CN1293663A - 2,3,4,5-tetrahydro-1H-[1,4] benzodiazepine-3-hydroxamix acids as matrix metal-protease - Google Patents

2,3,4,5-tetrahydro-1H-[1,4] benzodiazepine-3-hydroxamix acids as matrix metal-protease Download PDF

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CN1293663A
CN1293663A CN99804237A CN99804237A CN1293663A CN 1293663 A CN1293663 A CN 1293663A CN 99804237 A CN99804237 A CN 99804237A CN 99804237 A CN99804237 A CN 99804237A CN 1293663 A CN1293663 A CN 1293663A
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alkyl
carboxylic acid
tetrahydro
methoxybenzenesulfonyl
methyl
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J·D·阿尔布赖特
E·G·德洛斯桑托斯
X·杜
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Wyeth Holdings LLC
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American Cyanamid Co
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Abstract

Compounds are provided having formula (I), wherein R, R1, R2, R3 and R4 are defined in the specification, which have matrix metalloproteinase inhibiting activity.

Description

Be 2,3,4 of matrix metallo-proteinase inhibitor, 5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-hydroxamic acid
Invention field
The present invention relates to 4-(4-replaces-benzenesulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-hydroxamic acid, they can be used as matrix metallo-proteinase inhibitor and work.Compound of the present invention can be used for the treatment of by disease such as tumour, osteoarthritis, rheumatoid arthritis and the sex change cartilage of matrix metalloproteinase mediation to be lost.
Background of invention
Matrix metalloproteinase (MMP) is one group and destroys relevant enzyme with the pathologic of reticular tissue and basement membrane.These zinciferous endopeptidases are made up of the enzyme of several hypotypes, comprise collagenase, stromelysin and gelatinase.Shown that in these enzymes gelatinase is and growth of tumor and the most closely-related mmp enzyme of diffusion.
For example, people known in malignant tumour the gelatinase expression level raise, and gelatinase can be degraded and caused the basement membrane of metastases.Show also that recently the required vasculogenesis of solid tumor growth has the gelatinase component in its pathology, as in " Matrix Metalloproteinases; Novel Targes for Directed Cancer Therapy ", Drugs and Aging, 11: the report among the 229-244 (1997).
Other diseases by the MMP mediation comprises restenosis, the osteopenia of MMP-mediation, inflammatory disease of central nervous system, skin aging, osteoarthritis, rheumatoid arthritis, septic arthritis, keratohelcosis, unusual wound healing, osteopathia, proteinuria, the aortic aneurysm disease, the sex change cartilage that traumatic joint injury causes is lost, the neural system demyelinating disease, liver cirrhosis, renal glomerular disease, breaking in early days of fetal membrane, inflammatory bowel, periodontal disease, the macular degeneration that age is relevant, diabetic retinopathy, proliferative vitreous body retinopathy, retinopathy of prematurity, eye inflammation, the conicity cornea, the Sjogren Cotard, myopia, ocular tumor, ocular angiogenesis generation/neovascularity generates and corneal graft rejection.Visible with the research of these disease-relateds as Research Focus such as " matrix metallo-proteinase inhibitor research latest developments " R.P.Beckett, 1:16-26, (1996); Curr.Opin.Ther.Patents, 4 (1): 7-16, (1994); Curr.Medicinal Chem., 2:743-762, (1995); Exp.Opin.Ther.Patents., 5 (2): 1087-11O, (1995); Exp.Opin.Ther.Patents, 5 (12): 1287-1196, (1995); " restraining effect of matrix metalloproteinase: structure base design ", CurrentPharmaceutical Design, 2:524-661, (1996); " matrix metalloproteinase inhibition medicine ", Emerging Drugs, 2:205-230 (1997).
TNF-α conversion enzyme (TACE) can form TNF-α by catalytic film bonded TNF-αQian Tidanbai.TNF-α is a pro-inflammatory cytokine, it is believed that it also has effect to this factor in following disease except that its clear and definite antitumor character: rheumatoid arthritis, septic shock, graft-rejection, emaciation, apocleisis, inflammation, congestive heart failure, inflammatory disease of central nervous system, inflammatory bowel, insulin resistance and HIV infect.The formation that studies have shown that blocking-up TNF-α that the antibody of antagonism TNF-α carries out in transgenic animal can suppress arthritic development.This observation recently also extends to the mankind, and as at " TNF-α in HumanDiseases ", Current Pharmaceutical Design is described in the 2:662-667 (1996).
People expect that micromolecular MMP and tace inhibitor can be used for the treatment of various diseases.Although people have known various MMP and tace inhibitor, many be peptide and peptide analogs are arranged in these molecules, they all have bioavailability and pharmacokinetics problem.Therefore height need be used for the treatment of the available non-peptide MMP of long-acting, oral biology and/or the tace inhibitor of above-mentioned various diseases.
United States Patent (USP) the 5th, 455, disclose that 2-replaces for No. 258-2-(Arenesulfonyl amino) alcohol amide base acid and they are as the purposes of MMP inhibitor.WO 97/18194 discloses N-(aryl sulfonyl) Tetrahydroisoquinoli-promise ketone-alcohol amide base acid and relevant bicyclic derivatives and they purposes as the MMP inhibitor thereof.WO 97/20824 discloses 1-(aryl sulfonyl)-4-(replacement) piperazine-2-alcohol amide base acid, 4-(aryl sulfonyl)-morpholine-3-alcohol amide base acid, 4-(aryl sulfonyl)-tetrahydrochysene-2H; 1,4-thiazine-3-alcohol amide base acid, 3-(replacement-1-(aryl sulfonyl) six hydrogen-2-alcohol amide base acid is useful MMP inhibitor with relevant compound.
Summary of the invention
The present invention relates to MMP show is suppressed 2,3,4 of active new replacement, 5-tetrahydrochysene-1H-[1,4] derivative of benzodiazepine -3-formic acid oxyamide.Compound of the present invention and pharmacy acceptable salt thereof are represented by following formula 1:
Figure 9980423700291
Wherein
R is selected from hydrogen, (C 1-C 3) alkyl ,-CN ,-OR ' ,-SR ' ,-CF 3,-OCF 3, Cl, F, NH 2, NH (C 1-C 3) alkyl ,-N (R ') CO (C 1-C 3) alkyl ,-N (R ') (R '), NO 2,-CONH 2,-SO 2NH 2,-SO 2N (R ') (R ') or-N (R ') COCH 2O-(C 1-C 3) alkyl, wherein R ' is (C 1-C 3) alkyl or hydrogen;
R 4Be (C 1-C 6) alkyl-O-, (C 1-C 6) alkyl-S-,
Figure 9980423700292
R wherein " be hydrogen, halogen, cyano group, methyl or-OCH 3
R 1And R 2Independent separately is hydrogen or CH 3
R 3Be (C 1-C 8) alkyl, NH 2CH 2CO-, (C 1-C 6) alkyl NHCH 2CO-, HO (CH 2) mCO-, HCO-, aryl (CH 2) nCO-, heteroaryl (CH 2) nCO-, (C 1-C 3) alkyl-O-(CH 2) nCO-, (C 1-C 3) alkyl CO-, (C 1-C 3) alkyl CO-NHCH 2CO-, (C 3-C 7) cycloalkyl CO-, (C 1-C 3) alkyl SO 2-, aryl (CH 2) nSO 2-, heteroaryl (CH 2) nSO 2-, (C 1-C 3) alkyl-O-(CH 2) m-SO 2-, (C 1-C 3) alkyl-O-(CH 2) m, (C 1-C 3) alkyl-O-(C 1-C 3) alkyl-O-(C 1-C 3) alkyl, HO-(C 1-C 3) alkyl-O-(C 1-C 3) alkyl, aryl-O-CH 2CO-, heteroaryl-O-CH 2CO-, aryl CH=CHCO-, heteroaryl CH=CHCO-, (C 1-C 3) alkyl CH=CHCO-,
Figure 9980423700301
Aryl (C 1-C 3) alkyl, heteroaryl (C 1-C 3) alkyl, aryl CH=CHCH 2-, heteroaryl CH=CHCH 2-, (C 1-C 6) alkyl CH=CHCH 2-, R ' OCH 2CH (OR ') CO-, (R ' OCH 2) 2C (R ') CO-,
Figure 9980423700312
[(C 1-C 6) alkyl] 2-N-(C 1-C 6) alkyl CO-or (C 1-C 6) alkyl-NH-(C 1-C 6) alkyl CO-; Wherein
m=1-3；n=0-3；
Aryl is
Figure 9980423700313
With heteroaryl be
Figure 9980423700321
Wherein X is hydrogen, halogen, (C 1-C 3) alkyl or-OCH 3, R is identical with above-mentioned definition with R ';
L is hydrogen, (C 1-C 3) alkyl ,-CN ,-OR ' ,-SR ' ,-CF 3,-OCF 3, Cl, F, NH 2,-NH-(C 1-C 3) alkyl ,-N (R ') CO (C 1-C 3) alkyl, N (R ') (R ') ,-NO 2,-CONH 2,-SO 2NH 2,-SO 2N (R ') (R ') ,-N (R ') COCH 2O-(C 1-C 3) alkyl,
Figure 9980423700322
M is
Figure 9980423700331
Figure 9980423700332
Or N (R ') (and R '), wherein R ' is identical with above-mentioned definition;
W is O, S, NH or N (C 1-C 3) alkyl;
Y is hydrogen, F, Cl, CF 3Or OCH 3X ' is halogen, hydrogen, (C 1-C 3) alkyl, O-(C 1-C 3) alkyl or-CH 2OH.
At this used term C 1-C 3Alkyl comprises methyl, ethyl, n-propyl and sec.-propyl.At this used term C 1-C 6Alkyl comprises as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl and amyl group.At this used term C 3-C 7Cycloalkyl comprises saturated and undersaturated cycloalkyl, as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, 1-cyclopropenyl radical, 2-cyclopropenyl radical, 1-cyclobutene base and 2-cyclobutene base.
R is suitably for hydrogen, halogen or (C 1-C 3) alkyl, as hydrogen, chlorine or methyl.R 1Be suitably for hydrogen.R 2Be suitably for hydrogen.R 4Be suitably for (C 1-C 6Alkyl)-and O-, as methoxyl group.R 3Be fit to be selected from: (C 1-C 3) alkyl SO 2-, aryl (CH 2) nSO 2-, (C 1-C 3) alkyl-CO-, aryl-(CH 2) nCO-, heteroaryl (CH 2) nCO-, (C 1-C 3) alkyl-O-(CH 2) nCO-, (C 3-C 7) cycloalkyl-CO-, (C 1-C 3) alkyl-O-(CH 2) m-or aryl (C 1-C 3) alkyl-; as methylsulfonyl; the n-propyl alkylsulfonyl; 4-methyl-benzenesulfonyl; 4-anisole alkylsulfonyl; the methyl carbonyl; 3-trifluoromethyl carbonyl; 2-phenylethyl carbonyl; the methoxymethyl carbonyl; cyclopropyl carbonyl; cyclohexyl-carbonyl; the 2-methoxy ethyl; phenylcarbonyl group; 2-methyl-5-fluorophenyl carbonyl; 4-xenyl carbonyl; 2-xenyl carbonyl; 2; 4-dichlorophenyl carbonyl; the phenoxymethyl carbonyl; phenylcarbonyl group; 4-trifluoromethyl carbonyl; 2-imidazoles-1-base-phenylcarbonyl group; 2-morpholine-4-base-phenylcarbonyl group; 4-ethoxyl phenenyl carbonyl; 4-(4-methyl-imidazoles-1-yl)-2-chloro-phenylcarbonyl group; 2,4-Dimethoxyphenyl carbonyl; 4-methyl-piperazine-1-ylmethyl carbonyl; 3-pyridyl carbonyl; the 2-thienyl carbonyl; 4-pyridyl carbonyl; 2-furyl carbonyl or benzyl.
Preferred compound of the present invention is such formula 1 compound and pharmacy acceptable salt thereof, and wherein R is hydrogen, (C 1-C 3) alkyl ,-CN ,-OR ' ,-SR ' ,-CF 3,-OCF 3, Cl, F, NH 2, NH (C 1-C 3) alkyl ,-N (R ') CO (C 1-C 3) alkyl ,-N (R ') (R '), NO 2,-CONH 2,-SO 2NH 2,-SO 2N (R ') (R ') or-N (R ') COCH 2O-(C 1-C 3) alkyl, wherein R ' is (C 1-C 3) alkyl or hydrogen;
R 4Be (C 1-C 6) alkyl-O-, (C 1-C 6) alkyl-S-,
Figure 9980423700341
R wherein " be hydrogen, halogen, cyano group, methyl or-OCH 3
R 1And R 2Independent separately is hydrogen or CH 3
R 3Be (C 1-C 8) alkyl, NH 2CH 2CO-, (C 1-C 6) alkyl NHCH 2CO-, HO (CH 2) mCO-, HCO-, aryl (CH 2) nCO-, heteroaryl (CH 2) nCO-, (C 1-C 3) alkyl-O-(CH 2) nCO-, (C 1-C 3) alkyl CO-, (C 1-C 3) alkyl CO-NHCH 2CO-, (C 3-C 7) cycloalkyl CO-, aryl-O-CH 2CO-, heteroaryl O-CH 2CO-, aryl CH=CHCO-, heteroaryl CH=CHCO-, (C 1-C 3) alkyl CH=CHCO-, Wherein
m=1-3；n=0-3；
Aryl is
Figure 9980423700352
With heteroaryl be
Wherein X is hydrogen, halogen, (C 1-C 3) alkyl or-OCH 3, R is identical with above-mentioned definition with R '.
Compound more preferably of the present invention is such formula 1 compound and pharmacy acceptable salt thereof, and wherein R is hydrogen, (C 1-C 3) alkyl ,-CN ,-OR ' ,-SR ' ,-CF 3,-OCF 3, Cl, F, NH 2, NH (C 1-C 3) alkyl ,-N (R ') CO (C 1-C 3) alkyl ,-N (R ') (R '), NO 2,-CONH 2,-SO 2NH 2,-SO 2N (R ') (R ') ,-N (R ') COCH 2O-(C 1-C 3) alkyl, wherein R ' is (C 1-C 3) alkyl or hydrogen;
R 4Be (C 1-C 6) alkyl-O-, (C 1-C 6) alkyl-S-, R wherein " be hydrogen, halogen, cyano group, methyl or-OCH 3
R 1And R 2Independent separately is hydrogen or CH 3
R 3For
Figure 9980423700362
[(C 1-C 6) alkyl] 2-N-(C 1-C 6) alkyl CO-or (C 1-C 6) alkyl-NH-(C 1-C 6) alkyl CO-, wherein R ' is identical with above-mentioned definition.
Compound more preferably of the present invention comprises such formula 1 compound and pharmacy acceptable salt thereof, and wherein R is hydrogen, (C 1-C 3) alkyl ,-CN ,-OR ' ,-SR ' ,-CF 3,-OCF 3, Cl, F, NH 2, NH (C 1-C 3) alkyl ,-N (R ') CO (C 1-C 3) alkyl ,-N (R ') (R '), NO 2,-CONH 2,-SO 2NH 2,-SO 2N (R ') (R ') or-N (R ') COCH 2O-(C 1-C 3) alkyl, wherein R ' is (C 1-C 3) alkyl or hydrogen;
R 4Be (C 1-C 6) alkyl-O-, (C 1-C 6) alkyl-S-, R wherein " be hydrogen, halogen, cyano group, methyl or-OCH 3
R 1And R 2Independent separately is hydrogen or CH 3
R 3Be (C 1-C 3) alkyl SO 2-, aryl (CH 2) nSO 2-, heteroaryl (CH 2) nSO 2-or (C 1-C 3) alkyl-O-(CH 2) mSO 2, wherein
m=1-3；n=0-3；
Aryl is
Figure 9980423700372
With heteroaryl be
Wherein X is hydrogen, halogen, (C 1-C 3) alkyl or-OCH 3, R is identical with above-mentioned definition with R '.
The further preferred embodiment of the present invention comprises the compound and the pharmacy acceptable salt thereof of formula 1 representative, wherein
R is selected from hydrogen, (C 1-C 3) alkyl ,-CN ,-OR ' ,-SR ' ,-CF 3,-OCF 3, Cl, F, NH 2, NH (C 1-C 3) alkyl ,-N (R ') CO (C 1-C 3) alkyl ,-N (R ') (R '), NO 2,-CONH 2,-SO 2NH 2,-SO 2N (R ') (R ') or-N (R ') COCH 2O-(C 1-C 3) alkyl, wherein R ' is (C 1-C 3) alkyl or hydrogen;
R 4Be (C 1-C 6) alkyl-O-, (C 1-C 6) alkyl-S-, R wherein " be hydrogen, halogen, cyano group, methyl or-OCH 3
R 1And R 2Independent separately is hydrogen or CH 3
R 3Be (C 1-C 8) alkyl, aryl (C 1-C 3) alkyl, heteroaryl (C 1-C 3) alkyl, aryl CH=CHCH 2, heteroaryl CH=CHCH 2-or (C 1-C 6) alkyl CH=CHCH 2-, wherein
Aryl is With heteroaryl be
Figure 9980423700392
Wherein X is hydrogen, halogen, (C 1-C 3) alkyl or-OCH 3, R is identical with above-mentioned definition with R '.
The in addition preferred compound of the present invention comprises such formula 1 compound and pharmacy acceptable salt thereof, and wherein R is hydrogen, (C 1-C 3) alkyl ,-CN ,-OR ' ,-SR ' ,-CF 3,-OCF 3, Cl, F, NH 2, NH (C 1-C 3) alkyl ,-N (R ') CO (C 1-C 3) alkyl ,-N (R ') (R '), NO 2,-CONH 2,-SO 2NH 2,-SO 2N (R ') (R ') or-N (R ') COCH 2O-(C 1-C 3) alkyl, wherein R ' is (C 1-C 3) alkyl or hydrogen;
R 4Be (C 1-C 6) alkyl-O-, (C 1-C 6) alkyl-S-,
Figure 9980423700401
R wherein " be hydrogen, halogen, cyano group, methyl or-OCH 3
R 1And R 2Independent separately is hydrogen or CH 3
R 3For
Figure 9980423700402
Wherein
m=1-3；n=0-3；
L is hydrogen, (C 1-C 3) alkyl ,-CN ,-OR ' ,-SR ' ,-CF 3,-OCF 3, Cl, F, NH 2,-NH-(C 1-C 3) alkyl ,-N (R ') CO (C 1-C 3) alkyl, N (R ') (R ') ,-NO 2,-CONH 2,-SO 2NH 2,-SO 2N (R ') (R ') ,-N (R ') COCH 2O-(C 1-C 3) alkyl,
Figure 9980423700403
M is
Figure 9980423700412
Or N (R ') (and R '), wherein R ' is identical with above-mentioned definition;
W is O, S, NH or N (C 1-C 3) alkyl;
Y is hydrogen, F, Cl, CF 3Or OCH 3X ' is halogen, hydrogen, (C 1-C 3) alkyl, O-(C 1-C 3) alkyl or-CH 2OH.
By making suitable carboxylic acid halides such as acyl chlorides or acylbromide and azanol reaction can prepare compound of the present invention.Described carboxylic acid halides can react and prepare by making corresponding acid or its metal-salt and activator such as oxalyl chloride, oxalyl bromine, thionyl chloride, thionyl bromide, (chloro methylene radical) alkyl dimethyl ammonium chloride or (bromo methylene radical) dimethyl brometo de amonio.The carboxylic acid halides subsequently and the reaction of azanol suitably original position are carried out.
Make formula I aEster
Figure 9980423700413
R wherein 21Be (C 1-C 6) alkyl, benzyl or aralkyl, every other group is all identical with above-mentioned definition, can prepare metal-salt with alkali such as lithium hydroxide, potassium hydroxide, sodium hydroxide or hydrated barta reaction.This reaction can in the presence of the water or in the presence of anhydrous at solvent as (C 1-C 8) alcohol, tetrahydrofuran (THF), N, suitably carry out in dinethylformamide or the p-dioxane.The metal-salt that produces can be converted into required product, perhaps at first be translated into acid, as passing through with aqueous hydrochloric acid or acetic acid treatment.Perhaps pass through with mineral acid example hydrochloric acid, Hydrogen bromide or trifluoroacetic acid aqueous solution processing formula I aEster is converted into its acid, as mentioned above this acid is converted into required product then.
According to reaction process 1-7 preparation formula 1 compound easily.By the method known to those skilled in the art can to these flow processs carry out various improvement to increase productivity simultaneously amount and the character to product have no adverse effects.For example active group is protected, then in the standard conditions protection (for example, can protect hydroxyl, in the reactions steps of back, slough then) of going down with trimethyl silyl or t-butyldimethylsilyl with suitable blocking group.
Generally speaking, can be by Serine, Threonine or 3, the alkyl ester of 3-dimethyl-3-hydroxy-propionic acid (as methyl esters, ethyl ester, the tert-butyl ester etc.) comes synthesis type 1 compound.Reaction path of reaction process 1 expression.Can notice methyl esters all is shown in all reaction process, yet it should be understood that using methyl esters only is in order to illustrate, can to use other suitable alkyl esters or benzyl ester equally.
In reaction process 1; at first Serine, Threonine, beta-hydroxy Xie Ansuan and relevant derivative are converted into corresponding N-(4-replaces-benzenesulfonyl) derivative 3; then with suitably replace or unsubstituted 2-nitrobenzyl bromine or 2-nitrobenzyl chloride carry out alkylation, thereby obtain corresponding nitro-derivative 5.Under the conventional reduction condition [as catalytic hydrogenation (using Pd/C) or chemical reduction (as using SnCl 2Or FeCl 3)] reduce and can obtain aminoderivative 6.Make N-(2-aminobenzyl) derivative 6 and reactions in the presence of trialkylamine or pyridine (pyridene) such as alkane acyl chlorides, aryl sulfonyl chloride, aroyl chloride, assorted aroyl chloride, aryl sulfonyl chloride, heteroaryl SULPHURYL CHLORIDE, obtain dihydro alanine derivatives 7.Encircle closure by in alcoholic solvent such as methyl alcohol or ethanol, reacting, obtain [1,4] benzodiazepine compound with the alkali of gentleness such as sodium bicarbonate or saleratus 9Adopt the standard conditions of hydrolysis (sodium hydroxide), acyl chlorides formation and acyl chlorides and the azanol reaction comprise ester that described ester derivative 8 is converted into then and be hydroxamic acid 9.Under standard conditions, ester derivative 8 (wherein said ester official can be the tert-butyl ester) is converted into described acid with trifluoroacetic acid.
Shown in reaction process 2, use the Mitsunobu reaction and adopt 2-nitro or 2-aminobenzyl alcohol derivative to make hydroxy derivative 10 alkylations that contain protection, thereby obtain intermediate 12.Reduce wherein R 4For the 2-nitro of the derivative 12 of the amino of protection and slough hydroxy-protective group, simultaneously amino and hydroxyl-functional are gone protection, obtain midbody compound 13.Make intermediate 13 and the reaction of benzyloxy carbonyl chloride then, obtain closed hoop [1,4] benzodiazepine 14.Make reactions such as this compound and acyl chlorides, aroyl chloride, assorted aroyl chloride, alkyl sulfonyl chloride, aryl sulfonyl chloride and heteroaryl SULPHURYL CHLORIDE obtain intermediate 15.
Flow process 1
Wherein
n=0-3；
m=1-3；
R 1=(C 1-C 3) alkyl; R is hydrogen, halogen;-OCH 3NO 2NH 2CF 3NHCOCH 3NHCOCH 2OCH 3CONH 2-N (R ') (R ') ,-N (R ') CO (C 1-C 3) alkyl; (C 1-C 3) alkyl;
R 3=Ar (CH 2) nCO-; Heteroaryl (CH 2) nCO-, Ar (CH 2) nSO 2-; Heteroaryl (CH 2) nSO 2-; Alkyl-O-(CH 2) nCO-; Alkyl-O-(CH 2) mSO 2-; Alkyl CO-; Alkyl SO 2-; Alkyl CO-NHCH 2CO-; And cycloalkyl (C 3-C 7) CO-; And R 4Define identical with this paper.
Flow process 2
Wherein
n=0-3；
m=1-3；
Φ=phenyl;
The DEAD=diethylazodicarboxylate;
R 6=Ar (CH 2) n-; Alkyl-; Heteroaryl (CH 2) n-; Alkyl-O-(CH 2) n-; Cycloalkyl (C 3-C 7);
R 7=Ar (CH 2) n-; Alkyl-; Heteroaryl (CH 2) n-; Alkyl-O-(CH 2) m-;
R 8=Ar (CH 2) nCO-; Ar (CH 2) nSO 2-; Alkyl CO-; Alkyl SO 2-; Heteroaryl (CH 2) nCO-; Heteroaryl (CH 2) nSO 2-; Alkyl-O-(CH 2) nCO-; Alkyl-O-(CH 2) mSO 2-.
Method with reaction process 3 and 4 explanations prepares the arylmethyl-2,3,4 that 1-replaces, 5-tetrahydrochysene-1H[1,4]-benzodiazepine .In reaction process 3, make 3-hydroxyl-2-[4-anisole alkylsulfonyl)-(2-aminobenzyl) amino]-reductive alkylation reaction that methyl propionate 6 experience is carried out with aryl formaldehyde and heteroaryl formaldehyde, thus intermediate 17 obtained.The reaction conditions of standard as with triphenyl phosphine and diethylazodicarboxylate (DEAD) reaction or with triphenyl phosphine and tetracol phenixin or carbon tetrabromide reaction, can obtain " dehydroalanine " derivative 18, encircle closure then and obtain [1,4] benzodiazepine 20.
In the approach (flow process 4) of other preparation 3-hydroxamic acid derivs 21, reduce the ester and the amide functional of N-aromatic acyl derivative 22 with reductive agent such as borine or lithium aluminum hydride.With known standard reagent with 3-(hydroxymethyl)-1-(arylmethyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine 23 oxidations, thereby hydroxymethyl is converted into formic acid, described reagent is as containing catalyzer RuO 2NaIO 4(as referring to J.Org.Chem., 46:3936 (1981); Synlett, the 143rd page, (1996)).Make acid (via acyl chlorides) and azanol coupling obtain product 21 then.Some intermediate by formula 25 examples can be used borane reduction under mild conditions, obtain derivative 25a, and wherein amidocarbonylation is reduced by selectivity.Then by ester being hydrolyzed to acid and making acyl chlorides and azanol coupling and intermediate 25a is converted into hydroxamic acid derivs.
Flow process 3
Flow process 4
R wherein 8=alkyl, aralkyl, aryloxy alkyl, Heterocyclylalkyl or alkoxy alkoxy alkyl.
Preferred other compounds of the present invention are for having those compounds of basic group in 1-(carbonyl of replacement), they can prepare according to the method shown in the reaction process 5.The method of describing with reaction process 5 makes 2,3,4,5-tetrahydrochysene-1H-[1,4]-benzodiazepine 14 (at 1 unsubstituted) and phosgene derivatives reaction, obtain intermediate 25, be translated into acid 26 and hydroxamic acid 27 then.Make the 2-[(2-aminobenzyl)-(4-anisole alkylsulfonyl) amino]-3-hydroxy methyl propionate 6 and acyl chloride reaction also can synthetic intermediates 25, thus obtain " dehydroalanine " derivative 28.As previously mentioned, thereby can make gentle alkali such as sodium bicarbonate and these derivatives reactions carry out 1 at the position of double bond of intermediate 28, the 4-addition reaction encircles closure, obtains 7 yuan 2,3,4 thus, 5-tetrahydrochysene-1H-[1,4] diaza 25.
Flow process 5
Figure 9980423700501
Shown in reaction process 6; by the catalytic bromo aroyl of standard palladium or bromo 4-hetaroylpyrazol derivatives 29 and coupled reaction under known condition such as suitable aryl stannane, heteroaryl stannane, aryl boric acid, heteroaryl boric acid, aryl triflate, heteroaryl triflate, can synthesizing aryl-aryl carbonyl, heteroaryl-aryl carbonyl, aryl-heteroaryl carbonyl, heteroaryl-heteroaryl carbonyl derivative 30.For example see Synthesis, 563-566 (1997); J.Org.Chem., 62:3405-3406, (1997); Tetrahedron Lett., 36:5247-5250, (1995); Heterocycles, 45:467, (1997); Tetrahedron Lett., 38:1118-1182, (1997); Heterocycles, 42:189-194, (1996); Tetrahedron Lett., 5005-5006, (1993); Synthesis, 843, (1987); Heterocycles, 2711-2716, (1987); With Tetrahedron Lett., 4407-4410 (1986).
