CN1197452A - Azetidinone derivatives for treatment of atherosclerosis - Google Patents

Azetidinone derivatives for treatment of atherosclerosis Download PDF

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Publication number
CN1197452A
CN1197452A CN96196661A CN96196661A CN1197452A CN 1197452 A CN1197452 A CN 1197452A CN 96196661 A CN96196661 A CN 96196661A CN 96196661 A CN96196661 A CN 96196661A CN 1197452 A CN1197452 A CN 1197452A
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oxo
azetidin
benzyl
diastereomer
hexyl
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CN96196661A
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Chinese (zh)
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D·哈纳
D·M·B·希克伊
R·J·伊菲
C·A·利奇
D·G·图
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SmithKline Beecham Ltd
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SmithKline Beecham Ltd
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Priority claimed from GBGB9513442.5A external-priority patent/GB9513442D0/en
Priority claimed from GBGB9515056.1A external-priority patent/GB9515056D0/en
Priority claimed from GBGB9515206.2A external-priority patent/GB9515206D0/en
Priority claimed from GBGB9516985.0A external-priority patent/GB9516985D0/en
Priority claimed from GBGB9525132.8A external-priority patent/GB9525132D0/en
Priority claimed from GBGB9608651.7A external-priority patent/GB9608651D0/en
Priority claimed from GBGB9608650.9A external-priority patent/GB9608650D0/en
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of CN1197452A publication Critical patent/CN1197452A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C07D205/085—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a nitrogen atom directly attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C07D205/09—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a sulfur atom directly attached in position 4
    • C07D205/095—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a sulfur atom directly attached in position 4 and with a nitrogen atom directly attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

Azetidinone compounds of formule (I) in which: R<1> and R<2>, which may be the same or different, is each selected from hydrogen, halogen or C(1-8)alkyl; R<4> and R<5> which may be the same or different is each selected from hydrogen, C(1-6)alkyl, C(2-6)alkenyl, aryl, aryl(C1-4)alkyl and heteroaryl(C1-4)alkyl each of which may be optionally substituted or R<4> and R<5> may be linked together to form the remainder of a (C3-7)cycloalkyl ring; X is a linker group; Y is an optionally substituted aryl group; Z is oxygen and R<3> is C(1-8)alkyl, C(3-8)cycloalkyl, C(3-8)cycloalkylC(1-6)alkyl, heteroaryl, heteroaryl(C1-4)alkyl, aryl, or aryl(C1-4)alkyl, each of which may be optionally substituted or Z is S(O)n in which n is 0, 1 or 2 and R<3> is C(1-8)alkyl, C(3-8)cycloalkyl, C(3-8)cycloalkylC(1-6)alkyl, aryl, aryl(C1-4)alkyl, heteroaryl, or heteroaryl(C1-4)alkyl, each of which may be optionally substituted are inhibitors of the enzyme Lp PLA2 and are of use in therapy, in particular treating atherosclerosis.

Description

Be used for the treatment of atherosclerotic azetidinone derivatives
The present invention relates to some novel monocycle beta-lactam compound, its preparation method is used for the intermediate of its preparation, contain they pharmaceutical composition and they in treatment, especially treat the purposes in the atherosclerosis.
Lipoprotein and phospholipase A 2(Lp-PlA 2) relevant.The sequence of enzyme, its separation and purifying, the nucleic acid of separated coding enzyme, the reorganization main body cell that transforms with the DNA of codase is described in patent application WO95/00649 (Smith Kline Beecham plc).The therepic use that is used as the suggestion of enzyme inhibitors comprises atherosclerosis, diabetes, rheumatic arthritis, apoplexy, myocardial infarction, reperfusion injury and acute and chronic inflammation.Back one patent application (WO95/09921; IcosCorporation) with " nature " (people such as Tjoelker; 374 volumes; 6; April 1995; 549) relevantly in open same enzyme has been described, although be called " platelet activation factor ethanoyl lytic enzyme " (PAF ethanoyl lytic enzyme) and hint that it may have as being used to regulate the treatment albumen of pathology inflammation.
Lp-PlA 2When low-density lipoprotein (LDL) is converted into the form of its oxidation, phosphatidylcholine is responsible for to the conversion of lyso-phosphatidylcholine.The sn-2 ester of the phosphatidylcholine of the known hydrolysis oxidation of this enzyme provides the lipid acid of lyso-phosphatidylcholine and oxidative modification.Lp-PlA 2Two products of effect all are bioactive, lyso-phosphatidylcholine, and the composition of the LDL of oxidation, known is the chemical attractant of circulating monocytic cell.Therefore, lyso-phosphatidylcholine is considered to by playing an important role in atherosclerosis for stimulation cell of load cholesteryl ester in artery.Thereby expectation Lp-PlA 2The inhibition of enzyme stops the foundation (formation of the free fatty acids by suppressing lyso-phosphatidylcholine and oxidation) of the damage of these scavenger cell enrichments, and therefore is used for the treatment of atherosclerosis.
The lyso-phosphatidylcholine content of the LDL that the oxidisability that increases is modified also is considered to be responsible for suffering from the observed endothelial dysfunction of atherosclerotic patient.Lp-PlA 2Therefore inhibitor can prove when this phenomenon of treatment favourable.Lp-PlA 2Inhibitor also can comprise diabetes in other illness that shows endothelial dysfunction, hypertension, stenocardia and local asphyxia and find purposes after the perfusion again.
Lp-PlA 2Inhibitor also comprises the activatory monocyte in any disease, has general application in scavenger cell or the lymphocyte, and all these cell types are all expressed Lp-PlA 2This class examples of disorders comprises psoriasis.
Lp-PlA 2Inhibitor also has general application in any disease, comprise liposome peroxidation thing and Lp-PlA 2Active in producing two deleterious products, the lipid acid that lyso-phosphatidylcholine and oxidisability are modified.This class illness comprises aforementioned illness atherosclerosis, diabetes, rheumatic arthritis, apoplexy, encephalitis disease such as Alzheimer ' s disease, myocardial infarction, reperfusion injury, sepsis and acute and chronic inflammation.Other this class illness comprises various neuropsychopathys such as schizophrenia (see the psychopharmacology communique, 31,159-165,1995).
We are now definite a series of to be found as Lp-PlA 2The compound of inhibitor.
Correspondingly, the invention provides formula (I) compound:
Figure A9619666100181
Wherein: R 1And R 2, identical or different, be selected from hydrogen separately, halogen or C (1-8)Alkyl; R 4And R 5Can be identical or different, be selected from hydrogen separately, C (1-6)Alkyl, C (2-6)Thiazolinyl, aryl, aryl (C 1-4) alkyl and heteroaryl (C 1-4) alkyl, they can be substituted separately non-imposedly, or R 4And R 5Can be joined together to form (C 3-7) remainder of cycloalkyl ring; X connects base; Y is the aryl of non-imposed replacement; Z is oxygen and R 3Be C (1-8)Alkyl, C (3-8)Cycloalkyl, C (3-8)Cycloalkyl C (1-6)Alkyl, heteroaryl, heteroaryl (C 1-4) alkyl, aryl, aryl (C 1-4) alkyl, they can be replaced separately non-imposedly, or Z be S (O) n wherein n be 0,1 or 2, and R 3Be C (1-8)Alkyl, C (3-8)Cycloalkyl, C (3-8)Cycloalkyl C (1-6)Alkyl, aryl, aryl (C 1-4) alkyl, heteroaryl, heteroaryl (C 1-4) alkyl, they can be replaced separately non-imposedly; And get rid of following compound wherein: X is direct key; Radicals X 1(CH 2) m X wherein 1Be CO, CONR 6, COO, CONR 6CO, or CONR 6O is R wherein 6With m such as preceding definition; Or it is non-imposed by X 1The C that inserts (1-12)Alkylidene chain; Z be S (O) n wherein n be 0,1 or 2 and R 3Be C (1-8)Alkyl, C (3-8)Cycloalkyl, C (3-8)Cycloalkyl C (1-6)Alkyl, aryl or aryl (C 1-4) alkyl, they can be replaced separately non-imposedly; And R 4And R 5Each is hydrogen naturally.
Suitably, X is direct key; Radicals X 1(CH 2) m X wherein 1Be CO, CONR 6, COO, CONR 6CO, or CONR 6O is R wherein 6Be hydrogen or C (1-6)Alkyl and m are 0 or 1 to 12 integers; Group (X 1) aX 2Wherein a is 0 or 1 and X 2Be with the Y neighboring terminals by one or more O of being selected from, S (O) x, NR 6, the X of alkenyl or alkynyl 3Base inserts or terminated C (1-12)Alkylidene chain, wherein x is 0,1 or 2; Or it is non-imposed by X 1The C that inserts (1-12)Alkylidene chain;
Suitable the next compound in formula (I) scope comprises such compound, and wherein: (a) X is direct key; X as preceding definition 1(CH 2) m; Group (X as preceding definition 1) aX 2Or it is non-imposed by X 1The C that inserts (1-12)Alkylidene chain; Z is oxygen and R 3Be C (1-8)Alkyl, C (3-8)Cycloalkyl, C (3-8)Cycloalkyl C (1-6)Alkyl, heteroaryl, heteroaryl (C 1-4) alkyl, aryl, aryl (C 1-4) alkyl, they can be replaced separately non-imposedly, or Z be S (O) n wherein n be 0,1 or 2, and R 3Be heteroaryl or heteroaryl (C 1-4) alkyl, they can be replaced separately non-imposedly; R 4And R 5As preceding definition; Or (b) X is direct key; X as preceding definition 1(CH 2) m; Group (X as preceding definition 1) aX 2Or it is non-imposed by X 1The C that inserts (1-12)Alkylidene chain; Z be S (O) n wherein n be 0,1 or 2, and R 3Be C (1-8)Alkyl, C (3-8)Cycloalkyl, C (3-8)Cycloalkyl C (1-6)Alkyl, aryl or aryl (C 1-4) alkyl, they can be replaced separately non-imposedly; R 4And R 5Can be identical or different, be selected from hydrogen separately, C (1-6)Alkyl, C (2-6)Thiazolinyl, aryl, aryl (C 1-4) alkyl and heteroaryl (C 1-4) alkyl, they can be substituted separately non-imposedly, or R 4And R 5Can be joined together to form (C 3-7) remainder of cycloalkyl ring, condition is R 4And R 5Be not hydrogen simultaneously; Or (c) X is group (X as preceding definition 1) aX 2Z be S (O) n wherein n be 0,1 or 2, and R 3Be C (1-8)Alkyl, C (3-8)Cycloalkyl, C (3-8)Cycloalkyl C (1-6)Alkyl, aryl or aryl (C 1-4) alkyl, they can be replaced separately non-imposedly; R 4And R 5Each is hydrogen naturally.
Formula (I) compound is Lp-PLA 2Inhibitor, and wish to be used for the treatment of atherosclerosis and other above-mentioned illness.
R 1And R 2Representational example comprises hydrogen, bromine, methyl and ethyl.Suitably, R 1And R 2Each is hydrogen or R naturally 1And R 2One of be hydrogen and another is methyl (providing trans-methyl).Preferably, R 1And R 2Each is hydrogen naturally.
Work as R 3Be aryl (C 1-4) its representational value comprises aryl (C during alkyl 1-3) alkyl, wherein, the representative example of aryl comprises phenyl and naphthyl.R 3Suitable example comprises benzyl, 2-phenylethyl and 3-phenyl propyl, and phenyl ring can be by maximum 3 non-imposed replacements of substituting group therein.At R 3In suitable substituent when being used for the phenyl or naphthyl ring comprise halogen, hydroxyl, C (1-6)Alkyl, C (1-6)Alkoxyl group, C (1-6)Alkoxy carbonyl, C (2-6)Allyloxycarbonyl, carboxyl, carboxyl C (1-6)Alkyl and C (1-6)Alkoxy carbonyl C (1-6)Alkyl.More preferably, R 3Be 4-carboxyl benzyl or its corresponding C (1-6)Alkyl or C (2-6)Alkenyl esters.
Work as R 3Its representational example comprises phenyl and naphthyl when being aryl.Preferably, aryl is the phenyl of non-imposed replacement.The suitable substituent that is used for the phenyl or naphthyl ring comprises halogen, hydroxyl, C (1-6)Alkyl, C (1-6)Alkoxyl group, C (1-6)Alkoxy carbonyl, C (2-6)Allyloxycarbonyl, carboxyl, carboxyl C (1-6)Alkyl and C (1-6)Alkoxy carbonyl C (1-6)Alkyl.
Work as R 3Be C (1-8)Alkyl, C (3-8)Cycloalkyl or C (3-8)Cycloalkyl C (1-6)During alkyl, R 3Representative example comprise methyl, normal-butyl, the tertiary butyl and n-hexyl, cyclohexyl and cyclohexyl methyl are normal-butyl, the tertiary butyl or n-hexyl suitably.At R 3In be used for alkyl or cycloalkyl suitable substituent comprise halogen, hydroxyl, C (1-6)Alkyl, C (1-6)Alkoxyl group, C (1-6)Alkoxy carbonyl, C (2-6)Allyloxycarbonyl, carboxyl, carboxyl C (1-6)Alkyl and C (1-6)Alkoxy carbonyl C (1-6)Alkyl.
For R 3Further value comprises heteroaryl C (1-3)Alkyl, preferred heteroaryl methyl.Be used for R 3In the representative example of heteroaryl comprise pyridyl, pyridyl N-oxide compound, furyl, thienyl and thiazolyl.At R 3In suitable substituents on heteroaryl ring comprise halogen, hydroxyl, C (1-6)Alkyl, C (1-6)Alkoxyl group, C (1-6)Alkoxy carbonyl, C (2-6)Allyloxycarbonyl, carboxyl, carboxyl C (1-6)Alkyl and C (1-6)Alkoxy carbonyl C (1-6)Alkyl.
Should be understood that at R 3In, non-imposed substituting group can be connected alkyl, cycloalkyl, aryl and/or heteroaryl moieties.Preferably, substituting group is carboxyl or its C (1-6)Alkyl or C (2-6)Alkenyl esters.
Preferably, R 3Be aryl C (1-3)Alkyl or heteroaryl C (1-3)Alkyl, more preferably aryl C (1-3)Alkyl, benzyl most preferably, it can be substituted non-imposedly, especially by carboxyl or its C (1-6)Alkyl or C (2-6)Alkenyl esters replaces.
Preferably, Z is S (O) n.Preferably, n is 1 or 2, more preferably 1.
Preferably, S (O) nR 3Be the benzyl sulfinyl of non-imposed replacement, more preferably 4-carboxyl benzyl sulfinyl or its C (1-6)Alkyl or C (2-6)Alkenyl esters.
Work as R 4And R 5Its representational example comprises methyl when being alkyl, ethyl and propyl group.C (2-6)The representative example of thiazolinyl comprises allyl group.(C 3-7) representative example of cycloalkyl ring comprises cyclopropyl.Aryl C (1-4)Alkyl or heteroaryl C (1-4)The representative example of alkyl comprises benzyl and furyl methyl respectively.Work as R 4And R 5Its representative example comprises phenyl and benzyl when being aryl or aralkyl.Suitable, R 4And R 5All be hydrogen or R 4Be hydrogen and R 5It is methyl.
The representative example of X comprises CO (CH 2) m, CONH (CH 2) m, COO (CH 2) m, CONHCO (CH 2) m, CONHO (CH 2) m, and C (1-12)Alkylidene group.Preferably, X 1Be CO or CONR 6, more preferably CONH.Preferably, m is 1,2,5,6,7 or 9, preferred 6.
The further representative example of X comprises X 4(CH 2) pCH=CH (CH 2) q, X 4(CH 2) pCH ≡ CH (CH 2) q, or X 4(CH 2) p (O) r (CH 2) q (O) s X wherein 4Be direct key or CONR 6, p is 1 to 12 integer, q is 0 or 1 to 12 integer, and p+q≤12, suitably≤6, r is 0 or 1 and s is 1, or r is 1 and s is 0, condition is that r and s are 1, then q 〉=1.In the next preferred example of this compound, X is CONR 6(CH 2) 4C ≡ C or (CH 2) O (CH 2) 6
The preferred example of X comprises CONH (CH 2) 6, CONR 6(CH 2) 4C ≡ C and (CH 2) O (CH 2) 6
Suitably, Y is a phenyl ring, is replaced by maximum 3 substituting groups non-imposedly.Suitable substituents comprises halogen, hydroxyl, C (1-8)Alkyl and C (1-8)Alkoxyl group.Preferably, the phenyl that forcibly replaced of Y right and wrong by halogen.
The substituent useful combination that is used for formula (I) compound of giving an example at this paper is listed in the table below: R 3R 4R 5X4-carboxyl-benzyl sulfinyl hydrogen methyl CONH (CH 2) 65-carboxyl furans-2-methylsulfinyl hydrogen hydrogen CONH (CH 2) 6Benzyl sulfinyl hydrogen hydrogen (CH 2) O (CH 2) 6Benzyl sulfinyl hydrogen hydrogen CONR 6(CH 2) 4C ≡ C
Radicals R wherein 3The formula of doping carboxyl substituent (I) compound is found in the body inner model prevailingly, has improved activity for the target enzyme, especially for suppressing and Lp PLA 2The superpower ability of relevant spot.In this class research, if also find beginning with alkyl or alkenyl ester " prodrug " administration, this compounds has the better medicament kinetic property.This ester group is rapid hydrolysis release free carboxyl in liver then.Usually, have the substituent compound of Alpha-Methyl, i.e. R wherein 4/ R 5One of be that the compound of methyl is than corresponding demethylation compound effective force more.
Should understand easily on this professional people, the C-4 of beta-lactam nucleus is a chiral centre, and this will cause stereomeric existence.The present invention includes all these steric isomers.Work as R 4And R 5Not simultaneously, extra chiral centre will do not imported.This will cause extra stereomeric existence.The present invention includes all these steric isomers.
This professional person also should understand easily, and n is in 1 formula (I) compound therein, promptly in the sulfoxide compound, in the chiral centre introducing molecule that the existence of SO part will be extra, thereby causes the existence of extra steric isomer.The present invention includes all these steric isomers.
In preferred formula (I) compound, be respectively R and S at C-4 and SO absolute configuration partly.Working as R 4=H, R 5In preferred formula (I) compound of=Me, (connect R in the above at alpha-carbon 5) on absolute configuration be S.
In this article, term " alkyl " and similar terms comprise all straight chains and branched chain isomer as " alkoxyl group ".Its representative example comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl and n-hexyl.
For alkyl, suitable substituents comprises halogen, cyano group, azido-, nitro, carboxyl, (C 1-6) alkoxy carbonyl, formamyl, one-or two-(C 1-6) alkyl-carbamoyl, sulfo group, amino-sulfonyl, one-or two-(C 1-6) alkyl amino sulfonyl, amino, one-or two-(C 1-6) alkylamino, acyl amino, urea groups, (C 1-6) alkoxycarbonyl amino, 2,2,2-trichlorine ethoxy carbonyl amino, aryl, heteroaryl, hydroxyl, (C 1-6) alkoxyl group, acyloxy, oxo base, acyl group, 2-Thenoyl, (C 1-6) alkylthio, (C 1-6) alkyl sulphinyl, (C 1-6) alkyl sulphonyl, oxyimino, (C 1-6) Alkoximino, diazanyl, hydrazono-, benzo hydroxyl oxime acyl group, guanidine radicals, amido and imino alkyl amino.
Unless otherwise indicated, term used herein " aryl " comprises, at the most by 5, and the preferred phenyl or naphthyl of 3 non-imposed replacements of substituting group at the most.
Comprise for the aryl suitable substituents, for example, halogen, cyano group, (C 1-6) alkyl, (C 3-7) cycloalkyl, (C 1-6) alkoxyl group, halo (C 1-6) alkyl, hydroxyl, amino, one-or two-(C 1-6) alkylamino, amido, nitro, carboxyl, (C 1-6) alkoxy carbonyl, (C 1-6) allyloxycarbonyl, (C 1-6) alkoxy carbonyl (C 1-6) alkyl, (C 1-6) the alkyl-carbonyl oxygen base, carboxyl (C 1-6) alkoxyl group, (C 1-6) the alkyl-carbonyl oxygen base, (C 1-6) alkylthio, (C 1-6) alkyl sulphinyl, (C 1-6) alkyl sulphonyl, amino-sulfonyl, one-or two-(C 1-6) alkyl amino sulfonyl, formamyl, one-or two-(C 1-6) alkyl-carbamoyl, and heterocyclic radical.
Term used herein " heteroaryl " comprises single and condensed ring, and each ring comprises 4 at the most suitably, preferred 1 or 2, is selected from oxygen separately, the heteroatoms of nitrogen and sulphur.Each ring can have 4 to 7, preferred 5 or 6 annular atomses.The condensed hetero-aromatic ring can comprise carbocyclic ring and need include only a hetero-aromatic ring.Suitable fused heteroaromatic ring comprises bicyclic system.
Term used herein " heterocyclic radical " comprises that having at the most four is selected from oxygen, nitrogen and sulphur be positioned at heteroatomic aromatics and non-aromatic monocyclic or fused rings on the ring, and non-imposedly replaced by 3 substituting groups at the most.Suitable heterocycle comprises 4-7, preferred 5-6 annular atoms.The annelated heterocycles system comprises carbocyclic ring, and need include only a heterocycle.
When being substituted, heteroaryl or heterocyclic radical can have 3 substituting groups at the most.Those that this suitable class substituting group comprises that the front is mentioned for aryl and oxo base.Term used herein " halogen " and " halogen atom " comprise fluorine respectively, chlorine, bromine and iodine and fluorine, chlorine, bromine and iodine atom.
Preferred formula (I) compound comprises: [6-(4-chloro-phenyl-hexyl)]-2-[4-benzyl sulfinyl-2-aza-oxo-cyclobutane-1-yl] propionic acid amide, especially diastereomer 1b, 2a and 2b, particularly isomer 2b; (α-S, 4-R, SS)-N-[6-(4-fluorophenyl) hexyl]-2-[4-carboxyl benzyl sulfinyl]-2-aza-oxo-cyclobutane-1-base propionic acid amide and corresponding allyl ester; (+/-)-N-(the 6-[4-chloro-phenyl-] oneself-the 1-yl)-4-(3-furyl methyl sulfinyl)-2-aza-oxo-cyclobutane-1-yl acetamide (diastereomer 2); (+/-)-N-[6-(4-chloro-phenyl-hexyl)]-4-(5-methoxycarbonyl-2-furyl methyl sulfinyl)-2-aza-oxo-cyclobutane-1-yl acetamide (diastereomer 2); N-[6-(4-fluorophenyl) oneself-the 1-yl]-4-(5-allyloxy carbonyl furans-2-methylthio group)-2-aza-oxo-cyclobutane-1-yl acetamide; N-[6-(4-fluorophenyl) oneself-the 1-yl]-4-(5-carboxyl furans-2-methylsulfinyl)-2-aza-oxo-cyclobutane-1-yl acetamide (diastereomer 2) and its corresponding allyl group and methyl ester; N-(the 6-{4-chloro-phenyl-} hexyl)-4-(5-carboxyl furans-2-methylsulfinyl)-2-aza-oxo-cyclobutane-1-yl acetamide (diastereomer 2) and its corresponding allyl group and methyl ester.N-[6-(4-chloro-phenyl-) hexyl]-[4-(4-carboxyl methylphenoxy)-2-aza-oxo-cyclobutane-1-yl] ethanamide; N-[6-(4-chloro-phenyl-) hexyl]-[4-(2-fluorophenoxy-2-aza-oxo-cyclobutane-1-yl) ethanamide; N-(6-(4-chloro-phenyl-) hexyl]-4-(4-allyloxy carbonyl methylphenoxy)-2-aza-oxo-cyclobutane-1-yl) ethanamide; 1-(2-(6-(4-chloro-phenyl-) hexyloxy) ethyl)-4-benzyl sulfinyl-2-aza-oxo-cyclobutane (diastereomer 2); 1-(2-(6-(4-fluorophenyl) hexyloxy) ethyl)-4-(4-ethoxy carbonyl benzyl sulfinyl)-2-aza-oxo-cyclobutane (diastereomer 2); And 1-(2-(6-(4-fluorophenyl) hexyloxy) ethyl)-4-benzyl sulfinyl-2-aza-oxo-cyclobutane (diastereomer 2).
Preferred compound comprises: N-[6-(4-chloro-phenyl-hexyl)]-2-[4-benzyl sulfinyl-2-aza-oxo-cyclobutane-1-yl] propionic acid amide, especially diastereomer 1b, 2a and 2b, particularly isomer 2b (1); (α-S, 4-R, SS)-N-[6-(4-fluorophenyl) hexyl]-2-[4-carboxyl benzyl sulfinyl]-2-aza-oxo-cyclobutane-1-base propionic acid amide and corresponding allyl ester; N-[6-(4-fluorophenyl) oneself-the 1-yl]-4-(5-carboxyl furans-2-methylsulfinyl)-2-aza-oxo-cyclobutane-1-yl acetamide (diastereomer 2) and its corresponding allyl group and methyl ester N-(6-{4-chloro-phenyl-} hexyl)-4-(5-carboxyl furans-2-methylsulfinyl)-2-aza-oxo-cyclobutane-1-yl acetamide (diastereomer 2) and its corresponding allyl group and methyl ester; 1-(2-(6-(4-fluorophenyl) hexyloxy) ethyl)-4-benzyl sulfinyl-2-aza-oxo-cyclobutane (diastereomer 2); 1-(2-(6-(4-fluorophenyl) hexyloxy) ethyl)-4-(4-ethoxy carbonyl benzyl sulfinyl)-2-aza-oxo-cyclobutane (diastereomer 2); And 1-(2-(6-(4-chloro-phenyl-) hexyloxy) ethyl)-4-benzyl sulfinyl-2-aza-oxo-cyclobutane (diastereomer 2).
Because the compound of compound of the present invention, especially formula (I) tends to be used for pharmaceutical composition, it should be understood that they are with pure basically form, for example at least 50% is pure, and more suitably at least 75% is pure, preferably at least 95% pure (% is based on wt/wt).The prepared product of impure formula (I) compound can be used for preparing the purer form that is used for pharmaceutical composition.Although the purity of midbody compound of the present invention is not too crucial, to understand easily, pure basically form is preferably used for formula (I) compound.Preferably, if possible, compound of the present invention obtains with crystalline form.
When some compounds of the present invention during from organic solvent crystallization or recrystallization, the crystalline solvent may reside in the crystallized product.Present invention resides in this kind solvent thing in its scope.Similarly, some compounds of the present invention can be from aqueous organic solvent crystallization or recrystallization.Under this class situation, the water of hydration can form.Present invention resides in its scope stoichiometric hydrate and by as the compound of the water that contains variable quantity produced of freeze dried method.In addition, different crystallization condition can cause different polymorphous formation of crystallized product.Present invention resides in the polymorphic forms of all formulas (I) compound in its scope.
