CN101880246B - Substituted benzoyl urea compound and preparation method and application thereof - Google Patents

Substituted benzoyl urea compound and preparation method and application thereof Download PDF

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CN101880246B
CN101880246B CN200910050646A CN200910050646A CN101880246B CN 101880246 B CN101880246 B CN 101880246B CN 200910050646 A CN200910050646 A CN 200910050646A CN 200910050646 A CN200910050646 A CN 200910050646A CN 101880246 B CN101880246 B CN 101880246B
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urea
compound
fluorenes
benzoyl
cypa
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CN101880246A (en
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蒋华良
李剑
来鲁华
裴剑锋
黄瑾
沈旭
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Peking University
East China University of Science and Technology
Shanghai Institute of Materia Medica of CAS
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East China University of Science and Technology
Shanghai Institute of Materia Medica of CAS
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Abstract

The invention relates to a novel substituted benzoyl urea compound and a preparation method and application thereof. The compound has the structure general formula disclosed in (I), wherein definitions of R1, R2, and R3 are described in the specification, and the compound can be used as a micromolecule inhibitor of Cyclophilin A (CypA); the CypA is a protein with the activity of Peptidyl-prolyl cis-trans isomerase (PPIase), and is related to the in vivo protein folding, assembly and transfer. The current research shows that the CrpA takes part in various physiology approaches, such as autoimmunity depression, HIV-1 invasion infection and the like. Therefore, the compound of the invention can become a novel immunosuppressive drug or anti-HIV-1 drug.

Description

Substituted benzoyl urea compound
Technical field
The present invention relates to pharmaceutical chemistry and pharmacotherapeutics field; Be specifically related to one type as the substituted benzoyl urea compound of the non-peptide inhibitor of small molecules of cyclophilin A and preparation method thereof and pharmacological use, this compounds can be used as immunosuppressor and anti-HIV-1 medicine.
Background technology
Cyclophilin (Cyclophilin; CyP) discovery and name originate from it, and (CsA is widely used clinically a kind of immunosuppressive drug (.Science such as Handschumacher RE for Cyclosporin A, height affinity CsA) to ciclosporin; 1984,226:544-547).CyP be a conservative protein families (Gothel SF, Marahiel MA.Cell Mo.Life Sci, 1999,55:423-436), wait prokaryotic organism this proteinoid all to be arranged to Mammals from low.The common trait of this histone be have peptide cis-trans propyl isomerism enzyme (Peptidyl-prolyl cis-trans isomerase, PPIase) active (Takahashi N, HayanoT, Suzuki M.Nature, 1989,337:473-475).According to characteristics such as relative molecular weight and Subcellular Localization, there are 16 kinds of members such as CypA, CypB, CypC and CypD in known person CyP family at present, and people's cyclophilin A (hCypA) is most important; Also be to study member (Braaren D, Luban J.EMBO J, 2001 the most widely; 20:1300-1309), it is made up of 165 amino acid, relative molecular weight 18; 000, account for 0.1%～0.4% of cellular proteins total amount, mainly be positioned at kytoplasm.Except conjugated protein in the body as CsA, in vivo and in vitro, hCypA can both conjugated protein and catalysis quicken their folding, assembling and transhipment, play a part Chaperones Molecular (.Science such as Freskgard PO, 1992,258:466).
CypA comprises stereotyped writing antiparallel β lamella; These β lamellas are formed a barrel-like structure; Upper and lower opening at bucket respectively has the closed at both ends of one section α spiral with bucket, and the part binding pocket of CypA then is positioned at side (.Nature such as Kallen J, 1991 of this barrel-like structure; 353:276-279), mainly form: inferior pocket A and inferior pocket B by two big inferior pockets.Inferior pocket A mainly is made up of residues such as Thr73, Gly74, Asn102, Ala103, Thr107, Gly109, Ser110 and Gln111, and their major parts are the wetting ability residue; Inferior pocket B is a dark hydrophobicity groove, mainly is made up of residues such as Phe60, Met61, Phe113 and Leu122.
CypA and multiple disease are closely related; 1993, people such as Luban found that CypA and CypB can combine with the Gag protein-specific ground of I type HIV (HIV-1), and CsA can suppress the interaction (.Cell such as Luban J between the Gag-CypA effectively; 1993,73:1067-1078); 1994, Franke (Franke EK, Yuan HE.Nature; 1994,372:359-362) with people such as Thali (.Nature such as Thali M, 1994; 372:363-365) report that on Nature, publishes thesis respectively finds that CypA is incorporated in the HIV-1 virion specifically, and blocking-up CypA mixes, and suppresses duplicating of HIV-1; This explanation CypA and the proteic combination of Gag be function relevant (Luban J.Cell, 1996,87:1157-1159).The Gag albumen of HIV-1 is a polyprotein, it in virus assembling, the ripe and process of sprouting, play decisive role (.Cell such as Gamble TR, 1996,87:1285-1294).Capsid protein (Capsid, CA in CypA and the Gag albumen; 231 residues) zone combines, and through this effect, CypA is wrapped up in the HIV-1 virion specifically.But the disappearance of CypA do not influence virus assembling, sprout and ripe, it is essential at early stage (the viral rt begin before) of HIV-1 life cycle.Therefore, CypA possibly play a role in shelling (Uncoating) process after virus gets into host cell, helps nucleoid to separate assembling (Viral CA core disassembly).
The Jiang Hua of Shanghai Pharmaceutical Inst., Chinese Academy of Sciences very waits people (.Biochem Biophys ResCommun such as Luo C; 2004; 321:557-565) find: CA albumen though SARS-CoV does not encode through the means of information biology; But the proteic Val235 of SARS-CoV N～Pro369 segment and the proteic N end structure of HIV-1 CA territory (residue 1～151) have higher sequence similarity (36.7%), therefore infer that SARS-CoV N albumen possibly also interact with CypA.Afterwards, protein-protein combines activity experiment to confirm this hypothesis: SARS-CoV N albumen and CypA have very high affinity, and the KD value is about 6～160nM; Ensuing rite-directed mutagenesis experiment has confirmed that tentatively the proteic Trp302 of SARS-CoV N～Pro310 segment is for regional with the CypA bonded.Above presentation of results CypA probably participates in the vital movement process of SARS-CoV.
The mixture that hCypA and part form has provide protection to multiple neurone, for aixs cylinder, myelin after the damage all have significant short regeneration (Yoshimoto T, Siesjo BK.Brain Res, 1999,839:283-291).Confirmation CypA such as Andreeva are a kind of growth factors of oxidative stress secretion inducing; Mediation active oxygen medium pair cell external signal is regulated the activation and the vascular smooth muscle cell proliferation of kinases (ERK1/2); Show CypA in the vascular disease pathogenesis, play a significant role (Andreeva L, Heads R, Green CJ.Int JExp Path; 1999,80:305-315).
Except having above-mentioned physiological effect, hCypA is the most deep of research about the effect of immunosuppression aspect.The immunosuppressive action mechanism of generally acknowledging at present is: hCypA combines with intracytoplasmic part, the mixture of formation then with calcineurin (Calcineurin, CaN) phosphorylation activity of combination and inhibition CaN (.Cell such as Liu J, 1991,66:807-815).CaN has important effect in lymphocytic reactivation process; It is through dephosphorylation activating T cell nf (Nuclear factor of activated T cell; NF-AT), make it activation and in the entering nuclear that is shifted, participate in the transcription of IL-2 and some other factor then.The phosphorylation activity that has suppressed CaN has just suppressed to have the release of the cytokine of immunization, thus the performance immunosuppressive action.
In view of CypA plays a role in a plurality of physiological pathway, therefore the suppressor factor research about it is a focus always.Divide by structure, the CypA suppressor factor is divided into three major types: natural product and analogue thereof, peptide class and plan peptide compounds and organic synthesis micromolecular compound.In order to overcome the toxic side effect of natural product, and the easy metabolic of peptides, seeking high, the active strong organic synthesis small molecules CypA suppressor factor of selectivity becomes inevitable.