By with the palladium catalyst coupling, can prepare aryl-aryl, heteroaryl-aryl, aryl-heteroaryl and heteroaryl-heteroaryl carboxylates derivatives and these derivatives are converted into the carboxylic acid intermediate.Then these acid are converted into acyl chlorides, and make itself and 2-[(2-aminobenzyl shown in the intermediate 31 as derivative 6 is converted into)-(4-replaces-benzenesulfonyl) amino]-reaction of 3-hydroxy propionate.Following reference has been described the method for synthetic following compounds respectively: 3-aryl-pyrrolidine-4-methyl-formiate, J.Org.Chem., 62:2649-2651, (1997); (2-aminomethyl phenyl) methyl benzoate, J.Org.Chem., 62:3405-3406, (1997); With the methyl benzoate that is replaced by heterocycle such as furyl, thienyl or pyridyl, Tetrahedron Lett., 27:4407-4410, (1986).
Flow process 6
Figure 9980423700521
Y is H, F, Cl, CF 3, CH 3Or OCH 3
X is halogen, hydrogen or (C 1-C 3) alkyl;
R and R ' are with identical in this definition; With
R 4With identical in this definition.
Method with reaction process 7 examples can prepare intermediate 2,4,5 by glycinate, 6-tetrahydrochysene-1H-[1,4] benzodiazepine 39 and 38.In this route of synthesis; in the presence of salt of wormwood, at N; in dinethylformamide or the 1-Methyl-2-Pyrrolidone; carry out the alkylation of N-(4-replaces-benzenesulfonyl) derivative of glycine ethyl ester, tert-butyl glycinate or glycine methyl ester 33 with (R) or unsubstituted (R=H) 2-nitrobenzyl bromine that replaces, obtain intermediate 34.Perhaps at first make N-(4-replaces-benzenesulfonyl) glycinate such as methyl esters 33 and sodium hydride at N; react in dinethylformamide or the 1-Methyl-2-Pyrrolidone; make negatively charged ion and replacement or the unsubstituted 2-nitrobenzyl bromine reaction of generation subsequently, obtain compound 34.Under the standard reaction condition (as at Fieser and Fieser, 10:160-161; The condition that proposes among the 8:194), make derivative 34 and N, N-dimethyl (methylene radical) ammonium chloride or N, the reaction of N-dimethyl (methylene radical) ammonium iodide, obtain dimethylaminomethyl (Mannich type) compound, use it for the elimination reaction and obtain " dehydroalanine " derivative 37 or 36 direct cyclizations are obtained 39 by the elimination-addition reaction for intermediate.Compound 37 cyclizations obtain intermediate 38, are translated into hydroxamic acid.Be included in Lewis acid such as BF to being converted into the variation that 39 reaction conditions carries out with 36 3Exist and to heat or to heat 36 acid salt down and carry out the elimination-addition reaction.
Flow process 7
Figure 9980423700541
Can synthesize the intermediate carboxylic acid that is converted into tetrahydrochysene [1,4] benzodiazepine -3-formic acid oxyamide by the various approach shown in the flow process 1-8.During the required product of synthesis type 1, the approach shown in the approach preferred flow 8 relatively.Under these conditions, prepare wherein R 4Substituting group is the intermediate carboxylicesters of intermediate 41 of OH or the acid of intermediate 44.R wherein 4For the intermediate of OH can be by the wherein OH quilt derivative preparation of the alternative radical protection of sloughing subsequently.R wherein 4Be OCH 3Derivative 40 be the precursor that is fit to of required phenoloid 41 and 44, can separate by cracking oxygen methyl bond cleavage.Shown in flow process 8, the negatively charged ion of phenol OH can in-situ preparing and alkylation.Suitable alkali is alkaline carbonate, hydride, alcoholate and organic bases.With formula (C 1-C 6) reaction of alkylation group of alkyl-X (wherein X is reactive leavings group such as chlorion, bromide anion, iodide ion, O-tosylate O-methanesulfonate) representative can obtain derivative 42 and 45.
Alkylated reaction can be with carboxylicesters as 41 or carry out as 44 with carboxylic acid.Phenoloid 41 and 44 is reacted under the Mitsunobe reaction conditions, obtain O-alkyl derivative 42 and 45.Those reaction conditionss that standard Mitsunobe reaction conditions such as those are described in following document can be used for coupled reaction: J.Heterocyclic Chem., 34:349 (1997); Tetrahedron Lett.37:6349 (1996); J.Org.Chem., 56:7173 (1991); Tetrahedron Lett.5709 (1989); Synthesis 1:28 (1981).
Flow process 8
Have basic group compound of the present invention can with by pharmaceutically or the form of physiologically acceptable sour deutero-salt use.Such salt includes, but is not limited to the salt with mineral acid (example hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid) or organic acid (as acetate, oxalic acid, amber white acid and toxilic acid) formation.Salt with compound of acidic-group comprises the salt that forms with basic metal or alkaline-earth metal (as sodium, potassium, calcium and magnesium) or organic bases.
When using compound of the present invention, the pharmaceutically acceptable carrier of they and one or more such as solvent, thinner etc. can be mixed with the medicinal compositions form.Can be with tablet, capsule, can disperse powder, granule, suspension agent, syrup or elixir form per os to give this type of to contain compound compositions of the present invention; Also can give with aseptic injectable solution or form of suspension parenteral; Perhaps with form topical administrations such as creme, lotion, paste.This type of medicinal compositions can contain about 100mg of the 1-that has an appointment and carrier blended active ingredient.
The effective dose that is used for the treatment of the The compounds of this invention of concrete disease depends on employed particular compound, administering mode and the type and the severity of the disease of being treated.Yet, when the dosage with about 0.001-1000mg/kg body weight gives compound of the present invention, generally can obtain gratifying effect.
As mentioned above, can give compound of the present invention by per os, equally also can vein, intramuscular, subcutaneous or topical administration.The solid carrier that is used to prepare tablet, capsule etc. comprises starch, lactose, Lin Suanergai, Microcrystalline Cellulose, sucrose and kaolin.The liquid vehicle that is used to prepare the present composition comprises sterilized water, polyoxyethylene glycol, nonionogenic tenside and edible oil such as Semen Maydis oil, sesame oil and peanut oil.The conventional auxiliary that is used to prepare medicinal compositions also can comprise as correctives, tinting material, sanitas and antioxidant.
Biological activity according to following method test The compounds of this invention.
External gelatinase is measured
This mensuration is based on gelatinase to the ((cracking of Ac-Pro-Leu-Gly (2-sulfydryl-4-methyl-pentanoyl)-Leu-Gly-OEt) (derive from Bachem Bioscience) of sulphur peptide substrates; thereby release can ((5,5 '-dithio-two (2-nitro-phenylformic acid)) produce the substrate product of color reaction with DTNB.This mensuration is disclosed in " the Spectrophotometric Assay forVertebrate Collegenase " of Weingarten etc., Anal.Biochem., 147:437-440, (1985).Advance the speed according to color and to measure described enzymic activity.
Described sulphur peptide substrates is mixed with the fresh storing solution of 20mM with 100%DMSO, DTNB is dissolved in be mixed with the 100mM storing solution among the 100%DMSO and store in the dark place under room temperature.Before using described substrate and DTNB one are reinstated substrate buffer solution (50mM HEPES, pH 7.5,5mM calcium chloride) dilution and be 1mM.With measure damping fluid (50mM HEPES, pH7.5,5mM calcium chloride, 0.02%Brij) people's neutrophilic granulocyte gelatinase B being diluted to final concentration is 0.15nM.
To measure damping fluid, enzyme, DTNB/ substrate (final concentration is 500 μ M) and solvent or inhibitor and add to 96 well culture plates (total reaction volume is 200 μ l), read to increase by 5 minutes in 405nm punishment light detection color on the plate instrument.
With OD 405Increase mapping and calculate gained collinear slope.Slope is represented speed of reaction.Confirm the linearity (r of this speed of reaction 2＞0.85), the average of calculating contrast speed (x ± sem), and according to the significance,statistical (p＜0.05) of the multinomial comparing check comparison of DunnettShi with drug treating group speed.Obtain dose-response relationship with a plurality of drug doses, estimate the IC of 95%CI according to linear regression 50Value.
External collagenase is measured
This mensuration is based on collagenase to peptide substrates ((Dnp-Pro-Cha-Gly-Cys (Me)-His-Ala-Lys (NMa)-NH 2) (derive from Peptide Intemational, Inc.) cracking, thereby produce fluorescence NMa group, can be according to Bickett etc. at " A High ThroughoutFluorogenic Substrate for Interstitial Collagenase (MMP-1) andGelatinase (MMP-9) ", Anal.Biochem., 212:58-64, disclosed method is carried out quantitatively this group with photofluorometer in (1993).The fluorescence of NMa in the complete substrate of Dnp quencher.
This be determined at contain the people reassemble into the fibrocyte collagenase (brachymemma, mw=18,828, derive from Wyeth-Ayerst Research, Radnor, and HCBC mensuration damping fluid PA) (50mMHEPES, pH 7.0,5mM calcium ion, 0.02%Brij, 0.5% halfcystine) in carry out.Be dissolved in described substrate in the methyl alcohol and with 1mM equal portions refrigerated storage.With collagenase in damping fluid with 25 μ M equal portions refrigerated storage.When measuring, with described substrate be dissolved in the HCBC damping fluid to final concentration be 10 μ M and the final concentration of collagenase is 5nM.Testing compound is dissolved among methyl alcohol, DMSO or the HCBC.With HCBC dilution methyl alcohol and DMSO to＜1.0%.Described compound is added in 96 well culture plates that contain enzyme, and add substrate startup reaction.
Read reaction 10 minutes (exciting in 340nm), fluorescence is increased in time with linear mapping in the 444nm emission.Calculate this collinear slope of representing speed of reaction.Confirm the linearity (r of this speed of reaction 2＞0.85).The average of calculating contrast speed (x ± sem), and according to the significance,statistical (p＜0.05) of the multinomial comparing check comparison of DunnettShi with drug treating group speed.Obtain dose-response relationship with a plurality of drug doses, estimate the IC of 95%CI according to linear regression 50Value.
Measure the method that TACE suppresses
The DMSO solution (final concentration is 1 μ M, DMSO concentration＜1%) that in each hole of 96 hole black microtiter plates, adds the solution contain following material: 10 μ l TACE (deriving from Immunex) (final concentration is 1 μ g/mL), 70 μ L Tris damping fluids (pH7.4 also contains 10% the glycerine that final concentration is 10mM) and 10 μ l test-compounds.Under room temperature, culture plate was hatched 10 minutes.In each hole, add fluorescence peptide substrate (final concentration is 100 μ M) and shake startup reaction in 5 seconds at wobbler simultaneously.
Read reaction 10 minutes (exciting in 340nm), fluorescence is increased in time with linear mapping in the 444nm emission.Calculate this collinear slope of representing speed of reaction.Confirm the linearity (r of this speed of reaction 2＞0.85).The average of calculating contrast speed (x ± sem), and according to the significance,statistical (p＜0.05) of the multinomial comparing check comparison of DunnettShi with drug treating group speed.Obtain dose-response relationship with a plurality of drug doses, estimate the IC of 95%CI according to linear regression 50Value.
In table 1, provide the result that these standard test testing method obtain.
Table 1
Figure 9980423700591
Figure 9980423700601
Figure 9980423700611
Now the present invention will be described with reference to following indefiniteness embodiment.
With reference to embodiment 1
(L) N-(benzyloxycarbonyl)-O-benzyl serine tert-butyl
Be cooled in Xiang Zaibing-salt bath in-6 ℃ the 600ml dichloromethane solution of 25g (0.076mol) N-(benzyloxycarbonyl)-O-benzyl Serine and be blown into iso-butylene, simultaneously to wherein dripping the 4.1ml vitriol oil.This mixture was stirred 4 hours, and according to Synthetic Commun., 26:2723 handles described in (1996), obtains the product 29.24g into yellow oil.
With reference to embodiment 2
The L-serine tert-butyl is in 65 ℃, the 600ml methyl alcohol mixed liquor that 29.24g (0.076mol) is derived from (L) N-(benzyloxycarbonyl)-O-benzyl serine tert-butyl, 24.1g (0.38mol) ammonium formiate and 38.3g 10% palladium on carbon with reference to embodiment 1 heated 20 hours, stirred under room temperature and spent the night.By this mixed solution of diatomite filtration, use the methanol wash filter plate.Concentrated filtrate obtains 12.18g (99.6%) as Synthetic Commun., the product described in the 26:2723 (1996).
With reference to embodiment 3
N-(4-anisole alkylsulfonyl)-L-serine tert-butyl (3-hydroxyl-2-(4-anisole sulfonamido) propionic acid tert-butyl ester)
In the 160ml dichloromethane solution (in ice bath, cooling off) of 12.18g (0.0756mol) L-serine tert-butyl, 26.52ml triethylamine, add 16.1g (0.0771mol) 4-anisole sulphonyl nitrogen with aliquot.In 0 ℃ this mixed solution was stirred 0.5 hour, under room temperature, stir and spend the night.Water, 2N citric acid and this mixed solution of salt water washing are through dried over sodium sulfate.Vacuum is removed solvent, obtains the 25.34g solid, and it is ground with hexane.Make solid recrystallization from 120ml toluene, obtain 12.18g (48.7%) and be the product of white solid.Concentrated filtrate through silica gel column chromatography, as elutriant, obtains 5.71g (22.8%) white solid with hexane-ethyl acetate (7: 3) with residue.m．p．70-75℃。To C 14H 21NO 6S analyzes:
Calculated value: C, 50.7; H, 6.4; N, 4.2;
Measured value: C, 50.4; H, 6.3; N, 4.4.
With reference to embodiment 4
3-hydroxyl-2-[(4-anisole alkylsulfonyl)-(2-nitrobenzyl) amino] the propionic acid tert-butyl ester
50ml N to refrigerative 6.16g (18.6mmol) 3-hydroxyl-2-(4-anisole sulfonamido)-propionic acid tert-butyl ester in ice bath adds 0.781g (19.5mmol) sodium hydride in the dinethylformamide solution.After stopping to produce gas, drip the 18mlN of 4.02g (18.6mmol) 2-nitrobenzyl bromine, dinethylformamide solution.Under room temperature, nitrogen environment, this mixed solution was stirred 4 hours, add 1.0g 2-nitrobenzyl bromine.Under room temperature this mixed solution stirring is spent the night, vacuum is removed solvent.The dilute with water residue extracts with diazomethane.Water and salt water washing organic extract are through dried over sodium sulfate.Remove solvent, obtain the 11.2g solid, through silica gel column chromatography, use hexane-ethyl acetate (1: 1) and hexane-ethyl acetate (35: 65) it successively as elutriant.Merge the component that contains product, remove solvent then, obtain 7.7g (89%) solid.From the 3mmol sample, obtain jelly.To C 21H 26N 2O 8S analyzes:
Calculated value: C, 54.1; H, 5.6; N, 6.0;
Measured value: C, 54.0; H, 5.7; N, 6.0.
With reference to embodiment 5
The 2-[(2-aminobenzyl)-(4-anisole alkylsulfonyl) amino]-the 3-hydroxy-propionic acid tert-butyl ester
In 90 ℃, in oil bath with 0.60g (1.28mmol) 3-hydroxyl-2-[(4-anisole alkylsulfonyl)-(2-nitrobenzyl) amino] the propionic acid tert-butyl ester and 1.45g (6.45mmol) SnCl 22H 2The 20ml methyl alcohol mixed liquor heating of O 2 hours.Vacuum is removed solvent, adds ethyl acetate in residue.With saturated sodium hydrogen carbonate solution this mixed solution that neutralizes, pass through diatomite filtration.The separating ethyl acetate layer, water and salt water washing are through dried over sodium sulfate.Vacuum is removed solvent, obtains 0.30g (53%) jelly.To C 21H 28N 2O 6S analyzes:
Calculated value: C, 57.8; H, 6.5; N, 6.4;
Measured value: C, 57.8; H, 7.0; N, 6.2.
With reference to embodiment 6
The 2-[(2-aminobenzyl)-(4-anisole alkylsulfonyl) amino]-the 3-hydroxy-propionic acid
Under room temperature, with 0.75g (1.72mmol) 2-[(2-aminobenzyl)-(4-anisole alkylsulfonyl) amino]-the 6ml dichloromethane solution of the 3-hydroxy-propionic acid tert-butyl ester and 6ml trifluoroacetic acid stirred 3 hours, and vacuum concentration is to doing then.In residue, add entry, methylene dichloride and 1N sodium hydroxide to water layer pH be 8.Separate water layer then,, use ethyl acetate extraction with the acidifying of 2N citric acid.Water and salt water washing extract are through dried over sodium sulfate.Vacuum is removed solvent, obtains 0.35g (54%) solid.To C 17H 20N 2O 6S analyzes:
Calculated value: C, 53.7; H, 5.3; N, 7.4;
Measured value: C, 53.0; H, 5.3; N, 6.9.
With reference to embodiment 7
2-{ (2-[3-(trifluoromethyl benzoyl) aminobenzyl]-(4-anisole alkylsulfonyl) amino } tert-butyl acrylate
Under room temperature, with 0.43lg (1mmol) 2-[(2-aminobenzyl)-(4-anisole alkylsulfonyl) amino]-the 2ml methylene dichloride mixed solution of the 3-hydroxy-propionic acid tert-butyl ester, 0.474g (2.2mmol) 3-(trifluoromethyl) Benzoyl chloride and 1ml pyridine stirred 3.5 hours.This mixed solution is inclined to water, use dichloromethane extraction.Water, 2N citric acid, water, 1N sodium bicarbonate and salt water washing extract are through dried over sodium sulfate.Remove solvent, obtain the 0.72g solid.This solid is dissolved in the 2ml tetrahydrofuran (THF), to wherein adding the 1.5ml triethylamine.In 65 ℃ with this solution heated overnight, vacuum concentration is to doing.Use the dichloromethane extraction residue, wash extract with water, through dried over sodium sulfate.Vacuum is removed solvent, and obtaining 0.55g is the solid product.By similar method, product through silica gel column chromatography, with hexane-eluent ethyl acetate, is obtained solid, m.p.65-72 ℃.To C 29H 29F 3N 2O 6S analyzes:
Calculated value: C, 59.0; H, 5.0; N, 4.7;
Measured value: C, 59.2; H, 5.2; N, 4.4.
With reference to embodiment 8
4-(4-anisole alkylsulfonyl)-1-(3-trifluoromethyl benzoyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-t-butyl formate
Under room temperature; with 0.55g (0.932mmol) 2-{ (2-[3-(trifluoromethyl benzoyl) aminobenzoic acidic group]-(4-anisole alkylsulfonyl) amino the mixed solution of 4ml methyl alcohol of tert-butyl acrylate and 0.102g (1.21mmol) sodium bicarbonate stirs and spends the night, and removes solvent.Use the dichloromethane extraction residue, water and salt water washing extract are through dried over sodium sulfate.Remove solvent, obtain the 0.57g solid.This solid through thick-layer silica-gel plate chromatography, as solvent, is obtained the 0.30g faint yellow solid, m.p.57-60 ℃ with hexane-ethyl acetate (1: 1).To C 29H 29F 3N 2O 6S analyzes:
Calculated value: C, 59.0; H, 5.0; N, 4.7;
Measured value: C, 58.8; H, 5.0; N, 4.6.
With reference to embodiment 9
4-(4-anisole alkylsulfonyl)-1-(3-trifluoromethyl benzoyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
Under room temperature; with 0.36g (0.61mmol) 4-(4-anisole alkylsulfonyl)-1-(3-trifluoromethyl benzoyl)-2,3,4; 5-tetrahydrochysene-1H-[1,4] mixed solution of the 3ml methylene dichloride of benzodiazepine -3-t-butyl formate and 3ml trifluoroacetic acid stirred 3 hours.This mixed solution of vacuum concentration is used the dichloromethane extraction residue to doing.With 1N sodium bicarbonate washing dichloromethane layer,, use ethyl acetate extraction with 2N citric acid acidifying water layer (pH 8).Dry (sodium sulfate) extract.With 2N citric acid, water and salt water washing dichloromethane extract, through dried over sodium sulfate.Combined dichloromethane extract and acetic acid ethyl ester extract, vacuum is removed solvent, obtains the 0.3lg solid, m.p.105-110 ℃.To C 25H 21F 3N 2O 6S analyzes:
Calculated value: C, 56.2; H, 4.0; N, 5.2;
Measured value: C, 55.1; H, 3.7; N, 5.0.
With reference to embodiment 10
1-([1,1 '-xenyl]-2-carbonyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] and diaza -3-methyl-formiate
To in 0 ℃ of refrigerative 1.5g (3.8mmol) 2-[(2-aminobenzyl)-(4-anisole alkylsulfonyl) amino]-add the 6ml dichloromethane solution of [1,1 '-xenyl]-2-carbonyl chloride in the 12ml methylene dichloride mixed solution of 3-hydroxy methyl propionate and 2.65ml triethylamine.Under room temperature, this mixed solution stirring is spent the night, with methylene dichloride and water dilution.Separate organic layer, with 2N citric acid and salt water washing, through dried over sodium sulfate.Vacuum is removed solvent, obtains 2.2g white foam shape thing.To C 31H 28N 2O 6S analyzes:
Calculated value: C, 66.9; H, 5.1; N, 5.0;
Measured value: C, 67.3; H, 5.2; N, 4.7.
With reference to embodiment 11
4-(4-anisole alkylsulfonyl)-1-(2-methyl-5-fluoro benzoyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
To 1.5g (3.8mmol) the 2-[(2-aminobenzyl that is cooled to 0 ℃)-(4-anisole alkylsulfonyl) amino]-add 1.36g (11.4mmol) 2-methyl-5-fluorobenzoyl chloride in the mixed solution of the 15ml methylene dichloride of 3-hydroxy methyl propionate and 2.64ml (18.97mmol) triethylamine.Under room temperature, this mixed solution stirring is spent the night, dilute this solution, separate organic layer, with 2N citric acid and salt water washing, through dried over sodium sulfate with methylene dichloride and water.Vacuum is removed solvent, obtains 2.2g white foam shape thing.To C 26H 25FN 2O 6S analyzes:
Calculated value: C, 60.9; H, 4.9; N, 5.5;
Measured value: C, 60.9; H, 5.0; N, 5.0;
Mass spectrum (ES) 513.4 (M+H).
With reference to embodiment 12
4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
To 5.0g (12.68mmol) the 2-[(2-aminobenzyl that is cooled to 0 ℃)-(4-anisole alkylsulfonyl) amino]-add 9.05ml (63.4mmol) benzyl chloroformate in the mixed solution of the 50ml methylene dichloride of 3-hydroxy methyl propionate and 17.7ml (26.8mmol) triethylamine.This mixed solution stirring is spent the night, be cooled to 0 ℃ then, to wherein adding 8ml triethylamine and 9.05ml (63.4mmol) benzyl chloroformate.This mixed solution stirring is spent the night, and water, 2N citric acid and salt water washing then is through dried over sodium sulfate.Vacuum is removed solvent, obtains the 6.95g solid.This solid through silica gel column chromatography, with hexane-ethyl acetate (1: 1) wash-out, is obtained the product of 2.7g for sticking yellow oil.From 0.5g, obtain 0.178g oily matter by similar method.To C 18H 20N 2O 5S analyzes:
Calculated value: C, 57.4; H, 5.4; N, 7.4; S, 8.5;
Measured value: C, 57.9; H, 5.4; N, 6.7; S, 7.9;
Mass spectrum (ES) 377.2 (M+H).
With reference to embodiment 13
3-hydroxyl-2-(4-anisole sulfonamido) methyl propionate
To 5.0g (32.14mmol) D that is cooled to 0 ℃, drip 6.64g (32.14mmol) 4-anisole SULPHURYL CHLORIDE in the mixed solution of the 100ml methylene dichloride of L-serine methylester and 15.7ml (0.012mol) triethylamine.Under room temperature, ar gas environment, this mixed solution was stirred 2 days then.Dilute this mixed solution with the 100ml methylene dichloride, each 60ml washing of water, 2N citric acid and salt solution then is through dried over sodium sulfate.Vacuum is removed solvent, obtains solid.Crystallization from ethyl acetate obtains 5.0g (54%) white crystals.m．p．92-94℃。To C 11H 15NO 6S analyzes:
Calculated value: C, 45.7; H, 5.2; N, 4.8; S, 11.1;
Measured value: C, 45.6; H, 5.2; N, 4.8; S, 11.1.
With reference to embodiment 14
3-hydroxyl-2-[(4-anisole alkylsulfonyl)-(2-nitrobenzyl) amino] methyl propionate
125mlN to refrigerative 15.0g (51.85mmol) 3-hydroxyl-2-(4-anisole sulfonamido) methyl propionate in ice bath drips 2.29g (57.03mmol) sodium hydride (60% in oil) in the dinethylformamide solution.In 0 ℃ this mixed solution was stirred 20 minutes, drip the anhydrous N of 25ml of 12.32g (57.03mmol) 2-nitrobenzyl bromine then, dinethylformamide solution.Under room temperature with this solution stirring 48 hours, with 500ml ethyl acetate and water dilution.Separate organic layer, with 250ml ethyl acetate extraction water layer.Organic layer and extract that each the 200ml washing of water, 1N sodium bicarbonate and salt solution merges are through dried over sodium sulfate.Remove solvent, grind residual solid with ethyl acetate, cooling is also filtered, and obtains 13.5g (61%) white crystals, m.p.127-129 ℃.Sample (3.0g) obtains 2.32g white crystals, m.p.127-129 ℃.To C 18H 20N 2O 8S analyzes:
Calculated value: C, 50.9; H, 4.8; N, 6.6;
Measured value: C, 50.9; H, 4.8; N, 6.5.
With reference to embodiment 15
The 2-[(2-aminobenzyl)-(4-anisole alkylsulfonyl) amino]-the 3-hydroxy methyl propionate
Under nitrogen environment; to 1.5g (3.53mmol) 3-hydroxyl-2-[(4-anisole alkylsulfonyl)-(2-nitrobenzyl) amino] add 1.12g (17.69mmol) ammonium formiate in the mixed solution of 5ml dehydrated alcohol of methyl propionate, then add 0.50g 10% palladium on carbon.Under room temperature, this mixed solution stirring is spent the night, in 80 ℃ of heating 2 hours.By this mixed solution of diatomite filtration, vacuum concentrated filtrate obtains semisolid to doing.Grind with ethyl acetate, obtain 0.65g (47%) white crystals, m.p.138-140 ℃.To C 18H 21N 2O 6S analyzes:
Calculated value: C, 54.8; H, 5.6; N, 7.1;
Measured value: C, 53.0; H, 5.6; N, 6.8.
With reference to embodiment 16
3-hydroxyl-2-{ (4-anisole alkylsulfonyl)-[2-(2,2, the 2-trifluoroacetamido) benzyl] amino } methyl propionate
To 0.50g (1.27mmol) 2-[(2-aminobenzyl)-(4-anisole alkylsulfonyl) amino]-add 1.8ml (12.7mmol) trifluoroacetic anhydride in the 5ml dichloromethane solution of 3-hydroxy methyl propionate.With this solution stirring 1 hour, vacuum concentration was to doing.Add methyl alcohol in residue, vacuum is removed solvent.Repeat to add methyl alcohol and be concentrated into and do twice.Residue launches with hexane-ethyl acetate (1: 1) through silica gel thick laminate chromatography, obtains 0.50g flint glass shape thing.To C 20H 21F 3N 2O 7S analyzes:
Calculated value: C, 49.0; H, 4.3; N, 5.7;
Measured value: C, 49.0; H, 4.5; N, 5.4.
With reference to embodiment 17
2-[(4-anisole alkylsulfonyl)-(2-nitrobenzyl) amino] methyl acrylate
To 1.0g (2.356mmol) 3-hydroxyl-2-[(4-anisole alkylsulfonyl that is cooled to-10 ℃)-(2-nitrobenzyl) amino] add 0.539g (2.83mmol) 4-Methyl benzenesulfonyl chlorine in the 2ml pyridine solution of methyl propionate.With this solution cool overnight, add 4ml pyridine and 0.539g (2.83mmol) 4-Methyl benzenesulfonyl chlorine.Stir this mixed solution and cooled off dilute with water 24 hours in-10 ℃.With this mixed solution of ethyl acetate extraction, water, 2N citric acid and salt water washing extract, dry (sodium sulfate) then.Vacuum is removed solvent, obtains 1.2g oily matter.This oily matter is dissolved in the 6ml pyridine, to wherein adding 1.08g 4-Methyl benzenesulfonyl chlorine.Under room temperature, dilute with water is spent the night in this mixed solution stirring.With this mixed solution of ethyl acetate extraction, water, 2N citric acid and salt water washing extract are then through dried over sodium sulfate.Remove solvent, obtain the 1.0g brown oil.Make the crystallization from ethanol of this oily matter, obtain white crystals, m.p.65-67 ℃.To C 18H 18N 2O 7S analyzes:
Calculated value: C, 53.2; H, 4.5; N, 6.9;
Measured value: C, 53.7; H, 4.5; N, 7.2.