The compounds of this invention is and phospholipase A 2(Lp-PLA 2) inhibitor of involved enzyme lipoprotein, therefore wish to be used for the treatment of, especially treat atherosclerosis.Therefore, another aspect of the present invention formula (I) compound of being provided for treating.
Formula (I) compound is by Lp-PLA 2Therefore the inhibitor of the lyso-phosphatidylcholine that produces is also comprising endothelial dysfunction, atherosclerosis for example, diabetes, hypertension, stenocardia and local asphyxia and again perfusion have general application afterwards.In addition, formula (I) compound also has general application in any disease, comprise liposome peroxidation thing and enzymic activity together with, for example except that illness as atherosclerosis and diabetes, other illness such as rheumatic arthritis, apoplexy, encephalitis disease such as Alzheimer ' s disease, myocardial infarction, reperfusion injury, sepsis and acute and chronic inflammation.Other this class illness comprises various neuropsychopathys such as schizophrenia (see the psychopharmacology communique, 31,159-165,1995).
Further application comprises any disease, comprises the activatory monocyte, scavenger cell or lymphocyte, and all these cell types are all expressed Lp-PlA 2This class examples of disorders comprises psoriasis.
Therefore, on the other hand, the invention provides treatment and enzyme Lp-PlA 2The method of the relevant illness of activity, this method comprises the patient that need treat with the ihibitors for treatment of treatment significant quantity.This illness can with monocyte, involving of scavenger cell or lymphocytic increase is relevant; Relevant with the formation of the free fatty acids of lyso-phosphatidylcholine and oxidation; With Lp-PlA 2Active together with the liposome peroxidation thing relevant; Or it is relevant with endothelial dysfunction.
Compound of the present invention also can combine with anti--hyperlipidemia agent or antiatherosclerotic or antidiabetic or antianginal agent or anti-inflammatory agent or hypotensive agent and be used for the treatment of above-mentioned illness.Above-mentioned example comprises cholesterol synthesis inhibitor such as statins, antioxidant such as probucol, insulin sensitizers, calcium-channel antagonists and antiphlogiston such as NSAIDs.
In therepic use, compound of the present invention is usually with the administration of standard drug composition.On the other hand, the invention provides the pharmaceutical composition that comprises formula (I) compound and pharmaceutical carrier.
Suitable pharmaceutical compositions comprises and is fit to oral or parenteral administration or as those of suppository.
Be that active formula (I) compound can be formulated into liquid when oral administration, syrup for example, suspension agent or emulsifying agent, tablet, capsule and lozenge.
Liquid preparation generally at suitable liquid vehicle for example by compound or pharmaceutical salts, ethanol, glycerine, non-aqueous solvent, for example, polyoxyethylene glycol, oil, or have suspension agent, sanitas, suspension in the water of seasonings or tinting material or solution composition.
Can be with any suitable pharmaceutical carrier preparation that is usually used in preparing solid preparation with the composition of tablet form.The example of this class carrier comprises Magnesium Stearate, starch, lactose, sucrose and Mierocrystalline cellulose.
Composition with capsule form can prepare with the conventional capsule metallization processes.For example, the granule that contains activeconstituents can be inserted in the glutoid capsule then with the standard vector preparation; In addition, dispersion liquid or suspension can for example contain glue with any suitable pharmaceutical carrier, Mierocrystalline cellulose, and silicate or oil preparation, and dispersion liquid or suspension are inserted in the soft ' Yanming ' capsules for clearing then.
Typical parenteral composition by formula (I) compound at aseptic aqueous carrier or the acceptable oil of parenteral, polyoxyethylene glycol for example, Polyvinylpyrolidone (PVP), Yelkin TTS, solution in peanut oil or the Viscotrol C or suspension are formed.In addition, solution can just be dissolved with suitable solvent before administration then by freeze-drying again.
It is active formula (I) compound that typical suppository formulations comprises when with this administration, with tackiness agent and/or lubricant as gathering glycol, gelatin or theobroma oil or other low melting point plant or synthetic wax or fat.
Preferably, composition is unit dosage form such as tablet or capsule.
Be used for each oral dose unit and preferably contain 1 to 500mg (and preferably containing 0.1 to 25mg) formula (I) compound for the parenteral administration.
The per daily dose system that is used for adult patient can be, for example, oral dosage is between 1mg to 1000mg, preferably between 1mg to 500mg, or intravenously, subcutaneous, or intramuscular dosage is between 0.1mg to 100mg, formula (I) compound between 0.1mg to 25mg preferably, compound is by administration every day 1 to 4 time.Suitably, compound will be by with the administration of successive treatment cycle, for example a week or more.
Formula (I) compound can be from common raw material by this professional known synthesis technique preparation.A kind of suitable method comprises the alkylating agent with formula (III):
L 1CR 4R 5XY is L wherein 1Be suitable leaving group such as halogen or trifluoromethanesulfonic acid base; And R 4, R 5, X and Y such as preceding definition.In the presence of suitable alkali such as sodium hydride or potassium hydroxide,, in suitable alkylation solvent such as tetrahydrofuran (THF) (THF), handle the azetidinone of formula (II)-10 ℃ to 0 ℃ temperature ranges non-imposedly with quaternary ammonium salt such as Tetrabutylammonium bromide: N wherein, R 1, R 2, and R 3As preceding definition.
For Z wherein is formula (I) compound of S (O) n, the alkylated reaction that carries out easily therein n act on 0 formula (II) compound.
R wherein 4And R 5One of be that formula (I) compound of alkyl also can be from R wherein 4And R 5Formula (I) compound that all is hydrogen prepares by handling with alkylating agent under these conditions.This compounds is by under the abovementioned alkyl condition, with the compound of the alkylating agent processing formula (II) of formula (III) and obtain.
For R 4/ R 5Second alkyl, can be by at suitable alkali such as sodium hydride, potassium hydroxide or hexamethyl two silicon lithium nitrides exist down, in suitable alkylation solvent such as tetrahydrofuran (THF) (THF), in-80 ℃ to 10 ℃ scope, handle wherein R with alkylating agent 4And R 5One of be the formula that at first obtains (I) compound of hydrogen and introducing.
Wherein Z be S (O) n and n be 1 or 2 formula (I) compound can be easily be that 0 formula (I) compound is by preparing with suitable oxygenant such as metachloroperbenzoic acid oxidation from n wherein.If the pure compound of achirality, as (+)-or (-)-1, (people such as Komatsu, organic chemistry magazine 1993,58 7624-7626) can provide the diastereo-isomerism selectivity to 1 ' two-2-naphthalene alcohol/titanium isopropylates with the chiral oxidization agent.
Wherein Z is that S (O) n and n are that 0 formula (II) compound can be by in the presence of alkali such as sodium ethylate, in suitable solvent such as ethanol, 0 to 5 ℃ in temperature range, use mercaptan R 3SH handles 4-acetoxyl group azetidinone, 4-benzoyloxy azetidinone or 4-benzenesulfonyl azetidinone and obtain.When this displacement when in the presence of chiral base such as cinchovatin or cinchonine, carrying out, can obtain the enantiomerism enrichment compound (II) (Chemical Society's magazine, chemical communication, 1982,1324-5).
Wherein Z is that formula (II) compound of O can be by in the presence of alkali such as potassium tert.-butoxide, in suitable solvent such as THF 0 to 5 ℃ temperature range, usefulness phenol/pure R 3OH handles 4-acetoxyl group azetidinone, 4-benzoyloxy azetidinone or 4-benzenesulfonyl azetidinone and obtain.
Formula (III) compound can easily pass through known synthesis technique, according to concrete X value preparation.Common raw material is the aryl compound that suitably replaces, its processed then introducing side chain L 1CR 4R 5X-.
Wherein X refers to group CONR 6(CH 2) m, CONR 6X 2, CONR 6O (CH 2) m, or CONR 6OX 2Formula (I) compound can be easily by in the presence of activator such as chloro ethyl formate or dicyclohexylcarbodiimide (DCC), in suitable solvent such as chloroform or dimethyl formamide ,-10 to 20 ℃ temperature range, the amine of usefulness formula V:
NHR 6X 5The azanol of Y (V) or formula (VI):
NH 2OX 5Y (VI) is X wherein 5Be (CH 2) m or X 2And m, R 6, Y and X 2As preceding definition, the acid of processing formula (IV):
Figure A9619666100281
Z wherein, R 1, R 2, R 3, R 4And R 5As preceding definition; And prepare.
R wherein 4And R 5One of be hydrogen formula (IV) acid can by under the abovementioned alkyl condition with corresponding 2-bromo-ester, for example (C 1-7) alkanoic acid ester processing formula (II) compound; Then obtain with the such intermediate ester that forms of standard conditions hydrolysis.Second group, for example alkyl can be introduced by an alkyl ester alkylation that will form earlier then.
Wherein X refers to group COO (CH 2) m or COOX 2Formula (I) compound can be easily by from other ester, the methyl ester of formula (VII) especially:
Figure A9619666100282
Wherein: Z, R 1, R 2, R 3, R 4And R 5As preceding definition; Use for this class and react this professional known condition, for example the transesterification that in the presence of the sodium methylate of catalytic amount and alcohol, in toluene, heats and preparing.
R wherein 4And R 5One of be that formula (VII) compound of hydrogen can be by under foregoing alkylation conditions, with 2-bromine (C 1-7) the alkanoic acid methyl ester handles formula (II) compound and obtain.
In addition, wherein X refers to group COO (CH 2) m or COOX 2Formula (I) compound can be by using pure YX 5OH or its activatory derivative, for example methanesulfonates is handled formula (IV) compound and is prepared.
Wherein connecting formula (I) compound that basic X contains ether functional group can prepare by suitable ether coupled reaction, for example uses formula (IX) compound:
L 3(CH 2) qY (IX) processing formula (VIII) compound under the ether formation condition of standard:
Figure A9619666100291
Z wherein, R 1, R 2, R 3, R 4R 5And X 2As preceding definition; L wherein 2And L 3Be halogen or other suitable leaving group such as trifluoromethanesulfonic acid base or toluenesulphonic acids base, and another is OH or its suitable salt, and p and q such as preceding definition.
Wherein Z is that S (O) n and n are that 0 formula (I) compound also can be by such method preparation, and this method is included under the suitable alkylation conditions, for example, in solvent such as acetonitrile, the temperature about 25 ℃, with the alkylating agent of formula (XI):
R 3L 1(XI) R wherein 3And L 1As preceding definition; The compound of processing formula (X):
Figure A9619666100292
R wherein 1, R 2, R 4, R 5, X and Y such as preceding definition.
Formula (X) compound can obtain by handling suitable solvent such as methyl alcohol with Silver Nitrate and alkali from corresponding 4-acetylthio azetidinone.
If desired, the mixture of formula (I) diastereomer compound can split according to this professional known technology.For example sulfonyl compound (n=1) can separate by chromatogram and/or crystallization.The compound of chiral purity can pass through chiral chromatography, from the intermediate of chiral purity or by preparing with the chirality of chiral reagent or catalyzer is synthetic.Suitable chiral intermediate can be according to the skilled personnel's known method of this specialty, by fractionation or chiral induction or by using chiral reagent, and especially natural chiral molecules and obtaining.Synthetic for chirality, chiral raw material is the penicillin derivative that has preferred configuration at the C-4 of beta-lactam ring easily.The preparation of the intermediate that approach illustrated below is suitable The preparation of raw material (4-methoxy-benzyl-6-bromine penicillin base-1-oxide compound) is described in Chemical Society's magazine, Perkin Trans.1, and 1994, among the 179-188.An alkyl substituent (R 4/ R 5) can introduce with foregoing alkylation conditions at the latter stage of program.
The present invention will illustrate by the following example.In described below two diastereomers (a and b) of the center α of the relative configuration at the C-4 center in azetidinone and the N of azetidinone is unknown, but is considered to R, R/S, S (diastereomer a) and R, S/S, R (diastereomer b).Relative configuration at C4 and sulfonyl compound center is unknown, but is considered to R, R/S, S (diastereomer 1) or R, S/S, R (diastereomer 2).This class configuration begins x-ray analysis by the compound of limited quantity at it 1Remaining compound of extrapolation and obtaining on the basis of H NMR spectrum.(for example isomer (-) b2) all compounds all are racemic modification (for example diastereomer b2) unless otherwise indicated.All compounds mainly are described (non-mapping) isomer.All compounds are characterized by NMR, and are most of by trace analysis and mass spectral characteristi.Fusing point is not calibrated.Isomer and enantiomer are labeled as mentioned above to emphasize the synthetic explanation and to point out preferred compound.Preparation 4-(5-allyl group oxygen base carbonyl furans-2-methylthio group) azetidine-2-ketone is (chloromethyl)-methyl 2-furoate a.5-
With the Paraformaldehyde 96 under stirring (25.22g, 0.84mol), Zinc Chloride Anhydrous (108.06g), and methyl 2-furoate (100g, mixture 0.793mol) are cooled to 15 ℃ (ice baths), under agitation feed the HCl air-flow then.Make temperature rise to 25-30 ℃, after 1 hour mixture is poured in the frozen water.Separate organic layer, water layer is used dichloromethane extraction again.The extraction liquid that merges is dried in (sal epsom) and is evaporated to chocolate oily matter.Underpressure distillation provides light yellow solid (72.5g, 52% productive rate), b.p. (88 ℃/0.8mm Hg). 1H NMR δ (DMSO-d 6) 3.82 (3H, s, CH 3), 4.90 (2H, s, CH 2), 6.75,7.29 (each 1H, d, furan-H) b.5-(acetylthio methyl)-methyl 2-furoates
With 5-(chloromethyl)-methyl 2-furoate (50g 0.286mol) is dissolved in the exsiccant dimethyl formamide (300ml), and under agitation add thioacetic acid potassium (32.68g, 0.286mol).Initial heat release will be reflected at then under the room temperature and place 2 hours by cooling (ice bath) control.Evaporating solvent, the residuum water treatment, and fully extract with ether.The extraction liquid that merges is dried in (sal epsom), evaporates and pass through purification by flash chromatography (silica gel, ethyl acetate/petroleum ether) to provide oily product (40.9g, 67% productive rate). 1H NMR δ (CDCl 3) 2.36 (3H, s, CH 3CO), 3.88 (3H, s, CH 3O), 4.16 (2H, SCH 2), 6.36,7.09 (each 1H, d, furan-H) c.4-(5-allyl group oxygen base carbonyl furans-2-methylthio group) azetidines-2-ketone
(12.77g 0.114mol) stirs until obtaining solution completely in allyl alcohol (60ml) with potassium tert.-butoxide.Be added in 5-(acetylthio methyl) methyl furoate (22.17g in the allyl alcohol (60ml) then, 0.104mol), after 2 hours, with mixture cooling (ice bath), dripped 4-acetoxyl group azetidine-2-ketone (13.36g, 0.104mol) solution in exsiccant tetrahydrofuran (THF) (100ml) at 20 minutes.After 30 minutes, remove cryostat, then mixture was at room temperature stirred 3 hours.Evaporating solvent, ethyl acetate extraction is handled and used to residuum with salt solution.The extraction liquid that merges is dried in (sal epsom) and evaporation provides light yellow oily product (22.5g, 81% productive rate). 1HNMR δ (CDCl 3) 2.87 (1H, m, H 3a), 3.43 (1H, m, H 3b), 3.89 (2H, m, SCH 2), 4.79 (2H, m, CH 2O), 4.94 (1H, m, H 4), 5.38 (2H, m, CH 2CH-), 6.01 (1H, m, CHCH 2), 6.33,7.13 (each 1H, d, furan-H), 6.74 (1H, NH) 4-(2-fluorophenoxy) azetidine-2-ketone
With 2-fluorophenol (4.5g, 40mmol) with the solution of 18-hat-6 (5mg) in dry THF (100ml) potassium tert.-butoxide (4.5g, 40mmol) handle, and add 4-benzoyloxy azetidine-2-ketone (7.7g, 40mmol) solution in exsiccant THF.Mixture was stirred 1 hour and used aqueous citric acid solution and ethyl acetate cancellation.Tell organic layer, with the salt solution washing, dry (sodium sulfate) and evaporation.With ether/excessive normal hexane development and filtration, obtain m.p.95-96 ℃ of title compound solid (5.8g, 80%). 1H NMR δ (CDCl 315 according to claim 1, the following compounds or their salts: N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) - glycine Acid; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl)-β-amino Propionic acid; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - (L) - Glutamic acid; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - (L) - Phenylalanine; α-N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - (L) - lysine; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) - piperidine 2 - carboxylic acid ethyl ester; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) - piperidine -4 - Carboxylate; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) - piperidine -3 - Carboxylic acid ethyl ester; 7 - bromo-5 - (5 - nitro - benzimidazol-1 - yl) -1,4 - dihydro - quinoxaline -2,3 - Dione; 7 - bromo-5 - (6 - nitro - benzimidazol-1 - yl) -1,4 - dihydro - quinoxaline -2,3 - Dione; N-(7 - bromo-2 ,3 - dioxo-8-nitro - 1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl Yl) -4 - dimethylamino-piperidine; N-(7 - bromo-2 ,3 - dioxo-8-nitro - 1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl Yl) -1,2,3,4 - tetrahydro-quinoline; N-(7 - bromo-2 ,3 - dioxo-8-nitro - 1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl Yl)-β-amino acid; α-N-(7 - bromo-2 ,3 - dioxo-8-nitro - 1, 2,3,4 - tetrahydro-quinoxalin-5 - Ylmethyl) - (L) - lysine; N-(7 - bromo-2 ,3 - dioxo-8-nitro - 1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl Yl) - (L) - phenylalanine; N-(7 - bromo-2 ,3 - dioxo-8-nitro - 1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl Yl) - glycine; N-(7 - bromo-2 ,3 - dioxo-8-nitro - 1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl Yl) - piperidine-4 - carboxylic acid ethyl ester; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - piperazine -4 - carboxylic acid ethyl ester; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl)-β - Amino acid; α-N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - (D) - lysine; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - Gly Acid; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - (L) - Glutamic acid; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - (L) - Phenylalanine; α-N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - (L) - lysine; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxaline-6 ​​- yl methyl)-β - Amino acid; α-N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxaline-6 ​​- ylmethyl) - (L) - lysine; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxaline-6 ​​- ylmethyl) - (L) - Phenylalanine; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxaline-6 ​​- ylmethyl) - (L) - Glutamic acid; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - Gly Acid; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxaline-6 ​​- ylmethyl) - piperazine -4 - carboxylic acid; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxaline-6 ​​- ylmethyl) - piperazine -4 - carboxylic acid ethyl ester; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) - piperidine -4 - Carboxylic acid; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) - piperidine -4 - Carboxylic acid phenyl-amide; N-(7 - bromo-2 ,3 - dioxo-8-nitro - 1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl Yl) - piperidine-4 - carboxylic acid; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - piperazine -4 - carboxylic acid; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) - piperidine 2 - carboxylic acid; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) - piperidine -3 - Carboxylic acid; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) - piperidine -3 - Phenyl-carboxylic acid amide; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) - piperidine 2 - carboxylic acid phenyl-amide; 5 - amino-methyl-7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxaline; 3 - [(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - amino- Carbamoyl] - ethyl acrylate; 3 - [(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - amino- Carbamoyl] - acrylic acid; 3 - [(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - amino- Carbamoyl] - phenyl-acrylic acid amide; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - (3 - phenyl - ureido) - acetamide; {[(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - carbamoyl Yl] - methyl} - carbamic acid tert-butyl ester; {[(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - carbamoyl Yl] - methyl} - carbamic acid benzyl ester; 7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - methoxy-acetic acid; 7 - bromo-2 ,3 - dioxo -5 - (hydroxymethyl) -1,2,3,4 - tetrahydro-quinoxaline; 7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - methoxy acetate; (7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethoxy)-N-phenyl Base - acetamide; 7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl-acetic acid ethyl methyl sulfonamide Esters; 7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl-acetic acid methyl sulfonamide; (7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - sulfonamide group-ylmethyl) - N-phenyl - acetamide; 2 - amino -3 - (7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl) - Ethyl propionate; 2 - amino -3 - (7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl) - Acid; Furan-2 - carboxylic acid - (7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl Methyl) - amide; Cyclopropanecarboxylic acid (7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - Amide; 2 - Amino-N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl Yl) - acetamide; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl) -3,5 - Bis (trifluoromethyl) benzamide; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - benzoic Amide; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - acetyl Amines; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - trifluoro Acetamide; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - oxalyl Ethyl amine; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - propionyl Amine methyl; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - oxalyl Acid; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - (L) - Tyrosine; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - t - Leucine; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - (L) - Proline; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - (L) - Alanine; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - (D) - Alanine; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - muscle Acid; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - (L) - Valine; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - Grass Amide methyl ester; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - Grass Amide acid; 4 - [(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - amino- Carbamoyl] - methyl butyrate; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl)-N - Benzyl - glycine ethyl ester; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl)-N - Benzyl - glycine; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - ethyl Amide; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - phenyl Acetamide; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -3 - Phenyl - propanamide; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - thiophene 2 - carboxylic acid amide; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -3 - Thienyl - acetamide; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -3 - Methoxyphenyl acetamide; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl)-N - Methyl - benzylamine; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - furfuryl amine; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - Morpholino - ethylamine; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - two Ethylamine; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - (2 - pyridyl) - ethyl - methylamine; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - ring Propylamine; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - two Ethanolamine; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - Amino-2 - thiazoline; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - Aminopyrazine; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - Aminothiazole; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - benzene Amines; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -4 - Fluoro aniline; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -3 - Fluoro aniline; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - Fluoro aniline; [N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - Amino - 4 - thiazolyl] - acetate; [N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - Amino-4 - thiazolyl] - acetate; [N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - Amino - 4 - thiazolyl] - acetic acid; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl)-N - (2 - pyridylmethyl) - glycine; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -3 - Amino - acid; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - Methyl aziridine; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - N Oxetane; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -4 - Methylpiperidine; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl)-N ' - (4 - methoxyphenyl) piperazine; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - piperazine Pyridine; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl) -2,6 - Dimethyl piperidine; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) - pyridine Pyrrolidine; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -4 - Piperidone; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - Six Methylene-imine; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -3 - Pyrroline; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - Sulfur Miscellaneous morpholine; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - it Morpholine; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - thiophene Oxazolidine; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -3 - Pyrrolidinol; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl)-N - Methylpiperazine; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - (2 - hydroxyethyl) piperidine; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - piperazine Piperazine dihydrobromide; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -3 - Azabicyclo [3.2.2] nonane; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - Four Hydrogen pyridine; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) - pyridine Yl; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -3 - Ethoxycarbonyl - pyrazole; [1 - (2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl)-1H - Indol-3 - yl] - acetate; N-(2,3 - dioxo -7 - nitro-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -1,2,3,4 - Tetrahydroquinoline; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - methanesulfonamide Acid amide; N-methyl-2 - phenyl-acetic acid (7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - Ylmethyl) - amide; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl)-α- Amino acid; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -3 - (4 - methoxyphenyl) - urea; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -3 - (2 - methoxyphenyl) - urea; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -3 - (2 - ethoxycarbonyl-ethyl) - urea; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -3 - (2 - carboxyethyl) - urea; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -3 - Phenyl - urea; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -3 - (4 - trifluoromethoxy-phenyl) - urea; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - E Acid amide; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - naphthalene Carboxylic acid amides; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) -3,3 - Dimethyl - butyramide; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - (3 - Acetyloxy) - benzamide; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - Methoxy - acetamide; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl)-N ', N' - Dimethyl - Glycinamide; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) -3,4,5 - Trimethoxy - benzamide; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl) -3,5 - Dimethoxy-4 - hydroxy - benzamide; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl)-N ' - Acetyl - GLYCINAMIDE; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl)-N ' - Carbamoyl - glycinamide; 4 - [N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) Sulfamoyl] - benzamide; 2 - amino -3 - methyl-N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxaline -5 - ylmethyl) - butyramide; 2 - amino -3 - hydroxy-N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxaline -5 - ylmethyl) - butyramide; 2 - amino -4 - carboxy-N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxaline -5 - ylmethyl) - butyramide; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl)-N - Acetyl - tryptophan amide; 2 - Amino-N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl Methyl)-L-serine - amide; 2 - Amino-N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl Methyl)-D-Ser - amide; 2-L-amino-3 - carbamoyl-N-(7 - nitro-2 ,3 - dioxo-1 ,2,3,4 - Tetrahydro-quinoxalin-5 - ylmethyl) - propionamide; 2-D-amino-3 - carbamoyl-N-(7 - nitro-2 ,3 - dioxo-1 ,2,3,4 - Tetrahydro-quinoxalin-5 - ylmethyl) - propionamide; LN-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - Histidine - amide; DN-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - Histidine - amide; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - Hu Amber acid amide; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - o Acid amides; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - E Acid amides; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl)-N - (2 - diethylaminoethyl) - amine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl)-N - Methyl - amine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl)-N - (1,1 - dioxo-2, 3,4,5 - tetrahydro-thiophen-3 - yl) - amine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl)-N - Methyl-N-(2 - hydroxyethyl) - amine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl)-N - (3,4 - methylenedioxy-benzyl) - amine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl)-N - Methyl-N-methoxy-amine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl)-N - Isopropylamine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 tetrahydro-quinoxalin-5 - yl methyl)-N ' - Acetyl - ethylenediamine; Cis -2 - [N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - group A Yl) amino] - cyclohexane-1 - carboxamide; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl)-N - Methyl - taurine; Cis -3 - [N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - group A Yl) amino] - cyclohexane-1 - carboxylic acid; 3 - [N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) Amino] -3 - phenyl - propionic acid; Cis -2 - [N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - group A Yl) amino] - cyclopentane - carboxylic acid; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) - pyridine Slightly-2 - one; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -4 - (4 - chlorophenyl) - pyrrolidin-2 - one; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl)-N - (1 - Acetyl-2 - methyl - prop-2 - yl) - amine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl)-N - Cyclohexyl-N-methylamine; Cis -2 - [N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - group A Yl) amino] - cyclohexane-1 - carboxylic acid; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - Amino - acetic acid; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - amino Base - A phosphonic acid; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - amino Group - (3 - methoxyphenyl) - methyl phosphonic acid; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -3 - Amino - propane-1 - phosphate; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - Amino - acetic acid; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - Amino-2 - phenyl - ethane acid; Cis -2 - [N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - group A Yl) amino] - cyclopentane-1 - carboxylic acid; Trans -2 - [N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl Yl) amino] - cyclopropane-1 - phosphate; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - amino Group - (3 - pyridyl) - methyl phosphonic acid; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -3 - Amino-1 - carboxy - propane-1 - phosphate; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methylaminomethyl) Tetrazole; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl) -3,5 - Dimethyl - morpholine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) -4,4 - Ethylenedioxy - piperidine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -3 - Methyl - piperidine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -4 - Hydroxy - piperidine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - (Hydroxymethyl) - pyrrolidine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - Acetoxymethyl - pyrrolidine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -4 - Hydroxy - pyrrolidine-2 - carboxylic acid; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -3 - Hydroxy - piperidine; 2 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methylamino) - (L) - Butyric acid; 2 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methylamino) - (L) - Butyrate; 2 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methylamino) - iso Butyric acid; 2 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methylamino) - iso Butyrate; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methylamino) - ring Propane-1 - carboxylic acid; N-[N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) -N-methyl - (L) - alanine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - light Acid; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - (L) - Threonine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - Methyl-β-amino acid; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -4 - Pyridinemethanamine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - Pyridinemethanamine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - amino Yl-acetonitrile; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -4 - Benzylidene piperidine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -4 - Phenyl-piperidin-4 - carboxylate; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -4 - Carbamoyl-piperidine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -3 - Methyl-β-amino acid; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -4 - Phenyl-4 - methoxycarbonyl - piperidine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - 2nd Iminodiacetic acid; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -1,2,3,4 - Tetrahydroisoquinoline; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - Aminobenzothiazole; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methylamino) - ethyl Phosphonic acid; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl)-N - Acetyl - (L) - alanine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -4 - Phenyl - piperidine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -4 - (Hydroxymethyl) - piperidine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - (Hydroxymethyl) - piperidine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -4 - (1 - hydroxyethyl) - piperidine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -4 - Methoxy - piperidine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - Methyl - piperidine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -4 - Methoxy - 4 - methyl - piperidine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) -4,4 - Dimethoxy - piperidine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - (L) - Serine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl)-O - Acetyl - (L) - serine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - acridine Dioxepino -2 - ketone; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - piperazine -2 - one; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - Ethyl-4 - methylimidazole; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -4 - O - pyrrolidine-2 - carboxylic acid; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - Amino-5 - bromo - pyrimidine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl)-5 - Amino-2 - methoxy - pyridine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - Amino - pyrimidine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - Amino - pyridine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -3 - Amino - pyridine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - Amino - 4 - methyl - pyrimidine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -3 - Amino-5 - tert-butyl-isoxazole; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - Amino-4 ,5 - dicyano - imidazole; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - Amino-pyridinium bromide; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -3 - Amino-pyridinium bromide; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -4 - Amino-pyridinium bromide; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl)-N, N, N - Triethylammonium bromide; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) -1,2,4 - Triazole-3 - carboxylic acid; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) -1,2,4 - Triazole-5 - carboxylic acid; 4 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) -1,2,4 - Triazole-3 - carboxylic acid; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) -1,2,3 - Triazole-4 ,5 - dicarboxylic acid; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) -1,2,4 - Triazole; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) -1,2,4 - Triazole-5 - carboxylate; 2 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) -1,2,3 - Triazole-4 ,5 - dicarboxylic acid; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) -1,2,3 - Triazole-4 ,5 - dicarboxylate; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) -1,2,3 - Triazole-4 - carboxylic acid amide; 1 - (chloro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) -1,2,3 - Three -4 - carboxylic acid amide; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) -1,2,3 - Triazole-4 ,5 - dicarboxylate; 2 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) -1,2,3 - Triazole-4 ,5 - dicarboxylic acid; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - imidazole 2,4,5 - tricarboxylic acid; P-benzyl-- (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl) - Methane phosphonous acid; P-methyl - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl) - Methane phosphonous acid; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl) - carbamic Acyl A acid; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - Oxo-1 ,2 - dihydro-pyridine; 2 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -1,2,3,4 - Tetrahydro-isoquinolin-1 - one; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl) -2,3,4,5 - Tetrahydro-1H-1-benzo-azepin-2 - one; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - Oxo-3 - phenyl - piperidine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - Oxo-5 - phenyl - piperidine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl)-5 - Methyl - pyrrolidin-2 - one; 4 - (2 - oxa-imidazolidin-1 - yl)-N-(7 - nitro-2 ,3 - dioxo-1 ,2,3,4 - Tetrahydro-quinoxalin-5 - ylmethyl) - piperidine; N-{2 - [N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl Yl) amino] ethyl} - pyrrolidine-2 - one; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -3 - Phenyl - pyrrolidin-2 - one; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -4 - (4 - fluorobenzoyl) - piperidine; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - Oxo-2 - phenyl - acetamide; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - Propyl - acid amide; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) - (4 - Methyl-furan)-2 - carboxylic acid amide; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - thiophene -3 - Carboxylic acid amide; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - imidazole -4 - Carboxylic acid amide; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -3 - (Thiophen-3 - yl) - acrylic acid amide; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - Phenyl isobutyric acid amide; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) -1 - Phenyl cyclopropane - carboxylic acid amide; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - Propionic acid amide; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - Phenyl acid amide; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) - (3,4 - Dimethoxyphenyl) - acetamide; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) - (4 - Chlorophenyl) - acetamide; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - (3 - Chlorophenyl) - acetamide; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) - (2 - Chlorophenyl) - acetamide; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - (3 - Methylthiophene) -2 - carboxylic acid amide; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - (5 - Methylthiophene) -2 - carboxylic acid amide; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) - (1 - Methylpyrrole) -2 - carboxylic acid amide; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - nicotinic acid Amide; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) - (4 - Nitrophenyl) - acetamide; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - (3 - Nitrophenyl) - acetamide; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) - (2 - Nitrophenyl) - acetamide; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) - (3,4 - Methylenedioxy-phenyl) - acetamide; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - (3 - Phenoxy-phenyl) - acetamide; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) - pyridine Carboxylic acid amides; 7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl carbamic acid; 1 - (7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methylamino) - ethyl phosphine Acid; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl)-N- Benzyloxycarbonyl - amino - A phosphonic acid; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - benzyl Urethane; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - phenyl Urethane; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl)-N- Phenylacetyl - Amino - A phosphonic acid; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl)-N- Phenylacetyl - glycine; 3 - acetyl-1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl Methyl) - pyrrole; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) - pyrrole -3 - Carboxylic acid ethyl ester; N-methyl-N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl Yl) - phenyl-acetamide; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -3 - Acetoxy pyrrolidine; N-(7 - bromo-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -3 - Hydroxy-pyrrolidine; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) - pyrrole -3 - Carboxylic acid; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) - pyrrole 2 - carboxylic acid; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) - pyrrole 2 - carboxylic acid tert-butyl ester; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - indole -3 - Acid; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - indole -3 - Yl acetate; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - indole -3 - Carboxylic acid; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - indole 2 - carboxylic acid tert-butyl ester; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - indole 2 - carboxylic acid; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - imidazole; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -4 - (Hydroxymethyl) - imidazole; 1 - [1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - Imidazol-4 - yl] - acetic acid; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -4 - Methyl - imidazolium; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - Methyl - imidazolium; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - Ethyl - imidazole; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - pyrazole; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl) -3,5 - Dimethyl - pyrazole; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) -1,2,4 - Triazole; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) - pyrrole; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - piperazine 3 - one; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - oxazole -2 - one; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -4 - Methyl - piperazine-3, 5 - dione; 3 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl) -2,3,5,6 - Tetrahydro-4H-1, 2 - oxazine; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - amino Anthranilic acid; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - amino Carbomethoxyaniline; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - ylmethyl) - amino Fennel ethyl; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - Benzyl-4 - acetamido - piperidine; 1 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - Phenyl-4 - acetamido - piperidine; {3 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl) -2 - O 2,3,4 - tetrahydro - benzo [b] azepin--1 - yl} - acetic acid; N-(7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methyl)-N - Isopropyl-N-(quinolin-4 - yl methyl) - amine; 4 - (7 - nitro-2 ,3 - dioxo-1, 2,3,4 - tetrahydro-quinoxalin-5 - yl methylamino) -5 - Phenyl - pent-1 - ene; Acid; Acid; Acid; ...1H NMR δ (CDCl 3) 1.35 (3H, d, 7.6Hz), 3.55 (1H, m), 5.63 (1H, d, 4.0Hz), 6.83-7.38 (6H, m) N-(6-phenyl hexyl) bromo ethanamide
With refrigerative 6-phenyl hexyl amine (26.6g) (people such as Morse M.A.; cancer research; 1991,1846) and the solution of Hunig ' s alkali (19.5g) in exsiccant methylene dichloride (300ml) in methylene dichloride (50ml), handle with bromo ethanoyl chlorine (23.38g) at 0-5 ℃.After water treatment and chromatography, obtain N-(6-phenyl hexyl) bromo ethanamide colorless solid, 35.4g, (83%), m.p.29-32 ℃.N-(6-(4-chloro-phenyl-) hexyl) bromo ethanamide
With similar method 6-(4-chloro-phenyl-) hexyl amine (Lamattina J.L.EP 13,846,4A2 850424 (CA103:142000)) is provided title compound colorless solid, m.p.67-8 ℃ (93%) with the processing of bromo ethanoyl bromine.4-(benzylthio-) azetidine-2-ketone
Maintain the temperature between 20 ℃-25 ℃, and in mixture, feed nitrogen, with sodium (8.1g 0.35mol) is dissolved in ethanol (250ml), and dripped benzyl mercaptan at 20 minutes (45.2g, 0.37mol).After 15 minutes, reaction mixture is cooled to 5 ℃, is maintaining the temperature under 5 ℃ the situation, dripped 4-acetoxyl group azetidine-2-ketone (45.0g, ethanol 0.35mol) (50ml) solution at 15 minutes.Mixture is extremely done in stirring at room 60 minutes and reduction vaporization.Add entry (400ml), and the mixture methylene dichloride (2 * 300ml), be oily matter with extraction liquid drying (sal epsom) and reduction vaporization.This oily matter is cooled to-20 ℃ and also provides white solid with ether (400ml) development, gets (50.2g, 79%), mp50-51.0 ℃ by filtering separation.(4-benzyl sulfenyl-2-aza-oxo-cyclobutane-1-yl) methyl acetate
Toward 4-(benzyl sulfenyl) azetidine-2-ketone (5.0g, 25mmol), and the monobromo-acetic acid methyl esters (4.6g, 30mmol) and Tetrabutylammonium bromide (0.9g, 0.28mmol) add in the solution in exsiccant THF (150ml) Powdered potassium hydroxide (1.7g, 30mmol).The mixture that produces at room temperature stirs and added entry (50ml) in 2 hours then.Solution is with ethyl acetate (3 * 150ml part) extraction, with extraction liquid drying (sal epsom) and the evaporation that merges.Residuum is by the flash chromatography on silica gel purifying, and with 60 °-80 ° of sherwood oils: 4: 1 wash-outs of ethyl acetate provide (4-benzyl sulfenyl-2-aza-oxo-cyclobutane-1-yl) methyl acetate yellow oil (5g, 70%). 1H NMR δ (CDCl 3) 2.96 (1H, dd, J=2.5,16Hz H 3a), 3.24,3.99 (each 1H, d, J=18.00Hz, NCH 2), 3.4 (1H, dd, J=5,12.5Hz H 3b), 3.70 (3H, s, OCH 3), 3.77 (2H, s, SCH 2), 4.92 (1H, m, H 4), 7.28 (5H, m, Ph-H) (4-benzyl sulfenyl-2-aza-oxo-cyclobutane-1-yl) acetate
At 0 ℃, past (4-benzyl sulfenyl-2-aza-oxo-cyclobutane-1-yl) methyl acetate (2.5g, and dropping 1N sodium hydroxide solution in methyl alcohol 9.4mmol) (80ml) solution (9.9ml, 9.9mmol).To react stirring 1 hour and be evaporated to dried.Add entry (50ml), solution is acidified to pH3 with dilute hydrochloric acid and (3 * 100ml) extract with ethyl acetate.The extraction liquid that merges is dried in (sal epsom), evaporation, and residuum provides (4-benzyl sulfenyl-2-aza-oxo-cyclobutane-1-yl) acetate white solid (1.3g, 55%), mp 110-111 ℃ by recrystallization (hexane/ether) purifying. 1H NMR δ (CDCl 3) 2.99 (1H, dd, J=6.87,17.5Hz, H 3a), 3.27,4.06 (each 1H, d, J=18.40Hz, NCH 2), 3.39 (1H, dd, J=5,5.14Hz, H 3b), 3.77 (2H, s, SCH 2), 4.91 (1H, m, H 4), 7.27 (5H, m, Ph-H) .1-(amino)-6-(3-chloro-phenyl-) oneself-1-alkynes (3-chloro-phenyl-) hexin-1-alcohol a.6-
(14.3g, 60mmol), (2.1g, 1.8mmol) (5.9g, 60mmol) mixture in triethylamine (120ml) stirred 3 hours at 25 ℃ four (triphenyl phosphine) palladium, was distributed between water and the ether with 5-hexin-1-alcohol with 3-chloro phenyl-iodide.Tell the ether layer, the water extracted with diethyl ether.The ether extraction liquid that merges is washed and dry (sodium sulfate) with 1N HCl.With the ether evaporation, residuum is made eluent by the flash chromatography on silica gel purifying with methylene dichloride.Evaporate suitable cut provide oily product (11.5g, 92%) b. 1-(phthalimide-based)-6-(3-chloro-phenyl-) oneself-1-alkynes
With 6-(3-chloro-phenyl-) hexin-1-alcohol (11.5g, 55mmol), and triphenyl phosphine (14.5g, 55mmol) and phthalic imidine (8.1g, 55mmol) DEAD (9.6g, dry THF 55mmol) (20ml) the solution-treated several minutes of the solution in exsiccant THF (110ml).After 16 hours, vacuum is removed volatile matter, and residuum is handled with ether.Remove precipitated solid, with the filtrate evaporation, residuum is made eluent by the flash chromatography on silica gel purifying with methylene dichloride.Evaporate suitable cut provide 1-(phthalimide-based)-6-(3-chloro-phenyl-) oneself-1-alkynes solid (16.5g, 89%) c.1-(amino)-6-(3-chloro-phenyl-) oneself-1-alkynes
With 1-(phthalimide-based)-6-(3-chloro-phenyl-) oneself-1-alkynes (6.6g) and the mixture of hydrazine hydrate (2.24g) in ethanol (100ml) handled 18 hours under the cocurrent flow temperature.Cooling and filter after, evaporating solvent provides oily matter, it is dissolved in ether and with the salt solution washing, dry and evaporation provide 1-(amino)-6-(3-chloro-phenyl-) oneself-1-alkynes (3.1g, 77%).
With similar method prepare following 2 amine: 1-(amino)-6-(2-chloro-phenyl-) oneself-1-alkynes 1-(amino)-6-(1-naphthyl) oneself-1-alkynes 6-phenyl-3-hexin amine a.N-(6-phenyl-3-hexin base) phthalic imidine
With phthalic imidine (8.78g), 6-phenyl-3-l-hexyn-3-ol (J.Dijkink, N.Speckamp, tetrahedron, Vol.34,173-178,1978) (8.0g) and the mixture of triphenyl phosphine (12.04g) in exsiccant THF (75ml) in nitrogen, be cooled to 5 ℃.Maintain the temperature at 10 ℃, added the solution of diethylazodicarboxylate (8.0g) in exsiccant THF (20ml) at 10 minutes.Reaction was at room temperature stirred 20 hours, was evaporated to driedly, was dissolved in chloroform (250ml) and use 1N sodium hydroxide, salt solution, and 2N hydrochloric acid, saturated sodium bicarbonate, the salt solution washing, drying (sal epsom) also is evaporated to paste solid (28.1g).By the flash column chromatography purifying, with 10: 1 to 2: 1 sherwood oils: eluent ethyl acetate, and provide m.p.95-96 ℃ of N-(6-phenyl-3-hexin base) phthalic imidine colorless solid (8.25g, 59%) with ethyl alcohol recrystallization.B.6-phenyl-3-hexin amine
N-(6-phenyl-3-hexin base) phthalic imidine (3.0g) is handled with a hydrazine hydrate (0.96ml) in ethanol (150ml), and under refluxing, stirred 4 hours.Cooling be will react, dry doubling and water azeotropic will be evaporated to.Residuum extracts with the 1N sodium-hydroxide treatment and with ether (* 2).Organic extract liquid is merged, with 2N hydrochloric acid (* 2) extraction.Aqueous extract is merged, with sodium hydroxide (aq) alkalization, with ether (* 2) extraction.Merge organic extract liquid, wash with water, dry (sal epsom), evaporation provides 6-phenyl-3-hexin amine oily matter (1.52g, 89%).Z-6-phenyl-3-hexenyl amine a.Z-N-(6-phenyl-3-hexenyl) phthalic imidine
N-(6-phenyl-3-hexin base) phthalic imidine (4.4g) is used Lindlar ' s catalyzer (60mg) hydrogenation 105 minutes at 40psi/20 ℃ in ethanol (140ml).To react and filter and be evaporated to yellow oil (4.51g).By the flash column chromatography purifying, with 6: 1 to 4: 1 sherwood oils: eluent ethyl acetate provides Z-N-(6-phenyl-3-hexenyl) phthalic imidine colorless oil (4.15g, 94%).v C=c1656cm -1The nmr homonuclear decoupling closes and provides 3J H3-H4(alkene)=10.8Hz.B.Z-6-phenyl-3-hexenyl amine
Z-N-(6-phenyl-3-hexenyl) phthalic imidine (1.95g) is handled with a hydrazine hydrate (0.64g) in ethanol (100ml), and under refluxing, stirred 4.5 hours and at room temperature stirred 22 hours.With reactive evaporation to dry doubling and water azeotropic.Residuum mixes with 1N sodium hydroxide and extracts with ether (* 2).Organic extract liquid is merged, and with the salt solution washing, dry (sal epsom) is evaporated to dried.Provide Z-6-phenyl-3-hexamethyleneamine oily matter (containing 6-phenyl hexyl amine 10%) (0.89g, 80%) at 185-200 ℃/0.2mmHg Kugelrohr distillation purifying.E-6-phenyl-3-hexenyl amine a.E-N-(6-phenyl-3-hexenyl) phthalic imidine
With E-6-phenyl-3-hexenol (J.Dijkink, N.Speckamp, tetrahedron, Vol.34,173-178,1978) (6.35g), phthalic imidine (6.89g) and the mixture of triphenyl phosphine (9.45g) in exsiccant THF (50ml) cool off in nitrogen.Maintain the temperature at 10 ℃, added the solution of diethylazodicarboxylate (6.27g) in exsiccant THF at 10 minutes.Reaction was at room temperature stirred 20 hours and was evaporated to dried.Residuum mixes with methylene dichloride (100ml) and uses 1N sodium hydroxide, salt solution, and 1N hydrochloric acid, the salt solution washing, dry (sal epsom) also is evaporated to dried.By the flash column chromatography purifying, with 8: 1 to 4: 1 sherwood oils: eluent ethyl acetate provides m.p.75 ℃ of N-(6-phenyl-3-hexenyl) phthalic imidine colorless solid (6.96g, 63%).v C=c1670cm -1The nmr homonuclear decoupling closes and provides 3J H3-H4(alkene)=15Hz.B.E-6-phenyl-3-hexenyl amine
E-N-(6-phenyl-3-hexenyl) phthalic imidine (4.79g) and propyl group amine (5g) were stirred 2 hours under refluxing in ethanol (200ml), then 70 ℃ 18 hours.Reaction mixture is evaporated to dry doubling and ethanol azeotropic.Residuum mixes with 1N sodium hydroxide and extracts with ether (* 2).Merge organic extract liquid, with 2N hydrochloric acid (* 2) washing.Merge aqueous extract,, use sodium hydroxide (aq) alkalization then, with ether (* 2) extraction with the ether washing.Merge organic extract liquid, with the salt solution washing, dry (sal epsom) is evaporated to oily matter.Provide E-6-phenyl-3-hexenyl amine colorless oil (0.98g, 36%) at 180 ℃/0.5mmHgKugelrohr distillation purifying.5-phenoxy group amylamine is chloro-1-phenoxy group pentane a.5-
With phenol (2.67g, 0.028mol), 1, the 5-dichloropentane (20g, 0.148mol) and salt of wormwood (20g, 0.148mol) mixture in methyl ethyl ketone (300ml) refluxed 24 hours.After the cooling, reaction mixture is filtered, be evaporated to yellow oil (37.8g).It by the flash chromatography on silica gel purifying, is provided yellow oil (18g) with 15: 1 wash-outs of hexane/ethyl acetate.It is excessive 1 that it is removed with bath temperature＞80 ℃ evaporation with high vacuum, and 5-dichloropentane (b.p.63-65 ℃) provides yellow oil (5.8g).The further flash chromatography on silica gel purifying of this oily matter provides 5-chloro-1-phenoxy group pentane yellow oil (2.50g, 44%) with the hexane wash-out.B.N-5-phenoxy group amyl group phthalic imidine
(2.50g, 12.6mmol) among the molten fourth DMF (75ml), and (4.65g, 25.13mmol), mixture spent the night 18 hours 100 ℃ of stirrings to add potassium phthalimide with 5-chloro-1-phenoxy group pentane.With the DMF evaporation, solids constituent is assigned between ethyl acetate (75ml) and the water (50ml).Organic layer water (50ml) washing, dry (sal epsom) and evaporation provide yellow solid.This yellow solid provides white solid with ether/sherwood oil recrystallization, and this white solid provides N-5-phenoxy group amyl group phthalic imidine white solid (2.50g, 64%), m.p.62-64 ℃ with the ether recrystallization again.C.5-phenoxy group amylamine
(2.50g, 8.08mmol) (1.21g refluxes in 24.17mmol) and spent the night in 18 hours at ethanol (200ml) and a hydrazine hydrate with N-(phenoxy group)-5-amyl group phthalic imidine.Filter then and evaporate, then several times from the water evaporation, then from ethanol evaporation.Add 2M sodium hydroxide (500ml) and use ether (200ml * 2) extraction.Organic layer washes with water several times and is neutrality up to the pH of solution, and dry (sal epsom) and evaporation provide 5-phenoxy group amylamine yellow oil (1.13g, 78%) then.2-(2-phenoxy group oxyethyl group) ethylamine
The continuous processing 2 described in preparation (at a and b) in front with phenol/salt of wormwood/2-butanone and potassium phthalimide/DMF, 2 '-Dichlorodiethyl ether provides N-(2-(2-phenoxy group oxyethyl group) ethyl) phthalic imidine colorless solid.By the operation of front preparation (in c), in ethanol (200ml), handle this phthalic imidine (2.99g) with hydrazine hydrate (1.44g) and provide title amine yellow oil (0.81g, 47%).2-(3-phenyl propoxy-) ethylamine
At room temperature thanomin (1.53g) is added in dimethyl sulfone (DMSO) NaH (1.0g) (10ml), then adds 1-bromo-3-phenyl-propane (5g), mixture at room temperature stirred 0.5 hour.Obtain title compound yellow oil (1.6g, 36%) after the water treatment.6-phenyl hexyl oxygen base triflate is (6-phenyl hexyl oxygen base) ethanol a.2-
6-phenyl hexyl bromide (6.10g) and ethylene glycol (15.5g) are added in the solution of sodium hydroxide (1.08g) in water (1.1ml), and mixture was 100 ℃ of heating 30 hours.Add ether (75ml) and water (75ml), separately, the salt solution washing then of ether layer water, dried over mgso is evaporated to orange.It is distilled (225 ℃/0.2mm) follow silica gel column chromatography (40-60 petrol ether/ethyl acetate) purifying to provide b.2-(6-phenyl hexyl oxygen base) ethyl triflate of colorless oil (3.04g, 54%) by Kugelrohr
With 2-(6-phenyl hexyl oxygen base) ethanol (2.88g), pyridine (1.23g) and DMAP (20mg) are dissolved in exsiccant methylene dichloride (15ml), be cooled to-5 ℃, keep temperature＜0 ℃, be added in the trifluoromethanesulfanhydride anhydride (4.37g) in the methylene dichloride (10ml) at 5 minutes.Mixture stirred 1 hour at 0 ℃, water then, and the salt solution washing, dried over mgso also is evaporated to colorless oil (4.54g, 99%).