Bioactive molecule from the beginning design method is meant molecule under suitable algorithm control, and growth automatically finally forms complete ligand structure in receptor binding site.Different with the virtual screening based on molecular docking, bioactive molecule from the beginning design method can be taken a sample in bigger compound space, therefore can obtain the brand-new compound structure of structure.Bioactive molecule from the beginning design method last century the nineties obtain large development, developed the LEGEND program in 1992 like Japanese scientist, the Liu Haiyan professor of Chinese University of Science and Technology equals to deliver the DycoBlock program in 1999, and (Proteins 1999; 36,462-470), the Lai Luhua of Peking University professor seminar has delivered respectively at 1996 and 2000 and has been used for the RASSE program (J.Chem.Inf.Comput.Sci that brand new designs; 1996,36,1187-1194) with LigBuilder program (J.Mol.Model.2000; 6; 498-516), and on this basis, developed the LigBuilder2.0 program.The redaction function is more complete; Perfect combining site detecting function; And can carry out the prediction of preliminary designability to drug targets, and increased structure optimal module, key matching module and synthesizing property analysis module, formed from the beginning design cycle of complete medicine based on protein structure.Particularly this program has added built-in chemical reaction data storehouse (comprising 465 reactions at present); Can in the generation of molecule and output procedure, analyze the synthesizing property of molecule with reverse composition principle; Reduced the synthetic difficulty of the new chemical entities that from the beginning medicinal design obtains, broken through the molecule that from the beginning medicinal design program brings and be difficult to synthetic this bottleneck.
In sum, as target,, design and synthesize micromolecular compound, immunosuppressive drug or the anti-HIV-1 medicine of developing target CypA had important practical significance in conjunction with the from the beginning biological activity test test of drug design method and various levels with CypA.
Integrated use is drug design method and enzyme inhibition activity experiment from the beginning; The contriver has found a substituted benzene formyl carbamide compound; Utilization rational drug method of design carries out structural modification to this compound and obtains a compounds, and tested this compounds suppresses CypA in the horizontal experiment test of vitro enzyme activity.The result proves that the application's compound has stronger CypA and suppresses active.
Summary of the invention
An object of the present invention is to provide the new substituted benzoyl urea compound with inhibition CypA effect, its general structure is suc as formula shown in (I).
Another object of the present invention provides the preparation method of above-mentioned substituted benzoyl urea compound.
A further object of the present invention provides as the application in the pharmaceutical composition of substituted benzoyl urea compound aspect the relative disease (infecting like graft-rejection, the host disease that is caused by transplanting, autoimmune disease and HIV-1 invasion) of preparation prevention or treatment CypA mediation of CypA suppressor factor.
The present invention also provides and comprises one or more the above-mentioned substituted benzoyl urea compounds of treating significant quantity and the pharmaceutical composition of pharmaceutically acceptable vehicle, carrier or thinner.Wherein, above-mentioned substituted benzoyl urea compound accounts for the 0.001-99.9% of said pharmaceutical composition gross weight, more preferably accounts for the 0.1-90% of gross weight.
The present invention provides the substituted benzoyl urea compound with following general formula (I) structure:
Wherein:
R 1And R 2Be selected from hydrogen independently of one another, C 1-C 6The alkyl of straight or branched, alkoxyl group and alkylthio, hydroxyl, nitro, amino, halogen, cyanic acid, trifluoromethyl and benzyloxy.
R 3Be selected from following structure I I, III, IV, V, VI and VII:
Figure G200910050646XD00042
Wherein, X is selected from N, O and S; M is 0～2 integer; N is 1～3 integer; P is 0～3 integer;
R 4, R 5And R 6Be selected from hydrogen independently of one another, C 1-C 6The alkyl of straight or branched, C 1-C 4Alkoxyl group, halogen, cyanic acid, nitro, amino, hydroxyl, trifluoromethyl, carboxyl, sulfydryl and C 1-C 4Acyl group;
Aromatic base Ar is selected from and replaces or unsubstituted phenyl or naphthyl, and its substituting group is 1～4 and is selected from halogen, C 1-C 6Straight or branched alkyl, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4The C of unsaturated-oxyl, carboxyl, carboxyl substituted 1-C 6Alkoxyl group, cyanic acid, nitro, amino, trifluoromethyl, trifluoromethoxy, sulfydryl and C 1-C 4The group of acyl group.
Preferably, in the general formula (I), R 3Be selected from xanthenyl, fluorenyl, 2,3-dihydro-indenes-1-base, R 4Substituted cyclohexyl, R 5And R 6Substituted diphenyl-methyl and do not replace or be selected from halogen, C by 1～2 1-C 6Straight or branched alkyl, hydroxyl, C 1-C 4The substituted naphthyl of the group of alkoxyl group, carboxyl, cyanic acid, nitro, amino, trifluoromethyl, trifluoromethoxy and sulfydryl, phenyl, phenmethyl and styroyl; Wherein, R 4, R 5And R 6Be selected from hydrogen independently of one another, C 1-C 6The alkyl of straight or branched, C 1-C 4Alkoxyl group, halogen, cyanic acid, nitro, amino, hydroxyl, trifluoromethyl, carboxyl, sulfydryl and C 1-C 4In the acyl group.
First preferred embodiment of formula of the present invention (I) compound is compound (I A):
Figure G200910050646XD00051
Wherein, R 3Be selected from following structure:
Figure G200910050646XD00052
Wherein, X is selected from N, O and S; M is 0～2 integer; N is 1～3 integer; P is 0～3 integer; R 4, R 5And R 6Be selected from hydrogen independently of one another, C 1-C 6The alkyl of straight or branched, C 1-C 4Alkoxyl group, halogen, cyanic acid, nitro, amino, hydroxyl, trifluoromethyl, carboxyl, sulfydryl and C 1-C 4Acyl group; Aromatic base Ar is selected from and replaces or unsubstituted phenyl or naphthyl, and its substituting group is 1～4 and is selected from halogen, C 1-C 6Straight or branched alkyl, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4The C of unsaturated-oxyl, carboxyl, carboxyl substituted 1-C 6Alkoxyl group, cyanic acid, nitro, amino, trifluoromethyl, trifluoromethoxy, sulfydryl and C 1-C 4The group of acyl group.
Second preferred embodiment of formula of the present invention (I) compound is compound (I B):
Figure G200910050646XD00061
Wherein, R 1And R 2Be selected from hydrogen independently of one another, C 1-C 6The alkyl of straight or branched, alkoxyl group and alkylthio, hydroxyl, nitro, amino, halogen, cyanic acid, trifluoromethyl and benzyloxy.
The 3rd preferred embodiment of formula of the present invention (I) compound is compound (I C):
Figure G200910050646XD00062
Wherein, R 1Be amino or nitro; R 2Be selected from hydrogen, C 1-C 6The alkyl of straight or branched, alkoxyl group and alkylthio, hydroxyl, nitro, amino, halogen, cyanic acid, trifluoromethyl and benzyloxy.
Particularly, described substituted benzoyl urea compound is:
1-(1-xanthenyl)-3-(2; 6-dihydroxy-benzene formyl) urea, 1-naphthalene-3-(2; 6-dihydroxy-benzene formyl) urea, 1-phenmethyl-3-(2; 6-dihydroxy-benzene formyl) urea, 1-styroyl-3-(2; 6-dihydroxy-benzene formyl) urea, 1-cyclohexyl-3-(2; 6-dihydroxy-benzene formyl) urea, 1-phenyl-3-(2; 6-dihydroxy-benzene formyl) urea, 1-(4-fluorophenyl)-3-(2; 6-dihydroxy-benzene formyl) urea, 1-(2; 3-dihydro-indenes-1-yl)-3-(2,6-dihydroxy-benzene formyl) urea, 1-diphenyl-methyl-3-(2,6-dihydroxy-benzene formyl) urea, 1-fluorenes-3-(2-chlorobenzoyl) urea, 1-fluorenes-3-(2-cyanic acid benzoyl) urea, 1-fluorenes-3-(2-fluorobenzoyl) urea, 1-fluorenes-3-(2-methoxybenzoyl) urea, 1-fluorenes-3-(2-toluyl) urea, 1-fluorenes-3-(2-trifluoromethyl benzoyl) urea, 1-fluorenes-3-(2; 6-two fluorobenzoyl) urea, 1-fluorenes-3-(2, the 6-dichloro-benzoyl) urea, 1-fluorenes-3-(2-chloro-6-fluorobenzoyl) urea, 1-fluorenes-3-(benzoyl) urea, 1-fluorenes-3-(2-fluoro-6-first sulfydryl benzoyl) urea, 1-fluorenes-3-(2-fluoro-6-methoxybenzoyl) urea, 1-fluorenes-3-(2-chloro-6-first sulfydryl benzoyl) urea, 1-fluorenes-3-(2-chloro-6-methoxybenzoyl) urea, 1-fluorenes-3-(2-fluoro-6-benzyloxy benzoyl) urea, 1-fluorenes-3-(2-first sulfydryl benzoyl) urea, 1-fluorenes-3-(2-benzyloxy benzoyl) urea, 1-fluorenes-3-(2-oil of mirbane formyl) urea or 1-fluorenes-3-(2-amido benzoyl) urea.
