CN1271342A - Synthesis of clasto-lactacystin-beta-lactone and analogs thereof - Google Patents

Synthesis of clasto-lactacystin-beta-lactone and analogs thereof Download PDF

Info

Publication number
CN1271342A
CN1271342A CN98809526A CN98809526A CN1271342A CN 1271342 A CN1271342 A CN 1271342A CN 98809526 A CN98809526 A CN 98809526A CN 98809526 A CN98809526 A CN 98809526A CN 1271342 A CN1271342 A CN 1271342A
Authority
CN
China
Prior art keywords
aryl
alkyl
formula
optionally
alkaryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN98809526A
Other languages
Chinese (zh)
Inventor
F·索西
L·普拉蒙当
M·比恩克
W·罗史
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of CN1271342A publication Critical patent/CN1271342A/en
Pending legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/14—Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
    • C07C235/80—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms having carbon atoms of carboxamide groups and keto groups bound to the same carbon atom, e.g. acetoacetamides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C247/00—Compounds containing azido groups
    • C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C247/04—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
    • C07C69/675—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids of saturated hydroxy-carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Oncology (AREA)
  • Rheumatology (AREA)
  • Epidemiology (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pyrrole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The present invention is directed to an improved synthesis of clasto-lactacystin- beta -lactone, and analogs thereof, that proceeds in fewer steps and in much greater overall yield than syntheses described in the prior art. The synthetic pathway relies upon a novel stereospecific synthesis of an oxazoline intermediate and a unique stereoselective addition of a formyl amide to the oxazoline. Also described are novel clasto-lactacystin- beta -lactones, and analogs thereof and their use as proteosome inhibitors.