Be prepared as follows 2 triflate with similar method.2-(6-(4-chloro-phenyl-) hexyl oxygen base) ethyl triflate 2-(6-(4-fluorophenyl) hexyl oxygen base) ethyl triflate 3-phenoxy group-1-trifyl propane
In nitrogen atmosphere, with 3-phenoxy group third-1-alcohol (2.38g), pyridine (1.19g) and 4-dimethylaminopyridine (DMAP) mixture (0.10g) are cooled to-5 ℃.Between 0 ℃ to-5 ℃, dripped the trifluoromethanesulfanhydride anhydride (4.4g) that is dissolved in the exsiccant methylene dichloride (15ml) at 30 minutes, stirred 2 hours at 0 ℃ then.Mixture is poured in the water, tell organic layer, water (* 2) washing, dry (sal epsom), reduction vaporization is a chocolate oily matter, and it by the flash chromatography on silica gel purifying, is used 2: 1 wash-outs of 40 ℃ of-60 ℃/ethyl acetate of sherwood oil, the limpid oily matter that provides title compound is light brown/orange (3.22g, 73%).2-phenoxy group-1-trifyl ethane prepares from corresponding alcohol by similar method.(4-(4-ethoxycarbonyl) benzyl sulfenyl) azetidine-2-ketone is (brooethyl) ethyl benzoate a.4-
(25.75g 0.1197mol) is suspended in the sulfur oxychloride (50ml), adds dimethyl formamide (0.25ml) with 4-(brooethyl) phenylformic acid.Mixture heating up is refluxed 25 minutes until limpid, evaporation and with toluene (* 2) azeotropic.The oily matter that produces is dissolved in methylene dichloride (75ml), and (8.6ml, 0.1465mol), (10.5ml 0.1298mol) in the solution in exsiccant methylene dichloride (50ml), is cooled to 10 ℃ to pyridine to be added drop-wise to absolute ethanol at 10 minutes.Remove ice bath, will react and stir 45 minutes, then water, 2N hydrochloric acid, water, sodium hydrogen carbonate solution and salt solution washing.Organic solution drying (sal epsom) is also evaporated the mixture oily matter (25.6g, 94%) of 4-(brooethyl) ethyl benzoate: 4-(chloromethyl) ethyl benzoate that provides 60: 40 1H nmr δ (CDCl 3) 1.40 (3H, m, CH 3), 4.40 (2H, m, CH 2O), 4.50,4.61 (2H, 2xs, CH 2Cl/Br), 7.45 (2H, m, Ar-H), 8.01 (2H, m, Ar-H) b.4-(ethanoyl sulfenyl methyl) ethyl benzoates
With 60: 40 4-(brooethyl) ethyl benzoate: 4-(chloromethyl) ethyl benzoate (25.0g in exsiccant dimethyl formamide (150ml) that is cooled to 5 ℃, 0.111mol) usefulness thioacetic acid potassium (13.3g, 0.117mol) handle, temperature rises to 20 ℃.Reaction was at room temperature stirred 2 hours, poured in the water (250ml) also with ether (3 * 100ml) extractions.Organic extract liquid is merged, wash with water, fourth dry (sal epsom), activated carbon treatment and evaporation provide 4-(ethanoyl sulfenyl methyl) ethyl benzoate brown solid (26.0g, 99%), m.p.36-37 ℃. 1H nmr δ (CDCl 3) 1.38 (3H, t, J=7.1Hz, CH 3), 2.36 (3H, s, COCH 3), 4.14 (2H, s, CH 2S), 4.36 (2H, q, CH 2O), 7.35 (2H, d, J=8.2Hz, Ar-H), 7.97 (2H, d, J=8.2Hz, Ar-H) c.4-(4-ethoxycarbonyl) benzyl sulfenyl) azetidine-2-ketone
With sodium (1.87g, 0.0813mol) solution in absolute ethanol (300ml) at 3 minutes with 4-(ethanoyl sulfenyl methyl) ethyl benzoate (19.4g, 0.0814mol) solution-treated in absolute ethanol.To react and at room temperature stir 30 minutes, be cooled to-5 ℃, and at 5 minutes with 4-acetoxyl group azetidine-2-ketone (10.0g, 0.07745mol) solution-treated.Remove cryostat, will react and stir 2 hours, be evaporated to driedly, handle with salt solution (200ml), and (200ml 100ml) extracts with ethyl acetate.Organic extract liquid is merged, and with the salt solution washing, dry (sal epsom) also is evaporated to red oil.By the fast silica gel chromatogram purifying, with 3: 1 to 1: 2 sherwood oil 40-60 ℃: eluent ethyl acetate provides 4-(4-ethoxycarbonyl) benzyl sulfenyl) azetidine-2-ketone orange (18.64g, 91%). 1H nmr δ (CDCl 3) 1.38 (3H, t, J=7.1Hz, CH 3), 2.82,2.89 (1H, 2xm, H 3), 3.29,3.35 (1H, 2xm, H 3), 3.88 (2H, s, CH 2S), 4.37 (2H, q, CH 2O), 4.70 (1H, m, H 4), 5.70 (1H, bs, NH), 7.40 (2H, d, J=8.3Hz, Ar-H), 8.00 (2H, m, Ar-H) EXAMPLE Example 1 N-[6-(4-chloro-phenyl-hexyl)]-2-[4-benzylthio--2-aza-oxo-cyclobutane-1-yl] propionic acid amide (diastereomer b) (4-benzylthio--2-aza-oxo-cyclobutane-1-yl) methyl propionate a.2-
With fresh powdered potassium hydroxide (0.62g, 0.011mol) handle the 4-benzylthio-nitrogen heterocyclic din-2-ketone (1.93g in anhydrous tetrahydro furan (50ml), 0.01mol), DL-2-bromo propionic acid A ester (1.23ml, 0.011mol) and Tetrabutylammonium bromide (0.32g, 0.001mol) mixture, and in stirring at room 1 hour.Use ethyl acetate and water treatment subsequently, filter and remove insoluble yellow solid and discarded, filtrate is separated.Use ethyl acetate extraction water liquid layer again, again with the extraction liquid drying (MgSO that merges 4) and be evaporated to brown oil.Flash chromatography (silica gel, ethyl acetate/gasoline) purifying obtains being the title compound (water white oil) of non-enantiomer mixture, 0.5g, 18% productive rate. 1H NMR δ (CDCl 3) 1.55 (2x3H, d), 2.93 (2x1H, m), 3.29 (2x1H, m), 3.74 and3.75 (each 3H, s), 3.80 and 3.84 (each 2H, s), and 3.91 and 4.41 (each 1H, q), 4.70and 4.96 (each 1H, m), 7.30 (2x5H, m) b.2-(4-benzylthio--2-aza-oxo-cyclobutane-1-yl) propionic acid
Handle 2-(4-benzylthio--2-aza-oxo-cyclobutane-1-yl) methyl propionate (1.39g, stirred solution 0.005mol) in methyl alcohol (12ml) with 1 moles of hydrogen potassium oxide (5.47ml).After 2 hours, with the methyl alcohol evaporation, the dilute with water resistates is also used twice of extracted with diethyl ether.Be extracted in the ether with cooling (ice bath) acidifying of water liquid layer and with sedimentary oil.The extraction liquid drying (MG) that merges is also evaporated the solid title compound (mixture of diastereomer) that then obtains being white in color, m.p.78-82 ℃, 0.98g, 74% productive rate. 1H NMR δ (CDCl 3) 1.58 (2x3H, d), 2.94 (2x1H, m), 3.29 (2x1H, m), 3.80 and3.83 (each 2H, s), 3.80 and 4.39 (each 1H, q), and 4.73 and 4.95 (each 1H, m), 6.94 (2x1H, s), 7.30 (2x5H, m) c.N-[6-(4-chloro-phenyl-hexyl)]-2-[4-benzylthio--2-aza-oxo-cyclobutane-1-yl] propionic acid amide (diastereomer b)
Will be in room temperature in the 6-in the dimethyl formamide (10ml) (4-chloro-phenyl-) hexanamide (0.54g, 0.00256mol, Lamattina J.L.EP138464 A2 850424 (CA103:142000), I-hydroxybenzotriazole hydrate (0.35g, 0.00256mol), 2-(4-benzylthio--2-aza-oxo-cyclobutane-1-yl) propionic acid (0.68g, 0.00256mol) and carbodiimide (0.53g, mixture stirring 0.00256mol) 16 hours.Evaporating solvent is also handled resistates with ethyl acetate.Filter and discarded insoluble dicyclohexylurea (DCU), wash this filtrate with saturated sodium bicarbonate aqueous solution, dry (MG) and evaporation obtain oil.Separate non-enantiomer mixture with flash chromatography (silica gel, t-butyl methyl ether/gasoline), merge the part and the evaporation of the diastereomer that contains slow wash-out, obtain title compound (0.14g, 11.8% productive rate) into oil. 1H NMR δ (CDCl 3) 1.32 (4H, m), 1.51 (3H, d), 1.53 (4H, m), 2.55 (2H, t), 2.87 (1H, dd), 3.24 (3H, m), 3.82 (2H, s), 4.06 (1H, q), 4.69 (1H, dd), 6.51 (1H, m), 7.06-7.33 (9H, m). embodiment 2 N-[6-(4-chloro-phenyl-hexyl)]-2-[4-benzylthio--2-aza-oxo-cyclobutane-1-yl] (diastereomer is a) for propionic acid amide
The part of the diastereomer that contains very fast wash-out in evaporation the foregoing description obtains other diastereomer (0.54g, 46% productive rate) into water white oil. 1H NMR δ (CDCl 3) 1.33 (4H, m), 1.53 (3H, d), 1.57 (4H, m), 2.55 (2H, t), 2.83 (1H, dd), 3.26 (3H, m), 3.84 (2H, s), 3.92 (1H, q), 4.77 (1H, dd), 6.58 (1H, m), 7.05-7.36 (9H, m). embodiment 3 N-[6-(4-chloro-phenyl-hexyl)]-2-[4-benzylthio--2-aza-oxo-cyclobutane-1-yl] propionic acid amide (diastereomer b1﹠amp; B2)
Will be in the N-[6-in the methylene dichloride (25ml) (4-chloro-phenyl-hexyl-)]-2-[4-benzylthio--2-aza-oxo-cyclobutane-1-yl] solution (0.96g of propionic acid amide (diastereomer b), 0.0021mol) be cooled to-65--70 ℃ and in 15 minutes, drip m-chlorine peroxybenzoic acid in methylene dichloride (10ml) (0.43g, 0.0025mol).Wash this mixture with saturated sodium bicarbonate and saturated sodium sulfate mixture after 45 minutes, dry (MG) and evaporation obtain oil.To obtain diastereomer b1: b2 be 40: 60 title compound in crystallization from ethyl acetate-ether, fusing point 70-73 ℃.Embodiment 4 N-[6-(4-chloro-phenyl-hexyl)]-2-[4-benzylthio--2-aza-oxo-cyclobutane-1-yl] propionic acid amide (isomer (-) b2)
Obtain title compound with chromatography (HPLC, Chiracell OJ post is used silica gel, ethanol/hexane subsequently) this solid of purifying, white solid is single enantiomer.[a] D 20=-41.6 ° (c0.11, ethanol) 1H NMR δ (CDCl 3) 1.33 (4H, m), 1.55 (4H, m), 1.61 (3H, d), 2.56 (2H, t), 2.76 (1H, dd), 3.12 (1H, dd), 3.23 (2H, m), 3.96,4.09 (each 1H, d), 4.45 (1H, q), 4.58 (1H, dd), (9H m) obtains other 3 kinds of compositions (embodiment 5-7) of this mixture to 7.07-7.39 with identical chromatography.Embodiment 5 N-[6-(4-chloro-phenyl-hexyl)]-2-[4-benzylthio--2-aza-oxo-cyclobutane-1-yl] propionic acid amide (isomer (+) b2) [a] D 20=+34.5 ° (c0.11, ethanol); 99.2% purity. 1H NMR δ (CDCl 3) 1.33 (4H, m), 1.55 (4H, m), 1.61 (3H, d), 2.56 (2H, t), 2.76 (1H, dd), 3.12 (1H, dd), 3.23 (2H, m), 3.96,4.09 (each 1H, d), 4.45 (1H, q), 4.58 (1H, dd), 7.07-7.39 (9H, m) embodiment 6 N-[6-(4-chloro-phenyl-hexyl)]-2-[4-benzylthio--2-aza-oxo-cyclobutane-1-yl] propionic acid amide (isomer (+) b1) [a] D 20=+80.7 ° (c0.11, ethanol); 96.2% purity. 1H NMR δ (CDCl 3) 1.32 (4H, m), 1.42 (3H, d), 1.55 (4H, m), 2.55 (2H, t), 2.90 (1H, dd), 3.20 (2H, m), 3.45 (1H, dd), 3.88,4.06 (each 1H, d), 4.34 (1H, q), 4.48 (1H, dd), 6.95 (1H, m), 7.08-7.41 (9H, m) embodiment 7 N-[6-(4-chloro-phenyl-hexyl)]-2-[4-benzylthio--2-aza-oxo-cyclobutane-1-yl] propionic acid amide (isomer (-) b1) [a] D 20=-95.5 ° (c0.11, ethanol); 99.4% purity. 1H NMR δ (CDCl 3) 1.32 (4H, m), 1.42 (3H, d), 1.55 (4H, m), 2.55 (2H, t), 2.90 (1H, dd), 3.20 (2H, m), 3.45 (1H, dd), 3.88,4.06 (each 1H, d), 4.34 (1H, q), 4.48 (1H, dd), 6.95 (1H, m), 7.08-7.41 (9H, m) embodiment 8 N-[6-(4-chloro-phenyl-hexyl)]-2-[4-benzylthio--2-aza-oxo-cyclobutane-1-yl] propionic acid amide (diastereomer a1)
As embodiment 3 usefulness mCPBA Processing Examples 7 N-[6-(4-chloro-phenyl-hexyl)]-2-[4-benzylthio--2-aza-oxo-cyclobutane-1-yl] (diastereomer a) obtains title compound into non-enantiomer mixture to propionic acid amide.This mixture of recrystallization obtains the N-[6-(4-chloro-phenyl-hexyl) into clear crystal from ethyl acetate]-2-[4-benzylthio--2-aza-oxo-cyclobutane-1-yl] propionic acid amide (diastereomer a1), fusing point 168-170 ℃. 1H NMR δ (CDCl 3) 1.32 (4H, m), 1.49 (2H, m), 1.55 (3H, d), 1.60 (2H, m), 2.56 (2H, t), 2.83 (1H, dd), 3.20 (2H, m), 3.38 (1H, dd), 3.88,3.97 (each 1H, d), 4.08 (1H, q), 4.67 (1H, dd), 6.38 (1H, m), 7.08-7.40 (9H, m) embodiment 9 N-[6-(4-chloro-phenyl-hexyl)]-2-[4-benzylthio--2-aza-oxo-cyclobutane-1-yl] propionic acid amide (diastereomer a2)
Handle the mother liquor that obtains by above-mentioned recrystallization with sherwood oil (b.p.40-60), obtain being white crystal solid title compound, fusing point 79-81 ℃. 1H NMR δ (CDCl 3) 1.33 (4H, m), 1.52 (4H, m), 1.61 (3H, d), 2.56 (2H, t), 2.77 (1H, dd), 3.15 (1H, dd), 3.24 (2H, m), 4.01 (1H, q), 4.01,4.12 (each 1H, d), 4.58 (1H, dd), 7.08-7.41 (9H, m) embodiment 10 N-[6-(4-fluorophenyl hexyl)]-2-[4-benzylthio--2-aza-oxo-cyclobutane-1-yl] propionic acid amide (diastereomer b) a. (4-benzylthio--2-aza-oxo-cyclobutane-1-yl) methyl acetate
To the 4-benzylthio-nitrogen heterocyclic din-2-ketone in anhydrous THF (150ml) (5.0g, 25mmol), the monobromo-acetic acid methyl esters (4.6g, 30mmol) and Tetrabutylammonium bromide (0.9g, add in solution 0.28mmol) powdered potassium hydroxide (1.7g, 30mmol).And adding entry (50ml) before in stirring at room gained mixture 2 hours.Extract this solution with ethyl acetate (3 * 150ml part), and dry extraction liquid (MG) that merges and evaporation.By flash chromatography this resistates of purifying on silica gel, use 60-80 ° of sherwood oil: 4: 1 wash-outs of ethyl acetate obtain (4-benzylthio--2-aza-oxo-cyclobutane-1-yl) methyl acetate (5g, 70%) into yellow oil. 1H NMR δ (CDCl 3) 2.96 (1H, dd, J=2.5,16Hz H 3a), 3.24,3.99 (each 1H, d, J=18.00Hz, NCH 2), 3.4 (1H, dd, J=5,12.5Hz H 3b), 3.70 (3H, s, OCH 3), 3.77 (2H, s, SCH 2), 4.92 (1H, m, H 4), 7.28 (5H, m, Ph-H) b. 2-(4-benzylthio--2-aza-oxo-cyclobutane-1-yl) methyl propionates
(4-benzylthio--2-aza-oxo-cyclobutane-1-yl) methyl acetate (13.27g that will be in anhydrous tetrahydro furan, 0.05mol) stirred solution be cooled to-70 ℃ (acetone-ice (cardice) baths), under nitrogen, in 15 minutes, add two (trimethyl silyl) lithium nitrides (60ml), add 1 subsequently, 3-dimethyl-2-imidazolone (33ml).After 30 minutes, and the dropping methyl iodide (5.6ml, 0.09mol).After 4 hours, temperature of reaction is risen to-20 ℃, and then this mixture is chilled to-70 ℃ and drip Glacial acetic acid (5.6ml).Water should react cancellation and use extracted with diethyl ether 3 times.Dry extraction liquid (MG) that merges and evaporation obtain oil, are purified the non-enantiomer mixture product that obtains to yellow oil by flash chromatography (thin silica gel, ethyl acetate/petroleum naphtha), and polluting has 9% dimethylated product, 13.7g, 89% productive rate. 1H NMR δ (CDCl 3) 1.55 (2x3H, d), 2.93 (2x1H, m), 3.29 (2x1H, m), 3.74 and3.75 (each 3H, s), 3.80 and 3.84 (each 2H, s), and 3.91 and 4.41 (each 1H, q), 4.70and 4.96 (each 1H, m), 7.30 (2x5H, m) c.2-(4-benzylthio--2-aza-oxo-cyclobutane-1-yl) propionic acid
The 2-in methyl alcohol (4-benzylthio--2-aza-oxo-cyclobutane-1-yl) methyl propionate that handle to stir with 1 moles of hydrogen potassium oxide (5.47ml) (1.39g, 0.005mol).After 2 hours, evaporation methyl alcohol, water wash-out resistates and use the extracted with diethyl ether secondary is followed this water liquid layer of cooling (ice bath) acidifying and sedimentary oil is extracted in the ether.Dry extraction liquid (MG) that merges and evaporation obtain the acetonide (mixture of diastereomer) into white solid, and fusing point 78-82 ℃, 0.98g, 74% productive rate. 1H NMR δ (CDCl 3) 1.58 (2x3H, d), 2.94 (2x1H, m), 3.29 (2x1H, m), 3.80 and3.83 (each 2H, s), 3.80 and 4.39 (each 1H, q), and 4.73 and 4.95 (each 1H, m), 6.94 (2x1H, s), 7.30 (2x5H, m) d. N-[6-(4-fluorophenyl hexyl)]-2-[4-benzylthio--2-aza-oxo-cyclobutane-1-yl] propionic acid amide (diastereomer b)
6-in stirring at room in dimethyl formamide in (60ml) (4-fluorophenyl) hexanamide (3.0g, 0.0154mol), I-hydroxybenzotriazole hydrate (2.08g, 0.0154mol), 2-(4-benzylthio--2-aza-oxo-cyclobutane-1-yl) propionic acid (4.08g, 0.0154mol) and dicyclohexyl carbodiimide (3017g, mixture 0.0154mol) 16 hours.Evaporating solvent is also handled this resistates with ethyl acetate.Filter and discarded insoluble dicyclohexylurea (DCU), wash this filtrate with saturated sodium bicarbonate aqueous solution, dry (MG) and evaporation obtain oil.Separate non-enantiomer mixture with flash chromatography (thin silica gel, t-butyl methyl ether/gasoline), merge the part and the evaporation of the diastereomer that contains slow wash-out, obtain title compound, output 1.89g (28%) into oil. 1H NMR δ (CDCl 3) 1.33 (4H, m), 1.51 (3H, d), 1.53 (4H, m), 2.55 (2H, t), 2.87 (1H, dd), 3.24 (3H, m), 3.82 (2H, s), 4.06 (1H, q), 4.69 (1H, dd), 6.51 (1H, m), 6.91-7.33 (9H, m). embodiment 11 N-[6-(4-fluorophenyl hexyl)]-2-[4-benzylthio--2-aza-oxo-cyclobutane-1-yl] (diastereomer is a) for propionic acid amide
Also can obtain diastereomer into the very fast wash-out of oil, output 2.8g (41%) from above-mentioned column chromatography. 1H NMR δ (CDCl 3) 1.33 (4H, m), 1.53 (3H, d), 1.57 (4H, m), 2.55 (2H, t), 2.83 (1H, dd), 3.26 (3H, m), 3.84 (2H, s), 3.92 (1H, q), 4.77 (1H, dd), 6.58 (1H, m), 6.91-7.36 (9H, m). embodiment 12 N-[6-(4-fluorophenyl hexyl)]-2-[4-benzylthio--2-aza-oxo-cyclobutane-1-yl] propionic acid amide (diastereomer b1+b2)
Will be in the N-[6-in the methylene dichloride (30ml) (4-fluorophenyl hexyl)]-2-[4-benzylthio--2-aza-oxo-cyclobutane-1-yl] propionic acid amide (diastereomer b) (embodiment 11) (1.82g, 0.0041mol) solution be cooled to-65--70 ℃ and in 30 minutes, drip m-chlorine peroxybenzoic acid in methylene dichloride (30ml) (0.85g, 0.0049mol).Wash this mixture with saturated sodium bicarbonate and saturated sodium sulfate mixture after 2 hours, dry (MG) and evaporation obtain oil.Crystallization obtains the mixture (1.18g) (b1: b2 is 1: 3) of diastereomer, fusing point 75-78 ℃ from ethyl acetate-V.M.. naphtha.Embodiment 13 N-[6-(4-fluorophenyl hexyl)]-2-[4-benzylthio--2-aza-oxo-cyclobutane-1-yl] propionic acid amide (diastereomer (-) b2)
Is b1 and b2 by HPLC (Dynamax silicagel column, ethanol/hexane) with the mixture separation of above-mentioned diastereomer b1+b2.Again diastereomer b2 is separated into its composition enantiomorph by chirality HPLC (Chiralcel OD post, ethanol/hexane) then, obtains title compound, 0.06g into white solid. 1H NMR δ (CDCl 3) 1.33 (4H, m), 1.55 (4H, m), 1.61 (3H, d), 2.56 (2H, t), 2.75 (1H, dd), 3.11 (1H, dd), 3.23 (2H, m), 3.96,4.09 (each 1H, d), 4.45 (1H, q), 4.58 (1H, dd), 6.92-7.40 (9H, m) [a] D 20=-36.2 (c0.46, ethanol) embodiment 14 N-[6-(4-fluorophenyl hexyl)]-2-[4-benzylthio--2-aza-oxo-cyclobutane-1-yl] propionic acid amide (diastereomer (+) b2)
Also obtain (+) enantiomorph, output 0.06g into white solid. 1H NMR δ (CDCl 3) 1.33 (4H, m), 1.55 (4H, m), 1.61 (3H, d), 2.56 (2H, t), 2.75 (1H, dd), 3.11 (1H, dd), 3.23 (2H, m), 3.96,4.09 (each 1H, d), 4.45 (1H, q), 4.58 (1H, dd), 6.92-7.40 (9H, m) [a] D 20=+32.7 (c0.42, ethanol)
Press the method for embodiment 12 and handle N-[6-(4-fluorophenyl hexyl) with mCPBA (0.54g)]-2-[4-benzylthio--2-aza-oxo-cyclobutane-1-yl] propionic acid amide (1.15g) (diastereomer a, embodiment 10), two kinds of diastereomers (embodiment 15,16) embodiment 15 N-[6-(4-fluorophenyl hexyl) below after chromatography, obtaining]-2-[4-benzylthio--2-aza-oxo-cyclobutane-1-yl] propionic acid amide (diastereomer a1)
0.5g, white solid, fusing point 165-7 ℃, 1H NMR d (CDCl 3) (diagnostic peak of selection) 4.11 (1H, q, a-H), 4.70 (1H, m, H4); Actual measurement: C, 65.2, H, 6.7, N, 5.8%C 25H 31FN 2O 3S calculated value: C, 65.5, H6.8, N, 6.1% embodiment, 16 N-[6-(4-fluorophenyl hexyl)]-2-[4-benzylthio--2-aza-oxo-cyclobutane-1-yl] propionic acid amide (diastereomer a2)
0.28g, white solid, fusing point 73-5 ℃, 1H NMR d (CDCl 3) (diagnostic peak of selection) 4.00 (1H, q, a-H), 4.58 (1H, m, H4); Actual measurement: C, 65.3, H, 6.65, N, 5.7%C 25H 21FN 2O 3S calculated value: C, 65.5, H6.8, N, 6.1% embodiment, 17 N-[6-(4-fluorophenyl hexyl)]-2-[4-benzylthio--2-aza-oxo-cyclobutane-1-yl] (diastereomer is a) for propionic acid amide
Handle N-[6-(4-fluorophenyl hexyl) in room temperature with mCPBA (2.43g)]-2-[4-benzylthio--2-aza-oxo-cyclobutane-1-yl] propionic acid amide (2.7g) (diastereomer a, embodiment 10), obtain title compound (2.43g), fusing point 85-7 ℃ for white solid 1H NMRd (CDCl 3) (diagnostic peak of selection) 3.96 (1H, q, a-H), 4.75 (1H, m, H4); Actual measurement: C, 63.2, H, 6.45, N, 5.9% C 25H 31FN 2O4S calculated value: C, 63.3, H6.6, N, 5.9% embodiment, 18 N-[6-(4-fluorophenyl hexyl)]-2-[4-benzyl sulfinyl-2-aza-oxo-cyclobutane-1-yl] propionic acid amide (diastereomer b)
Handle N-[6-(4-fluorophenyl hexyl) in room temperature with mCPBA (0.22g)]-2-[4-benzylthio--2-aza-oxo-cyclobutane-1-yl] propionic acid amide (0.39g) (diastereomer b, embodiment 11), obtain title compound (0.29g), fusing point 90-2 ℃ for white solid; 1H NMRd (CDCl 3) (diagnostic peak of selection) 4.27 (1H, q, a-H), 4.64 (1H, m, H4); Actual measurement: C, 63.0; H, 6.4; N, 5.85% C 25H 31FN 2O4S calculated value: C, 63.3; H6.6; N, 5.9% embodiment, 19 N-(benzyl)-2-[4-benzylthio--2-aza-oxo-cyclobutane-1-yl] (diastereomer is a) for propionic acid amide
Under the described condition of embodiment 10c, handle 2-[4-benzylthio--2-aza-oxo-cyclobutane-1-yl with benzylamine] propionic acid (embodiment 10b), obtain having the transparent buttery title compound (1.19g) of chromatographic higher rf product; 1H NMR d (CDCl 3) (diagnostic peak of selection) 4.27 (1H, q, a-H), 4.80 (1H, m, H4); Embodiment 20 N-(benzyl)-2-[4-benzylthio--2-aza-oxo-cyclobutane-1-yl] propionic acid amide (diastereomer b)
Through above-mentioned chromatographic separation, the title compound (1.44g) that low rf partly combines and obtains colorless solid; Fusing point 70-2 ℃; 1H NMR d (CDCl 3) (diagnostic peak of selection) 4.10 (1H, q, a-H), 4.69 (1H, m, H4); Embodiment 21 N-[6-(4-fluorophenyl hexyl)]-2-[4-carbalkoxy benzylthio--2-aza-oxo-cyclobutane-1-yl] (diastereomer is (brooethyl) phenylformic acid allyl ester a) a.4-for propionic acid amide
4-(brooethyl) phenylformic acid (103g, 0.48 mole) is suspended in the thionyl chloride (200ml), and to wherein adding dimethyl formamide (1ml).This mixture reflux is up to transparent, evaporation and with methylbenzene azeotropic (2 * 150ml).Resulting oil is dissolved in the methylene dichloride, is added drop-wise to again in the cooling fluid of pyridine (42ml) in methylene dichloride and vinyl carbinol (40ml).After this mixture at room temperature stirs 1 hour, water, 2M hydrogenchloride, sodium hydrogen carbonate solution and salt water washing.Dry and evaporation then obtains being transparent buttery 4-(brooethyl) phenylformic acid allyl ester (98g, 84% productive rate) with this organic solution. 1HNMR?d(CDCl 3)4.61(2H，s，CH 2)，4.82(2H，m，CH 2O)，5.34(2H，m，CH 2CH-)，6.05(1H，m，CHCH 2)，7.45(2H，d，Ph-H)，8.03(2H，d，Ph-H)。B.4-(ethanoyl sulphomethyl) phenylformic acid allyl ester
To be added drop-wise in the cooling suspension of the thioacetic acid potassium (46g, 0.4 mole) in dry state dimethyl formamide (200ml) in 4-(brooethyl) the phenylformic acid allyl ester in the dry state dimethyl formamide (100ml).With cooling bath remove, mixture stirs a whole liquid.To extract in this mixture impouring water and with ethyl acetate (* 3) again.This bonded extract of water and salt water washing.Dry and evaporation then obtains being orange buttery 4-(ethanoyl sulphomethyl) phenylformic acid allyl ester (100g, 100% productive rate) with this mixture solution. 1H?NMRd(CDCl 3)2.36(3H，s，COCH 3)，4.13(2H，s，CH 2)，4.82(2H，m，CH 2O)，5.32(2H，m，CH 2CH-)，6.05(1H，m，CHCH 2)，7.35(2H，d，Ph-H)，7.98(2H，d，Ph-H)。C.4-(4-(allyloxycarbonyl) benzylthio-) nitrogen heterocyclic din-2-ketone
To be added drop-wise at the vinyl carbinol (27ml) in the dry tetrahydrofuran (50ml) in the potassium tert.-butoxide (4.93g, 0.044 mole) in dry tetrahydrofuran (100ml).After stirring in 5 minutes, will drip wherein at the 4-in the dry tetrahydrofuran (100ml) (ethanoyl sulfenyl methyl) phenylformic acid allyl ester (10.1g, 0.04 mole).After stirring in 15 minutes, 4-acetoxyl group nitrogen heterocyclic din-2-ketone (5.16g, 0.04 mole) is dripped wherein.Again this mixture is stirred evaporation after 1 hour.Residue distributes between ethyl acetate and water, the aqueous-phase material ethyl acetate extraction.With this bonded extract of salt water washing, dry and evaporation.Flash chromatography (silica gel, ethyl acetate-gasoline) then obtains buttery 4-(4-(allyloxycarbonyl) benzylthio-) nitrogen heterocyclic din-2-ketone (9.1g, 82% productive rate). 1H NMR d (CDCl 3) 2.84 (1H, dd, H3a), 4.31 (1H, dd, H3b), 3.88 (2H, s, S-CH2), 4.68 (1H, dd, H4), 4.78 (2H, m, CH 2O), 5.35 (2H, m, CH 2CH-), 6.05 (1H, m, CHCH 2), 6.07 (1H, br.singlet, N-H), 7.40 (2H, d, Ph-H), 8.03 (2H, d, Ph-H) .d. 4-(4-(allyloxycarbonyl) benzylthio-)-2-oxo-azetidin-1-guanidine-acetic acid methyl esters
To in the 4-of dry tetrahydrofuran (40ml) (4-(allyloxycarbonyl) benzylthio-) nitrogen heterocyclic din-2-ketone (2.55g, 9.2 Tetrabutylammonium bromide (0.33g mole),, 1.02 mole) and monobromo-acetic acid methyl esters (1.06ml, 11.2 in stirring liquid mole), add pulverous potassium hydroxide (0.63g, 11.2 mmole), adopt cooling bath to keep temperature of reaction to be lower than 30.After 2 hours, this mixture dilute with water and with 3 times ethyl acetate extraction.With this bonded extract drying (MgSO 4) and evaporation.Residue (thin silica gel, ethyl acetate-gasoline) after chromatogram then obtains transparent buttery title compound (2.66g, 83% productive rate). 1H NMR δ (CDCl 3) 2.97 (1H, dd, H3a), 3.26,4.07 (each 1H, CH 2CO, d), 3.42 (1H, dd, H3b), 3.70 (3H, s, CH 3O), 3.81 (2H, s, SCH 2), 4.83 (2H, m, CH 2O), 4.93 (1H, dd, H4), 5.35 (2H, m, CH 2CH), 6.03 (1H, m, CHCH 2), 7.39 (2H, d, Ph-H), 8.02 (2H, d, Ph-H) e.4-(4-(allyloxycarbonyl) benzylthio-)-2-oxo-azetidin-2-base methyl propionates
Under-65 ℃ nitrogen, in dry tetrahydrofuran, stir 4-(4-(allyloxycarbonyl) benzylthio-)-2-oxo-azetidin-1-guanidine-acetic acid methyl esters, and with two (TMS) lithamides (1.0 molar solutions in hexane of 8.6ml), keep temperature-65 ℃.This mixture is stirred after 5 minutes with 1, and 3-methylimidazole quinoline diketone (44.6ml) drips to handle with the assurance temperature and does not rise.This mixture stirred after 30 minutes, dripped methyl iodide (7.6ml).Then, again this mixture is stirred 1 hour post-heating to-20 ℃.After the cooling, mixture is handled with acetate (7ml) again, in the impouring water, with ethyl acetate extraction (* 6).This bonded extract becomes orange oil through super-dry and evaporation.Flash chromatography (thin silica gel, ethyl acetate-gasoline) then obtains desired 4-(4-(allyloxycarbonyl) benzylthio-)-2-oxo-azetidin-2-base methyl propionate (15.2g, 62% productive rate), is a kind of mixture of diastereomer of yellow oil. 1H NMR δ (CDCl 3) 1.56 (3H, d), 2.85-2.96 (2H, m, diastereomer A and B, H 3a), 3.24-3.35 (2H, m, diastereomer A and B, H 3b), 3.74 (3H, s), 3.76 (3H, s), 3.87 (2H, d), 3.97 (1H, q, diastereomer B, N-CH), 4.43 (1H, q, diastereomer A, N-CH), 4.71 (1H, m, diastereomer B, H 4), 4.82 (2H, m), 4.97 (1H, m, diastereomer A, H 4), 5.27-5.46 (2H, m), 5.96-6.10 (1H, m), 7.39 (2H, d), 8.02 (2H, d) .f.4-(4-(allyloxycarbonyl) benzylthio-)-2-oxo-azetidin-2-base propionic acid
To the 4-in tetrahydrofuran (THF) (100ml) (4-(allyloxycarbonyl) benzylthio-)-2-oxo-azetidin-2-base methyl propionate (9.0g, 0.0248 mole) in the solution, dripped the 1M potassium hydroxide solution of 29.7ml in the clock time at 20 minutes), keep 0-5 ℃ of temperature.With this mixture stir dilute with water after 20 minutes, with ether extraction (* 2).This aqueous solution cools off with the dilute hydrochloric acid dilution again, uses ether extraction (* 2) again.This bonded extract becomes the title compound (8.5g, 98% productive rate) of yellow oil through super-dry and evaporation. 1H NMR δ (CDCl 3) 1.50-1.6 (3H, m), 2.86-2.98 (2H, m, diastereomer A andB, H 3a), 3.24-3.35 (2H, m, diastereomer A and B, H 3b), 3.87 (2H, d), 3.95 (1H, q, diastereomer B, N-CH), 4.45 (1H, q, diastereomer A, N-CH), 4.75 (1H, m, diastereomer B, H 4), 4.82 (2H, m), 4.98 (1H, m, diastereomer A, H 4), 5.27-5.46 (2H, m), 5.96-6.10 (1H, m), 7.39 (2H, d), 8.02 (2H, d) .g. (+/-)-N-[6-(4-fluorophenyl hexyl)]-2-[4-(allyloxycarbonyl) benzylthio-)-2-oxo-azetidin-2-yl] (diastereomer is a) for propionic acid amide
Will be at the dicyclohexyl carbodiimide (4.75g of dried dimethyl formamide (50ml), 23 mmoles) be added drop-wise to 4-(4-(allyloxycarbonyl) benzylthio-)-2-oxo-azetidin in dried dimethyl formamide (50ml)-2-base propionic acid (8.0g, 23 mmoles), I-hydroxybenzotriazole hydrate (3.11g, 23 mmoles) and in 6-(4-fluorophenyl) hexylamine (4.5g, 23 mmoles).Remove cooling, stir this mixture a whole night.With the dimethyl formamide evaporation, residue then obtains sample by flash chromatography purification (thin silica gel is used ethyl acetate after the t-butyl methyl ether), and it mainly is diastereomer a (4.6g), diastereomer b (2.7g) and mixing portion.