With reference to embodiment 18
2-{ (4-anisole alkylsulfonyl)-[2-(4-pyridyl carbonyl) aminobenzyl] amino } methyl acrylate
To 1.5g (3.80mmol) the 2-[(2-aminobenzyl that is cooled to 0 ℃)-(4-anisole alkylsulfonyl) amino]-add 1.7g (9.5mmol) 4-pyridyl carbonyl chloride (different nicotinoyl chlorine) in the 15ml methylene fluoride mixed solution of 3-hydroxy methyl propionate and 3.0ml (21.6mmol) triethylamine.Under room temperature, this mixed solution stirring is spent the night, dilute with methylene dichloride.Water, 2N citric acid and this mixed solution of salt water washing are then through dried over sodium sulfate.Remove solvent, obtain the filbert solid of 1.8g; To C 24H 23N 3O 6S analyzes:
Calculated value: C, 59.9; H, 4.8; N, 8.7; S, 6.6;
Measured value: C, 59.0; H, 4.8; N, 8.5; S, 6.9;
Mass spectrum (ES) 482.6 (M+H).
Employing is with reference to embodiment 18 described methods, by suitable unsubstituted 2-[(2-aminobenzyl)-(4-anisole alkylsulfonyl) amino]-3-hydroxy methyl propionate or the 2-[(that suitably replaces replace-the 2-aminobenzyl)-(4-anisole alkylsulfonyl) amino]-the 3-hydroxy methyl propionate can prepare following midbody compound.
With reference to embodiment 19
2-{ (4-anisole alkylsulfonyl)-[2-(2,2, the 2-trifluoroacetamido) benzyl] amino } the methyl acrylate white crystals, m.p.120-121 ℃.To C 20H 19F 3N 2O 6S analyzes:
Calculated value: C, 50.9; H, 4.1; N, 5.9;
Measured value: C, 50.8; H, 4.2; N, 5.6.
With reference to embodiment 20
2-[(2-benzamido benzyl)-(4-anisole alkylsulfonyl) amino] the methyl acrylate yellow oil.To C 25H 24N 2O 6S analyzes:
Calculated value: C, 62.5; H, 5.0; N, 5.8;
Measured value: C, 62.7; H, 5.3; N, 5.0.
With reference to embodiment 21
2-[(2-kharophen benzyl)-(4-anisole alkylsulfonyl) amino] methyl acrylate
With reference to embodiment 22
2-((4-anisole alkylsulfonyl)-and 2-[(3-pyridyl carbonyl) amino] benzyl } amino) methyl acrylate
Pale solid.To C 25H 23N 3O 6S analyzes:
Calculated value: C, 59.9; H, 4.8; N, 8.7; S, 6.6;
Measured value: C, 58.9; H, 4.8; N, 8.4; S, 6.4.
Mass spectrum (ES) 482.8 (M+H)
With reference to embodiment 23
2-((4-anisole alkylsulfonyl)-{ [(2-thienyl carbonyl) amino] benzyl } amino) methyl acrylate brown solid.To C 23H 22N 2O 6S 2Analyze:
Calculated value: C, 56.8; H, 4.6; N, 5.8;
Measured value: C, 55.7; H, 4.4; N, 4.9.
With reference to embodiment 24
2-{[2-(methoxyl group kharophen) benzyl]-(4-anisole sulfonamido } the methyl acrylate yellow oil.To C 21H 24N 2O 7S analyzes:
Calculated value: C, 56.2; H, 5.4; N, 6.3;
Measured value: C, 55.3; H, 5.6; N, 5.8.
With reference to embodiment 25
2-{ (4-(anisole alkylsulfonyl)-[2-(just-and sulfonyl propyl amino) benzyl] amino } the filbert oily thing of methyl acrylate.To C 21H 26N 2O 7S 2Analyze:
Calculated value: C, 52.3; H, 5.4; N, 5.8;
Measured value: C, 51.9; H, 5.4; N, 5.7.
With reference to embodiment 26
2-{[2-(3-phenyl propionyl) aminobenzyl]-(4-anisole alkylsulfonyl) amino } the filbert oily thing of methyl acrylate.To C 27H 28N 2O 6S analyzes:
Calculated value: C, 63.8; H, 5.6; N, 5.5;
Measured value: C, 66.7; H, 5.8; N, 4.1.
With reference to embodiment 27
2-{[2-(3-trifluoromethyl benzoyl) aminobenzyl]-(4-anisole alkylsulfonyl) amino } tert-butyl acrylate
Yellow solid; M.p.65-72 ℃
With reference to embodiment 28
2-{[2-(4-xenyl carbonyl) aminobenzyl]-(4-anisole alkylsulfonyl) amino } the methyl acrylate white solid.To C 31H 28N 2O 6S analyzes:
Calculated value: C, 66.9; H, 5.1; N, 5.0;
Measured value: C, 66.1; H, 5.0; N, 5.1.
With reference to embodiment 29
2-{[2-(cyclopropyl carbonyl) aminobenzyl]-(4-anisole alkylsulfonyl) amino } the methyl acrylate yellow oil.To C 22H 24N 2O 6S analyzes:
Calculated value: C, 59.5; H, 5.4; N, 6.3;
Measured value: C, 60.0; H, 5.7; N, 6.0.
Mass spectrum (ES) 445.5 (M+H)
With reference to embodiment 30
2-{[2-(cyclohexyl-carbonyl) aminobenzyl]-(4-anisole alkylsulfonyl) amino } methyl acrylate white foam shape thing.To C 25H 30N 2O 6S analyzes:
Calculated value: C, 61.7; H, 6.2; N, 5.8;
Measured value: C, 59.1; H, 6.0; N, 5.4.
Mass spectrum (ES) 487.5 (M+H)
With reference to embodiment 31
2-{[2-(3-fluoro benzoyl) aminobenzyl]-(4-anisole alkylsulfonyl) amino } methyl acrylate
With reference to embodiment 32
2-{[2-(3-chlorobenzene formacyl) aminobenzyl]-(4-anisole alkylsulfonyl) amino } methyl acrylate
With reference to embodiment 33
2-{[2-(2,4 dichloro benzene formyl radical) aminobenzyl]-(4-anisole alkylsulfonyl) amino } methyl acrylate
With reference to embodiment 34
2-{[2-(2, the 3-difluoro benzoyl) aminobenzyl]-(4-anisole alkylsulfonyl) amino } methyl acrylate
With reference to embodiment 35
2-{[2-(2-chloro-4-fluoro benzoyl) aminobenzyl]-(4-anisole alkylsulfonyl) amino } methyl acrylate
With reference to embodiment 36
2-{[2-(2-furyl carbonyl) aminobenzyl]-(4-anisole alkylsulfonyl) amino } the methyl acrylate pale solid.To C 23H 22N 2O 7S analyzes:
Calculated value: C, 58.7; H, 4.7; N, 6.0;
Measured value: C, 58.0; H, 4.1; N, 3.8.
Mass spectrum (ES) 470.9 (M+H)
With reference to embodiment 37
2-((4-anisole alkylsulfonyl)-and the 2-[(3-thienyl carbonyl) amino] benzyl } amino) methyl acrylate
With reference to embodiment 38
2-{[2-(2-kharophen ethanoyl) aminobenzyl]-(4-anisole alkylsulfonyl) amino } methyl acrylate
With reference to embodiment 39
2-{[2-(2-dimethyl ethanoyl) aminobenzyl]-(4-anisole alkylsulfonyl) amino } methyl acrylate
With reference to embodiment 40
2-{[2-(cyclobutyl carbonyl) aminobenzyl]-(4-anisole alkylsulfonyl) amino } methyl acrylate
With reference to embodiment 41
1-methoxyl group ethanoyl-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
To 0.449g (1mmol) 2-[[2-(2-methoxyl group kharophen)-benzyl]-(4-anisole alkylsulfonyl) amino } add the anhydrous sodium bicarbonate of 0.109g (1.3mmol) in the 5ml anhydrous methanol mixed solution of methyl acrylate.This mixed solution stirred under room temperature spend the night solvent removed in vacuo.In above-mentioned residue, add ethyl acetate and water.Separate organic layer, water and salt water washing are also used dried over sodium sulfate.Removing desolvates obtains the 0.41g solid.With the crystallization in ethyl acetate of this solid, obtain the 0.28g white crystals, m.p.160-163 ℃.To C 21H 24N 2O 7S analyzes:
Calculated value: C, 56.2; H, 5.4; N, 6.3;
Measured value: C, 56.1; H, 5.3; N, 6.3; S, 6.9;
Mass spectrum (ES) 449.1 (M+H)
Employing is with reference to the method for embodiment 41, can be by suitable 2-{ (4-anisole alkylsulfonyl)-[2-(amino of replacement) benzyl] amino } methyl acrylate prepares following midbody compound.
With reference to embodiment 42
4-(4-anisole alkylsulfonyl)-1-(4-Methyl benzenesulfonyl base)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
White foam shape thing.To C 25H 26N 2O 7S 2Analyze:
Calculated value: C, 56.6; H, 4.9; N, 5.3;
Measured value: C, 56.2; H, 5.2; N, 5.2.
With reference to embodiment 43
1,4-pair-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
White solid.To C 25H 26N 2O 8S 2Analyze:
Calculated value: C, 54.9; H, 4.8; N, 5.1;
Measured value: C, 54.8; H, 4.9; N, 5.1.
With reference to embodiment 44
1-methylsulfonyl-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
White crystals, m.p.136-137 ℃.To C 19H 22N 2O 7S 2Analyze:
Calculated value: C, 50.2; H, 4.9; N, 6.2;
Measured value: C, 50.1; H, 4.9; N, 6.4.
With reference to embodiment 45
1-benzoyl-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
Brown solid.To C 25H 24N 2O 2S analyzes:
Calculated value: C, 62.2; H, 5.4; N, 5.8;
Measured value: C, 62.3; H, 5.2; N, 5.6.
With reference to embodiment 46
1-ethanoyl-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
White crystals, m.p.150-155 ℃.To C 20H 22N 2O 6S analyzes:
Calculated value: C, 57.4; H, 5.3; N, 6.7;
Measured value: C, 56.6; H, 5.2; N, 6.5.
With reference to embodiment 47
4-(4-anisole alkylsulfonyl)-1-(3-pyridyl carbonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
Pale solid.To C 24H 23N 3O 6S analyzes:
Calculated value: C, 59.9; H, 4.8; N, 8.7;
Measured value: C, 59.2; H, 4.8; N, 8.3;
Mass spectrum (ES) 482.2 (M+H).
With reference to embodiment 48
4-(4-anisole alkylsulfonyl)-1-(3-thienyl carbonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
Pale solid.To C 24H 22N 2O 6S 2Analyze:
Calculated value: C, 56.8; H, 4.6; N, 5.8;
Measured value: C, 56.0; H, 4.6; N, 5.2.
With reference to embodiment 49
4-(4-anisole alkylsulfonyl)-1-(4-pyridyl carbonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
The canescence crystallization, m.p.162-164 ℃.To C 24H 23N 3O 6S analyzes:
Calculated value: C, 59.9; H, 4.8; N, 8.7;
Measured value: C, 59.9; H, 4.8; N, 8.7.
With reference to embodiment 50
1-(4-xenyl carbonyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
White solid.To C 31H 28N 2O 6S analyzes:
Calculated value: C, 66.9; H, 5.1; N, 5.0;
Measured value: C, 65.8; H, 5.2; N, 5.0;
Mass spectrum (ES) 557.6 (M+H).
With reference to embodiment 51
4-(4-anisole alkylsulfonyl)-1-(propane-1-alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
Yellow oil.To C 21H 26N 2O 7S 2Analyze:
Calculated value: C, 52.3; H, 5.4; N, 5.8;
Measured value: C, 51.8; H, 5.4; N, 5.6.
With reference to embodiment 52
1-([1,1 '-xenyl]-2-carbonyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
White foam shape thing.To C 31H 28N 2O 6S analyzes:
Calculated value: C, 66.9; H, 5.1; N, 5.0;
Measured value: C, 67.3; H, 5.2; N, 4.7;
Mass spectrum (ES) 557.6 (M+H).
With reference to embodiment 53
1-(3-fluoro benzoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 54
4-(4-anisole alkylsulfonyl)-1-(2-methyl-5-fluoro benzoyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
White solid; To C 26H 25FN 2O 6S analyzes:
Calculated value: C, 60.9; H, 4.9; N, 5.5;
Measured value: C, 60.9; H, 5.0; N, 5.0.
With reference to embodiment 55
4-(4-anisole alkylsulfonyl)-1-(2-methyl-3-fluoro benzoyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 56
4-(4-anisole alkylsulfonyl)-1-(3-phenyl propionyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
White solid; To C 27H 28N 2O 6S analyzes:
Calculated value: C, 63.8; H, 5.6; N, 5.5;
Measured value: C, 64.0; H, 5.7; N, 5.3; S, 6.5.
With reference to embodiment 57
4-(4-anisole alkylsulfonyl)-1-(2-trifluoromethyl benzoyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 58
1-(2-oxygen-6-trifluoromethyl benzoyl)-4 (4-anisole alkylsulfonyls)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 59
1-(4-fluoro-2-trifluoromethyl benzoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 60
1-(2-fluoro-6-trifluoromethyl benzoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 61
4-(4-anisole alkylsulfonyl)-1-(2-methyl benzoyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] the assorted of benzo dichloro-3-methyl-formiate
With reference to embodiment 62
4-(4-anisole alkylsulfonyl)-1-(2-methyl-6-chlorobenzene formacyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 63
1-(2, the 4-dimethylbenzoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 64
1-(2, the 5-dimethylbenzoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 65
1-(2-chloro-4-fluoro benzoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 66
1-(2-chlorobenzene formacyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 67
1-(2-fluoro benzoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 68
1-(2-chloro-6-fluoro benzoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 69
1-(2, the 3-difluoro benzoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 70
1-(2,4 dichloro benzene formyl radical)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
Method preparation according to reference embodiment 10; White solid.To C 25H 22Cl 2N 2O 6S analyzes:
Calculated value: C, 54.7; H, 4.0; N, 5.1;
Measured value: C, 54.4; H, 3.8; N, 4.9;
Mass spectrum (548.9) (M+H); 550.9 (M+H).
With reference to embodiment 71
1-(2,3-dichloro-benzoyl base)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 72
1-(2,5-dichloro-benzoyl base)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 73
1-(2-anisoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 74
1-(4-chloro-2-anisoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 75
4-(4-anisole alkylsulfonyl)-1-(2-methylthio phenyl formyl radical)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 76
4-(4-anisole alkylsulfonyl)-1-(3-methyl-2-thienyl carbonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 77
4-(4-anisole alkylsulfonyl)-1-(4-methyl-2-thienyl carbonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 78
1-(3-chloro-2-thienyl carbonyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 79
1-(2-furyl carbonyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
Pale solid, m.p.165-167 ℃.To C 23H 22N 2O 7S analyzes:
Calculated value: C, 58.7; H, 4.7; N, 6.0;
Measured value: C, 58.4; H, 4.6; N, 5.7;
Mass spectrum (ES) 470.9 (M+H).
With reference to embodiment 80
4-(4-anisole alkylsulfonyl)-1-(3-methyl-2-furyl carbonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 81
4-(4-anisole alkylsulfonyl)-1-(4-methyl-2-furyl carbonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 82
1-(5-chloro-2-furyl carbonyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 83
1-(5-chloro-2-thienyl carbonyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 84
1-propionyl-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 85
1-caproyl-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 86
1-(3-methoxy propyl acyl group)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 87
4-(4-anisole alkylsulfonyl)-1-(3-thienyl carbonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 88
1-(3-furyl carbonyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 89
1-(anti--crotonyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 90
1-(methacryloyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 91
1-(chloracetyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
According to reference embodiment 18 described methods, make 3.0g (7.61mmol) 2-[2-aminobenzyl)-4-(4-methoxyl group-benzenesulfonyl)-amino]-3-hydroxyl-methyl propionate and the reaction of 1.82ml (22.8mmol) chloro-acetyl chloride, obtain the 4.0g solid.Make solvent through silica gel column chromatography with ethyl acetate-hexane (1: 1), obtain 1.5g2-[(2-chloro acetylamino benzyl)-(4-anisole alkylsulfonyl)-amino]-methyl acrylate.1.3g aforesaid compound and 0.312g anhydrous sodium bicarbonate are reacted under room temperature in the 10ml anhydrous methanol spend the night, then in 80 ℃ of heating 5 hours.Remove solvent, residue is allocated between water and the ethyl acetate.With salt water washing acetic acid ethyl ester extract,, remove solvent through dried over sodium sulfate.Grind residue with hexane-ethyl acetate, cooling and filtration obtain product; Mass spectrum (ES) 453.1 (M+H).
With reference to embodiment 92
1-(kharophen ethanoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 93
1-(N, N-dimethylamino ethanoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 94
1-(cyclopropyl carbonyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
White crystals, m.p.98-100 ℃.To C 22H 24N 2O 6S analyzes:
Calculated value: C, 59.5; H, 5.4; N, 6.3;
Measured value: C, 59.3; H, 5.6; N, 6.2;
Mass spectrum (ES) 445.1 (M+H).
With reference to embodiment 95
1-(cyclobutyl carbonyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 96
4-(4-anisole alkylsulfonyl)-1-(trifluoroacetyl group)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
To 1.0g (2.54mmol) 3-hydroxyl-2-{ (4-anisole alkylsulfonyl)-[2-(2,2, the 2-trifluoroacetamido) benzyl] amino } the 10ml dichloromethane solution of methyl propionate adds 1.8ml (12.7mmol) trifluoroacetic anhydride.After following 1 hour, remove solvent in room temperature.Add methylene dichloride for several times, add final vacuum at every turn and remove solvent.Add methyl alcohol twice then, vacuum is removed solvent, obtains 2-{ (4-anisole alkylsulfonyl)-[2-(2,2, the 2-trifluoroacetamido) benzyl]-amino } methyl acrylate, be glassy mass.Glassy mass is dissolved in the methyl alcohol, adds the 0.213g anhydrous sodium bicarbonate.Under room temperature this mixed solution stirring is spent the night, vacuum concentration is to doing.In residue, add ethyl acetate and water.Separate organic layer, water and salt water washing are through dried over sodium sulfate.Remove solvent, residue (1.0g) through silica gel thick laminate chromatography, is made solvent with hexane-ethyl acetate (1: 1), obtain the product that 0.365g is a glassy mass.To C 20H 19F 3N 2O 6S analyzes:
Calculated value: C, 50.9; H, 4.1; N, 5.9; F, 12.1; S, 6.7;
Measured value: C, 50.8; H, 4.4; N, 5.5; F, 11.7; S, 6.7;
Mass spectrum (ES) 473.1 (M+H).
With reference to embodiment 97
4-(4-anisole alkylsulfonyl)-1-(4-Methyl benzenesulfonyl base)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
To 0.50g (1.26mmol) the 2-[(2-aminobenzyl that is cooled to 0 ℃)-(4-anisole alkylsulfonyl) amino]-add 0.284g (2.59mmol) toluene sulfonyl chloride in the 5ml pyridine solution of 3-hydroxy propionate.Stirred this mixed solution 2 hours, the concentrated then solvent of removing in 0 ℃.In residue, add the 8ml dehydrated alcohol, with this mixed-liquor return 2 days.This mixed solution is concentrated into dried, adds ethyl acetate.Water, 2N citric acid and this mixed solution of salt water washing are through dried over sodium sulfate.Filter this filtrate by the thin pad of hydrous magnesium silicate, wash filter bed with ethyl acetate.Concentrated filtrate obtains the 0.60g foam to doing.To C 25H 26N 2O 7S 2Analyze:
Calculated value: C, 56.6; H, 4.9; N, 5.3; S, 12.1;
Measured value: C, 56.2; H, 5.2; N, 5.2; S, 11.4;
Mass spectrum (ES) 431.6 (M+H).
With reference to embodiment 98
2-[(4-anisole alkylsulfonyl)-(2-sulfonyloxy methyl amino benzyl) amino] methyl acrylate
In being cooled to-5 ℃ the 10ml pyridine solution of 1.0g (2.54mmol) [(2-aminobenzyl)-(4-anisole alkylsulfonyl) amino]-3-hydroxy methyl propionate, add 0.432ml (5.58mmol) methylsulfonyl chloride.In 0 ℃ this mixed solution was stirred 48 hours.In this mixed solution, add ice and water, with this mixed solution of ethyl acetate extraction.Water, 2N citric acid and this extract of salt water washing are through dried over sodium sulfate.Vacuum is removed solvent, grinds residue with ethyl acetate-hexane, obtains the 0.90g solid, 128-142 ℃.To C 19H 22N 2O 7S 2Analyze:
Calculated value: C, 50.2; H, 4.9; N, 6.2; S, 14.1;
Measured value: C, 49.6; H, 5.0; N, 6.9; S, 14.0;
Mass spectrum (ES) 455.5 (M+H).
With reference to embodiment 99
1, two (the 4-anisole alkylsulfonyls)-2,3,4 of 4-, 5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
To 1.0g (2.34mmol) the 2-[(2-aminobenzyl that is cooled to 0 ℃ to-5 ℃)-(4-anisole alkylsulfonyl) amino]-add 1.07g (5.18mmol) 4-anisole SULPHURYL CHLORIDE in the 6ml pyridine solution of 3-hydroxy methyl propionate.After 2 hours, this mixed solution of vacuum concentration is to doing.In residue, add 12ml ethanol, this mixed-liquor return is spent the night.Vacuum is removed solvent, and residue as solvent, obtains 0.83g (60%) and is the product of white foam shape thing with ethyl acetate-hexane (1: 1) through silica gel slab chromatography; To C 25H 26N 2O 8S 2Analyze: C, 54.9; H, 4.8; N, 5.1; S, 11.7.Measured value: C, 54.8; H, 4.9; N, 5.0; S, 11.5; Mass spectrum (ES) 547.1 (M+H); And obtain second kind of component (0.38g), be 2-{[2-(4-anisole alkylsulfonyl) aminobenzyl]-(4-anisole alkylsulfonyl) amino }-the 3-hydroxy methyl propionate.To C 25H 28N 2O 9S 2Analyze:
Calculated value: C, 53.2; H, 5.0; N, 5.0; S, 11.4;
Measured value: C, 51.8; H, 5.1; N, 4.7; S, 11.3;
Mass spectrum (ES) 565.2 (M+H).
With reference to embodiment 100
1-ethanoyl-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
To 0.70g (1.52mmol) 2-[(2-diacetylamino benzyl)-(4-anisole alkylsulfonyl) amino] add 0.332g (3.95mmol) anhydrous sodium bicarbonate in the 5ml absolute methanol solution of methyl acrylate.Under room temperature this mixed solution stirring is spent the night, vacuum is removed solvent.In residue, add ethyl acetate and water.Separate organic layer, use the salt water washing, through dried over sodium sulfate.Remove solvent, the vacuum-drying residue obtains the 0.59g white crystals, m.p.150-155 ℃.To C 20H 22N 2O 6S analyzes:
Calculated value: C, 57.4; H, 5.3; N, 6.7; S, 7.7;
Measured value: C, 56.6; H, 5.2; N, 6.5; S, 7.5;
Mass spectrum (ES) 419.9 (M+H).
With reference to embodiment 101
3-acetoxyl group-2-[(2-diacetylamino benzyl)-and 4-(4-anisole alkylsulfonyl) amino] methyl propionate
In 100 ℃, with 1.0g (2.54mmol) 2-[(2-aminobenzyl)-(4-anisole alkylsulfonyl) amino]-the mixed solution heating of the 8ml toluene of 3-hydroxy methyl propionate and 1.3ml diacetyl oxide 2 hours.Concentrate this mixed solution, to wherein adding the 3ml diacetyl oxide.In 100 ℃ with this mixed solution heated overnight, high vacuum is concentrated into dried, obtains oily matter.In this oily matter of 75 ℃ of vacuum-dryings 48 hours, obtain the 1.2g yellow oil.To C 24H 28N 2O 9S analyzes:
Calculated value: C, 54.5; H, 5.2; N, 5.5; S, 6.2;
Measured value: C, 54.6; H, 5.1; N, 5.4; S, 6.4;
Mass spectrum (ES) 520.8 (M+H).
With reference to embodiment 102
2-[(2-diacetylamino benzyl)-(4-anisole alkylsulfonyl) amino] methyl acrylate
Under room temperature with 1.0g (1.97mmol) 3-acetoxyl group-2-[(2-diacetylamino benzyl)-(4-anisole alkylsulfonyl) amino] mixed solution of 5ml methylene dichloride of methyl propionate and 0.826ml (5.92mmol) triethylamine stirs and spends the night.Dilute this solution with the 30ml methylene dichloride, each the 20ml washing of water, 2N citric acid and salt solution is through dried over sodium sulfate.Vacuum is removed solvent, obtains brown oil.To C 22H 24N 2O 7S analyzes:
Calculated value: C, 57.4; H, 5.3; N, 6.1; S, 7.0;
Measured value: C, 56.2; H, 5.5; N, 5.6; S, 7.2.
With reference to embodiment 103
2-{ (4-anisole alkylsulfonyl)-[2-(2,2, the 2-trifluoroacetamido) benzyl] amino } methyl acrylate
To 1.0g (2.54mmol) 2-[(2-aminobenzyl)-(4-anisole alkylsulfonyl) amino]-add 1.8ml (12.7mmol) trifluoroacetic anhydride (solid dissolving) in the 10ml toluene suspension of 3-hydroxy methyl propionate.Under room temperature with this solution stirring 2 hours, in 100 ℃ of heated overnight.This mixed solution of vacuum concentration is to doing then.In residue, add the 0.9ml trifluoroacetic anhydride, under room temperature,, be concentrated into dried this solution stirring 1.5 hours.In residue, add 10ml toluene, with this mixed-liquor return 2 hours.This mixed solution is cooled to room temperature, adds the 2.5ml triethylamine, under room temperature, stir this mixed solution and spend the night.Concentrate this solution to doing, residue is dissolved in the ethyl acetate.Water and salt water washing ethyl acetate are through dried over sodium sulfate.Vacuum is removed solvent, obtains the 1.0g colorless oil.Crystallization from ethyl acetate-hexane obtains the 0.625g colourless crystallization, m.p.120-121 ℃.
To C 20H 19F 3N 2O 6S analyzes:
Calculated value: C, 50.9; H, 4.1; N, 5.9; S, 6.7; F, 12.1;
Measured value: C, 50.8; H, 4.2; N, 5.6; S, 6.8; F, 11.9;
Mass spectrum (ES) 473.1 (M+H).
With reference to embodiment 104
4-(4-anisole alkylsulfonyl)-1-(2-methyl-5-fluoro benzoyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
To 1.9g (3.71mmo1) 4-(4-anisole alkylsulfonyl)-1-(2-methyl-5-fluoro benzoyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] add 5ml (4.82mmol) 1NNaOH in the 10ml tetrahydrofuran (THF) mixed solution of benzodiazepine -3-methyl-formiate.With this solution stirring 1.5 hours, vacuum was removed solvent under room temperature.In residue, add ethyl acetate, with 1N HCl this mixed solution that neutralizes.Separate organic layer, use the salt water washing, through dried over sodium sulfate.Vacuum is removed solvent, obtains the 1.41g white solid.To C 25H 23FN 2O 6S analyzes:
Calculated value: C, 60.2; H, 4.7; N, 5.6;
Measured value: C, 60.2; H, 4.8; N, 5.4; S, 6.4; F, 3.6;
Mass spectrum (ES) 497.5 (M-H).
Employing prepares following benzodiazepine -3-formic acid with reference to embodiment 104 described methods.
With reference to embodiment 105
4-(4-anisole alkylsulfonyl)-1-(4-Methyl benzenesulfonyl base)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
White foam shape thing.To C 24H 24N 2O 7S 2Analyze:
Calculated value: C, 55.8; H, 4.7; N, 5.4;
Measured value: C, 53.9; H, 5.1; N, 4.8;
Mass spectrum (ES) 512.2 (M+H).
With reference to embodiment 106
1,4-pair-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
Pale solid.To C 24H 24N 2O 8S 2Analyze:
Calculated value: C, 54.1; H, 4.5; N, 5.3;
Measured value: C, 52.4; H, 4.8; N, 4.7;
Mass spectrum (ES) 533.1 (M+H).
With reference to embodiment 107
1-methylsulfonyl-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
White solid.To C 18H 20N 2O 7S 2Analyze:
Calculated value: C, 49.1; H, 4.6; N, 6.3;
Measured value: C, 47.5; H, 5.0; N, 5.5;
Mass spectrum (ES) 441.1 (M+H).
With reference to embodiment 108
1-benzoyl-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
White foam shape thing.To C 24H 22N 2O 6S analyzes:
Calculated value: C, 61.5; H, 5.2; N, 6.0;
Measured value: C, 60.8; H, 5.2; N, 5.7;
Mass spectrum (ES) 467.9 (M+H).
With reference to embodiment 109
1-ethanoyl-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
White solid.To C 19H 22N 2O 6S analyzes:
Calculated value: C, 56.4; H, 5.0; N, 6.9;
Measured value: C, 55.2; H, 4.9; N, 6.6; S, 7.8;
Mass spectrum (ES) 404.9 (M+H).
With reference to embodiment 110
4-(4-anisole alkylsulfonyl)-1-(3-pyridyl carbonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
White solid; M.p.250-255 ℃.To C 23H 21N 3O 6S analyzes:
Calculated value: C, 59.1; H, 4.5; N, 9.0;
Measured value: C, 58.3; H, 4.7; N, 8.3;
Mass spectrum (ES) 468.2 (M+H).
