, s), 8.48 (1H, d, J=8.0Hz), 8.43 (1H, d, J=8.0Hz), 7.89 (1H, dd, J=7.8,7.8Hz), 7.75 (1H, s), 7.45 (1H, d, J=8.6Hz), 7.34 (2H, m), 7.15 (1H, d, J=7.4Hz), 7.09 (1H, d, J=7.5Hz), 5.12 (2H, s), 3.12 (3H, s), 2.88 (3H, s), 2.33 (3H, s), 2.28 (3H, s).
The chloro-N-of embodiment 5:4 [3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-3-nitrobenzamide (compound #3)
Chloro-3 nitrobenzoyl chlorides of 4-are raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 82%: nucleus magnetic resonance 1h-NMR (400MHz, DMSO-d 6) δ 10.65 (1H, s), 8.65 (1H, s), 8.28 (1H, d, J=8.4Hz), 8.01 (1H, d, J=8.4Hz), 7.72 (1H, s), 7.42 (1H, d, J=8.4Hz), 7.33 (2H, m), 7.15 (1H, d, J=7.7Hz), 7.09 (1H, d, J=7.4Hz), 5.11 (2H, s), 3.12 (3H, s), 2.87 (3H, s), 2.32 (3H, s), 2.28 (3H, s).
N-[3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) the phenyl]-benzamide (compound #4) of embodiment 6:3,4-dichloro
3,4 dichlorobenzoyl chlorides are raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 69%: nucleus magnetic resonance 1h-NMR (400MHz, DMSO-d 6) δ 10.51 (1H, s), 8.23 (1H, s), 7.97 (1H, d, J=8.4Hz), 7.85 (1H, d, J=8.4Hz), 7.73 (1H, s), 7.42 (1H, d, J=7.6Hz), 7.31 (2H, m), 7.15 (1H, d, J=7.7Hz), 7.09 (1H, d, J=7.6Hz), 5.10 (2H, s), 3.12 (3H, s), 2.87 (3H, s), 2.32 (3H, s), 2.28 (3H, s).
Embodiment 7: naphthalic acid [3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-acid amides (compound #5)
Naphthalene-2-carbonyl acyl chlorides was raw material, according to program technic stirred at ambient temperature three days.Product is white solid, productive rate 72%: nucleus magnetic resonance 1h-NMR (400MHz, DMSO-d 6) δ 10.56 (1H, s), 8.60 (1H, s), 8.12 (4H, m), 7.82 (1H, s), 7.67 (2H, m), 7.50 (1H, d, J=8.5Hz), 7.33 (2H, m), 7.16 (1H, d, J=7.8Hz), 7.10 (1H, d, J=7.3Hz), 5.13 (2H, s), 3.13 (3H, s), 2.88 (3H, s), 2.34 (3H, s), 2.29 (3H, s).
Embodiment 8: biphenyl-4-carboxylic acid [3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-acid amides (compound #6)
Biphenyl-4-carbonyl acyl chlorides was raw material, according to program technic stirred at ambient temperature three days.Product is white solid, productive rate 73%: nucleus magnetic resonance 1h-NMR (400MHz, DMSO-d 6) δ 10.42 (1H, s), 8.09 (2H, d, J=7.9Hz), 7.88 (2H, d, J=7.8Hz), 7.81 (1H, s), 7.79 (2H, d, J=7.2Hz), 7.54 (4H, m), 7.33 (2H, m), 7.16 (1H, d, J=7.7Hz), 7.10 (1H, d, J=7.5Hz), 5.12 (2H, s), 3.12 (3H, s), 2.87 (3H, s), 2.33 (3H, s), 2.28 (3H, s).
Embodiment 9:4-cyano group N-[3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-benzamide (compound #7)
4-cyano-benzoyl chloride is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 75%: nucleus magnetic resonance 1h-NMR (400MHz, DMSO-d 6) δ 10.60 (1H, s), 8.13 (2H, d, J=8.4Hz), 8.06 (2H, d, J=8.2Hz), 7.75 (1H, d, J=1.7Hz), 7.43 (1H, dd, J=1.9,8.5Hz), 7.32 (2H, m), 7.15 (1H, d, J=7.7Hz), 7.09 (1H, d, J=7.7Hz), 5.11 (2H, s), 3.12 (3H, s), 2.87 (3H, s), 2.32 (3H, s), 2.28 (3H, s).
Embodiment 10:3-cyano group N-[3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-benzamide (compound #8)
3-cyano-benzoyl chloride is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 71%: nucleus magnetic resonance 1h-NMR (400MHz, DMSO-d 6) δ 10.54 (1H, s), 8.42 (1H, s), 8.27 (1H, d, J=7.8Hz), 8.10 (1H, d, J=7.7Hz), 7.80 (2H, m), 7.43 (1H, d, J=8.5Hz), 7.32 (2H, m), 7.15 (1H, d, J=7.7Hz), 7.09 (1H, d, J=7.8Hz), 5.11 (2H, s), 3.12 (3H, s), 2.87 (3H, s), 2.32 (3H, s), 2.28 (3H, s).
Embodiment 11:4 bromine N-[3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-benzamide (compound #9)
4-bromo-benzoyl chloride is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 80%: nucleus magnetic resonance 1h-NMR (400MHz, DMSO-d 6) δ 10.43 (1H, s), 7.93 (2H, d, J=8.2Hz), 7.79 (2H, d, J=8.5Hz), 7.75 (1H, s), 7.40 (1H, m), 7.31 (2H, m), 7.15 (1H, d, J=7.7Hz), 7.09 (1H, d, J=7.7Hz), 5.10 (2H, s), 3.11 (3H, s), 2.87 (3H, s), 2.32 (3H, s), 2.28 (3H, s).
Embodiment 12: benzo [1,3] dioxolane base-5-carboxylic acid [3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-acid amides (compound #10)
1,3-dihydroisobenzofuran-5-carbonyl chlorine is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 71%: nucleus magnetic resonance 1h-NMR (400MHz, DMSO-d 6) δ 10.18 (1H, s), 7.75 (1H, s), 7.60 (1H, d, J=8.1Hz), 7.52 (1H, s), 7.41 (1H, dd, J=1.5,8.4Hz), 7.31 (1H, s), 7.28 (1H, d, J=8.5Hz), 7.15 (1H, d, J=7.6Hz), 7.09 (2H, d, J=8.0Hz), 5.09 (2H, s), 3.11 (3H, s), 2.86 (3H, s), 2.32 (3H, s), 2.28 (3H, s).
Embodiment 13:N-[3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-3,4,5-trimethoxy-benzamides (compound #11)
3,4,5-trimethoxy-benzoyl chloride is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 93%: nucleus magnetic resonance 1h-NMR (400MHz, DMSO-d 6) δ 10.26 (1H, s), 7.76 (1H, s), 7.36 (5H, m), 7.13 (1H, d, J=7.7Hz), 7.09 (1H, d, J=7.7Hz), 5.11 (2H, s), 3.89 (6H, s), 3.75 (3H, s), 3.12 (3H, s), 2.87 (3H, s), 2.32 (3H, s), 2.28 (3H, s).