Description

Synthesizing of clasto-lactacystin-β-lactone and analogue thereof
Background of invention
Invention field
The present invention relates generally to the preparation method of lactacystin and related compound, and the new analogue of lactacystin and clasto-lactacystin (clasto-lactacystin)-β-lactone, and they are as the purposes of proteoplast inhibitor.
Description of related art
Streptomyces metabolite lactacystin (1) suppress the cell cycle process and in the neuroblast oncocyte of cultivating, bring out aixs cylinder grow (people such as Omura, " microbiotic magazine " (J.Antibiotics), 44:117 (1991); People such as Omura, " microbiotic magazine " (J.Antibiotics), 44:113 (1991); People such as Fenteany, " institute of NAS newspaper " (Proc.Natl.Acad.Sci. (USA)), 91:3358 (1994)).The cellular targets that mediates these effects is the 20S proteoplast, i.e. the proteolysis core of 26S proteoplast, and it is the main ingredient of the ubiquitin-proteoplast approach of intracellular protein degraded.Its mechanism research is had been found that, instrumentality lactacystin by reactive specy clasto-lactacystin-β-lactone (2) can the arrestin body, this lactone (2) is the N-terminal threonine residues of acylated protein body X/MB1 subunit (people such as Fenteany specifically, " science " (Science), 268:726 (1995); People such as Dick, " journal of biological chemistry " (J.Biol.Chem.), 271:7273 (1996)).People such as Fenteany also disclose Lactacystin analogs (WO96/32105).
Figure A9880952600241
In multiple important physical process, all relate to ubiquitin-proteoplast approach (people such as Goldberg, " chemistry and biology " (Chemistry ﹠amp; Biology), 2:503 (1995); Ciechanover, " cell " (Cell), 79:13 (1994); Deshaies, " trend of cytobiology " (Trends Cell Biol.), 5:431 (1995)).In fact, the great majority of cell protein all are hydrolyzed by this approach.At first be conjugated on a plurality of molecules of small protein ubiquitin the mark protein substrate so that degrade by covalency.Then, gained multiubiquitination protein is discerned by the 26S proteoplast and is degraded.Through the long-term understanding to its effect in the degradation process of intracellular protein that damage or sudden change, people know also that now this approach is responsible for multiple adjusting Selected degradation of proteins.For example, the orderly cell cycle procedural ubiquitination and degraded of crossing the range request cyclin.Ubiquitin-proteoplast approach also mediate numerous other cyclins and tumor suppressor protein degraded (for example, p21, p27, p53).The activation of transcription factor NF-KB depends on ubiquitination and the degraded of repressible protein I κ B-α, this transcription factor aspect the immunity generegulation effect relevant, play an important role with inflammatory reaction (people such as Palombella, WO95/25533).In addition, intracellular protein realizes that by ubiquitin-proteoplast approach the continuity turnover is the process antigen peptide so that present necessary (Goldberg and Rock, WO 94/17816) on the MHC I quasi-molecule.
The biological activity that lactacystin and clasto-lactacystin-β-lactone is interesting and the deficiency of natural matter, and the controversial chemical structure of these molecules have encouraged people to make great efforts synthetic lactacystin and related analogs.Corey and Reichard (" JACS " (J.Am.Chem.Soc.), 114:10677 (1992); " tetrahedron communication " (Tetrahedron Lett.), 34:6977 (1993)) realized that the complete synthesis first of lactacystin, this building-up reactions had 15 steps, overall yield is 10%.The key feature of this building-up reactions is to construct C (6)-C (7) key along-oxazoline aldehyde by the Stereoselective aldol reaction from N-benzyl Serine deutero-.Stereoselective Mukaiyama-aldol reaction from D-Pyrrolidonecarboxylic acid deutero-Shuan phosphine-oxazoline silyl enol ether intermediate in the synthetic method of people such as Uno (" JACS ", 116:2139 (1994)) report is used to construct C (5)-C (9) key.This building-up reactions had 19 steps, and overall yield is 5%.The aldol reaction that carries out under the alkaline condition of similar Shuan phosphine-oxazoline intermediate constitutes the model research basis of people (" tetrahedron communication ", 36:6131 (1995)) reports such as Dikshit.
The notable feature of the aldol reaction of oxazoline deutero-enolate is synthetic (people such as Suazuka, " JACS ", the 115:5302 (1993) by the lactacystin of Smith and co-worker thereof report; People such as Nagamitsu, " JACS ", 118:3584 (1996)) and synthetic (Corey and Choi, " tetrahedron communication ", the 34:6969 (1993) of (the 6R)-lactacystin of Corey and Choi report; Doctor's Choi paper, Harvard University, 44 (1995)).In preceding a kind of synthetic method (20 steps were arranged, and overall yield is 9%), enolate and formaldehyde condensation are introduced a single carbon atom, it must be processed in many additional steps then.In Corey and Choi synthetic method, the aldol reaction selectivity provides undesirable stereochemistry product, causes finally making C (6) epimer that does not have bioactive lactacystin.
People prepare lactacystin (people such as Chida, " Chemical Society magazine, chemical communication " (J.Chem.Soc., Chem.Commun.), 793 (1995)) with 2% overall yield from D-glucose with 22 steps.Related biosynthetic pathway has carried out studying people such as (, " tetrahedron communication ", 35:5009 (1994)) Nakagawa by the charging experiment that relates to enrichment 13C compound in the natural product production.
The lactacystin synthetic method time of above-mentioned report is long, and productive rate is low, and does not have a kind of synthetic method to be applicable to the synthetic of analogue.Therefore need the preparation lactacystin, the improving one's methods of clasto-lactacystin-β-lactone and analogue thereof.
Summary of the invention
A first aspect of the present invention relates to the preparation method of formula VI lactacystin or its analogue or formula VII clasto-lactacystin-β-lactone or its analogue,
Figure A9880952600271
Wherein
R 1Be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkaryl, aralkyl, wherein said aryl, any one loop section can optionally be substituted in aralkyl or the alkaryl;
R 2Be alkyl, cycloalkyl, aryl, alkaryl, aralkyl, alkoxyl group, hydroxyl, alkoxyalkyl or amido, wherein said aryl, any one loop section can optionally be substituted in aralkyl or the alkaryl; And
R 7Be alkyl, aryl, alkaryl, aralkyl, wherein said alkyl, aryl, any one can optionally be substituted in aralkyl or the alkaryl.
A second aspect of the present invention relates to the preparation method of formula XIV formyl radical methane amide, Wherein
R 2Be alkyl, cycloalkyl, aryl, alkaryl, aralkyl, alkoxyl group, hydroxyl, alkoxyalkyl or amido, wherein said aryl, any one loop section can optionally be substituted in aralkyl or the alkaryl; And
R 5And R 6Be respectively one of alkyl and alkaryl; Or R 5And R 6Coupled nitrogen-atoms forms a 5-7 element heterocycle together, and this heterocycle can optionally be substituted, and can optionally contain another Sauerstoffatom or nitrogen-atoms.
A third aspect of the present invention relates to the preparation method of formula Ia or Ib San substituted oxazole quinoline, Wherein
R 1Be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkaryl, aralkyl, wherein said aryl, any one loop section can optionally be substituted in aralkyl or the alkaryl; And R 4Be aryl or heteroaryl, the two can optionally be substituted.Formula Ia or Ib San substituted oxazole quinoline can be as preparing lactacystin by methods described herein, the starting raw material of clasto-lactacystin-β-lactone and analogue thereof.
A fourth aspect of the present invention relates to the lactacystin of formula VI and VII, clasto-lactacystin-β-lactone or analogue, and they have beyond thought biological activity.Lactacystin, clasto-lactacystin-β-lactone and analogue thereof have the biological activity as the proteoplast inhibitor.They can be used for treating the disease that is directly mediated by the proteoplast function, and as amyotrophy, or by the indirect disease that mediates of protein, said protein is processed by proteoplast such as transcription factor NF-KB.
A fifth aspect of the present invention relates to pharmaceutical composition, and it contains formula VI or formula VII compound and pharmaceutically acceptable carrier or thinner.
A sixth aspect of the present invention relates to arrestin body function or treats the method for the disease that is directly or indirectly mediated by the proteoplast function, comprises that administration has beyond thought highly active formula VI or formula VII compound aspect the arrestin body.Preferred embodiment relates to formula VI or VII compound and prevents infraction or reduce to block size after vascular occlusion, for example, and the neurone loss after the treatment apoplexy.Another preferred embodiment relates to said compound and is used for the treatment of asthma.
A seventh aspect of the present invention relates to the composition of the enantiomorph enrichment of formula XIV formyl radical methane amide.
A eighth aspect of the present invention relates to each new intermediate, suc as formula II aldol and formula III aminodiol,
Figure A9880952600291
And lactacystin, each step among the multistep preparation method of clasto-lactacystin-β-lactone or its various analogues.
A ninth aspect of the present invention relates to each intermediate, suc as formula XVII, and XVIII and XIX compound,
Figure A9880952600292
Figure A9880952600301
Wherein X is a halogen, preferred Cl, Br or I, and each step among the multistep preparation method of formula I replacement De oxazoline.
Further feature of the present invention or advantage will obviously be found out from following detailed argumentation and appended claims.
The accompanying drawing summary
Fig. 1 is the histogram of intravenous injection compound 3b to the effect of rat (n=6-8) infarct volume.
Fig. 2 is the histogram of intravenous injection compound 3b to the effect of rat (n=6-8) neurological scoring.
The detailed description of preferred embodiment
The present invention relates to actacystin, the changing of clasto-lactacystin-β-lactone and analog thereof The multistep synthetic method of advancing, it lacks than synthetic method step of the prior art, the gross production rate height. The treatment step that some are single and chemical intermediate make route of synthesis of the present invention be different from existing skill Route of synthesis in the art. For example, the new solid of this route of synthesis Yi Lai Yu oxazoline intermediate Have to select and synthesize and the unique Stereoselective addition of formoxyl formamide Dao oxazoline.
The invention still further relates to and have unexpected bioactive new-type VI and VII analog. Breast Cystine, clasto-lactacystin-β-lactone and analog thereof have as the proteosome inhibitor Biologically active. They can be used for treating the disease that is directly mediated by the proteosome function, such as muscle Atrophy, or by the indirect disease that mediates of protein, said protein is as transcribing by proteosome Factor NF-κ B processes. The invention still further relates to CKIs body function or treatment by proteosome Function is the method for the disease of mediation directly or indirectly, comprises that administration has aspect the CKIs body Beyond thought highly active formula VI or VII compound. Of the present invention preferred aspect, administration Contain the pharmaceutical composition of formula VI or formula VII compound to be used for the treatment of ischaemic or again perfusion Damage. For example, said compound is used to treatment, prevention or improves in preferred embodiments Neurone loss after the apoplexy. Synthetic method
First aspect present invention relates to the preparation method of formula VI actacystin and analog and formula VII clasto-lactacystin-β-lactone and analog thereof:
Figure A9880952600321
Wherein
R 1Alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkaryl, aralkyl, its In said aryl, in aralkyl or the alkaryl any one loop section can be optionally by Replace;
R 2Alkyl, cycloalkyl, aryl, alkaryl, aralkyl, alkoxyl, hydroxyl, alkane Oxygen base alkyl or acylamino-, wherein said aryl is any one in aralkyl or the alkaryl Loop section can optionally be substituted; And
R 7Alkyl, aryl, alkaryl, aralkyl, said alkyl wherein, aryl, virtue Any one can optionally be substituted in alkyl or the alkaryl.
The preparation method of these compounds depends on the formation of the common carboxylic acid intermediate of formula V:R wherein1And R2Definition with top definition in formula VI and VII, the step of the method comprises:
(a) by processing the aryl that formula I replaces-or Za Fang oxazolin with highly basic,
Figure A9880952600331
R wherein1Define as above,
R 3Alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkaryl, wherein any one Individual can optionally being substituted; And
R 4Be aryl or heteroaryl, the two can optionally be substituted; With the aryl of said replacement-or Za Fang oxazolin deprotonation, form enolate;
(b) with one of following metal said enolate is carried out metal transfer: titanium, aluminium, tin, zinc, magnesium and boron are processed with formula XIV formoxyl formamide then,
Figure A9880952600332
R wherein2Definition with top definition in formula VI and VII; And
R 5And R6Respectively be one of alkyl or alkaryl; Or R5And R6Coupled nitrogen-atoms forms an optionally substituted 5-7 element heterocycle together, and this heterocycle can optionally contain another oxygen atom or nitrogen-atoms, forms formula II adduct,R wherein1-R 6Definition as above;
(c) the said formula II adduct of catalytic hydrogenation forms formula IV gamma-lactam,
Figure A9880952600341
R wherein1，R 2And R3Definition as above;
(d) the said formula IV gamma-lactam of saponification forms formula V lactams carboxylic acid,
Figure A9880952600342
R wherein1And R2Definition as above.
Formula V carboxylic acid intermediate can be by processing and cyclisation with cyclizing agent, and the formula VII of formation splits-actacystin-β-lactone or its analog, and can choose wantonly further and mercaptan (R7CH) as The NAC reaction forms formula VI actacystin or its analog.
Perhaps, directly with formula V carboxylic acid intermediate and mercaptan (R7CH) such as N-acetyl group half Guang ammonia The acid coupling forms formula VI actacystin or its analog.
Second aspect present invention relates to the preparation method of the formyl radical methane amide of formula XIV enantiomorph enrichment,
Figure A9880952600343
R wherein 2, R 5And R 6Define as above, said method comprises:
(a) with formula VIII compound deprotonation,
Figure A9880952600351
R wherein 8Be sec.-propyl or benzyl, subsequently, use R 2CH 2COCl forms formula IX Xian oxazolidinone with gained negatively charged ion acidylate, R wherein 2And R 8Definition as above;
(b) formula IX Xian oxazolidinone and benzyloxymethyl chlorine are carried out stereospecific reaction, form the alcohol of formula X protection, R wherein 2And R 8Definition as above;
(c) alcohol of hydrolyzing type X protection forms formula XI carboxylic acid,
Figure A9880952600354
R wherein 2Definition as above;
(d) with said formula XI acid and acid amides R 5R 6NH 2Coupling obtains formula XII acid amides,
Figure A9880952600361
R wherein 2, R 5And R 6Definition as above;
(e) catalytic hydrogenation formula XII acid amides forms formula XIII alcohol,
Figure A9880952600362
R wherein 2, R 5And R 6Definition as above;
(f) the formula XIII alcohol of oxidation gained obtains formula XIV formyl radical methane amide.
Third aspect present invention relates to the preparation method that formula Ia three replaces along-oxazoline compounds, Wherein
R 1Be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkaryl, aralkyl, wherein said aryl, any one loop section can optionally be substituted in aralkyl or the alkaryl;
R 3Be alkyl, cycloalkyl, aryl, alkaryl, wherein any one can optionally be substituted; And
R 4Be aryl or heteroaryl, the two can optionally be substituted; Said method comprises:
(a) asymmetric dihydroxy formula XV alkene intermediate, Form the optically active glycol of formula XVIa,
(b) reaction under acid (Lewis or Bronsted acid) katalysis with the optically active glycol of said formula XVIa and aromatic carboxylic acid's deutero-ortho ester; obtain mixing ortho ester; then; in the presence of alkali with gained mixing ortho ester intermediate and following reagent react: low-grade alkane acidyl halogenide; haloid acid (HX; wherein X is a halogen), acyl chlorides and halogen-containing Lewis acid (for example, BBr 3, SnCl 4, Ti (OR) 2Cl 2, Ti (OR) 3Cl, Me 3SiX etc., wherein X is a halogen, or the like), form formula XVIIa derivative,
Figure A9880952600372
Wherein X is a halogen, preferred Cl, Br or I;
(c) with said formula XVIIa derivative and an alkali metal azide reaction, form formula XVIIIa trinitride,
Figure A9880952600373
(d) the said trinitride of catalytic hydrogenation forms formula XIXa compound,
Figure A9880952600374
(e) formula XIXa compound is placed under the closed loop condition, form the aryl that said formula I replaces-or Za Fang oxazolin, configuration takes a turn for the worse on the carbon that oxygen replaces, and production Ia is along-oxazolines; Wherein for each formula XV, XVIa, XVIIa, XVIIIa and XIXa, R 1, R 3And R 4With defining among the top formula I.
Perhaps, third aspect present invention relates to the preparation method that formula Ib three replaces anti--oxazoline compounds, comprising:
(a) asymmetric dihydroxy formula XV alkene intermediate, Form the optically active glycol of formula XVIb,
(b) reaction under acid (Lewis or Bronsted acid) katalysis with the optically active glycol of said formula XVIb and aromatic carboxylic acid's deutero-ortho ester; obtain mixing ortho ester; then; in the presence of alkali with gained mixing ortho ester intermediate and following reagent react: low-grade alkane acidyl halogenide; haloid acid (HX; wherein X is a halogen), acyl chlorides and halogen-containing Lewis acid (for example, BBr 3, SnCl 4, Ti (OR) 2Cl 2, Ti (OR) 3Cl, Me 3SiX etc., wherein X is a halogen, or the like), form formula XVIIb derivative,
Figure A9880952600383
Wherein X is a halogen, preferred Cl, Br or I;
(c) with said formula XVIIb derivative and an alkali metal azide reaction, form formula XVIIIb trinitride,
Figure A9880952600391
(d) the said trinitride of catalytic hydrogenation forms formula XIXb compound, and
Figure A9880952600392
(e) formula XIXb compound is placed under the closed loop condition, form the aryl that said formula Ib replaces-or Za Fang oxazolin, wherein ring-closure reaction is along with production Ib anti-oxazoline is carried out in the maintenance of configuration on the carbon that replaces at oxygen; Wherein for each formula XV, XVI, XVII, XVIII and XIX, R 1, R 3And R 4With defining among the top formula I.
About aforesaid method, following preferred connotation is suitable for:
R 1Preferred connotation be C 1-12Alkyl, particularly C 1-8Alkyl, C 3-8Cycloalkyl, particularly C 3-6Cycloalkyl, C 2-8Alkenyl, C 2-8Alkynyl, C 6-14Aryl, particularly C 6-10Aryl, C 6-10Aryl (C 1-6) alkyl or C 1-6Alkyl (C 6-10) aryl, wherein said aryl, any one loop section can optionally be substituted in aralkyl or the alkaryl.Can optionally appear at R 1The part aryl rings on substituting group comprise one or more, preferably one or two, hydroxyl, nitro, trifluoromethyl, halogen, C 1-6Alkyl, C 6-10Aryl, C 1-6Alkoxyl group, C 1-6Aminoalkyl group, C 1-6Aminoalkoxy, amino, C 2-6Carbalkoxy, carboxyl, C 1-6Hydroxyalkyl, C 2-6The hydroxy alkoxy base, C 1-6Alkyl sulphonyl, C 6-10Aryl sulfonyl, C 1-6Alkyl sulphinyl, C 1-6Alkyl sulfonyl amino, C 6-10Arenesulfonyl amino, C 6-10Aryl (C 1-6) alkyl sulfonyl amino, C 1-6Alkyl, C 1-6Hydroxyalkyl, C 6-10Aryl, C 6-10Aryl (C 1-6) alkyl, C 1-6Alkyl-carbonyl, C 2-6Carboxyalkyl, cyano group and trifluoromethoxy.
R 1More preferably be C 1-3Alkyl, as ethyl, propyl group or sec.-propyl; Cycloalkyl is as cyclohexyl; Or C 6-10Aryl is as phenyl.Sec.-propyl most preferably.
R 2Preferred connotation be C 1-8Alkyl, C 3-8Cycloalkyl, particularly C 3-6Cycloalkyl, C 1-8Alkoxyl group, C 2-8Alkenyl, C 2-8Alkynyl, C 6-14Aryl, particularly C 6-10Aryl, C 6-10Aryl (C 1-6) alkyl or C 1-6Alkyl (C 6-10) aryl, wherein said aryl, any one loop section can be optionally by top R in aralkyl or the alkaryl 1Described in any substituting group replace.
R 2More preferably be C 1-4Alkyl, as methyl, ethyl, propyl group or butyl; Or C 1-4Alkoxyl group is as methoxy or ethoxy.Most preferably methyl, ethyl, propyl group and butyl.