The substituted benzoyl urea compound with general formula (I) structure that the present invention also provides the application to require to protect (is specially I A, I BAnd I C) and the preparation method of midbody compound VIII, IX, X, XI, XII, XIII, XIV and XV, concrete compound method is following.
Method one: I ASynthetic:
1) with benzylalcohol sodium and 2, the 6-difluorobenzonilyile is dissolved in the methyl-sulphoxide, is rapidly heated after 110～130 ℃, to stir 5～10 hours.Be chilled to room temperature, in reaction solution, add frozen water, stirred 30 minutes, separate out a large amount of solids, suction filtration, washing, drying gets white solid.Get the white plates crystal 2 with ethyl alcohol recrystallization, 6-dibenzyloxy benzene nitrile (VIII).
2) compound VIII that step 1) is obtained is dissolved in the benzylalcohol, and adds Pottasium Hydroxide and less water, and 120～140 ℃ were stirred 10～15 hours down.Underpressure distillation removes and desolvates, and in resistates, adds frozen water, stirs 30 minutes, separates out a large amount of solids, suction filtration, and washing, drying gets white solid.It is used silica gel column chromatography separating purification, obtain white powder solid 2,6-benzyloxy BM (IX).
3) TRIPHOSGENE 99.5 is dissolved in 1, in the 2-ethylene dichloride, ice bath is cooled to 0～5 ℃, will be dissolved in 1, the R of 2-ethylene dichloride 3Substitutional amine-group compound (R 3-NH 2) slowly be added dropwise in the reaction solution that contains TRIPHOSGENE 99.5, finishing, stirring reaction is 30 minutes under the cooling of continuation ice bath; After be warming up to room temperature reaction 1 hour, be heated to backflow then, when reaction solution is the water white transparency shape; Triethylamine is added in the reaction solution, continue to reflux 30 minutes.Underpressure distillation removes and desolvates, and adds toluene, suction filtration, and the filtrating evaporate to dryness obtains faint yellow solid, is R 3Substituted isocyanic ester (X).
4) with step 2) and step 3) the compound I X and the X that obtain dissolve in the toluene, be heated to back flow reaction 10～15 hours.Remove reaction solvent under reduced pressure and obtain faint yellow solid, it is used silica gel column chromatography separating purification, obtain 1-R 3Replacement-3-(2,6-benzyloxy benzoyl-) urea (XI).
5) the compounds X I that step 4) is obtained adds in 45% the hydrogen bromide acetic acid solution, and temperature control stirred 5～10 hours down for 50～70 ℃.In reaction solution impouring frozen water, stirred 30 minutes, separate out a large amount of solids, suction filtration, washing, drying gets 1-R 3Replacement-3-(2,6-dihydroxy-benzene formyl radical) urea (I A).
Figure G200910050646XD00071
Wherein, R 3Definition the same.Preferably, R 3Be xanthenyl, naphthyl, phenmethyl, styroyl, cyclohexyl, phenyl, 4-fluorophenyl, 2,3-dihydro-indenes-1-base or diphenyl-methyl.
Method two: I BSynthetic:
1) 9-Fluorenone and oxammonium hydrochloride are added in 70% aqueous ethanolic solution refluxing and stirring 2～5 hours.In reaction solution impouring frozen water, separate out a large amount of yellow solids, suction filtration, washing, drying gets yellow solid 9-fluorenes oxime (XII).
2) the compounds X II that step 1) is obtained adds and contains in the acetum of less water, is heated to backflow.The Zn powder is slowly added in the reaction solution, continue reaction 1～3 hour.Reaction solution is taken advantage of heat filtering, and filtrating is removed most of solvent through underpressure distillation, and suction filtration gets 9-fluorenamine acetate.It is added in the Hydrogen chloride, and the ice bath cooling was stirred 10～15 hours down.Suction filtration gets 9-fluorenamine hydrochloride.With stirring 1～3 hour suction filtration, ammonia scrubbing and drying in the 9-fluorenamine hydrochloride adding ammoniacal liquor.Use the sherwood oil recrystallization, get white, needle-shaped crystals 9-fluorenamine (XIII).
3) TRIPHOSGENE 99.5 is dissolved in 1, in the 2-ethylene dichloride, ice bath is cooled to 0～5 ℃; To be dissolved in 1, the 9-fluorenamine XIII of 2-ethylene dichloride slowly is added dropwise in the reaction solution that contains TRIPHOSGENE 99.5, finishes; Continue ice bath cooling stirring reaction 30 minutes down, after be warming up to room temperature reaction 1 hour, be heated to backflow then; When reaction solution is the water white transparency shape, triethylamine is added in the reaction solution, continue to reflux 30 minutes.Underpressure distillation removes and desolvates, and adds toluene, suction filtration, and the filtrating evaporate to dryness obtains faint yellow solid, is 9-fluorenes isocyanic ester (XIV).
4) the compounds X IV and the R that step 3) are obtained 1, R 2-disubstituted benzenes methane amide dissolves in the toluene, is heated to back flow reaction 10～15 hours.Remove reaction solvent under reduced pressure and obtain faint yellow solid, it is used silica gel column chromatography separating purification, obtain 1-fluorenes-3-(R 1, R 2-disubstituted benzenes formyl radical) urea (I B).
Figure G200910050646XD00081
Wherein, R 1And R 2Definition the same.
Preferably, R 1During for hydrogen, R 2Be 2-chlorine, 2-cyanic acid, 2-fluorine, 2-methoxyl group, 2-methyl, 2-trifluoromethyl, hydrogen, 2-first sulfydryl or 2-benzyloxy;
R 1During for the 2-fluorine, R 2Be 6-fluorine, 6-first sulfydryl, 6-methoxyl group or 6-benzyloxy;
R 1During for 2-chlorine, R 2Be 6-chlorine, 6-fluorine, 6-first sulfydryl or 6-methoxyl group.
Method three: I CSynthetic:
1) with 2-nitro-R 2Replacement-BM is dissolved in the dry toluene, and 20～30 ℃ of temperature controls slowly drip oxalyl chloride; The question response heat release reflux 3-5 hour, all dissolves suspended solids after finishing; Reaction solution becomes clarification and does not have hydrogen chloride gas and emit; Finish reaction, excessive toluene and oxalyl chloride are removed in the reaction solution underpressure distillation, get 2-nitro-R 2Replacement-benzoyl isocyanic ester (XV).
2) the compounds X V and the I that step 1) are obtained BThe 9-fluorenamine (XIII) that step 3) obtains in synthetic dissolves in the toluene, is heated to back flow reaction 10～15 hours.Remove reaction solvent under reduced pressure, resistates is used silica gel column chromatography separating purification, obtain 1-fluorenes-3-(2-nitro-R 2Substituted 4-benzoyl) urea (I C-1).
3) with step 2) compound I that obtains C-1, ammonium chloride and Fe powder are put among the THF, back flow reaction 1～3 hour.Be chilled to room temperature, suction filtration, filtrating is depressurized to steam and desolventizes, and resistates is used silica gel column chromatography separating purification, gets 1-fluorenes-3-(2-amino-R 2Substituted 4-benzoyl) urea (I C-2).
Figure G200910050646XD00091
Wherein, R 2Definition the same.Preferably, R 2Be hydrogen.
Description of drawings
Fig. 1 is a compound I A-3 couples of amount effect curve figure that the CypA enzyme is lived and suppressed.
Fig. 2 is a compound I A-5 couples of amount effect curve figure that the CypA enzyme is lived and suppressed.
Fig. 3 is a compound I B-1 couple of amount effect curve figure that the CypA enzyme is lived and suppressed.
Fig. 4 is a compound I B-2 couples of amount effect curve figure that the CypA enzyme is lived and suppressed.