Embodiment 14:N-[3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-piperamide (compound #12)
Pepper acyl chlorides is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 88%: nucleus magnetic resonance 1h-NMR (400MHz, DMSO-d 6) δ 10.00 (1H, s), 7.58 (1H, s), 7.28 (1H, s), 7.23 (1H, d, J=8.5Hz), 7.16 (1H, s), 7.14 (1H, d, J=7.6Hz), 7.08 (1H, d, J=7.6Hz), 5.06 (2H, s), 3.08 (3H, s), 2.84 (3H, s), 2.36 (2H, dd, J=7.5,6.4Hz), 2.30 (3H, s), 2.27 (3H, s), 1.10 (3H, dd, J=7.5,7.6Hz).
Embodiment 15: palmitinic acid [3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-acid amides (compound #13)
N-Hexadecane acyl chlorides is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 98%: nucleus magnetic resonance 1h-NMR (400MHz, DMSO-d 6) δ 10.03 (1H, s), 7.59 (1H, s), 7.28 (1H, s), 7.20 (4H, m), 5.06 (2H, s), 3.08 (3H, s), 2.84 (3H, s), 2.30 (3H, s), 2.27 (3H, s), 1.58 (2H, br), 1.23 (26H, br), 0.87 (3H, dd, J=5.1,6.6Hz).
Embodiment 16:2,4-dichloro, N-[3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-benzamide (compound #14)
2,4 dichlorobenzyl chloride is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 80%: nucleus magnetic resonance 1h-NMR (400MHz, DMSO-d 6) δ 10.68 (1H, s), 7.79 (1H, s), 7.61 (1H, s), 7.64 (1H, d, J=8.2Hz), 7.59 (1H, d, J=8.4Hz), 7.29 (3H, br), 7.14 (1H, d, J=7.4Hz), 7.08 (1H, d, J=7.4Hz), 5.09 (2H, s), 3.12 (3H, s), 2.87 (3H, s), 2.31 (3H, s), 2.27 (3H, s).
Embodiment 17:N-[3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-3-trifluoromethyl benzamide (compound #15)
3-trifluoromethyl benzoyl chloride is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 93%: nucleus magnetic resonance 1h-NMR (400MHz, DMSO-d 6) δ 10.61 (1H, s), 8.30 (2H, m), 8.00 (1H, d, J=7.6Hz), 7.81 (2H, m), 7.44 (1H, d, J=8.5Hz), 7.32 (1H, s), 7.32 (1H, d, J=8.4Hz), 7.15 (1H, d, J=7.6Hz), 7.09 (1H, d, J=7.6Hz), 5.11 (2H, s), 3.12 (3H, s), 2.87 (3H, s), 2.32 (3H, s), 2.28 (3H, s).
Embodiment 18:N-[3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-3,4-dimethoxybenzarnide (compound #16)
3,4-dimethoxy-benzoyl chloride is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 93%: nucleus magnetic resonance 1h-NMR (400MHz, CDCl 3) δ 8.025 (2H, m), 7.510 (1H, J=2Hz), 7.434 (1H, dd, J=8.4,2Hz), 7.309 (1H, J=8.8Hz), 7.162 (1H, s), 7.109 (2H, m), 6.919 (1H, d, J=8.4Hz), 6.832 (1H, dd, J=2,8.4Hz), 5.067 (2H, s), 3.957 (3H, s), 3.952 (3H, s), 3.195 (3H, s), 2.707 (3H, s), 2.335 (3H, s), 2.320 (3H, s).
Embodiment 19:N-[3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-(3,4-Dimethoxyphenyl) ethanamide (compound #17)
(3,4-Dimethoxyphenyl) Acetyl Chloride 98Min. is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 95%: nucleus magnetic resonance 1h-NMR (400MHz, CDCl 3) δ 7.844 (1H, d, J=2.4Hz), 7.240 (2H, m), 7.141 (1H, s), 7.103 (2H, m), 6.893 (2H, m), 6.825 (1H, d, J=1.6Hz), 6.555 (1H, dd, J=2.4,8.4Hz), 5.029 (2H, s), 3.907 (3H, s), 3.898 (3H, s), 3.696 (2H, s), 3.157 (3H, s) 2.683 (3H, s), 2.322 (3H, s), 2.312 (3H, s).
Embodiment 20:N-[3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-4-methoxy benzamide (compound #18)
4-methoxy benzoyl chloride is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 96%: nucleus magnetic resonance 1h-NMR (400MHz, CDCl 3) δ 8.022 (1H, d, J=2.4Hz), 7.864 (3H, m), 7.330 (1H, d, J=8.4Hz), 7.175 (1H, s), 7.113 (2H, m), 6.995 (2H, m), 6.823 (1H, dd, J=2.4,8.4Hz), 5.086 (2H, s), 3.886 (3H, s), 3.198 (3H, s), 2.712 (3H, s), 2.345 (3H, s), 2.325 (3H, s).
Embodiment 21:N-[3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-2-methoxy benzamide (compound #19)
2-methoxy benzoyl chloride is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 97%: nucleus magnetic resonance 1h-NMR (400MHz, CDCl 3) δ 9.932 (1H, s), 8.283 (1H, dd, J=2,8Hz), 8.202 (1H, d, J=2.4Hz), 7.535 (1H, m), 7.342 (1H, d, J=8.4Hz), 7.106 (5H, m), 6.759 (1H, dd, J=2,8.4Hz), 5.119 (2H, s), 4.079 (3H, s), 3.201 (3H, s), 2.706 (3H, s), 2.361 (3H, s), 2.329 (3H, s).
Embodiment 22:N-[3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-3-methoxy benzamide (compound #20)
3-methoxy benzoyl chloride is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 91%: nucleus magnetic resonance 1h-NMR (400MHz, CDCl 3) δ 8.021 (1H, d, J=2.4Hz), 7.938 (1H, s), 7.445 (1H, m), 7.406 (2H, m), 7,344 (1H, d, J=8.4Hz), 7.177 (1H, s), 7.121 (3H, m), 6.848 (1H, dd, J=2.4,8.4Hz), 5.093 (2H, s), 3.885 (3H, s), 3.201 (3H, s), 2.714 (3H, s), 2.349 (3H, s), 2.327 (3H, s).
Embodiment 23:N-[3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-3-methoxyl group-2,4,5-benzamide trifluoroacetate (compound #21)
3-methoxyl group-2,4,5-trifluorobenzoyl chloride is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 98%: nucleus magnetic resonance 1h-NMR (400MHz, CDCl 3) δ 8.381 (1H, d, J=14.8Hz), 7.927 (1H, s), 7.680 (1H, m), 7.362 (1H, d, J=8.4Hz), 7.180 (1H, s), 7.115 (2H, m), 6.880 (1H, d, J=8.4Hz), 5.094 (2H, s), 4.106 (3H, s), 3.199 (3H, s), 2.719 (3H, s), 2.358 (3H, s), 2.328 (3H, s).