With reference to embodiment 111
4-(4-anisole alkylsulfonyl)-1-(2-thienyl carbonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
White solid.To C 22H 20N 2O 6S 2Analyze:
Calculated value: C, 55.9; H, 4.3; N, 5.9;
Measured value: C, 54.9; H, 4.4; N, 5.4;
Mass spectrum (ES) 473.1 (M+H).
With reference to embodiment 112
1-methoxyl group ethanoyl-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
White crystals, m.p.193-194 ℃.To C 20H 22N 2O 7S analyzes:
Calculated value: C, 55.3; H, 5.1; N, 6.5;
Measured value: C, 55.1; H, 4.9; N, 6.2;
Mass spectrum (ES) 433.1 (M-H).
With reference to embodiment 113
4-(4-anisole alkylsulfonyl)-1-(4-pyridyl carbonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
White crystals, m.p.258-261 ℃.To C 23H 21N 3O 6S analyzes:
Calculated value: C, 59.1; H, 4.5; N, 9.0;
Measured value: C, 58.8; H, 4.5; N, 8.8;
Mass spectrum (ES) 483.3 (M+H).
With reference to embodiment 114
1-(4-xenyl carbonyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
White foam shape thing.To C 30H 26N 2O 6S analyzes:
Calculated value: C, 66.4; H, 4.8; N, 5.2;
Measured value: C, 64.7; H, 5.2; N, 4.8;
Mass spectrum (ES) 543.6 (M+H).
With reference to embodiment 115
4-(4-anisole alkylsulfonyl)-1-(propane-1-alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
White foam shape thing.To C 20H 24N 2O 7S 2Analyze:
Calculated value: C, 51.3; H, 5.2; N, 6.0;
Measured value: C, 50.3; H, 5.3; N, 5.7;
Mass spectrum (ES) 467.3 (M-H).
With reference to embodiment 116
1-([1,1 '-xenyl]-2-carbonyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
White foam shape thing; M.p.106-145 ℃.To C 30H 26N 2O 6S analyzes:
Calculated value: C, 66.4; H, 4.8; N, 5.2;
Measured value: C, 65.7; H, 5.0; N, 4.8;
Mass spectrum (ES) 541.1 (M-H).
With reference to embodiment 117
1-(3-fluoro benzoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
With reference to embodiment 118
4-(4-anisole alkylsulfonyl)-1-(2-methyl-3-fluoro benzoyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
With reference to embodiment 119
4-(4-anisole alkylsulfonyl)-1-(3-phenyl propionyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
White solid.To C 26H 26N 2O 6S analyzes:
Calculated value: C, 63.1; H, 5.3; N, 5.7;
Measured value: C, 61.5; H, 5.4; N, 5.2;
Mass spectrum (ES) 493.2 (M-H).
With reference to embodiment 120
4-(4-anisole alkylsulfonyl)-1-(2-trifluoromethyl benzoyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
With reference to embodiment 121
1-(2-chloro-6-trifluoromethyl benzoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
With reference to embodiment 122
1-(4-fluoro-2-trifluoromethyl benzoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
With reference to embodiment 123
1-(2-fluoro-6-trifluoromethyl benzoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
With reference to embodiment 124
4-(4-anisole alkylsulfonyl)-1-(2-methyl benzoyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
With reference to embodiment 125
4-(4-anisole alkylsulfonyl)-1-(2-methyl-6-chlorobenzene formacyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
With reference to embodiment 126
1-(2, the 4-dimethylbenzoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
With reference to embodiment 127
1-(2, the 5-dimethylbenzoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
With reference to embodiment 128
1-(2-chloro-4-fluoro benzoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
With reference to embodiment 129
1-(2-chlorobenzene formacyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
With reference to embodiment 130
1-(2-fluoro benzoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
With reference to embodiment 131
1-(2-chloro-6-fluoro benzoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
With reference to embodiment 132
1-(2,3-dichloro-benzoyl base)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
With reference to embodiment 133
1-(2,4 dichloro benzene formyl radical)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
White solid.To C 24H 20Cl 2N 2O 6S analyzes:
Calculated value: C, 53.8; H, 3.8; N, 5.2;
Measured value: C, 52.8; H, 3.9; N, 4.9;
Mass spectrum (ES) 533 (M-H).
With reference to embodiment 134
1-(2,3-dichloro-benzoyl base)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
With reference to embodiment 135
1-(2,5-dichloro-benzoyl base)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
With reference to embodiment 136
1-(2-anisoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
With reference to embodiment 137
1-(4-chloro-2-anisoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
With reference to embodiment 138
4-(4-anisole alkylsulfonyl)-1-(2-methylthio phenyl formyl radical)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
With reference to embodiment 139
4-(4-anisole alkylsulfonyl)-1-(3-methyl-2-thienyl carbonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
With reference to embodiment 140
4-(4-anisole alkylsulfonyl)-1-(4-methyl-2-thienyl carbonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
With reference to embodiment 141
1-(3-chloro-2-thienyl carbonyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
With reference to embodiment 142
1-(2-furyl carbonyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
White solid.To C 22H 20N 2O 7S analyzes:
Calculated value: C, 57.9; H, 4.4; N, 6.1;
Measured value: C, 56.5; H, 4.5; N, 5.7;
Mass spectrum (ES) 455.1 (M-H).
With reference to embodiment 143
4-(4-anisole alkylsulfonyl)-1-(3-methyl-2-furyl carbonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
With reference to embodiment 144
4-(4-anisole alkylsulfonyl)-1-(4-methyl-2-furyl carbonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
With reference to embodiment 145
1-(5-chloro-2-furyl carbonyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
With reference to embodiment 146
1-(5-chloro-2-thienyl carbonyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
With reference to embodiment 147
1-propionyl-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
With reference to embodiment 148
1-caproyl-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
With reference to embodiment 149
1-(3-methoxy propyl acyl group)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
With reference to embodiment 150
4-(4-anisole alkylsulfonyl)-1-(3-thienyl carbonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
With reference to embodiment 151
4-(3-furyl carbonyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
With reference to embodiment 152
1-(trans crotonyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
With reference to embodiment 153
1-(methacryloyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
With reference to embodiment 154
1-(pyrrolidyl ethanoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
With reference to embodiment 155
1-(kharophen ethanoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
With reference to embodiment 156
1-(cyclopropyl carbonyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
White crystals, m.p.131-135 ℃.To C 21H 22N 2O 6S analyzes:
Calculated value: C, 58.6; H, 5.2; N, 6.5;
Measured value: C, 58.1; H, 5.5; N, 5.8;
Mass spectrum (ES) 431.5 (M+H).
With reference to embodiment 157
1-(cyclobutyl carbonyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
With reference to embodiment 158
1-(cyclohexyl-carbonyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
White solid.To C 24H 28N 2O 6S analyzes:
Calculated value: C, 61.0; H, 6.0; N, 5.9;
Measured value: C, 57.0; H, 5.7; N, 5.4;
Mass spectrum (ES) 471.5 (M-H).
With reference to embodiment 159
(D, L) N-(4-anisole alkylsulfonyl)-O-(2-THP trtrahydropyranyl) serine methylester
With 1.44g (5mmol) N-(4-anisole alkylsulfonyl) serine methylester, 1.05g (12.5mmol) 3; the mixed-liquor return of the 5ml tetrahydrofuran (THF) of 4-dihydro-2H-pyrans and 9.5mg 4-toluene sulfonic acide monohydrate spends the night, and this mixed solution of vacuum concentration is to doing.Use the dichloromethane extraction residue, with 2N sodium bicarbonate and salt water washing extract, through dried over sodium sulfate.Filter this solution by the thin pad of hydrous magnesium silicate, use the washed with dichloromethane filter bed.Concentrated filtrate with three parts of (every part of 50ml) hot hexane extraction residues (2.3g), obtains the product that 1.92g is a yellow oil to doing; Mass spectrum (ES) 374.4 (MH +).
With reference to embodiment 160
3-hydroxyl-2-{[4-anisole alkylsulfonyl]-[2-(4-morpholino carbonyl amino) benzyl } methyl propionate
To in 0 ℃ to-10 ℃ refrigerative 1.0g (2.54mmol) 2-[(2-aminobenzyl)-(4-anisole alkylsulfonyl) amino]-add 740 μ l (6.34mmol) morpholino carbonyl chlorides in the 8ml pyridine mixed solution of 3-hydroxy methyl propionate.This mixed solution is spent the night in 0 ℃ of-5 ℃ of maintenance.This mixed solution of vacuum concentration dilutes with ethyl acetate.Water, 2N citric acid and this solution of salt water washing are through dried over sodium sulfate.Vacuum is removed solvent, obtains 1.61g solid (yellowish-orange foam).This solid as solvent, obtains the 0.86g solid with hexane-ethyl acetate (1: 3) through thick-layer silica-gel plate chromatography.To C 23H 29N 3O 8S analyzes:
Calculated value: C, 54.4; H, 5.8; N, 8.3;
Measured value: C, 53.9; H, 5.7; N, 8.1;
Mass spectrum (ES) 508.4 (M+H).
With reference to embodiment 161
2-{ (4-anisole alkylsulfonyl)-[2-(4-morpholino carbonyl amino) benzyl] amino } methyl acrylate
To 0.70g (1.38mmol) 3-hydroxyl-2-{[4-anisole alkylsulfonyl that is cooled to 0 ℃]-[2-(4-morpholino carbonyl amino) benzyl] amino } add 0.386g (2.03mmol) 4-Methyl benzenesulfonyl chlorine in the 8ml dichloromethane solution of methyl propionate and 769 μ L (5.54mmol) triethylamines.Under room temperature this mixed solution was stirred 2 hours, dilute with water is used dichloromethane extraction.With 2N citric acid and salt water washing extract, through dried over sodium sulfate.Remove solvent, obtain the 0.67g yellow oil.To C 23H 27N 3O 7S analyzes:
Calculated value: C, 56.4; H, 5.6; N, 8.6; S, 6.6;
Measured value: C, 56.1; H, 5.8; N, 8.3; S, 6.6.
With reference to embodiment 162
4-(4-anisole alkylsulfonyl)-1-(4-morpholino carbonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4]-benzodiazepine -3-methyl-formiate
Under room temperature, with 0.50g (1.02mmol) 2-{ (4-anisole alkylsulfonyl)-[2-(4-morpholino carbonyl amino) benzyl] amino } mixed solution of the 5ml anhydrous methanol of methyl acrylate and 0.111g (1.32mmol) anhydrous sodium bicarbonate stirred 16 hours.Add the 55mg sodium bicarbonate again, under room temperature, this mixed solution was stirred 2 hours.Vacuum is removed solvent, and the dilute with water residue is used ethyl acetate extraction.With salt water washing extract, through dried over sodium sulfate.Remove solvent, grind residue, obtain the 0.36g yellow solid with hexane-ethyl acetate; To C 23H 27N 3O 7S analyzes: calculated value: C, 56.4; H, 5.6; N, 8.6; S, 6.6; Measured value: C, 56.5; H, 5.7; N, 8.4; S, 6.7; Mass spectrum (ES) 490.3 (M+H).
With reference to embodiment 163
4-(4-anisole alkylsulfonyl)-1-(4-morpholino carbonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4]-benzodiazepine -3-formic acid
Under room temperature; with 0.36g (0.735mmol) 4-(4-anisole alkylsulfonyl)-1-(4-morpholino carbonyl)-2,3,4; 5-tetrahydrochysene-1H-[1,4]-mixed solution of the 5ml tetrahydrofuran (THF) of benzodiazepine -3-methyl-formiate and lml (0.95mmol) 1N sodium hydroxide stirred 1 hour.This mixed solution of vacuum concentration is with 1N hcl acidifying and cooling.Filter this mixed solution, wash solid with water, obtain the 0.26g white solid.To C 22H 25N 3O 7S analyzes:
Calculated value: C, 55.6; H, 5.3; N, 8.8;
Measured value: C, 53.5; H, 5.6; N, 8.3;
Mass spectrum (ES) 474.3 (M-H).
With reference to embodiment 164
The 3-[(2-THP trtrahydropyranyl) oxygen base]-2-[(4-anisole alkylsulfonyl)-(2-nitro-4-benzyl chloride base) amino] methyl propionate
(D L) drips 0.766g (4.4mmol) diethylazodicarboxylate's 1ml tetrahydrofuran solution in the mixed solution of the 4.5ml tetrahydrofuran (THF) of N-(4-anisole alkylsulfonyl)-O-(2-THP trtrahydropyranyl) serine methylester, 0.825g (4.4mol) 4-chloro-2-nitrobenzyl alcohol and 1.16g (4.4mmol) triphenyl phosphine to 1.67g (4.4mmol).Under room temperature this mixed solution stirring is spent the night, vacuum is removed solvent.Grind residue with ether, filter and approach pad and filter filtrate by hydrous magnesium silicate.With the thin pad of ethyl acetate washing, total filtrate is concentrated into dried under vacuum, obtain the 4.54g solid.This solid uses hexane-ethyl acetate (55: 45) as solvent through silica gel column chromatography.Merge the component that contains product, remove solvent, obtain 0.55g oily solid; Mass spectrum (ES) 543.1 (M+H).
With reference to embodiment 165
2-{[2-(4-pyridyl methene amido) benzyl]-[4-anisole alkylsulfonyl] amino }-the 3-hydroxy methyl propionate
With 0.50g (1.268mmol) 2-[(2-aminobenzyl)-(4-anisole alkylsulfonyl) amino]-mixed-liquor return of the 7ml dehydrated alcohol of 3-hydroxy methyl propionate and 1.268mmol 4-pyridylaldehyde 1.5 hours, this mixed solution of vacuum concentration is to doing.In residue, add entry and ethyl acetate.The separating ethyl acetate layer, vacuum concentration is to doing.Through this solid of silica gel thick-layer chromatography purification, as solvent, obtain 0.40g solid product (adding a small amount of raw material) with hexane-ethyl acetate.To C 24H 25N 3O 6S analyzes:
Calculated value: C, 59.6; H, 5.2; N, 8.7;
Measured value: C, 57.6; H, 5.7; N, 7.4;
Mass spectrum (ES) 484 (M+H)-products; 395.1 (M+H)-raw material.
With reference to embodiment 166
1-(cyclohexyl-carbonyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
To 0.80g (1.64mmol) 2-{[2-(cyclohexyl-carbonyl)-aminobenzyl)-(4-anisole alkylsulfonyl) amino } add 0.207g (2.46mmol) anhydrous sodium bicarbonate in the 10ml methanol solution of methyl acrylate.This mixed solution was stirred two days, and then add the 0.207g sodium bicarbonate.This mixed solution stirring is spent the night, and vacuum is removed solvent.In residue, add entry and ethyl acetate, separate organic layer.With salt water washing acetic acid ethyl ester extract, through dried over sodium sulfate, vacuum is removed solvent, obtains the product that 0.83g is a yellow oil.To C 25H 30N 2O 6S analyzes: calculated value: C, 61.7; H, 6.2; N, 5.8;
Measured value: C, 61.0; H, 6.4; N, 5.3;
Mass spectrum (ES) 487.0 (M+H).
With reference to embodiment 167
3-hydroxyl-2-[(4-anisole alkylsulfonyl)-(4-chloro-2-nitrobenzyl) amino] methyl propionate
4mlN to refrigerative 0.289g (1mmol) 3-hydroxyl-2-(4-anisole sulfonamido) methyl propionate in ice bath adds 40mgNaH (60% in oil) (1mmol) in the dinethylformamide solution.Gas adds 0.165g (1.1mmol) sodium iodide after stopping to produce, and then adds the 1ml dimethyl formamide solution of 0.226g (1.1mmol) 4-chloro-2-nitrobenzyl chloride.This solution becomes purple, stirs weekend under room temperature.Vacuum is removed solvent, uses the dichloromethane extraction residue.Water and salt water washing extract are through dried over sodium sulfate.Remove solvent, obtain the 0.53g solid, through thick-layer silica-gel plate chromatography, as solvent, obtaining 0.143g (31%) is the crystalline product, m.p.112-114 ℃ with hexane-ethyl acetate (2: 1) with it.To C 18H 19ClN 2O 8S analyzes:
Calculated value: C, 47.2; H, 4.2; N, 6.1;
Measured value: C, 47.0; H, 4.1; N, 6.0;
Mass spectrum (ES) 459.2 (M+H).
With reference to embodiment 168
3-hydroxyl-2-[(4-anisole alkylsulfonyl)-(4-chloro-2-aminobenzyl) amino] methyl propionate
With 0.454g (1mmol) 3-hydroxyl-2-[(4-anisole alkylsulfonyl)-(4-chloro-2-nitrobenzyl) amino] methyl propionate and 0.451g (2mmol) SnCl 22H 2The mixed-liquor return of the 12ml methyl alcohol of O 2 hours.Add 0.451g (2mmol) SnCl again 22H 2O was with this mixed-liquor return 2 hours.Remove solvent, add ethyl acetate.With 1N sodium bicarbonate this mixed solution that neutralizes, stirred then 1 hour and filtered.The separating ethyl acetate layer, water and salt water washing are through dried over sodium sulfate.Remove solvent, must be to the 0.42g solid, through thick-layer silica-gel plate chromatography, as solvent, obtaining 60mg is the product (R of glassy mass with hexane-ethyl acetate (45: 55) with it F0.66), m.p.99 ℃-112 ℃.To C 18H 21ClN 2O 6S analyzes:
Calculated value: C, 50.4; H, 4.9; N, 6.5;
Measured value: C, 49.7; H, 4.9; N, 6.4;
Mass spectrum (ES) 429.1 (M+H).
With reference to embodiment 169
3-hydroxyl-2-[(4-anisole alkylsulfonyl)-(4-chloro-2-aminobenzyl) amino] methyl propionate
To 0.458g (1mmol) 3-hydroxyl-2-[(4-anisole alkylsulfonyl)-(4-chloro-2-nitrobenzyl) amino] add 0.045g10%Pd/C (wet-50% water) in the 25ml ethanol of methyl propionate and the 25ml ethyl acetate solution.Under 35 pounds of hydrogen per square inch with the jolting 3 hours on Parr hydrogenation instrument of this mixed solution.By this mixed solution of diatomite filtration, vacuum concentrated filtrate is to doing, and obtaining 0.47g is solid product (purity about 90%).Silica gel thin-layer chromatography, NMR and mass spectrum (ES) 429.1 (M+H) 395.1 (M+H) show and contain 10% the dechlorination derivative of having an appointment.
With 4.74g 3-hydroxyl-2-[(4-anisole alkylsulfonyl)-(4-chloro-2-nitrobenzyl) amino] mixed solution of 200ml ethyl acetate-ethanol (1: 1) of methyl propionate and 0.470g 10%Pd/C (wet-50% water) is in jolting 4 hours on Parr hydrogenation instrument under the 35psi hydrogen.By this mixed solution of diatomite filtration, remove solvent, obtain the 4.5g solid.With this solid on Waters Prep instrument with 4 * 30cm silicagel column through HPLC, carry out gradient elution with hexane-ethyl acetate (9: 1 to 6: 4 to 1: 1 to 0: 100), obtain the 1.56g glassy mass, m.p.110 ℃-123 ℃.To C 18H 21ClN 2O 6S analyzes:
Calculated value: C, 50.4; H, 4.9; N, 6.5; Cl, 8.3;
Measured value: C, 50.3; H, 4.8; N, 6.5; Cl, 7.8.
With reference to embodiment 170
N-(4-anisole alkylsulfonyl)-glycine methyl ester
In the 120ml methylene dichloride mixed solution of refrigerative 12.5g (0.1mol) glycine methyl ester hydrochloride in ice bath, add 41.7ml (0.3mol) triethylamine, then drip the 40ml dichloromethane solution of 20.65g (0.1mol) 4-anisole SULPHURYL CHLORIDE.Under room temperature, this mixed solution stirring is spent the night, incline to water then.Separate organic layer, with 2N citric acid, water, 1N sodium bicarbonate and salt water washing, through dried over sodium sulfate.Vacuum is removed solvent, obtains the 24.6g residue, grinds with ethyl acetate, obtains the 19.9g crystallization, m.p.59 ℃-61 ℃.To C 10H 13NSO 5Analyze:
Calculated value: C, 46.3; H, 5.1; N, 5.4;
Measured value: C, 46.2; H, 5.0; N, 5.2.
With reference to embodiment 171
2-[(4-anisole alkylsulfonyl)-(2-nitrobenzyl) amino] methyl acetate
To the 50mlN that stirs refrigerative 1.2g (30mmol) sodium hydride (58% in oil), drip the 40ml N of 7.78g (30mmol) N-(4-anisole alkylsulfonyl) glycine methyl ester in the dinethylformamide mixed solution, dinethylformamide.After gas stops to produce, in mixed solution, drip the 40ml N of 6.80g (32mmol) 2-nitrobenzyl bromine, dinethylformamide solution.Under room temperature, nitrogen environment this mixed solution stirring is spent the night then, vacuum is removed solvent.Use the dichloromethane extraction residue, water, 2N citric acid, water, 1N sodium bicarbonate and salt water washing extract are through dried over sodium sulfate.Filter this solution by the thin pad of hydrous magnesium silicate, use the washed with dichloromethane filter bed.Vacuum concentrated filtrate obtains the 11.79g solid.Grind with ethyl acetate, obtain 2.64g (22%) crystallization.m．p．114℃-116℃。To C 17H 18N 2O 7S analyzes:
Calculated value: C, 51.8; H, 4.6; N, 7.1;
Measured value: C, 51.7; H, 4.6; N, 7.1.
By in 0 ℃ of cooling and filtrated stock, from mother liquor, obtain 6.49g (55%) crystallized product again.
With reference to embodiment 172
The 2-[(2-aminobenzyl)-(4-anisole alkylsulfonyl) amino] methyl acetate
(A) to 2.15g (5.45mmol) 2-[(4-methoxyl group-benzenesulfonyl)-(2-nitrobenzyl) amino] add the 0.42g10% palladium on carbon in the mixed solution of 10ml anhydrous methanol of methyl acetate and 1.57g (25mmol) ammonium formiate.Under room temperature, this mixed solution was stirred 1.5 hours, pass through diatomite filtration then.Vacuum concentrated filtrate is to doing, and water (25ml) dilution residue is with methylene dichloride (75ml) extraction.With salt water washing extract, through dried over sodium sulfate, remove solvent, obtain the 0.45g solid.Crystallization from ethyl acetate obtains the 0.124g white crystals, m.p.100 ℃-102 ℃.To C 17H 20N 2O 5S analyzes:
Calculated value: C, 56.0; H, 5.5; N, 7.7;
Measured value: C, 56.1; H, 5.6; N, 7.6.
(B) to 4.2g2-[(4-anisole alkylsulfonyl)-(2-nitrobenzyl) amino] add 0.42g10% palladium on carbon (wet-50% water) in 200ml ethanol-ethyl acetate (1: 1) solution of methyl acetate, under the room temperature, under 35 pounds of hydrogen per square inch with the jolting 4.5 hours on Parr hydrogenation instrument of this mixed solution.By this mixed solution of diatomite filtration, vacuum concentrated filtrate obtains the 0.40g crystallization, m.p.100 ℃-102 ℃ to doing.
With reference to embodiment 173
The 2-[(2-aminobenzyl)-(4-anisole alkylsulfonyl) amino] acetate
To 5.14g (14.1mmol) 2-[(2-aminobenzyl)-(4-anisole alkylsulfonyl) amino] add 2.86ml 10N sodium hydroxide in 50ml methyl alcohol-tetrahydrofuran (THF) (1: 1) solution of methyl acetate, with this mixed-liquor return 2 hours.Vacuum is removed solvent, and residue is allocated between water and the ether.Separate water layer, with the acidifying of 2N citric acid.Cross filter solid, wash with water,, obtain 4.45g (91%) crystallization, m.p.145 ℃-147 ℃ in dry in vacuum drying oven under the room temperature.To C 16H 18N 2O 5S analyzes:
Calculated value: C, 54.9; H, 5.2; N, 8.0;
Measured value: C, 55.1; H, 5.2; N, 7.9.
With reference to embodiment 174
4-(4-anisole alkylsulfonyl)-1-(phenoxy group ethanoyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
1.5g (3.8mmol) 2-[(2-aminobenzyl to cooling (0 ℃))-(4-anisole alkylsulfonyl) amino]-add 1.58g (11.4mol) phenoxy group Acetyl Chloride 98Min. in the mixed solution of the 15ml methylene dichloride of 3-hydroxy methyl propionate and 2.7ml (19mmol) triethylamine.Under room temperature, this mixed solution stirred and spend the night and filter.Water, 2N citric acid and salt solution wash filtrate are through dried over sodium sulfate.Remove solvent, obtain the 2-{ that 2.4g is an oily matter (4-anisole alkylsulfonyl)-[2-(phenoxy group kharophen) benzyl] amino the methyl acrylate crude product.To C 26H 26N 2O 7S analyzes:
Calculated value: C, 61.2; H, 5.1; N, 5.5;
Measured value: C, 62.6; H, 5.1; N, 4.0;
Mass spectrum (ES) 511 (M+H).
In the 15ml methanol solution of 2.0g (3.92mmol) aforesaid compound sample, add the 0.494g anhydrous sodium bicarbonate, this mixed solution was stirred 5 hours.This mixed solution of vacuum concentration adds ethyl acetate and water in residue.Filter this mixed solution, the organic layer of separating filtrate is used the salt water washing, through dried over sodium sulfate.Remove solvent, obtaining 0.36g is canescence crystalline product, m.p.151 ℃-153 ℃.To C 26H 26N 2O 7S analyzes:
Calculated value: C, 61.2; H, 5.1; N, 5.5;
Measured value: C, 61.1; H, 5.1; N, 5.4;
Mass spectrum (ES) 511 (M+H).
With reference to embodiment 175
3-methylol-4-(4-anisole alkylsulfonyl)-1-(3-pyridylmethyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine
With 0.100g (0.208mmol) 4-(4-anisole alkylsulfonyl)-1-(3-pyridyl carbonyl)-2; 3; 4,5-tetrahydrochysene-1H-[1,4] mixed-liquor return of tetrahydrofuran (THF) (1.0M) of benzodiazepine -3-methyl-formiate and 3ml borine-tetrahydrofuran (THF) mixture spends the night.This solution is cooled to room temperature,, removes solvent with the methyl alcohol dilution.Add methyl alcohol for several times, all remove solvent after each the adding.In residue, add the 1N sodium bicarbonate.This mixed solution was stirred 45 minutes, use ethyl acetate extraction then.Concentrate this extract, water and salt water washing then is through dried over sodium sulfate.Vacuum is removed solvent, and residue is through thick-layer silica-gel plate chromatography, as solvent, obtains 60mg solid (RF0.26) with the ethyl acetate solution of 10% methyl alcohol.Crystallization from ethyl acetate obtains the 30mg white crystals.To C 23H 25N 3O 4S analyzes:
Calculated value: C, 62.8; H, 5.7; N, 9.6; S, 7.3;
Measured value: C, 61.1; H, 5.6; N, 9.2; S, 7.3;
Mass spectrum (ES) 440.2 (M+H).
With reference to embodiment 176
4-(4-anisole alkylsulfonyl)-1-(2-methoxypyridine base-3-carbonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
1.0g (2.54mmol) 2-[(2-aminobenzyl to cooling (0 ℃))-(4-anisole alkylsulfonyl) amino]-add the 4ml dichloromethane solution of 0.957g (5.58mol) 2-methoxypyridine-3-carbonyl chloride in the mixed solution of the 10ml methylene dichloride of 3-hydroxy methyl propionate and 1.8ml (12.68mmol) triethylamine.Under room temperature this mixed solution stirring is spent the night, water and methylene dichloride dilution separate organic layer.Water, 2N citric acid and salt water washing organic layer are through dried over sodium sulfate.Vacuum is removed solvent, obtains the 1.2g solid.This solid as solvent, obtains the yellow foam of 0.27g with ethyl acetate-hexane (3: 1) through thick-layer silica-gel plate chromatography.To C 25H 25N 3O 7S analyzes:
Calculated value: C, 58.7; H, 4.93; N, 8.21;
Measured value: C, 57.8; H, 4.5; N, 8.3; S, 6.2.
With reference to embodiment 177
5-methyl-2-nitrobenzyl bromine
In acetate (3ml) mixed solution of 30%HBr of cooling (ice-water bath), add 2.5g 5-methyl-2-nitrobenzyl alcohol, with refrigerative solution stirring 2 hours.This mixed solution is inclined to frozen water, use extracted with diethyl ether.Water and salt water washing extract, vacuum is removed solvent, obtains the mixture of product (50%) and raw material (50%).