Fig. 5 is a compound I B-3 couples of amount effect curve figure that the CypA enzyme is lived and suppressed.
Fig. 6 is a compound I B-6 couples of amount effect curve figure that the CypA enzyme is lived and suppressed.
Fig. 7 is a compound I B-7 couples of amount effect curve figure that the CypA enzyme is lived and suppressed.
Fig. 8 is a compound I B-8 couples of amount effect curve figure that the CypA enzyme is lived and suppressed.
Fig. 9 is a compound I B-9 couples of amount effect curve figure that the CypA enzyme is lived and suppressed.
Figure 10 is a compound I B-11 couples of amount effect curve figure that the CypA enzyme is lived and suppressed.
Figure 11 is a compound I B-17 couples of amount effect curve figure that the CypA enzyme is lived and suppressed.
Figure 12 is a compound I C-1 couple of amount effect curve figure that the CypA enzyme is lived and suppressed.
Embodiment
In following embodiment, will further illustrate the present invention.These embodiment only are used to explain the present invention, but do not limit the present invention in any way.All parameters among the embodiment and remaining explanation unless otherwise indicated, all are to be unit with quality (gram).
Embodiment 12,6-dibenzyloxy benzene nitrile (midbody VIII)
Figure G200910050646XD00101
0.5 gram benzylalcohol sodium is dissolved in 10 milliliters of methyl-sulphoxides, stirs adding 2 down, the 6-difluorobenzonilyile.Be rapidly heated to 115 ℃ of continued stirrings 8 hours.Be chilled to room temperature, in 100 milliliters of frozen water impouring reaction solutions, stirred 30 minutes, separate out a large amount of solids, suction filtration, washing, drying gets white solid.Get white plates crystal midbody VIII with ethyl alcohol recrystallization. 1H-NMR(400Hz，DMSO-d 6)δ：5.19(4H，s，-CH 2)，6.60(2H，d，Ar-H)，7.30-7.35(3H，m，Ar-H)，7.38(4H，t)，7.45(4H，d)。
Embodiment 22,6-benzyloxy BM (intermediate compound I X)
Figure G200910050646XD00102
With 0.4 gram 2,6-dibenzyl benzene nitrile (VIII) is dissolved in 7 milliliters of benzylalcohols, and adds 0.6 gram KOH and 0.1 ml water, and 130 ℃ were stirred 12 hours down.Underpressure distillation removes and desolvates, and in 100 milliliters of frozen water impouring reaction solutions, stirs 30 minutes, separates out a large amount of solids, suction filtration, and washing, drying gets white solid.Silica gel column chromatography separates (petrol ether/ethyl acetate=12/1), obtains white powder solid intermediate IX. 1H-NMR(400Hz，DMSO-d 6)δ：5.15(4H，s，-CH 2)，6.60(2H，d，Ar-H)，7.18-7.48(12H，m，Ar-H)；EI-MS?m/z?333.2(M +)，91.1(100％)。
Embodiment 3 1-(1-xanthenyl)-3-(2,6-benzyloxy benzoyl) urea (intermediate X I-1)
Figure G200910050646XD00103
0.5 gram TRIPHOSGENE 99.5 is dissolved in 3 milliliter 1, and in the 2-ethylene dichloride, ice bath is stirred to dissolving.0.25 gram xanthene amine is dissolved in 10 milliliter 1, in the 2-ethylene dichloride, and slowly is added dropwise in the reaction solution that contains TRIPHOSGENE 99.5, the reaction solution muddiness that is white in color.Continue ice bath after 0.5 hour, be warming up to 25 ℃ of reactions 1 hour, when reflux to reaction solution is the water white transparency shape then, continuing to reflux 0.5 hour in 1 milliliter of triethylamine adding reaction solution.Underpressure distillation removes and desolvates, and adds 10 milliliters of toluene, suction filtration, and filtrating is without aftertreatment, to wherein adding 0.25 gram 2,6-benzyloxy BM (IX), back flow reaction 10 hours.Remove solvent under reduced pressure, add elutriation and go out solid, it is used silica gel column chromatography separating purification, eluent is ethyl acetate/petroleum ether=1/4, obtains white solid product intermediate X I-1.Yield 44%; 1H-NMR (400Hz, DMSO-d 6) δ: 5.13 (4H, s ,-CH), 6.39 (1H, d, Ar-H), 6.56 (2H, t, Ar-H), 6.81 (2H, d, Ar-H), 7.03 (2H, d, Ar-H), 7.19 (2H, t, Ar-H), 7.29 (3H, t, Ar-H), 7.39-7.50 (10H, m, Ar-H), 9.13 (1H, d ,-NH).
Embodiment 4 1-(1-xanthenyl)-3-(2,6-dihydroxy-benzene formyl) urea (compound I AA kind of (I A-1))
Figure G200910050646XD00111
0.3 gram 1-(1-xanthenyl)-3-(2,6-benzyloxy benzoyl) urea (XI-1) is added in 4 milliliter of 45% hydrogen bromide acetic acid solution, and 60 ℃ were stirred 6 hours down.In 150 milliliters of frozen water of reaction solution impouring, stirred 30 minutes, separate out a large amount of solids, suction filtration, washing, the dry pale solid that gets, a small amount of ether cleans, and gets the white solid compound I A-1.Yield 40%; 1H-NMR (400Hz, DMSO-d 6) δ: 6.23 (1H, d, Ar-H), 6.60 (2H, t, Ar-H), 6.86 (2H, d, Ar-H), 7.05 (2H, d, Ar-H), 7.24 (2H, t, Ar-H), 7.29 (3H, t, Ar-H), 9.34 (1H, d ,-NH); EI-MS m/z 376.1 (M +), 180.1 (100%).
Embodiment 5 1-naphthalene-3-(2,6-dihydroxy-benzene formyl) urea (compound I AA kind of (I A-2))
Xanthene amine among the embodiment 3 is replaced to naphthalidine, and all the other desired raw materials, reagent and preparation method get the pale solid compound I with embodiment 1～4 A-2.Yield 50%; Mp 203-208 ℃; 1H-NMR (400Hz, DMSO-d 6) δ: 6.46 (1H, d ,-CH), 7.26 (1H, s, Ar-H), 7.47-7.64 (5H, m, Ar-H), 7.66 (1H, d, Ar-H, 7.93-8.08 (3H, m, Ar-H), 8.21 (1H, d, Ar-H); EI-MS m/z322 (M +), 169.1 (100%).
Embodiment 6 1-phenmethyl-3-(2,6-dihydroxy-benzene formyl) urea (compound I AA kind of (I A-3))
Figure G200910050646XD00121
Xanthene amine among the embodiment 3 is replaced to benzylamine, and all the other desired raw materials, reagent and preparation method are together
Embodiment 1～4, gets the pale solid compound I A-3.Yield 52%; Mp 210-215 ℃; 1H-NMR (400Hz, DMSO-d 6) δ: 4.42 (2H, d ,-CH 2), 6.42 (2H, d, Ar-H), 7.18-7.33 (6H, m, Ar-H), 8.34 (1H, br, Ar-H), 10.54 (1H, s ,-NH), 11.74 (2H, s ,-OH); EI-MS m/z286.1 (M +), 136.0 (100%).
Embodiment 7 1-styroyl-3-(2,6-dihydroxy-benzene formyl) urea (compound I AA kind of (I A-4))
Figure G200910050646XD00122
Xanthene amine among the embodiment 3 is replaced to phenylethylamine, and all the other desired raw materials, reagent and preparation method get khaki color solid chemical compound I with embodiment 1～4 A-4.Yield 67%; Mp 208-212 ℃; 1H-NMR (400Hz, DMSO-d 6) δ: 2.80 (2H, t ,-CH 2), 3.44 (2H, q ,-CH 2), 6.41 (2H, d, Ar-H), 7.21-7.30 (6H, m, Ar-H), 8.34 (1H, br, Ar-H), 10.54 (1H, s ,-OH), 11.74 (2H, s ,-OH); EI-MS m/z 300.1 (M +), 136.0 (100%).