Embodiment 24:N-[3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-2-ethyl butyramide (compound #22)
2-ethyl-butyryl chloride is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 96%: nucleus magnetic resonance 1h-NMR (400MHz, CDCl 3) δ 8.049 (1H, d, J=2.4Hz), 7.296 (1H, s), 7.275 (1H, s), 7.157 (1H, s), 7.108 (2H, m), 6.673 (1H, dd, J=2.4,8.8Hz), 5.064 (2H, s), 3.172 (3H, s), 2.691 (3H, s), 2.339 (3H, s), 2.318 (3H, s), 2.08 (1H, m), 1.70 (4H, m), 0.970 (6H, t, J=7.6Hz).
Embodiment 25:N-[3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-ring valeramide (compound #23)
Ring valeryl chloride is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 93%: nucleus magnetic resonance 1h-NMR (400MHz, CDCl 3) δ 7.998 (1H, d, J=2Hz), 7.357 (1H, s), 7.265 (1H, d, J=8.4Hz), 7.149 (1H, s), 7.106 (2H, m), 6.641 (1H, dd, J=2.4,8.4Hz), 5.045 (2H, s), 3.169 (3H, s), 2.703 (1H, m), 2.690 (3H, s), 2.327 (3H, s), 2.318 (3H, s), 1.921 (4H, m), 1.80 (2H, m), 1.641 (2H, m).
Embodiment 26:N-[3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-2-phenyl-acetamides (compound #24)
Phenylacetyl chlorine is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 99%: nucleus magnetic resonance 1h-NMR (400MHz, CDCl 3) δ 7.867 (1H, d, J=2.4Hz), 7.399 (5H, m), 7.239 (1H, d, J=8.4Hz), 7.187 (1H, s), 7.102 (3H, m), 6.535 (1H, dd, J=3,9Hz), 5.026 (2H, s), 3.757 (2H, s), 3.156 (3H, s), 2.679 (3H, s), 2.320 (3H, s), 2.312 (3H, s).
Embodiment 27:N-[3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-1-naphthoamide (compound #25)
1-naphthoyl chloride is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 83%: nucleus magnetic resonance 1h-NMR (400MHz, CDCl 3) δ 8.350 (1H, d, J=8Hz), 8.105 (1H, s), 7.992 (1H, d, J=8.4Hz), 7.921 (1H, m), 7.865 (1H, s), 7.741 (1H, d, J=6.4Hz), 7.543 (3H, m), 7.345 (1H, d, J=8.4Hz), 7.199 (1H, s), 7.116 (2H, m), 6.845 (1H, dd, J=2,8.4Hz), 5.129 (2H, s), 3.208 (3H, s), 2.711 (3H, s), 2.365 (3H, s), 2.336 (3H, s).
Two (trifluoromethyl) benzamide (compound #26) of embodiment 28:N-[3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-3,5-
Two (trifluoromethyl) Benzoyl chloride of 3,5-is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 93%: nucleus magnetic resonance 1h-NMR (400MHz, CDCl 3) δ 8.348 (3H, s), 8.067 (1H, s), 7.892 (1H, s), 7.289 (1H, d, J=10.8Hz), 7.173 (1H, s), 7.108 (2H, m), 6.908 (1H, d, J=8.4Hz), 5.051 (2H, s), 3.193 (3H, s), 2.754 (3H, s), 2.342 (3H, s), 2.309 (3H, s).
Embodiment 29:N-[3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-3-brombenzamide (compound #27)
3-bromo-benzoyl chloride is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 99%: nucleus magnetic resonance 1h-NMR (400MHz, CDCl 3) δ 8.022 (2H, m), 7.947 (1H, d, J=2.4Hz)), 7.810 (1H, d, J=8Hz), 7.698 (1H, d, J=8Hz), 7.404 (1H, t, J=8Hz), 7.320 (1H, d, J=8.4Hz), 7.172 (1H, s), 7.114 (2H, m), 6.867 (1H, dd, J=2.4,8.4Hz), 5.072 (2H, s), 3.199 (3H, s), 2.726 (3H, s), 2.343 (3H, s), 2.322 (3H, s).
Embodiment 30:N-[3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-4-chlorobenzamide (compound #28)
4-chloro-benzoyl chloride raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 99%: nucleus magnetic resonance 1h-NMR (400MHz, CDCl 3) δ 8.066 (2H, m), 7.955 (1H, d, J=2Hz), 7.844 (2H, m), 7.503 (3H, m), 7.302 (1H, d, J=8.4Hz), 7.167 (1H, s), 7.111 (2H, m), 6.840 (1H, dd, J=2.4,8.4Hz), 5.061 (2H, s), 3.198 (3H, s), 2.721 (3H, s), 2.337 (3H, s), 2.319 (3H, s).
Embodiment 31:N-[3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-4-iodobenzamide (compound #29)
4-iodobenzoyl chloride is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 96%: nucleus magnetic resonance 1h-NMR (400MHz, DMSO-d 6) δ 10.408 (1H, s), 7.939 (2H, m), 7.748 (3H, m), 7.398 (1H, dd, J=2.4,8.8Hz), 7.291 (2H, m), 7.124 (2H, m), 5.090 (2H, s), 3.105 (3H, s), 2.858 (3H, s), 2.311 (3H, s), 2.270 (3H, s).
Embodiment 32:N-[3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-4-methylthio benzamide (compound #30)
4-first sulphur Benzoyl chloride is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 92%: nucleus magnetic resonance 1h-NMR (400MHz, CDCl 3) δ 8.017 (1H, d, J=2.4Hz), 7.868 (1H, s), 7.799 (2H, m), 7.327 (3H, m), 7.177 (1H, s), 7.116 (3H, m), 6.834 (1H, dd, J=2,8.4Hz), 5.093 (2H, s), 3.200 (3H, s), 2.715 (3H, s), 2.543 (3H, s), 2.348 (3H, s), 2.326 (3H, s).
Embodiment 33:N-[3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-4-dimethylamino benzamide (compound #31)
4-dimethylamino Benzoyl chloride is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 66%: nucleus magnetic resonance 1h-NMR (400MHz, CDCl 3) δ 8.086 (1H, d, J=2.4Hz), 7.823 (1H, s), 7.789 (2H, d, J=9.2Hz), 7.321 (2H, d, J=8.4Hz), 7.174 (1H, s), 7.110 (2H, m), 6.790 (1H, dd, J=2,8.4Hz), 6.720 (2H, d, J=9.2Hz), 5.089 (2H, s), 3.194 (3H, s), 3.064 (6H, s), 2.703 (3H, s), 2.343 (3H, s), 2.324 (3H, s).