As for R 3, on this position, can use various ester functional group.Preferred connotation is C 1-8Alkyl, C 3-8Cycloalkyl, particularly C 4-7Cycloalkyl, C 2-8Alkenyl, C 2-8Alkynyl, C 6-14Aryl, particularly C 6-10Aryl, C 6-10Aryl (C 1-6) alkyl or C 1-6Alkyl (C 6-10) aryl, wherein any one can optionally be substituted.Can optionally appear at R 3On substituting group comprise one or more, preferred one or two R in the above 1Described in substituting group.
R 3More preferably be C 1-4Alkyl, C 6-10Aryl or C 6-10Aryl (C 1-6) alkyl.Most preferably methyl, ethyl, the tertiary butyl and benzyl.
R 4C preferably 6-10Aryl, preferred phenyl, or heteroaryl comprise thienyl, benzo [b] thienyl, furyl, pyranyl, isobenzofuran-base, benzoxazolyl, 2H-pyrryl, pyrryl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, indolizine base, pseudoindoyl, 3H-indyl, indyl, indazolyl, purine radicals, 4H-quinolizinyl, isoquinolyl, quinolyl or triazolyl.These phenyl or heteroaryl can be by R above one or two 1Described in substituting group optionally replace.Phenyl and most preferably by halogen, C 1-6Alkyl, C 1-6Alkoxyl group, carboxyl, amino, C 1-6Alkylamino and/or two (C 1-6) phenyl that replaces of alkylamino.
R 5And R 6Be respectively alkyl, one of aralkyl or alkaryl; Or R 5And R 6Coupled nitrogen-atoms forms the 5-7 element heterocycle together, and this heterocycle can optionally be substituted, and can optionally contain another Sauerstoffatom or nitrogen-atoms.Optional substituting group is listed in top about R 1Definition in.
R 5And R 6C preferably 1-6Alkyl, C 6-10Aryl (C 1-6) alkyl or C 1-6Alkyl (C 6-10) aryl, or coupled nitrogen-atoms forms the 5-7 element heterocycle together, and this heterocycle can optionally be substituted, and can optionally contain another Sauerstoffatom or nitrogen-atoms.NR 5R 6Most preferred connotation is a dimethylamino, diethylin, pyrrolidyl, piperidino-(1-position only), morpholino ， oxazolidone and by halogen, C 1-6Alkyl, C 6-10Aryl (C 1-6) alkyl, C 1-6Alkoxyl group, carboxyl and/or the amino De oxazolidone that replaces.
R 7C preferably 1-8Alkyl, C 3-8Cycloalkyl, C 6-10Aryl, C 6-10Aryl (C 1-6) alkyl, C 1-6Alkyl (C 6-10) aryl, wherein any one can optionally be substituted.Can optionally appear at R 7One or two ring go up or chain on substituting group comprise one or more, preferred one or two R in the above 1Described in substituting group.R 7Preferred coupled sulphur atom constitutes halfcystine or cysteine derivative, as N-acetylcysteine, gsh etc.
Flow process 1 is from replacing the general flow that De oxazoline starting raw material prepares lactacystin and clasto-lactacystin-β-lactone analogue.
Flow process 1
Figure A9880952600421
Qi beginning Yuan Liao oxazoline I both can be that suitable configuration (Ia) also can be an anti-configuration (Ib), carried out deprotonation with highly basic, formed enolate.The alkali that is applicable to this reaction is for example organic bases, comprises the acid amides alkali that is obstructed, as diisopropylaminoethyl lithium (LDA), and tetramethyl piperidine lithium (LiTMP), hexamethyl two silicon lithium nitrides, sodium or potassium (LiHMDS, NaHMDS, KHMDS) etc.; Or the alkyl lithium reagents that is obstructed, as s-butyl lithium, tert-butyl lithium etc.This reaction is carried out in tetrahydrofuran (THF) (THF) or the glycol dimethyl ether (DME) preferably at low temperatures at ether solvent such as ether.Temperature of reaction preferably pact-100-approximately-30 ℃ of scopes carry out, more preferably-85 ℃ to-50 ℃, most preferably-85 ℃ to-75 ℃.Temperature of reaction determine subsequently to the stereochemistry of the addition reaction of aldehyde very important as a result the time because lesser temps just can obtain selectivity preferably.
After taking off the alpha proton reaction step, carry out metal transfer: titanium, aluminium, tin, zinc, magnesium and boron with the said enolate of following metal pair.The preferred reagent that is suitable for this step reaction comprises titanium or aluminium Lewis acid, for example Me 2AlCl or (i-PrO) 3TiCl, or the mixture of the two.The 2-3 molar equivalent is more preferably used in the preferred Lewis acid of using the 1-3 molar equivalent, most preferably uses about 2.2-2.3 normal.Use formyl radical acid amides (XIV) to handle enolate then, obtain adducts II.Wash excessive aldehyde off with sodium bisulfate, crude product need not to be further purified and promptly can be used for the next step.Use 2.2-2.3 equivalent Me 2AlCl can optionally generate (6S) product (in lactacystin), and ratio generally is better than about 10: 1, and uses 1 equivalent Me 2AlCl, then selectivity forms (6R) product, and ratio is about 5: 1.
Adducts II as the mixture of (6S)-and (6R)-epimer generates desired gamma-lactam (IV) through catalytic hydrogenation, sometimes as with the mixture of aminodiol III:
Figure A9880952600431
Be applicable to that this catalyst for reaction comprises palladium black, palladium-gac, palladium hydroxide/charcoal etc.The organic solvent that is applicable to this reaction comprises low-level chain triacontanol such as methyl alcohol, ethanol or Virahol, lower alkanoic acid ester such as ethyl acetate, lower alkanols alkanoic acid such as acetate, or their mixture.This is reflected in the hydrogen and carries out, and hydrogen pressure is about 15-100psi, more preferably from about 30-50psi.Perhaps, can adopt the transfer hydrogenation method (people such as R.A.W.Johnstone, " chemistry comment " (Chem.Rev.), 85:129 (1985)), promptly under atmospheric pressure handle adducts II with catalyzer and hydrogen donor.
Crude mixture through heating after, make aminodiol III be transformed into gamma-lactam IV, overall yield that then can about 60-75% is separated from II.Heating steps carries out the filtrate reflux then easily by used catalyzer in the first filtering step of hydrogenation.If there is not aminodiol III in the crude mixture, can omit heating steps.Through ester saponification reaction and cyclization subsequently, can the 40-90% productive rate, generally greater than 60% productive rate, obtain β-lactone VII.Can finish cyclization with coupler well known in the prior art, wherein said coupler comprises aryl sulfonyl chloride, phosphofluoric acid benzotriazole-1-base oxygen three (dimethylamino) Phosphonium (bop reagent), Tetrafluoroboric acid O-(1H-benzotriazole-1-yl)-N, N, N ', N '-tetramethyl-urea (TBTU), alkyl, aryl or alkenyl chloro-formic ester etc.The different propylene ester of chloroformic acid is the preferred reagent of this step reaction, because all by products all are volatile, and does not need product is carried out chromatogram purification.
According to the method for document record people such as (, " tetrahedron communication ", 34:6977 (1993)) Corey, clasto-lactacystin-β-lactone can be changed into lactacystin with N-acetylcysteine processing β-lactone.Carry out like the response class of β-lactone VII and other mercaptan.Perhaps, carboxylic acid intermediate V and mercaptan coupling are formed corresponding mercaptan ester VI, make Lactacystin analogs.Therefore, the inventive method is used to the synthetic of lactacystin and clasto-lactacystin-β-lactone and analogue thereof.
The formyl radical acid amides XIV that is used in the enantiomorph enrichment in the aldolisation is a new compound.They can prepare in proper order according to the representative reactions described in flow process 2.As for the term among the present invention " the enantiomorph enrichment ", be meant that a kind of enantiomorph is excessive with respect to another kind of enantiomorph, promptly a kind of content of enantiomorph surpasses 50% in mixture.Term " stereospecific reaction " is used to refer to synthetic or reactions steps makes the output of a kind of enantiomorph or diastereomer surpass another kind of enantiomorph or other diastereomer.
Flow process 2
Figure A9880952600451
(S)-(-)-4-benzyl-2-oxazolidone (VIIIa) or (S)-(-)-4-sec.-propyl-2-oxazolidone (VIIIb) (R wherein 8Be benzyl or sec.-propyl) negatively charged ion generate Xian oxazolidinone IX through acylation reaction to surpass 80% productive rate.Pass through Stereoselective benzyloxymethyl reaction (people such as Evans subsequently; " JACS "; 112:8215 (1990)) to surpass the pure X that 80% productive rate is protected; condition is that the benzyl chloride methyl ether is freshly prepd (people such as Conner; " organic synthesis " (Organic Syntheses), 52:16 (1974)).Hydrolysis through peroxide-mediated obtains sour XI, and itself and amine coupling are obtained acid amides XII, and overall yield generally surpasses 50%.Benzyl is through hydrogenolysis, and the alcohol that will obtain (XIII) carries out oxidizing reaction then, can obtain formyl radical acid amides XIV by the 80-85% productive rate.The preferred Pearlmans catalyzer (Pd (OH) that uses in the hydrogenolysis step 2).The last described periodo alkane of the most handy Dess-Martin of oxidation step (periodinane) (" organic chemistry magazine " (J.Org.Chem.), 48:4156 (1983)) or with 2,2,6,6-tetramethyl--1-piperidines oxygen base (TEMPO) radical and the buffered hypochlorite in the presence of bromide anion (" organic chemistry magazine ", 50:4888 (1985); " organic synthesis collected works " (Org.Synth.Coll.), 8:367 (1993)) finish.Other gentle oxygenant also can use as crossing ruthenic acid tetrapropyl ammonium (TPAP).By with sodium borohydride reduction aldehyde and with R-(+)-α-methoxyl group-α-(trifluoromethyl) phenyl Acetyl Chloride 98Min. (people such as Dale; " organic chemistry magazine ", 34:2543 (1969)) alcohol of gained being changed into corresponding M osher ester can make formyl radical acid amides XIV show as enantiomer-pure.300MHz's 1H NMR analyzes and has shown single diastereomer.Aldehyde configuration according to flow process 2 preparations is stable, when being stored in 0 ℃, does not have enantiomorph deterioration sign to occur after the week.This aldehyde configuration under the aldehyde alcohol reaction conditions also is stable, and forms adducts II, and need not to carry out substituent R in C (7) position 2Epimerization.
This synthetic method will have pair highly basic and any one R 1Substituting group participate in.Sec.-propyl is to make end product have good proteoplast to suppress active preferred substituents.
Flow process 3
The invention still further relates to the new way of Zhi Bei oxazoline starting raw material I.Entire synthesis process comprised for 5 steps (seeing flow process 3), obtained suitable-replacement De oxazoline Ia at last, and after this, it is used to aforesaid method.The first step of flow process 3 is the asymmetric dihydroxy reaction of the Sharpless of alkene XV (people such as Sharpless, " organic chemistry magazine ", 57:2768 (1992); People such as Kolb, " chemistry comment ", 94:2483 (1994); Shao and Goodman, " organic chemistry magazine ", 61:2582 (1996)).If can't buy, can utilize the Wittig condensation reaction between aldehyde and the ethoxycarbonyl methylene tri Phenylphosphine to prepare alkene XV (people such as Hale, " tetrahedron ", 50:9181 (1994)).Other olefination process also is well known in the prior art.Dihydroxy reaction preferably carries out in the presence of Toluidrin with AD-mixing-β (Aldrich chemical company), obtains glycol XVIa Stereoselective, as the face selective rule of Sharpless predicted.For scale operation, dihydroxy reaction preferably uses N-methylmorpholine-N-oxide compound (NMO) to replace being present in K among the AD-mixing-β as reoxidizing agent 3Fe (CN) 6Carry out.Though the enantio-selectivity of this method is low slightly, it allows with denseer reaction mixture, and can simplify procedure of processing greatly.Can adopt recrystallization method to improve the enantiomeric purity of product.
Next step handles glycol XVIa with ortho ester under Lewis or the effect of Bronsted acid catalysis, obtain mixing ortho ester, handles people such as (, " tetrahedron communication ", 37:4525 (1996)) Haddad with carboxylic acid halides and can convert it into halogen ester XVIIa then and there.Though preferred carboxylic acid halides, particularly acetyl halide, other carboxylic acid halides such as HCl, HBr, HI, the Me of adopting of this reaction 3SiCl, Me 3SiI, Me 3SiBr etc. also can use.Formula ML nThe halogen-containing Lewis acid of X is as BBr 3, SnCl 4, Ti (OR) 2Cl 2, Ti (OR) 3Cl etc. also can use.In the following formula, M is selected from following metal: B, Ti, Sn, Al, Zn and Mg; L is any part that is fit to above-mentioned metal, preferred alkoxide or halogen group; N is the integer that can obtain stable compound; And X is a halogen.Preferably prepare halogen ester XVIIa with acetyl bromide.The ortho ester that is used for this reaction is preferably derived from aromatics or heteroaromatic carboxylic acids.More preferably ortho ester is derived from phenylformic acid, as former phenylformic acid trimethyl.When preparation mixes ortho ester, preferably make the Lewis acid catalyst, but other is sour as HBr, SnCl with the boron trifluoride etherate 4, TiCl 4, BBr 3Deng also using.
After the processing, transmit organic solvent such as methyl-sulphoxide (DMSO) or N, handle with an alkali metal azide in the N-dimethyl methyl acyl group methane amide (DMF), thick halogenide XVIIa is transformed into trinitride XVIIIa in aprotic, polar.In ethyl acetate with the catalytic hydrogenation of palladium catalyst trinitride XVIIIa along with (people such as Wang, " organic chemistry magazine ", 59:5014 (1994)) carried out in the migration of aroyl, obtain oxyamide XIXa.
In methylene dichloride, handle the reverse that XIXa realizes the carbon atom configuration that closed loop and hydroxyl replace, generate suitable-replacement De oxazoline starting raw material Ia with thionyl chloride.Other reagent that is applicable to this reaction comprises SULPHURYL CHLORIDE, phosphorus trichloride, phosphoryl chloride and (methoxycarbonyl sulfamyl)-hydroxide triethyl ammonium inner salt (Burgess reagent).Handle XIXa down in Mitsunobu condition (Mitsunobu, " synthesizing ", 1 (1981)) and also can realize closed loop.Predetermined C (the 9)-hydroxyl that becomes among end product VI and the VII of Sauerstoffatom on the oxazoline ring.Under equilibrium conditions (sodium methylate, methyl alcohol), the reverse by ester substituting group configuration makes along-oxazolines (Ia) and is transformed into anti--oxazolines (Ib), simultaneously R 1Substituent retention of configuration is fixed.Suitable-as to may be used to the method shown in the flow process 1 with anti--oxazolines, can produce result of equal value.
In another method of Zai Zhi Bei oxazoline starting raw material I, tosic acid (p-TsOH) is used to realize closed loop (flow process 4).In this case, the carbon atom configuration that closed loop replaces hydroxyl is kept, and obtains anti--oxazolines (Ib).For the three-dimensional chemical configuration that on the C (9) of end product, obtains being fit to, must be chosen to be at the chiral ligand that uses in the dihydroxy reaction so that provide and the opposite face selectivity described in the flow process 3.For example, replace AD-mixing-β with AD-mixing-α.All ensuing other steps are similar to along those steps described in-oxazoline Ia synthetic.
Flow process 4
Figure A9880952600481
Compound
Above-mentioned chemical compound lot is a new compound; These new compounds all are the prescription protections.
The present invention fourth, fifth and six aspects relate to can be by the Lactacystin analogs of route of synthesis preparation described herein; Relate to the pharmaceutical composition that contains this compounds; And the method that relates to the patient who treats the disease of suffering from the protein mediation that processes by proteoplast, this method comprises the pharmaceutical composition disclosed herein of taking significant quantity to the patient.These methods can be treated the sick matter of alzheimer's disease ， Evil, cancer, inflammation, as the inflammatory reaction relevant: transformation reactions, marrow or solid organ transplantation, or morbid state with following disease, include, but is not limited to sacroiliitis, multiple sclerosis, enteritis and parasitosis such as malaria), psoriasis, restenosis, apoplexy and myocardial infarction.
Formula VI disclosed herein and VII compound have highly selective to proteoplast, but do not suppress other proteolytic enzyme such as trypsinase, alpha-chymotrypsin, (need) calpain I, (need) calpain II, papoid and cathepsin B.
As people such as Fenteany are disclosed (WO 96/32105, and this article all is hereby incorporated by reference), lactacystin, clasto-lactacystin-β-lactone and analogue thereof have the biological activity of arrestin body.They can be used for treating the disease that is directly mediated by the proteoplast function, and as amyotrophy, or by the indirect disease that mediates of protein, said protein is processed by proteoplast such as transcription factor NF-KB.Compound with the inventive method preparation can also be used to determining whether cell, growth or physiological process or output are regulated by the proteolytic activity of proteoplast.
Having beyond thought proteoplast function, to suppress active compound be formula VI and VII compound or their salt,
Figure A9880952600501
Wherein
R 1Be C 1-12Alkyl, C 3-8Cycloalkyl, C 2-8Alkenyl, C 2-8Alkynyl, C 6-14Aryl, C 6-10Aryl (C 1-6) alkyl or C 1-6Alkyl (C 6-10) aryl;
R 2Be C 2-6Alkyl; And
R 7Be C 1-8Alkyl, C 3-8Cycloalkyl, C 6-10Aryl, C 6-10Aryl (C 1-6) alkyl, C 1-6Alkyl (C 6-10) aryl, wherein any one can optionally be substituted.Can optionally appear at R 7One or two ring go up or chain on substituting group comprise one or more, preferred one or two R in the above 1Described in substituting group.
Preferred compound is R wherein 1Be C 1-4Alkyl, the more preferably compound of sec.-propyl.R 2Preferably ethyl, n-propyl, normal-butyl or isobutyl-.R 7Preferred coupled sulphur atom forms halfcystine or cysteine derivative such as N-acetylcysteine, gsh etc. together.
Seventh aspect present invention relates to formyl radical methane amide or its salt of formula XIV enantiomorph enrichment,
Figure A9880952600502
Wherein
R 2Be C 1-8Alkyl, C 3-8Cycloalkyl, C 2-8Alkenyl, C 2-8Alkynyl, C 6-14Aryl, C 6-10Aryl (C 1-6) alkyl or C 1-6Alkyl (C 6-10) aryl; And
R 5And R 6Be respectively C 1-6Alkyl, C 6-10Aryl (C 1-6) alkyl or C 1-6Alkyl (C 6-10) aryl, or coupled nitrogen-atoms forms the 5-7 element heterocycle together, and this heterocycle can optionally be substituted, and can optionally contain another Sauerstoffatom or nitrogen-atoms.
Preferred R 2Be C 2-6The compound of alkyl.
Eighth aspect present invention relates to formula II and III compound or its salt,
Figure A9880952600511
Wherein
R 1Be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkaryl, aralkyl, wherein said aryl, any one loop section can optionally be substituted in aralkyl or the alkaryl;
R 2Be alkyl, cycloalkyl, aryl, alkaryl, aralkyl, alkoxyl group, hydroxyl, alkoxyalkyl or amido, wherein said aryl, any one loop section can optionally be substituted in aralkyl or the alkaryl;
R 3Be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkaryl, wherein any one can optionally be substituted;
R 4Be optionally substituted aryl or optionally substituted heteroaryl; And
R 5And R 6Be respectively one of alkyl or alkaryl; Or R 5And R 6Coupled nitrogen-atoms forms the 5-7 element heterocycle together, and this heterocycle can optionally be substituted, and can optionally contain another Sauerstoffatom or nitrogen-atoms.Most preferred NR 5R 6Be dimethylamino, diethylin, pyrrolidyl, piperidino-(1-position only), morpholino ， oxazolidone and, C by halogen 1-6Alkyl, C 6-10Aryl (C 1-6) alkyl, C 1-6Alkoxyl group, carboxyl and/or the amino De oxazolidone that replaces.
Preferred formula II and III compound are the following compounds of substituting group connotation wherein:
R 1Be C 1-12Alkyl, C 3-8Cycloalkyl, C 2-8Alkenyl, C 2-8Alkynyl, C 6-14Aryl, C 6-10Aryl (C 1-6) alkyl or C 1-6Alkyl (C 6-10) aryl, wherein said aryl, any one loop section can optionally be substituted in aralkyl or the alkaryl;
R 2Be C 1-8Alkyl, C 3-8Cycloalkyl, C 2-8Alkenyl, C 2-8Alkynyl, C 6-14Aryl, C 6-10Aryl (C 1-6) alkyl, or C 1-6Alkyl (C 6-10) aryl, wherein said aryl, any one loop section can optionally be substituted in aralkyl or the alkaryl;
R 3Be C 1-8Alkyl, C 3-8Cycloalkyl, C 2-8Alkenyl, C 2-8Alkynyl, C 6-14Aryl, C 6-10Aryl (C 1-6) alkyl or C 1-6Alkyl (C 6-10) aryl, wherein any one can optionally be substituted;
R 4Be optionally substituted C 6-10Aryl, or following optionally substituted heteroaryl: thienyl, benzo [b] thienyl, furyl, pyranyl, isobenzofuran-base, benzoxazole quinoline, 2H-pyrryl, pyrryl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, indolizine base, pseudoindoyl, 3H-indyl, indyl, indazolyl, purine radicals, 4H-quinolizinyl, isoquinolyl, quinolyl or triazolyl; And