Diastereomer a: yellow oil, 4.6g, 38% productive rate. 1H NMR δ (CDCl 3) 1.23-1.63 (11H, m), 2.55 (2H, t), 2.81 (1H, dd, H 3a), 3.20-3.30 (3H, m, CH 2And H 3b), 3.90 (2H, d), 4.04 (1H, q, N-CH), 4.78-4.84 (3H, m, CH 2And H 4), 5.27-5.45 (2H, m), 5.95-6.09 (1H, m), 6.50 (1H, br.triplet, NH), 6.90-6.98 (2H, m), and 7.06-7.26 (2H, m), 7.40 (2H, d), 8.02 (2H, d). embodiment 22 (+/-)-N-[6-(4-fluorophenyl hexyl)]-2-[4-(allyloxycarbonyl) benzylthio-)-2-oxo-azetidin-2-yl] propionic acid amide (diastereomer b)
Obtain the diastereomer b (2.7g, 22% productive rate) of yellow oily by above-mentioned chromatography.
1H?NMRδ(CDCl 3)1.23-1.63(11H，m)，2.55(2H，t)，2.85(1H，dd，H 3a)，3.19-3.23
(2H，m)，3.28(1H，dd，H 3b)，3.91(2H，s)，4.09(1H，q，N-CH)，4.69(1H，dd，H 4)，
4.82(2H，d)，5.25-5.45(2H，m)，5.95-6.09(1H，m)，6.43(1H，br.triplet.NH)，6.90-
6.98 (2H, m), 7.06-7.26 (2H; m), 7.40 (2H, d); 8.02 (2H, m). embodiment 23 (+/-)-N-[6-(4-fluorophenyl hexyl)]-2-[6-(4-(allyloxycarbonyl) benzyl sulfinyl)-2-oxo-azetidin-2-yl] propionic acid amide (diastereomer b2+b1 3: 2)
In-65 ℃ of (+/-)-N-[6-(4-fluorophenyl hexyl) that are stirred in the methylene dichloride (50ml)]-2-[4-(allyloxycarbonyl) benzylthio-)-2-oxo-azetidin-2-yl] propionic acid amide (2.5g, 4.75 (diastereomer b) solution mmole), use again methylene dichloride (30ml) between-chlorine peroxybenzoic acid (1.0g, 5.7 mmoles) solution-treated.Stirred this mixture 1 hour, in the solution of impouring sodium bicarbonate and S-WAT, separation, water dichloromethane extraction.With this bonded extract of salt water washing, drying and flash to oily matter.Purifying then obtains the title compound (1.3g, 50% productive rate) of yellow oily, is the mixture of sulfoxide diastereomer 2 and 1 by flash chromatography (thin silica gel, ethyl acetate).Embodiment 24 (+/-)-N-[6-(4-fluorophenyl hexyl)]-2-[4-(4-(allyloxycarbonyl) benzyl sulfinyl)-2-oxo-azetidin-2-yl] propionic acid amide (diastereomer b2)
Separate the title compound that above-mentioned sulfoxide diastereomer obtains the yellow oily of 100mg by HPLC.
1H?NMRδ(CDCl 3)1.32-1.34(4H，m)，1.44-1.63(4H，m)，1.61(3H，d)，2.55(2H，t)，
2.84(1H，dd，H 3a)，3.15-3.31(3H，m，H 3b?and?CH 2)，4.01?and?4.09(1H?each，d)，
4.50(1H，q，N-CH)，4.61(1H，dd，H 4)，4.83(2H，d)，5.29-5.45(2H，m)，5.95-6.09
(1H, m), 6.90-6.98 (2H, m); 7.06-7.26 (2H, m), 7.37 (2H; d), 8.08 (2H, m). embodiment 25 (+/-)-N-[6-(4-fluorophenyl hexyl)]-2-[4-(4-(allyloxycarbonyl) benzyl sulfinyl)-2-oxo-azetidin-2-yl] propionic acid amide (diastereomer b1)
Also obtain the buttery title compound of 50mg by above-mentioned chromatography.
1H?NMRδ(CDCl 3)1.32-1.34(4H，m)，1.44-1.63(4H，m)，1.45(3H，d)，2.54(2H，t)，
2.90(1H，dd，H 3a)，3.18-3.22(2H，m，CH 2)，3.43(1H，dd，H 3b)3.94?and?4.02(1H
each，d)，4.34(1H，q，N-CH)，4.53(1H，dd，H 4)，4.83(2H，d)，5.29-5.45(2H，m)，
5.95-6.09(1H，m)，6.80(1H，br.triplet，?NH)，6.90-6.98(2H，m)，7.06-7.26(2H，m)，
7.37 (2H, d), 8.08 (2H, m). embodiment 26 (+/-)-N-[6-(4-fluorophenyl hexyl)]-2-[4-(4-(allyloxycarbonyl) benzyl sulfinyl)-2-oxo-azetidin-2-yl] propionic acid amide (diastereomer a1)
Use mCPBA to handle N-[6-(4-fluorophenyl hexyl) by embodiment 23 described methods]-2-[4-(allyloxycarbonyl) benzyl sulfinyl)-2-oxo-azetidin-2-yl] propionic acid amide (diastereomer a; embodiment 21); through chromatography with from ethyl acetate, obtain the title compound of white crystal behind the recrystallization; fusing point 175-177 ℃, 27% productive rate.
1H?NMRδ(CDCl 3)1.32-1.34(4H，m)，1.38-1.65(4H，m)，1.54(3H，d)，2.55(2H，t)，
2.82(1H，dd，H 3a)，3.20(2H，dt，CH 2)，3.35(1H，dd，H 3b)3.94(2H，d)，4.17(1H，q，
N-CH)，4.78(1H，dd，H 4)，4.83(2H，d)，5.29-5.45(2H，m)，5.95-6.09(1H，m)，6.35
(1H，br.triplet，NH)，6.90-6.98(2H，m)，7.06-7.26(2H，m)，7.37(2H，d)，8.08(2H，
M). embodiment 27 (+/-)-N-[6-(4-fluorophenyl hexyl)]-2-[4-(4-(allyloxycarbonyl) benzyl sulfinyl)-2-oxo-azetidin-2-yl] propionic acid amide (diastereomer a2)
Pass through above-mentioned reaction (embodiment 26), pass through chromatography and from diethyl ether, obtain canescence crystalline title compound behind the recrystallization, fusing point 75-76 ℃, 22% productive rate.
1H?NMRδ(CDCl 3)1.32-1.34(4H，m)，1.38-1.65(4H，m)，1.62(3H，d)，2.56(2H，t)，
2.82(1H，dd，H 3a)，3.17-3.30(3H，m，CH 2?and?H 3b)，4.00-4.15(3H，m，CH 2?and?N-CH
)，4.63(1H，dd，H 4)，4.83(2H，d)，5.29-5.45(2H，m)，5.95-6.09(1H，m)，6.90-
6.98 (2H, m), 7.06-7.26 (3H, m), 7.37 (2H, d), 8.08 (2H, m). embodiment 28 (+/-)-N-[6-(4-fluorophenyl hexyl)]-2-[4-(4-(carbonyl) benzyl sulfinyl)-2-oxo-azetidin-1-yl] propionic acid amide (3: 2)
Under nitrogen, in methylene dichloride (40ml), handle mixture (b2+b1 3: 2) at the diastereomer of embodiment 23 generations (+/-) N-[6-(4-fluorophenyl hexyl) with triphenylphosphine (0.165g), pyridine (0.045g) and four (triphenylphosphine palladium (0))]-2-[4-(allyloxycarbonyl) benzyl sulfinyl)-2-oxo-azetidin-2-yl] propionic acid amide 16 hours; then handle the title compound (0.155g) that obtains white solid through water; fusing point 122-150 ℃; 51% productive rate is the mixture with b1. 1H NMR (some diagnostic peak): δ (CDCl 3) 4.7 (m, the H4 of diastereomer b2), 4.6 (m, the H4 of diastereomer b1).Embodiment 29 (+/-)-N-[6-(4-fluorophenyl) hexyl)]-2-(4-benzylthio-)-2-oxo-azetidin-1-base-3-(3-furyl) propionic acid amide (diastereomer a and b) (benzylthio-) nitrogen heterocyclic din-2-ketone a.4-
Sodium (8.1g, 037 mole) is dissolved in the ethanol (250ml), and benzyl sulfhydrate (45.2g, 0.37 mole) was added drop-wise to wherein at 20 minutes, maintained the temperature at 20-25 ℃, blasted nitrogen by miscellany simultaneously.After 15 minutes, reactant is cooled to, 4-acetoxyl group nitrogen heterocyclic din-2-ketone (45.0g, the 0.37 mole) solution of ethanol (50ml) was dripped in 15 minutes, holding temperature is at 5 ℃ simultaneously.At room temperature stirred this mixture 60 minutes, reduction vaporization is to dry.Add entry (400ml), (2 * 300ml) extract this mixture, with extracting solution drying (MgSO with methylene dichloride 4) and reduction vaporization one-tenth oil.This oily matter is cooled to-20 ℃, with ether (400ml) titration, obtains a kind of white solid (50.2g, 79%), fusing point 50-51.0 ℃ by filtering separation. 1H NMR δ (CDCl 3) 2.86 (1H, m, H 3a), 3.30 (1H, m, H 3b), 3.85 (2H, s, SCH 2), 4.68 (1H, m, H 4), 7.31 (5H, m, Ph-H) .b. methyl-(4-benzylthio--2-oxo-azetidin-1-yl) ethyl acetate
To 4-(benzylthio-) nitrogen heterocyclic din-2-ketone (5.0g that is doing among the THF (150ml), 25 mmoles), monobromo-acetic acid methyl esters (4.6g, 30 mmoles) and the solution of Tetrabutylammonium bromide (0.9g, 0.28 mmole) add pulverous potassium hydroxide (1.7g, 30 mmoles).The mixture that obtains was at room temperature stirred 2 hours, add entry (50ml) then.This solution extracts with ethyl acetate (3 * 150ml umber), dry (MgSO 4) and evaporate the bonded extract.Residue is purified on silica gel by flash chromatography, and with 60 ℃～80 ℃ of sherwood oils: ethyl acetate=4: 1 wash-outs then obtains methyl-(4-benzylthio--2-oxo-azetidin-1-yl) ethyl acetate (5g, 70%) of yellow oily.
1H?NMRδ(CDCl 3)2.96(1H，dd，J＝2.5，16Hz?H 3a)，3.24，3.99(each?1H，d，J＝18.00
Hz，NCH 2)，3.4(1H，dd，J＝5，12.5Hz?H 3b)，3.70(3H，s，OCH 3)，3.77(2H，s，SCH 2)，
4.92 (1H, m, H 4), 7.28 (5H, m, Ph-H) brooethyl furans c.3-
N-bromosuccinimide (5.74g with solid part, 0.03225 mmole) in the triphenylphosphine (8.45g of 0 ℃ of processing in dry dichloromethane (30ml), 0.0322 mmole) and 3-(methylol) furans (2.93g, 0.02987 mmole) solution 10 minutes.This reactant stirred 10 minutes down in 0 ℃, and reheat to 15 is ℃ above 1.5 hours.Reactant is purified on silica gel by flash chromatography, with 40～60 ℃ of wash-outs of sherwood oil, then obtains the 3-brooethyl furans (3.25g, 68%) of light yellow oily.D. methyl 2-(4-benzylthio--2-oxo-azetidin-1-yl)-3-(furyl) propionic ester
Be used in THF (13.8g, 0.0186 two (trimethyl silyl) lithamide solution of the 1M mmole) are in-78 ℃ of processing methyl-(4-benzylthio--2-oxo-azetidin-1-yl) ethyl acetate (3.0g in dry tetrahydrofuran (60ml), 0.01131 mmole) solution is 10 minutes, keeps temperature to be lower than-74 ℃.Add 1,3-methylimidazole quinoline-2-ketone (7.5ml, 0.0687 mmole) keeps temperature to be lower than-74 ℃.This generates suspended substance and stirred 30 minutes down in-78 ℃, and 3-bromomethyl furans (3.0g, the 0.0186 mmole) solution-treated in doing THF (10ml) is 10 minutes then, keeps temperature to be lower than-73 ℃.This reactant stirred 1 hour down in-78 ℃, reheat to-20 ℃ above 30 minutes.This reactant is cooled to-75 ℃, uses Glacial acetic acid (1.5ml) cancellation again, distributes between salt solution (150ml) and ethyl acetate (150ml).Organic layer washes with water, dry (MgSO 4) and flash to chromatic oily matter (7.81g).Purify on silica gel by flash column chromatography, with 40 ℃～60 ℃ of 2: 1 sherwood oils: eluent ethyl acetate, then obtain methyl-(4-benzylthio--2-oxo-azetidin-1-yl)-3-(furyl) propionic ester (2.35g, 60%, 85: the 15 diastereomer A: B) of yellow oily.
1H?NMRδ(CDCl 3)2.83，2.90(dd，J＝2.4，15.5Hz，1?of?H 3A)，3.17(m，CH 2-furyl，
H 3B，3A)，3.54，3.80(2H，2xs，SCH 2A+B)，3.77(3H，s，CO 2CH 3)，3.95，4.26(1H，
2xm，CH A+B)，4.60，4.64(1H，2xm，H 4A+B)，6.30(1H，m，furyl-H)，7.30(6H，m，
Ph-H, furfyl-H) e.2-(4-benzylthio--2-oxo-azetidin-1-yl)-3-(3-furyl) propionic acid
With 1N sodium hydroxide solution (8.5ml, 0.0085 mole) in the methyl of 10 ℃ of processing in methyl alcohol (50ml)-(4-benzylthio--2-oxo-azetidin-1-yl)-3-(furyl) propionic ester (2.93g, 0.00848 mole) solution 30 minutes.Remove cooling bath, reaction stirred 1 hour.Add 1N NaOH (1.0ml), reaction stirred 30 minutes, water (50ml) dilution, revaporization is removed methyl alcohol.Residue mixes with water (50ml), extracts with diethyl ether (50ml).Water is used diethyl ether (2 * 75ml) extractions again with rare HCL acidifying.These organic extractions combine, with salt water washing, drying (MgSO 4) and the evaporation obtain creamy solid 2-(4-benzylthio--2-oxo-azetidin-1-yl)-3-(3-furyl) propionic acid (2.73g, 97%, 50: 50 diastereomer A: B), fusing point 77-80 ℃.
1H?NMRδ(CDCl 3)2.86，2.92(dd，J＝2.3，15.4Hz，H 3)，3.10(m，CH 2-furyl，H 3)，
3.54，3.79(2H，m+s，SCH 2A+B)，3.89(m，CH B)，4.19(m，CH A)，4.23(1H，bs，
CO 2H)，4.57，4.64(1H，2xm，H 4A+B)，6.30，6.37(1H，2xbs，furyl-H A+B)，7.30(6H，
M, Ph-H, furfyl-H) f.N-[6-(4-fluorophenyl) hexyl)]-2-(4-benzylthio-)-2-oxo-azetidin-1-base-3-(3-furyl) propionic acid amide (diastereomer a and b)
Will be at 6-(the 4-fluorobenzene hexyl) hexylamine (1.59g that does DMF (75ml), 0.00814 mmole) join 2-(4-benzylthio--2-oxo-azetidin-1-yl)-3-(3-furyl) propionic acid (2.7g, 0.00814 I-hydroxybenzotriazole (1.1g mmole),, 0.00814 mmole) and 1-(cyclohexyl)-3-(morpholino ethyl) carbonization imide methoxyl group-right-tosylate (3.5g, 0.00826 in mixture mmole), at room temperature stir the solution 19 hours of this generation.This suspension is at NaHCO 3Distribute between the aqueous solution (175ml) and the diethyl ether (75ml).Each layer separated, and wash with diethyl ether (75ml) in the waterbearing stratum.With the organic extraction combination, and with salt solution (* 2) washing, dry (MgSO 4) and flash to bisque oily matter (3.76g).Purify on silica gel by flash column chromatography, with 40 ℃～60 ℃ of 2: 1 sherwood oils: eluent ethyl acetate then obtains the title compound of colorless oil.
Diastereomer a, 1.17g, 28% (containing 20% diastereomer b)
1H?NMRδ(CDCl 3)1.2-1.6(8H，m，4xCH 2)，2.55(2H，t，J＝7.9Hz，CH 2Ph)，2.75，
2.80(dd，H 3)，3.15(m，CH 2-furyl，H 3)，3.75(3H，m，CH，SCH 2)，4.30(1H，m，H 4)，
6.23(1H，bs，furyl-H)，6.85(1H，m，NH)，6.9-7.4(11H，m，pF-Ph-H，Ph-H，furyl-H)
Diastereomer b, 1.36g, 33% (contains 20% diastereomer a)
1H?NMRδ(CDCl 3)1.2-1.6(8H，m，4xCH 2)，2.55(2H，t，J＝7.9Hz，CH 2Ph)，2.81，
2.87(dd，H 3)，3.15(m，CH 2-furyl，H 3)，3.70(2H，s，SCH 2)，4.12(1H，m，CH)，
4.57(1H，m，H 4)，6.25(1H，bs，furyl-H)，6.4(1H，m，NH)，6.9-7.4(11H，m，pF-Ph-H，
Ph-H, furyl-H) embodiment 30 (+/-)-N-[6-(4-fluorophenyl) hexyl)]-2-(4-benzylthio-)-2-oxo-azetidin-1-base-3-(3-furyl) propionic acid amide
To be cooled to--70 ℃ the N-[6-at methylene dichloride (25ml) (4-fluorophenyl) hexyl)]-2-(4-benzylthio-)-2-oxo-azetidin-1-base-3-(3-furyl) propionic acid amide (80% diastereomer b) (0.30g, 0.00256 mmole) solution is used in the 3-chloro peroxide acid (0.80g in the methylene dichloride (25ml), 0.00255 mmole) solution-treated maintained the temperature at-70 ℃ more than 1 hour.Remove cooling bath, stirred this reaction mixture 1 hour, obtain colourless solution.This reaction mixture is used 10% sodium sulfite aqueous solution, sodium hydrogen carbonate solution, water washing again with methylene dichloride (50ml) dilution, dry (MgSO 4) and flash to the colourless oily matter that contains diastereomer b1+b2 mixture.Purify on silica gel by flash column chromatography repeatedly, with 40 ℃～60 ℃ of 1: 1 to 3: 1 sherwood oils: eluent ethyl acetate, then recrystallization from 40 ℃～60 ℃ of ethyl acetate/petroleum ether, then obtain (+/-)-N-[6-(4-fluorophenyl) hexyl of colorless solid)]-2-(4-benzylthio-)-2-oxo-azetidin-1-base-3-(3-furyl) propionic acid amide (diastereomer b2) (0.38g, 28%), fusing point 90-91 ℃.