Embodiment 34:N-[3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-4-ethoxy benzamide (compound #32)
4-ethoxy benzoyl chloride is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 70%: nucleus magnetic resonance 1h-NMR (400MHz, CDCl 3) δ 8.014 (1H, d, J=2Hz), 7.925 (1H, s), 7.847 (2H, m), 7.316 (2H, d, J=8.4Hz), 7.168 (1H, s), 7.110 (2H, m), 6.972 (2H, m), 6.822 (1H, dd, J=2.4,8.4Hz), 5.074 (2H, s), 4.111 (2H, q, J=7.2Hz), 3.195 (3H, s), 2.708 (3H, s), 2.340 (3H, s), 2.320 (3H, s), 1.455 (3H, t, J=7.2Hz).
Embodiment 35:N-[3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-4-buserelin (compound #33)
4-ethylamino benzonitrile acyl chlorides is raw material, according to program technic room temperature for overnight.Product is light yellow solid, output 64%: nucleus magnetic resonance 1h-NMR (400MHz, CDCl 3) δ 8.038 (1H, d, J=2.4Hz), 7.987 (1H, s), 7.814 (2H, m), 7.327 (3H, m), 7.173 (1H, s), 7.112 (2H, m), 6.834 (1H, dd, J=2.4,8.4Hz), 5.083 (2H, s), 3.197 (3H, s), 2.733 (2H, q, J=7.6Hz), 2.708 (3H, s), 2.343 (3H, s), 2.324 (3H, s), 1.276 (3H, t, J=7.6Hz).
Embodiment 36:N-[3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-4-trifluoromethyl benzamide (compound #34)
4-trifluoromethyl benzoyl chloride is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 84%: nucleus magnetic resonance 1h-NMR (400MHz, DMSO-d 6) δ 10.590 (1H, s), 8.157 (2H, d, J=8Hz), 7.941 (2H, d, J=8Hz), 7.753 (1H, d, J=2.4Hz), 7.419 (1H, dd, J=2.4,8.8Hz), 7.307 (2H, m), 7.129 (2H, m), 5.107 (2H, s), 3.116 (3H, s), 2.871 (3H, s), 2.319 (3H, s), 2.275 (3H, s).
Embodiment 37:N-[3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-4-trifluoromethoxy-benzamide (compound #35)
4-trifluoromethoxy Benzoyl chloride is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 79%: nucleus magnetic resonance 1h-NMR (400MHz, CDCl 3) δ 7.954 (4H, m), 7.350 (3H, m), 7.177 (1H, s), 7.117 (2H, m), 7.848 (1H, dd, J=2.4,8.4Hz), 5.088 (2H, s), 3.204 (3H, s), 2.724 (3H, s), 2.349 (3H, s), 2.324 (3H, s).
Embodiment 38:N-[3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-4-methyl benzamide (compound #36)
4-methyl benzoyl chloride is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 69%: nucleus magnetic resonance 1h-NMR (400MHz, CDCl 3) δ 8.032 (1H, d, J=2Hz), 7.956 (1H, s), 7.786 (2H, m), 7.339 (1H, s), 7.309 (2H, d, J=7.6Hz), 7.175 (1H, s), 7.113 (2H, m), 6.834 (1H, dd, J=2,8.4Hz), 5.084 (2H, s), 3.198 (3H, s), 2.710 (3H, s), 2.438 (3H, s), 2.344 (3H, s), 2.324 (3H, s).
Embodiment 39:N-[3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-furans-2-methane amide (compound #37)
2 furoyl chloride is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 66%: nucleus magnetic resonance 1h-NMR (400MHz, CDCl 3) δ 8.159 (1H, s), 8.004 (1H, d, J=2.4Hz), 7.551 (1H, m), 7.352 (1H, d, J=8.4Hz), 7.268 (1H, m), 7.180 (1H, s), 7.119 (2H, m), 6.875 (1H, dd, J=2.4,8.8Hz), 6.595 (1H, dd, J=2,3.6Hz), 5.091 (2H, s), 3.202 (3H, s), 2.720 (3H, s), 2.3513H, s), 2.328 (3H, s).
Embodiment 40:N-[3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-thiophene-2-carboxamide derivatives (compound #38)
2-thiophenecarbonyl groups chlorine is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 72%: nucleus magnetic resonance 1h-NMR (400MHz, CDCl 3) δ 7.986 (1H, d, J=2.4Hz), 7.877 (1H, s), 7.668 (1H, dd, J=1.2,3.6Hz), 7.589 (1H, dd, J=1.2,5.2Hz), 7.323 (1H, d, J=8.4Hz), 7.144 (4H, m), 6.816 (1H, dd, J=2.4,8.8Hz), 5.072 (2H, s), 3.197 (3H, s), 2.718 (3H, s), 2.341 (3H, s), 2.324 (3H, s).
Embodiment 41:N-[3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-isoxazole-5-methane amide (compound #39)
Isoxazole-5-carbonyl chlorine is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 99%: nucleus magnetic resonance 1h-NMR (400MHz, CDCl 3) δ 8.418 (1H, d, J=2Hz), 8.360 (1H, s), 7.849 (1H, dd, J=2.4Hz), 7.391 (1H, d, J=8.4Hz), 7.181 (1H, s), 7.126 (2H, m), 7.060 (1H, d, J=2Hz), 7.005 (1H, dd, J=2.4,8.4Hz), 5.095 (2H, s), 3.211 (3H, s), 2.741 (3H, s), 2.357 (3H, s), 2.329 (3H, s).
In example 3-41, the building-up reactions step of compound #1-39 is as follows:
1 R=4-nitro-phenyl (88%)
2 R=3-nitro-phenyl (86%)
3 R=4-chloro-3-nitro-phenyl (82%)
4 R=3,4-dichloro--phenyl (69%)
5 R=2-naphthyls (72%)
6 R=4-xenyls (73%)
7 R=4-cvano-phenyl (75%)
8 R=3-cvano-phenyl (71%)
9 R=4-bromo-phenyl (80%)
10 R=5-benzos [1,3] dioxolane base (71%)
11 R=3,4,5-trimethoxv-henvl (93%)
12 R=propyl group (88%)
13 R=hexadecyls (98%)
14 R=2,4-dichloro--phenyl (80%)
15 R=3-trifluoromethoxy-phenyl (93%)
16 R=3,4-dimethoxy-phenyl (93%)
17 R=3,4-dimethoxy-benzyl (95%)
18 R=4-methoxy-phenyl (96%)
19 R=2-methoxy-phenyl (97%)
20 R=3-methoxy-phenyl (91%)
21 R=3-methoxy-2,4,5-trifluorophenyls (98%)
22 R=3-amyl groups (96%)
23 R=cyclopentyl (93%)
24 R=benzyls (99%)
25 R=1-naphthyls (83%)
Two (the trifluoromethyl)-phenyl (93%) of 26 R=3,5-
27 R=3-bromo phenyl (99%)
28 R=4-chlorophenyls (99%)
29 R=4-iodine substituted phenyls (96%)
30 R=4-first sulfur phenenyls (92%)
31 R=4-Dimethylamino-phenyl (66%)
32 R=4-ethoxy-phenyl (70%)
33 R=4-Ethyl-phenyl (64%)
34 R=4-trifluoromethyl-phenyls (84%)
35 R=4-trifluoro methoxy-phenyl (79%)
36 R=4-methylphenyl (69%)
37 R=2-furyls (66%)
38 R=2-thienyls (72%)
39 R=5-isoxazolyl e (99%)
Embodiment 42:N-[3-(2,5-dimethoxy-benzyloxy)-4-(methylsulfonyl-methylamino) phenyl]-4-iodobenzamide (compound #40)
4-iodobenzoyl chloride is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 62%: nucleus magnetic resonance 1h-NMR (400MHz, CDCl 3) δ 7.940 (1H, s), 7.872 (3H, m), 7.608 (2H, m), 7.323 (1H, d, J=8.4Hz), 7.011 (1H, d, J=2.8Hz), 6.879 (1H, d, J=2.4Hz), 6.854 (2H, m), 5.127 (2H, s), 3.782 (3H, s), 3.778 (3H, s), 3.232 (3H, s), 2,814 (3H, s).