R 5And R 6Be respectively C 1-6Alkyl, C 6-10Aryl (C 1-6) alkyl or C 1-6Alkyl (C 6-10) aryl, or coupled nitrogen-atoms forms the 5-7 element heterocycle together, and this heterocycle can optionally be substituted, and can optionally contain another Sauerstoffatom or nitrogen-atoms.Most preferred NR 5R 6Be dimethylamino, diethylin, pyrrolidyl, piperidino-(1-position only), morpholino ， oxazolidone and, C by halogen 1-6Alkyl, C 6-10Aryl (C 1-6) alkyl, C 1-6Alkoxyl group, carboxyl and/or the amino De oxazolidone that replaces.
Ninth aspect present invention relates to formula XVIIa, XVIIb, and XVIIIa, XVIIIb, XIXa or XIXb compound or its salt,
Figure A9880952600521
Wherein
R 1Be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkaryl, aralkyl, wherein said aryl, any one loop section can optionally be substituted in aralkyl or the alkaryl;
R 3Be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkaryl, wherein any one can optionally be substituted; And
R 4Be optionally substituted aryl or optionally substituted heteroaryl.
Preferred formula XVII, XVIII or XIX compound are wherein
R 1Be C 1-12Alkyl, C 3-8Cycloalkyl, C 2-8Alkenyl, C 2-8Alkynyl, C 6-14Aryl, C 6-10Aryl (C 1-6) alkyl or C 1-6Alkyl (C 6-10) aryl, wherein said aryl, any one loop section can optionally be substituted in aralkyl or the alkaryl;
R 3Be C 1-8Alkyl, C 3-8Cycloalkyl, C 2-8Alkenyl, C 2-8Alkynyl, C 6-14Aryl, C 6-10Aryl (C 1-6) alkyl or C 1-6Alkyl (C 6-10) aryl, wherein any one can optionally be substituted; And
R 4Be optionally substituted C 6-10Aryl, or following optionally substituted heteroaryl: thienyl, benzo [b] thienyl, furyl, pyranyl, isobenzofuran-base, benzoxazolyl, 2H-pyrryl, pyrryl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, indolizine base, pseudoindoyl, the 3H-indyl, indyl, indazolyl, purine radicals, the 4H-quinolizinyl, isoquinolyl, quinolyl or triazolyl, compound.Definition
Term used herein " alkyl " refers to have 12 carbon atoms at the most, the straight chain and the side chain residue of preferred 1-8 carbon atom, and as methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, isobutyl-, amyl group, hexyl, isohexyl, the 1-ethyl propyl, heptyl, 4,4-dimethyl amyl group, octyl group, 2,2, the 4-tri-methyl-amyl, nonyl, decyl, undecyl and dodecyl.
Term used herein " alkyl of replacement " refers to contain one, two or three following substituent alkyl defined above: halogen, hydroxyl, nitro, trifluoromethyl, halogen, C 1-6Alkyl, C 6-10Aryl, C 1-6Alkoxyl group, C 1-6Aminoalkyl group, C 1-6Aminoalkoxy, amino, C 2-6Carbalkoxy, carboxyl, C 1-6Hydroxyalkyl, C 2-6The hydroxy alkoxy base, C 1-6Alkyl sulphonyl, C 6-10Aryl sulfonyl, C 1-6Alkyl sulphinyl, C 1-6Alkyl sulfonyl amino, C 6-10Arenesulfonyl amino, C 6-10Aryl (C 1-6) alkyl sulfonyl amino, C 1-6Alkyl, C 1-6Hydroxyalkyl, C 6-10Aryl, C 6-10Aryl (C 1-6) alkyl, C 1-6Alkyl-carbonyl, C 2-6Carboxyalkyl, cyano group and trifluoromethoxy and/or carboxyl substituent.
Term used herein " cycloalkyl " refers to contain 3-12 carbon atom, and the saturated cyclic of preferred 3-8 carbon atom comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, ring decyl and ring undecyl, wherein any group can be replaced by following substituting group: halogen, C 1-6Alkyl, C 1-6Alkoxyl group and/or hydroxyl.
Term used herein " heteroaryl " refers to contain 5-14 annular atoms, preferred 5,6,9 or 10 annular atomses; 6,10 or 14 total πDian Zis on the ring array; And contain carbon atom and 1,2 or 3 oxygen, the group of nitrogen or sulfur heteroatom, the example of heteroaryl comprises thienyl, benzo [b] thienyl, naphtho-[2,3-b] thienyl, thianthrenyl, furyl, pyranyl, isobenzofuran-base, benzoxazolyl, benzopyranyl, xanthenyl, benzene oxathiene base (phenoxathiinyl), 2H-pyrryl, pyrryl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, indolizine base, pseudoindoyl, the 3H-indyl, indyl, indazolyl, purine radicals, the 4H-quinolizinyl, isoquinolyl, quinolyl, 2, the 3-phthalazinyl, naphthyridine base, tetrazyl, quinazolyl, cinnolines base, pteridyl, 4 α H-carbazyls, carbazyl, β-Ka Lin base, phenanthridinyl, acridyl,  pyridine base, the phenanthroline base, phenazinyl, isothiazolyl, phenothiazinyl ， isoxazolyl, the furazan base is with phenoxazinyl.
Term used herein " aryl ", no matter itself or as the part of another group, all refer on ring, contain the monocycle or the Bicyclic base of 6-12 carbon atom, as phenyl, naphthyl or tetralyl.
Term used herein " aralkyl " or " arylalkyl ", no matter itself or as the part of another group, all refer to above-mentioned C 1-6Have aryl substituent on the alkyl, as benzyl, styroyl or 2-menaphthyl.
Term used herein " alkaryl " or " alkylaryl ", no matter itself or as the part of another group, all refer to have C on the above-mentioned aryl 1-6Alkyl substituent, as tolyl, ethylphenyl or methyl naphthyl.
Term " optionally replace " and if aryl, aralkyl, alkaryl or 5-, 6-, 9-or the coupling of 10-element heterocycle base refer to that then the loop section of said group can optionally be replaced by one or two substituting group that is selected from following groups respectively: C 1-6Alkyl, C 3-8Cycloalkyl, C 1-6Alkyl (C 3-8) cycloalkyl, C 2-8Alkenyl, C 2-8Alkynyl, cyano group, amino, C 1-6Alkylamino, two (C 1-6) alkylamino, benzylamino, dibenzyl amino, nitro, carboxyl, (C 1-6) carbalkoxy, trifluoromethyl, halogen, C 1-6Alkoxyl group, C 6-10Aryl, C 6-10Aryl (C 1-6) alkyl, C 6-10Aryl (C 1-6) alkoxyl group, hydroxyl, C 1-6Alkylthio, C 1-6Alkyl sulphinyl, C 1-6Alkyl sulphonyl, C 6-10Arylthio, C 6-10Aryl sulfonyl kia, C 6-10Aryl sulfonyl, C 6-10Aryl, C 1-6Alkyl (C 6-10) aryl or halo (C 6-10) aryl.
Term " alkoxyl group " refers to connect the abovementioned alkyl of Sauerstoffatom.
Term used herein " halogen " or " halogen ", no matter himself or as the part of another group, all refer to chlorine, bromine, fluorine or iodine.
Term used herein " amido " nail amido, alkyl-carbonyl-amino or aryl-amino-carbonyl.Purposes
Table 1 provides the pharmacology data with the clasto-lactacystin-β-lactone of the inventive method preparation.Because the N-terminal threonine residues of acidylate X/MBI subunit, these compounds all are the irreversible inactivators of 20S proteoplast.K Obs/ [I] value is the observed value of enzyme-deactivating speed.Several compounds show the activity of improvement, and are promptly faster than these compound deactivation speed of clasto-lactacystin-β-lactone (2).The compound that tool is renderd a service in enzymatic determination is 7-methoxy derivatives (3f).But, carry out if be determined in the cell culture, then 3f is poorer than 2 effectiveness.
Lactonic ring not only is subjected to the threonine residues of proteoplast X/MB1 subunit, and is subjected to water and carries out nucleophillic attack.Hydrolysis causes the formation of alcohol acid V, and it does not possess the activity as the proteoplast inhibitor.Relative effectivenes in cell culture is determined by multiple factor, comprises the effectiveness of enzyme, Premeabilisation of cells ability and hydrolysis rate.Although than 2 effective forces more, its hydrolysis is also rapider to enzyme for 3f, the result, 3f is active in cell culture to want much weak.On the contrary, not only in enzymatic determination, and in cell culture, analogue 3a-3d shows the effectiveness of beyond thought improvement.
Compound disclosed by the invention is used to treat the disease by the direct mediation of proteolysis function of proteoplast, and as amyotrophy, or by the indirect disease that mediates of protein, said protein is processed by proteoplast such as NF-κ B.Proteoplast participates in cell and regulates (for example, cell cycle, genetic transcription and pathways metabolism), related proteinic rapid eliminating and translate post-treatment in cell communication and the immune response (for example, antigen presentation).Specific examples comprises amyloid-beta and regulates albumen, as cyclin and transcription factor NF-KB.Here said treatment comprises to improve or the mode of stable conditions of patients reverses, alleviates or stops symptom, the basic symptom of clinical symptom and illness.
The present invention other embodiment She is Ji sick matter of Evil and amyotrophic disease.Make the reticulocyte maturation and making proteoplast degraded multiple protein in the fibroblastic growth.Proteolysis speed improves one times nearly in cell that loses Regular Insulin or serum.
The arrestin body can reduce proteolysis, and then reduces nitrogen load on mytolin loss and kidney or the liver.The proteoplast inhibitor is used to treat cancer, chronic infectious disease, and fever, muscle is useless in (atrophy) and denervation, nerve injury, fasting, illnesss such as renal failure relevant with oxypathy and liver failure.Referring to the United States Patent (USP) 5,340 of Goldberg, 736 (1994).
Therefore, embodiment of the present invention comprises degradation rate that reduces mytolin in the cell and the method that reduces the degradation rate of intracellular protein.Every kind of method all comprises the step that makes cell (in the body or external, for example, patient's muscle) and compound (for example, the pharmaceutical composition) contact of the open structural formula of the present invention of significant quantity.
The NF-κ B processing in vitro and in vivo of proteoplast inhibitor blocking-up omnipresenceization.The proteoplast inhibitor is also blocked the degraded of I κ B-α and the activation of NF-κ B (people such as Palombella; Reach people such as Traenckner, EMBO J., 13:5433-5441 (1994)).One embodiment of the invention are to suppress the method for I κ B-α degraded, comprise cell is contacted with the compound of structural formula described herein.Another embodiment of the invention is to reduce the method for the cell content of NF-κ B in cell, muscle, organ or study subject, comprises cell, muscle, organ or study subject are contacted with the compound of structural formula described herein.Other embodiments comprise compound administration treatment and the transformation reactions by structural formula described herein, marrow or solid organ transplantation, or the method for the relevant inflammatory reaction of morbid state, said inflammation includes, but is not limited to sacroiliitis, enteritis, asthma and multiple sclerosis.A preferred embodiment of the present invention relates to through type VI or formula VII compound, most preferred compound 3b administration, treatment asthma.
The proteoplast inhibitor also can be used for treating local asphyxia or reperfusion injury, particularly after vascular occlusion, after the vascular occlusion that takes place during apoplexy or the heart attack, prevent infraction or reduce to block size, as described in the following document: Brand, Application No. _ _ _ _ (ProScript Docket No.102.603.173), February 17 1998 applying date; Application No. 08/988,339, December 3 1997 applying date; And Application No. 08/801,936, February 15 1998 applying date.The proteoplast inhibitor also block the parasitic dependent protein body of protazoan conversion (people such as Gonzalez, " The Journal of Experimental Medicine " (J.Exp.Med.), 184:1909 (1996)).Therefore, other embodiment of the present invention comprises the method by compound administration treatment infraction disclosed herein or protazoan parasitosis.The preferred aspect of the present invention is that formula VI or formula VII compound administration can prevent infraction or reduce to block size after the vascular occlusion.In order to treat or to reduce neurone loss after the local asphyxia outbreak, can be after apoplexy takes place carry out the administration of said compound in about 0-10 hour.Compound 3b is this one side most preferred of the present invention.
The proteoplast inhibitor is also blocked cyclin, as the kinase inhibitor of cyclin and cyclin dependent, and the degraded of tumor suppressor protein such as p53.Therefore, other embodiments of the present invention comprise with the compounds block cell cycle of structural formula described herein and treatment cell proliferative diseases such as cancer, the method for psoriasis and restenosis.
Term " inhibitor " is used for describing blocking-up or reduces the active compound of enzyme (for example, proteoplast, or the X/MB1 subunit of 20S proteoplast).Inhibitor can be brought into play competitiveness, uncontested property or noncompetitive restraining effect.Inhibitor can reversible or irreversibly combination.Therefore, this term comprises the compound of the suicide substrate that is enzyme.Inhibitor can the modification enzyme activity position on or near one or more site, perhaps cause the conformational change of other parts of enzyme.
The those of ordinary skill of clinical field can be determined the dosage and the dosage regimen of proteoplast inhibitor of the present invention and composition at an easy rate.Generally, the dosage of the present composition will change according to following factor: the type of composition therefor; Age; Healthy state; The state of an illness for the treatment of; If any, the kind of the treatment of carrying out simultaneously, therapeutic frequency and the essence that will be effective; The degree of disorganization; Sex; The time that symptom continues; If any, opposite therapy, and will be by other variable of each doctor's adjusting.Needed dosage can once or divide administration several times to obtain needed effect.The pharmaceutical composition that contains proteoplast inhibitor of the present invention can be unit dosage form.
The composition that belongs to the scope of the invention comprises all compositions of the The compounds of this invention that contains the significant quantity that can reach its intended purposes.Although individual factor needs to change, the optimum range of the effective level of every kind of composition can be determined by those skilled in the art.Usually, the compound of using for Mammals such as people, every day, oral dosage was its pharmacologically acceptable salt of 0.0025-50mg/kg (body weight) or equal parts, this is to carry out the disease of proteoplast mediation such as the mammiferous dosage of apoplexy or treating asthma to needs.For intramuscular injection, dosage is typically about half of oral dosage.
Preventing to block or reducing to block that this compound can be by the intravenous injection administration in the method for size, dosage is about 0.01-10mg/kg, preferably about 0.025-1mg/kg.
Oral single agent can contain the 0.01-50mg that has an appointment, preferably about 0.1-10mg compound.Single agent can be administered once or repeatedly, take one or more pieces at every turn and contain the 0.1-10mg that has an appointment every day, is generally the tablet of about 0.25-50mg compound or its solvate.For apoplexy treatment, preferred single agent administration, in incident the back takes place about 0-10 hour, carried out administration in preferably about 0-6 hour.
The following example will illustrate and unrestricted method and composition of the present invention.To general that run into and it will be apparent to those skilled in the art that condition and diversified other suitable change of parameter and adaptation all belong to the spirit and scope of the present invention.
The synthetic method of preparation formyl radical methane amide XIV described in the flow process 2 is illustrated by embodiment 1-6.Embodiment 1 Xian oxazolidinone (IX) a. Xian oxazolidinone IXb (R 2=n-Pr; R 8=CH 2Ph)
With the hexane of 2.5M n-BuLi (9.1ml, 22.6mmol) solution-treated cold (78 ℃) (S)-(-)-4-benzyl-2-oxazolidone (4.0g, 75ml anhydrous THF solution 22.6mmol) 15 minutes.After 5 minutes, (2.95ml 24.9mmol) is added drop-wise in the mixture and mixture was stirred 45 minutes at-78 ℃ with purified valeryl chloride.Allow mixture rise to room temperature, restir 90 minutes is used the saturated NH of 50ml then 4The Cl solution-treated.Add methylene dichloride (50ml), and usefulness salt water washing organic phase (2 * 30ml), MgSO 4Drying, vacuum concentration, obtaining the desired Xian oxazolidinone of 5.94g (100%) IXb is limpid water white oil. 1H NMR (300MHz, CDCl 3) δ 7.36-7.20 (m, 5H), 4.71-4.64 (m, 1H); 4.23-4.14 (m, 1H), 3.40 (dd, J=13.3; 3.2Hz, 1H), and 3.04-2.84 (m, 2H); 2.77 (dd, J=13.3,9.6Hz, 1H); 1.74-1.63 (m, 2H), 1.46-1.38 (m, 2H); 0.96 (t, J=7.3Hz, 3H) .b. Xian oxazolidinone IXa (R 2=Et; R 8=CH 2Ph)
With being similar to the method for preparing Xian oxazolidinone IXb, the lithium negatively charged ion with butyryl chloride processing (S)-(-)-4-benzyl-2-oxazolidone obtains Xian oxazolidinone IXa with 94% productive rate. 1H NMR (300MHz, CDCl 3) δ 7.37-7.20 (m, 5H), 4.68 (ddd, J=13.1,7.0; 3.4Hz, 1H), and 4.23-4.13 (m, 2H); 3.30 (dd, J=13.3,9.6Hz, 1H); 3.02-2.82 (m, 2H), 2.77 (dd, J=13.3; 9.6Hz, 1H), 1.73 (q, J=7.3Hz; 2H), 1.01 (t, J=7.3Hz, 3H) .c. Xian oxazolidinone IXc (R 2=n-Bu; R 8=CH 2Ph)
With being similar to the method for preparing Xian oxazolidinone IXb, the lithium negatively charged ion with caproyl chloride processing (S)-(-)-4-benzyl-2-oxazolidone obtains Xian oxazolidinone IXc with 96% productive rate. 1H?NMR(300MHz，CDCl 3)δ
7.36-7.20(m，5H)，4.68(m，1H)，4.23-4.14(m，2H)，3.30(dd，J＝13.3，3.3Hz，
1H)，3.02-2.83(m，2H)，2.76(dd，J＝13.3，9.6Hz，1H)，1.70(m，2H)，1.43-1.34
(m, 4H), 0.92 (t, J=3.3Hz, 3H) .d. Xian oxazolidinone IXd (R 2=i-Bu; R 8=CH 2Ph)
I.4-methylpent acyl chlorides
Follow these steps to prepare 4-methylpent acyl chlorides: handle cold (0 ℃) 4-methylvaleric acid (1.85ml, the anhydrous CH of 50ml 15.0mmol) that contains 10ml DMF with 1.95 μ l oxalyl chlorides (22.5mmol) with commodity 4-methylvaleric acid 2Cl 2Solution.Mixture was at room temperature stirred 3 hours, and vacuum concentration filters then, and obtaining the desired acyl chlorides of 1.65g (100%) is colourless liquid.
Ii. Xian oxazolidinone IXd (R 2=i-Bu; R 8=CH 2Ph)
With being similar to the method for preparing Xian oxazolidinone IXb, the lithium negatively charged ion with 4-methylpent acyl chlorides processing (S)-(-)-4-benzyl-2-oxazolidone obtains Xian oxazolidinone IXd with 85% productive rate.
1H NMR (300MHz, CDCl 3) δ 7.37-7.20 (m, 5H), 4.70-4.63 (m, 1H); 4.23-4.15 (m, 2H), 3.30 (dd, J=13.2; 3.2Hz, 1H), and 2.98-2.90 (m, 2H); 2.76 (dd, J=13.3,9.6Hz; 1H), and 1.68-1.54 (m, 3H); 0.94 (d, J=6.2Hz, 3H) .e. Xian oxazolidinone IXe (R 2=CH 2Ph; R 8=CH 2Ph)
With being similar to the method for preparing Xian oxazolidinone IXb, the lithium negatively charged ion with hydrocinnamoyl chloride processing (S)-(-)-4-benzyl-2-oxazolidone obtains Xian oxazolidinone IXe with 82% productive rate. 1H NMR (300MHz, CDCl 3) δ 7.35-7.16 (m, 10H), 4.70-4.63 (m, 1H), 4.21-4.14 (m; 2H), and 3.38-3.19 (m, 3H), 3.08-2.98 (m, 2H); 2.75 (dd, J=13.4,9.5Hz, 1H). embodiment 2 acyl oxazolidinone (X) a. acyl oxazolidinone Xb (R 2=n-Pr; R 8=CH 2Ph)
Use 2.52ml TiCl 4(23.1mmol) handle cold (0 ℃ of) Xian oxazolidinone IXb (5.74g, the anhydrous CH of 110ml 22.0mmol) 2Cl 2Solution forms abundant precipitation.After 5 minutes, (4.22ml 24.2mmol), at room temperature stirred gained dark-brown solution 35 minutes then slowly to add diisopropylethylamine.(6.0ml 44.0mmol), at room temperature stirred mixture 5 hours then to add the benzyl chloride methyl ether rapidly.Add 50ml CH 2Cl 2Solution and 75ml 10%NH 4The Cl aqueous solution forms yellow jelly matter.This suspension of vigorous stirring was transferred to supernatant liquor in the separating funnel after 10 minutes, then gluey residuum was dissolved in 1: 1 10%NH of 100ml 4The Cl aqueous solution/CH 2Cl 2In.Merge organic phase, use the 1N HCl aqueous solution successively, saturated NaHCO 3With salt water washing, MgSO 4Drying, vacuum concentration.From EtOAc/ hexane recrystallization, obtaining the desired Xian oxazolidinone of 6.80g (81%) Xb is white solid with thick solid product. 1H NMR (300MHz, CDCl 3) δ 7.34-7.18 (m, 10H), 4.77-4.69 (m, 1H), 4.55 (s, 2H), 4.32-4.23 (m, 1H), 4.21-4.10 (m, 2H), 3.80 (t, J=9.0Hz, 1H), 3.65 (dd, J=9.0,5.0Hz, 1H), 3.23 (dd, J=13.5,3.3Hz, 1H), 2.69 (dd, J=13.5,9.3Hz, 1H), and 1.74-1.64 (m, 1H), 1.54-1.44 (m, 1H), 1.40-1.28 (m, 2H), 0.91 (t, J=7.3Hz, 3H) .LRMS (FAB) m/e 382 (M+H +) b. Xian oxazolidinone Xa (R 2=Et; R 8=CH 2Ph)
With being similar to the method for preparing Xian oxazolidinone Xb, obtain Xian oxazolidinone Xa with 80% productive rate. 1H NMR (300MHz, CDCl 3) δ 7.36-7.18 (m, 10H), 4.55 (s, 2H), 4.21-4.11 (m; 3H), 3.81 (t, J=9.0Hz, 1H), 3.66 (dd; J=9.0,5.0Hz, 1H), 3.23 (dd; J=13.5,3.2Hz, 1H), 2.70 (dd; J=13.5,9.3Hz, 1H), 1.78-1.57 (m; 2H), 0.94 (t, J=7.5Hz, 3H) .c. Xian oxazolidinone Xc (R 2=n-Bu; R 8=CH 2Ph)
With being similar to the method for preparing Xian oxazolidinone Xb, obtain Xian oxazolidinone Xc with 91% productive rate. 1H?NMR(300MHz，CDCl 3)δ
7.38-7.17 (m, 10H), 4.72 (m, 1H), 4.54 (s; 2H), and 4.27-4.10 (m, 2H), 3.79 (t, J=8.7Hz; 1H), 3.65 (dd, J=9.1,5.0Hz, 1H); 3.23 (dd, J=13.5,3.3Hz, 1H), 2.68 (dd; J=13.5,9.3Hz, 1H), 1.75-1.68 (m, 1H); 1.31-1.26 (m, 4H), 0.87 (t, J=6.8Hz, 3H) .d. Xian oxazolidinone Xd (R 2=i-Bu; R 8=CH 2Ph)