1H?NMRδ(CDCl 3)1.2-1.6(8H，m，4xCH 2)，2.57(2H，t，J＝7.6Hz，CH 2Ph)，2.67，
2.73(1H，dd，J＝2.5，15.4Hz，H 3)，2.94，3.01(1H，dd，J＝5.5，15.4Hz，H 3)，3.22(4H，
m，CH 2-furyl，CH 2NH)，3.92，4.05(each?1H，2xd，J＝13.1Hz，SOCH 2)，4.41(1H，m，
H 4)，4.58(1H，dd，J＝6，10Hz，CH)，6.29(1H，d，J＝0.77Hz，furyl-H)，6.9-7.4(12H，
M, pF-Ph-H, furyl-H, Ph-H, NH) embodiment 31 N-[6-(4-fluorophenyl) hexyl)]-2-(4-benzylthio-)-2-oxo-azetidin-1-base-3-(3-furyl) propionic acid amide (diastereomer a2)
To be cooled to--70 ℃ the N-[6-at methylene dichloride (25ml) (4-fluorophenyl) hexyl)]-2-(4-benzylthio-)-(80% diastereomer is (1.13g a) for 2-oxo-azetidin-1-base-3-(3-furyl) propionic acid amide, 0.00222 mmole) solution is used in the 3-chloro peroxide acid (0.70g in the methylene dichloride (25ml), 0.00223 mmole) solution-treated maintained the temperature at-70 ℃ more than 1 hour.Remove cooling bath, stirred this reaction mixture 1 hour, obtain colourless solution.This reaction mixture is used 10% sodium sulfite aqueous solution, sodium hydrogen carbonate solution, water washing again with methylene dichloride (50ml) dilution, dry (MgSO 4) and flash to the colourless oily matter that contains non-enantiomer mixture.Purify on silica gel by flash column chromatography, with 40 ℃～60 ℃ of 1: 1 to 4: 1 sherwood oils: eluent ethyl acetate, then obtain (+/-)-N-[6-(4-fluorophenyl) hexyl of water white oil)]-2-(4-benzylthio-)-2-oxo-azetidin-1-base-3-(3-furyl) propionic acid amide (diastereomer a2) (0.31g, 26%).
1H?NMRδ(CDCl 3)1.2-1.6(8H，m，4xCH 2)，2.57(2H，t，J＝7.6Hz，CH 2Ph)，2.76，
2.79(1H，dd，J＝2，15.2Hz，H 3)，3.00，3.04(1H，dd，J＝5.2，15.2Hz，H 3)，3.30(4H，m，
CH 2-furyl，CH 2NH)，3.93，4.08(4H，2xm，CH，H 4，SOCH 2)，6.29(1H，s，furyl-H)，
6.9-7.4 (11H, m, pF-Ph-H, furyl-H, Ph-H), (7.88 1H, m, NH) embodiment 32 (+/-)-N-[6-(4-fluorophenyl) hexyl)]-2-[4-benzylthio--2-oxo-azetidin-1-base-3-phenyl] (95% diastereomer is a. methyl 2-(4-benzylthio--2-oxo-azetidin-1-yl)-3-phenylpropionic acid methyl esters a) for propionic acid amide
Be used in hexane (9.2ml, 0.092mol) in two (trimethyl silyl) lithamide solution of 1M handle methyl-(4-benzylthio--2-oxo-azetidin-1-yl) ethyl ester (2.03g in dry tetrahydrofuran (40ml) down in-75 ℃ of nitrogen, 0.00765 mole) solution kept temperature to be lower than-68 ℃ more than 5 minutes.Add 1,3-methylimidazole quinoline-2-ketone (5.0ml, 0.0457 mole) keeps temperature to be lower than-70 ℃.This generates suspended substance and stirred 30 minutes down in-75 ℃, uses cylite (2.36g, 0.0138 mole) solution-treated more than 5 minutes then, keeps temperature to be lower than-70 ℃.This reactant stirred 1.5 hours, and z reaches-20 ℃ during this period.This reactant is cooled to-75 ℃, uses Glacial acetic acid (1.0ml) cancellation again, distributes between salt solution (100ml) and ethyl acetate (100ml).Organic layer washes with water, dry (MgSO 4) and flash to chromatic oily matter.Purify on silica gel by flash column chromatography, with 40 ℃～60 ℃ of 2: 1 sherwood oils: eluent ethyl acetate then obtains methyl-(4-benzylthio--2-oxo-azetidin-1-yl)-3-phenylpropionic acid ester (1.78g, 65% of yellow solid, 9: 1 diastereomer a: b), fusing point 66-67 ℃.
1H?NMRδ(CDCl 3)2.83(1H，m，H 3)，3.12(1H，m，H 3)，3.35(2H，m，CH 2Ph)，3.76
(5H, m, OCH 3, SCH 2), 4.06 (m, CH B), 4.75 (m, H 4, CH A), 7.23 (10H, m, 2xPh-H) b.2-(4-benzylthio--2-oxo-azetidin-1-yl)-3-phenylpropionic acids
With 1N sodium hydroxide solution (4.92ml, 0.00492 mole) in methyl-(4-benzylthio--2-oxo-azetidin-1-yl)-3-phenylpropionic acid ester (1.75g, the 0.00492 mole) solution of 10 ℃ of processing in methyl alcohol (75ml) above 40 minutes.Remove cooling bath, reaction stirred 2 hours.Add 1N NaOH (0.2ml), reaction stirred 60 minutes, water (50ml) dilution, revaporization is removed methyl alcohol.Residue mixes with water (75ml), extracts with ethyl acetate (50ml).Water is used ethyl acetate (2 * 75ml) extractions again with rare 1NHCL acidifying.These organic extractions combine, with salt water washing, drying (MgSO 4) and the evaporation obtain creamy solid 2-(4-benzylthio--2-oxo-azetidin-1-yl)-3-phenylpropionic acid (1.37g, 82%, 40: 60 diastereomer a: b), fusing point 125-131 ℃. 1H NMR δ (CDCl 3) 2.8 (1H, m, H 3), 3.15,3.35 (3H, 2xm, CH 2-furyl, H 3), 3.53 (m, SCH 2B), 3.73 (s, SCH 2A), 4.0,4.15 (1H, 2xm, CH A+B), 4.07,4.59 (1H, 2xm, H 4), 5.47 (1H, bs, CO 2H), 7.08-7.37 (10H, m, 2xPh-H) c (+/-)-N-[6-(4-fluorophenyl) hexyl)]-2-(4-benzylthio-)-2-oxo-azetidin-1-base-3-Phenylpropionamide
Will be at 6-(the 4-fluorobenzene hexyl) hexylamine (0.76g that does DMF (40ml), 0.00389 mole) join 2-(4-benzylthio--2-oxo-azetidin-1-yl)-3-phenylpropionic acid (1.33g, 0.00389 I-hydroxybenzotriazole (0.52g mole),, 0.00385 mole) and N, in the mixture of N '-dicyclohexyl carbonization imide, at room temperature stirred solution is 4 hours.This suspension dilutes with ethyl acetate (100ml), residue and NaHCO 3The aqueous solution (125ml) mixes, with ethyl acetate (2 * 75ml) washings.With the organic extraction combination, and with salt water washing, drying (MgSO 4) and flash to oily matter (3.76g).With the product of itself and separating reaction (from 0.33g, 0.96g 2-(4-benzylthio--2-oxo-azetidin-1-yl)-3-phenylpropionic acid) combination, purify on silica gel by flash column chromatography repeatedly, P.E sherwood oil with 3: 1: eluent ethyl acetate, then obtain the title compound (0.79g of waxy colorless solid, 20%, contain 5% diastereomer b), to a:
1H?NMRδ(CDCl 3)1.2-1.6(8H，m，4xCH 2)，2.56(2H，t，J＝7.8Hz，CH 2Ph)，2.68，
2.74(1H，dd，J＝2.3，15.4Hz，H 3)，2.99，3.05(1H，dd，J＝5.2，15.4Hz，H 3)，3.26(4H，
m，NHCH 2，CH 2Ph)，3.70(2H，s，SCH 2)，3.81(2H，m，CH，H 4)，6.9-7.4(15H，m，
PF-Ph-H, 2xPh-H, NH) embodiment 33 (+/-)-N-[6-(4-fluorophenyl) hexyl)]-2-(4-benzylthio-)-2-oxo-azetidin-1-base-3-Phenylpropionamide (98% diastereomer b)
Above-mentioned chromatography obtains the title compound of colorless solid, and (1.01g, 20% productive rate contain 2% diastereomer a), fusing point 78-80 ℃.
1H?NMRδ(CDCl 3)1.2-1.6(8H，m，4xCH 2)，2.56(2H，t，J＝7.8Hz，CH 2Ph)，2.76，
2.80(1H，dd，J＝2.4，15.6Hz，H 3)，3.06，3.10(1H，dd，J＝5.2，15.6Hz，H 3)，3.24，3.34
(4H，m，NHCH 2，CH 2Ph)，3.51(2H，s，SCH 2)，4.16(1H，dd，J＝5.6，10.4Hz，CH)，
4.54 (1H, m, H 4), 6.35 (1H, m, NH), 6.9-7.4 (14H, m, pF-Ph-H, 2xPh-H) embodiment 34 N-[6-(4-fluorophenyl) hexyl)]-2-(4-benzyl sulfinyl)-2-oxo-azetidin-1-base-3-Phenylpropionamide (diastereomer a2)
With the N-[6-at methylene dichloride (25ml) (4-fluorophenyl) hexyl that is cooled to-70 ℃)]-2-(4-benzylthio-)-2-oxo-azetidin-1-base-3-Phenylpropionamide (0.76g, 0.00147 mole) solution is used in the 3-chloro peroxide acid (0.46g in the methylene dichloride (25ml), 0.00147 mole) solution-treated maintained the temperature at-70 ℃ more than 1 hour.Remove cooling bath, stirred this reaction mixture 2 hours, obtain colourless solution.This reactant is with 10% sodium sulfite aqueous solution, sodium hydrogen carbonate solution, water washing, dry (MgSO 4) and flash to colourless oily matter (0.89g).Purify on silica gel by flash column chromatography repeatedly, with 40 ℃～60 ℃ of 1: 1 to 2: 31 sherwood oils: eluent ethyl acetate, recrystallization then obtains N-[6-(4-fluorophenyl) hexyl of colorless solid from diethyl ether/sherwood oil again)]-2-(4-benzylthio-)-2-oxo-azetidin-1-base-3-Phenylpropionamide (diastereomer a2) (0.26g, 33%), fusing point 62-63 ℃.
1H?NMRδ(CDCl 3)1.2-1.6(8H，m，4xCH 2)，2.57(2H，t，J＝7.6Hz，CH 2Ph)，2.77，
2.87(1H，dd，J＝2.2，15.3Hz，H 3)，2.88，2.93(1H，dd，J＝5.2，15.3Hz，H 3)，3.38(4H，
m，CH 2Ph，CH 2NH)，3.61(1H，m，H 4)，3.83，4.05(each?1H，2xd，J＝13Hz，SOCH 2)，
3.99(1H，m，CH)，6.9-7.4(14H，m，pF-Ph-H，2xPh-H)，8.06(1H，m，NH)
v c＝o?1785?cm -1；Found：C，69.3；H，6.5；N，5.3％；C 31H 35FN 2O 3S?requires：C，
69.6; H, 6.6; N, 5.2% embodiment, 35 N-[6-(4-fluorophenyl) hexyl)]-2-(4-benzylthio-)-2-oxo-azetidin-1-base-3-Phenylpropionamide (79% diastereomer a1)
Evaporate the title compound (0.21g, 27% productive rate contain 22% diastereomer a2) that composition on the above-mentioned chromatographic post obtains the colourless foam shape, fusing point 78-80 ℃.Mnr to a1:
1H?NMRδ(CDCl 3)1.2-1.6(8H，m，4xCH 2)，2.57(2H，t，J＝7.8Hz，CH 2Ph)，2.62，
2.68(1H，dd，J＝4.7，14.8Hz，H 3)，3.3(5H，m，H 3，CH 2-Ph，CH 2NH)，3.80(4H，m，
H 4, SOCH 2, CH), 6.60 (1H, m, NH), 6.9-7.4 (14H, m, pF-Ph-H, 2xPh-H) embodiment 36 (+/-)-N-[6-(4-fluorophenyl) hexyl)]-2-(4-benzyl sulfinyl)-2-oxo-azetidin-1-base-3-Phenylpropionamide (diastereomer b1)
To be cooled to--(+/-) at methylene dichloride (25ml)-N-[6-(4-fluorophenyl) hexyl of 70 ℃)]-2-(4-benzylthio-)-2-oxo-azetidin-1-base-3-Phenylpropionamide (diastereomer b) (0.95g, 0.00183 mole) solution uses the 3-chloro peroxide acid (0.57g in methylene dichloride (25ml), 0.00182 mole) solution-treated surpasses 45 minutes, maintains the temperature at-70 ℃.Remove cooling bath, stirred this reaction mixture 2 hours, obtain colourless solution.This reactant is with 10% sodium sulfite aqueous solution, sodium hydrogen carbonate solution, water washing, dry (MgSO 4) and flash to colourless oily matter (0.89g).Purify on silica gel by flash column chromatography repeatedly, with 40 ℃～60 ℃ of 1: 1 to 1: 3 sherwood oils: eluent ethyl acetate is to separate the diastereomer product.The higher mobile isomer of cooling in diethyl ether then obtains N-[6-(4-fluorophenyl) hexyl of colorless solid)]-2-(4-benzyl sulfinyl)-2-oxo-azetidin-1-base-3-Phenylpropionamide (diastereomer b1) (0.071g; 7%) 128 ℃ of fusing points (containing 4.8% diastereomer b2).
1H?NMRδ(CDCl 3)1.2-1.6(8H，m，4xCH 2)，2.56(2H，t，J＝7.8Hz，CH 2Ph)，2.62，
2.68(1H，dd，J＝4.9，14.7Hz，H 3)，2.85(1H，m)，3.25(2H，m，CH 2NH)，3.36，3.42
(1H，dd，J＝2.2，14.7Hz，H 3)，3.52(1H，m，1?of?CHCH 2)，3.70，4.05(each?1H，2xd，
J＝10Hz，SOCH 2)，4.20(1H，m，H 4)，4.67(1H，dd，J＝5，11Hz，CH)，6.7-7.4(15H，m，
pF-Ph，2xPh-H.NH)
Found:C, 68.9; H, 6.5; N, 5.1%; C 31H 35FN 2O 3S requires:C, 69.6; H, 6.6; N, 5.2% embodiment 37 (+/-)-N-[6-(4-fluorophenyl) hexyl)]-2-(4-benzyl sulfinyl)-2-oxo-azetidin-1-base-3-Phenylpropionamide (79% diastereomer a1)
To then obtain N-[6-(4-fluorophenyl) hexyl of colorless solid from low mobile isomer recrystallization from ethyl acetate/diethyl ether that above-mentioned chromatography obtains)]-2-(4-benzyl sulfinyl)-2-oxo-azetidin-1-base-3-Phenylpropionamide (diastereomer b2) (0.328g; 33%), fusing point 84-85 ℃.
1H?NMRδ(CDCl 3)1.2-1.6(8H，m，4xCH 2)，2.56(2H，t，J＝7.8Hz，CH 2Ph)，2.60，
2.65(1H，dd，J＝2.4，15.6Hz，H 3)，2.84，2.87(1H，dd，J＝5.6，15.6Hz，H 3)，3.21(3H，
m，1?of?PhCH 2CH)，3.53，3.59(1H，dd，J＝6.4，14.9Hz，1?of?PhCH 2CH)，3.91，4.02
(each?1H，2xd，J＝13.1Hz，SOCH 2)，4.34(1H，m，H 4)，4.70，4.74(1H，dd，J＝6.4，10，
CH)，6.9-7.4(15H，m，pF-Ph-H，2xPh-H，NH)
Found：C，69.0；H，6.5，N，5.1％；C 31H 35FN 2O 3S，1.0％H 2O?requires：C，68.9；H，
6.6; N, 5.2% embodiment 38 (+)-N-[6-(4-fluorophenyl) hexyl)]-2-(4-benzyl sulfinyl)-2-oxo-azetidin-1-base-3-Phenylpropionamide (diastereomer (+) b2)
Separate above-mentioned b2 diastereomer by chirality HPLC and then obtain the colloidal title compound.
1H?NMRδ(CDCl 3)1.2-1.6(8H，m，4xCH 2)，2.56(2H，t，J＝7.8Hz，CH 2Ph)，2.60，
2.65(1H，dd，J＝2.4，15.6Hz，H 3)，2.84，2.87(1H，dd，J＝5.6，15.6Hz，H 3)，3.21(3H，
m，1?of?CH 2NH)，3.53，3.59(1H，dd，J＝6.4，14.9Hz，1?of?CH 2Ph)，3.91，4.02(each
1H，2xd，J＝13.1Hz，SOCH 2)，4.34(1H，m，H 4)，4.70，4.74(1H，dd，J＝6.4，10，CH)，
6.9-7.4(15H，m，pF-Ph-H，2xPh-H，NH)
a D=+35.8 ° of (c=0.4%w/v ethanol) 20 ℃ of embodiment 39 of at (-)-N-[6-(4-fluorophenyl) hexyl)]-2-(4-benzyl sulfinyl)-2-oxo-azetidin-1-base-3-Phenylpropionamide (diastereomer (-)-b2)
Separate above-mentioned b2 diastereomer by chirality HPLC and then obtain the colloidal title compound.
1H?NMRδ(CDCl 3)1.2-1.6(8H，m，4xCH 2)，2.56(2H，t，J＝7.8Hz，CH 2Ph)，2.60，
2.65(1H，dd，J＝2.4，15.6Hz，H 3)，2.84，2.87(1H，dd，J＝5.6，15.6Hz，H 3)，3.21(3H，
m，1?of?CH 2NH)，3.53，3.59(1H，dd，J＝6.4，14.9Hz，1?of?CH 2Ph)，3.91，4.02(each
1H，2xd，J＝13.1Hz，SOCH 2)，4.34(1H，m，H 4)，4.70，4.74(1H，dd，J＝6.4，10，CH)，
6.9-7.4(15H，m，pF-Ph-H，2xPh-H，NH)
a D20 ℃ of embodiment 40 of=-43.7 ° of (c=0.3%w/v ethanol) at (+/-)-N-[6-(4-fluorophenyl) hexyl)]-(diastereomer is a. methyl 2-(4-benzylthio--2-oxo-azetidin-1-yl)-2-allyl acetate a) for 2-[4-benzylthio--2-oxo-azetidin-1-base-2-allyl group ethanamide
Be used in THF (23.0ml, 0.023mol) in two (trimethyl silyl) lithamide solution of 1M handle methyl-(4-benzylthio--2-oxo-azetidin-1-yl) acetic ester (5.0g in dry tetrahydrofuran (100ml) down in-75 ℃ of nitrogen, 0.01884 mole) solution kept temperature to be lower than-68 ℃ more than 5 minutes.Add 1,3-methylimidazole quinoline-2-ketone (12.5ml, 0.1143 mole) keeps temperature to be lower than-70 ℃.This generates suspended substance and stirred 30 minutes down in-75 ℃, uses allyl iodide (3.1ml, 0.0339 mole) solution-treated more than 5 minutes then.Improve temperature to-65 ℃.This reactant stirred 30 minutes at-78 ℃, was warmed up to-20 ℃ at 30 minutes.This reactant is cooled to-75 ℃, uses Glacial acetic acid (5ml) cancellation again, distributes between salt solution (150ml) and ethyl acetate (175ml).Organic layer salt water washing, drying (MgSO 4) and flash to chromatic oily matter.Purify on silica gel by flash column chromatography, with 40 ℃～60 ℃ of 4: 1 sherwood oils: eluent ethyl acetate, then obtain methyl-(4-benzylthio--2-oxo-azetidin-1-yl)-2-allyl acetate (4.48g, 78%, 85: the 15 diastereomer a: b) of yellow oil.
1H?NMRδ(CDCl 3)2.7(2H，m，CH 2)，2.90(1H，m，H 3)，3.27(1H，m，H 3)，3.80(5H，
m，CO 2CH 3，SCH 2)，3.92，4.23(1H，2xm，CH A+CH B)，4.55，4.90(1H，2xm，H 4)，
5.16 (2H, m, CH=CH 2), 5.80 (1H, m, CH=CH2), 7.31 (5H, m, Ph-H) (4-benzylthio--2-oxo-azetidin-1-yl)-2-allyl acetic acid b.2-
With 1N sodium hydroxide solution (14.3ml, 0.0143 mole) in methyl-(4-benzylthio--2-oxo-azetidin-1-yl)-2-allyl acetate (4.38g, the 0.01434 mole) solution of 10 ℃ of processing in methyl alcohol (100ml) above 15 minutes.Remove cooling bath, during reaction stirred 1.5.Add 1N NaOH (2.0ml), reaction stirred 30 minutes, water (100ml) dilution, revaporization is removed methyl alcohol.Residue extracts with diethyl ether (100ml).Water is used diethyl ether (100ml, 50ml) extraction again with rare 1NHCL acidifying.These organic extractions combine, with salt water washing, drying (MgSO 4) and evaporate 2-(4-benzylthio--2-oxo-azetidin-1-yl)-2-allyl acetic acid (3.97g, 95%, 60: the 40 diastereomer a: b) that obtain yellow oil.
1H?NMRδ(CDCl 3)2.7(2H，m，CH 2)，2.90(1H，m，H 3)，3.27(1H，m，H 3)，3.80(m，
CH B，CO 2CH 3，SCH 2)，4.12(m，CH A)，4.65，4.85(1H，2xm，H 4)，5.16(2H，m，
CH=CH 2), 5.80 (1H, m, CH=CH2), 7.31 (5H, m, Ph-H) c. (+/-)-N-[6-(4-fluorophenyl) hexyl)]-2-(4-benzylthio-)-2-oxo-azetidin-1-base-(90%, diastereomer is a) for 2-allyl group ethanamide
Will be at 6-(4-fluorophenyl) hexylamine (2.5g that does DMF (75ml), 0.0128 mole) join 2-(4-benzylthio--2-oxo-azetidin-1-yl)-2-allyl acetic acid (3.73g, 0.00128 I-hydroxybenzotriazole (1.75g mole),, 0.00129 mole) and 1-cyclohexyl-3-carbonization imide methoxyl group-right-toluene (5.42g, 0.0128 in mixture mole), at room temperature stirred solution is 19 hours.This suspension distributes between sodium hydrogen carbonate solution (300ml) and diethyl ether (150ml).Each layer separated, and wash with diethyl ether (100ml) in the waterbearing stratum.With the organic extraction combination, and wash with water, dry (MgSO 4) and flash to oily matter (5.92g).Purify on silica gel by flash column chromatography repeatedly, with 40-60 ℃ of 2: 1 P.E sherwood oil: eluent ethyl acetate then obtains the title compound (1.27g, 21 productive rate %) of colorless oil.
1H?NMRδ(CDCl 3)1.35-1.6(8H，m，4xCH 2)，2.56(2H，t，J＝7Hz，CH 2Ph)，2.65
(2H，m，CH 2)，2.79，2.85(1H，dd，J＝2.4，15.4Hz，H 3)，3.25(3H，m，H 3，NHCH 2)，
3.71(1H，dd，J＝6Hz，CH)，3.82(2H，s，SCH 2)，4.65(1H，m，H 4)，5.15(2H，m，
CH＝CH 2)，
5.72 (1H, m, CH=CH 2), 6.85 (1H, m, NH), 6.9-7.3 (9H, m, Ph-H, Ar-H) embodiment 41 (+/-)-N-[6-(4-fluorophenyl) hexyl)]-2-(4-benzylthio-)-2-oxo-azetidin-1-base-2 allyl group ethanamide (80% diastereomer b)
Above-mentioned chromatography is separated the title compound (1.11g, 19% productive rate) that obtains colorless oil.
1H?NMRδ(CDCl 3)1.25-1.6(8H，m，4xCH 2)，2.56(2H，t，J＝7Hz，CH 2Ph)，2.78
(2H，m，CH 2)，2.84，2.91(1H，dd，J＝2.3，15.3Hz，H 3)，3.25(3H，m，H 3，NHCH 2)，
3.82(2H，s，SCH 2)，4.03(1H，dd，J＝6Hz，CH)，4.65(1H，m，H 4)，5.08(2H，m，
CH＝CH 2)，
5.72 (1H, m, CH=CH 2), 6.51 (1H, m, NH), 6.9-7.3 (9H, m, Ph-H, Ar-H) embodiment 42 (+/-)-N-[6-(4-fluorophenyl) hexyl)]-2-(4-benzylthio-)-2-oxo-azetidin-1-base-2-allyl group ethanamide (diastereomer a2+a1)
Use the foregoing description 34 described steps to handle (+/-)-N-[6-(4-fluorophenyl) hexyl of 1.2g (0.00256 mole) with mCPBA)]-2-(4-benzylthio-)-2-oxo-azetidin-1-base-(90% diastereomer is a) for 2-allyl group ethanamide, similar processing of process and chromatography obtain the title compound (0.04g, 33% productive rate) of colorless oil.
1H NMR (diastereomer a2) δ (CDCl 3) 1.2-1.6 (8H, m, 4xCH 2), 2.56 (2H, t,
J＝7Hz，CH 2Ph)，2.7-3.3(6H，m，CHCH 2，H 3，NHCH 2)，3.80-4.20(3H，m，SOCH 2，
CH)，4.48(1H，m，H 4)，5.13(2H，m，CH＝CH 2)，5.72(1H，m，CH＝CH 2)，6.9-7.4
(10H, m, Ph-H, Ar-H), 7.46 (1H, m, NH) embodiment 43 (+/-)-N-[6-(4-fluorophenyl) hexyls)]-2-(4-benzylthio-)-2-oxo-azetidin-1-base-2-allyl group ethanamide
Use the foregoing description 34 described steps to handle (+/-)-N-[6-(4-fluorophenyl) hexyl of 1.2g (0.00256 mole) with mCPBA)]-2-(4-benzylthio-)-2-oxo-azetidin-1-base-2-allyl group ethanamide (80% diastereomer b), similar processing of process and chromatography obtain the title compound (0.38g, 35% productive rate) of lurid oily matter.
1H?NMRδ(CDCl 3)1.2-1.6(8H，m，4xCH 2)，2.56(2H，t，J＝7Hz，CH 2Ph)，2.6-3.3
(6H，m，CHCH 2，H 3，NHCH 2)，3.95，4.09(each?1H，2xd，J＝11.6Hz，SOCH 2)，4.47
(1H，m，CH)，4.57(1H，m，H 4)，5.11(2H，m，CH＝CH 2)，5.72(1H，m，CH＝CH 2)，
(6.9-7.4 10H, m, NH, Ph-H, Ar-H) embodiment 44 (+/-)-N-[6-(4-fluorophenyl) hexyl)]-2-[4-benzyl sulfinyl-2-oxo-azetidin-1-yl] butyramide a. methyl 2-(4-benzylthio--2-oxo-azetidin-1-yl) butyric ester
Be used in hexane (5.4ml, 0.054mol) in the hexamethyl two silicon Lithium Azide solution of 1M in methyl 2-(4-benzylthio--2-oxo-azetidin-1-yl) acetic ester (1.2g of-78 ℃ of processing in dry tetrahydrofuran (20ml), 0.0045 mixture mole) 30 minutes forms the throw out with the violent stirring fragmentation.Then (0.64ml is 0.008mol) in (the insoluble yellow solid dissolving of this dissolved forms yellow solution for 5.4ml, 0.054mol)-78 ℃ processing down with iodoethane.This reaction mixture solution-20 ℃ left standstill 16 hours.After this reactant is cooled to-75 ℃, use acetic acid (0.5ml) to handle again, between salt solution and ethyl acetate, distribute.Water is used ethyl acetate extraction again, with bonded extract drying (MgSO 4) and flash to brown oily matter.Purify by flash chromatography (silica gel ethyl acetate/petroleum ether), then obtain the title compound (0.03g, 23% productive rate, the mixture of diastereomer) of colorless oil.