Embodiment 8 1-cyclohexyl-3-(2,6-dihydroxy-benzene formyl) urea (compound I AA kind of (I A-5))
Figure G200910050646XD00123
Xanthene amine among the embodiment 3 is replaced to hexahydroaniline, and all the other desired raw materials, reagent and preparation method get the pale solid compound I with embodiment 1～4 A-5.Yield 41%; Mp＞300 ℃; 1H-NMR (400Hz, DMSO-d 6) δ: 1.52-1.68 (10H, m ,-CH 2), 3.60 (1H, d ,-CH), 6.42 (2H, d, Ar-H), 7.22 (1H, s, Ar-H), 8.214 (1H, br, Ar-H), 10.52 (1H, s N-H), 11.68 (2H, s ,-OH); EI-MS m/z 278.1 (M +), 136.0 (100%).
Embodiment 9 1-phenyl-3-(2,6-dihydroxy-benzene formyl) urea (compound I AA kind of (I A-6))
Figure G200910050646XD00124
Xanthene amine among the embodiment 3 is replaced to aniline, and all the other desired raw materials, reagent and preparation method get the white solid compound I with embodiment 1～4 A-6.Yield 40%; Mp 251-255 ℃; 1H-NMR (400Hz, DMSO-d 6) δ: 7.02 (2H, d, Ar-H), 7.10 (2H, d, Ar-H), 7.38 (2H, t, Ar-H), 7.34 (1H; T, Ar-H), 7.34-7.53 (7H, m, Ar-H), 7.62 (2H, d, Ar-H), 7.78 (1H, d; Ar-H), 7.81 (2H, d, Ar-H), 8.69 (1H, d, Ar-H), 11.23 (1H, s ,-OH).EI-MS?m/z?272.1(M +)，136.0(100％)。
Embodiment 10 1-(4-fluorophenyl)-3-(2,6-dihydroxy-benzene formyl) urea (compound I AA kind of (I A-7))
Figure G200910050646XD00131
Xanthene amine among the embodiment 3 is replaced to the 4-fluoroaniline, and all the other desired raw materials, reagent and preparation method get the pale solid compound I with embodiment 1～4 A-7.Yield 49%; Mp 192-195 ℃; 1H-NMR (400Hz, DMSO-d 6) δ: 7.15 (3H, t, Ar-H), 7.35 (3H, dd, Ar-H), 8.8 (1H, d, Ar-H); EI-MS m/z 290.1 (M +), 136.0 (100%).
Embodiment 11 1-(2,3-dihydro-indenes-1-yl)-3-(2,6-dihydroxy-benzene formyl) urea (compound I AA kind of (I A-8))
Figure G200910050646XD00132
Xanthene amine among the embodiment 3 is replaced to 2,3-dihydro-indenes-1-amine, all the other desired raw materials, reagent and preparation method get light brown solid chemical compound I with embodiment 1～4 A-8.Yield 82%; Mp 250-252 ℃; 1H-NMR (400Hz, DMSO-d 6) δ: 1.65 (2H, m ,-CH 2), 2.38 (2H, m ,-CH 2), 2.76-2.87 (4H, m ,-CH 2), 5.13 (1H, dd ,-CH), 6.15 (1H, d ,-CH), 6.38 (1H, d, Ar-H), 7.17-7.30 (7H, m, Ar-H), 8.54 (1H, d, Ar-H), 11.65 (1H, s, Ar-H); EI-MS m/z312.1 (M +), 132.1 (100%).
Embodiment 12 1-diphenyl-methyl-3-(2,6-dihydroxy-benzene formyl) urea (compound I AA kind of (I A-9))
Figure G200910050646XD00133
Xanthene amine among the embodiment 3 is replaced to benzhydrylamine, and all the other desired raw materials, reagent and preparation method get khaki color solid chemical compound I with embodiment 1～4 A-9.Yield 70%; Mp 222-224 ℃; 1H-NMR (400Hz, DMSO-d 6) δ: 6.08 (1H, d ,-CH), 6.24 (2H, d, Ar-H), 7.11 (1H, t, Ar-H), 7.10-7.12 (2H, m, Ar-H), 7.32-7.37 (8H, m, Ar-H), 9.19 (1H, d, Ar-H); EI-MS m/z 361.1 (M +), 302.1 (100%)
Embodiment 13 9-fluorenes oximes (intermediate X II)
Figure G200910050646XD00141
5 gram 9-Fluorenones and 5 gram oxammonium hydrochlorides are joined in 50 milliliter of 70% ethanolic soln refluxing and stirring 3 hours.In 100 milliliters of frozen water of reaction solution impouring, separate out a large amount of yellow solids, suction filtration, washing, the dry yellow solid product intermediate X II (4.9g, 90%) that gets.EI-MS?m/z?195.1(M +)，179.1(100％)。
Embodiment 14 9-fluorenamines (intermediate X III)
Figure G200910050646XD00142
3 gram 9-fluorenes oximes (XII) are joined in 50 milliliter of 95% aqueous acetic acid, be heated to backflow.6 gram Zn powder are slowly added in the reaction solution, continue reaction 1 hour.Reaction solution is taken advantage of heat filtering, and filtrating is removed most of solvent through underpressure distillation, and suction filtration gets crystalline acetate solid.Continue to add 60 milliliters of 5N hydrochloric acid, stirred 12 hours down in ice bath.With reacting liquid filtering, get white 9-fluorenamine hydrochloride solid.With stirring 2 hours suction filtration, ammonia scrubbing and drying in 100 milliliters of ammoniacal liquor of 9-fluorenamine hydrochloride adding.Use the sherwood oil recrystallization, get white, needle-shaped crystals intermediate X III. 1H-NMR(400Hz，DMSO-d 6)δ：4.91(d，2H，Ar-H)，7.32(t，2H)，7.45(t，2H，Ar-H)，7.71(d，2H，Ar-H)，7.79(d，2H，Ar-H)，7.71(m，1H)；EI-MS?m/z?180.1(M +)，180.1(100％)。
Embodiment 15 1-fluorenes-3-(2-chlorobenzoyl) urea (compound I BA kind of (I B-1))
Figure G200910050646XD00143
0.5 gram TRIPHOSGENE 99.5 is dissolved in 3 milliliter 1, and in the 2-ethylene dichloride, ice bath is stirred to dissolving.0.25 gram 9-fluorenamine (XIII) is dissolved in 10 milliliter 1, in the 2-ethylene dichloride, and slowly is added dropwise in the reaction solution that contains TRIPHOSGENE 99.5, the reaction solution muddiness that is white in color.Continue ice bath and be warming up to 25 ℃ of reactions 1 hour after 0.5 hour, when reflux to reaction solution is the water white transparency shape then, continued in 1 milliliter of triethylamine adding reaction solution was refluxed 0.5 hour.Underpressure distillation removes and desolvates, and adds 10 milliliters of toluene and filters.In filtrating, add 0.15 gram 2-chlorobenzamide, back flow reaction 12 hours.Remove solvent under reduced pressure, it is used silica gel column chromatography separating purification, eluent is ethyl acetate/petroleum ether=1/2, drying.Obtain the white solid product compound I B-1.Yield 41%; Mp 203-205 ℃; 1H-NMR (400Hz, DMSO-d 6) δ: 5.97 (1H, d, C-H), 7.37-7.57 (8H, m, Ar-H), 7.64 (2H, d, Ar-H), 7.88 (1H, d, Ar-H), 8.66 (1H, d, N-H), 11.61 (1H, s, N-H); EI-MS m/z 362.2 (M +), 180.1 (100%).
Embodiment 16 1-fluorenes-3-(2-cyanic acid benzoyl) urea (compound I BA kind of (I B-2))
Figure G200910050646XD00151
2-chlorobenzamide among the embodiment 15 is replaced to 2-cyanic acid BM, and all the other desired raw materials, reagent and preparation method get the white solid compound I with embodiment 13～15 B-2.Yield 45%; Mp224-226 ℃; 1H-NMR (400Hz, DMSO-d 6) δ: 5.97 (1H, d, C-H), 7.29-7.47 (4H, m, Ar-H), 7.56-7.71 (3H, m, Ar-H), 7.75-7.91 (5H, m, N-H), 8.55 (1H, d, N-H), 11.47 (1H, s, Ar-H); EI-MS m/z 353.2 (M +), 207.1 (100%).