Embodiment 43:N-[3-(2,5-diformazan benzyloxy)-4-(methylsulfonyl-methylamino) phenyl]-4-methoxy benzamide (compound #41)
4-anisoyl chlorine is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 60%: nucleus magnetic resonance 1H-NMR (400MHz, CDCl3) δ 7.932 (1H, d, J=2.4Hz), 7.863 (3H, m), 7.327 (1H, d, J=8.4Hz), 7.004 (3H, m), 6.853 (3H, m), 5.138 (2H, s), 3.886 (3H, s), 3.782 (6H, s), 3.232 (3H, s), 2.807 (3H, s).
Embodiment 44:N-[3-(2,5-diformazan benzyloxy)-4-(methylsulfonyl-methylamino) phenyl]-4-brombenzamide (compound #42)
4-bromo-benzoyl chloride is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 91%: nucleus magnetic resonance 1H-NMR (400MHz, CDCl3) δ 7.933 (1H, s), 7.875 (1H, d, J=2Hz), 7.759 (2H, m), 7.647 (2H, m), 7.327 (1H, d, J=8.4Hz), 7.012 (1H, d, J=2.8Hz), 6.882 (1H, d, J=2Hz), 6.857 (2H, m), 5.130 (2H, s), 3.783 (3H, s), 3.779 (3H, s), 3.234 (3H, s), 2.816 (3H, s).
Embodiment 45:N-[3-(2,5-dimethoxy-benzyloxy)-4-(methylsulfonyl-methylamino) phenyl]-piperonyl acid amides (compound #43)
Piperonyl acyl chlorides is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 66%: nucleus magnetic resonance 1H-NMR (400MHz, CDCl3) δ 7.890 (1H, d, J=2.4Hz), 7.857 (1H, s), 7.412 (1H, dd, J=1.6, 8Hz), 7.368 (1H, d, J=1.6Hz), 7.318 (1H, d, J=8.4Hz), 7.012 (1H, d, J=2.4Hz), 6.891 (1H, d, J=8Hz), 6.852 (3H, m), 6.070 (2H, s), 5.128 (2H, s), 3.781 (6H, s), 3.230 (3H, s), 2.810 (3H, s).
Embodiment 46:N-[3-(2,5-dimethoxy-benzyloxy)-4-(methylsulfonyl-methylamino) phenyl]-3,4-dimethoxybenzarnide (compound #44)
3,4-dimethyl chloride is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 80%: nucleus magnetic resonance 1H-NMR (400MHz, CDCl3) δ 7.942 (1H, d, J=2.4Hz), 7.925 (1H, s), 7.504 (1H, d, J=2Hz), 7.411 (1H, dd, J=2, 8.4Hz), 7.332 (1H, d, J=8.4Hz), 7.016 (1H, d, J=2.4Hz), 6.928 (1H, d, J=8.4Hz), 6.861 (3H, m), 5.138 (2H, s), 3.968 (3H, s), 3.961 (3H, s), 3.783 (3H, s), 3.781 (3H, s), 3.236 (3H, s), 2.810 (3H, s).
Embodiment 47:N-[3-(2,5-dimethoxy-benzyloxy)-4-(methylsulfonyl-methylamino) phenyl]-2-naphthoamide (compound #45)
2-naphthoyl chloride is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 83%: nucleus magnetic resonance 1H-NMR (400MHz, CDCl3) δ 8.402 (1H, s), 8.153 (1H, s), 7.947 (5H, m), 7.607 (2H, m), 7.355 (1H, d, J=8.4Hz), 7.028 (1H, d, J=2.8 Hz), 6.940 (1H, dd, J=2.4,8.4Hz), 6.855 (2H, m), 5.159 (2H, s), 3.786 (3H, s), 3.782 (3H, s), 3.248 (3H, s), 2.818 (3H, s).
In example 42-47, the building-up reactions step of compound #40-45 is as follows:
40 R=4-iodine substituted phenyls (62%)
41 R=4-methoxy-phenyl (60%)
42 R=4-bromo phenyl (91%)
43 R=3,4-(methylenedioxy)-phenyl (66%)
44 R=3,4-dimethoxy-phenyl (80%)
45 R=2-naphthyls (83%)
Embodiment 48:N-[3-(2,5-dichloro-benzyloxy)-4-(methylsulfonyl-methylamino) phenyl]-4-brombenzamide (compound #46)
4-bromo-benzoyl chloride is raw material, at room temperature stirs spend the night according to program.Product is white solid, productive rate 65%: nucleus magnetic resonance 1H-NMR (400MHz, CDCl3) δ 8.153 (1H, s), 7.795 (1H, s), 7.778 (2H, d, J=8.4Hz), 7.635 (2H, d, J=8.4Hz), 7.553 (1H, d, J=2Hz), 7.365 (1H, d, J=8.4Hz), 7.303 (2H, m), 6.946 (1H, dd, J=2,8.8Hz), 5.086 (2H, s), 3.252 (3H, s), 2.878 (3H, s).
Embodiment 49:N-[3-(2,5-dichloro-benzyloxy)-4-(methylsulfonyl-methylamino) phenyl]-4-methoxy benzamide (compound #47)
4-anisoyl chlorine is raw material, at room temperature stirs spend the night according to program.Product is white solid, productive rate 70%: nucleus magnetic resonance 1H-NMR (400MHz, CDCl3) δ 7.959 (1H, s), 7.919 (1H, d, J=2Hz), 7.860 (2H, d, J=9.2Hz), 7.550 (1H, d, J=2.4Hz), 7.311 (3H, m), 6.988 (2H, d, J=8.8Hz), 6.903 (1H, dd, J=2.4,8.4Hz), 5.164 (2H, s), 3.884 (3H, s), 3.249 (3H, s), 2.850 (3H, s).