1H?NMRδ(CDCl 3)1.02(3H，d?of?d，CH 2CH 3)，2.07(2H，m，SCH 2)，2.92?and?3.25
(each?1H，m，H4s)，3.76(2H，d，CH 2)，3.83(2H，d，CH 2)，3.67，4.16(1H，m，CH)，
4.64 and 4.94 (1H, m, H3), 7.28 (2x5H, m, Ph) b.2-(4-benzylthio--2-oxo-azetidin-1-yl) butyric acid
Handle the stirring liquid of methyl-(4-benzylthio--2-oxo-azetidin-1-yl) butyric ester (1.40g, 0.047 mole) in methyl alcohol (12ml) with 1 moles of hydrogen potassium oxide solution (5.47ml).After 16 hours, evaporative removal methyl alcohol, residue dilute with water.Water cooling (ice bath) acidifying, sedimentary oil extracts in the ethyl acetate.With bonded extract drying (MgSO 4) and evaporate the oily solid title compound (1.36g, 100% productive rate, the mixture of diastereomer) that obtains white.
1H?NMRδ(CDCl 3)1.02(3H，m，CH 2CH 3)，2.07(2H，m，SCH 2)，2.92?and?3.35
(each?1H，m，H4s)，3.74(2H，s，CH 2)，3.84(2H，s，CH 2)，3.53，4.10(1H，m，CH)，
4.71 and 4.94 (1H, m, H3), 6.99, (1H, bs, OH), 7.28 (2x5H, m, PhH) c. N-[6-(4-fluorophenyl hexyl)]-2-[4-benzylthio--2-aza-oxo-cyclobutane-1-yl] butyramide (mixture of diastereomer a+b)
6-in stirring at room in dimethyl formamide in (50ml) (4-fluorophenyl) hexane (0.95g, 0.0048mol, Lamattina J.L.EP138464 A2 850424 (CA103:142000)), I-hydroxybenzotriazole hydrate (0.56g, 0.042mol), 2-(4-benzylthio--2-aza-oxo-cyclobutane-1-yl) butyric acid (1.2g, 0.043mol) and dicyclohexyl carbodiimide (0.089g, mixture 0.043mol) 16 hours.Evaporating solvent is also handled this resistates with ethyl acetate.Filter and discarded insoluble dicyclohexylurea (DCU), wash this with saturated sodium bicarbonate aqueous solution and leach thing, dry (MgSO 4) and evaporation obtain oil.Purify with flash chromatography (fine silica, ethyl acetate/gasoline), obtain title compound (1.47g, 75% productive rate) into oil.
1H?NMRδ(CDCl 3)0.83-.98，(3H，m，CH 3)，1.1-17(6H，m，CH 2)，1.8-2.15(4H，m，CH 2)
2.55(2H，t，CH 2)，2.88(1H，m，CH 2)，2.99，(2H，m，CH 2)，3.46，(1H，q，CH 2)，3.85，
4.12(1H，q，CH)，3.85(2H，s，CH 2)，3.86(1H，d，CH 2)，4.65(1H，m，H4)，6.5(1H，t，NH)，
6.75 (1H, t, NH), 6.9-7.33 (9H, m, PhH). embodiment 45 N-[6-(4-fluorophenyl) hexyl)]-2-[4-benzyl sulfinyl)-2-oxo-azetidin-1-yl] butyramide
Will be at the N-[6-of methylene dichloride (20ml) (4-fluorophenyl) hexyl)]-2-(4-benzylthio-)-2-oxo-azetidin-1-base-butyramide (diastereomer a﹠amp; B) (1.27g, 0.0028 mole) solution is cooled to 65 ℃-70 ℃, be used in the methylene dichloride (20ml) between-chlorine peroxybenzoic acid (0.58g, 0.0033 mole) solution drips more than 15 minutes.This mixture washs with saturated sodium bicarbonate and saturated sodium sulfite mixing solutions after 3 hours, dry (MgSO 4) and flash to non-enantiomer mixture a1.a2.b1, the title compound of b2 oily matter.(1.47g，100％)。
1H?NMRδ(CDCl 3)0.93-1.04，(3H，m，CH 2CH 3)，1.1-1.7(6H，bm，-CH 2)，1.8-
2.25(2H，m，CH 3CH 2)2.55(2H，t，CH 2Ar)，2.6-3.0(1H，m，3H)，3.05-3.55
(3H，m，CH 2，H3)，3.7(1H，q，CH)，3.85，4.12(1H，q，CH)，3.85-4.25(2H，m，SCH 2)，4.5-
4.85(1H，m，H4)，6.45(1H，t，NH)，6.85(1H，t，NH)，6.9-8.1(9H，m，PhH).
By chromatography (HOLC, Beckmang silicagel column, ethanol/hexane) the above-mentioned oil of purification 0.8g, then obtain the isomer among the embodiment 46-48.Embodiment 46 (+/-)-N-[6-(4-fluorophenyl) hexyl)]-2-[4-benzyl sulfinyl)-2-oxo-azetidin-1-yl] butyramide (isomer a1) isomer a1, oil, (0.05g)
1H?NMRδ(CDCl 3)0.83-.98，(3H，t，CH 3)，1.2-1.75(6H，m，CH 2)，1.99(2H，
q，CH 3CH 2)，2.56(2H，m，CH 2Ar)，2.78，3.34，(2H，m，H3)3.21，(2H，m，NHCH 2)，3.87
(3H, m, CH, PhCH 2), 4.71 (1H, m, H4), 6.25 (1H, t, NH), 6.9-7.39 (9H, m, PhH). embodiment 47 (+/-)-N-[6-(4-fluorophenyl) hexyl)]-2-[4-benzyl sulfinyl)-2-oxo-azetidin-1-yl] butyramide (isomer b1 and b2,1: 3)
Above-mentioned steps obtains buttery 0.05g title compound (b1: b2,1: 3)
1H?NMRδ(CDCl 3)0.93，(3H，t，CH 3)，1.01，(3H，t，CH 3)，1.22-1.38(6H，m，CH 2)，1.99-
2.1(2H，m，CH 3CH 2)，2.1-2.25(2H，m，CH 3CH 2)，2.56(2H，m，CH 2Ar)，
2.55，3.08，(2H，m，H3)2.68，3.55，(2H，m，H3)，3.18，3.25，(2H，2xm，NHCH 2)，3.87-4.25
(3H，m，CH，PhCH 2)，4.45，4.51(1∶3)(1H，2xm，H4)，6.75(1H，t，NH)，6.9-7.40(9H，
M, PhH). embodiment 48 N-[6-(4-fluorophenyl) hexyl)]-2-[4-benzyl sulfinyl)-2-oxo-azetidin-1-yl] butyramide (isomer a2)
Above-mentioned steps obtains buttery 0.05g title compound.
1H?NMRδ(CDCl 3)0.98，(3H，t，CH 3)，1.3-1.61(6H，m，CH 2)，2.08(2H，
q，CH 3CH 2)，2.56(2H，m，CH 2Ar)，2.75，3.19(each?1H，m，H3)，3.26(2H，m，NHCH 2)，
3.85 (1H, m, CH), 4.05 (1H, d of d, ArCH 2), 4.54 (1H, m; H4); 6.92-7.40 (9H, m, PhH). embodiment 49 (+/-)-N-[6-(4-fluorophenyl) hexyl)]-2-[4-benzyl sulfinyl-2-oxo-azetidin-1-yl] valeramide a. methyl 2-(4-benzylthio--2-oxo-azetidin-1-yl) valerate
(4g 0.023mol) replace iodoethane, and other reagent uses the amount identical with embodiment 44a with propyl iodide, purify by flash chromatography (silica gel ethyl acetate/petroleum ether), then obtain the title compound (1.05g, 25.3% productive rate, the mixture of diastereomer) of colorless oil.
1H?NMRδ(CDCl 3)0.96(3H，d?of?d，CH 2CH 3)，1.36(2H，m，CH 3CH 2)，1.96(2H，
m，CH 2CH 2)，2.90，3.29(each?1H，m，H3s)，3.74(3H，d，OCH 3，)，3.79(2H，d，SCH 2)，
4.27 (1H, m, CH), 4.64 and 4.94 (1H, m, H4), 7.29 (5H, m, Ph) b.2-(4-benzylthio--2-oxo-azetidin-1-yl) valeric acids
With methyl-(4-benzylthio--2-oxo-azetidin-1-yl) valerate (1..4g, 0.0033 mole) replace methyl-(4-benzylthio--2-oxo-azetidin-1-yl) butyric ester, and other reagent use the amount identical with embodiment 44b, then obtain the title compound (0.8g of colorless oil, 82% productive rate, the mixture of diastereomer).
1H?NMRδ(CDCl 3)0.96(3H，d?of?d，CH 2CH 3)，1.40(2H，m，CH 3CH 2)，1.91(2H，
m，CH 2CH 2)，2.90，3.29(each?1H，m，H3s)，3.64(1H，m，OCH 3，)，3.84(2H，d，
SCH 2), 4.24 (1H, m, CH), 4.64,4.94 (1H, m, H4), 6.4 (1H, bs, OH), 7.29 (5H, m, Ph) c. (+/-)-N-[6-(4-fluorophenyl hexyl)]-2-[4-benzylthio--2-aza-oxo-cyclobutane-1-yl] propionic acid amide
With 2-(4-benzylthio--2-oxo-azetidin-1-yl) propionic acid (0.8g, 0.0027 mole) replace 2-(4-benzylthio--2-oxo-azetidin-1-yl) butyric acid, and other reagent use the amount identical with embodiment 44c, then obtain the title compound (1.4g, 100% productive rate) of oily matter. 1H NMR (complex spectrum) δ (CDCl 3) 0.93, (3H, m, CH 3), 1.2-1.6 (4H, m, CH 2), 1.8-2.15 (4H, m, CH 2) 2.55 (2H, t, CH 2), 2.88 (1H, m, CH 2), 2.8,3.3 (1H, d of d, 3H), and 2.9, (2H, s, CH 2) 2.95, (2H, s, CH 2) 3.28, (2H, m, CH 2), 3.85 (2H, m, CH 2), 4.62 (1H, q, CH), 4.74 (1H, m; H4), 6.5 (1H, t, NH), 6.76 (1H, t; NH), 6,9-7.3 (9H, m, PhH). embodiment 50 (+/-)-N-[6-(4-chloro-phenyl-) hexyl)]-2-[4-benzyl sulfinyl)-2-oxo-azetidin-1-yl] propionic acid amide
Will be at the N-[6-of methylene dichloride (5ml) (4-fluorophenyl) hexyl)]-2-(4-benzylthio-)-2-oxo-azetidin-1-yl] valeramide (diastereomer a﹠amp; B) (0.2g, 0.00042 mole) solution is cooled to 65 ℃-70 ℃, be used in the methylene dichloride (5ml) between-chlorine peroxybenzoic acid (0.09g, 0.00051 mole) solution drips more than 15 minutes.This mixture washs with saturated sodium bicarbonate and saturated sodium sulfite mixing solutions after 1 hour, dry (MgSO 4) and flash to non-enantiomer mixture a1.a2.b1, the title compound of b2 oily matter (0.2g, 100% productive rate). 1H NMR (complex spectrum) δ (DMSO d 6) 0.83-0.95, (3H, m, CH 2CH 3), 1.1-1.7 (6H, bm ,-CH 2), 2.7 (2H, s, CH 2Ar), 2.9 (2H, s, CH 2Ar), 3.05-3.55 (3H, m, CH 2, H3), 3.7 (1H, q, CH), 3.85,4.12 (1H, q, CH), 3.70-4.25 (2H, m, SCH 2), 4.6-5.15 (1H, ms, H4), 7.0-8.2 (9H, m, PhH). and embodiment 51 N-benzyl-2-[4-benzyl sulfinyl-2-oxo-azetidin-1-yl] propionic acid amide (diastereomer b1 and b2,1: 1.5)
Under the condition of embodiment 12, handle N-benzyl-2-[4-benzylthio--2-oxo-azetidin-1-yl with mCPBA] propionic acid amide (diastereomer b1; embodiment 20) (1.31) processor obtains non-enantiomer mixture (b1: b2; 1: 1.5) title compound (1.14g, fusing point 110-3 ℃) embodiment 52 N-(benzyl)-2-[4-benzyl sulfinyl-2-aza-oxo-cyclobutane-1-yl of colorless solid] propionic acid amide (89% diastereomer a1)
Under embodiment 12 described conditions, handle N-(benzyl)-2-[4-benzyl sulfenyl-2-aza-oxo-cyclobutane-1-yl with mCPBA] propionic acid amide (diastereomer a; embodiment 19) (1.31g) provide the non-enantiomer mixture of title compound; it is provided prevailing diastereomer a1 colorless solid by Crystallization Separation, m.p.150-3 ℃ of embodiment 53 N-(benzyl)-2-[4-benzyl sulfinyl-2-aza-oxo-cyclobutane-1-yl] propionic acid amide (82% diastereomer a2)
Provide prevailing title compound diastereomer a2,0.67g, m.p.134-5 ℃ from above-mentioned crystalline mother liquid evaporation and recrystallization.Embodiment 54 R-methyl-4-[(4-allyl group oxygen base carbonyl) benzyl sulfenyl]-2-aza-oxo-cyclobutane-1-yl acetate a. (-)-R-4-[(4-allyl group oxygen base carbonyl) the benzyl sulfenyl]-2-aza-oxo-cyclobutane-1-guanidine-acetic acid
4-(4-allyl group oxygen base carbonyl) benzyl sulfenyl)-2-aza-oxo-cyclobutane-1-yl acetate (3.41g, 10.2mmol) and cinchovatin (2.99g 10.2mmol) is heated to boiling in ethanol (40ml), obtain limpid solution.After placing 90 molecules, leach crystalline salt, from ethanol (20ml) recrystallization.The solid of gained and ether and water vigorous stirring are used the dilute hydrochloric acid acidifying simultaneously, obtain completely solution after, layering, water is further used extracted with diethyl ether.The extraction liquid that merges is dried in (sal epsom) and is evaporated to oily matter, and it is provided the title compound white crystal with light sherwood oil development crystallization, and m.p.74-6 ℃, 6.7g, 50% productive rate
α D 25＝-24.2(c.0.7w/v?CHCl 3，25℃)
1HNMRδ(CDCl 3)2.97(1H，dd，H3a)，3.26，4.07(each?1H，CH 2CO，d)，3.42(1H，
dd，H3b)，3.70(3H，s，CH 3O)，3.81(2H，s，SCH 2)，4.83(2H，m，CH 2O)，4.93(1H，
dd，H4)，5.35(2H，m，CH 2CH)，6.03(1H，m，CHCH 2)，7.39(2H，d，Ph-H)，8.02(2H，
D, Ph-H) b. R-methyl-4-[(4-allyl group oxygen base carbonyl) the benzyl sulfenyl]-2-aza-oxo-cyclobutane-1-yl acetate
With Anhydrous potassium carbonate (8.88g), R-4-[(4-allyl group oxygen base carbonyl) benzyl sulfenyl]-methyl-iodide (10.94g) processing of the suspension of 2-aza-oxo-cyclobutane-1-guanidine-acetic acid (21.55g) in N-Methyl pyrrolidone (100ml), and at room temperature stirred 2 hours.Add after (1.0g) methyl-iodide, reaction is stirred 30 minutes, is distributed between salt solution (500ml) and the ether (500ml) again.Water layer merges organic extract liquid with ether (500ml) washing, water (* 2), and the salt solution washing, dry (sal epsom) is evaporated to orange (22.1g).By the silicagel column purification by flash chromatography, with [1: 1] P.E.40-60 ℃: eluent ethyl acetate provides R-methyl-4-[(4-allyl group oxygen base carbonyl) the benzyl sulfenyl]-2-aza-oxo-cyclobutane-1-yl acetate yellow oil (20.0g, 89%).
1H?NMRδ(CDCl 3)2.94，3.01(1H，dd，J＝2.2，15.3Hz，H 3)，3.26(1H，d，J＝18.1Hz，1
of?NCH 2)，3.39，3.46(1H，dd，J＝5.1，15.3Hz，H 3)，3.7(3H，s，CO 2CH 3)，3.81(2H，
s，SCH 2)，4.03(1H，d，J＝18.1Hz，1?of?NCH 2)，4.83(2H，m，CO 2CH 2)，4.93(1H，m，
H 4)，5.37(2H，m，CH 2＝CH)，6.04(1H，m，CH 2＝CH)，7.39(2H，m，Ar-H)，8.02(2H，
M, Ar-H) c.R, R-methyl-2-(4-[(4-allyl group oxygen base carbonyl) benzyl sulfenyl]-2-aza-oxo-cyclobutane-1-yl) propionic ester and S, S-methyl-2-(4-[(4-allyl group oxygen base carbonyl) benzyl sulfenyl]-2-aza-oxo-cyclobutane-1-yl) propionic ester
With R-methyl-4-[(4-allyl group oxygen base carbonyl) the benzyl sulfenyl]-the 2-aza-oxo-cyclobutane-solution of 1-yl acetate (13.2g) in anhydrous tetrahydro furan (250ml) is cooled to-75 ℃ in nitrogen, keep temperature to be lower than-70 ℃, THF (46.3ml) solution-treated of usefulness 1M two (trimethyl silyl) lithamide 10 minutes.Red solution is cooled to-75 ℃, remains below-70 ℃, add 1,3-methylimidazole alkane ketone (30.5ml).The suspension that produces stirred 30 minutes at-75 ℃, used methyl-iodide (4.3ml) to handle then 1 minute, temperature was risen to-68 ℃.Be reflected at-75 ℃ and stirred 1 hour, be warmed to-20 ℃ at 30 minutes then.Reaction is cooled to-75 ℃,, is distributed between water (300ml) and the ether (250ml) with glacial acetic acid (3.5ml) cancellation.Water with ether (250ml) washing, is merged organic extract liquid, and with salt solution (* 3) washing, dry (sal epsom) also is evaporated to colorless oil (7.81g). 1H nmr shows that ratio approximately is 50%R, and R (diastereomer a): 35%S, R (diastereomer b): 15% raw material.By repeating the flash chromatography on silica gel purifying, with [2: 1] sherwood oil 40-60 ℃: eluent ethyl acetate provides the product (12.6g, 88%) of various mixtures.D.R, R-2-{-4-[(4-allyl group oxygen base carbonyl) the benzyl sulfenyl]-2-aza-oxo-cyclobutane-1-yl } propionic acid and S, S-{-4-[(4-allyl group oxygen base carbonyl) the benzyl sulfenyl]-2-aza-oxo-cyclobutane-1-yl } propionic acid
With 2-{-4-[(4-allyl group oxygen base carbonyl) the benzyl sulfenyl]-2-aza-oxo-cyclobutane-1-yl tetrahydrofuran (THF) (50ml) solution of methyl propionate (2.65g) is cooled to 3 ℃, and at 1 hour with 1N sodium hydroxide solution (7.5ml) solution-treated.Remove cryostat, reaction mixture was stirred 30 minutes, add 1.0ml 1N sodium hydroxide solution again.To react and stir 30 minutes, and add salt solution (75ml), reaction mixture extracts with ether (75ml).Water 2N hcl acidifying is with ether (2 * 75ml) extractions.Combining extraction liquid washes with water, dry (sal epsom), evaporation provides (R, 4-R) and (S, 4-R)-2-{-4-[(4-allyl group oxygen base carbonyl) benzyl sulfenyl]-2-aza-oxo-cyclobutane-1-yl propionic acid and remove Alpha-Methyl analogue orange (2.50g, 98%) mixture.E. (S, 4-R)-N-[6-(4-fluorophenyl) hexyl]-2-[(4-allyl group oxygen base carbonyl) the benzyl sulfenyl]-2-aza-oxo-cyclobutane-1-base propionic acid amide
With 6-(4-fluorophenyl) hexyl amine (1.38g), 2-{4-[(4-allyl group oxygen base carbonyl) benzyl sulfenyl]-2-azetidine-1-yl propionic acid (non-enantiomer mixture) (2.47g), I-hydroxybenzotriazole (0.95g) and the mixture of dicyclohexylcarbodiimide (1.46g) in dimethyl formamide (50ml) were stirring at room 4 hours.Dicyclohexylurea (DCU) is handled and removed by filter to reaction mixture with ether (100ml).Filtrate is used saturated sodium bicarbonate solution, the salt solution washing, and dry (sal epsom) also is evaporated to dried.By the flash chromatography on silica gel purifying, provide S with [2: 1] P.E.40-60 ℃ of wash-out, R-N-[6-(4-fluorophenyl) hexyl]-2-[(4-allyl group oxygen base carbonyl) the benzyl sulfenyl]-2-aza-oxo-cyclobutane-1-base propionic acid amide (diastereomer b) yellow oil (0.479g, 13.4%) 1H NMR δ (CDCl 3) 1.32-1.6 (13H, m, CH 3, 4xCH 2), 2.56 (2H, t, J=7.6Hz, CH 2Ph), 2.83,2.87 (1H, dd, J=2.3,15.3Hz, H 3), 3.1-3.3 (3H, m, NHCH 2, H 3), 3.86 (2H, s, SCH 2), 4.10 (1H, q, CHCH 3), 4.69 (1H, m, H 4), 4.83 (2H, m, CO 2CH 2), 5.37 (2H, m, CH 2=CH), 6.02 (1H, m, CH 2=CH), 6.43 (1H, m, NH), 6.94 (2H, m, p-F-Ph-N), 7.10 (2H, m, p-F-Ph-H), 7.37 (2H, m, Ar-H), 8.09 (2H, m, Ar-H) embodiment 55. (α-S, 4-R, SS)-N-[6-(4-fluorophenyl) hexyl]-2-[(4-allyl group oxygen base carbonyl) the benzyl sulfenyl]-2-aza-oxo-cyclobutane-1-base propionic acid amide
With S, 4-R-N-[6-(4-fluorophenyl) hexyl]-2-[(4-allyl group oxygen base carbonyl) the benzyl sulfenyl]-methylene dichloride (25ml) solution of 2-aza-oxo-cyclobutane-1-base propionic acid amide (1.20g) is cooled to-75 ℃, dripped mcpba (0.71g, methylene dichloride 1eq) (25ml) solution-treated at 1 hour.Remove cryostat, reaction mixture was stirred 2 hours, with methylene dichloride (25ml) dilution, and with 10% S-WAT (50ml), saturated sodium bicarbonate solution (50ml), water washing.Dry (sal epsom) is evaporated to orange.Use earlier the silicagel column purification by flash chromatography, use eluent ethyl acetate, provide S, R, S-N-[6-(4-fluorophenyl) hexyl by preparation property hplc then]-2-[(4-allyl group oxygen base carbonyl) the benzyl sulfenyl]-2-aza-oxo-cyclobutane-1-base propionic acid amide (diastereomer b2) colorless oil.Place and solidify (0.24g, 19.4%).
1H?NMRδ(CDCl 3)1.32-1.6(13H，m，CH 3，4xCH 2)，2.56(2H，t，J＝7.6Hz，CH 2Ph)，
2.83，2.87(1H，dd，J＝2.4，15.3Hz，H 3)，3.1-3.3(3H，m，NHCH 2，H 3)，3.96，4.08(2H，
2xd，J＝13Hz，SOCH 2)，4.4(1H，q，CHCH 3)，4.60(1H，m，H 4)，4.84(2H，m，
CO 2CH 2)，5.37(2H，m，CH 2＝CH)，6.04(1H，m，CH 2＝CH)，6.94(3H，m，NH，p-F-Ph-H
), 7.10 (2H, m, p-F-Ph-H), 7.37 (2H, m, Ar-H), 8.09 (2H, m, Ar-H) embodiment 56. (α-S, 4-R, SS)-N-[6-(4-fluorophenyl) hexyl]-2-[4-carboxyl benzyl sulfinyl]-2-aza-oxo-cyclobutane-1-base propionic acid amide
With (α-S, 4-R, SS)-N-[6-(4-fluorophenyl) hexyl]-2-[(4-allyl group oxygen base carbonyl) the benzyl sulfenyl]-the 2-aza-oxo-cyclobutane-(embodiment 55 for 1-base propionic acid amide, diastereomer b2) (0.24g), four (triphenyl phosphine) palladium (0) (15mg) and the solution of triphenyl phosphine (6mg) in exsiccant methylene dichloride (5ml) handle with pyridine (0.039ml), be reflected at stirring at room 20 hours.Reaction mixture is handled with methylene dichloride (50ml) and water (25ml), uses the 2N hcl acidifying.Salt solution (75ml) is added in the emulsion, layering, (2 * 25ml) wash water layer with methylene dichloride.Organic extract liquid is dried in (sal epsom) and is evaporated to yellow jelly (0.22g); by the flash chromatography on silica gel purifying; with 50: 50: 1 methylene dichloride: acetone: acetate provided (α-S; 4-R; SS)-N-[6-(4-fluorophenyl) hexyl]-2-[4-carboxyl benzyl sulfinyl]-2-aza-oxo-cyclobutane-1-base propionic acid amide brown foam (0.123g, 56%).
1H?NMRδ(CDCl 3)1.32-1.6(13H，m，CH 3，4xCH 2)，2.55(2H，t，J＝7.6Hz，CH 2Ph)，
2.84，2.88(1H，dd，J＝2.4，15.2Hz，H 3)，3.1-3.3(3H，m，NHCH 2，H 3)，4.04，4.10(2H，
2xd，J＝13Hz，SOCH 2)，4.4(1H，q，CHCH 3)，4.68(1H，m，H 4)，6.94(3H，m，NH，
P-F-Ph-H), 7.10 (2H, m, p-F-Ph-H), 7.39 (2H, m, Ar-H), 8.06 (2H, m, Ar-H) a) (+/-)-4-(pyridyl-2 methylthio group) nitrogen heterocyclic din-2-ketone of embodiment 101 (+/-)-4-(pyridine-2-methylthiol)-1-(4-phenyl-2-oxo butyl) nitrogen heterocyclic din-2-ketone
(0.953g 40mmol) is dissolved in the ethanol (100ml), and (5.0g is 40mmol) and in stirring at room 10 minutes to add 2-(mercapto methyl) pyridine then with sodium.Drip the 4-acetoxyl group nitrogen heterocyclic din-2-ketone in ethanol (50ml), continuously stirring is 30 minutes again.Evaporating solvent adds entry and product is extracted in the ethyl acetate.Dry and evaporation obtains oil, obtains title compound (5.3g), fusing point 99-100 ℃ with its slow crystallization and with the sherwood oil development.