With reference to embodiment 178
3-hydroxyl-2-[(4-anisole alkylsulfonyl)-(5-methyl-2-nitrobenzyl) amino] methyl propionate
The anhydrous N of 120ml with 23.14g (0.08mol) 3-hydroxyl-2-(4-anisole sulfonamido) methyl propionate, the dinethylformamide drips of solution adds to the 120ml N of 3.2g (0.08mol) sodium hydride (57% in oil) of stirring, in the dinethylformamide suspension.After the gas generation stops, this mixed solution of cooling in ice bath, the 100ml N of adding 16.4g (0.084mol) 5-methyl-2-nitrobenzyl chloride, dinethylformamide solution.In this mixed solution, add 12.6g (0.084mol) anhydrous sodium iodide, cooling this mixed solution and stirring 20 minutes in ice bath.Make this mixed solution be warmed to room temperature, stirring is spent the night.Vacuum is removed solvent, with 200ml water dilution residue, uses the 500ml ethyl acetate extraction.With 200ml ethyl acetate extraction water layer.The extract that water and salt water washing merge is through dried over sodium sulfate.Remove solvent, obtain 41.18g crude product product.This product as solvent, obtains 8.14g (R with hexane-ethyl acetate (1: 1) through silica gel column chromatography F0.38) be yellow semisolid product.When (1mmol) carries out on a small scale, with product on the thick-layer silica-gel plate through twice chromatographic, make solvent with hexane-ethyl acetate (1: 1), it is yellow semi-solid to obtain 0.12g.To C 19H 22N 2SO 8Analyze:
Calculated value: C, 52.0; H, 5.1; N, 6.4;
Measured value: C, 51.7; H, 5.1; N, 6.0.
With reference to embodiment 179
3-hydroxyl-2-[(4-anisole alkylsulfonyl)-(2-amino-5-methyl-benzyl) amino] methyl propionate
To 3.4g 3-hydroxyl-2-[(4-anisole alkylsulfonyl)-(5-methyl-2-nitrobenzyl)-amino] add 0.34g 10%Pd/C (wet-50% water) in 200ml ethanol-ethyl acetate (1: 1) solution of methyl propionate.Then with this mixed solution in jolting 2.5 hours on Parr hydrogenation instrument under the 35psi hydrogen.By this mixed solution of diatomite filtration, vacuum concentrated filtrate obtains the 2.86g brown oil.To C 19H 24N 2O 6S analyzes:
Calculated value: C, 55.9; H, 5.9; N, 6.9;
Measured value: C, 55.6; H, 5.9; N, 6.4;
Mass spectrum (ES) 409 (M+H).
With reference to embodiment 180
The 3-[(2-THP trtrahydropyranyl) oxygen base] 2-[(4-anisole alkylsulfonyl)-(5-methyl-2-nitrobenzyl) amino] methyl propionate
To 1.75g (4.68mmol) (D, L) dropping (15 minutes) 0.815g (4.68mmol) diethylazodicarboxylates' (DEAD) 1ml tetrahydrofuran solution in the mixed solution of the 4.5ml anhydrous tetrahydro furan of N-(4-anisole alkylsulfonyl)-O-(2-THP trtrahydropyranyl) serine methylester, 0.790g (4.68mmol) 5-methyl-2-nitrobenzyl alcohol and 1.23g (4.68mmol) triphenyl phosphine.Under room temperature this mixed solution stirring is spent the night, vacuum is removed solvent.Grind residue with ether, the filtering solid.Vacuum concentrated filtrate obtains the 4.67g solid to doing.This solid through silica gel column chromatography, is launched with hexane-ethyl acetate (1: 1), obtain 0.56g product (R F0.48).
With reference to embodiment 181
1-methoxyl group ethanoyl-4-(4-anisole alkylsulfonyl)-7-methyl-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
1.598g (3.91mmol) 3-hydroxyl-2-[(4-anisole alkylsulfonyl to cooling (0 ℃))-and (2-amino-5-methyl-benzyl) amino] add 0.787ml (8.60mmol) methoxyacetyl chloride in the mixed solution of 15ml methylene dichloride of methyl propionate and 1.97g (19.5mmol) triethylamine.Under room temperature, this mixed solution stirring is spent the night.Dilute this mixed solution with methylene dichloride then, water, 2N citric acid, water and salt water washing are through dried over sodium sulfate.Filter this solution by the thin pad of hydrous magnesium silicate, concentrated filtrate obtains the 2-{[2-that 1.94g is a brown oil (methoxyl group kharophen)-5-methyl-benzyl]-(4-methoxyl group-benzenesulfonyl)-amino] the methyl acrylate crude product.Mass spectrum (ES) 463.4 (M+H).
In the 15ml absolute methanol solution of 1.62g (3.52mmol) aforesaid compound, add 0.382g (4.50mmol) anhydrous sodium bicarbonate, under room temperature, this mixed solution stirring is spent the night.Vacuum is removed solvent, and residue is allocated between 100ml ethyl acetate and the 20ml water.The separating ethyl acetate layer, water and salt water washing are through dried over sodium sulfate.Filter this solution by the thin pad of hydrous magnesium silicate, vacuum concentrated filtrate obtains yellow oil.Grind with ethyl acetate-hexane, obtain the crystallization of 1.26g (78%) brown, m.p.122 ℃-124 ℃.To C 22H 26N 2O 7S analyzes:
Calculated value: C, 57.1; H, 5.7; N, 6.1;
Measured value: C, 57.4; H, 5.7; N, 6.0.
With reference to embodiment 182
1-benzoyl-4-(4-anisole alkylsulfonyl)-7-methyl-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
1.465g (3.586mmol) 3-hydroxyl-2-[(4-anisole alkylsulfonyl to cooling (0 ℃))-and (2-amino-5-methyl-benzyl) amino] add 0.915ml (7.89mmol) benzoyl nitrogen in the mixed solution of 20ml methylene dichloride of methyl propionate and 2.49ml (17.93mmol) triethylamine.Under room temperature this mixed solution preservation is spent the night, dilute this mixed solution with methylene dichloride, water, 2N citric acid, water and salt water washing organic layer are through dried over sodium sulfate.Filter this solution by the thin pad of hydrous magnesium silicate, vacuum concentrated filtrate, obtaining 1.8g is the 2-[(2-benzamido-5-methyl-benzyl of brown oil)-(4-anisole alkylsulfonyl) amino] the methyl acrylate crude product.To C 26H 26N 2O 6S analyzes:
Calculated value: C, 63.1; H, 5.3; N, 5.7;
Measured value: C, 63.9; H, 5.2; N, 5.2.
According to reference embodiment 181 described methods, 1.825g (3.68mmol) aforesaid compound is stirred in 1.5ml methyl alcohol with 0.402g (4.78mmol) sodium bicarbonate, obtain oily matter.Grind (adding several ethyl acetate) with hexane, obtain crystallization, m.p.58 ℃-62 ℃.
With reference to embodiment 183
1-(trans-crotonyl)-4-(4-anisole alkylsulfonyl)-7-methyl-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
According to reference embodiment 181 and 182 described methods, with 1.41g (3.455mmol) 3-hydroxyl-2-[(4-anisole alkylsulfonyl)-(2-amino-5-methyl-benzyl) amino] mixed solution of 15ml methylene dichloride of methyl propionate, 1.75g (17.3mmol) triethylamine and the trans crotonyl chloride of 0.809ml stirs and spends the night, obtain 1.52g 2-{[2-(trans-crotonoyl amino)-5-methyl-benzyl]-4-(4-anisole alkylsulfonyl) amino } methyl acrylate, be brown oil; Mass spectrum (ES) 459.4 (M+H).
According to reference embodiment 181 described methods, the aforementioned product of 1.52g (3.31mmol) stirred under room temperature in 15ml methyl alcohol with 0.362g (4.3mmol) sodium bicarbonate spend the night.In this mixed solution, add the 0.056g sodium bicarbonate, this mixed solution in 80 ℃ of heating 3 hours, is handled according to reference embodiment 181, obtain 1.05g yellow glass shape thing, m.p.75 ℃-84 ℃.Mass spectrum (ES) 459.4 (M+H).
With reference to embodiment 184
1-(trans-crotonyl)-4-(4-anisole alkylsulfonyl)-7-methyl-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
Under room temperature; with 1.26g (2.72mmol) 1-(trans-crotonyl)-4-(4-anisole alkylsulfonyl)-7-methyl-2; 3; 4; 5-tetrahydrochysene-1H-[1,4] mixed solution of the 10ml tetrahydrofuran (THF) of benzodiazepine -3-methyl-formiate and 3.53ml (3.53mmol) 1N sodium hydroxide stirred 3 hours.Vacuum is removed solvent, residue is dissolved in the water, with this solution of ethyl acetate extraction.With 1N hcl acidifying (pH 2) water layer, use dichloromethane extraction.Through the dried over sodium sulfate dichloromethane extract, remove solvent, obtain 1.06g solid (after the vacuum-drying), m.p.101 ℃-105 ℃.
With reference to embodiment 185
1-(benzoyl)-4-(4-anisole alkylsulfonyl)-7-methyl-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
Under room temperature; with 1.18g (2.38mmol) 1-(benzoyl)-4-(4-anisole alkylsulfonyl)-7-methyl-2; 3; 4; 5-tetrahydrochysene-1H-[1; 4] storage of the mixed solution of the 10ml tetrahydrofuran (THF) of benzodiazepine -3-methyl-formiate and 3.09ml (3.09mmol) 1N sodium hydroxide is spent the night, and vacuum is removed solvent.With the residue dilute with water, with this solution of ethyl acetate extraction, with 2N citric acid acidifying water layer.With this mixed solution of dichloromethane extraction, water and salt water washing dichloromethane extract are through dried over sodium sulfate.Remove solvent, obtain 0.82g pale-yellow galss shape thing, m.p.95 ℃-100 ℃; Mass spectrum (ES) 481.4 (M+H).
With reference to embodiment 186
4-(4-anisole alkylsulfonyl)-1-(2-methoxy ethyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With 1.6g (3.57mmol) 1-(methoxyl group ethanoyl)-4-(4-anisole alkylsulfonyl)-2; 3; 4,5-tetrahydrochysene-1H-[1,4] mixed solution of tetrahydrofuran (THF) (1.0M) of benzodiazepine -3-methyl-formiate and 32ml borine flows through night next time at nitrogen environment.Add methyl alcohol, remove solvent.In residue, add 25ml methylene dichloride and 25ml 2N hydrochloric acid, under room temperature, stirred this mixed solution 1 hour.Separate organic layer, wash with water, be concentrated into dried.Grind residue with ethyl acetate-hexane, cooling and filtration obtain the 1.2g white crystals, m.p.86 ℃-90 ℃; Mass spectrum (ES) 435.4 (M+H).To C 21H 26N 2O 6S analyzes:
Calculated value: C, 58.1; H, 6.0; N, 6.5;
Measured value: C, 58.5; H, 6.0; N, 6.5.
With reference to embodiment 187
4-(4-anisole alkylsulfonyl)-1-(2-methoxy ethyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
Under room temperature, with 1.0g (2.3mmol) 4-(4-anisole alkylsulfonyl)-1-(2-methoxy ethyl)-2,3; 4; 5-tetrahydrochysene-1H-[1,4] mixed solution of the 10ml tetrahydrofuran (THF) of benzodiazepine -3-methyl-formiate and 3.0ml 1N sodium hydroxide stirred 2 hours, removed solvent.In residue, add entry, with this mixed solution of 1N hcl acidifying.With this mixed solution of ethyl acetate extraction, with salt water washing extract, through dried over sodium sulfate.Remove solvent, grind residue with ethyl acetate-hexane, cooling is also filtered, and obtains the 0.65g white crystals, m.p.164 ℃-165 ℃; Mass spectrum (ES) 421.4 (M+H).To C 20H 24N 2O 6S analyzes:
Calculated value: C, 57.1; H, 5.8; N, 6.7;
Measured value: C, 57.3; H, 5.7; N, 6.4.
With reference to embodiment 188
1-(benzyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With 0.20g (0.416mmol) 1-(benzoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] mixed-liquor return of the tetrahydrofuran (THF) (1.0M) of benzodiazepine -3-methyl-formiate and 4ml borine spends the night, and removes solvent.In residue, add 5ml methylene dichloride and 5ml 2N hydrochloric acid, this mixed solution was stirred 1 hour.Separate organic layer, be concentrated into dried.This residue as solvent, obtains the 0.140g colorless oil with hexane-ethyl acetate (2: 1) through thick-layer silica-gel plate chromatography; Mass spectrum (ES) 467.5 (M+H).
With reference to embodiment 189
4-(4-anisole alkylsulfonyl)-1-[4-(trifluoromethoxy) benzoyl]-8-chloro-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
According to reference embodiment 18 described methods, make 1.46g (3.40mmol) 2-[(2-amino-4-benzyl chloride base)-(4-anisole alkylsulfonyl) amino]-3-hydroxy methyl propionate and the reaction of 4-(trifluoromethoxy) Benzoyl chloride, obtain the 2-{2-[4-that 2.59g is a yellow oil (trifluoromethoxy) benzoyl] amino-4-benzyl chloride base] amino } methyl acrylate; Mass spectrum (ES) 599.3 (M+H).Under room temperature, aforesaid compound was stirred 16 hours in 15ml methyl alcohol with 0.445g (5.29mmol) anhydrous sodium bicarbonate, then in 80 ℃ of heating 2 hours.Remove solvent, use the ethyl acetate extraction residue.Water and salt water washing extract are through dried over sodium sulfate.Remove solvent, make residue crystallization from ethyl acetate-hexane, obtain 4-(4-anisole alkylsulfonyl)-1-[4-(trifluoromethoxy) benzoyl into yellow crystal]-8-chloro-2; 3,4,5-tetrahydrochysene-1H-[1; 4] benzodiazepine -3-methyl-formiate, m.p.149 ℃-151 ℃.To C 26H 22ClF 3N 3O 7S analyzes:
Calculated value: C, 52.1; H, 3.7; N, 4.7; Cl, 6.0; F, 9.5;
Measured value: C, 51.8; H, 3.6; N, 4.7; Cl, 5.9; F, 9.4.
Under room temperature, 1.58g (2.64mmol) aforesaid compound was stirred 2 hours in the 10ml tetrahydrofuran (THF) with 3.43ml 1N sodium hydroxide, handle according to reference embodiment 104 described methods, obtain the 1.52g product.Crystallization from ethyl acetate-hexane obtains the 1.2g white crystals, m.p.184 ℃-186 ℃.
With reference to embodiment 190
4-(4-anisole alkylsulfonyl)-1-(4-morpholino ethanoyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
Under room temperature, with 0.10g (0.22mmol) 1-(chloracetyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate, Morpholine and N, the mixed solution of the 3ml methylene dichloride of N-diisopropylethylamine stir and spend the night.Add again Morpholine, under room temperature with this solution stirring 2 days.Dilute this mixed solution with methylene dichloride, water and salt water washing are through dried over sodium sulfate.Remove solvent, obtain being the solid product, mass spectrum (ES) 504.3 (M+H).To C 24H 29N 3O 7S analyzes:
Calculated value: C, 57.2; H, 5.8; N, 8.3;
Measured value: C, 56.5; H, 5.6; N, 8.1.
With reference to embodiment 191
4-(4-anisole alkylsulfonyl)-1-[2-(1-pyrazolyl) phenylcarbonyl group]-7-methyl-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
According to Tetrahedron, the general reaction method of 2-ethyl fluoro benzoate described in the 53:7557-7576 (1997) and amine, make 2-ethyl fluoro benzoate and pyrazoles at the N that refluxes, react in the dinethylformamide, obtain 2-(1-pyrazolyl) ethyl benzoate into dense yellow oil.To C 12H 12N 2O 2Analyze: calculated value: C, 66.7; H, 5.6; N, 13.0; Measured value: C, 66.5; H, 5.4; N, 12.9; Mass spectrum (ES) 217.2 (M+H).40ml ethanol-tetrahydrofuran (THF) (2: 1) solution of this compound sample (7.02g) and 8.42ml 5N sodium hydroxide was refluxed 2 hours, remove solvent.With the 2N citric acid residue is transferred to acidity (pH 6), the solid of filtering-depositing obtains the 3.7g product.The pH of filtrate is transferred to 4.5, use ethyl acetate extraction.The concentrating residues thing obtains the 1.5g product to doing.Merge gained twice, obtain 5.2g2-(1-pyrazolyl) phenylformic acid, mp 140-142 ℃.The dichloromethane solution and the 0.085ml N that in 5ml methylene dichloride (in ice bath, the cooling off) solution of aforesaid compound (2.07g), add 11.1ml 2M oxalyl chloride, dinethylformamide.Make this mixed solution be warmed to room temperature and stirred 4 hours.Remove solvent, add 25ml toluene (twice), vacuum is removed, and obtains 2-(1-pyrazolyl) Benzoyl chloride into yellow solid.
According to reference embodiment 181 described methods; 2.3g aforesaid compound sample and 1.5g are reacted in 15ml methylene dichloride and 5.12ml triethylamine with reference to the compound of embodiment 179, obtain 2-[(4-anisole alkylsulfonyl)-2-[2-(1-pyrazolyl) phenylcarbonyl group] amino-5-methyl-benzyl }-amino] methyl acrylate.According to reference embodiment 181 described methods; make the cyclisation in methyl alcohol of this compound with sodium bicarbonate; obtain 4-(4-anisole alkylsulfonyl)-1-[2-(1-pyrazolyl) phenylcarbonyl group]-7-methyl-2; 3; 4; 5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate (m.p.240-242 ℃).
According to reference embodiment 104 described methods; with 2.69ml 1N sodium hydroxide hydrolysis 1.16g aforesaid compound sample in the 10ml tetrahydrofuran (THF); obtain 0.71g4-(4-anisole alkylsulfonyl)-1-[2-(1-pyrazolyl) phenylcarbonyl group]-7-methyl-2; 3; 4; 5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid (m.p.149-151 ℃).
With reference to embodiment 192
4-(4-anisole alkylsulfonyl)-1-[2-(4-morpholino) phenylcarbonyl group]-8-chloro-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
Will be according to Tetrahedron, 53:7557, the 2-morpholino ethyl benzoate of the preparation of method described in (1997) refluxed 1.5 hours in tetrahydrofuran-ethyl alcohol (8: 2) with 10N sodium hydroxide, obtained 2-morpholino phenylformic acid, mp 156-157 ℃.5ml methylene dichloride (refrigerative) solution of this compound sample of 1.8g is added in the dichloromethane solution (2M) of 7.9ml oxalyl chloride, then add 0.058ml N, dinethylformamide.Under room temperature,, remove solvent with this solution stirring 6 hours.Add toluene (twice) and removal, obtain 2-(4-morpholino) Benzoyl chloride into yellow solid.
According to reference embodiment 181 and 189 described methods; make aforesaid 2-(4-morpholino) Benzoyl chloride and 2-[(2-amino-4-benzyl chloride base)-(4-anisole alkylsulfonyl) amino]-reaction of 3-hydroxy methyl propionate; this product is stirred in methyl alcohol with sodium bicarbonate; obtain 4-(4-anisole alkylsulfonyl)-1-[2-(4-morpholino) phenylcarbonyl group for white solid]-8-chloro-2; 3,4,5-tetrahydrochysene-1H-[1; 4] benzodiazepine -3-methyl-formiate, mp is 100-105 ℃.
In the 10ml of this compound of 0.90g tetrahydrofuran solution, add 1.95ml 1N sodium hydroxide, under room temperature, this solution stirring is spent the night.With the acidifying of 2N citric acid, obtain 0.82g 4-(4-anisole alkylsulfonyl)-1-[2-(4-morpholino)-phenylcarbonyl group]-8-chloro-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid (mp 136-143 ℃).
With reference to embodiment 193
1-(4-phenetole formyl radical)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
Under room temperature; with the 4-(4-anisole alkylsulfonyl)-2,3,4 of 0.270g with reference to embodiment 12; 5-tetrahydrochysene-1H-[1,4] mixed solution of the 5ml methylene dichloride of benzodiazepine -3-methyl-formiate, 0.291g4-ethoxy benzoyl chloride and 500 μ l triethylamines stirs and spends the night.Dilute this mixed solution with methylene dichloride and water, the separate dichloromethane layer also is concentrated into dried.Grind residue with ethyl acetate, obtain the 1-that 0.276g is a white crystals (4-phenetole formyl radical)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate (mp 187-190 ℃).
Sample with 1.2ml 1N sodium hydroxide this compound of hydrolysis 0.47g in the 4ml tetrahydrofuran (THF).Dilute with water is used the 1N hcl acidifying, obtains the acid that 0.40g is a white solid, mp 144-152 ℃.
With reference to embodiment 194
4-(4-anisole alkylsulfonyl)-1-[2-chloro-4-(3-methyl isophthalic acid-pyrazolyl) phenylcarbonyl group }-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
According to embodiment 65 described methods; make 4-(4-anisole alkylsulfonyl)-2; 3,4,5-tetrahydrochysene-1H-[1; 4] benzodiazepine -3-methyl-formiate and 4-(3-methyl isophthalic acid-pyrazolyl)-2-chloro-benzoyl chloride reaction; obtain 4-(4-anisole alkylsulfonyl)-1-[2-chloro-4-(3-methyl isophthalic acid-pyrazolyl) phenylcarbonyl group for white solid]-2,3,4; 5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate.To C 29H 27ClN 4O 6S analyzes:
Calculated value: C, 58.3; H, 4.6; N, 9.4;
Measured value: C, 58.2; H, 4.9; N, 8.9.
According to reference embodiment 185 described methods,, obtain benzodiazepine -3-carboxylic acid derivatives into white solid with 1N sodium hydroxide this compound of hydrolysis in tetrahydrofuran (THF).
With reference to embodiment 195
1-benzyl-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid
Under nitrogen environment, 1.7g is spent the night with reference to the compound of embodiment 45 and tetrahydrofuran (THF) mixed solution (1.0M) backflow of 25ml borine.In this solution, add 5ml methyl alcohol, methylene dichloride (40ml) and 30ml 2N hydrochloric acid, under room temperature, this mixed solution was stirred 1.5 hours.Separate organic layer, use the salt water washing,, remove solvent through dried over sodium sulfate.Make residue crystallization from ethanol-hexane, obtaining 1.15g is the 1-benzyl-4-(4-anisole alkylsulfonyl)-2,3,4 of white crystals, 5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate, mp120-122 ℃.According to reference embodiment 104 described methods, with 2.8ml 1N sodium hydroxide this compound sample of hydrolysis (1.0g) in the 7ml tetrahydrofuran (THF), obtaining 0.64g is 2 of white crystals, 3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-carboxylic acid derivatives (mp183-185 ℃).
With reference to embodiment 196
1-(2,4-dimethoxy benzoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
Derive from 4-(4-anisole alkylsulfonyl)-2 to the 1.0g (2.66mmol) of cooling (0 ℃) with reference to embodiment 12; 3; 4; 5-tetrahydrochysene-1H-[1; 4] add 1.17g (6.65mmol) 2, the 4-dimethoxy-benzoyl chloride in the 8ml dichloromethane solution of benzodiazepine -3-manthanoate and 1.85ml (13.3mmol) triethylamine.Under room temperature, this mixed solution stirring is spent the night, with the methylene dichloride dilution, with the washing of 2N citric acid.Water, 1N yellow soda ash and salt water washing organic layer are through dried over sodium sulfate.Remove solvent; residue is through thick-layer silica-gel plate chromatography; with ethyl acetate-hexane (1: 1) as elutriant; obtaining 1.0g is the 1-(2 of white foam shape thing; 4-dimethoxy benzoyl)-4-(4-anisole alkylsulfonyl)-2,3,4; 5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate.To C 27H 28H 2O 8S analyzes:
Calculated value: C, 60.0; H, 5.2; N, 5.2;
Measured value: C, 60.0; H, 5.2; N, 5.1;
Mass spectrum (ES): 541.0 (M+H).
Under room temperature, 0.80g (1.48mmol) aforesaid compound sample and 1.92ml (1.92mmol) 1N sodium hydroxide were stirred 1.5 hours in the 5ml tetrahydrofuran (THF).Remove solvent, the dilute with water residue.With this solution of 1N hcl acidifying, obtain the 1-that 0.70g is a white solid (2,4-dimethoxy benzoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4 after cooling and the filtration] benzodiazepine -3-formic acid.To C 26H 26N 2O 8S analyzes:
Calculated value: C, 59.3; H, 5.0; N, 5.3;
Measured value: C, 56.1; H, 4.8; N, 5.0;
Mass spectrum (ES): 527.0 (M+H).
With reference to embodiment 197
4-(4-anisole alkylsulfonyl)-1-[2-(4-methylpiperazine-1-yl) ethanoyl]-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
Derive from 4-(4-anisole alkylsulfonyl)-2 to the 2.5g (6.64mmol) that is cooled to 0 ℃ with reference to embodiment 12; 3; 4; 5-tetrahydrochysene-1H-[1,4] add 1.65g (14.63mmol) chloroacetyl chloride in the mixing solutions of the 40ml methylene dichloride of benzodiazepine -3-methyl-formiate and 4.63ml (33.2mmol) triethylamine.Under room temperature,, be cooled to 0 ℃, to wherein adding 926 μ l triethylamines and 750mg chloroacetyl chloride with this solution stirring two days.Under room temperature, this mixed solution stirring is spent the night, with methylene dichloride and water dilution.The filtering insoluble solid.The organic layer of separating filtrate is used the salt water washing, through dried over sodium sulfate and pass through diatomite filtration.Remove solvent, with the ethanol grinding residue of ethyl acetate and trace.Cooling is also filtered, and obtains 0.75g 1-(chloracetyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate (with reference to embodiment 91).To C 20H 21ClN 2O 6S analyzes:
Calculated value: C, 53.0; H, 4.7; N, 6.2;
Measured value: C, 51.6; H, 4.6; N, 5.7;
Mass spectrum (ES): 453.0 (M+H).
Add 1.2ml (6.79mmol) N in being cooled to 0 ℃ the 12ml dichloromethane solution of 1.4g (3.09mmol) aforesaid compound, the N-diisopropylethylamine then adds 753.2 μ l (6.79mmol) 1-methylpiperazines.Under room temperature, this mixed solution stirring is spent the night, with the methylene dichloride dilution, with 2N citric acid, water, 1M sodium bicarbonate and salt water washing, through dried over sodium sulfate.With saturated sodium bicarbonate the citric acid washings is transferred to alkalescence, use dichloromethane extraction then.Through the dried over sodium sulfate extract, vacuum is removed solvent, obtains the 4-that 1.10g is a white glass shape thing (4-anisole alkylsulfonyl)-1-[2-(4-methylpiperazine-1-yl) ethanoyl]-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate.
Under room temperature, the 5ml methyl alcohol mixed liquor of 1.0g (1.94mmol) aforesaid compound and 2.3ml (2.3mmol) 1N potassium hydroxide was stirred 2 hours.Vacuum is removed solvent.In residue, add toluene (twice), add final vacuum at every turn and remove solvent.In 65 ℃ of vacuum-drying solids 6 hours, obtain the 4-that 1.1g is a white solid (4-anisole alkylsulfonyl)-1-[2-(4-methylpiperazine-1-yl) ethanoyl]-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-potassium formiate.
With reference to embodiment 198
1-ethanoyl-4-(4-hydroxybenzene alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
2.0g (4.78mmol) 1-ethanoyl-4-(4-anisole alkylsulfonyl)-2 to cooling (0 ℃); 3; 4; 5-tetrahydrochysene-1H-[1,4] drip the dichloromethane solution of the boron tribromide of 143.3ml (14.3mmol) 1.0M in the 14ml dichloromethane solution of benzodiazepine -3-methyl-formiate.Under room temperature, this mixed solution was stirred 1.5 hours.In this reaction mixture, add ice and water, filtering insolubles.With methylene dichloride and water dilution filtrate, the separate dichloromethane layer is used the salt water washing, through dried over sodium sulfate.Vacuum is removed solvent, obtains 1.5g white foam shape thing.This solid as solvent, obtains foam with hexane-ethyl acetate (1: 1) through silica gel column chromatography, and it is dry under vacuum, obtains the product that 0.52g is a white foam shape thing; To C 19H 20N 2O 6S analyzes: calculated value: C, 56.4; H, 5.0; N, 6.9; Measured value: C, 55.1; H, 4.7; N, 6.5.
With reference to embodiment 199
4-(4-hydroxybenzene alkylsulfonyl)-1-(2-thienyl carbonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
To 4.0g (8.22mmol) 4-(4-anisole the alkylsulfonyl)-1-(2-thienyl carbonyl)-2 that is cooled to 0 ℃; 3; 4; 5-tetrahydrochysene-1H-[1,4] slowly add the dichloromethane solution of the boron tribromide of 16.4ml (16.44mmol) 1.0M in the 17ml dichloromethane solution of benzodiazepine -3-methyl-formiate.Under room temperature, this mixed solution stirring is spent the night, dilute with methylene dichloride.Filter this mixed solution, with methylene dichloride and water washing solid.Dilute with water filtrate is separated organic layer.Vacuum is removed solvent, and solid as solvent, obtains 0.80g canescence foam with hexane-ethyl acetate (1: 1) through silica gel column chromatography; Mass spectrum (ES) 473.5 (M+H); To C 22H 20N 2O 6S 2Analyze: calculated value: C, 55.9; H, 4.3; N, 5.9; Measured value: C, 54.5; H, 4.4; N, 5.5.