With being similar to the method for preparing Xian oxazolidinone Xb, obtain Xian oxazolidinone Xd with 98% productive rate. 1H NMR (300MHz, CDCl 3) δ 7.38-7.17 (m, 10H), 4.75-4.67 (m, 1H), 4.57 (d; J=12.0Hz, 1H), 4.51 (d, J=12.0Hz; 1H), and 4.41-4.36 (m, 1H), 4.20-4.09 (m; 2H), 3.74 (t, J=9.0Hz, 1H); 3.65 (dd, J=9.0,5.1Hz, 1H); 3.23 (dd, J=13.5,3.2Hz, 1H); 2.63 (dd, J=13.5,9.5Hz, 1H); 1.74-1.52 (m, 2H), 1.35 (dd, J=13.1; 6.1Hz, 1H), 0.92 (d, J=2.9Hz; 3H), 0.90 (d, J=2.9Hz, 3H) .e. Xian oxazolidinone Xe (R 2=CH 2Ph; R 8=CH 2Ph)
With being similar to the method for preparing Xian oxazolidinone Xb, obtain Xian oxazolidinone Xe with 84% productive rate. 1H NMR (300MHz, CDC1 3) δ 7.38-7.15 (m, 15H), 4.62-4.50 (m, 4H), 4.03 (dd, J=9.0,2.7Hz, 1H), 3.93-3.82 (m, 2H), 3.66 (dd, J=9.2,4.8Hz, 1H), 3.19 (dd, J=13.5,3.2 Hz, 1H), 2.98 (dd, J=13.4,8.2Hz, 1H), 2.88 (dd, J=13.4,7.3Hz, 1H), 2.68 (dd, J=13.5,9.3Hz, 1H). embodiment 3 carboxylic acids (XI) a. carboxylic acid XIb (R 2=n-Pr)
Use 6.95ml 35%H successively 2O 2The aqueous solution and lithium hydroxide monohydrate (1.46g, 20ml H 34.6mmol) 2O solution-treated cold (0 ℃ of) Xian oxazolidinone Xb (6.60g, 320ml THF/H 17.3mmol) 2O solution.Mixture was stirred 16 hours at 0 ℃, use Na earlier 2SO 355ml H (10.5g) 2O solution is used NaHCO again 3100ml H (4.35g) 2O solution is careful to be handled.Mixture was at room temperature stirred 30 minutes, and vacuum concentration is removed THF then.Use CH 2Cl 2(4 * 75ml) washing gained aqueous mixtures are cooled to 0 ℃, with 6N HCl acidified aqueous solution, use CH again 2Cl 2Extraction (1 * 200ml and 3 * 100ml).Merge organic phase, MgSO 4Drying, vacuum concentration, obtaining the desired sour XIb of 3.47g (90%) is limpid water white oil. 1H NMR (300MHz, CDCl 3) δ 7.38-7.26 (m, 5H), 4.55 (s, 2H), 3.67 (m, 1H), 3.57 (dd, J=9.2,5.2Hz, 1H), 2.75 (m, 1H), 1.72-1.31 (m, 4H), 0.93 (t, J=7.2Hz, 3H) .LRMS (FAB) m/e 223 (M+H +) b. carboxylic acid XIa (R 2=Et)
With being similar to the method for preparing Xian oxazolidinone XIb, obtain Xian oxazolidinone XIa with 48% productive rate. 1H NMR (300MHz, CDCl 3) δ 7.36-7.27 (m, 5H), 4.55 (s, 2H), 3.68 (dd, J=9.2,7.9Hz, 1H), 3.59 (dd, J=9.2,5.4Hz, 1H), 2.68-2.65 (m, 1H), 1.71-1.62 (m, 2H), 0.97 (t, J=7.5Hz, 3H) .c. carboxylic acid XIc (R 2=n-Bu)
With being similar to the method for preparing Xian oxazolidinone XIb, obtain Xian oxazolidinone XIc with 96% productive rate. 1H NMR (300MHz, CDCl 3) δ 7.37-7.28 (m, 5H), 4.55 (s, 2H), 3.67 (dd, J=9.1,8.1Hz, 1H), 3.57 (dd, J=9.2,5.3Hz, 1H), 2.72 (m, 1H), 1.67-1.51 (m, 2H), 1.36-1.27 (m, 4H), 0.89 (t, J=6.9Hz, 3H) .d. carboxylic acid XId (R 2=i-Bu)
With being similar to the method for preparing Xian oxazolidinone XIb, obtain Xian oxazolidinone XId with 80% productive rate. 1H NMR (300MHz, CDCl 3) δ 7.37-7.28 (m, 5H), 4.55 (s, 2H), 3.64 (t, J=9.1Hz, 1H), 3.54 (dd, J=9.1,5.1Hz, 1H), 2.81 (m, 1H), 1.68-1.54 (m, 2H), 1.36-1.27 (m, 1H), 0.92 (d, J=4.9Hz, 3H), 0.90 (d, J=4.9Hz, 3H) .e. carboxylic acid XIe (R 2=CH 2Ph)
With being similar to the method for preparing Xian oxazolidinone XIb, obtain Xian oxazolidinone XIe with 92% productive rate. 1HNMR (300MHz, CDCl 3) δ 7.38-7.16 (m, 10H), 4.53 (d, J=12.1Hz, 1H), 4.50 (d, J=12.1Hz, 1H), 3.68-3.57 (m, 2H), 3.09-2.85 (m, 3H). embodiment 4 diethylamide (XII) a. diethylamide XIIb (R 2=n-Pr; R 5=R 6=Et)
In 1.5 hours, use diisopropylethylamine (6.7ml, 38.2mmol) handle (syringe pump) and contain diethylamine (2.36ml, 23.0mmol) and Tetrafluoroboric acid 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-urea (TBTU, 5.89g, 18.4mmol) carboxylic acid XIb (3.40g, 1: 1 MeCN/CH 15.3mmol) 2Cl 2(150ml) cold (0 ℃) solution.With the mixture vacuum concentration, then at ether (200ml) and H 2Distribute between the O (100ml).Water with extracted with diethyl ether (2 * 100ml), the organic phase of merging use successively the 1N HCl aqueous solution (3 * 50ml), saturated NaHCO 3The aqueous solution and salt water washing, MgSO 4Dry also vacuum concentration.Chromatogram purification (230-400 order SiO 2, with 1: 3AcOEt/ hexane wash-out), obtaining the desired diethylamide XIIb of 4.24g (97%) is limpid water white oil. 1H NMR (300MHz, CDCl 3) δ 7.35-7.23 (m, 5H), 4.52 (d, J=12.0Hz, 1H), 4.44 (d, J=12.0Hz, 1H), 3.67 (t, J=8.6Hz, 1H), 3.51 (dd, J=8.7,5.5Hz, 1H), 3.46-3.27 (m, 4H), 2.96 (m, 1H), 1.67-1.57 (m, 1H), and 1.48-1.22 (m, 4H), 1.20-1.10 (m, 6H), 0.90 (t, J=7.2Hz, 3H) .LRMS (FAB) m/e 278 (M+H +) b. diethylamide XIIa (R 2=Et; R 5=R 6=Et)
With being similar to the method for preparing diethylamide XIIb, obtain diethylamide XIIa with 73% productive rate. 1H NMR (300MHz, CDCl 3) δ 7.33-7.26 (m, 5H), 4.52 (d, J=12.0Hz, 1H), 4.44 (d, J=12.0Hz, 1H), 3.68 (t, J=8.6Hz, 1H), and 3.53-3.33 (m, 5H), 2.90 (m, 1H), and 1.75-1.50 (m, 2H), 1.18 (t, J=7.1Hz, 3H), 1.13 (t, J=7.1Hz, 3H), 0.89 (t, J=7.4Hz, 3H) .c. diethylamide XIIc (R 2=n-Bu; R 5=R 6=Et)
With being similar to the method for preparing diethylamide XIIb, obtain diethylamide XIIc with 94% productive rate. 1H NMR (300MHz, CDCl 3) δ 7.35-7.25 (m, 5H), 4.51 (d, J=12.0Hz, 1H), 4.44 (d, J=12.0Hz, 1H), 3.67 (t, J=8.6Hz, 1H), 3.51 (dd, J=8.8,5.5Hz, 1H), and 3.46-3.29 (m, 1H), 2.94 (m, 1H), and 1.66-1.62 (m, 2H), 1.33-1.10 (m, 9H), 0.85 (t, J=7.0Hz, 3H) .d. diethylamide XIId (R 2=i-Bu; R 5=R 6=Et)
With being similar to the method for preparing diethylamide XIIb, obtain diethylamide XIId with 95% productive rate. 1H NMR (300MHz, CDCl 3) δ 7.35-7.23 (m, 5H), 4.51 (d, J=12.0Hz, 1H), 4.44 (d, J=12.0Hz, 1H), 3.65 (t, J=8.7Hz, 1H), 3.54-3.28 (m, 5H), 3.03 (m, 1H), 1.63-1.49 (m, 2H), 1.33-1.24 (m, 1H), 1.18 (t, J=7.1Hz, 3H), 1.12 (t, J=7.1Hz, 3H), 0.90 (t, J=6.4Hz, 3H) .e. diethylamide XIIe (R 2=CH 2Ph; R 5=R 6=Et)
With being similar to the method for preparing diethylamide XIIb, obtain diethylamide XIIe with 89% productive rate. 1H NMR (300MHz, CDCl 3) δ 7.35-7.16 (m, 10H), 4.53 (d, J=12.1Hz, 1H), 4.47 (d, J=12.1Hz, 1H), 3.77 (t, J=8.5 Hz, 1H), 3.59 (dd, J=8.8,5.7Hz, 1H), 3.40 (m, 1H), 3.22-2.89 (m, 5H), 2.79 (dd, J=13.0,5.1Hz, 3H), 1.01 (t, J=7.1Hz, 3H), 0.85 (t, J=7.2Hz, 3H). embodiment 5 alcohol (XIII) a. alcohol XIIIb (R 2=n-Pr; R 5=R 6=Et)
(4.08g adds 20%Pd (OH) in 140ml MeOH solution 14.7mmol) to diethylamide XIIb 2/ C (400mg) is then with suspension hydrogenation 15 hours under normal atmosphere and room temperature.Filter catalyzer, vacuum concentrated filtrate obtains the desired primary alconol XIIIb of 2.84g (100%). 1HNMR (300MHz, CDCl 3) δ 3.74 (br.d, J=4.2Hz, 1H), 3.61-3.15 (m, 5H), 2.71 (m, 1H), 1.69-1.24 (m, 4H), 1.20 (t, J=7.1Hz, 3H), 1.12 (t, J=7.1Hz, 3H), 0.92 (t, J=7.2Hz, 3H) .LRMS (FAB) m/e 188 (M+H +) .b. alcohol XIIIa (R 2=Et; R 5=R 6=Et)
Method with being similar to the pure XIIIb of preparation obtains pure XIIIa with 100% productive rate. 1H NMR (300MHz, CDCl 3) δ 3.76 (m, 2H), 3.58-3.19 (m, 4H), 2.64 (m, 1H), 1.71-1.65 (m, 2H), 1.21 (t, J=7.1Hz, 3H), 1.13 (t, J=7.1Hz, 3H), 0.96 (t, J=7.4Hz, 3H) .c. alcohol XIIIc (R 2=n-Bu; R 5=R 6=Et)
Method with being similar to the pure XIIIb of preparation obtains pure XIIIc with 100% productive rate.
1H NMR (300MHz, CDCl 3) δ 3.76 (d, J=4.5Hz, 2H), 3.58-3.19 (m, 4H), 2.72-2.65 (m, 2H), 1.68-1.55 (m, 2H), 1.40-1.24 (m, 4H), 1.20 (t, J=7.1Hz, 3H), 1.12 (t, J=7.1Hz, 3H), 0.90 (t, J=6.9Hz, 3H) .d. alcohol XIIId (R 2=i-Bu; R 5=R 6=Et)
Method with being similar to the pure XIIIb of preparation obtains pure XIIId with 100% productive rate.
1H NMR (300MHz, CDCl 3) δ 3.78-3.68 (m, 2H), 3.57-3.15 (m, 4H), 2.81-2.73 (m, 1H), 1.70-1.60 (m, 2H), 1.40-1.28 (m, 1H), 1.21 (t, J=7.1Hz, 3H), 1.12 (t, J=7.1Hz, 3H), 0.92 (m, 6H) .e. alcohol XIIIe (R 2=CH 2Ph; R 5=R 6=Et)
Method with being similar to the pure XIIIb of preparation obtains pure XIIIe with 100% productive rate.
1H NMR (300MHz, CDCl 3) δ 7.29-7.16 (m, 5H), 3.81-3.71 (m, 2H), 3.61-3.50 (m, 1H), 3.15-2.87 (m, 6H), 1.05 (t, J=7.1Hz, 3H), 0.98 (t, J=7.1Hz, 3H). embodiment 6 aldehyde (XIV) a. aldehyde XIVb (R 2=n-Pr; R 5=R 6=Et)
To pure XIIIb (2.34g, wet CH 12.7mmol) 2Cl 2(125ml is with CH 2Cl 2Stir with water, separate organic phase then and make) add in the solution Dess-Martin periodo alkane (8.06g, 19.0mmol).Mixture was at room temperature stirred 40 minutes, pour into then and contain 5.2g NaHCO 35%Na 2S 2O 3In the mixture of the aqueous solution (250ml) and ether (200ml).With two-phase mixture vigorous stirring 5 minutes, water 15%CH 2Cl 2/ Et 2O extraction (2 * 100ml).The organic phase that merges is successively used H 2O (3 * 75ml) and the salt water washing, MgSO 4Drying is filtered vacuum concentration then, and obtaining the desired aldehyde XIVb of 2.06g (88%) is limpid water white oil. 1H NMR (300MHz, CDCl 3) δ 9.60 (d, J=3.5Hz, 1H), 3.49-3.30 (m, 5H), 1.96-1.85 (m, 2H), 1.39-1.31 (m, 2H), 1.19 (t, J=7.1Hz, 3H), 1.13 (t, J=7.1Hz, 3H), 0.95 (t, J=7.3Hz, 3H) .b. aldehyde XIVb (R 2=n-Pr; R 5=R 6=Et)
(1.25g, toluene 6.68mmol) (20ml) add 2,2,6 in the mixture solution of ethyl acetate (20ml) and water (3ml), 6-tetramethyl--1-piperidines oxygen base (TEMPO), free radical (9mg) to thick pure XIIIb.Mixture is cooled to 0 ℃, adds by containing 1.6g NaHCO with 30 fens clock times then in batches 3The 20ml aqueous solution in add the chlorine bleach liquor that 4.3ml aqueous sodium hypochlorite solution (the available chlorine of 10-13%) is made.Add Sodium Bromide (660mg), solution becomes greenish orange look.The color reverses back of reaction mixture is to cream-coloured within the several minutes.Divide several adding clorox (4.7ml) to impel reaction to finish again.Isolate water, with toluene (20ml) and ethyl acetate (2 * 20ml) extractions.The organic extract liquid that the merges 10%KHSO of KI (70mg) 4Solution washing.Then, organic phase is with 5% Na 2S 2O 3With the phosphate buffered saline buffer washing of pH7, Na 2SO 4Drying, concentrating and obtaining XIVb is light yellow oil (1.1g).The spectral data of this compound conforms to the spectral data of top embodiment 6a product.C. aldehyde XIVa (R 2=Et; R 5=R 6=Et)
Method with being similar to the pure XIVb of preparation obtains aldehyde XIVa with 80% productive rate.
1H NMR (300MHz, CDCl 3) δ 9.61 (d, J=3.6Hz, 1H), 3.48-3.29 (m, 5H), 2.02-1.90 (m, 2H), 1.19 (t, J=7.1Hz, 3H), 1.14 (t, J=7.1Hz, 3H), 0.96 (t, J=7.4Hz, 3H) .d. aldehyde XIVc (R 2=n-Bu; R 5=R 6=Et)
Method with being similar to the pure XIVb of preparation obtains aldehyde XIVc with 98% productive rate.
1HNMR (300MHz, CDCl 3) δ 9.59 (d, J=3.6Hz, 1H), 3.48-3.29 (m, 5H), 1.97-1.87 (m, 2H), 1.39-1.22 (m, 4H), 1.18 (t, J=7.2Hz, 3H), 1.13 (t, J=7.2Hz, 3H), 0.90 (t, J=7.0Hz, 3H) .e. aldehyde XIVd (R 2=i-Bu; R 5=R 6=Et)
Method with being similar to the pure XIVb of preparation obtains aldehyde XIVd with 96% productive rate.
1H NMR (300MHz, CDCl 3) δ 9.57 (d, J=3.7Hz, 1H), 3.51-3.27 (m, 5H), 1.83 (t, J=7.1Hz, 3H), 1.66-1.55 (m, 1H), 1.20 (t, J=7.1Hz, 3H), 1.13 (t, J=7.1Hz, 3H), 0.93 (d, J=6.6Hz, 6H) .f. aldehyde XIVe (R 2=CH 2Ph; R 5=R 6=Et)
Method with being similar to the pure XIVb of preparation obtains aldehyde XIVe with 97% productive rate.
1HNMR(300MHz，CDCl 3)δ9.69(d，J＝2.9Hz，1H)，7.29-7.16(m，5H)，3.65(m，1H)，3.53-3.42(m，1H)，3.30(dd，J＝13.5，9.3Hz，1H)，3.23-3.13(m，2H)，3.06-2.91(m，2H)，1.04(t，J＝7.1Hz，3H)，0.93(t，J＝7.1Hz，3H).
The synthetic method of flow process 1 generalized preparation clasto-lactacystin-β-lactone and analogue thereof is illustrated by embodiment 7-9.Embodiment 7 aldehyde alcohol adducts (II) a. aldehyde alcohol adducts IIb (R 2=n-Pr; R 1=i-Pr; R 3=Me; R 4=Ph; R 5=R 6=Et)
To anti--oxazoline Ia (R 1=i-Pr; R 4Add in=Ph) ether (35ml) cold (78 ℃) solution two (trimethyl silyl) lithium amides (the 1M hexane solution of 2.17ml, 2.17mmol).After 30 minutes, (4.55ml, 1M hexane solution 4.55mmol) is handled the gained orange solution, is being cooled to-85 ℃ (liquid nitrogen is added in the dry ice/acetone batch) before with mixture restir 60 minutes to drip chlorodimethylalumiu.(420mg, ether 2.27mmol) (4ml) solution is added in the mixture along flask walls aldehyde XIVb to use 10 minutes then.Allow mixture to be warming up to-40 ℃, then by adding the saturated NH of 35ml with 2.5 hour time 4The Cl aqueous solution and 25ml AcOEt cancellation reaction.Add enough 2N HCl (adding 15ml approximately) up to obtaining two clearly phases.(2 * 20ml), the organic phase of merging is used the 0.5N HCl aqueous solution (20ml), H to water successively with the AcOEt extraction 2O (20ml), 0.5M NaHSO 3The aqueous solution (2 * 15ml), saturated NaHCO 3The aqueous solution and salt water washing, Na 2SO 4Drying, vacuum concentration obtains the thick aldehyde alcohol product IIb of 879mg (＞100%) then, and its purity is enough to be directly used in the next step. 1H?NMR(300MHz，CDCl 3)δ8.02-7.97?and?7.53-7.39(m，5H)，6.58(d，J＝9.9Hz，1H)，4.82(d，J＝2.4Hz，1H)，3.73(s，3H)，3.69-3.61(m，2H)，3.49-3.39(m，2H)，3.24-3.16(m，1H)，3.05(m，1H)，2.89(m，1H)，2.28-2.23(m，1H)，1.98-1.91(m，1H)，1.37-1.20(m，6H)，1.19-1.06(m，6H)，0.87(t，J＝7.1Hz，3H)，0.70(d，J＝6.7Hz，3H).
Can also use and the similar method of aforesaid method, but, obtain aldehyde alcohol product IIb with 100% productive rate with replace anti-oxazoline Ia along-oxazoline Ib (seeing below).B. aldehyde alcohol adducts IIb (R 2=n-Pr; R 1=i-Pr; R 3=Me; R 4=Ph; R 5=R 6=Et)
Xiang anti-oxazoline Ia (R 1=i-Pr; R 4=Ph) add two (trimethyl silyl) lithium amides (the 1M hexane solution of 92.4ml) in the THF of (20.74g) (280ml) cold (78 ℃) solution.After 30 minutes, drip 1M hexane (202ml) the solution-treated gained orange solution of chlorodimethylalumiu, be cooled to-85 ℃ (liquid nitrogen is added in the dry ice/acetone batch) before with mixture restir 40 minutes.With THF (50ml) solution that added aldehyde XIVb (19.43g) in 45 minutes.Allow mixture to be warming up to-50 ℃, be warming up to-20 ℃ with 25 minutes again with 40 fens clock times.The yellow reaction mixture is cooled to-78 ℃ once more, carefully adds the saturated NH of 40ml then 4Cl aqueous solution cancellation reaction.Slowly pour reaction mixture into 460ml saturated NH 4The Cl aqueous solution.Add 500ml AcOEt and under fully stirring,, obtain two clearly phases with 6N HCl acidified reaction mixture.(2 * 200ml), the organic phase of merging is used H to water successively with the AcOEt extraction 2O (2 * 200ml), saturated NaHCO 3The aqueous solution (2 * 200ml) and salt solution (2 * 300ml) washing.Organic extract liquid Na 2SO 4And MgSO 4Drying, vacuum concentration obtains the thick aldehyde alcohol product of 41.55g IIb then, and its purity is enough to be directly used in the next step.The spectral data of this compound conforms to the spectral data of top embodiment 7a product.C. aldehyde alcohol adducts IIa (R 2=Et; R 1=i-Pr; R 3=Me; R 4=Ph; R 5=R 6=Et)
With being similar to the method for preparing aldehyde alcohol adducts IIb, handle anti-oxazoline Ia (R with chlorodimethylalumiu and aldehyde XIVa successively 1=i-Pr; R 4=Ph) lithium negatively charged ion obtains aldehyde alcohol adducts IIa with 95% productive rate.
1H NMR (300MHz, CDCl 3) δ 8.00-7.97 and 7.51-7.39 (m, 5H), 6.50 (d, J=9.9Hz, 1H), 4.80 (d, J=2.4Hz, 1H), 3.81-3.64 (m, 2H), 3.74 (s, 3H), 3.45 (m, 2H), 3.19 (m, 2H), 2.93-2.84 (m, 2H), 2.24 (m, 1H), 1.89 (m, 1H), 1.73-1.64 (m, 4H), 1.29 (t, J=7.2Hz, 3H), 1.12 (d, J=6.9Hz, 3H), 1.07 (d, J=7.2Hz, 3H), 0.70 (d, J=6.7Hz, 3H) .d. aldehyde alcohol adducts IIc (R 2=n-Bu; R 1=i-Pr; R 3=Me; R 4=Ph; R 5=R 6=Et)
With being similar to the method for preparing aldehyde alcohol adducts IIb, handle anti--oxazoline Ia (R with chlorodimethylalumiu and aldehyde XIVc successively 1=i-Pr; R 4=Ph) lithium negatively charged ion obtains aldehyde alcohol adducts IIc with 100% productive rate. 1H NMR (300MHz, CDCl 3) δ 8.02-7.98 and 7.53-7.33 (m, 5H), 6.57 (d, J=10.0Hz, 1H), 4.81 (d, J=2.3Hz, 1H), 3.73 (s, 3H), and 3.68-3.60 (m, 2H), 3.49-3.17 (m, 2H), 3.00 (m, 1H), 2.90 (m, 1H), and 1.98-1.87 (m, 2H), 1.38-0.83 (m, 16H), 0.70 (d, J=6.7Hz, 3H) .e. aldehyde alcohol adducts IId (R 2=i-Bu; R 1=i-Pr; R 3=Me; R 4=Ph; R 5=R 6=Et)
With being similar to the method for preparing aldehyde alcohol adducts IIb, handle anti-oxazoline Ia (R with chlorodimethylalumiu and aldehyde XIVd successively 1=i-Pr; R 4=Ph) lithium negatively charged ion obtains aldehyde alcohol adducts IId with 100% productive rate. 1H NMR (300MHz, CDCl 3) δ 8.01-7.80 and 7.55-7.20 (m, 5H), 4.87 (d, J=2.3Hz, 1H), 3.73 (s, 3H), 3.69-3.58 (m, 2H), and 3.51-3.32 (m, 2H), 2.98-2.87 (m, 1H), and 2.33-2.24 (m, 1H), 2.12-2.02 (m, 1H), 1.83 (t, J=7.1Hz, 1H), 1.35 (t, J=7.1Hz, 3H), 1.25-1.05 (m, 5H), 0.93 (d, J=6.6Hz, 3H), 0.89 (d, J=6.5Hz, 3H), 0.80 (d, J=6.5Hz, 3H), 0.69 (d, J=6.7Hz, 3H) .f. aldehyde alcohol adducts IIe (R 2=CH 2Ph; R 1=i-Pr; R 3=Me; R 4=Ph; R 5=R 6=Et)
With being similar to the method for preparing aldehyde alcohol adducts IIb, handle anti--oxazoline Ia (R with chlorodimethylalumiu and aldehyde XIVe successively 1=i-Pr; R 4=Ph) lithium negatively charged ion obtains aldehyde alcohol adducts IIe with 100% productive rate. 1H NMR (300MHz, CDCl 3) δ 8.01-7.93 and 7.54-7.10 (m, 10H), 4.71 (d, J=2.5Hz, 1H), 3.73 (s, 3H), and 3.68-3.58 (m, 2H), 3.48-2.79 (m, 6H), 2.17 (m, 1H), and 1.12-0.91 (m, 9H), 0.68 (d, J=6.7Hz, 3H). embodiment 8 gamma-lactams (IV) a. gamma-lactam IVb (R 2=n-Pr; R 1=i-Pr; R 3=Me)
(4.72g, 100ml 10.9mmol) in AcOH/MeOH solution adds 4.8g 20%Pd (OH) at 1: 9 at aldehyde alcohol adducts IIb 2/ C is then at the H of 55psi 2In acutely shook 60 hours.Before filtering mixture is dropped to normal temperature, then vacuum concentration.With gained solid purification by flash chromatography (SiO 2, with 1: 1 AcOEt/ hexane wash-out of 1%AcOH), obtaining 2.23g (75%) the gamma-lactam IVb that wants is white solid. 1HNMR (300MHz, CDCl 3) δ 7.89 (br.s, 1H), 4.77 (br.d, J=11.5Hz, 1H), 4.47 (dd, J=11.5,5.6Hz, 1H), 4.08 (dd, J=9.4,5.0Hz, 1H), 3.83 (s, 3H), 2.93 (m, 1H), 1.78-1.39 (m, 6H), 1.02-0.88 (m, 9H) .b. gamma-lactam IVa (R 2=Et; R 1=i-Pr; R 3=Me)
With being similar to the method for preparing gamma-lactam IVb, hydrogenation of aldehydes alcohol adducts IIa is 48 hours under 55psi, obtains gamma-lactam IVa with 72% productive rate. 1H NMR (300MHz, CDCl 3) δ 7.79 (br.s, 1H), 4.62 (br.d, J=11.2Hz, 1H), 4.51 (dd, J=11.2,5.4Hz, 1H), 3.83 (s, 3H), 2.85 (m, 1H), and 1.77-1.64 (m, 3H), 1.01 (t, J=7.4Hz, 3H), 0.98 (d, J=6.9Hz, 3H), 0.95 (d, J=6.9Hz, 3H) .c. gamma-lactam IVc (R 2=n-Bu; R 1=i-Pr; R 3=Me)
(361mg, 6ml 0.80mmol) in AcOH/MeOH solution adds 250mg 20%Pd (OH) at 1: 9 at aldehyde alcohol adducts IIc 2/ C is then at the H of 50psi 2In acutely shook 24 hours.Add the 100mg catalyzer again, and with the H of mixture at 50psi 2In shook again 24 hours.After this mixture is dropped to normal temperature, filter then.With filtrate reflux 30 minutes, cool to room temperature, vacuum concentration then.With gained solid and toluene coevaporation once, with purification by flash chromatography (SiO 2, use 4%MeOH/CHCl 3Wash-out), obtaining the desired gamma-lactam IVc of 140mg (61%) is white solid. 1H NMR (300MHz, CDCl 3) δ 8.02 (br.s, 1H), 4.93 (br.d, J=11.3Hz, 1H), 4.46 (dd, J=11.3,5.5Hz, 1H), and 4.15-4.08 (m, 1H), 3.83 (s, 3H), and 2.94-2.87 (m, 1H), 1.80-1.34 (m, 6H), 0.94 (d, J=6.9Hz, 3H), 0.89 (t, J=7.2Hz, 3H) .d. gamma-lactam IVd (R 2=i-Bu; R 1=i-Pr; R 3=Me)
With being similar to the method for preparing gamma-lactam IVc, hydrogenation of aldehydes alcohol adducts IId 40 hours and reflux are 30 minutes under 50psi, obtain gamma-lactam IVd with 61% productive rate. 1HNMR (300MHz, CDCl 3) δ 7.92 (br.s, 1H), 4.81 (br.d, J=11.5Hz, 1H), 4.46 (m, 1H), 4.09 (m, 1H), 3.83 (s, 3H), 3.04-2.98 (m, 1H), 1.78-1.73 (m, 2H), 1.66-1.47 (m, 3H), 1.00-0.90 (m, 12H) .e. gamma-lactam IVe (R 2=CH 2Ph; R 1=i-Pr; R 3=Me)
With being similar to the method for preparing gamma-lactam IVc, hydrogenation of aldehydes alcohol adducts IIe 24 hours and reflux are 30 minutes under 50psi, obtain gamma-lactam IVe with 71% productive rate. 1H NMR (300MHz, CDCl 3) δ 8.01 (br.s, 1H), 7.35-7.15 (m, 5H), 5.02 (br.d, J=11.7Hz, 1H), 4.40-4.34 (m, 1H), 4.06-4.01 (m, 1H), 3.84 (s, 3H), 3.34-3.27 (m, 1H), 3.10-3.04 (m, 2H), 1.84-1.72 (m, 1H), 0.98 (d, J=6.7Hz, 3H), 0.93 (d, J=6.9Hz, 3H). embodiment 9 β-lactone (VII) a. β-lactone VIIb (R 2=n-Pr; R 1=i-Pr)
Gamma-lactam IVb (2.20g, add in 100ml EtOH 8.06mmol) cold (0 ℃) solution 0.1N NaOH aqueous solution (100ml, 10.0mmol).Mixture was at room temperature stirred 15 hours, add H then 2O (50ml) and AcOEt (100ml).(vacuum concentration is to about 60ml volume for 2 * 50ml) washings, 6N HCl acidified aqueous solution with AcOEt for water.Freezing this solution and freeze-drying.The gained solid suspension in THF, is filtered sodium-chlor, vacuum concentration then, obtaining the desired dihydroxy acid of 2.05g (98%) is white solid. 1H?NMR(300MHz，CD 3OD)δ4.42(d，J＝5.8Hz，1H)，3.90(d，J＝6.5Hz，1H)，2.84(m，1H)，1.70-1.24(m，6H)，0.95-0.84(m，9H).