Embodiment 50:N-[3-(2,5-dichloro-benzyloxy)-4-(methylsulfonyl-methylamino) phenyl]-3,4-dimethoxybenzarnide (compound #48)
3,4-dimethyl chloride is raw material, at room temperature stirs spend the night according to program.Product is white solid, productive rate 86%: nucleus magnetic resonance 1H-NMR (400MHz, CDCl3) δ 8.047 (1H, s), 7.925 (1H, d, J=2.4Hz), 7.548 (1H, d, J=2.4Hz), 7.502 (1H, d, J=2Hz), 7.435 (1H, dd, J=2,8.4Hz), 7.334 (3H, m), 6.911 (2H, m), 5.152 (2H, s), 3.960 (3H, s), 3.955 (3H, s), 3.250 (3H, s), 2.858 (3H, s).
Embodiment 51:N-[3-(2,5-dichloro-benzyloxy)-4-(methylsulfonyl-methylamino) phenyl]-4-iodobenzamide (compound #49)
4-iodobenzoyl chloride is raw material, at room temperature stirs spend the night according to program.Product is white solid, productive rate 85%: nucleus magnetic resonance 1H-NMR (400MHz, DMSO-d6) δ 7.941 (2H, m), 7.773 (1H, d, J=2.4Hz), 7.745 (2H, m), 7.681 (1H, d, J=2.4Hz), 7.593 (1H, d, J=8.4Hz), 7.501 (1H, dd, J=2.8,8.4Hz), 7.464 (1H, dd, J=2.4,8.4Hz), 7.329 (1H, d, J=8.4Hz), 5.215 (2H, s), 3.139 (3H, s), 2.931 (3H, s).
Embodiment 52:N-[3-(2,5-dichloro-benzyloxy)-4-(methylsulfonyl-methylamino) phenyl]-2-naphthoamide (compound #50)
2-naphthoyl chloride is raw material, at room temperature stirs spend the night according to program.Product is white solid, productive rate 98%: nucleus magnetic resonance 1h-NMR (400MHz, CDCl 3) δ 8.413 (1H, s), 8.264 (1H, s), 7.948 (5H, m), 7.579 (3H, m), 7.360 (2H, m), 7.291 (1H, dd, J=2.8,8.8Hz), 6.988 (1H, dd, J=2,8.4Hz), 5.164 (2H, s), 3.262 (3H, s), 2.861 (3H, s).
Embodiment 53:N-[3-(2,5-dichloro-benzyloxy)-4-(methylsulfonyl-methylamino) phenyl]-piperonyl acid amides (compound #51)
Piperonyl acyl chlorides is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 84%: nucleus magnetic resonance 1h-NMR (400MHz, CDCl 3) δ 7.953 (1H, s), 7.864 (1H, d, J=2.4Hz), 7.548 (1H, d, J=2.4Hz), 7.428 (1H, dd, J=1.6,8Hz), 7.370 (2H, m), 7.311 (2H, m), 6.898 (2H, m), 6.067 (2H, s), 5.143 (2H, s), 3.247 (3H, s), 2.860 (3H, s).
In example 48-53, the building-up reactions step of compound #46-51 is as follows:
46 R=4-bromo phenyl (65%)
47 R=4-methoxy-phenyl (70%)
48 R=3,4-dimethoxy-phenyl (86%)
49 R=4-iodine substituted phenyls (85%)
50 R=2-naphthyls (98%)
51 R=3,4-(methylenedioxy)-phenyl (84%)
Embodiment 54:N-[3-(2-methyl-5-trifluoromethyl benzyloxy)-4-(methylsulfonyl-methylamino) phenyl]-4-brombenzamide (compound #52)
4-bromo-benzoyl chloride is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 78%: nucleus magnetic resonance 1h-NMR (400MHz, CDCl 3) δ 8.026 (2H, m), 7.759 (2H, m), 7.704 (1H, s), 7.653 (2H, m), 7.548 (1H, d, J=8Hz), 7.365 (1H, d, J=8Hz), 7.330 (1H, d, J=8.4Hz), 6.835 (1H, dd, J=2.4,8.4Hz), 5.160 (2H, s), 3.228 (3H, s), 2.783 (3H, s), 2.457 (3H, s).
Embodiment 55:N-[3-(2-methyl-5-trifluoromethyl benzyloxy)-4-(methylsulfonyl-methylamino) phenyl]-4-methoxy benzamide (compound #53)
4-anisoyl chlorine is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 97%: nucleus magnetic resonance 1h-NMR (400MHz, CDCl 3) δ 8.081 (1H, d, J=2.4Hz), 7.959 (1H, s), 7.860 (2H, m), 7.702 (1H, s), 7.543 (1H, d, J=8Hz), 7.362 (1H, d, J=8Hz), 7.330 (1H, d, J=8.8Hz), 6.990 (2H, m), 6.815 (1H, dd, J=2,8.4Hz), 5.163 (2H, s), 3.883 (3H, s), 3.224 (3H, s), 2.770 (3H, s), 2.455 (3H, s).
Embodiment 56:N-[3-(2-methyl-5-trifluoromethyl benzyloxy)-4-(methylsulfonyl-methylamino) phenyl]-3,4-dimethoxybenzarnide (compound #54)
3,4-veratroyl chlorine is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 91%: nucleus magnetic resonance 1h-NMR (400MHz, CDCl 3) δ 8.087 (1H, s), 8.032 (1H, s), 7.707 (1H, s), 7.534 (2H, m), 7.432 (1H, d, J=8Hz), 7.345 (2H, m), 6.922 (1H, d, J=8Hz), 6.826 (1H, d, J=8.4Hz), 5.161 (2H, s), 3.965 (3H, s), 3.955 (3H, s), 3.227 (3H, s), 2.775 (3H, s), 2.453 (3H, s).
Embodiment 57:N-[3-(2-methyl-5-trifluoromethyl benzyloxy)-4-(methylsulfonyl-methylamino) phenyl]-4-iodobenzamide (compound #55)
4-iodobenzoyl chloride is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 87%: nucleus magnetic resonance 1h-NMR (400MHz, CDCl 3) δ 8.064 (1H, s), 8.018 (1H, d, J=2.4Hz), 7.855 (2H, d, J=8.4Hz), 7.703 (1H, s), 7.616 (2H, d, J=8.8Hz), 7.546 (1H, d, J=8.4Hz), 7.363 (1H, d, J=7.6Hz), 7.314 (1H, d, J=8.4Hz), 6.833 (1H, dd, J=2.4,8.4Hz), 5.149 (2H, s), 3.225 (3H, s), 2.781 (3H, s), 2.451 (3H, s).