With reference to embodiment 200
1-benzoyl-4-(4-hydroxybenzene alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
To 9.8g (20.39mmol) 1-benzoyl-4-(4-anisole alkylsulfonyl)-2 that is cooled to 0 ℃; 3; 4; 5-tetrahydrochysene-1H-[1,4] slowly add the dichloromethane solution of the boron tribromide of 40.8ml (40.8mmol) 1.0M in the 50ml dichloromethane solution of benzodiazepine -3-methyl-formiate.Under the room temperature nitrogen environment, this mixed solution stirring is spent the night.Add ice and water, dilute this mixed solution with methylene dichloride.Separate organic layer, use the ethyl acetate extraction water layer.The organic extract (methylene dichloride+ethyl acetate) that vacuum concentration merges is dissolved in residue in the ethyl acetate.Water and salt solution washing soln are through dried over sodium sulfate.Filter this solution by the thin pad of hydrous magnesium silicate, concentrated filtrate is to doing.Residue is carried out silica gel column chromatography, as solvent, obtain the product that 8g is the canescence foam with hexane-ethyl acetate; Mass spectrum (ES) 467 (M+H); To C 24H 22N 2O 6S analyzes: calculated value: C, 61.8; H, 4.8; N, 6.0; Measured value: C, 61.3; H, 4.6; N, 5.8.
Employing is with reference to the described method of embodiment 191-193, prepare that following 1-replaces-4-hydroxybenzene alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate.
With reference to embodiment 201
4-(4-hydroxybenzene alkylsulfonyl)-1-(4-Methyl benzenesulfonyl base)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 202
1-methylsulfonyl-4-(4-hydroxybenzene alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
Adopt 6.0g (13.2mmol) to be prepared,, as solvent, obtain 0.82g white foam shape thing with ethyl acetate-hexane (1: 1) through silica gel column chromatography with reference to the compound of embodiment 44 and the dichloromethane solution of 22.6ml (22.6mmol) boron tribromide; Mass spectrum (ES) 440.9 (M+H).
With reference to embodiment 203
4-(4-hydroxybenzene alkylsulfonyl)-1-(3-pyridyl carbonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 204
4-(4-hydroxybenzene alkylsulfonyl)-1-(4-pyridyl carbonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 205
1-(4-xenyl carbonyl) 4-(4-hydroxybenzene alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 206
4-(4-hydroxybenzene alkylsulfonyl)-1-(propane-1-alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 207
1-([1,1 '-xenyl]-2-carbonyl)-4-(4-hydroxybenzene alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 208
1-(3-fluoro benzoyl)-4-(4-hydroxybenzene alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 209
4-(4-hydroxybenzene alkylsulfonyl)-1-(2-methyl-5-fluoro benzoyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 210
4-(4-hydroxybenzene alkylsulfonyl)-1-(2-methyl-3-fluoro benzoyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 211
4-(4-hydroxybenzene alkylsulfonyl)-1-(3-phenyl propionyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 212
4-(4-hydroxybenzene alkylsulfonyl)-1-(2-trifluoromethyl benzoyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 213
1-(2-nitrogen-6-trifluoromethyl benzoyl)-4-(4-hydroxybenzene alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 214
1-(4-fluoro-2-trifluoromethyl benzoyl)-4-(4-hydroxybenzene alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 215
1-(2-fluoro-6-trifluoromethyl benzoyl)-4-(4-hydroxybenzene alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 216
4-(4-hydroxybenzene alkylsulfonyl)-1-(2-methyl benzoyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 217
4-(4-hydroxybenzene alkylsulfonyl)-1-(2-methyl-6-chlorobenzene formacyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 218
1-(2, the 4-dimethylbenzoyl)-4-(4-hydroxybenzene alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 219
1-(2, the 5-dimethylbenzoyl)-4-(4-hydroxybenzene alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 220
1-(2-chloro-4-fluoro benzoyl)-4-(4-hydroxybenzene alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 221
1-(2-chlorobenzene formacyl)-4-(4-hydroxybenzene alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 222
1-(2-fluoro benzoyl)-4-(4-hydroxybenzene alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 223
1-(2-chloro-6-fluoro benzoyl)-4-(4-hydroxybenzene alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 224
1-(2, the 3-difluoro benzoyl)-4-(4-hydroxybenzene alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 225
1-(2,4 dichloro benzene formyl radical)-4-(4-hydroxybenzene alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 226
1-(2,3-dichloro-benzoyl base)-4-(4-hydroxybenzene alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 227
1-(2,5-dichloro-benzoyl base)-4-(4-hydroxybenzene alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 228
4-(4-hydroxybenzene alkylsulfonyl)-1-(2-methylthio phenyl formyl radical)-2,3,4,5-tetrahydrochysene-1H, [1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 229
4-(4-hydroxybenzene alkylsulfonyl)-1-(3-methyl-2-thienyl carbonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 230
4-(4-hydroxybenzene alkylsulfonyl)-1-(4-methyl-2-thienyl carbonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 231
1-(3-chloro-2-thienyl carbonyl)-4-(hydroxybenzene alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 232
1-(2-furyl carbonyl)-4-(4-hydroxybenzene alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
To 3.0g (6.38mmol) 1-(2-the furyl carbonyl)-4-(4-anisole alkylsulfonyl)-2 that is cooled to 0 ℃; 3; 4; 5-tetrahydrochysene-1H-[1,4] drip the dichloromethane solution (1.0M dichloromethane solution) of 12.8ml (2.8mmol) boron tribromide in the 15ml dichloromethane solution of benzodiazepine -3-methyl-formiate.Under room temperature, this mixed solution was stirred 3 days,, add ice then with the methylene dichloride dilution.Separate organic layer, water and salt water washing are through dried over sodium sulfate.Remove solvent, residue uses ethyl acetate-hexane (1: 1) as solvent through silica gel column chromatography (post fast).Merge the component that contains product, remove solvent, grind residue with ethyl acetate.Cooling is also filtered, and obtains the 1-that 0.72g is a white solid (2-furyl carbonyl)-4-hydroxybenzene alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate, mp204-206 ℃; To C 22H 20N 2O 7S analyzes: calculated value: C, 57.9; H, 4.2; N, 6.1; Measured value: C, 57.2; H, 4.3; N, 6.0; Mass spectrum (ES) 457.1 (M+H).
With reference to embodiment 233
4-(4-hydroxybenzene alkylsulfonyl)-1-(3-methyl-2-furyl carbonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 234
4-(4-hydroxybenzene alkylsulfonyl)-1-(4-methyl-2-furyl carbonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 235
1-(5-chloro-2-furyl carbonyl)-4-(4-hydroxybenzene alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 236
1-(5-chloro-2-thienyl carbonyl)-4-(4-hydroxybenzene alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 237
1-propionyl-4-(4-hydroxybenzene alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 238
1-caproyl-4-(4-hydroxybenzene alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 239
4-(4-hydroxybenzene alkylsulfonyl)-1-(3-thienyl carbonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 240
1-(3-furyl carbonyl)-4-(4-hydroxybenzene alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 241
1-(kharophen ethanoyl)-4-(4-hydroxybenzene alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 242
1-(N, N-dimethylamino ethanoyl)-4-(4-hydroxybenzene alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
With reference to embodiment 243
1-(cyclopropyl carbonyl)-4-(4-hydroxybenzene alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
To 4.44g (10mmol) 1-(the cyclopropyl carbonyl)-4-(4-hydroxybenzene alkylsulfonyl)-2 that is cooled to 0 ℃; 3; 4; 5-tetrahydrochysene-1H-[1,4] drip the dichloromethane solution (1.0M solution) of 22ml (22mmol) boron tribromide in the 25ml dichloromethane solution of benzodiazepine -3-methyl-formiate.This mixed solution stirring is spent the night, cool off and dilute with ice and water.Add methylene dichloride, separate organic layer, water and salt water washing are through dried over sodium sulfate.Vacuum is removed solvent, obtains solid, with it through silica gel column chromatography, as solvent, obtain the 1-that 1.0g is a foam (cyclopropyl carbonyl)-4-(4-hydroxybenzene alkylsulfonyl)-2,3 with ethyl acetate-hexane (1: 1), 4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate; Mass spectrum (ES) 431.3 (M+H).
With reference to embodiment 244
4-(4-hydroxybenzene alkylsulfonyl)-1-(trifluoroacetyl group)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate
Embodiment 1
4-(4-anisole alkylsulfonyl)-1-(3-trifluoromethyl benzoyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Derive from 4-(4-anisole alkylsulfonyl)-1-(3-trifluoromethyl benzoyl)-2 to 0.297g (0.556mmol) with reference to embodiment 9; 3; 4; 5-tetrahydrochysene-1H-[1; 4] add the dichloromethane solution and the 0.044ml N of 0.556ml (1.11mmol) 2.0M oxalyl chloride in the 5ml dichloromethane solution of benzodiazepine -3-formic acid, dinethylformamide.Under room temperature, nitrogen environment, this mixed solution was stirred 1.5 hours, in ice bath, cool off.In this solution, add 0.156g (2.24mmol) hydroxylamine hydrochloride and the 1.39ml tetrahydrofuran (THF) of 4.68ml (3.36mmol) triethylamine and the cooling mixed liquid of 0.33ml water.Under room temperature, this mixed solution stirred and spend the night and dilute with methylene dichloride.With 2N citric acid, water, 1N sodium bicarbonate and this mixed solution of salt water washing, through dried over sodium sulfate.Vacuum is removed solvent, obtains the 0.29g solid.Through thick-layer silica-gel plate chromatography, as solvent, obtain the 60mg solid, m.p.128-130 ℃ with ethyl acetate-methyl alcohol (9: 1).To C 25H 22F 3N 3O 6S analyzes:
Calculated value: C, 54.6; H, 4.0; N, 7.7;
Measured value: C, 54.1; H, 4.2; N, 7.3.
Adopt embodiment 1 described method, by suitable 1-replace-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid prepares following compounds.
Embodiment 2
4-(4-anisole alkylsulfonyl)-1-(4-Methyl benzenesulfonyl base)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Solid.To C 24H 25N 3O 7S 2Analyze:
Calculated value: C, 54.2; H, 4.7; N, 7.9;
Measured value: C, 53.5; H, 5.2; N, 7.3.
Embodiment 3
1-methylsulfonyl-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Solid.To C 18H 21N 3O 7S 2Analyze:
Calculated value: C, 47.5; H, 4.7; N, 9.2;
Measured value: C, 46.8; H, 4.8; N, 8.5.
Embodiment 4
1,4-pair-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Solid.To C 24H 25N 3O 8S 2Analyze:
Calculated value: C, 52.6; H, 4.6; N, 7.7;
Measured value: C, 52.2; H, 4.8; N, 7.3.
Embodiment 5
1-benzoyl-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
White solid.To C 24H 23N 3O 6S analyzes:
Calculated value: C, 59.9; H, 4.8; N, 8.7;
Measured value: C, 59.2; H, 4.6; N, 8.6; S, 6.4;
Mass spectrum (ES) 482.3 (M+H).
Embodiment 6
1-ethanoyl-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
White crystals.m．p．195-197℃。To C 19H 21N 3O 6S analyzes:
Calculated value: C, 54.4; H, 5.1; N, 10.0;
Measured value: C, 52.6; H, 4.9; N, 9.4.
Embodiment 7
4-(4-anisole alkylsulfonyl)-1-(3-pyridyl carbonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
White crystals.m．p．167-169℃。To C 23H 22N 4O 6S analyzes:
Calculated value: C, 57.3; H, 4.6; N, 11.6;
Measured value: C, 55.3; H, 4.6; N, 10.6.
Embodiment 8
4-(4-anisole alkylsulfonyl)-1-(2-thienyl carbonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
White solid.To C 22H 21N 3O 6S 2Analyze:
Calculated value: C, 54.2; H, 4.3; N, 8.6;
Measured value: C, 53.7; H, 4.4; N, 8.1.
Embodiment 9
1-methoxyl group ethanoyl-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
White crystals, m.p.143-145 ℃.To C 20H 23N 3O 7S analyzes:
Calculated value: C, 53.4; H, 5.2; N, 9.4;
Measured value: C, 53.9; H, 5.6; N, 8.5.
Embodiment 10
4-(4-anisole alkylsulfonyl)-1-(propane-1-alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Pale solid.To C 20H 25N 3O 7S 2Analyze:
Calculated value: C, 49.7; H, 5.2; N, 8.7;
Measured value: C, 48.9; H, 5.3; N, 8.4.
Embodiment 11
4-(4-anisole alkylsulfonyl)-1-(2-methyl-5-fluoro benzoyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Pale solid.To C 25H 24FN 3O 6S analyzes:
Calculated value: C, 58.5; H, 4.7; N, 8.2;
Measured value: C, 57.1; H, 4.8; N, 7.6.
Embodiment 12
4-(4-anisole alkylsulfonyl)-1-(3-phenyl propionyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Solid.To C 26H 27N 3O 6S analyzes:
Calculated value: C, 61.3; H, 5.3; N, 8.3;
Measured value: C, 59.8; H, 5.3; N, 7.5.
Embodiment 13
4-(4-anisole alkylsulfonyl)-1-(4-pyridyl carbonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
White crystals, m.p.155-165 ℃.To C 23H 22N 4O 6S analyzes:
Calculated value: C, 57.3; H, 4.6; N, 11.6;
Measured value: C, 56.8; H, 4.9; N, 10.9.
Embodiment 14
1-([1,1 '-xenyl]-2-carbonyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
As solvent,, obtain white solid with hexane-ethyl acetate through silica gel thick laminate chromatography purification; M.p.176-178 ℃.To C 30H 27N 3O 6S analyzes:
Calculated value: C, 64.6; H, 4.9; N, 7.5;
Measured value: C, 63.7; H, 4.6; N, 7.1.
Embodiment 15
1-(4-xenyl carbonyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
As solvent,, obtain white solid with hexane-ethyl acetate (1: 1) through silica gel thick laminate chromatography purification; M.p.160-168 ℃.To C 30H 27N 3O 6S analyzes:
Calculated value: C, 64.6; H, 4.9; N, 7.5;
Measured value: C, 61.2; H, 4.9; N, 7.0;
Mass spectrum (ES) 558.1 (M+H).
Embodiment 16
1-(3-fluoro benzoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 17
4-(4-anisole alkylsulfonyl)-1-(2-methyl-3-fluoro benzoyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 18
4-(4-anisole alkylsulfonyl)-1-(2-methyl-3-trifluoromethyl benzoyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 19
1-(2-chloro-6-trifluoromethyl benzoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 20
1-(4-fluoro-2-trifluoromethyl benzoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 21
1-(2-fluoro-6-trifluoromethyl benzoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 22
4-(4-anisole alkylsulfonyl)-1-(2-methyl benzoyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 23
4-(4-anisole alkylsulfonyl)-1-(2-methyl-6-chlorobenzene formacyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 24
1-(2, the 4-dimethylbenzoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 25
1-(2, the 5-dimethylbenzoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 26
1-(2-chloro-4-fluoro benzoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 27
1-(2-chlorobenzene formacyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 28
1-(2-fluoro benzoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 29
1-(2-chloro-6-fluoro benzoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 30
1-(2, the 3-difluoro benzoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 31
1-(2,4 dichloro benzene formyl radical)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
White crystals, m.p.158-162 ℃.To C 24H 21Cl 2N 3O 6S analyzes:
Calculated value: C, 52.4; H, 3.9; N, 7.6;
Measured value: C, 52.1; H, 3.8; N, 7.5;
Mass spectrum (ES) 549.9 (M+H); 552.0 (M+H).
Embodiment 32
1-(2,3-dichloro-benzoyl base)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 33
1-(2,5-dichloro-benzoyl base)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 34
1-(2-anisoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 35
1-(4-chloro-2-anisoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 36
4-(4-anisole alkylsulfonyl)-1-(2-methylthio phenyl formyl radical)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 37
4-(4-anisole alkylsulfonyl)-1-(3-methyl-2-thienyl carbonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 38
4-(4-anisole alkylsulfonyl)-1-(4-methyl-2-thienyl carbonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 39
1-(3-chloro-2-thienyl carbonyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 40
1-(2-furyl carbonyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
White solid.To C 22H 21N 3O 7S analyzes:
Calculated value: C, 56.0; H, 4.5; N, 8.9;
Measured value: C, 55.6; H, 4.8; N, 8.3;
Mass spectrum (ES) 472.0 (M+H).
Embodiment 41
4-(4-anisole alkylsulfonyl)-1-(3-methyl-2-furyl carbonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 42
4-(4-anisole alkylsulfonyl)-1-(4-methyl-2-furyl carbonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 43
1-(5-chloro-2-furyl carbonyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 44
1-(5-chloro-2-thienyl carbonyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 45
1-propionyl-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 46
1-caproyl-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 47
1-(3-methoxy propyl acyl group)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 48
4-(4-anisole alkylsulfonyl)-1-(3-thienyl carbonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 49
1-(3-furyl carbonyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 50
1-(trans-crotonyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 51
1-(methacryloyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 52
1-(kharophen ethanoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 53
1-(glycyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 54
1-(N, N-dimethylamino ethanoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 55
1-(cyclopropyl carbonyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Pale solid.To C 21H 23N 3O 6S analyzes:
Calculated value: C, 56.6; H, 5.2; N, 9.4;
Measured value: C, 55.1; H, 5.2; N, 8.8;
Mass spectrum (ES) 446.5 (M+H).
Embodiment 56
1-(cyclobutyl carbonyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 57
1-(cyclohexyl-carbonyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Pale solid.To C 24H 29N 3O 6S analyzes:
Calculated value: C, 59.1; H, 6.0; N, 8.6;
Measured value: C, 58.0; H, 6.0; N, 8.1;
Mass spectrum (ES) 488.6 (M+H).
Embodiment 58
4-(4-anisole alkylsulfonyl)-1-(phenoxy group ethanoyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Under room temperature; with 0.70g (1.37mmol) 4-(4-anisole alkylsulfonyl)-1-(phenoxy group ethanoyl)-2,3,4; 5-tetrahydrochysene-1H-[1,4] mixed solution of the 3ml tetrahydrofuran (THF) of benzodiazepine -3-methyl-formiate and 1.8ml (1.78mmol) 1N sodium hydroxide stirred 2 hours.Dilute this mixed solution with 3ml water, obtain gummy solid with the 1N hcl acidifying.To wherein adding ethyl acetate, cool off this mixed solution and spend the night.Obtain being crystalline 4-(4-anisole alkylsulfonyl)-1-(phenoxy group ethanoyl)-2,3,4,5-tetrahydrochysene-1H-[1,4 after the filtration] benzodiazepine -3-formic acid, m.p.188 ℃-191 ℃.
In being cooled to 0 ℃ the 5ml dichloromethane solution of 0.496g (1mmol) aforesaid compound sample, add 1ml (2mmol) oxalyl chloride, then add 77.4 μ l (1mmol) N, dinethylformamide.Under room temperature, nitrogen environment, this mixed solution (being called solution A) was stirred 1 hour.In other flask, add 0.278g (4mmol) hydroxylamine hydrochloride, 0.5ml water and 836.3 μ l (5mmol) triethylamines.This mixed solution (being called solution B) was stirred 20 minutes, be cooled to 0 ℃ then.In the solution A that the refrigerative solution B is added to cooling (0 ℃) and stir, make this mixed solution be warmed to room temperature then and stir and spend the night.This mixed solution of vacuum concentration, with the methylene dichloride dilution, water, 2N citric acid, 1N sodium bicarbonate and salt water washing are through dried over sodium sulfate.Remove solvent, make residue crystallization from hexane-ethyl acetate (3: 97), obtain the 0.396g white crystals.m．p．159℃-163℃。To C 25H 25N 3O 7S analyzes:
Calculated value: C, 58.7; H, 4.9; N, 8.2;
Measured value: C, 58.4; H, 5.1; N, 7.8;
Mass spectrum (ES) 512 (M+H).
Embodiment 59
1-methoxyl group ethanoyl-4-(4-anisole alkylsulfonyl)-7-methyl-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Under room temperature; 1.26g (2.72mmol) is derived from 1-methoxyl group ethanoyl-4-(4-anisole alkylsulfonyl)-7-methyl-2 with reference to embodiment 181; 3; 4; 5-tetrahydrochysene-1H-[1,4] mixed solution of benzodiazepine -3-methyl-formiate, 3.53ml 1N sodium hydroxide and 10ml tetrahydrofuran (THF) stirred 3 hours.Vacuum is removed solvent then, and residue is dissolved in the water, and uses ethyl acetate extraction.With 1N hcl acidifying water layer, use dichloromethane extraction.Through the dried over sodium sulfate dichloromethane layer, remove solvent, obtain solid.This material through the vacuum drying oven drying, is obtained the 1.06g solid, m.p.101-105 ℃.
With 1-methoxyl group ethanoyl-4-(4-anisole the alkylsulfonyl)-7-methyl-2,3,4 of the above preparation of 1.02g (2.27mmol), 5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid is dissolved in the potassium hydroxide of 2.57ml1N.Add toluene for several times, solvent is removed in each back that adds.Dried residue in vacuum drying oven obtains 1.1g sylvite.20ml methylene dichloride mixed solution in 0 ℃ of cooling 2.26ml (4.52mmol) oxalyl chloride drips 0.351ml (4.52mmol) N, dinethylformamide (DMF).This mixed solution was stirred 5 minutes, add sylvite (1.1g).Make this mixed solution be warmed to room temperature and stirred 2 hours down in nitrogen environment.With this mixed solution cooling (0 ℃), add to then in the mixed solution of 1ml tetrahydrofuran (THF)-water (8: 2) of 0.628g (9.04mmol) hydroxylamine hydrochloride, 1.89ml (13.56mmol) triethylamine of cooling (0 ℃).Stir this mixed solution and in 0 ℃ the cooling 10 minutes, under room temperature, stir then and spend the night.Vacuum is removed solvent, with methylene dichloride-water dilution residue, with 2N citric acid acidifying (pH 4).The separate dichloromethane layer, water, 1N sodium bicarbonate, water and salt water washing are through dried over sodium sulfate.Filter this solution by the thin pad of hydrous magnesium silicate, vacuum is removed solvent, obtains the 0.73g solid.Crystallization from ethyl acetate obtains the 0.32g crystallization, m.p.146 ℃-148 ℃.
Embodiment 60
1-benzoyl-4-(4-anisole alkylsulfonyl)-7-methyl-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Adopt embodiment 59 described methods; with 1.87ml 1N potassium hydroxide 0.83g (1.71mmol) is derived from 1-benzoyl-4-(4-anisole alkylsulfonyl)-7-methyl-2 with reference to embodiment 185; 3; 4; 5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid is converted into sylvite, with this sylvite and oxalyl chloride-DMF reaction; obtain acyl chlorides, make itself and azanol reaction.From this reactant methylene dichloride, obtain the 0.20g yellow solid, m.p.137 ℃-139 ℃.
Embodiment 61
4-(4-anisole alkylsulfonyl)-1-[4-(trifluoromethoxy) benzoyl]-8-chloro-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Adopt embodiment 59 described methods; derive from 4-(4-anisole alkylsulfonyl)-1-[4-(trifluoromethoxy) benzoyl with 1.20g with reference to embodiment 189]-8-chloro-2; 3; 4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid prepares sylvite; m.p.184 ℃-186 ℃; with oxalyl chloride-DMF reaction, make acyl chlorides and azanol reaction, obtain the 1.20g solid.Through thick-layer silica-gel plate chromatography, as solvent, obtain the 0.58g solid, m.p.134 ℃ (decomposition) with ethyl acetate-methyl alcohol (95: 5); Mass spectrum (ES) 601 (M+H).
Embodiment 62
4-(4-anisole alkylsulfonyl)-1-(2-methoxy ethyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Adopt embodiment 1 described method, make 0.55g derive from 4-(4-anisole alkylsulfonyl)-1-(2-methoxy ethyl)-2,3 with reference to embodiment 187; 4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid and oxalyl chloride reaction; make the acyl chlorides and the azanol reaction that obtain, obtain the 0.40g solid.As solvent,, obtain the product that 0.150g is the canescence foam with ethyl acetate-methyl alcohol (7: 3) through thick-layer silica-gel plate chromatography; Mass spectrum (ES) 434.3 (M-H).To C 20H 25N 3O 6S analyzes:
Calculated value: C, 55.2; H, 5.8; N, 9.7;
Measured value: C, 54.0; H, 5.8; N, 9.3.
Embodiment 63
4-(4-anisole alkylsulfonyl)-1-[2-(1-pyrazolyl) phenylcarbonyl group]-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
According to Tetrahedron, the general reaction method of 2-ethyl fluoro benzoate described in the 53:7557-7576 (1997) and amine, make 2-ethyl fluoro benzoate and pyrazoles at the N that refluxes, react in the dinethylformamide, obtain 2-(1-pyrazolyl) ethyl benzoate into dense yellow oil.To C 12H 12N 2O 2Analyze: calculated value: C, 66.7; H, 5.6; N, 13.0; Measured value: C, 66.5; H, 5.4; N, 12.9; Mass spectrum (ES) 217.2 (M+H).40ml ethanol-tetrahydrofuran (THF) (2: 1) solution of this compound sample (7.02g) and 8.42ml 5N sodium hydroxide was refluxed 2 hours, remove solvent.With the 2N citric acid residue is transferred to acidity (pH 6), the solid of filtering-depositing obtains the 3.7g product.The pH of filtrate is transferred to 4.5, use ethyl acetate extraction.Concentrate extract to doing, obtain the 1.5g product.Merge gained twice, obtain 5.2g 2-(1-pyrazolyl) phenylformic acid, mp140-142 ℃.The dichloromethane solution and the 0.085ml N that in 5ml methylene dichloride (in ice bath, the cooling off) solution of aforesaid compound (2.07g), add 11.1ml 2M oxalyl chloride, dinethylformamide.Make this mixed solution be warmed to room temperature and stirred 4 hours.Remove solvent, add 25ml toluene (twice), vacuum is removed, and obtains 2-(1-pyrazolyl) Benzoyl chloride into yellow solid.
According to reference embodiment 181 described methods; 2.3g aforesaid compound sample and 1.5g are reacted in 15ml methylene dichloride and 5.12ml triethylamine with reference to the compound of embodiment 179, obtain 2-[(4-anisole alkylsulfonyl)-2-[2-(1-pyrazolyl) phenylcarbonyl group] amino-5-methyl-benzyl }-amino] methyl acrylate.According to reference embodiment 181 described methods; make the cyclisation in methyl alcohol of this compound with sodium bicarbonate; obtain 4-(4-anisole alkylsulfonyl)-1-[2-(1-pyrazolyl) phenylcarbonyl group]-7-methyl-2; 3; 4; 5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate, m.p.240-242 ℃.
According to reference embodiment 104 described methods; with 2.69ml 1N sodium hydroxide hydrolysis 1.16g aforesaid compound sample in the 10ml tetrahydrofuran (THF); obtain 0.71g 4-(4-anisole alkylsulfonyl)-1-[2-(1-pyrazolyl) phenylcarbonyl group]-7-methyl-2; 3; 4; 5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid, m.p.149-151 ℃.
According to embodiment 59 described methods, the 1.1g aforesaid compound is converted into sylvite, and successively with oxalyl chloride and azanol reaction, obtain product, m.p.194-196 ℃ into the above-mentioned evaluation of white crystals.
Embodiment 64
4-(4-anisole alkylsulfonyl)-1-[2-(4-morpholino) phenylcarbonyl group]-8-chloro-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Will be according to Tetrahedron, 53:7557, the 2-morpholino ethyl benzoate of the preparation of method described in (1997) refluxed 1.5 hours in tetrahydrofuran-ethyl alcohol (8: 2) with 10N sodium hydroxide, obtained 2-morpholino phenylformic acid, mp156-157 ℃.5ml methylene dichloride (refrigerative) solution of this compound sample of 1.8g is added in the dichloromethane solution (2M) of 7.9ml oxalyl chloride, then add 0.058ml N, dinethylformamide.Under room temperature,, remove solvent with this solution stirring 6 hours.Add toluene (twice) and removal, obtain 2-(4-morpholino) Benzoyl chloride into yellow solid.
According to reference embodiment 181 and 189 described methods; make aforesaid 2-(4-morpholino) Benzoyl chloride and 2-[(2-amino-4-benzyl chloride base)-(4-anisole alkylsulfonyl) amino]-reaction of 3-hydroxy methyl propionate; this product is stirred in methyl alcohol with sodium bicarbonate; obtain 4-(4-anisole alkylsulfonyl)-1-[2-(4-morpholino) phenylcarbonyl group for white solid]-8-chloro-2; 3,4,5-tetrahydrochysene-1H-[1; 4] benzodiazepine -3-methyl-formiate, mp is 100-105 ℃.