(1.90g adds Tetrafluoroboric acid 2-(1H-benzotriazole-1-yl)-1,1 in anhydrous THF (36ml) solution 7.33mmol) at dihydroxylated acid, 3,3-tetramethyl-urea (TBTU, 2.59g, 8.06mmol) anhydrous MeCN (36ml) solution, add then triethylamine (0.72ml, 22.0mmol).Stir under the room temperature after 70 minutes, add some toluene, with the mixture vacuum concentration, again with twice of toluene coevaporation.Purification by flash chromatography (SiO 2, with 2: 3 AcOEt/ hexane wash-outs), obtaining the desired β of 1.44g (81%)-lactone VIIb is white solid. 1H NMR (300MHz, CDCl 3) δ 6.07 (br.s, 1H), 5.26 (d, J=6.1Hz, 1H), 3.97 (dd, J=6.4,4.4Hz, 1H), 2.70-2.63 (m, 1H), 2.03 (d, J=6.4Hz, 3H), and 1.93-1.44 (m, 5H), 1.07 (d, J=7.0Hz, 3H), 0.99 (d, J=7.3Hz, 3H), 0.91 (d, J=6.7Hz, 3H) .LRMS (FAB) m/e 242 (M+H +) .b. β-lactone VIIa (R 2=Et; R 1=i-Pr)
Method hydrolysis IVa with handling IVb above similar obtains corresponding dihydroxylated acid with 100% productive rate. 1H?NMR(300MHz，CD 3OD)δ4.45(d，J＝5.8Hz，1H).3.90(d，J＝6.4Hz，1H)，2.74(m，1H)，1.71-1.53(m，3H)，0.94(t，J＝7.4Hz，3H)，0.92(d，J＝6.8Hz，3H)，0.88(d，J＝6.8Hz，3H).
With being similar to the method for preparing β-lactone VIIb, obtain β-lactone VIIa with 79% productive rate. 1H NMR (300MHz, CDCl 3) δ 6.17 (br.s, 1H), 5.30 (d, J=6.0Hz, 1H), 3.98 (dd, J=6.4,4.4Hz, 1H), 2.60 (m, 1H), 2.08 (d, J=6.4Hz, 3H), 1.97 (m, 2H), 1.75 (m, 1H), 1.12 (t, J=7.5Hz, 3H), 1.07 (d, J=6.8Hz, 3H), 0.92 (d, J=6.8Hz, 3H) .c. β-lactone VIIc (R 2=n-Bu; R 1=i-Pr)
Method hydrolysis IVc with handling IVb above similar obtains corresponding dihydroxy acid with 100% productive rate. 1HNMR(300MHz，CD 3OD)δ4.42(d，J＝5.8Hz，1H)，3.90(d，J＝6.4Hz，1H)，2.86-2.79(m，1H)，1.70-1.24(m，8H)，0.97-0.86(m，9H).
With being similar to the method for preparing β-lactone VIIb, obtain β-lactone VIIc with 40% productive rate. 1H NMR (300MHz, CDCl 3) δ 6.14 (br.s, 1H), 5.27 (d, J=6.1Hz, 1H), 3.97 (d, J=4.4Hz, 1H), 2.68-2.61 (m, 1H), 1.94-1.86 (m, 2H), 1.72-1.36 (m, 7H), 1.07 (d, J=7.0Hz, 3H), 0.93 (t, J=7.1Hz, 3H), 0.91 (d, J=6.8Hz, 3H) .LRMS (FAB) m/e 256 (M+H +) d. β-lactone VIId (R 2=i-Bu; R 1=i-Pr)
Method hydrolysis IVd with handling IVb above similar obtains corresponding dihydroxy acid with 100% productive rate. 1HNMR(300MHz，CD 3OD)δ4.50(d，J＝5.8Hz，1H)，4.00(d，J＝6.5Hz，1H)，3.09-3.02(m，1H)，1.90-1.61(m，3H)，1.49-1.40(m，2H)，1.02(d，J＝6.7Hz，3H)，0.98(d，J＝6.5Hz，3H)，0.97(d，J＝6.7Hz，3H).
With being similar to the method for preparing β-lactone VIIb, obtain β-lactone VIId with 62% productive rate. 1H NMR (300MHz, CDCl 3) δ 6.16 (br.s, 1H), 5.25 (d, J=6.1Hz, 1H), 3.97 (d, J=4.4Hz, 1H), 2.71 (dd, J=15.1,6.2Hz, 1H), and 1.95-1.66 (m, 5H), 1.08 (d, J=6.9Hz, 3H), 0.99 (d, J=6.3Hz, 3H), 0.98 (d, J=6.3Hz, 3H), 0.92 (d, J=6.7Hz, 3H) .LRMS (FAB) m/e 256 (M+H +) .e. β-lactone VIIe (R 2=CH 2Ph; R 1=i-Pr)
Method hydrolysis IVe with handling IVb above similar obtains corresponding dihydroxy acid with 88% productive rate. 1H?NMR(300MHz，CD 3OD)δ7.25-7.04(m，5H)，4.29(d，J＝5.7Hz，1H)，3.83(d，J＝6.4Hz，1H)，3.01-2.82(m，3H)，1.65(m，1H)，0.90(d，J＝6.6Hz，3H)，0.86(d，J＝6.8Hz，3H).
With being similar to the method for preparing β-lactone VIIb, obtain β-lactone VIIe with 77% productive rate. 1H?NMR(300MHz，CDCl 3)δ7.36-7.20(m，5H)，6.57(br.s，1H)，5.08(d，J＝5.4Hz，1H)，3.94(d，J＝4.5Hz，1H)，3.25(d，J＝10.1Hz，1H)，3.01-2.89(m，2H)，1.92-1.81(m，1H)，1.05(d，J＝6.9Hz，3H)，0.86(d，J＝6.7Hz，3H).LRMS(FAB)m/e?290(M+H +).
Flow process 3 and 4 generalized preparations are illustrated by embodiment 10 and 11 along the synthetic method of-oxazolines and anti--oxazolines.Embodiment 10 suitable-oxazolines (Ia) are (sec.-propyl) ethyl propenoate (XV a.3-; R 1=i-Pr; R 3=Me)
At 0 ℃ of methoxycarbonyl methylene tri Phenylphosphine (56.04g, anhydrous CH 167.6mmol) to stirring 2Cl 2(168ml) drip in the solution isobutyric aldehyde (17.4ml, 191.6mmol).After 5 minutes, reaction mixture is risen to room temperature, and stirred 24 hours.Solvent removed in vacuo adds pentane in white oily solid, produce the triphenylphosphine oxide precipitation.The filtering solid, vacuum concentrated filtrate.Repeat this process more once, obtaining thick alkene (20.00g, 93%) is yellow oil, and its purity is enough to be directly used in the next step. 1H NMR (300MHz, CDCl 3) δ 6.95 (and dd, J=15.7,6.6Hz, 1H), 5.77 (dd, J=15.7,1.5Hz), 3.72 (s, 3H), 2.44 (m, 1H), 1.06 (d, J=6.7Hz, 6H) .b. (2S, 3R)-2,3-dihydroxyl-3-(sec.-propyl) methyl propionate (XVIa; R 1=i-Pr; R 3=Me)
With AD-mixing-β (100.00g), Toluidrin (6.78g, 71.3mmol) and tertiary butanol and water (1: 1,720ml) vigorous stirring 5 minutes at room temperature was cooled to reaction mixture 0 ℃ then.Add alpha, beta-unsaturated esters XV (R with the Pasteur volumetric pipette 1=i-Pr; R 3=Me) (9.14g, 71.3mmol).After 96 hours, add Na 0 ℃ of stirring 2SO 3(3.0g), then stirring at room 1 hour.With ethyl acetate (200ml) diluted mixture thing, then it is transferred in the separating funnel.Remove organic phase, water ethyl acetate extraction (2 * 100ml).Organic phase drying (the Na that merges 2SO 3), obtain yellow oil behind filtration and the vacuum concentration.Make it pass through the silica gel backing plate,, obtain glycol XVIa (R with 1: 1 hexane/ethyl acetate wash-out 1=i-Pr; R 3=Me) (11.48g, 94%) be yellow solid. 1H NMR (300MHz, CDCl 3) δ 4.28 (dd, J=5.6,1.8Hz, 1H), 3.80 (s, 3H), 3.48 (m, 1H), 3.28 (m, 1H), 2.33 (d, J=9.3Hz, 1H), 1.87 (m, 1H), 1.02 (d, J=6.7Hz, 3H), 0.95 (d, J=6.7Hz, 3H) .c. (2R, 3R)-2-bromo-3-dihydroxyl-3-(sec.-propyl) methyl propionate (XVIIa; R 1=i-Pr; R 3=Me)
Will (2S, 3R)-2,3-dihydroxyl-3-(sec.-propyl) methyl propionate XVIa (R 1=i-Pr; R 3=Me) (1.0g, 6.17mmol) (1.02ml 80.1mmol) is dissolved in CH with former phenylformic acid trimethyl 2Cl 2(20ml), and use BF 3OEt 2(40.0 μ l 0.32mmol) handle.Stir after 75 minutes, mixture is concentrated 35 minutes down in high vacuum (0.05mmHg).Mixture is dissolved in CH again 2Cl 2(20.0ml), be cooled to 0 ℃, use Et successively 3N (43.0 μ l, 0.31mmol) and acetyl bromide (0.48ml 6.49mmol) handles.0 ℃ stir 4 hours after, the saturated NaHCO of reaction mixture 3Solution (12ml) is handled, and allows to rise to room temperature.Separate each phase, water CH 2Cl 2(2 * 20ml) extractions.Organic phase drying (the Na that merges 2SO 3), obtain thick α-bromo-β-benzoic ether XVIIa (R behind filtration and the vacuum concentration 1=i-Pr; R 3=Me) (1.36g, 85%) be limpid water white oil. 1H NMR (300MHz, CDCl 3) δ 8.05-8.00 (m, 2H), 7.47-7.40 (m, 3H), 5.57 (dd, J=8.8,3.9Hz, 1H), 4.47 (d, J=8.8Hz, 1H), 3.67 (s, 3H), 2.45 (m, 1H), 1.01 (d, J=6.8Hz, 6H) .d. (2S, 3R)-2-azo-3-dihydroxyl-3-(sec.-propyl) methyl propionate (XVIIIa; R 1=i-Pr; R 3=Me)
Will (2R, 3R)-2-bromo-3-dihydroxyl-3-(sec.-propyl) methyl propionate XVIIa (R 1=i-Pr; R 3=Me) (2.00g, (790.0mg 12.2mmol) handles 15ml DMSO solution 6.07mmol) with sodiumazide.In stirring at room after 12 hours, with mixture at H 2Distribute between O and the ethyl acetate (each 50ml).The water ethyl acetate extraction, the organic phase MgSO of merging 4Drying, and vacuum concentration, obtaining desired α-azo-β-benzoic ether (1.55g, 87%) is yellow oil. 1HNMR(300MHz，CDCl 3)δ8.07-8.02(m，2H)，7.55-7.43(m，3H)，5.40(dd，J＝8.8，2.8Hz，1H)，3.73(s，3H)，2.24(m，1H)，1.04(d，J＝5.8Hz，3H)，0.98(d，J＝5.8Hz，3H).
Repeat said process, just replace DMSO as solvent, obtain desired α-azo-β-benzoic ether with 85% productive rate with DMF.E. benzoyl methane amide XIXa (R 1=i-Pr; R 3=Me)
Will (2S, 3R)-2-azo-3-dihydroxyl-3-(sec.-propyl) methyl propionate XVIIIa (R 1=i-Pr; R 3=Me) (1.50g, 5.15mmo1) 25ml ethyl acetate solution is with 200mg 20%Pd (OH) 2/ C handles, and with suspension at H 2In and the swelling pressure under vigorous stirring.After 12 hours, filtering mixt refluxes 4 hours to finish the migration of benzoyl.With the mixture cool to room temperature, vacuum concentration, obtaining desired benzoyl methane amide (1.25g, 92%) is yellow oil. 1H NMR (300MHz, CDCl 3) δ 7.85-7.83 (m, 2H), 7.46-7.40 (m, 3H), 6.99 (br.d, J=9.1Hz, 1H), 5.05 (dd, J=9.1,1.9Hz, 1H), 3.77 (s, 3H), 1.79 (m, 1H), 1.03 (d, J=6.7Hz, 3H) .0.99 (d, J=6.7Hz, 3H) the suitable-oxazoline Ia (R of .f. 1=i-Pr; R 3=Me)
With benzoyl methane amide XIXa (R 1=i-Pr; R 3=Me) (500mg, CH 18.8mmol) 2Cl 2(20ml) solution is handled with 4.50ml thionyl chloride (61.7mmol).In stirring at room after 24 hours, with mixture CH 2Cl 2Dilution, saturated NaHCO 3Solution washing, Na 2SO 4Drying, vacuum concentration then.Through chromatogram purification (silica gel, 1: 1 hexane/ethyl acetate), obtaining desired is light yellow oil along-oxazolines (248mg, 53%).
1H NMR (300MHz, CDCl 3) δ 8.01-7.97 (m, 2H), 7.52-7.38 (m, 3H), 4.94 (d, J=9.8Hz, 1H), 4.53 (dd, J=9.8,7.8Hz, 1H), 3.76 (s, 3H), 2.09 (m, 1H), 1.05 (d, J=6.5Hz, 3H), 1.01 (d, J=6.7Hz, 3H). embodiment 11 anti--oxazolines (Ib) are (sec.-propyl) ethyl propenoate (XV a.3-; R 1=i-Pr; R 3=Me)
At 0 ℃ of methoxycarbonyl methylene tri Phenylphosphine (56.04g, anhydrous CH 167.6mmol) to stirring 2Cl 2(168ml) drip in the solution isobutyric aldehyde (17.4ml, 191.6mmol).After 5 minutes, reaction mixture is risen to room temperature, and stirred 24 hours.Solvent removed in vacuo adds pentane in white oily solid, produce the triphenylphosphine oxide precipitation.The filtering solid, vacuum concentrated filtrate.Repeat this process more once, obtaining thick alkene (20.00g, 93%) is yellow oil, and its purity is enough to be directly used in the next step. 1H NMR (300MHz, CDCl 3) δ 6.95 (and dd, J=15.7,6.6Hz, 1H), 5.77 (dd, J=15.7,1.5Hz), 3.72 (s, 3H), 2.44 (m, 1H), 1.06 (d, J=6.7Hz, 6H) .b. (2R, 3S)-2,3-dihydroxyl-3-(sec.-propyl) methyl propionate (XVIb; R 1=i-Pr; R 3=Me)
25 ℃ with syringe pump (syringe connect a pipe, syringe nozzle is immersed in the solution all the time during entire reaction) through 48 hours with purified alkene XV (R 1=i-Pr; R 3=Me) (9.0g 70.2mmol) is added to and contains K 2OsO 2(OH) 4(246.1mg, 0.67mmol, 0.95mol%), hydroquinine 1,4-naphthyridine two basic diether (555.1mg, 0.71mmol, 1.01mol%), N-methylmorpholine N-oxide compound (50wt% in the water, 25.0ml, 0.106mol, 1.51 equivalents), t-BuOH (84ml) and H 2In the limpid yellow solution of O (58ml).The orange solution restir that gained is limpid 60 minutes adds ethyl acetate (200ml) and Na afterwards 2SO 3H (15.0g) 2O (150ml) solution, and with gained mixture stirring 4 hours.Separate each phase, water ethyl acetate extraction (2 times).Merge organic phase, use 0.3M H 2SO 4Saturated Na 2SO 4Solution extraction (2 * 100ml).Separate each phase once more, water ethyl acetate extraction (1 time).Merge organic phase, Na 2SO 4Drying is filtered and vacuum concentration, obtains the white oily solid of 11.4g (about 100%).With 1H NMR is at the C of two pure and mild three [3-(seven fluoropropyl hydroxyl methylene radical)-(-)-dextrocamphoric acid] europium solution of 1: 1 mole 6D 6In measure, the result shows that this solid is 70%e.e.Recrystallization from 35-60 ℃ of sherwood oil, obtain 6.8g (60%) (2S, 3R)-2,3-dihydroxyl-3-(sec.-propyl) methyl propionate (XVIb; R 1=i-Pr; R 3=Me), be about 100%e.e, be white crystal.Mp=32-34 ℃;=-110.6 ° of (c1.04, CHCl 3)]. 1H NMR (300MHz, CDCl 3) δ 4.28 (dd, J=5.6,1.8Hz, 1H), 3.80 (s, 3H), 3.48 (m, 1H), 3.28 (m, 1H), 2.33 (d, J=9.3Hz, 1H), 1.87 (m, 1H), 1.02 (d, J=6.7Hz, 3H), 0.95 (d, J=6.7Hz, 3H) .c. (2S, 3S)-2-bromo-3-dihydroxyl-3-(sec.-propyl) methyl propionate (XVIIb; R 1=i-Pr; R 3=Me)
Will (2R, 3S)-2,3-dihydroxyl-3-(sec.-propyl) methyl propionate XVIb (R 1=i-Pr; R 3=Me) (30.0g, 185.2mmol) (41.3ml 240.7mmol) is dissolved in CH with former phenylformic acid trimethyl 2Cl 2(400ml), and use BF 3-OEt 2(1.16ml 9.25mmol) handles.After 2 hours, (1.8ml, 13mmol), vacuum concentrated mixture also was placed on high vacuum (0.05mmHg) following 70 minutes to add triethylamine.Residuum is dissolved in CH again 2Cl 2(400ml), be cooled to 0 ℃, (14.3ml 194.5mmol) handles to drip acetyl bromide.After 2 hours, add again acetyl bromide (0.68ml, 9.25mmol).After 30 minutes, add saturated NaHCO 3Solution (500ml), and with mixture vigorous stirring 5-10 minute.Separate each phase, water CH 2Cl 2(2 * 20ml) extractions.Organic phase drying (the Na that merges 2SO 3), obtain thick α-bromo-β-benzoic ether XVIIb (R behind filtration and the vacuum concentration 1=i-Pr; R 3=Me) (66.23g) be limpid water white oil, contain the 9.3wt% methyl benzoate of having an appointment.For product: 1H NMR (300MHz, CDCl 3) δ 8.05-8.00 (m, 2H), 7.47-7.40 (m, 3H), 5.57 (dd, J=8.8,3.9Hz, 1H), 4.47 (d, J=8.8Hz, 1H), 3.67 (s, 3H), 2.45 (m, 1H), 1.01 (d, J=6.8Hz, 6H) .d. (2R, 3S)-2-azo-3-dihydroxyl-3-(sec.-propyl) methyl propionate (XVIIIb; R 1=i-Pr; R 3=Me)
(24g 370mmol) is added among the 230ml DMSO, and mixture is at room temperature stirred spend the night with sodiumazide.In gained solution, add (2S, 3S)-2-bromo-3-dihydroxyl-3-(sec.-propyl) methyl propionate (XVIIb; R 1=i-Pr; R 3=Me) (61g, 20ml DMSO solution 185mmol).After 11 hours, pour mixture into H in stirring at room 2In O (1.5L) and the ether (200ml), vigorous stirring 10-15 minute.Add ether (100ml), separate each phase.Water with extracted with diethyl ether (2 * 100ml), the organic phase water of merging (2 * 100ml) and salt solution (100ml) wash MgSO 4Drying, and vacuum concentration obtain crude product (57.5g), contain have an appointment 3% starting raw material and 8% by product that will remove.For product:
1H NMR (300MHz, CDCl 3) δ 8.07-8.02 (m, 2H), 7.55-7.43 (m, 3H), 5.40 (dd, J=8.8,2.8Hz, 1H), 3.73 (s, 3H), 2.24 (m, 1H), 1.04 (d, J=5.8Hz, 3H), 0.98 (d, J=5.8Hz, 3H) .e. benzoyl methane amide XIXb (R 1=i-Pr; R 3=Me)
(2R, 3S)-2-azo-3-dihydroxyl-3-(sec.-propyl) methyl propionate XVIIIb (R 1=i-Pr; R 3=Me) add 94ml 4M HCl/ diox and 2.75g Pd (OH) in the methyl alcohol of (55g) (300ml) cold (0-5 ℃) solution 2/ C.With hydrogen purge mixture, and at room temperature stir.Per 30 minutes with hydrogen purge mixture once to remove the nitrogen of release.After 4 hours, use the purging with nitrogen gas reaction mixture, and add 1.3g Pd (OH) again 2/ C.Again once with per 4 hours purge reaction mixtures of hydrogen.Filtering mixt and vacuum concentration.Residuum is dissolved in water, extracts with EtOAc.Water NaHCO 3Alkalize, and then extract with EtOAc.The organic extract liquid salt water washing that merges, Na 2SO 4Drying concentrates then, obtains N-and O-benzoylation mixture of products, and it is directly used in the next step.F. anti-oxazoline Ib (R 1=i-Pr; R 3=Me)
(37.3g 141mmol) is dissolved in toluene (350ml) to the crude product IXb that top embodiment 10e is obtained.(2.68g 14.1mmol), refluxes mixture heating up to add tosic acid.Remove with Dean Stark trap and to anhydrate.After 3 hours, collect about 2.5ml water.Reaction mixture with EtOAc (100ml) dilution, is used saturated NaHCO successively 3(2 * 100ml) and salt solution (100ml) washing, MgSO 4Drying concentrates then.Residuum is gone up purifying at silica gel backing plate (about 400g), with 25-30%EtOAc/ hexane wash-out, obtains anti-oxazoline Ib (R 1=i-Pr; R 3=Me). 1H NMR (300MHz, CDCl 3) δ 8.01-7.97 (m, 2H), 7.52-7.38 (m, 3H), 4.68 (apparent t, J=7Hz, 1H), 4.57 (d, J=7Hz, 1H), 3.81 (s, 3H), 2.00-1.93 (m, 1H), 1.04 (d, J=6.7Hz, 3H), 1.00 (d, J=6.8Hz, 3H). the active passivation of embodiment 12 proteoplasts
The purge process of 20S proteoplast and proteoplast activator PA28 can be carried out according to foregoing method (people such as Dick, " journal of biological chemistry ", 271:7273 (1996)).
2ml is measured damping fluid, and (pH8.0) methyl-sulphoxide with Suc-Leu-Leu-Val-Tyr-AMC is added in the 3ml fluorescence cuvette, cuvette is placed on the cover cassette holder of Hitachi F-2000 spectrophotofluorometer then for 20mM HEPES, 0.5mM EDTA.Maintain the temperature at 37 ℃ with circulator bath.Add 0.34mg PA28, by supervision follow free AMC to produce to take place at 440nm (λ Ex=the increase of 380nm) locating fluorescence monitors reaction process.This progress curve table reveals a lasting 1-2 minute lag-phase, and this is slowly formed by the 20S-PA28 mixture and causes.After substrate hydrolysis reaches stable state, add lactacystin and make ultimate density reach 1mM, and monitor reaction 1 hour.On minicomputer, collect fluorescence (F) and the data that the time (t) concerns, by following linear function data are carried out non-linear least square method and be similar to, estimate K with LAB CALC (Galactic) software InactValue:
F=A (1-e -kt)+C wherein, C=F T=0And A=F T=∞-F T=0Embodiment 13 suppresses the degraded of intracellular protein in the C2C12 cell
With 35S-methionine mark C2C12 cell (mouse sarcoplast system) 48 hours.Wash these cells, preincubation is 2 hours in the same medium that is supplemented with the unlabelled methionine(Met) of 2mM.Outwell this substratum, change a freshly prepd preincubation substratum that contains 50% serum and certain density testing compound.Outwell this substratum, be mixed with 10% TCA, centrifugal then.TCA solubility radioactivity is counted.The restraining effect of the percentage calculation proteolysis that reduces with TCA solubility radioactivity.Go out the IC of each compound from this data computation 50Embodiment 14 lactone hydrolysis
β-lactone analogue is hydrolyzed into the transformation period (t of corresponding dihydroxy acid 1/2) measurement be under 37 ℃ with the concentration of 200mM at 20mM HEPES, 0.5mM EDTA carries out among the pH7.8.Absorption at the 230nm place will be measured 5 transformation period (about 1 hour) at least, the difference maximum of lactone and dihydric optical extinction coefficient under this wavelength.Analyze (Gutfreund, " enzyme: physical principle " (Enzymes:Physical Principle) with Guggenheim; Wiley ﹠amp; Sons:New York, 1975, pp118-119) calculate the transformation period.Embodiment 12-14 the results are shown in table 1.
Table 1
Suppress the 20S proteoplast and suppress the kinetics that intracellular protein is degraded
Figure A9880952600801
Compound R 2Kobs/[I] (M -1s -1) aIC 50(μ M) bt 1/2Min c2 Me 20,000 0.7-1.1,13 3a Et 39,000 0.32 15.3 3b n-Pr 46,500 0.29 15.3 3c n-Bu 38,000 0.33 17 3d i-Bu 17,000 0.51 16.8 3e CH2Ph 6,400-6.8 3f OMe 82,200 86 3.7 aThe active passivation of chymotrypsin-like of PA28 activatory 20S proteoplast. bSuppress the degraded of intracellular protein in the C2C12 cell cHydrolysising half-life.The minimizing method of embodiment 15 infraction sizes and neurone loss
With halo ethane with male Sprague Dawly rat (250-400g) anesthesia, and with nylon wire ligation arteria cerebri media (MCA) 2 hours.Remove nylon wire, before rat is condemned to death, blocking tissue was poured into 24 hours again.
Give a mark to rat with the neurological points-scoring system immediately after removing nylon wire.The neurological scoring represents that with 0 to 100 yardstick 0 expression does not have neurological deficit, and 10 expressions have serious neurological deficit.After 24 hours and before putting to death, give a mark to animal for the second time with same neurological points-scoring system.
(2.0mm * 7-8) painted situation utilizes image analysis to estimate to determine the infraction size under the blind test condition to give the coronal section of whole brain with triphenyltetrazolium chloride (TTC).Dosage regimen
Gave injection (1.0ml/kg) carrier (50% propylene glycol/salt solution in the rat vein with syringe in 2 hours behind the ligation MCA; N=8) or 7-n-propyl-clasto-lactacystin-β-lactone (3b) (0.3mg/kg; N=7).Other two groups of rats behind ligation MCA 0 minute, 2 hours and 6 hours intravenous injection 3b (1.0mg/kg).One group of (0.1mg/kg * 3; N=6) accept the injection of a 0.1mg/kg at each time point, and another group (0.3mg/kg * 3; N=7) accept the injection of a 0.3mg/kg in each of three time points.The result
In the animal with single agent 7-n-propyl-clasto-lactacystin-β-lactone (3b) treatment, infarct volume reduces 50% (Fig. 1,0.3 * 1).And in 0.1mg/kg * 3 dosage groups or 0.3mg/kg * 3 dosage groups, infarct volume does not obviously reduce (Fig. 1).
The scoring of neurological at once 2 hours all animals of local asphyxia after date is 10 ± 0.After 24 hours, with the rat of vehicle treated be equally divided into 8.7 ± 0.6, and the mouse of handling with the single agent of 7-n-propyl-clasto-lactacystin-β-lactone (3b) 0.3mg/kg be equally divided into 4 ± 1 (Fig. 2).These data show that the animal after the pharmacological agent obtains 60% neurological and improves.And in 0.1mg/kg * 3 dosage groups or 0.3mg/kg * 3 dosage groups, do not observe obvious improvement the (Fig. 2) of neurological scoring.Conclusion
7-n-propyl-clasto-lactacystin-β-lactone will be in case administration after local asphyxia will provide remarkable protection aspect neurological deficit and the infraction brain damage two.From these preliminary datas, single agent scheme obviously than multi-agent scheme more preferably.
To abundant description of the present invention, those of ordinary skills should be appreciated that by above, are not influencing under the scope of the invention or its any embodiment situation, can implement the present invention in the scope broad and of equal value of some condition, prescription and other parameter.All patents and publication that this paper quoted are all incorporated by reference at this.