Embodiment 17 1-fluorenes-3-(2-fluorobenzoyl) urea (compound I BA kind of (I B-3))
Figure G200910050646XD00152
2-chlorobenzamide among the embodiment 15 is replaced to the 2-fluorobenzamide, and all the other desired raw materials, reagent and preparation method get the white solid compound I with embodiment 13～15 B-3.Yield 49%; Mp 272-275 ℃; 1H-NMR (400Hz, DMSO-d 6) δ: 6.19 (1H, d, C-H), 7.22 (1H, q, Ar-H), 7.28-7.36 (3H, m, Ar-H); 7.41-7.45 (2H, t, Ar-H), 7.58 (1H, m, Ar-H), 7.70 (2H, d, Ar-H); 7.73 (2H, d, Ar-H), 8.02 (1H, td, Ar-H), 8.71-8.75 (2H, m, N-H); EI-MS m/z346.2 (M +), 180.1 (100%).
Embodiment 18 1-fluorenes-3-(2-methoxybenzoyl) urea (compound I BA kind of (I B-4))
2-chlorobenzamide among the embodiment 15 is replaced to the 2-methoxy benzamide, and all the other desired raw materials, reagent and preparation method get the white solid compound I with embodiment 13～15 B-4.Yield 37%; Mp206-209 ℃; 1H-NMR (400Hz, DMSO-d 6) δ: 3.92 (3H, s ,-OCH 3), 6.00 (1H, d, C-H), 7.03 (1H, q, Ar-H), 7.19 (1H, d, Ar-H), 7.34-7.38 (2H; D, Ar-H), 7.40-7.47 (2H, m, Ar-H), 7.57 (2H, t, Ar-H), 7.63 (2H, d; Ar-H), 7.88 (2H, d, Ar-H), 8.88 (1H, s, N-H), 10.43 (1H, d, N-H); EI-MS m/z 358.2 (M +), 180.1 (100%).
Embodiment 19 1-fluorenes-3-(2-toluyl) urea (compound I BA kind of (I B-5))
Figure G200910050646XD00162
2-chlorobenzamide among the embodiment 15 is replaced to the 2-methyl benzamide, and all the other desired raw materials, reagent and preparation method get the white solid compound I with embodiment 13～15 B-5.Yield 47%; Mp206-209 ℃; 1H-NMR (400Hz, DMSO-d 6) δ: 2.43 (3H, s ,-CH 3), 5.99 (1H, d, C-H), 7.27 (2H, d, Ar-H), 7.38 (3H, m, Ar-H), 7.46 (3H, t, Ar-H), 7.65 (2H, m, Ar-H), 7.88 (2H, d, Ar-H), 7.88 (2H, d, Ar-H),, 8.86 (1H, d, N-H), 11.25 (1H, s, N-H); EI-MS m/z 342.2 (M +), 180.1 (100%).
Embodiment 20 1-fluorenes-3-(2-trifluoromethyl benzoyl) urea (compound I BA kind of (I B-6))
2-chlorobenzamide among the embodiment 15 is replaced to the 2-trifluoromethyl benzamide, and all the other desired raw materials, reagent and preparation method get khaki color solid chemical compound I with embodiment 13～15 B-6.Yield 44%; Mp 272-275 ℃; 1H-NMR (400Hz, DMSO-d 6) δ: 5.97 (1H, d, C-H), 7.37-7.46 (4H, m, Ar-H), 7.60 (2H, d, Ar-H), 7.69 (2H, d, Ar-H), 7.70-7.82 (2H, m, Ar-H), 7.88 (2H, d, Ar-H), 8.60 (1H, d, N-H), 11.25 (1H, s, N-H); EI-MS m/z 396.2 (M +), 180.1 (100%).
Embodiment 21 1-fluorenes-3-(2,6-two fluorobenzoyl) urea (compound I BA kind of (I B-7))
Figure G200910050646XD00171
2-chlorobenzamide among the embodiment 15 is replaced to 2, the 6-difluorobenzamide, all the other desired raw materials, reagent and preparation method get khaki color solid chemical compound I with embodiment 13～15 B-7.Yield 68%; Mp252-255 ℃; 1H-NMR (400Hz, DMSO-d 6) δ: 5.94 (1H, d, C-H), 7.20 (2H, d, Ar-H), 7.36-7.60 (4H, m, Ar-H), 7.87 (3H, m, Ar-H), 7.88 (2H, d, Ar-H), 8.54 (1H, d, N-H), 11.44 (1H, s, N-H); EI-MS m/z 464.2 (M +), 180.1 (100%).
Embodiment 22 1-fluorenes-3-(2, the 6-dichloro-benzoyl) urea (compound I BA kind of (I B-8))
Figure G200910050646XD00172
2-chlorobenzamide among the embodiment 15 is replaced to 2, the 6-dichloro-benzamide, all the other desired raw materials, reagent and preparation method get the light yellow solid compound I with embodiment 13～15 B-8.Yield 42%; Mp240-242 ℃; 1H-NMR (400Hz, DMSO-d 6) δ: 5.99 (1H, d, C-H), 7.27-7.50 (6H, m, Ar-H), 7.50-7.72 (3H, m, Ar-H), 7.38 (2H, t, Ar-H), 7.88 (2H, d, Ar-H), 8.58 (1H, d, N-H), 11.51 (1H, s, N-H); EI-MS m/z 396.2 (M +), 180.1 (100%).
Embodiment 23 1-fluorenes-3-(2-chloro-6-fluorobenzoyl) urea (compound I BA kind of (I B-9))
2-chlorobenzamide among the embodiment 15 is replaced to 2-chloro-6-fluorobenzamide, and all the other desired raw materials, reagent and preparation method get the light yellow solid compound I with embodiment 13～15 B-9.Yield 46%; Mp236-238 ℃; 1H-NMR (400Hz, DMSO-d 6) δ: 5.99 (1H, d, C-H), 7.27-7.50 (6H, m, Ar-H), 7.50-7.72 (3H, m, Ar-H), 7.38 (2H, t, Ar-H), 7.88 (2H, d, Ar-H), 8.58 (1H, d, N-H), 11.51 (1H, s, N-H); EI-MS m/z 380.2 (M +), 180.1 (100%).
Embodiment 24 1-fluorenes-3-(benzoyl) urea (compound I BA kind of (I B-10))
Figure G200910050646XD00181
2-chlorobenzamide among the embodiment 15 is replaced to BM, and all the other desired raw materials, reagent and preparation method get the white solid compound I with embodiment 13～15 B-10.Yield 80%; Mp 241-243 ℃; 1H-NMR (400Hz, DMSO-d 6) δ: 5.97 (1H, m), 6.40 (4H, m, Ar-H), 7.22 (1H, t, Ar-H), 7.35 (3H, t, Ar-H), 7.45 (3H, t, Ar-H), 7.62 (2H, d, Ar-H), 7.88 (2H, d, Ar-H), 8.68 (1H, dd, Ar-H); EI-MS m/z 328.2 (M +), 180.1 (100%).
Embodiment 25 1-fluorenes-3-(2-fluoro-6-first sulfydryl benzoyl) urea (compound I BA kind of (I B-11))
Figure G200910050646XD00182
2-chlorobenzamide among the embodiment 15 is replaced to 2-fluoro-6-first sulfydryl BM, and all the other desired raw materials, reagent and preparation method get the pale solid compound I with embodiment 13～15 B-11.Yield 32%; Mp 241-243 ℃; 1H-NMR (400Hz, DMSO-d 6) δ: 2.9 (3H, s ,-SCH 3), 5.99 (1H, d, C-H), 7.13 (1H, t, Ar-H), 7.24 (1H, d, Ar-H), 7.38 (2H, t, Ar-H), 7.43-7.52 (3H, m, Ar-H), 7.62 (2H, d, Ar-H), 7.88 (2H, d, Ar-H), 8.78 (1H, d, N-H), 11.03 (1H, s, N-H); EI-MS m/z 392.2 (M +), 180.1 (100%).
Embodiment 26 1-fluorenes-3-(2-fluoro-6-methoxybenzoyl) urea (compound I BA kind of (I B-12))
Figure G200910050646XD00183
2-chlorobenzamide among the embodiment 15 is replaced to 2-fluoro-6-methoxy benzamide, and all the other desired raw materials, reagent and preparation method get the white solid compound I with embodiment 13～15 B-12.Yield 45%; Mp 112-114 ℃; 1H-NMR (400Hz, DMSO-d 6) δ: 3.75 (3H, s ,-OCH 3), 5.89 (1H, d, C-H), 6.87 (1H, t, Ar-H), 6.97 (1H, d, Ar-H), 7.38 (2H, t, Ar-H), 7.41-7.48 (3H, m, Ar-H), 7.62 (2H, d, Ar-H), 7.89 (2H, d, Ar-H), 8.78 (1H, d, N-H), 11.03 (1H, s, N-H); EI-MS m/z 376.2 (M +), 180.1 (100%).