Embodiment 58:N-[3-(2-methyl-5-trifluoromethyl benzyloxy)-4-(methylsulfonyl-methylamino) phenyl]-2-naphthoamide (compound #56)
2-naphthoyl chloride is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 97%: nucleus magnetic resonance 1h-NMR (400MHz, DMSO-d 6) δ 10.580 (1H, s), 8.592 (1H, s), 8.070 (4H, m), 7.925 (1H, s), 7.833 (1H, d, J=2Hz), 7.654 (3H, m), 7.506 (2H, m), 7.351 (1H, d, J=8.4Hz), 5.264 (2H, s), 3.146 (3H, s), 2.909 (3H, s), 2.470 (3H, s).
Embodiment 59:N-[3-(2-methyl-5-trifluoromethyl benzyloxy)-4-(methylsulfonyl-methylamino) phenyl]-piperonyl methane amide (compound #57)
Piperonyl formyl chloride is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 84%: nucleus magnetic resonance 1h-NMR (400MHz, CDCl 3) δ 8.032 (1H, s), 7.943 (1H, s), 7.701 (1H, s), 7.542 (1H, d, J=8Hz), 7.371 (4H, m), 6.888 (1H, d, J=8Hz), 6.812 (1H, d, J=8Hz), 6.065 (2H, s), 5.153 (2H, s), 3.223 (3H, s), 2.780 (3H, s), 2.453 (3H, s).
In embodiment 54-59, the building-up reactions step of compound #52-57 is as follows:
52 R=4-bromo phenyl (78%)
53 R=4-methoxy-phenyl (97%)
54 R=3,4-dimethoxy-phenyl (91%)
55 R=4-iodine substituted phenyls (87%)
56 R=2-naphthyls (97%)
57 R=3,4-(methylenedioxy)-phenyl (84%)
Embodiment 60:N-[3-(2,5-dimethoxybenzyloxycarbonyl base)-4-acetylamino phenyl]-4-methoxy benzamide (compound #59)
4-anisoyl chlorine is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 90%: nucleus magnetic resonance 1h-NMR (400MHz, DMSO-d 6) δ 10.063 (1H, s), 9.171 (1H, s), 7.950 (2H, d, J=8.8Hz), 7.677 (1H, d, J=8.4Hz), 7.623 (1H, s), 7.355 (1H, d, J=8.8Hz), 7.141 (1H, d, J=2.8Hz), 7.058 (2H, d, J=8.8Hz), 6.981 (1H, d, J=9.2Hz), 6.859 (1H, dd, J=2.8, 8.8Hz), 5.097 (2H, s), 3.838 (3H, s), 3.805 (3H, s), 3.718 (3H, s), 2.070 (3H, s).
Embodiment 61:N-[3-(2,5-dimethoxybenzyloxycarbonyl base)-4-acetylamino phenyl]-3,4-veratroyl amine (compound #60)
3,4-veratroyl chlorine is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 84%: nucleus magnetic resonance 1h-NMR (400MHz, DMSO-d 6) δ 10.056 (1H, s), 9.172 (1H, s), 7.690 (1H, d, J=8.8Hz), 7.606 (2H, m), 7.522 (1H, d, J=1.6Hz), 7.327 (1H, d, J=9.2Hz), 7.142 (1H, d, J=3.2Hz), 7.080 (1H, d, J=8.4z), 6.982 (1H, d, J=8.8Hz), 6.861 (1H, dd, J=2.8, 8.8Hz), 5.099 (2H, s), 3.842 (3H, s), 3.837 (3H, s), 3.804 (3H, s), 3.720 (3H, s), 2.072 (3H, s).
Embodiment 62:N-[3-(2,5-dimethoxybenzyloxycarbonyl base)-4-acetylamino phenyl]-4-brombenzamide (compound #61)
4-bromo-benzoyl chloride is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 75%: nucleus magnetic resonance 1h-NMR (400MHz, DMSO-d 6) δ 10.286 (1H, s), 9.192 (1H, s), 7.901 (2H, d, J=8.4Hz), 7.748 (2H, d, J=8.4Hz), 7.710 (1H, d, J=8.8Hz), 7.600 (1H, d, J=2Hz), 7.357 (1H, d, J=8.4Hz), 7.133 (1H, d, J=2.8Hz), 6.981 (1H, d, J=9.2Hz), 6.860 (1H, dd, J=3.2,8.8Hz), 5.102 (2H, s), 3.803 (3H, s), 3.715 (3H, s), 2.075 (3H, s).
Embodiment 63:N-[3-(2,5-dimethoxybenzyloxycarbonyl base)-4-acetylamino phenyl]-4-iodobenzamide (compound #62)
4-iodobenzoyl chloride is raw material, according to program technic room temperature for overnight.Product is white solid, productive rate 89%: nucleus magnetic resonance 1h-NMR 1h-NMR (400MHz, DMSO-d 6) δ 10.263 (1H, s), 9.188 (1H, s), 7.924 (2H, m), 7.730 (3H, m), 7.599 (1H, d, J=2Hz), 7.253 (1H, dd, J=2,8.8Hz), 7.131 (1H, d, J=3.2Hz), 6.979 (1H, d, J=8.8Hz), 6.858 (1H, dd, J=3.2,9.2Hz), 5.099 (2H, s), 3.801 (3H, s), 3.714 (3H, s), 2.073 (3H, s).
In embodiment 60-63, the building-up reactions step of compound #59-62 is as follows:
Synthetic method is similar to sulphonyl analog derivative, but is raw material with Acetyl Chloride 98Min., and final step reaction is similar with above-mentioned synthesis.
59 R=4-methoxy-phenyl (97%)
60 R=3,4-dimethoxy-phenyl (91%)
61 R=4-bromo phenyl (78%)
62 R=4-iodine substituted phenyls (87%)
Embodiment 64: the test of the activity of compound
SKBR-3 breast cancer cell is from ATCC (Maryland, USA).SKBR-3 cell maintains in the DMEM nutrient solution containing 10% calf serum, and this nutrient solution also contains 2mM L-glutaminate, 100U/mL penicillin, Streptomycin sulphate.Bovine serum will use after the heating in water bath deactivation in 30 minutes of 56 DEG C.Cell cultures, in 37 DEG C, has certain humidity in the CO2 incubator containing 5%CO2.In all experiments, cell is inoculated in 96 well culture plates, every hole about 5000 cell.
Phenylene diamine compound provided by the present invention is tested in SKBR-3 cell to 2H-Thiazolyl blue tetrazolium bromide method (MTT) by (4,5-dimethyl-2-base)-2,5 phenylbenzene the growth-inhibiting of tumour cell.First cell to be seeded in 96 orifice plates and to make its self-sow 24 hours, then uses such compound treatment.Control group accepts DMSO (final concentration 0.1%) process.Stop process after 48 hours, in every hole, add 200 microlitres contain the new nutrient solution of 0.5 mg/ml (4,5-dimethyl-2-base)-2,5 phenylbenzene to 2H-Thiazolyl blue tetrazolium bromide.Then give cell and carry out MTT dye conversion in 1 hour, absorb all nutrient solutions, in every hole, add the dyestuff of 200 μ LDMSO dissolved cells and conversion.Absorbancy is measured at 570nm place.Drug level (IC50 value) needed for comparable 50% cell growth inhibiting lists in table 6 (compound #1-#45 and 58).