In the 10ml of this compound of 0.90g tetrahydrofuran solution, add 1.95ml 1N sodium hydroxide, under room temperature, this solution stirring is spent the night.With the acidifying of 2N citric acid, obtain the 0.82g solid, mp136-143 ℃.With compound 4-(4-anisole alkylsulfonyl)-1-[2-(4-morpholino)-phenylcarbonyl group]-8-chloro-2; 3; 4; 5-tetrahydrochysene-1H-[1; 4] benzodiazepine -3-formic acid (0.78g) is converted into sylvite, and according to embodiment 63 described at first with the oxalyl chloride reaction, then with azanol reaction; obtain 0.276g faint yellow solid product, mp132 ℃.
Embodiment 65
1-(4-phenetole formyl radical)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Under room temperature; with the 4-(4-anisole alkylsulfonyl)-2,3,4 of 0.270g with reference to embodiment 12; 5-tetrahydrochysene-1H-[1,4] mixed solution of the 5ml methylene dichloride of benzodiazepine -3-methyl-formiate, 0.291g4-ethoxy benzoyl chloride and 500 μ l triethylamines stirs and spends the night.Dilute this mixed solution with methylene dichloride and water, the separate dichloromethane layer also is concentrated into dried.Grind residue with ethyl acetate, obtain the 1-that 0.276g is a white crystals (4-phenetole formyl radical)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate, mp187-190 ℃.
Sample with 1.2ml 1N sodium hydroxide this compound of hydrolysis 0.47g in the 4ml tetrahydrofuran (THF).Dilute with water is used the 1N hcl acidifying, obtains the acid that 0.40g is a white solid, mp144-152 ℃.According to embodiment 1 described method, (0.35g) is converted into above-mentioned title compound with aforesaid compound, obtains the 0.195g solid, mp136-142 ℃.
Embodiment 66
4-(4-anisole alkylsulfonyl)-1-[2-chloro-4-(3-methyl isophthalic acid-pyrazolyl) phenylcarbonyl group }-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
According to embodiment 65 described methods; make 4-(4-anisole alkylsulfonyl)-2; 3,4,5-tetrahydrochysene-1H-[1; 4] benzodiazepine -3-methyl-formiate and 4-(3-methyl isophthalic acid-pyrazolyl)-2-chloro-benzoyl chloride reaction; obtain 4-(4-anisole alkylsulfonyl)-1-[2-chloro-4-(3-methyl isophthalic acid-pyrazolyl) phenylcarbonyl group for white solid }-2,3,4; 5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate.To C 29H 27ClN 4O 6S analyzes:
Calculated value: C, 58.3; H, 4.6; N, 9.4;
Measured value: C, 58.2; H, 4.9; N, 8.9.
According to reference embodiment 185 described methods,, obtain benzodiazepine -3-carboxylic acid derivatives into white solid with 1N sodium hydroxide this compound of hydrolysis in tetrahydrofuran (THF).According to embodiment 1 described method, make the reaction of this compound and oxalyl chloride, then with azanol reaction, obtain product, mp189-191 ℃ into white crystals.
Embodiment 67
1-benzyl-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Under nitrogen environment, 1.7g is spent the night with reference to the mixed-liquor return of the tetrahydrofuran (THF) (1.0M) of the compound of embodiment 45 and 25ml borine.In this solution, add 5ml methyl alcohol, methylene dichloride (40ml) and 30ml 2N hydrochloric acid, under room temperature, this mixed solution was stirred 1.5 hours.Separate organic layer, use the salt water washing,, remove solvent through dried over sodium sulfate.Make residue crystallization from ethanol-hexane, obtaining 1.15g is the 1-benzyl-4-(4-anisole alkylsulfonyl)-2,3,4 of white crystals, 5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate, mp120-122 ℃.According to reference embodiment 104 described methods, with 2.8ml 1N sodium hydroxide this compound sample of hydrolysis (1.0g) in the 7ml tetrahydrofuran (THF), obtaining 0.64g is 2 of white crystals, 3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-carboxylic acid derivatives, mp183-185 ℃.
According to embodiment 1 described method, this compound sample of 0.55g is converted into acyl chlorides, make itself and azanol reaction, obtain product into the light brown foam; Mass spectrum (ES) 468.1 (M+H).
Adopt the foregoing description 65 described methods, the preparation following compounds.
Embodiment 68
4-(4-anisole alkylsulfonyl)-1-(4-(2-thienyl) phenyl-carbonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 69
4-(4-anisole alkylsulfonyl)-1-(4-(3-thienyl) phenyl-carbonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 70
4-(4-anisole alkylsulfonyl)-1-[2-(3-pyrazolyl) phenyl-carbonyl]-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Embodiment 71
1-(2,4-dimethoxy benzoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Derive from 4-(4-anisole alkylsulfonyl)-2 to the 1.0g (2.66mmol) of cooling (0 ℃) with reference to embodiment 12; 3; 4; 5-tetrahydrochysene-1H-[1; 4] add 1.17g (6.65mmol) 2, the 4-dimethoxy-benzoyl chloride in the solution of the 8ml methylene dichloride of benzodiazepine -3-manthanoate and 1.85ml (13.3mmol) triethylamine.Under room temperature, this mixed solution stirring is spent the night, with the methylene dichloride dilution, with the washing of 2N citric acid.Water, 1N yellow soda ash and salt water washing organic layer are through dried over sodium sulfate.Remove solvent; with ethyl acetate-hexane (1: 1) as eluent; residue is through thick-layer silica-gel plate chromatography; obtaining 1.0g is the 1-(2 of white foam shape thing; 4-dimethoxy benzoyl)-4-(4-anisole alkylsulfonyl)-2,3,4; 5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate.To C 27H 28N 2O 8S analyzes:
Calculated value: C, 60.0; H, 5.2; N, 5.2;
Measured value: C, 60.0; H, 5.2; N, 5.1;
Mass spectrum (ES): 541.0 (M+H).
Under room temperature, the 5ml tetrahydrofuran solution of 0.80g (1.48mmol) aforesaid compound sample and 1.92ml (1.92mmol) 1N sodium hydroxide was stirred 1.5 hours.Remove solvent, the dilute with water residue.With this solution of 1N hcl acidifying, cooling is also filtered, and obtains the 1-that 0.70g is a white solid (2,4-dimethoxy benzoyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid.To C 26H 26N 2O 8S analyzes:
Calculated value: C, 59.3; H, 5.0; N, 5.3;
Measured value: C, 56.1; H, 4.8; N, 5.0;
Mass spectrum (ES): 527.0 (M+H).
10ml methylene dichloride cooling (0 ℃) solution of 0.80g (1.52mmol) aforesaid compound sample is added in 1.52ml (3.04mmol) oxalyl chloride (dichloromethane solution of 2.0M).Add 118 μ l (1.52mmol) N in this solution, dinethylformamide stirs this solution (mixed liquor A) 1.5 hours in 0 ℃.In other flask, prepare 0.422g (6.08mmol) hydroxylamine hydrochloride, 1.27ml (9.14mmol) triethylamine, 5ml N, the mixed solution of dinethylformamide and 0.5ml water (mixed liquid B), under room temperature, stirred 20 minutes, in ice bath, be cooled to 0 ℃ then.Refrigerative mixed liquor A solution is added in the refrigerative mixed liquid B, under room temperature, stir then and spend the night.Dilute this mixed solution with methylene dichloride, add the 2N citric acid.Separate organic layer, water and salt water washing are through dried over sodium sulfate.Remove solvent, make residue crystallization from ethanol, obtain the product that 0.40g is a white crystals, mp189-191 ℃.To C 26H 27N 3O 8S analyzes:
Calculated value: C, 57.7; H, 5.0; N, 7.7;
Measured value: C, 57.6; H, 4.9; N, 7.7;
Mass spectrum (ES): 542.2 (M+H).
Embodiment 72
4-(4-anisole alkylsulfonyl)-1-[2-(4-methylpiperazine-1-yl) ethanoyl]-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
Derive from 4-(4-anisole alkylsulfonyl)-2 to the 2.5g (6.64mmol) that is cooled to 0 ℃ with reference to embodiment 12; 3; 4; 5-tetrahydrochysene-1H-[1,4] add 1.65g (14.63mmol) chloroacetyl chloride in the mixing solutions of the 40ml methylene dichloride of benzodiazepine -3-methyl-formiate and 4.63ml (33.2mmol) triethylamine.Under room temperature,, be cooled to 0 ℃, to wherein adding 926 μ l triethylamines and 750mg chloroacetyl chloride with this solution stirring two days.Under room temperature, this mixed solution stirring is spent the night, with methylene dichloride and water dilution.The filtering insoluble solid.The organic layer of separating filtrate is used the salt water washing, through dried over sodium sulfate and pass through diatomite filtration.Remove solvent, residue grinds with the ethanol of ethyl acetate and trace.Cooling is also filtered, and obtains 0.75g 1-(chloracetyl)-4-(4-anisole alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate (with reference to embodiment 91).To C 20H 21ClN 2O 6S analyzes:
Calculated value: C, 53.0; H, 4.7; N, 6.2;
Measured value: C, 51.6; H, 4.6; N, 5.7;
Mass spectrum (ES): 453.0 (M+H).
Add 1.2ml (6.79mmol) N in being cooled to 0 ℃ the 12ml dichloromethane solution of 1.4g (3.09mmol) aforesaid compound, the N-diisopropylethylamine then adds 735.2 μ l (6.79mmol) 1-methylpiperazines.Under room temperature, this mixed solution stirring is spent the night, with the methylene dichloride dilution, with 2N citric acid, water, 1M sodium bicarbonate and salt water washing, through dried over sodium sulfate.With saturated sodium bicarbonate the citric acid washings is transferred to alkalescence, use dichloromethane extraction then.Through the dried over sodium sulfate extract, vacuum is removed solvent, obtains the 4-that 1.10g is a white glass shape thing (4-anisole alkylsulfonyl)-1-[2-(4-methylpiperazine-1-yl) ethanoyl]-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate.
Under room temperature, the mixed solution of the 5ml methyl alcohol of 1.0g (1.94mmol) aforesaid compound and 2.3ml (2.3mmol) 1N potassium hydroxide was stirred 2 hours.Vacuum is removed solvent.In residue, add toluene (twice), add final vacuum at every turn and remove solvent.Drying solid is 6 hours under 65 ℃ of vacuum, obtains the 4-that 1.1g is a white solid (4-anisole alkylsulfonyl)-1-[2-(4-methylpiperazine-1-yl) ethanoyl]-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-potassium formiate.
In being cooled to 0 ℃ the dichloromethane solution of oxalyl chloride of 1.85ml (3.69mmol) 2.0M, slowly add 286 μ l (3.69mmol) N, dinethylformamide (forming precipitation).The 5ml dichloromethane solution that in the mixed solution of this stirring, adds 1.0g (1.85mmol) aforesaid compound.Under nitrogen environment, this mixed solution (mixed liquor A) was stirred 2 hours.
In other flask, under room temperature, stir the mixed solution of the tetrahydrofuran (THF)-water (4: 1) of 0.514g (7.4mmol) hydroxylamine hydrochloride, 1.55ml (11.1mmol) triethylamine, be cooled to 0 ℃ and stirred 5 minutes then.In this mixed solution, add the mixed liquor A of cooling (0 ℃), under room temperature, the solution stirring that produces is spent the night then.This mixed solution of vacuum concentration adds methylene dichloride.Separate organic layer and be concentrated into driedly, obtain the 1.4g product.As solvent, this product obtains the 65mg brown solid through thick-layer silica-gel plate chromatography with methylene chloride-methanol-ammonium hydroxide (45: 6: 1):
Mass spectrum (ES): 518.3 (M+H).
Embodiment 73
4-[4-(4-chlorophenoxy) benzenesulfonyl]-1-(methoxyl group ethanoyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
A.N-[4-(4-chlorophenoxy benzenesulfonyl) serine methylester (3-hydroxyl-2-[4-(4-chlorophenoxy) phenylsulfonamido) methyl propionate.In the 60ml dichloromethane solution that is cooled to 0 ℃ 3.42g (22mmol) serine methyl ester hydrochloride and 10.7ml (77.0mmol) triethylamine, add 6.063g (20mmol) 4-(4-chlorophenoxy) benzene sulfonyl chloride.Under room temperature, this mixed solution stirring is spent the night, with the methylene dichloride dilution, with 2N citric acid, water, 1N sodium bicarbonate and salt water washing, through dried over sodium sulfate.Remove solvent, obtain oily matter, it through 68 ℃ of following vacuum-dryings, is obtained solid.Grind with hexane-ethyl acetate, obtain the crystallization of 5.85g canescence, mp90-94 ℃.To C 16H 16ClNO 6S analyzes:
Calculated value: C, 49.8; H, 4.2; N, 3.6;
Measured value: C, 50.1; H, 4.1; N, 3.8;
Mass spectrum (ES): 385.9 (M+H).
B.3-hydroxyl-2-{[4-(4-chlorophenoxy) benzenesulfonyl]-(2-nitrobenzyl) amino } methyl propionate.Derive from the anhydrous N of 60ml of the compound of A part to the 5.5g (14.76mmol) that is cooled to 0 ℃, in the dinethylformamide solution by part adding 0.682g (17mmol) sodium hydride (60% in oil).After gas stops to produce, slowly add the 15ml N of 3.7g (17mmol) 2-nitrobenzyl bromine, dinethylformamide solution.Under room temperature, this mixed solution stirring is spent the night, with 200ml ethyl acetate and the dilution of 150ml water.Separate organic layer, water and salt water washing are through dried over sodium sulfate.Vacuum is removed solvent, and as elutriant, residue obtains the 4.7g brown oil through silica gel column chromatography with hexane-ethyl acetate (2: 1).To C 23H 21ClN 2O 8S analyzes:
Calculated value: C, 53.0; H, 4.1; N, 5.4;
Measured value: C, 53.2; H, 4.2; N, 5.1;
Mass spectrum (ES): 521.2 (M+H).
C.2-{ (2-aminobenzyl)-[4-(4-chlorophenoxy) benzenesulfonyl] amino }-the 3-hydroxy methyl propionate.300ml ethyl acetate-ethanol (1: the 1) mixed solution that 3.0g (5.77mmol) is derived from the wet palladium on carbon (50% aqueous solution) of the compound of B part and 0.300g 10% is in jolting 4 hours on Parr hydrogenation instrument under the 35psi hydrogen.By this mixed solution of diatomite filtration, vacuum is removed solvent.In the following 65 ℃ of dried residue of vacuum, obtain the 2.63g pale solid.To C 23H 23ClN 2O 6S analyzes:
Calculated value: C, 56.3; H, 4.7; N, 5.7;
Measured value: C, 56.6; H, 4.6; N, 5.6;
Mass spectrum (ES): 491.1 (M+H).
D.2-{[4-(4-chlorophenoxy) benzenesulfonyl]-[2-(methoxyl group-kharophen) benzyl] amino } methyl acrylate.In deriving from the 8ml methylene dichloride mixed solution of the compound of C part and 1.14ml (8.15mmol) triethylamine, the 0.80g (1.63mmol) that is cooled to 0 ℃ adds 328 μ l (3.58mmol) methoxyacetyl chlorides.Under room temperature this mixed solution stirring is spent the night, with the methylene dichloride dilution, water, 2N citric acid and salt water washing are through dried over sodium sulfate.Vacuum is removed solvent, and as solvent, residue obtains 0.48g white foam shape thing through thick-layer silica-gel plate chromatography with hexane-ethyl acetate (2: 1).To C 26H 25ClN 2O 7S analyzes:
Calculated value: C, 57.3; H, 4.6; N, 5.1;
Measured value: C, 56.7; H, 4.7; N, 5.0;
Mass spectrum (ES): 545.2 (M+H).
E.4-[4-(4-chlorophenoxy) benzenesulfonyl]-1-(methoxyl group ethanoyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate.0.45g (0.827mmol) being derived from the compound of D part and the 5ml anhydrous methanol mixed solution stirring of 0.09g anhydrous sodium bicarbonate under room temperature spends the night.Remove solvent, add ethyl acetate, water and this mixed solution of salt water washing are through dried over sodium sulfate.Remove solvent, obtain the 0.43g pale solid C 26H 25ClN 2O 7S analyzes:
Calculated value: C, 57.3; H, 4.6; N, 5.1;
Measured value: C, 57.6; H, 4.6; N, 5.0;
Mass spectrum (ES): 545.2 (M+H).
F.4-[(4-benzenesulfonyl chlorophenoxy)]-1-(methoxyl group ethanoyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid.0.52g (0.956mmol) being derived from the compound of E part and the 8ml methyl alcohol mixed liquor of 1.2ml (1.2mmol) 1N potassium hydroxide under room temperature stirred 2 hours.Add 0.6ml 1N potassium hydroxide again, under room temperature, this mixed solution stirring is spent the night.Concentrate this mixed solution, dilute with water is used ethyl acetate extraction.With salt water washing extract, through dried over sodium sulfate.Remove solvent, desciccate under 65 ℃, vacuum obtains 0.49g canescence foam.To C 25H 23ClN 2O 7S analyzes:
Calculated value: C, 56.6; H, 4.4; N, 5.3;
Measured value: C, 56.6; H, 4.3; N, 5.0;
Mass spectrum (ES): 531.2 (M+H).
In deriving from the 4ml dichloromethane solution of compound of F part, the 0.45g (0.848mmol) that is cooled to 0 ℃ adds 850 μ l (1.69mmol) oxalyl chlorides (dichloromethane solution of 2.0M), add 50.2 μ l (0.848mmol) N then, dinethylformamide.Under nitrogen environment, this mixed solution (solution A) was stirred 2 hours.In other flask, the mixed solution of 2.12g (5.0mmol) hydroxylamine hydrochloride, 1.07ml (7.65mmol) triethylamine, 4ml tetrahydrofuran (THF) and 0.4ml water was stirred 15 minutes, be cooled to 0 ℃.The solution A that adds cooling (0 ℃) in this mixed solution is spent the night this mixed solution stirring under room temperature.This mixed solution of vacuum concentration, with the ethyl acetate dilution, water, 1N sodium bicarbonate, 2N citric acid and salt water washing are through dried over sodium sulfate.Vacuum is removed solvent, and as solvent, residue obtains the product that 0.20g is this embodiment of brown solid through thick-layer silica-gel plate chromatography with the ethyl acetate solution of 2% methyl alcohol.To C 25H 24CIN 3O 7S analyzes:
Calculated value: C, 55.0; H, 4.4; N, 7.7;
Measured value: C, 53.1; H, 5.0; N, 6.7;
Mass spectrum (ES): 546.3 (M+H).
Embodiment 74
4-[4-(4-chlorophenoxy) benzenesulfonyl]-1-(2-thienyl carbonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
D, E and the described method of F part according to embodiment 73 are carried out following reaction.Make 1.4g (2.85mmol) 2-{ (2-aminobenzyl)-[4-(4-chlorophenoxy) benzenesulfonyl] amino }-3-hydroxy methyl propionate sample (compound of embodiment 73C part) and the reaction of 1.25g (8.55mmol) 2 thiophen carbonyl chloride, obtain the 2-{[4-that 1.7g is a yellow oil (4-chlorophenoxy) benzenesulfonyl]-[2-(2-thienyl carbonyl-amino) benzyl] amino } methyl acrylate.
Mass spectrum (ES): 583.1 (M+H).
1.5g aforesaid compound and 0.251g sodium bicarbonate are reacted in 8ml methyl alcohol; obtain the 4-[4-that 1.6g is a yellow oil (4-chlorophenoxy) benzenesulfonyl)-1-(2-thienyl carbonyl)-2,3,4; 5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate.
Mass spectrum (ES): 583.1 (M+H).
The 1.5g aforesaid compound is hydrolyzed in the 6ml tetrahydrofuran (THF) with 3.3ml 1N sodium hydroxide; obtain the 4-[4-that 1.2g is the canescence foam (4-chlorophenoxy) benzenesulfonyl]-1-(2-thienyl carbonyl)-2,3,4; 5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid.According to embodiment 73 described methods, make the reaction of the aforementioned benzodiazepine of 1.0g-3-formic acid and oxalyl chloride, then with azanol reaction, obtain product into this embodiment of solid (canescence foam).
Mass spectrum (ES): 584.2 (M+H).
Embodiment 75
4-[4-(4-chlorophenoxy) benzenesulfonyl]-1-(benzoyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
D, E and the described method of F part according to embodiment 73 are carried out following reaction.Make the compound and the reaction of 710 μ l (6.10mmol) Benzoyl chlorides of 1.0g (2.04mmol) embodiment 73C part, obtain the 2-{[4-that 1.25g is a brown oil (4-chlorophenoxy) benzenesulfonyl]-[2-(benzamido) benzyl] amino } methyl acrylate.
Mass spectrum (ES): 577.2 (M+H).
1.1g (1.9mmol) aforesaid compound and 0.208g (2.48mmol) sodium bicarbonate are reacted in 8ml methyl alcohol; obtain the 4-[4-that 1.1g is a brown oil (4-chlorophenoxy) benzenesulfonyl)-1-(benzoyl)-2; 3; 4; 5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate.
Mass spectrum (ES): 577.1 (M+H).
1.0g (1.73mmol) aforesaid compound sample is hydrolyzed in the 5ml tetrahydrofuran (THF) with 2.3ml (2.75mmol) 1N sodium hydroxide; obtain the 4-[4-that 0.50g is a white foam shape thing (4-chlorophenoxy) benzenesulfonyl]-1-(benzoyl)-2; 3; 4; 5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid.According to embodiment 73 described methods, make the reaction of the aforementioned benzodiazepine of 0.460g (0.817mmol)-3-formic acid and oxalyl chloride, then with azanol reaction, obtain product into this embodiment of light brown solid.
Mass spectrum (ES): 578.2 (M+H).
Embodiment 76
4-[4-(4-pyridyl oxygen base) benzenesulfonyl]-1-(methoxyl group ethanoyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
A. to refrigerative 6.84g (44mmol) D, add the 50ml dichloromethane solution of 10.78g (40mmol) 4-(4-pyridyl oxygen base) benzene sulfonyl chloride in the 90ml methylene dichloride mixed solution of L-serine methyl ester hydrochloride and 21.4 (144mmol) triethylamine.Under room temperature this mixed solution stirring is spent the night, with the dilution of 50ml methylene dichloride, water, 1N sodium bicarbonate, 2N citric acid and this solution of salt water washing are through dried over sodium sulfate.Vacuum is removed solvent, obtains solid.With saturated sodium bicarbonate the 2N aqueous citric acid solution is transferred to alkalescence, use dichloromethane extraction then.Remove solvent, obtain solid.Merge two step gained solids, water and hexane wash successively.In 80 ℃ of these solids of drying, obtaining 10.95g is 3-hydroxyl-2-[4-(4-pyridyl oxygen the base)-phenylsulfonamido of white crystals] methyl propionate, mp.137-139 ℃.
B. derive from the anhydrous N of 35ml of the product of A part to the 4.5g (12.78mmol) that is cooled to 0 ℃, add 0.662g (16.61mmol) sodium bicarbonate (60% in oil) by part in the dinethylformamide solution.This mixed solution was stirred 15 minutes, to the 15ml N that wherein adds 3.59g (16.61mmol) 2-nitrobenzyl bromine, dinethylformamide solution.Under room temperature, this mixed solution stirring is spent the night, with ethyl acetate (200ml) and water (100ml) dilution.Separate organic layer, water and salt water washing are through dried over sodium sulfate.Remove solvent, obtain the 5.9g solid.As elutriant,, obtain the 2-{ that 1.4g is a pale solid (2-nitrobenzyl)-[4-(4-pyridyl oxygen base) benzenesulfonyl]-amino with ethyl acetate-hexane (10: 1) through silica gel column chromatography }-the 3-hydroxy methyl propionate.
Mass spectrum (ES): 488.1 (M+H).
According to D, E and the described method of F part of embodiment 73, the compound of B part is converted into the product of this embodiment.
Embodiment 77
1-(benzoyl)-4-(4-amyl phenyl ether alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
12ml toluene and 3ml N to 1.249 (4.82mmol) triphenyl phosphine that stirs; add 524 μ l (4.82mmol) 1-amylalcohols and 1.59 (3.22mmol) 1-(benzoyl)-4-(4-hydroxybenzene alkylsulfonyl)-2 in the dinethylformamide solution; 3; 4; 5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-methyl-formiate.In the mixed solution of this stirring, add 259 μ l (4.82mmol) diethylazodicarboxylates, this mixed solution is stirred spend the night.Remove solvent, as solvent, residue is through silica gel column chromatography with ethyl acetate-hexane (1: 3).Concentrate the component that contains product, obtain the 1.59g white solid; Mp170-172 ℃; To C 29H 32N 2O 6Analyze: calculated value: C, 64.9; H, 6.0; N, 5.2; Measured value: C, 64.7; H, 6.0; N, 5.4.
Under room temperature, the 7ml tetrahydrofuran (THF) mixed solution of 1.4g (2.61mmol) aforesaid compound sample and 3.4g (3.4mmol) 1N potassium hydroxide was stirred 2 hours, vacuum is removed solvent.In residue, add toluene, remove solvent (repeating twice).Dried residue is spent the night under 85 ℃, vacuum, obtains the 1-that 1.5g is a sylvite (benzoyl)-4-(4-amyl phenyl ether alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid.In the 10ml methylene dichloride, add methylene dichloride (2.0M) solution of 4.8ml (9.6mmol) oxalyl chloride, this solution is cooled to 0 ℃.In refrigerative solution, add 740 μ l (9.56mmol) N, the anhydrous N of 5ml of the aforementioned sylvite of dinethylformamide and 1.34g (2.39mmol), dinethylformamide solution.Under room temperature, this mixed solution was stirred 1.5 hours, be cooled to 0 ℃, add in the 10ml tetrahydrofuran solution of 50% aqueous hydroxylamine of 2.2ml (35.9mmol) of cooling (0 ℃).Under room temperature, this mixed solution stirring is spent the night, dilute with methylene dichloride.The separate dichloromethane layer washes with water and vacuum concentration is extremely done.As solvent, residue is through silica gel column chromatography with ethyl acetate-hexane (1: 1).Concentrate the component that contains product and extremely do, residue is dissolved in the ethyl acetate.Water is this solution washing three times, with the salt water washing once, and through dried over sodium sulfate.Remove solvent, dried residue is spent the night under 85 ℃, vacuum, obtains the product that 0.96g is a white foam shape thing; Mass spectrum (ES) 538.0 (M+H).
Embodiment 78
1-ethanoyl-4-(4-hydroxybenzene alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-[1,4] benzodiazepine -3-formic acid oxyamide
To 1-ethanoyl-4-(4-hydroxybenzene alkylsulfonyl)-2; 3; 4; 5-tetrahydrochysene-1H-[1; 4] the 5ml N of benzodiazepine -3-formic acid (0.55g) and N-hydroxyl-benzotriazole (0.414g) adds 0.684g 1-[3-(dimethylamino) propyl group in the dinethylformamide crude product mixed solution]-the 3-ethyl-carbodiimide hydrochloride.Under room temperature, this mixed solution was stirred 1 hour, add 750 μ l aqueous hydroxylamines (50%) then, under room temperature, this mixed solution stirring is spent the night.Dilute this mixed solution with ethyl acetate, water, 2N citric acid and salt water washing then is through dried over sodium sulfate.Vacuum is removed solvent, obtains solid.As solvent,, obtain solid with the ethyl acetate solution of 10% methyl alcohol,, obtain the canescence foam its dried overnight under 78 ℃, vacuum through silica gel column chromatography; Mass spectrum (ES) 406.1 (M+H); To C 18H 19N 3O 6S analyzes: calculated value: C, 53.3; H, 4.7; N, 10.4; Measured value: C, 52.6; H, 5.2; N, 10.4.
Under the situation that does not depart from aim of the present invention or marrow, the present invention also can show as other specific form, therefore should be with reference to appending claims rather than aforesaid specification sheets about scope of the present invention.