Embodiment 27 1-fluorenes-3-(2-chloro-6-first sulfydryl benzoyl) urea (compound I BA kind of (I B-13))
2-chlorobenzamide among the embodiment 15 is replaced to 2-chloro-6-first sulfydryl BM, and all the other desired raw materials, reagent and preparation method get off-white color solid chemical compound I with embodiment 13～15 B-13.Yield 56%; Mp 230-235 ℃; 1H-NMR (400Hz, DMSO-d 6) δ: 3.34 (3H, s ,-SCH 3), 5.99 (1H, d, C-H), 7.30-7.51 (9H, m, Ar-H), 7.58-7.62 (2H, d, Ar-H), 7.92 (2H, d, Ar-H), 8.68 (1H, d, N-H), 11.33 (1H, s, N-H); EI-MS m/z 408.2 (M +), 180.1 (100%).
Embodiment 28 1-fluorenes-3-(2-chloro-6-methoxybenzoyl) urea (compound I BA kind of (I B-14))
Figure G200910050646XD00192
2-chlorobenzamide among the embodiment 15 is replaced to 2-chloro-6-methoxy benzamide, and all the other desired raw materials, reagent and preparation method get off-white color solid chemical compound I with embodiment 13～15 B-14.Yield 44%; Mp 258-260 ℃; 1H-NMR (400Hz, DMSO-d 6) δ: 3.75 (3H, s), 5.89 (1H, d, C-H), 7.02 (2H, d, Ar-H), 7.10 (2H; D, Ar-H), 7.38 (2H, t, Ar-H), 7.34 (1H, t, Ar-H), 7.34-7.53 (7H; M, Ar-H), 7.62 (2H, d, Ar-H), 7.78 (1H, d, Ar-H), 7.81 (2H; D, Ar-H), 8.69 (1H, d, N-H), 11.23 (1H, s, N-H); EI-MS m/z 392.2 (M +), 180.1 (100%).
Embodiment 29 1-fluorenes-3-(2-fluoro-6-benzyloxy benzoyl) urea (compound I BA kind of (I B-15))
Figure G200910050646XD00193
2-chlorobenzamide among the embodiment 15 is replaced to 2-fluoro-6-benzyloxy BM, and all the other desired raw materials, reagent and preparation method get off-white color solid chemical compound I with embodiment 13～15 B-15.Yield 36%; Mp 242-244 ℃; 1H-NMR (400Hz, DMSO-d 6) δ: 5.15 (2H, s ,-OCH 2), 5.97 (1H, d, C-H), 6.95 (2H, d, Ar-H), 7.24-7.73 (13H, m, Ar-H), 7.42-750 (3H, m, Ar-H), 7.54 (1H, d, Ar-H), 7.62 (2H, d, Ar-H), 7.88 (2H, d, Ar-H), 8.78 (1H, d, N-H), 11.03 (1H, s, N-H); EI-MS m/z 542.3 (M +), 206.1 (100%).
Embodiment 30 1-fluorenes-3-(2-first sulfydryl benzoyl) urea (compound I BA kind of (I B-16))
Figure G200910050646XD00201
2-chlorobenzamide among the embodiment 15 is replaced to 2-first sulfydryl BM, and all the other desired raw materials, reagent and preparation method get the white solid compound I with embodiment 13～15 B-16.Yield 46%; Mp204-207 ℃; 1H-NMR (400Hz, DMSO-d 6) δ: 2.40 (3H, s ,-SCH 3), 5.99 (1H, d, C-H), 7.22 (2H, d, Ar-H), 7.35-7.40 (3H, m, Ar-H), 7.42-750 (3H, m, Ar-H), 7.54 (1H, d, Ar-H), 7.62 (2H, d, Ar-H), 7.88 (2H, d, Ar-H), 8.78 (1H, d, N-H), 11.03 (1H, s, N-H); EI-MS m/z 374.2 (M +), 180.1 (100%).
Embodiment 31 1-fluorenes-3-(2-benzyloxy benzoyl) urea (compound I BA kind of (I B-17))
Figure G200910050646XD00202
2-chlorobenzamide among the embodiment 15 is replaced to 2-benzyloxy BM, and all the other desired raw materials, reagent and preparation method get the light yellow solid compound I with embodiment 13～15 B-17.Yield 43%; Mp204-207 ℃; 1H-NMR (400Hz, DMSO-d 6) δ: 5.27 (2H, s ,-CH 2), 5.98 (1H, d ,-CH), 7.06 (1H, q, Ar-H), 7.28 (1H, d, Ar-H), 7.32-7.46 (7H; M, Ar-H), 7.53 (3H, d, Ar-H), 7.63 (2H, d, Ar-H), 7.65 (2H, dd; Ar-H), 7.88 (2H, d, Ar-H), 8.79 (1H, s, N-H), 10.54 (1H, d, N-H); EI-MS m/z 434.3 (M +), 180.1 (100%).
Embodiment 32 ortho-nitrophenyl formyl isocyanic ester (intermediate X V)
Figure G200910050646XD00203
1.66 gram ortho-nitrophenyl methane amides are dissolved in 10 milliliters of dry toluene, slowly drip 2.52 gram oxalyl chlorides under the room temperature, after the question response heat release finishes; Reflux 5 hours is all dissolved suspended solids, and reaction solution becomes clarification and do not have hydrogen chloride gas and emit; Finish reaction, excessive toluene and oxalyl chloride are removed in the reaction solution underpressure distillation, get pale yellow oily liquid body intermediate X V; Need not be further purified, be used for next step reaction immediately or seal preservation subsequent use.
Embodiment 33 1-fluorenes-3-(2-oil of mirbane formyl) urea (compound I CA kind of (I C-1))
Figure G200910050646XD00211
0.2 gram ortho-nitrophenyl formyl isocyanic ester (XV) and 0.18 gram 9-fluorenamine (XIII) are joined in 10 milliliters of toluene back flow reaction 10 hours.Remove solvent under reduced pressure, resistates separates (ethyl acetate/petroleum ether=1/1) with silica gel column chromatography, obtains the yellow solid product compound I C-1.Yield 37%; Mp 230-232 ℃; 1H-NMR (400Hz, DMSO-d 6) δ: 5.96 (1H, d, C-H), 7.36 (2H, t, Ar-H), 7.43 (2H, t, Ar-H), 7.60 (2H, d, Ar-H), 7.84-8.16 (3H, m, Ar-H), 8.16 (1H, d, Ar-H), 8.53 (1H, d, N-H), 11.28 (1H, s, N-H); EI-MS m/z 373.2 (M +), 180.1 (100%).
Embodiment 34 1-fluorenes-3-(2-amido benzoyl) urea (compound I CA kind of (I C-2))
Figure G200910050646XD00212
1-fluorenes-3-(the 2-oil of mirbane formyl) urea (I that in 25 milliliters of eggplant type bottles, adds 35 milligrams C-1), 0.75 milligram of ammonium chloride, 50 milligrams of Fe powder, back flow reaction is 1 hour in 10 milliliters of THF.Reacted filtration, the filtrating evaporate to dryness with a small amount of ether washing, gets the faint yellow solid compound I C-2.Yield 90%; Mp 194-197 ℃; 1H-NMR (400Hz, DMSO-d 6) δ: 6.02 (1H, d, C-H), 6.49 (1H, t, Ar-H), 6.72 (1H, d, Ar-H); 7.18 (1H, t, Ar-H), 7.21 (2H, t, Ar-H), 7.35 (2H, d; Ar-H), 7.63 (2H, d, Ar-H), 7.70 (1H, d, Ar-H), 7.87 (2H; D, Ar-H), 8.95 (1H, d, N-H), 10.56 (1H, s, N-H); EI-MS m/z 353.2 (M +), 207.1 (100%).