Claims (73)

1. the method for preparation formula V gamma-lactam or its salt,
Figure A9880952600021
Wherein
R 1Be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkaryl, aralkyl, wherein said aryl, any one loop section can optionally be substituted in aralkyl or the alkaryl;
R 2Be alkyl, cycloalkyl, aryl, alkaryl, aralkyl, alkoxyl group, hydroxyl, alkoxyalkyl or amido, wherein said aryl, any one loop section can optionally be substituted in aralkyl or the alkaryl; And this method comprises:
(a) by handling the aryl that formula I replaces-or Za Fang oxazolin with highly basic, R wherein 1Define as above,
R 3Be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkaryl, wherein any one can optionally be substituted; And
R 4Be aryl or heteroaryl, the two can optionally be substituted; With the aryl of said replacement-or Za Fang oxazolin deprotonation, form enolate;
(b) with one of following metal said enolate is carried out metal transfer: titanium, aluminium, tin, zinc, magnesium and boron are handled with formula XIV formyl radical methane amide then,
Figure A9880952600031
R wherein 2Definition as above; And
R 5And R 6Respectively be one of alkyl or alkaryl; Or R 5And R 6Coupled nitrogen-atoms forms one together and can optionally substituted 5-7 person encircle, and this ring can optionally contain another Sauerstoffatom or nitrogen-atoms, forms formula II adducts,
Figure A9880952600032
R wherein 1-R 6Definition as above;
(c) the said formula II adducts of catalytic hydrogenation forms formula IV gamma-lactam,
Figure A9880952600033
R wherein 1, R 2And R 3Definition as above;
(d) the said formula IV gamma-lactam of saponification forms formula V carboxylic acid.
2. the method for claim 1 further comprises with cyclizing agent and handles formula V carboxylic acid, forms formula VII clasto-lactacystin-β-lactone, R wherein 1And R 2Definition is with claim 1.
3. the method for claim 2, wherein said cyclisation can be undertaken by following reagent: aryl sulfonyl chloride, phosphofluoric acid benzotriazole-1-base oxygen base three (dimethylamino) Phosphonium, Tetrafluoroboric acid O-(1H-benzotriazole-1-yl)-N, N, N ', N '-tetramethyl-urea and alkyl, aryl or alkenyl chloro-formic ester.
4. the method for claim 2 further comprises formula VII clasto-lactacystin-β-lactone and mercaptan R 7The SH reaction forms formula VI lactacystin, R wherein 1And R 2Definition is with claim 1; And
R 7Be alkyl, aryl, alkaryl, aralkyl, wherein said alkyl, aryl, any one can optionally be substituted in aralkyl or the alkaryl.
5. the method for claim 4 is transformed into lactacystin by handling β-lactone with the N-acetylcysteine with clasto-lactacystin-β-lactone.
6. the process of claim 1 wherein that formula V carboxylic acid intermediate directly and mercaptan R 7The SH coupling forms formula VI lactacystin R wherein 1And R 2Definition is with claim 1; And
R 7Be alkyl, aryl, alkaryl, aralkyl, wherein said alkyl, aryl, any one can optionally be substituted in aralkyl or the alkaryl.
7. the process of claim 1 wherein that said highly basic is following compound in the step (a): acid amides alkali is obstructed; Basic metal hexamethyl two silicon nitrides; Or the alkyl lithium reagents that is obstructed.
8. the process of claim 1 wherein that the reaction in the step (a) is to carry out at low temperatures in ether solvents.
9. the method for claim 8, wherein said ether solvents is selected from ether in the step (a), tetrahydrofuran (THF) and glycol dimethyl ether, said temperature of reaction is from-100 ℃ to-30 ℃ approximately approximately.
10. the process of claim 1 wherein in the step (b) that said enolate carries out metal transfer with titanium or aluminium or their mixture.
11. in the step of the process of claim 1 wherein (b) said enolate by with Me 2Metal transfer is carried out in the AlCl reaction.
12. the method for claim 10 has wherein been used the said metal of 1-3 molar equivalent.
13. said adducts II obtains the mixture of desired gamma-lactam (IV) and aminodiol III through catalytic hydrogenolytic cleavage in the step of the process of claim 1 wherein (c), R wherein 1-R 6Definition is with claim 1.
14. the method for claim 13, wherein said hydrogenolysis is in the presence of one of following catalyzer: palladium black, palladium/gac and palladium hydroxide/charcoal, and in the presence of one of following organic solvent, carry out: low-level chain triacontanol, lower alkanoic acid ester, lower alkanols alkanoic acid, or their mixture.
15. the method for claim 14, wherein said organic solvent is selected from methyl alcohol, ethanol, and Virahol, ethyl acetate, acetate, and composition thereof.
16. the method for claim 13, wherein said crude mixture is transformed into gamma-lactam IV through heating with aminodiol III.
17. the process of claim 1 wherein
R 1Be C 1-12Alkyl, C 3-8Cycloalkyl, C 2-8Alkenyl, C 2-8Alkynyl, C 6-14Aryl, C 6-10Aryl (C 1-6) alkyl or C 1-6Alkyl (C 6-10) aryl;
R 2Be C 1-8Alkyl, C 3-8Cycloalkyl, C 2-8Alkenyl, C 2-8Alkynyl, C 6-14Aryl, C 6-10Aryl (C 1-6) alkyl or C 1-6Alkyl (C 6-10) aryl;
R 3Be C 1-8Alkyl, C 3-8Cycloalkyl, C 2-8Alkenyl, C 2-8Alkynyl, C 6-14Aryl, C 6-10Aryl (C 1-6) alkyl or C 1-6Alkyl (C 6-10) aryl;
R 4Be C 6-10Aryl, or following heteroaryl comprise thienyl, benzo [b] thienyl, furyl, pyranyl, isobenzofuran-base, benzoxazolyl, 2H-pyrryl, pyrryl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, indolizine base, pseudoindoyl, 3H-indyl, indyl, indazolyl, purine radicals, 4H-quinolizinyl, isoquinolyl, quinolyl or triazolyl; And
R 5And R 6Be respectively C 1-6Alkyl, C 6-10Aryl (C 1-6) alkyl or C 1-6Alkyl (C 6-10) aryl, or coupled nitrogen-atoms forms a 5-7 element heterocycle together, and this heterocycle can optionally be substituted, and can optionally contain another Sauerstoffatom or nitrogen-atoms.
18. the method for claim 17, wherein
R 1Be C 1-6Alkyl, C 3-6Cycloalkyl, or C 6-10Aryl;
R 2Be methyl, ethyl, propyl group, butyl, methoxyl group, or oxyethyl group;
R 3Be methyl, ethyl, the tertiary butyl or benzyl;
R 4Be phenyl or by halogen, C 1-6Alkyl, C 1-6Alkoxyl group, carboxyl or the amino phenyl that replaces; And
NR 5R 6Be one of following groups: dimethylamino, diethylin, pyrrolidyl, piperidino-(1-position only), morpholino, by halogen, C 1-6Alkyl, C 6-10Aryl (C 1-6) alkyl, C 1-6Alkoxyl group, carboxyl, or the amino De oxazolidone that replaces.
19. preparation formula II replaces the method for De oxazoline compound,
Figure A9880952600071
This method comprises:
(a) by handling the aryl that formula I replaces-or Za Fang oxazolin with highly basic,
Figure A9880952600072
With the aryl of said replacement-or Za Fang oxazolin deprotonation, form enolate; And
(b) with one of following metal said enolate is carried out metal transfer: titanium, aluminium, tin, zinc, magnesium and boron are handled with formula XIV formyl radical methane amide then, Wherein, for formula I, each among II and the XIV:
R 1Be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkaryl, aralkyl, wherein said aryl, any one loop section can optionally be substituted in aralkyl or the alkaryl;
R 2Be alkyl, cycloalkyl, aryl, alkaryl, aralkyl, alkoxyl group, hydroxyl, alkoxyalkyl or amido, wherein said aryl, any one loop section can optionally be substituted in aralkyl or the alkaryl;
R 3Be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkaryl, wherein any one can optionally be substituted;
R 4It is aryl that optionally replaces or the heteroaryl that optionally replaces; And
R 5And R 6Be respectively one of alkyl or alkaryl; Or R 5And R 6Coupled nitrogen-atoms forms one together and can optionally substituted 5-7 person encircle, and this ring can optionally contain another Sauerstoffatom or nitrogen-atoms.
20. the method for claim 19 further comprises the said formula II oxazoline of catalytic hydrogenation compound, therefore optional then backflow gained reaction mixture forms formula IV beta-lactam, R wherein 1, R 2And R 3Definition is with claim 19.
21. the method for claim 20 further comprises the said formula IV compound of saponification, carries out cyclisation then, forms formula VII clasto-lactacystin-β-lactone compound,
Figure A9880952600082
R wherein 1And R 2Definition is with claim 19.
22. the method for the Fang oxazolin compound that preparation formula Ia replaces, Wherein
R 1Be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkaryl, aralkyl, wherein said aryl, the loop section of aralkyl or alkaryl can optionally be substituted;
R 3Be alkyl, cycloalkyl, aryl, alkaryl, wherein any one can optionally be substituted; And
R 4It is aryl that optionally replaces or the heteroaryl that optionally replaces; Said method comprises:
(a) asymmetric dihydroxy formula XV alkene intermediate,
Figure A9880952600091
Form the optically active glycol of formula XVIa,
Figure A9880952600092
(b) optically active glycol of said formula XVIa and ortho ester are reacted under the acid catalysis effect, obtain mixing ortho ester, then, in the presence of alkali with gained mixing ortho ester intermediate and following reagent react: acyl halide, HCl, HBr, HI, Me 3SiCl, Me 3SiI, Me 3SiBr and halogen-containing Lewis acid form formula XVIIa haloester derivative,
Figure A9880952600093
Wherein X is Cl, Br or I;
(c) with said haloester derivative and an alkali metal azide reaction, form formula XVIIIa trinitride, (d) the said trinitride of catalytic hydrogenation forms formula XIXa compound,
Figure A9880952600102
(e) formula XIXa compound is placed under the closed loop condition, form the Ben oxazolin that said formula Ia replaces; Wherein for each formula XVa, XVIa, XVIIa, XVIIIa and XIXa, R 1, R 3And R 4Define among the cotype Ia.
23. the method for claim 22, wherein the dihydroxy reaction in the step (a) carries out with AD-mixing-β in the presence of Toluidrin, obtains formula XVIa glycol Stereoselective.
24. the method for claim 22, wherein the dihydroxy reaction in the step (a) reoxidizes agent with the N-oxide compound and carries out.
25. the method for claim 22, wherein said formula XVIa glycol is handled under Lewis or the effect of Bronsted acid catalysis with ortho ester in the step (b), obtain mixing ortho ester, X is the halogen ester of the formula XVIIa of Br by being converted into the mixing ortho ester wherein then and there with the acetyl bromide processing.
26. the method for claim 25, the ortho ester that wherein is used for this reaction are aromatic carboxylic acid's ortho ester.
27. the method for claim 26, wherein ortho ester is former phenylformic acid trimethylammonium ester.
28. the method for claim 25, wherein said acid catalyst is HBr, SnCl 4, TiCl 4, BBr 3Or boron trifluoride.
29. the method for claim 22, wherein the thick halogen ester of step (c) Chinese style XVIIa is converted to formula XVIIIa trinitride by transmitting in the organic solvent in aprotic, polar with an alkali metal azide processing.
30. the method for claim 22, wherein the catalytic hydrogenation of said formula XVIIIa trinitride is carried out in being added with the ethyl acetate of palladium catalyst in the step (d).
Carry out 31. the method for claim 30, wherein said catalytic hydrogenation are accompanied by the migration of aroyl, obtain formula XIXa oxyamide.
32. the method for claim 22, wherein said formula XIXa hydroxyl acid amides is handled in methylene dichloride with thionyl chloride in the step (e), encircles obturation to reverse along with hydroxyl, production Ia is suitable-replace the De oxazoline.
33. the method for claim 32 wherein is converted to anti--oxazolines along the reverse by ester substituting group configuration under equilibrium conditions of-oxazolines.
34. the method for the Fang oxazolin compound that preparation formula Ib replaces,
Figure A9880952600111
Wherein
R 1Be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkaryl, aralkyl, wherein said aryl, the loop section of aralkyl or alkaryl can optionally be substituted;
R 3Be alkyl, cycloalkyl, aryl, alkaryl, wherein any one can optionally be substituted; And
R 4It is aryl that optionally replaces or the heteroaryl that optionally replaces; Said method comprises:
(a) asymmetric dihydroxy formula XV alkene intermediate,
Figure A9880952600112
Form the optically active glycol of formula XVIb,
(b) optically active glycol of said formula XVIb and ortho ester are reacted under the acid catalysis effect, obtain mixing ortho ester, then, in the presence of alkali with gained mixing ortho ester intermediate and following reagent react: acyl halide, HCl, HBr, HI, Me 3SiCl, Me 3SiI, Me 3SiBr and halogen-containing Lewis acid form formula XVIIb haloester derivative,
Figure A9880952600122
Wherein X is Cl, Br or I;
(c) with said haloester derivative and an alkali metal azide reaction, form formula XVIIIb trinitride,
(d) the said trinitride of hydrogenation forms formula XIXb compound,
Figure A9880952600124
(e) formula XIXb compound is placed under the closed loop condition, form the Ben oxazolin that said formula Ib replaces; Wherein for each formula XVb, XVIb, XVIIb, XVIIIb and XIXb, R 1, R 3And R 4Define among the cotype Ib.
35. the method for claim 34, wherein the dihydroxy reaction in the step (a) carries out with AD-mixing-α in the presence of Toluidrin, obtains formula XVIb glycol Stereoselective.
36. the method for claim 34, wherein the dihydroxy reaction in the step (a) reoxidizes agent with the N-oxide compound and carries out.
37. the method for claim 34, wherein said formula XVIb glycol is handled under Lewis or the effect of Br nsted acid catalysis with ortho ester in the step (b), obtain mixing ortho ester, X is the halogen ester of the formula XVIIb of Br by being converted into the mixing ortho ester wherein then and there with the acetyl bromide processing.
38. the method for claim 37, the ortho ester that wherein is used to react are aromatic carboxylic acid's ortho ester.
39. the method for claim 38, wherein ortho ester is former acid+benzoic acid trimethylammonium ester.
40. the method for claim 37, wherein said acid catalyst is HBr, SnCl 4, TiCl 4, BBr 3Or boron trifluoride.
41. the method for claim 34, wherein the thick halogen ester of step (c) Chinese style XVIIb is converted to formula XVIIIb trinitride by transmitting in the organic solvent in aprotic, polar with an alkali metal azide processing.
42. the method for claim 34, wherein the catalytic hydrogenation of said formula XVIIIb trinitride is carried out in the ethyl acetate of palladium catalyst in the step (d).
Carry out 43. the method for claim 42, wherein said catalytic hydrogenation are accompanied by the migration of aroyl, obtain formula XIXb oxyamide.
44. the method for claim 34, wherein said formula XIXb hydroxyl acid amides is handled in methylene dichloride with thionyl chloride in the step (e), encircles obturation along with hydroxyl reverses, production Ib is suitable-replace the De oxazoline.
45. the method for preparation formula XIXa compound,
Figure A9880952600141
Said method comprises: hydrogenation of formula XVIIIa azide chemical compound,
Figure A9880952600142
Wherein, in formula XIXa and XVIIIa,
R 1Be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkaryl, aralkyl, wherein said aryl, any one loop section can optionally be substituted in aralkyl or the alkaryl;
R 3Be alkyl, cycloalkyl, aryl, alkaryl, wherein any one can optionally be substituted; And
R 4Be aryl or heteroaryl, the two can optionally be substituted.
46. the method for claim 45 further comprises formula XIXa compound is placed under the closed loop condition, forms formula Ia and replaces De oxazoline compound, R wherein 1, R 3And R 4Definition is with claim 45.
47. the method for preparation formula XIXb compound,
Figure A9880952600151
Said method comprises: hydrogenation of formula XVIIIb azide chemical compound,
Figure A9880952600152
Wherein, in formula XIXb and XVIIIb,
R 1Be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkaryl, aralkyl, wherein said aryl, any one loop section can optionally be substituted in aralkyl or the alkaryl;
R 3Be alkyl, cycloalkyl, aryl, alkaryl, wherein any one can optionally be substituted; And
R 4Be aryl or heteroaryl, the two can optionally be substituted.
48. the method for claim 47 further comprises formula XIXb compound is placed under the closed loop condition, forms formula Ib and replaces De oxazoline compound, R wherein 1, R 3And R 4Definition is with claim 47.
49. formula VI or VII compound or their salt, Wherein
R 1Be C 1-12Alkyl, C 3-8Cycloalkyl, C 2-8Alkenyl, C 2-8Alkynyl, C 6-14Aryl, C 6-10Aryl (C 1-6) alkyl or C 1-6Alkyl (C 6-10) aryl;
R 2Be C 2-6Alkyl; And
R 7Be alkyl, aryl, aralkyl, alkaryl, wherein any one can optionally be substituted.
50. the compound of claim 49, wherein R 1Be C 1-4Alkyl.
51. the compound of claim 50, wherein R 1It is sec.-propyl.
52. the compound of claim 49, wherein R 2Be ethyl, n-propyl, normal-butyl or isobutyl-.
53. the compound of claim 52, wherein R 2It is ethyl.
54. the compound of claim 52, wherein R 2It is n-propyl.
55. the compound of claim 52, wherein R 2It is normal-butyl.
56. the compound of claim 52, wherein R 2It is isobutyl-.
57. the formyl radical methane amide of formula XIV enantiomorph enrichment or its salt, Wherein
R 2Be C 1-8Alkyl, C 3-8Cycloalkyl, C 2-8Alkenyl, C 2-8Alkynyl, C 6-14Aryl, C 6-10Aryl (C 1-6) alkyl or C 1-6Alkyl (C 6-10) aryl; And
R 5And R 6Be respectively C 1-6Alkyl, C 6-10Aryl (C 1-6) alkyl or C 1-6Alkyl (C 6-10) aryl, or coupled nitrogen-atoms forms a 5-7 element heterocycle together, and this heterocycle can optionally be substituted, and can optionally contain another Sauerstoffatom or nitrogen-atoms.
58. a pharmaceutical composition comprises compound and pharmaceutically acceptable carrier or the thinner of one of claim 49-56.
59. formula II compound or its salt, Wherein
R 1Be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkaryl, aralkyl, wherein said aryl, any one loop section can optionally be substituted in aralkyl or the alkaryl;
R 2Be alkyl, cycloalkyl, aryl, alkaryl, aralkyl, alkoxyl group, hydroxyl, alkoxyalkyl or amido, wherein said aryl, any one loop section can optionally be substituted in aralkyl or the alkaryl;
R 3Be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkaryl, wherein any one can optionally be substituted;
R 4It is aryl that optionally replaces or the heteroaryl that optionally replaces; And
R 5And R 6Be respectively one of alkyl or alkaryl; Or R 5And R 6Coupled nitrogen-atoms forms one together and can optionally substituted 5-7 person encircle, and this ring also optionally contains another Sauerstoffatom or nitrogen-atoms.
60. the compound of claim 59, wherein
R 1Be C 1-12Alkyl, C 3-8Cycloalkyl, C 2-8Alkenyl, C 2-8Alkynyl, C 6-14Aryl, C 6-10Aryl (C 1-6) alkyl or C 1-6Alkyl (C 6-10) aryl, wherein said aryl, any one loop section can optionally be substituted in aralkyl or the alkaryl;
R 2Be C 1-8Alkyl, C 3-8Cycloalkyl, C 2-8Alkenyl, C 2-8Alkynyl, C 6-14Aryl, C 6-10Aryl (C 1-6) alkyl or C 1-6Alkyl (C 6-10) aryl, wherein said aryl, any one loop section can optionally be substituted in aralkyl or the alkaryl;
R 3Be C 1-8Alkyl, C 3-8Cycloalkyl, C 2-8Alkenyl, C 2-8Alkynyl, C 6-14Aryl, C 6-10Aryl (C 1-6) alkyl or C 1-6Alkyl (C 6-10) aryl, wherein any one can optionally be substituted;
R 4Be optionally substituted C 6-10Aryl, or following optionally substituted heteroaryl: thienyl, benzo [b] thienyl, furyl, pyranyl, isobenzofuran-base, benzoxazolyl, 2H-pyrryl, pyrryl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, indolizine base, pseudoindoyl, 3H-indyl, indyl, indazolyl, purine radicals, 4H-quinolizinyl, isoquinolyl, quinolyl or triazolyl; And
R 5And R 6Be respectively C 1-6Alkyl, C 6-10Aryl (C 1-6) alkyl or C 1-6Alkyl (C 6-10) aryl, or coupled nitrogen-atoms forms a 5-7 element heterocycle together, and this heterocycle can optionally be substituted, and can optionally contain another Sauerstoffatom or nitrogen-atoms.
61. the formula III compound or its salt,
Figure A9880952600181
Wherein
R 1Be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkaryl, aralkyl, wherein said aryl, any one loop section can optionally be substituted in aralkyl or the alkaryl;
R 2Be alkyl, cycloalkyl, aryl, alkaryl, aralkyl, alkoxyl group, hydroxyl, alkoxyalkyl or amido, wherein said aryl, any one loop section can optionally be substituted in aralkyl or the alkaryl;
R 3Be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkaryl, wherein any one can optionally be substituted; And
R 5And R 6Be respectively one of alkyl or alkaryl; Or R 5And R 6Coupled nitrogen-atoms forms one together can optionally substituted 5-7 element heterocycle, and this heterocycle can optionally contain another Sauerstoffatom or nitrogen-atoms.
62. the compound of claim 61, wherein
R 1Be C 1-12Alkyl, C 3-8Cycloalkyl, C 2-8Alkenyl, C 2-8Alkynyl, C 6-14Aryl, C 6-10Aryl (C 1-6) alkyl or C 1-6Alkyl (C 6-10) aryl, wherein said aryl, any one loop section can optionally be substituted in aralkyl or the alkaryl;
R 2Be C 1-8Alkyl, C 3-8Cycloalkyl, C 2-8Alkenyl, C 2-8Alkynyl, C 6-14Aryl, C 6-10Aryl (C 1-6) alkyl or C 1-6Alkyl (C 6-10) aryl, wherein said aryl, any one loop section can optionally be substituted in aralkyl or the alkaryl;
R 3Be C 1-8Alkyl, C 3-8Cycloalkyl, C 2-8Alkenyl, C 2-8Alkynyl, C 6-14Aryl, C 6-10Aryl (C 1-6) alkyl or C 1-6Alkyl (C 6-10) aryl, wherein any one can optionally be substituted; And
R 5And R 6Be respectively C 1-6Alkyl, C 6-10Aryl (C 1-6) alkyl or C 1-6Alkyl (C 6-10) aryl, or coupled nitrogen-atoms forms a 5-7 element heterocycle together, and this heterocycle can optionally be substituted, and can optionally contain another Sauerstoffatom or nitrogen-atoms.
63. formula XVIIa or XVIIb compound or its salt,
Figure A9880952600191
Wherein
R 1Be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkaryl, aralkyl, wherein said aryl, any one loop section can optionally be substituted in aralkyl or the alkaryl;
R 2Be Cl, Br or I;
R 3Be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkaryl, wherein any one can optionally be substituted; And
R 4It is aryl that optionally replaces or the heteroaryl that optionally replaces.
64. formula XVIIIa or XVIIIb compound or its salt,
Figure A9880952600201
Wherein
R 1Be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkaryl, aralkyl, wherein said aryl, any one loop section can optionally be substituted in aralkyl or the alkaryl;
R 3Be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkaryl, wherein any one can optionally be substituted; And
R 4It is aryl that optionally replaces or the heteroaryl that optionally replaces.
65. the formyl radical methane amide of formula XIV enantiomorph enrichment or the preparation method of its salt,
Figure A9880952600202
Wherein
R 2Be alkyl, cycloalkyl, aryl, alkaryl, aralkyl, alkoxyl group, hydroxyl, alkoxyalkyl or amido, wherein said aryl, any one loop section can optionally be substituted in aralkyl or the alkaryl; And
R 5And R 6Be respectively one of alkyl or alkaryl; Or R 5And R 6Coupled nitrogen-atoms forms one together can optionally substituted 5-7 element heterocycle, and this heterocycle can optionally contain another Sauerstoffatom or nitrogen-atoms; Said method comprises:
(a) use R 2CH 2The negatively charged ion of COCl acidylate formula VIII compound, R wherein 8Be sec.-propyl or benzyl, form formula IX Xian oxazolidinone,
Figure A9880952600212
R wherein 2And R 8Definition as above;
(b) formula IX Xian oxazolidinone and benzyloxymethyl chlorine are carried out stereospecific reaction, form the alcohol of formula X protection, R wherein 2And R 8Definition as above;
(c) alcohol of hydrolyzing type X protection forms formula XI carboxylic acid, R wherein 2Definition as above;
(d) with said formula XI acid and acid amides R 5R 6NH 2Coupling obtains formula XII acid amides,
Figure A9880952600222
R wherein 2, R 5And R 6Definition as above;
(e) catalytic hydrogenation formula XII acid amides forms formula XIII alcohol,
Figure A9880952600223
R wherein 2, R 5And R 6Definition as above; And
(f) the formula XIII alcohol of oxidation gained obtains formula XIV formyl radical methane amide.
66. the compound of claim 65, wherein
R 2Be C 1-8Alkyl, C 3-8Cycloalkyl, C 2-8Alkenyl, C 2-8Alkynyl, C 6-14Aryl, C 6-10Aryl (C 1-6) alkyl or C 1-6Alkyl (C 6-10) aryl; And
R 5And R 6Be respectively C 1-6Alkyl, C 6-10Aryl (C 1-6) alkyl or C 1-6Alkyl (C 6-10) aryl, or coupled nitrogen-atoms forms a 5-7 element heterocycle together, and this heterocycle can optionally be substituted, and can optionally contain another Sauerstoffatom or nitrogen-atoms.
67. suppress the method for intracellular protein body function, comprise said cell is contacted with the compound of claim 49.
68. suppress the method for proteoplast function in the Mammals, comprise compound to the claim 49 of said administration arrestin body function significant quantity.
69. the method for treatment inflammation comprises 49 compounds of using the claim of anti-inflammatory significant quantity to the patient.
70. the treatment method for cancer comprises the compound of using the claim 49 of antitumor or anti-metastasis significant quantity to the patient.
71. the method for treatment Mammals local asphyxia or reperfusion injury comprises the compound to the claim 49 of said administration significant quantity.
72. the method for claim 71, wherein local asphyxia is the result of vascular occlusion.
73. the method for claim 71, wherein said vascular occlusion occurs in during the apoplexy.
CN98809526A 1997-08-15 1998-08-14 Synthesis of clasto-lactacystin-beta-lactone and analogs thereof Pending CN1271342A (en)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US91211197A 1997-08-15 1997-08-15
US5584897P 1997-08-15 1997-08-15
US6735297P 1997-12-03 1997-12-03
US60/055,848 1997-12-03
US60/067,352 1997-12-03
US08/912,111 1997-12-03