Table 6:IC 50
The broad-spectrum anti-tumor activity test of embodiment 65: three exemplary compounds.
The restraining effect of three exemplary compounds (compound #10, compound #41, compound #40) to 60 tumour cells is shown.
What Fig. 1-9 represented is dose response curve, for compound #10 is to leukemia, and nonsmall-cell lung cancer, colorectal carcinoma, central nerve neuroma, melanoma, ovarian cancer, kidney, prostate cancer, the Cell suppression test of mammary cancer.Its effective concentration lists in table 7.
Table 7. wherein tumor type comprises leukemia (leukemia), Non-Small cell lung cancer (nonsmall-cell lung cancer), colon cancer (colorectal carcinoma), CNS cancer (central nerve neuroma), Melanoma (melanoma), Ovarian cancer (ovarian cancer), Renal cancer (kidney), prostate cancer (prostate cancer), breast cancer (mammary cancer)
Embodiment 66: Primary Anti-Tumor study mechanism
Verified, 2-APB (the two phenyl ester of the amino ethoxy of boric acid 2-), endoplasmic reticulum calcium channel (inositol-1-2,4,5-triphosphate receptor, an IP3 acceptor) blocker partly can save the necrocytosis that compound #10 causes.Figure 10 shows compound #10 inducing cell death, and compound #10 and 2-APB shows lighter cell mortality.Result in Figure 10 shows, compound #10 inducing cell death, is relevant with calcium cell signal at least partly.In an experiment, first 2-APB adds, and after two hours, compound 10# adds with different concns.Cell survival rate was tested after 48 hours.
Embodiment 67: activity in vivo is studied
According to broad-spectrum anti-tumor test result, compound #10 effectively inhibits various tumor cell strains to comprise the growth of HT29 colon cancer cell.HT29 colon cancer tumours model in nude mice is a generally acknowledged tumour In vivo model, and its tumour is very fast at nude mice tumor growth.Therefore, this model is used to assessment compound #10 activity in vivo.Result as shown in figure 11.Under 5mg/kg/day dosage, No. #10, compound can dramatically the growth of Tumor suppression, thus demonstrates this compound and also have good activity in vivo.Specific experiment is as follows, and HT29 cell is transplanted in all large BALB/c nude mouses of 5-6.After tumour reaches (namely 2-4 week) 150-200 cubic millimeter, these animals are divided into two groups (often organizing 3) at random, compound is by intraperitoneal injection (PBS of 1%Tween80 is carrier), and the growth of tumour and tumor weight all measure after experiment terminates.

Claims (6)

1. such as formula the compound shown in (I), or its pharmacy acceptable salt:
Wherein, R 10, R 11, R 12, R 13and R 14in, wherein R 10and R 13be C1-C6 alkoxyl group independently of one another, all the other are hydrogen;
Rb is selected from C1-C6 alkyl;
X is selected from sulphur atom, and n equals 2;
Rf is selected from C1-C6 alkyl; With
R 3be selected from 4-iodine substituted phenyl, 4-methoxyphenyl, 4-bromo phenyl, 3,4-(methylene-dioxy) phenyl, 3,4-Dimethoxyphenyls or 2-naphthyl.
2. compound according to claim 1 or its pharmacy acceptable salt, wherein, in formula (I) compound, R 10, R 11, R 12, R 13and R 14in, wherein R 10and R 13be methoxyl group independently of one another, all the other are hydrogen;
Rb is selected from methyl;
X is selected from sulphur atom, and n equals 2;
Rf is selected from methyl, ethyl and propyl group; With
R3 is selected from 4-iodine substituted phenyl, 4-methoxyphenyl, 4-bromo phenyl, 3,4-(methylene-dioxy) phenyl, 3,4-Dimethoxyphenyls or 2-naphthyl.
3. compound according to claim 2 or its pharmacy acceptable salt, wherein, in formula (I) compound, R 10, R 11, R 12, R 13and R 14, wherein R 10and R 13be methoxyl group independently of one another, all the other are hydrogen;
Rb is selected from methyl;
X is selected from sulphur atom, and n equals 2;
Rf is selected from methyl; With
R 3be selected from 4-iodine substituted phenyl, 4-methoxyphenyl, 4-bromo phenyl, 3,4-(methylene-dioxy) phenyl, 3,4-Dimethoxyphenyls or 2-naphthyl.
4. be selected from following compound, or its pharmacy acceptable salt:
Benzo [1,3] dioxolane base-5-carboxylic acid [3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-acid amides;
N-[3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-4-methoxy benzamide;
N-[3-(2,5-benzyloxy-dimethyl)-4-(methylsulfonyl-methylamino) phenyl]-4-iodobenzamide;
N-[3-(2,5-dimethoxy-benzyloxy)-4-(methylsulfonyl-methylamino) phenyl]-4-iodobenzamide;
N-[3-(2,5-dimethoxy-benzyloxy)-4-(methylsulfonyl-methylamino) phenyl]-4-methoxy benzamide;
N-[3-(2,5-dimethoxy-benzyloxy)-4-(methylsulfonyl-methylamino) phenyl]-4-brombenzamide;
N-[3-(2,5-dimethoxy-benzyloxy)-4-(methylsulfonyl-methylamino) phenyl]-piperonyl acid amides;
N-[3-(2,5-dimethoxy-benzyloxy)-4-(methylsulfonyl-methylamino) phenyl]-3,4-dimethoxybenzarnide; Or
N-[3-(2,5-dimethoxy-benzyloxy)-4-(methylsulfonyl-methylamino) phenyl]-2-naphthoamide.
5. one kind comprises the pharmaceutical composition of compound or its pharmaceutically-acceptable salts described in arbitrary claim in Claims 1-4.
6. in Claims 1-4, compound described in arbitrary claim or its pharmaceutically-acceptable salts are preparing the application in antitumor drug.
CN201110149737.6A 2011-06-03 2011-06-03 Substituted phenylenediamine derivative and preparation method and application thereof Expired - Fee Related CN102807514B (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7741520B2 (en) * 2006-02-03 2010-06-22 The Ohio State University Research Foundation Sulfonanilide analogs as selective aromatase modulators (SAMs)

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US8802895B2 (en) * 2010-10-18 2014-08-12 Cleveland State University Amide derivatives of benzene-sulfonanilide, pharmaceutical composition thereof and method for cancer treatment using the same

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7741520B2 (en) * 2006-02-03 2010-06-22 The Ohio State University Research Foundation Sulfonanilide analogs as selective aromatase modulators (SAMs)

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* Cited by examiner, † Cited by third party
Title
A COX-2 inhibitor nimesulide analog selectively induces apoptosis in Her2 overexpressing breast cancer cells via cytochrome c dependent mechanisms;Bin Chen, et al;《Biochemical Pharmacology》;20091231;第77卷;1787-1794 *

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