Embodiment 35 The compounds of this invention suppress active mensuration to CypA peptidyl cis-trans propyl isomerism enzyme percentage
(1) proteic expression of CypA and purifying
The plasmid PET15b-CypA that builds changed over to obtain expressing engineering bacteria in the e. coli bl21; Engineering bacteria is incubated at overnight cultures (peptone 10g/L in the 10mL LB substratum that contains 100 μ g/mL penbritins; Yeast extract 5g/L, sodium-chlor 10g/L).Go into 1L by switching in 1: 100 then and contain in the fresh LB substratum of penbritin 37 ℃ of 220 rev/mins of cultivations.Work as OD 600Reach at about 0.8 o'clock, add IPTG (isopropyl ss-D thiogalactoside, 1M solution), reduce the temperature to 25 ℃ of cultivations simultaneously and carried out induction expression of protein in 5 hours to final concentration 0.5mM.4000 rev/mins of centrifugal 30 minutes collection thalline are put in-80 ℃ of Ultralow Temperature Freezers preservations and spend the night after collection is good.(the 5mM imidazoles pH8.0) hangs for 20mM Tris-Cl, 0.5M NaCl, with ultrasonic disruption on the suspension-s ice bath (300W worked 30 minutes, one time 5 seconds, midfeather 10 seconds) with the binding buffer liquid of 20mL with thalline.The cell homogenates that obtains after the fragmentation 4 ℃ with 10000 rev/mins centrifugal 30 minutes, keep supernatant.This protein crude extract injects and uses the good Ni-NTA resin of binding buffer liquid balance in advance afterwards, fully combines 1 hour at 4 ℃, uses the binding buffer liquid of 10 times of column volumes and cleaning buffer solution (the 20mM Tris-Cl of 10 times of column volumes more respectively; 0.5M NaCl, 60mM imidazoles, pH8.0) flushing resin; Remove the foreign protein that non-specific adsorption is arranged with resin, use elution buffer (20mM Tris-Cl, 0.5M NaCl at last; The 100mM imidazoles, pH8.0) 10mL wash-out resin, the hCypA of collection wash-out.Detect proteic molecular weight and purity with SDS-PAGE.The albumen that dialysis is good can carry out enzyme activity determination.
(2) The compounds of this invention suppresses active mensuration to CypA
(Biochemistry 1991,30 (25): 6127-6134), measure peptide prolyl cis-trans isomerase (PPIase) activity of target compound in establishing criteria Chymotrypsin coupling test.Whole test is carried out under 4 ℃ of constant temperature, and zymolyte is Suc-Ala-Ala-cis-Pro-Phe-pNA, is dissolved into the mother liquor of 3.8mM with the THF that contains 400mM LiCl.Chymotrypsin is dissolved in the HCl solution of 1mM, is made into the mother liquor of 3mg/mL.At first to 519 μ L reaction buffer (50mM HEPES; 100mM NaCl) the middle testing compound solution (final concentration is 10 μ M) that adds 30 μ L hCyPA albumen mother liquors (final concentration 10 μ g/ml) and be dissolved in DMSO; In precooling on ice; They are added in the quartz curette, add 15 μ L Chymotrypsins again, add 12 μ L substrate initial actions at last.Whenever detected the variation of optical absorption intensity and collect data through the U-2010 spectrophotometer at 4 ℃ of following 390nM places at a distance from 0.1 second, after 1 minute, reaction finishes.Each reaction repetition 3 times.Utilize the slope (K) of the preceding 6 seconds linear growth of reaction to represent that the vigor of CypA enzyme is big or small.Draw testing compound percent inhibition under 10 μ M with formula,
Calculation formula is:
(positive controls K value-experimental group K value)/(positive controls K value-negative experimental group K value) * 100%
Wherein positive controls K value is not for adding testing compound institute measured value, and negative control group K value is not for adding testing compound and CypA institute measured value.
(3) compound activity test result
Table 1 substituted benzoyl urea compound is to CypA inhibiting rate data
Figure G200910050646XD00231
Can find out that by table 1 the substituted benzoyl urea compound major part with general structure (I) of the present invention has stronger CypA and suppresses active, explains that compound of the present invention is the CypA suppressor factor.
Embodiment 36 part of compounds of the present invention are to CypA half effective inhibition concentration (IC 50) mensuration
Choose 10 μ M inhibiting rates and survey IC at the compound more than 50% 50, select the suitable compound concentration gradient, experimental technique and system such as embodiment 35.According to the speed of reaction K that compound is lived to the CypA enzyme under different concns, the inhibiting rate that the computerized compound is lived to the CypA enzyme under different concns uses the Sigmoidal formula to carry out the IC that match obtains compound with origin software 50Value, the result sees table 2 and accompanying drawing.
Table 2 substituted benzoyl urea compound is lived to the CypA enzyme and is suppressed IC 50Value
Can find out by table 2, the part substituted benzoyl urea compound with general structure (I) of the present invention have receive rub the level (nM) the CypA protease inhibiting activity, explain that compound of the present invention is the CypA suppressor factor.
Compound I A-3, I A-5, I B-1, I B-2, I B-3, I B-6, I B-7, I B-8, I B-9, I B-11, I B-17 and I C-1 couple of CypA enzyme amount effect curve figure that suppresses alive sees Fig. 1～Figure 12.Can find out that by amount effect curve figure these 12 suppressor factor have concentration dependent preferably to the inhibition activity of CypA enzyme.
The possibility of utilizing on the industry
Advantage such as the preparation method of substituted benzoyl urea compound of the present invention has that reaction conditions gentleness, abundant raw material are easy to get, operation and aftertreatment are simple.
Substituted benzoyl urea compound of the present invention is in medicinal design from the beginning and in the CypA inhibition test, all shown positive findings, has confirmed its pharmacological mechanism.Therefore, compound of the present invention can be used for preparing the CypA suppressor factor and develops into immunosuppressive drug or the anti-HIV-1 medicine.

Claims (5)

1. a substituted benzoyl urea compound is characterized in that, said compound is:
1-(1-xanthenyl)-3-(2; 6-dihydroxy-benzene formyl) urea, 1-naphthalene-3-(2; 6-dihydroxy-benzene formyl) urea, 1-phenmethyl-3-(2; 6-dihydroxy-benzene formyl) urea, 1-cyclohexyl-3-(2; 6-dihydroxy-benzene formyl) urea, 1-(4-fluorophenyl)-3-(2; 6-dihydroxy-benzene formyl) urea, 1-(2; 3-dihydro-indenes-1-yl)-3-(2,6-dihydroxy-benzene formyl) urea, 1-diphenyl-methyl-3-(2,6-dihydroxy-benzene formyl) urea, 1-fluorenes-3-(2-chlorobenzoyl) urea, 1-fluorenes-3-(2-cyanic acid benzoyl) urea, 1-fluorenes-3-(2-fluorobenzoyl) urea, 1-fluorenes-3-(2-methoxybenzoyl) urea, 1-fluorenes-3-(2-trifluoromethyl benzoyl) urea, 1-fluorenes-3-(2; 6-two fluorobenzoyl) urea, 1-fluorenes-3-(2, the 6-dichloro-benzoyl) urea, 1-fluorenes-3-(2-chloro-6-fluorobenzoyl) urea, 1-fluorenes-3-(2-fluoro-6-first sulfydryl benzoyl) urea, 1-fluorenes-3-(2-chloro-6-first sulfydryl benzoyl) urea, 1-fluorenes-3-(2-chloro-6-methoxybenzoyl) urea, 1-fluorenes-3-(2-first sulfydryl benzoyl) urea, 1-fluorenes-3-(2-benzyloxy benzoyl) urea, 1-fluorenes-3-(2-oil of mirbane formyl) urea or 1-fluorenes-3-(2-amido benzoyl) urea.
2. the application of the described substituted benzoyl urea compound of claim 1 in the medicine of the disease of preparation prevention or treatment CypA mediation.
3. application according to claim 2 is characterized in that, the disease of said CypA mediation comprises that graft-rejection, the host disease, autoimmune disease and the HIV-1 that are caused by transplanting invade infection.
4. a pharmaceutical composition is characterized in that, this pharmaceutical composition comprises the described substituted benzoyl urea compound of one or more claims 1 of treating significant quantity and pharmaceutically acceptable vehicle, carrier or thinner.
5. pharmaceutical composition according to claim 4 is characterized in that described substituted benzoyl urea compound accounts for the 0.001-99.9% of this pharmaceutical composition gross weight.
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EP0136745A2 (en) * 1983-09-01 1985-04-10 Duphar International Research B.V Benzoyl urea derivatives having anti-tumor activity
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