Claims (12)

1. formula 1 compound and pharmacy acceptable salt thereof:
Figure 9980423700021
Wherein
R is selected from hydrogen, (C 1-C 3) alkyl ,-CN ,-OR ' ,-SR ' ,-CF 3,-OCF 3, Cl, F, NH 2, NH (C 1-C 3) alkyl ,-N (R ') CO (C 1-C 3) alkyl ,-N (R ') (R '), NO 2,-CONH 2,-SO 2NH 2,-SO 2N (R ') (R ') ,-N (R ') COCH 2O-(C 1-C 3) alkyl, wherein R ' is (C 1-C 3) alkyl or hydrogen;
R 4Be hydroxyl, (C 1-C 6) alkyl-O-, (C 1-C 6) alkyl-S-, R wherein " be hydrogen, halogen, cyano group, methyl or-OCH 3
R 1And R 2Independent separately is hydrogen or CH 3
R 3Be (C 1-C 8) alkyl, NH 2CH 2CO-, (C 1-C 6) alkyl NHCH 2CO-, HO (CH 2) mCO-, HCO-, aryl (CH 2) nCO-, heteroaryl (CH 2) nCO-, (C 1-C 3) alkyl-O-(CH 2) nCO-, (C 1-C 3) alkyl CO-, (C 1-C 3) alkyl CO-NHCH 2CO-, (C 3-C 7) cycloalkyl CO-, (C 1-C 3) alkyl SO 2-, aryl (CH 2) nSO 2-, heteroaryl (CH 2) nSO 2-, (C 1-C 3) alkyl-O-(CH 2) m-SO 2-, (C 1-C 3) alkyl-O-(CH 2) m, (C 1-C 3) alkyl-O-(C 1-C 3) alkyl-O-(C 1-C 3) alkyl, HO-(C 1-C 3) alkyl-O-(C 1-C 3) alkyl, aryl-O-CH 2CO-, heteroaryl-O-CH 2CO-, aryl CH=CHCO-, heteroaryl CH=CHCO-, (C 1-C 3) alkyl CH=CHCO-, Aryl (C 1-C 3) alkyl, heteroaryl (C 1-C 3) alkyl, aryl CH=CHCH 2-, heteroaryl CH=CHCH 2-, (C 1-C 6) alkyl CH=CHCH 2-,
Figure 9980423700032
R ' OCH 2CH (OR ＇) CO-, (R ' OCH 2) 2C (R ') CO-,
Figure 9980423700041
[(C 1-C 6) alkyl] 2-N-(C 1-C 6) alkyl CO-or (C 1-C 6) alkyl-NH-(C 1-C 6) alkyl CO-; Wherein
m=1-3；n=0-3?；
Aryl is Heteroaryl is
Wherein X is hydrogen, halogen, (C 1-C 3) alkyl or-OCH 3, R is identical with above-mentioned definition with R ';
L is hydrogen, (C 1-C 3) alkyl ,-CN ,-OR ' ,-SR ' ,-CF 3,-OCF 3, Cl, F, NH 2,-NH-(C 1-C 3) alkyl ,-N (R ') CO (C 1-C 3) alkyl, N (R ') (R ') ,-NO 2,-CONH 2,-SO 2NH 2,-SO 2N (R ') (R ') ,-N (R ') COCH 2O-(C 1-C 3) alkyl,
Figure 9980423700044
M is
Figure 9980423700052
Or N (R ') (and R '), wherein R ' is identical with above-mentioned definition;
W is O, S, NH or N (C 1-C 3) alkyl;
Y is hydrogen, F, Cl, CF 3Or OCH 3X ' is halogen, hydrogen, (C 1-C 3) alkyl, O-(C 1-C 3) alkyl or-CH 2OH.
2. the compound of claim 1 and pharmacy acceptable salt thereof, wherein
R is hydrogen, (C 1-C 3) alkyl ,-CN ,-OR ' ,-SR ' ,-CF 3,-OCF 3, Cl, F, NH 2, NH (C 1-C 3) alkyl ,-N (R ') CO (C 1-C 3) alkyl ,-N (R ') (R '), NO 2,-CONH 2,-SO 2NH 2,-SO 2N (R ') (R ') or-N (R ') COCH 2O-(C 1-C 3) alkyl, wherein R ' is (C 1-C 3) alkyl or hydrogen;
R 4Be (C 1-C 6) alkyl-O-, (C 1-C 6) alkyl-S-,
Figure 9980423700061
R wherein " be hydrogen, halogen, cyano group, methyl or-OCH 3
R 1And R 2Independent separately is hydrogen or CH 3
R 3Be (C 1-C 8) alkyl, NH 2CH 2CO-, (C 1-C 6) alkyl NHCH 2CO-, HO (CH 2) mCO-, HCO-, aryl (CH 2) nCO-, heteroaryl (CH 2) nCO-, (C 1-C 3) alkyl-O-(CH 2) nCO-, (C 1-C 3) alkyl CO-, (C 1-C 3) alkyl CO-NHCH 2CO-, (C 3-C 7) cycloalkyl CO-, aryl-O-CH 2CO-, heteroaryl OCH 2CO-, aryl CH=CHCO-, heteroaryl CH=CHCO-, (C 1-C 3) alkyl CH=CHCO-,
Figure 9980423700062
Wherein
m=1-3；n=0-3；
Aryl is Heteroaryl is
Wherein X is hydrogen, halogen, (C 1-C 3) alkyl or-OCH 3, R is identical with above-mentioned definition with R '.
3. the compound of claim 1 and pharmacy acceptable salt thereof, wherein
R is hydrogen, (C 1-C 3) alkyl ,-CN ,-OR ' ,-SR ' ,-CF 3,-OCF 3, Cl, F, NH 2, NH (C 1-C 3) alkyl ,-N (R ') CO (C 1-C 3) alkyl ,-N (R ') (R '), NO 2,-CONH 2,-SO 2NH 2,-SO 2N (R ') (R ') ,-N (R ') COCH 2O-(C 1-C 3) alkyl, wherein R ' is (C 1-C 3) alkyl or hydrogen;
R 4Be (C 1-C 6) alkyl-O-, (C 1-C 6) alkyl-S-, R wherein " be hydrogen, halogen, cyano group, methyl or-OCH 3
R 1And R 2Independent separately is hydrogen or CH 3
R 3For
Figure 9980423700081
[(C 1-C 6) alkyl] 2-N-(C 1-C 6) alkyl CO-or (C 1-C 6) alkyl-NH-(C 1-C 6) alkyl CO-, wherein R ' is identical with above-mentioned definition.
4. the compound of claim 1 and pharmacy acceptable salt thereof, wherein
R is hydrogen, (C 1-C 3) alkyl ,-CN ,-OR ' ,-SR ' ,-CF 3,-OCF 3, Cl, F, NH 2, NH (C 1-C 3) alkyl ,-N (R ') CO (C 1-C 3) alkyl ,-N (R ') (R '), NO 2,-CONH 2,-SO 2NH 2,-SO 2N (R ') (R ') ,-N (R ') COCH 2O-(C 1-C 3) alkyl, wherein R ' is (C 1-C 3) alkyl or hydrogen;
R 4Be (C 1-C 6) alkyl-O-, (C 1-C 6) alkyl-S-, R wherein " be hydrogen, halogen, cyano group, methyl or-OCH 3
R 1And R 2Independent separately is hydrogen or CH 3
R 3Be (C 1-C 3) alkyl SO 2-, aryl (CH 2) nSO 2-, heteroaryl (CH 2) nSO 2-or (C 1-C 3) alkyl-O-(CH 2) m-SO 2, wherein
m=1-3；n=0-3；
Aryl is Heteroaryl is
Figure 9980423700093
Wherein X is hydrogen, halogen, (C 1-C 3) alkyl or-OCH 3, R is identical with above-mentioned definition with R '.
5. the compound of claim 1 and pharmacy acceptable salt thereof, wherein
R is hydrogen, (C 1-C 3) alkyl ,-CN ,-OR ' ,-SR ' ,-CF 3,-OCF 3, Cl, F, NH 2, NH (C 1-C 3) alkyl ,-N (R ') CO (C 1-C 3) alkyl ,-N (R ') (R '), NO 2,-CONH 2,-SO 2NH 2,-SO 2N (R ') (R ') or-N (R ') COCH 2O-(C 1-C 3) alkyl, wherein R ' is (C 1-C 3) alkyl or hydrogen;
R 4Be (C 1-C 6) alkyl-O-, (C 1-C 6) alkyl-S-, R wherein " be hydrogen, halogen, cyano group, methyl or-OCH 3
R 1And R 2Independent separately is hydrogen or CH 3
R 3Be (C 1-C 8) alkyl, aryl (C 1-C 3) alkyl, heteroaryl (C 1-C 3) alkyl, aryl CH=CHCH 2, heteroaryl CH=CHCH 2-or (C 1-C 6) alkyl CH=CHCH 2-, wherein
Aryl is
Figure 9980423700102
Heteroaryl is
Wherein X is hydrogen, halogen, (C 1-C 3) alkyl or-OCH 3, R is identical with above-mentioned definition with R '.
6. the compound of claim 1 and pharmacy acceptable salt thereof, wherein
R is hydrogen, (C 1-C 3) alkyl ,-CN ,-OR ' ,-SR ' ,-CF 3,-OCF 3, Cl, F, NH 2, NH (C 1-C 3) alkyl ,-N (R ') CO (C 1-C 3) alkyl ,-N (R ') (R '), NO 2,-CONH 2,-SO 2NH 2,-SO 2N (R ') (R ') or-N (R ') COCH 2O-(C 1-C 3) alkyl, wherein R ' is (C 1-C 3) alkyl or hydrogen;
R 4Be (C 1-C 6) alkyl-O-, (C 1-C 6) alkyl-S-,
Figure 9980423700112
R wherein " be hydrogen, halogen, cyano group, methyl or-OCH 3
R 1And R 2Independent separately is hydrogen or CH 3
R 3For Wherein
m=1-3；n=0-3；
L is hydrogen, (C 1-C 3) alkyl ,-CN ,-OR ' ,-SR ' ,-CF 3,-OCF 3, Cl, F, NH 2,-NH-(C 1-C 3) alkyl ,-N (R ') CO (C 1-C 3) alkyl, N (R ') (R ') ,-NO 2,-CONH 2,-SO 2NH 2,-SO 2N (R ') (R ') ,-N (R ') COCH 2O-(C 1-C 3) alkyl,
Figure 9980423700122
M is
Figure 9980423700132
Or N (R ') (and R '), wherein R ' is identical with above-mentioned definition;
W is O, S, NH or N (C 1-C 3) alkyl;
Y is hydrogen, F, Cl, CF 3Or OCH 3X ' is halogen, hydrogen, (C 1-C 3) alkyl, O-(C 1-C 3) alkyl or-CH 2OH.
7. Any one of claims 1 to 6 A compound selected from the following compounds: 4 - (4 - methoxybenzenesulfonyl) -1 - (3 - (trifluoromethyl) benzoyl) -2,3,4,5 - tetrahydro-1H- [1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 4 - (4 - methoxybenzenesulfonyl) -1 - (4 - methyl-benzenesulfonyl) -2,3,4,5 - tetrahydro-1H-[1,4] Benzodiazepin -3 - carboxylic acid hydroxyamide, 1 - (methylsulfonyl) -4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro-1H-[1,4] benzodiazepin Aza -3 - carboxylic acid hydroxyamide, 1,4 - bis - (4 - hydroxyphenyl sulfonyl) -2,3,4,5 - tetrahydro-1H-[1,4] benzodiazepin- -3 - Carboxylic acid hydroxyamide, 1 - benzoyl-4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro-1H-[1,4] benzodiazepines Miscellaneous -3 - carboxylic acid hydroxyamide, 1 - acetyl-4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro-1H-[1,4] benzodiazepine -3 - carboxylic acid hydroxyamide, 4 - (4 - methoxybenzenesulfonyl) -1 - (3 - pyridinyl-carbonyl) -2,3,4,5 - tetrahydro-1H-[1,4] benzene And diaza -3 - carboxylic acid hydroxyamide, 4 - (4 - methoxybenzenesulfonyl) -1 - (2 - thienyl-carbonyl) -2,3,4,5 - tetrahydro-1H-[1,4] benzene And diaza -3 - carboxylic acid hydroxyamide, 1 - methoxy-acetyl-4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro-1H-[1,4] benzo- Diaza -3 - carboxylic acid hydroxyamide, 4 - (4 - methoxybenzenesulfonyl) -1 - (propane-1 - sulfonyl) -2,3,4,5 - tetrahydro-1H-[1,4] benzene And diaza -3 - carboxylic acid hydroxyamide, 4 - (4 - methoxybenzenesulfonyl) -1 - (2 - methyl-5 - fluoro-benzoyl) -2,3,4,5 - tetrahydro-1H- [1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 4 - (4 - methoxybenzenesulfonyl) -1 - (4 - pyridyl-carbonyl) -2,3,4,5 - tetrahydro-1H-[1,4] benzene And diaza -3 - carboxylic acid hydroxyamide, 4 - (4 - methoxybenzenesulfonyl) -1 - (3 - phenyl-propionyl) -2,3,4,5 - tetrahydro-1H-[1,4] benzene And diaza -3 - carboxylic acid hydroxyamide, 1 - ([1,1 '- biphenyl]-2 - carbonyl) -4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro-1H- [1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 1 - (4 - biphenylcarbonyl) -4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro-1H-[1,4] benzene And diaza -3 - carboxylic acid hydroxyamide, 1 - (3 - fluoro-benzoyl) -4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro-1H-[1,4] benzene And diaza -3 - carboxylic acid hydroxyamide, 4 - (4 - methoxybenzenesulfonyl) -1 - (2 - methyl - 3 - fluoro-benzoyl) -2,3,4,5 - tetrahydro-1H- [1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 4 - (4 - methoxybenzenesulfonyl) -1 - (2 - methyl -3 - (trifluoromethyl) benzoyl) -2,3,4,5 - Four Hydrogen-1H-[1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 1 - (2 - chloro-6 - (trifluoromethyl) benzoyl) -4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro- -1H-[1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 1 - (4 - fluoro-2 - (trifluoromethyl) benzoyl) -4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro- -1H-[1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 1 - (2 - fluoro-6 - (trifluoromethyl) benzoyl) -4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro- -1H-[1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 4 - (4 - methoxybenzenesulfonyl) -1 - (2 - methyl-benzoyl) -2,3,4,5 - tetrahydro-1H-[1,4] Benzodiazepin -3 - carboxylic acid hydroxyamide, 4 - (4 - methoxybenzenesulfonyl) -1 - (2 - methyl-6 - chloro-benzoyl) -2,3,4,5 - tetrahydro-1H- [1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 1 - (2,4 - dimethyl-benzoyl) -4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro-1H- [1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 1 - (2,5 - dimethyl-benzoyl) -4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro-1H- [1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 1 - (2 - chloro-4 - fluoro-benzoyl) -4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro-1H- [1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 1 - (2 - chlorobenzoyl) -4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro-1H-[1,4] benzene And diaza -3 - carboxylic acid hydroxyamide, 1 - (2 - fluoro-benzoyl) -4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro-1H-[1,4] benzene And diaza -3 - carboxylic acid hydroxyamide, 1 - (2 - chloro-6 - fluoro-benzoyl) -4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro-1H- [1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 1 - (2,3 - difluoro-benzoyl) -4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro-1H- [1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 1 - (2,4 - dichloro benzoyl) -4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro-1H- [1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 1 - (2,3 - dichlorobenzoyl) -4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro-1H- [1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 1 - (2,5 - dichlorobenzoyl) -4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro-1H- [1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 1 - (2 - methoxy-benzoyl) -4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro-1H- [1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 1 - (4 - chloro-2 - methoxy-benzoyl) -4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro - 1H-[1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 4 - (4 - methoxybenzenesulfonyl) -1 - (2 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro-1H- [1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 4 - (4 - methoxybenzenesulfonyl) -1 - (3 - methyl - 2 - thienyl-carbonyl) -2,3,4,5 - tetrahydro-1H- [1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 4 - (4 - methoxybenzenesulfonyl) -1 - (4 - methyl - 2 - thienyl-carbonyl) -2,3,4,5 - tetrahydro-1H- [1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 1 - (3 - chloro-2 - thienyl-carbonyl) -4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro-1H- [1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 1 - (2 - furanylcarbonyl) -4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro-1H-[1,4] benzene And diaza -3 - carboxylic acid hydroxyamide, 4 - (4 - methoxybenzenesulfonyl) -1 - (3 - methyl - 2 - furyl ylcarbonyl) -2,3,4,5 - tetrahydro-1H- [1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 4 - (4 - methoxybenzenesulfonyl) -1 - (4 - methyl - 2 - furyl ylcarbonyl) -2,3,4,5 - tetrahydro-1H- [1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 1 - (5 - chloro-2 - furyl carbonyl) -4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro-1H- [1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 1 - (5 - chloro-2 - thienyl-carbonyl) -4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro-1H- [1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 1 - propanoyl-4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro-1H-[1,4] benzodiazepine -3 - carboxylic acid hydroxyamide, 1 - hexanoyl -4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro-1H-[1,4] benzodiazepine -3 - carboxylic acid hydroxyamide, 1 - (3 - methoxy-propionyl) -4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro-1H-[1,4] Benzodiazepin -3 - carboxylic acid hydroxyamide, 4 - (4 - methoxybenzenesulfonyl) -1 - (3 - thienyl-carbonyl) -2,3,4,5 - tetrahydro-1H-[1,4] benzene And diaza -3 - carboxylic acid hydroxyamide, 1 - (3 - furyl carbonyl) -4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro-1H-[1,4] benzene And diaza -3 - carboxylic acid hydroxyamide, 1 - (trans - crotonyl) -4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro-1H-[1,4] benzene And diaza -3 - carboxylic acid hydroxyamide, 1 - (methacrylic acid) -4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro-1H-[1,4] benzo- Diaza -3 - carboxylic acid hydroxyamide, 1 - (acetyl-acetylamino) -4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro-1H-[1,4] Benzodiazepin -3 - carboxylic acid hydroxyamide, 1 - (acetyl-amino) -4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro-1H-[1,4] benzo- Diaza -3 - carboxylic acid hydroxyamide, 1 - (N, N-dimethylamino-acetyl) -4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro - 1H-[1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 1 - (cyclopropylcarbonyl) -4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro-1H-[1,4] benzo- Diaza -3 - carboxylic acid hydroxyamide, 4 - (4 - methoxybenzenesulfonyl) -1 - (4 - (2 - thienyl) phenyl - carbonyl) -2,3,4,5 - tetrahydro - 1H-[1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 4 - (4 - methoxybenzenesulfonyl) -1 - (4 - (3 - thienyl) phenyl-carbonyl) -2,3,4,5 - tetrahydro - 1H-[1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 4 - (4 - methoxybenzenesulfonyl) -1 - [2 - (1 - pyrazolyl) phenylcarbonyl] -2,3,4,5 - tetrahydro - 1H-[1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 4 - (4 - methoxybenzenesulfonyl) -1 - [2 - (3 - pyrazolyl) phenylcarbonyl] -2,3,4,5 - tetrahydro - 1H-[1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 1 - (cyclohexyl-carbonyl) -4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro-1H-[1,4] benzo- Diaza -3 - carboxylic acid hydroxyamide, 1 - methoxy-acetyl-4 - (4 - methoxybenzenesulfonyl)-7 - methyl-2 ,3,4,5 - tetrahydro-1H- [1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 1 - benzoyl-4 - (4 - methoxybenzenesulfonyl)-7 - methyl-2 ,3,4,5 - tetrahydro-1H-[1,4] Benzodiazepin -3 - carboxylic acid hydroxyamide, 4 - (4 - methoxybenzenesulfonyl) -1 - [(4 - trifluoromethoxy) benzoyl]-8 - chloro-2 ,3,4,5 - Tetrahydro-1H-[1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 4 - (4 - methoxybenzenesulfonyl) -1 - [2 - chloro-4 - (3 - methyl-1 - pyrazolyl) phenylcarbonyl] - 2,3,4,5 - tetrahydro-1H-[1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 4 - (4 - methoxybenzenesulfonyl) -1 - [2 - (1 - pyrazolyl) phenylcarbonyl]-7 - methyl-2 ,3,4,5 - Tetrahydro-1H-[1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 4 - (4 - methoxybenzenesulfonyl) -1 - [2 - (4 - morpholino) phenylcarbonyl]-8 - chloro-2 ,3,4,5 - Four Hydrogen-1H-[1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 1 - (4 - ethoxy-benzoyl) -4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro-1H- [1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 1 - (cyclobutylcarbonyl) -4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro-1H-[1,4] benzo- Diaza -3 - carboxylic acid hydroxyamide, 4 - (4 - methoxybenzenesulfonyl) -1 - (phenoxyacetyl) -2,3,4,5 - tetrahydro-1H-[1,4] benzene And diaza -3 - carboxylic acid hydroxyamide, 4 - (4 - methoxybenzenesulfonyl) -1 - (2 - methoxy-ethyl) -2,3,4,5 - tetrahydro-1H-[1,4] benzene And diaza -3 - carboxylic acid hydroxyamide, 1 - benzyl-4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro-1H-[1,4] benzodiazepine 3 - carboxylic acid hydroxyamide, 1 - (2,4 - dimethoxy-benzoyl) -4 - (4 - methoxybenzenesulfonyl) -2,3,4,5 - tetrahydro - 1H-[1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 4 - (4 - methoxybenzenesulfonyl) -1 - [2 - (4 - methyl-piperazin-1 - yl) acetyl] -2,3,4,5 - Four Hydrogen-1H-[1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 4 - [4 - (4 - chlorophenoxy) benzenesulfonyl] -1 - (methoxyacetyl (acetal)) -2,3,4,5 - four Hydrogen-1H-[1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 4 - [4 - (4 - chlorophenoxy) benzenesulfonyl] -1 - (2 - thienyl-carbonyl) -2,3,4,5 - tetrahydro-1H- [1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide, 4 - [4 - (4 - chlorophenoxy) benzenesulfonyl] -1 - (benzoyl-2 ,3,4,5 - tetrahydro-1H-[1,4] benzene And diaza -3 - carboxylic acid hydroxyamide, And 4 - [4 - (4 - pyridyloxy) benzenesulfonyl] -1 - (formyl, acetyl) -2,3,4,5 - tetrahydro - 1H-[1,4] benzodiazepin- -3 - carboxylic acid hydroxyamide. ...
8. medicinal compositions, it contains formula 1 compound and pharmacy acceptable salt thereof: Wherein
R is selected from hydrogen, (C 1-C 3) alkyl ,-CN ,-OR ' ,-SR ' ,-CF 3,-OCF 3, Cl, F, NH 2, NH (C 1-C 3) alkyl ,-N (R ') CO (C 1-C 3) alkyl ,-N (R ') (R '), NO 2,-CONH 2,-SO 2NH 2,-SO 2N (R ') (R ') ,-N (R ') COCH 2O-(C 1-C 3) alkyl, wherein R ' is (C 1-C 3) alkyl or hydrogen;
R 4Be hydroxyl, (C 1-C 6) alkyl-O-, (C 1-C 6) alkyl-S-,
Figure 9980423700192
R wherein " be hydrogen, halogen, cyano group, methyl or-OCH 3
R 1And R 2Independent separately is hydrogen or CH 3
R 3Be (C 1-C 8) alkyl, NH 2CH 2CO-, (C 1-C 6) alkyl NHCH 2CO-, HO (CH 2) mCO-, HCO-, aryl (CH 2) nCO-, heteroaryl (CH 2) nCO-, (C 1-C 3) alkyl-O-(CH 2) nCO-, (C 1-C 3) alkyl CO-, (C 1-C 3) alkyl CO-NHCH 2CO-, (C 3-C 7) cycloalkyl CO-, (C 1-C 3) alkyl SO 2-, aryl (CH 2) nSO 2-, heteroaryl (CH 2) nSO 2-, (C 1-C 3) alkyl-O-(CH 2) m-SO 2-, (C 1-C 3) alkyl-O-(CH 2) m, (C 1-C 3) alkyl-O-(C 1-C 3) alkyl-O-(C 1-C 3) alkyl, HO-(C 1-C 3) alkyl-O-(C 1-C 3) alkyl, aryl-O-CH 2CO-, heteroaryl-O-CH 2CO-, aryl CH=CHCO-, heteroaryl CH=CHCO-, (C 1-C 3) alkyl CH=CHCO-, Aryl (C 1-C 3) alkyl, heteroaryl (C 1-C 3) alkyl, aryl CH=CHCH 2-, heteroaryl CH=CHCH 2-, (C 1-C 6) alkyl CH=CHCH 2-, R ' OCH 2CH (OR ') CO-, (R ' OCH 2) 2C (R ') CO-, [(C 1-C 6) alkyl] 2-N-(C 1-C 6) alkyl CO-or (C 1-C 6) alkyl-NH-(C 1-C 6) alkyl CO-; Wherein
m=1-3；n=0-3；
Aryl is
Figure 9980423700211
With heteroaryl be
Figure 9980423700212
Wherein X is hydrogen, halogen, (C 1-C 3) alkyl or-OCH 3, R is identical with above-mentioned definition with R ';
L is hydrogen, (C 1-C 3) alkyl ,-CN ,-OR ' ,-SR ' ,-CF 3,-OCF 3, Cl, F, NH 2,-NH-(C 1-C 3) alkyl ,-N (R ') CO (C 1-C 3) alkyl, N (R ') (R ') ,-NO 2,-CONH 2,-SO 2NH 2,-SO 2N (R ') (R ') ,-N (R ') COCH 2O-(C 1-C 3) alkyl,
Figure 9980423700213
M is
Figure 9980423700221
Figure 9980423700222
Or N (R ') (and R '), wherein R ' is identical with above-mentioned definition;
W is O, S, NH or N (C 1-C 3) alkyl;
Y is hydrogen, F, Cl, CF 3Or OCH 3X ' is halogen, hydrogen, (C 1-C 3) alkyl, O-(C 1-C 3) alkyl or-CH 2OH.
9. treat the method for the disease of the Mammals matrix metalloproteinase mediation that needs this treatment, this method comprises formula 1 compound and the pharmacy acceptable salt thereof that gives described Mammals significant quantity: Wherein
R is selected from hydrogen, (C 1-C 3) alkyl ,-CN ,-OR ' ,-SR ' ,-CF 3,-OCF 3, Cl, F, NH 2, NH (C 1-C 3) alkyl ,-N (R ') CO (C 1-C 3) alkyl ,-N (R ') (R '), NO 2,-CONH 2,-SO 2NH 2,-SO 2N (R ') (R ') ,-N (R ') COCH 2O-(C 1-C 3) alkyl, wherein R ' is (C 1-C 3) alkyl or hydrogen;
R 4Be hydroxyl, (C 1-C 6) alkyl-O-, (C 1-C 6) alkyl-S-, R wherein " be hydrogen, halogen, cyano group, methyl or-OCH 3
R 1And R 2Independent separately is hydrogen or CH 3
R 3Be (C 1-C 8) alkyl, NH 2CH 2CO-, (C 1-C 6) alkyl NHCH 2CO-, HO (CH 2) mCO-, HCO-, aryl (CH 2) nCO-, heteroaryl (CH 2) nCO-, (C 1-C 3) alkyl-O-(CH 2) nCO-, (C 1-C 3) alkyl CO-, (C 1-C 3) alkyl CO-NHCH 2CO-, (C 3-C 7) cycloalkyl CO-, (C 1-C 3) alkyl SO 2-, aryl (CH 2) nSO 2-, heteroaryl (CH 2) nSO 2-, (C 1-C 3) alkyl-O-(CH 2) m-SO 2-, (C 1-C 3) alkyl-O-(CH 2) m, (C 1-C 3) alkyl-O-(C 1-C 3) alkyl-O-(C 1-C 3) alkyl, HO-(C 1-C 3) alkyl-O-(C 1-C 3) alkyl, aryl-O-CH 2CO-, heteroaryl-O-CH 2CO-, aryl CH=CHCO-, heteroaryl CH=CHCO-, (C 1-C 3) alkyl CH=CHCO-,
Figure 9980423700232
Aryl (C 1-C 3) alkyl, heteroaryl (C 1-C 3) alkyl, aryl CH=CHCH 2-, heteroaryl CH=CHCH 2-, (C 1-C 6) alkyl CH=CHCH 2-,
Figure 9980423700241
R ' OCH 2CH (OR ') CO-, (R ' OCH 2) 2C (R ') CO-,
Figure 9980423700242
[(C 1-C 6) alkyl] 2-N-(C 1-C 6) alkyl CO-or (C 1-C 6) alkyl-NH-(C 1-C 6) alkyl CO-; Wherein
m=1-3；n=0-3；
Aryl is With heteroaryl be
Figure 9980423700251
Wherein X is hydrogen, halogen, (C 1-C 3) alkyl or-OCH 3, R is identical with above-mentioned definition with R ';
L is hydrogen, (C 1-C 3) alkyl ,-CN ,-OR ' ,-SR ' ,-CF 3,-OCF 3, Cl, F, NH 2,-NH-(C 1-C 3) alkyl ,-N (R ') CO (C 1-C 3) alkyl, N (R ') (R ') ,-NO 2,-CONH 2,-SO 2NH 2,-SO 2N (R ') (R ') ,-N (R ') COCH 2O-(C 1-C 3) alkyl, M is
Figure 9980423700261
Or N (R ') (and R '), wherein R ' is identical with above-mentioned definition;
W is O, S, NH or N (C 1-C 3) alkyl;
Y is hydrogen, F, Cl, CF 3Or OCH 3X ' is halogen, hydrogen, (C 1-C 3) alkyl, O-(C 1-C 3) alkyl or-CH 2OH.
10. as any one claimed compounds among the claim 1-7 of medicine.
11. the purposes of any one claimed compounds in the medicine of the disease of preparation treatment matrix metalloproteinase mediation among the claim 1-7.
12. the method for the compound of any one formula 1 required for protection among the preparation claim 1-7, this method comprises makes corresponding carboxylic acid halides and azanol reaction.
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WO1999037625A1 (en) 1999-07-29
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PL342045A1 (en) 2001-05-21
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IL137162A0 (en) 2001-07-24
NO20003828D0 (en) 2000-07-26
HUP0100277A2 (en) 2002-02-28
AR017230A1 (en) 2001-08-22
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