Publications (1)

Publication Number Publication Date
CN1271342A true CN1271342A (en) 2000-10-25

Family

ID=27368920

Family Applications (1)

Application Number Title Priority Date Filing Date
CN98809526A Pending CN1271342A (en) 1997-08-15 1998-08-14 Synthesis of clasto-lactacystin-beta-lactone and analogs thereof

Country Status (11)

Country Link
EP (1) EP1021407A4 (en)
JP (1) JP2001515064A (en)
KR (1) KR20010022950A (en)
CN (1) CN1271342A (en)
AU (1) AU749857B2 (en)
BR (1) BR9811304A (en)
CA (1) CA2301054A1 (en)
HU (1) HUP0002724A3 (en)
IL (1) IL134538A (en)
NZ (1) NZ503169A (en)
WO (1) WO1999009006A1 (en)

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2402045T3 (en) 2000-11-16 2013-04-26 The Regents Of The University Of California Marine actionomycete taxon for the discovery of drugs and fermentation products
CA2443813A1 (en) * 2001-04-09 2002-10-17 Allan Christian Shaw Method for identification of proteins from intracellular bacteria
US7179834B2 (en) 2002-06-24 2007-02-20 The Regents Of The University Of California Salinosporamides and methods for use thereof
US7176232B2 (en) 2002-06-24 2007-02-13 The Regents Of The University Of California Salinosporamides and methods for use thereof
WO2004012732A2 (en) * 2002-07-31 2004-02-12 Charité-Universitätsmedizin Berlin Use of a proteasome inhibitor in the treatment of endothelial dysfunction and/or in a low-dose proteasome inhibitor therapy
PL2441767T3 (en) 2003-06-20 2015-11-30 Univ California Salinosporamides and methods for use thereof
AU2004253478A1 (en) 2003-06-20 2005-01-13 Nereus Pharmaceuticals, Inc. Use of [3.2.0] heterocyclic compounds and analogs thereof for the treatment of cancer, inflammation and infectious diseases
MXPA06012421A (en) 2004-04-30 2007-01-31 Nereus Pharmaceuticals Inc Heterocyclic compounds and methods of using the same.
US7579371B2 (en) 2004-04-30 2009-08-25 Nereus Pharmaceuticals, Inc. Methods of using [3.2.0] heterocyclic compounds and analogs thereof
DK1830838T3 (en) 2004-12-03 2013-01-21 Dana Farber Cancer Inst Inc Compositions and Methods for Treating Neoplastic Diseases
US7842814B2 (en) 2006-04-06 2010-11-30 Nereus Pharmaceuticals, Inc. Total synthesis of salinosporamide A and analogs thereof
WO2008095195A2 (en) 2007-02-02 2008-08-07 Nereus Pharmaceuticals, Inc. Lyophilized formulations of salinosporamide a
US8394816B2 (en) 2007-12-07 2013-03-12 Irene Ghobrial Methods of using [3.2.0] heterocyclic compounds and analogs thereof in treating Waldenstrom's Macroglobulinemia
MX2010009860A (en) 2008-03-07 2010-09-30 Nereus Pharmaceuticals Inc Total synthesis of salinosporamide a and analogs thereof.
KR20110011645A (en) 2008-05-12 2011-02-08 니리어스 파마슈티컬즈, 인코퍼레이션 Salinosporamide derivatives as proteasome inhibitors

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU7008896A (en) * 1995-08-21 1997-03-12 Duke University A method to increase the density of antigen on antigen presenting cells

Also Published As

Publication number Publication date
AU8906298A (en) 1999-03-08
WO1999009006A1 (en) 1999-02-25
NZ503169A (en) 2001-12-21
IL134538A0 (en) 2001-04-30
KR20010022950A (en) 2001-03-26
AU749857B2 (en) 2002-07-04
IL134538A (en) 2005-11-20
EP1021407A4 (en) 2001-07-04
EP1021407A1 (en) 2000-07-26
HUP0002724A3 (en) 2001-04-28
HUP0002724A2 (en) 2001-02-28
CA2301054A1 (en) 1999-02-25
BR9811304A (en) 2001-11-13
JP2001515064A (en) 2001-09-18

Similar Documents

Publication Publication Date Title
US6294560B1 (en) Synthesis of clasto-lactacystin β-lactone and analogs thereof
CN1271342A (en) Synthesis of clasto-lactacystin-beta-lactone and analogs thereof
CN1305839C (en) Phenylglycine derivatives
CN1061046C (en) Process for preparing cephalosporins derivants
CN1122105A (en) Treatment of tumors with compounds having RXR retinoid receptor agonist activity
CN1034176C (en) Tetrahydropyrrolo (1,2-a) pyrazine-4-spiro-3'-pyrrolidine derivatives, processes for preparation thereof and pharmaceutical compositions containing same
CN1304447A (en) Treatment of parasitic diseases by inhibition of cysteine proteases of papain superfamily
CN1372566A (en) Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis
CN1205328A (en) Sulfonylaminocarboxylic acids
CN1331076A (en) Condensed pyrazole compound, composition containing it and its application
CN1956951A (en) Method for producing diphenyl azetidinone derivatives
CN1278809A (en) Substituted benzodihydropyran derivatives
CN1343217A (en) New amidinobenzylamine derivatives and their use as thrombin inhibitors
CN1031619C (en) Oxazolidone derivative
CN1043042C (en) Cephalosporins derivatives and process for preparing them
CN1291197A (en) Novel acetamide derivative and use thereof
CN1099032A (en) Benzo-oxazine derivative, its preparation method and medicinal
EP1726586A1 (en) Dihydronaphthalene derivative compounds and agent comprising the derivative as active ingredient
CN1203074C (en) Pentacycle taxane compounds
CN1252049A (en) 2-substituted benzoyl-cycloalkyl-1-carboxylic acid derivatives
CN1118476C (en) Antiviral protease inhibitors
CN1377269A (en) Vitronectin receptor antagonists
CN1191528A (en) Benzocycloalkene compounds with melatonine receptor binding affinity, their production and use
CN1239944A (en) New pentaerythritol derivatives, their production, and use and intermdiates for their synthesis
CN1109880A (en) 3-(2-aminoethyl)-4-[3-(trifluoromethyl) benzoyl]-3,4-dihydro-1,4-benzoxazine derivative and preparation of same

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C53 Correction of patent of invention or patent application
CB02 Change of applicant information

Applicant after: MIllennium Pharmaceuticals Inc

Applicant before: F * Sousi

Applicant before: L * Pramonton

Applicant before: M * Bienke

Applicant before: W * Luo Shi

COR Change of bibliographic data

Free format text: CORRECT: APPLICANT; FROM: F. SAUCY L. PLAMONDON; M. BEHNKE W-HISTORY TO: MILLENNIUM MEDICINE CO.,LTD.

C02 Deemed withdrawal of patent application after publication (patent law 2001)
WD01 Invention patent application deemed withdrawn after publication