1H NMR (CDCl 3) δ 2.84 (1H, dd), 3.34 (1H, dd), 3.95 (2H, s), 4.86 (1H, dd), 6.58 (1H, br s), and 7.17-7.34 (2H, m), 7.65-7.72 (1H, m), 8.50-8.53 (1H, m) .b) (+/-)-4-(pyridine-2-methylthiol)-1-(4 phenyl-2-oxo butyl) nitrogen heterocyclic din-2-ketone
Will (+/-)-4-(pyridyl-2 methylthio group) nitrogen heterocyclic din-2-ketone (5.3g in room temperature, 27mmol), 1-bromo-4-phenyl-2-butanone (6.8g, 30mmol), Tetrabutylammonium bromide (0.87g, 2.7mmol), finely powdered KOH (1.7g, 30mmol) and the miscellany of anhydrous THF (100ml) stirred 2 hours, pour in the water then and use extracted with diethyl ether.Organic extraction liquid-liquid chromatography (silica gel, methylene dichloride) separated and from ether crystallization obtain required product (2.5g), fusing point 56-58 ℃.
1H NMR (CDCl 3) δ 2.70 (2H, t), 2.90 (2H, t); 3.01 (1H, dd), 3.43 (1H, dd); 3.57 (1H, d), 4.11 (1H, d); 3.84 (2H, s), 4.98 (1H, dd); 7.15-7.32 (7H, m), 7.60-7.67 (1H; m), 8.48-8.51 (1H, m). embodiment 102 (+/-)-4-(pyridine-2-ylmethyl sulfinyl)-1-(4 phenyl-2-oxo butyl) nitrogen heterocyclic din-2-ketone (diastereomer 1)
Will be in methylene dichloride (50ml) (+/-)-4-(pyridyl-2-methylthiol)-1-(4 phenyl-2-oxo butyl) nitrogen heterocyclic din-2-ketone (2.4g, 7mmol) solution is chilled to-60 ℃, and drip m-chloro peroxidation phenylformic acid in methylene dichloride (50ml) (1.46g, 8.4mmol).In this temperature continuously stirring 1 hour, then this miscellany is poured in S-WAT and the sodium bicarbonate aqueous solution.Dry and evaporation is developed this resistates with ethyl acetate with organic layer.Recrystallization obtains single diastereomer (0.66g) from ethyl acetate, fusing point 123-125 ℃.
1H NMR δ (CDCl 3) 2.74 (2H, t), 2.92 (2H, t), 3.01 (1H, dd), 3.33 (1H, dd), 3.84 (1H, d), 3.98 (1H, d), 4.13 (1H, d), 4.40 (1H, d), 4.92 (1H, dd), 7.15-7.35 (7H, m), 7.70-7.80 (1H, m), 8.56 (1H, m) .v C=o1785 cm -1(CCl 4) actual measurement: C, 63.63; H, 5.62; N, 7.97%; C 19H 20N 2O 3S calculated value: C, 64.02; H, 5.66; N, 7.86% embodiment 103 (+/-)-4-(pyridine-2-ylmethyl sulfinyl)-1-(4 phenyl-2-oxo butyl) nitrogen heterocyclic din-2-ketone (diastereomer 2)
Mother liquor recrystallization from ethylacetate/ether of the ethyl acetate among the embodiment 102 development is obtained the sample of second kind of diastereomer for twice, contain 20% diastereomer 1 (0.34g), fusing point 70-72 ℃.
1H
NMRδ(CDCl 3)2.69-2.77(2H，m)，2.77(1H，dd)，2.90(2H，t)，3.26(1H，dd)，4.17
(2H，s)，4.22(1h，d)，4.37(1H，d)，4.79(1H，dd)，7.14-7.34(7H，m)，7.69-7.74(1H，
m)，8.56-8.57(1H，m).
v C=o1785 cm -1(CCl 4) actual measurement: C, 64.07; H, 5.65; N, 8.22%; C 19H 20N 2O 3S calculated value: C, 64.02; H, 5.66; N, 7.86% embodiment 104 (+/-)-N-(6-phenyl oneself-1-yl)-4-(pyridin-4-yl methylthio group)-2-aza-oxo-cyclobutane-1-yl acetamide be (+/-)-4-(pyridine-2-methylthiol) nitrogen heterocyclic din-2-ketone a)
According to the method for embodiment 1a, with respectively synthesizing for the 4-of 20mmol (acetylthio methyl) pyridine and 4-acetoxyl group nitrogen heterocyclic din-2-ketone.(silica gel, 0-4% is in CH for chromatography 2Cl 2In MeOH) obtain title compound (2.7g) after separating into oil.
1H NMR (CDCl 3) 2.87 (1H, dd), 3.34 (1H; dd); 3.80 (2H, s), 4.70 (1H; dd); (7.03 1H br.singlet), and 7.26-7.30 (2H, m); (8.51-8.59 2H, m) .b) (+/-)-N-(6-phenyl oneself-1-yl)-4-(pyridin-4-yl methylsulfinyl)-2-aza-oxo-cyclobutane-1-yl acetamide
According to the method for embodiment 101b, be used for (+/-)-4-(pyridine-2-methylthiol) nitrogen heterocyclic din-2-ketone (8.5mmol), N-(6-phenyl oneself-1-yl)-2-bromo ethanamide (9.4mmol), Tetrabutylammonium bromide (0.94mmol) and the powdery KOH (9.4mmol) of the 8.5mmol of anhydrous THF (50ml).After separating, chromatography (silica gel, the 0-2% MeOH in EtOAc) obtains title compound (2.2g) into oil.
1H?NMRδ(CDCl 3)1.27(4H，m)，1.46-1.66(4H，m)，
2.59(2H，t)，2.91(1H，dd)，3.22(2H，m)，3.39(1H，dd)，3.47，(1H，d)，3.72-3.89(3H，
M), 4.91 (1H, dd); 6.23 (1H, br.triplet), 7.14-7.30 (7H; m), and 8.53-8.57 (2H, m). embodiment 105 (+/-)-N-(6-phenyl oneself-1-yl)-4-(pyridin-4-yl methylsulfinyl)-2-aza-oxo-cyclobutane-1-yl acetamide (diastereomer 1)
With (+/-)-N-(6-phenyl oneself-1-yl)-(2.1g 5.1mmol), synthesizes according to the method for embodiment 102 4-(pyridin-4-yl methylthio group)-2-aza-oxo-cyclobutane-1-yl acetamide.Crude product recrystallization from ethylacetate/ether is obtained single diastereomer (0.55g), fusing point 126-127 ℃.
1H?NMRδ(CDCl 3)1.31-1.35(4H，m)，1.48-
1.64(4H，m)，2.59(2H，t)，3.01(1H，dd)，3.23(2H，dt)，3.46(1H，dd)，3.82-3.90(3H，
m)，4.03(1H，d)，4.70(1H，dd)，6.36(1H，br?triplet)，7.15-7.29(7H，m)，8.64-6.66
(2H, 7m) .v C=o1794,1745cm -1(CCl 4) actual measurement: C, 64.37; H, 6.74; N, 9.75%; C 23H 29N 3O 3S calculated value: C, 64.61; H, 6.84; N, 9.83% embodiment 106 (+/-)-N-(6-phenyl oneself-1-yl)-4-(pyridin-4-yl methylsulfinyl)-2-aza-oxo-cyclobutane-1-yl acetamide (diastereomer 2)
Mother liquor crystallization from ethylacetate/ether of embodiment 105 is obtained containing the sample (0.5g) of 20% the second diastereomer, fusing point 89-91 ℃.
1H NMR δ (CDCl 3) 1.33-1.37 (and 4H, m) 1.50-1.60 (4H, m) 2.60 (2H, t), 3.00 (1H, dd), 3.21-3.33 (3H, m), 3.95-4.03 (3H, m), 4.18 (1H, d), 4.71 (1H, dd), 6.70 (1H, br.triplet), 7.15-7.29 (8H, m), 8.64-8.66 (2H, m), n C=o(CCl 4) 1795,1766. actual measurements: C, 64.53; H, 6.72; N, 9.84%; C 23H 29N 3O 3S calculated value: C, 64.61; H, 6.84; N, 9.83% embodiment 107 (+/-)-N-(6-phenyl oneself-1-yl)-4-(1-oxo pyridine-4-ylmethyl alkylsulfonyl)-2-aza-oxo-cyclobutane-1-yl acetamide (diastereomer 2)
In room temperature will (+/-)-N-(6-phenyl oneself-1-yl)-4-(pyridin-4-yl methylsulfinyl)-2-aza-oxo-cyclobutane-1-yl acetamide (0.2g; 0.47mmol) and the solution stirring of m-chloro peroxybenzoic acid (excessive) 2 hours, handle as embodiment 102 then.(silica gel, 0-5% is in CH for chromatography 2Cl 2In MeOH) obtain title compound (0.17g), fusing point 72-74 ℃ after separating.
1H?NMRδ(CDCl 3)1.33-1.37(4H，m)，1.50-1.65
(4H，m)，2.60(2H，t)，3.24-3.30(2H，m)，3.38(1H，dd)，3.86(1H，d)，4.06(1H，d)，
4.30(1H，d)，4.54(1H，d)，5.00(1H，dd)，5.76(1H，br.triplet)，7.15-7.20(3H，m)
7.26-7.30 (2H, m), 7.40 (2H, d), 8.22 (2H, d) .v C=o1780 cm -1(KBr) actual measurement: C, 59.41; H, 6.18; N, 9.05%; C 23H 29N 3O 5S calculated value: C, 59.64; H, 6.41; N, 9.07% embodiment 108 (+/-)-N-(6-phenyl oneself-1-yl)-4-(2-furyl methylthio group)-2-aza-oxo-cyclobutane-1-yl acetamide be (+/-)-(2-furyl methylthio group) nitrogen heterocyclic din-2-ketone a)
According to the method for embodiment 1a, synthesize with furfuryl mercaptan (42.5mmol) and 4-acetoxyl group nitrogen heterocyclic din-2-ketone (38mmol).Chromatography (silica gel, 1: 1 sherwood oil/CH 2Cl 2) obtain title compound (5.5g) after the separation into oil.
1H NMR δ (CDCl 3) 2.86 (1H, dd), 3.36 (1H, dd), 3.86 (2H, s), 4.79 (1H, dd), 6.06 (1H, br.singlet), and 6.21-6.23 (1H, m), 6.33-6.35 (11H, m), 7.37-7.39 (1H, m) .b) (+/-)-N-(6-phenyl oneself-1-yl)-4-(2-furyl methylthio group)-2-aza-oxo-cyclobutane-1-yl acetamide
According to the method for embodiment 101b, be used for (+/-)-4-(2-furyl methylthio group) nitrogen heterocyclic din-2-ketone (10mmol), N-(6-phenyl oneself-1-yl)-2-bromo ethanamide (10mmol), Tetrabutylammonium bromide (1mmol) and the powdery KOH (11mmol) of anhydrous THF (150ml).(obtain title compound (3.4g) after (silica gel, EtOAc/ sherwood oil) separation through chromatography into oil.
1H?NMRδ(CDCl 3)1.31-1.40(2H，m)，2.60(2H，t)，2.97(1H，dd)，3.19-3.28
(2H，m)，3.43(1H，dd)，3.65(1H，d)，3.83(1H，d)，3.84(2H，d)，4.91(1H，dd)，6.13
(1H, br.triplet), 6.22 (1H, m), 6.31 (1H, m), 7.14-7.36 (6H, m). embodiment 109 (+/-)-N-(6-phenyl oneself-1-yl)-4-(2-furyl methyl sulfinyl)-2-aza-oxo-cyclobutane-1-yl acetamide (diastereomer 1)
With (+/-)-N-(6-phenyl oneself-1-yl)-(2.9g 7.2mmol), synthesizes according to the method for embodiment 102 4-(2-furyl methylthio group)-2-aza-oxo-cyclobutane-1-yl acetamide.Crude product recrystallization from ethylacetate/ether is obtained containing about 99% diastereomer, 1 sample (0.2g), fusing point 160-161 ℃.
1H NMR δ (CDCl 3) 1.32-1.36 (and 4H, m) 1.50-1.63 (4H, m), 2.60 (2H, t), 3.01 (1H, dd), 3.18-3.30 (2H, m), 3.42 (1H, dd), 3.76 (1H, d), 4.00 (1H, d), 4.10-4.16 (2H, m), 4.60 (1H, dd), 6.42 (2H, m), 6.55 (1H, br.triplet), 7.16-7.19 (3H, m), 7.25-7.29 (2H, m), 7.43 (1H, m) .n C=o1748,1791cm -1(CCl 4) actual measurement: C, 63.18; H, 6.59; N, 6.77%; C 22H 28N 2O 4S calculated value: C, 63.44; H, 6.78; N, 9.73% embodiment 110 (+/-)-N-(6-phenyl oneself-1-yl)-4-(2-furyl methyl sulfinyl)-2-aza-oxo-cyclobutane-1-yl acetamide (diastereomer 2)
(silica gel, 0-2% is in CH by chromatography 2Cl 2In MeOH) purifying embodiment 109 mother liquor and from ethylacetate/ether recrystallization obtain containing diastereomer 2 samples (1.08g) of 5% diastereomer 1, fusing point 61-62 ℃.
1H?NMRδ
(CDCl 3)1.33-1.37(4H，m)，1.51-1.63(4H，m)，2.60(2H，t)，3.00(1H，dd)，3.23-3.30
(3H，m)，3.98(1H，d)，4.29(1H，d)，4.12(1H，d)，4.24(1H，d)，4.61(1H，dd)，6.42
(2H，m)，7.15-7.18(3H，m)，7.25-7.31(3H，m)，7.44-7.45(1H，m).v c＝o?1793cm -1
(CCl 4) actual measurement: C, 63.41; H, 6.63; N, 6.80%; C 22H 28N 2O 4S calculated value: C, 63.44; H, 6.78; N, 9.73% embodiment 111 (+/-)-N-(6-phenyl oneself-1-yl)-4-(2-furyl methyl alkylsulfonyl)-2-aza-oxo-cyclobutane-1-yl acetamide
Synthesize according to embodiment 107 methods with N-(6-phenyl oneself-1-yl)-4-(2-furyl methyl sulfinyl)-2-aza-oxo-cyclobutane-1-yl acetamide (0.10g).With the ether development, obtain title compound (0.065g), fusing point 102-104 ℃.
1H?NMR(CDCl 3)1.32-1.36
(4H，m)，1.49-1.64(4H，m)，2.60(2H，t)，3.12(1H，dd)，3.22-3.29(3H，m)，3.94(1H，
d)，4.03(1H，d)，4.38(1H，d)，4.45(1H，d)，4.89(1H，dd)，6.00(1H，br.triplet)，6.44-
6.46(1H，m)，6.55-6.56(1H，m)，7.16-7.19(3H，m)，7.25-7.29(2H，m)，7.46-7.47
(1H, m) .v C=o1797 cm -1(CCl 4) Found:C, 60.15; H, 6.32; N, 6.50%C 22H 28N 2O 5S.0.3H 2Orequires:C, 60.34; H, 6.58; N, 6.40% embodiment 112 (+/-)-N-(the 6-[4-fluorophenyl] oneself-the 1-yl)-4-(2-furyl methylthio group)-2-aza-oxo-cyclobutane-1-yl acetamide
Be used for (+/-)-4-(2-furyl methylthio group)-azetidine-2-ketone (15mmol), N-(6-(4-fluorophenyl) oneself-1-yl)-2-bromo ethanamide * (15mmol), Tetrabutylammonium bromide (1.5mmol) and the powdery KOH (16.5mmol) of anhydrous THF (100ml), synthesize according to embodiment 101b method.(silica gel is in CH for chromatography 2Cl 2In 0-2%MeOH) obtain title compound (3.4g) into oil.
1H?NMRδ(CDCl 3)1.25-1.64(8H，m)，2.57(2H，t)，2.98
(1H，dd)，3.23(2H，dt)，3.43(1H，dd)，3.67(1H，d)，3.76-3.91(3H，m)，4.90(1H，dd)，
6.10(1H，br.triplet)，6.22(1H，d)，6.31(1H，dd)，6.90-6.98(2H，m)，7.08-7.18
(2H, m), 7.36 (1H, m). ★6-(4-fluorophenyl) hexanamide (2.0g) and Hunig ' the s alkali (1.33g) handled in anhydrous methylene chloride (25ml) by the bromo acetyl bromide (2.07g) that is used for methylene dichloride (10ml) in 0-5 ℃ obtain.Embodiment 113 (+/-)-N-(the 6-[4-fluorophenyl] oneself-the 1-yl)-4-(2-furyl methyl sulfinyl)-2-aza-oxo-cyclobutane-1-yl acetamide (diastereomer 1)
With (+/-)-N-(the 6-[4-fluorophenyl] oneself-the 1-yl)-(2.0g 4.8mmol), synthesizes according to the method for embodiment 102 4-(2-furyl methylthio group)-2-aza-oxo-cyclobutane-1-yl acetamide.Thick product crystallization from ethyl acetate obtains containing the sample (0.35g) of about 93% diastereomer 1, fusing point 157-8 ℃.
1H NMR δ (CDCl 3) 1.31-1.35 (4H, m), 1.50-1.58 (4H, m), 2.56 (2H, t), 3.02 (1H, dd), 3.20-3.26 (2H, m), 3.42 (1H, dd), 3.74 (1H, d), 4.00 (1H, d), 4.10-4.17 (2H, m), 4.59 (1H, dd), 6.42 (2H, m), 6.65 (1H, br.triplet), 6.92-6.97 (2H, m), and 7.09-7.13 (2H, m), 7.43-7.44 (1H, m) .n C=o1791cm -1Found:C, 58.85; H, 6.00; N, 6.36%C 22H 27FN 2O 4S.0.68H 2Orequires:C, 59.14; H, 6.40; N, 6.27% embodiment 114 (+/-)-N-(the 6-[4-fluorophenyl] oneself-the 1-yl)-4-(2-furyl methyl sulfinyl)-2-aza-oxo-cyclobutane-1-yl acetamide (diastereomer 2)
The mother liquor of evaporation embodiment 113 and from ethylacetate/ether crystallization obtain containing the sample (0.62g) of about 97% diastereomer 2, fusing point 100-101 ℃.
1H NMR δ (CDCl 3) 1.33-1.35 (4H, m), 1.50-1.60 (4H, m), 2.56 (2H, t), 3.01 (1H, dd), 3.22-3.31 (3H, m), 3.98 (1H, d), 4.11 (1H, d), 4.23 (1H, d), 4.29 (1H, d), 4.60 (1H, dd), 6.41-6.42 (2H, m), 6.92-6.96 (2H, m), 7.09-7.13 (2H, m) 7.26 (1H, br.triplet), 7.44-7.45 (1H, m) .n C=o1794 cm -1Found:C, 60.70; H, 6.22; N, 6.44%C 22H 27FN 2O 4S requires:C, 60.81; H, 6.26; N, 6.45% embodiment 115 (+/-)-N-(the 6-[4-fluorophenyl] oneself-the 1-yl)-4-(2-furyl methyl alkylsulfonyl)-2-aza-oxo-cyclobutane-1-yl acetamide
Synthesize according to embodiment 107 methods with N-(6-(4-fluorophenyl) oneself-1-yl)-4-(2-furyl methyl sulfinyl)-2-aza-oxo-cyclobutane-1-yl acetamide (1.0g).Develop thick product with ether, obtain title compound (0.29g), fusing point 114-115 ℃ from the ethyl acetate/petroleum ether crystallization.
1H?NMRδ(CDCl 3)1.31-1.35(4H，m)，
1.49-1.60(4H，m)，2.57(2H，t)，3.12(1H，dd)，3.22-3.29(3H，m)，3.95(1H，d)，4.03
(1H，d)，4.38(1H，d)，4.45(1H，d)，4.88(1H，dd)，6.01(1H，br.triplet)，6.44-6.45
(1H，m)，6.55-6.56(1H，m)，6.93-6.97(2H，m)，7.09-7.13(2H，m)，7.46-7.47(1H，m).
n c＝o?1797?cm -1
Found：????????????????????????C，58.27；H，5.96；N，6.20％
C 22H 27FN 2O 5S requires:C, 58.65; H, 6.04; N, 6.22% embodiment 116 (+/-)-N-(the 6-[4-chloro-phenyl-] oneself-the 1-yl)-4-(2-furyl methylthio group)-2-aza-oxo-cyclobutane-1-yl acetamide
Be used for (+/-)-4-(2-furyl methylthio group)-azetidine-2-ketone (12mmol), N-(6-(4-chloro-phenyl-) oneself-1-yl)-2-bromo ethanamide (12mmol), Tetrabutylammonium bromide (1.2mmol) and the powdery KOH (13.2mmol) of anhydrous THF (100ml), synthesize according to embodiment 101b method.Chromatography (silica gel, the 50-100%EtOAc in sherwood oil) obtains the title compound (3.9g) into oil.
1H NMR δ (CDCl 3) 1.23-1.61 (8H, m), 2.56 (2H, t), 2.97 (1H; dd), 3.23 (2H, dt), 4.05 (1H, dd); 3.62-3.91 (4H, m), 4.91 (1H, dd); 6.18 (1H, br.triplet), 6.22 (1H, d); 6.30 (1H, dd), 7.08 (2H, d); 7.20-7.26 (2H, m), 7.36 (1H, d). embodiment 117 (+/-)-N-(the 6-[4-chloro-phenyl-] oneself-the 1-yl)-4-(2-furyl methyl sulfinyl)-2-aza-oxo-cyclobutane-1-yl acetamide (diastereomer 1)
With (+/-)-N-(the 6-[4-chloro-phenyl-] oneself-the 1-yl)-(3.8g 8.7mmol), synthesizes according to the method for embodiment 102 4-(2-furyl methylthio group)-2-aza-oxo-cyclobutane-1-yl acetamide.Thick product obtains the sample (0.49g) of diastereomer 1 from the ether development, fusing point 171-2 ℃.
1H?NMRδ(CDCl 3)1.31-1.34(4H，m)，1.49-1.61(4H，m)，2.56(2H，
t)，3.02(1H，dd)，3.20-3.26(2H，m)，3.42(1H，dd)，3.75(1H，d)，4.00(1H，d)，4.10-
4.17(2H，m)，4.60(1H，dd)，6.42(2H，m)，6.60(1H，br.triplet)，7.08-7.10(2H，m)，
7.22-7.26(2H，m)，7.43-7.44(1H，m).n c＝o?1791?cm -1
Found：??????????????????????????C，58.16；H，5.91；N，6.25％
C 22H 27ClN 2O 4S requires:C, 58.59; H, 6.03; N, 6.21% embodiment 118 (+/-)-N-(the 6-[4-chloro-phenyl-] oneself-the 1-yl)-4-(2-furyl methyl sulfinyl)-2-aza-oxo-cyclobutane-1-yl acetamide (diastereomer 2)
The mother liquor of evaporation embodiment 117 and from ether crystallization obtain the sample (1.2g) of diastereomer 2, fusing point 100-101 ℃.
1H?NMRδ(CDCl 3)1.32-1.34
(4H，m)，1.50-1.59(4H，m)，2.56(2H，t)，3.01(1H，dd)，3.24-3.31(3H，m)，3.98(1H，
d)，4.11(1H，d)，4.25(1H，d)，4.27(1H，d)，4.60(1H，dd)，6.41-6.42(2H，m)，7.08-
7.10(2H，m)，7.21-7.26(2H，m)，7.35(1H，br.triplet)，7.44-7.45(1H，m).n c＝o?1794
cm -1
Found：???????????????????????????C，58.32；H，5.95；N，6.23％
C 22H 27ClN 2O 4S requires:C, 58.59; H, 6.03; N, 6.21% embodiment 119 (+/-)-N-(the 6-[4-chloro-phenyl-] oneself-the 1-yl)-4-(2-furyl methyl alkylsulfonyl)-2-aza-oxo-cyclobutane-1-yl acetamide
With N-(6-(4-chloro-phenyl-) oneself-1-yl)-4-(2-furyl methyl sulfinyl)-2-aza-oxo-cyclobutane-1-yl acetamide, synthesize according to embodiment 107 methods.Develop thick product with ether and obtain title compound (0.6g), fusing point 107-8 ℃.
1H NMR δ (CDCl 3) 1.31-1.35 (4H, m), 1.49-1.60 (4H, m), 2.57 (2H, t), 3.12 (1H, dd), 3.22-3.29 (3H, m), 3.95 (1H, d), 4.03 (1H, d), 4.38 (1H, d), 4.45 (1H, d), 4.88 (1H, dd), 6.03 (1H, br triplet), and 6.44-6.46 (1H, m), 6.55-6.56 (1H, m), 7.08-7.11 (2H, m) 7.21-7.26 (2H, m), 7.45-7.47 (1H, m) .n C=o1797cm -1Found:C, 56.54; H, 5.74; N, 6.02%C 22H 27ClN 2O 5S requires:C, 56.58; H, 5.83; N, 6.00% embodiment 120 (+/-)-N-(6-[4-chloro-phenyl-] oneself-1-yl)-4-(3-furyl methylthio group)-2-aza-oxo-cyclobutane-1-yl acetamide be (+/-)-4-(3-furyl methylthio group) azetidine-2-ketone a)
With 3-(ethanoyl sulfenyl methyl) furans (64mmol) and 4-acetoxyl group nitrogen heterocyclic din-2-ketone (64mmol), synthesize according to embodiment 101a method, obtain title compound (10g) from ether/sherwood oil crystallization, fusing point 60-61 ℃.
1H NMR δ (CDCl 3) 2.90 (1H, dd), 3.35 (1H, dd), 3.68 (2H, d), 4.70 (1H, dd), 6.14 (1H, br s), 6.42 (1H, m), 7.38-7.42 (2H, m) .b) (+/-)-N-(the 6-[4-chloro-phenyl-] oneself-the 1-yl)-4-(3-furyl methylthio group)-2-aza-oxo-cyclobutane-1-yl acetamide
Be used for (+/-)-4-(3-furyl methylthio group)-azetidine-2-ketone (13.6mmol), N-(6-(4-chloro-phenyl-) oneself-1-yl)-2-bromo ethanamide (13.6mmol), Tetrabutylammonium bromide (1.36mmol) and the powdery KOH (14mmol) of anhydrous THF (100ml), synthesize according to embodiment 101b method.Chromatography (silica gel, the 50-100%EtOAc in sherwood oil) obtains the title compound (4.0g) into oil.
1H?NMRδ(CDCl 3)1.25-1.36(4H，m)，1.40-1.68
(4H，m)，2.56(2H，t)，2.96(1H，dd)，3.20-3.28(2H，m)，3.41(1H，dd)，3.61-3.73
(3H，m)，3.85(1H，d)，4.84(1H，dd)，6.12(1H，dd)，6.39(1H，m)，7.06-7.10(2H，m)，
7.21-7.26 (2H, m), 7.37-7.39 (2H, m). embodiment 121 (+/-)-N-(the 6-[4-chloro-phenyl-] oneself-the 1-yl)-4-(3-furyl methyl sulfinyl)-2-aza-oxo-cyclobutane-1-yl acetamide (diastereomer 1)
With (+/-)-N-(the 6-[4-chloro-phenyl-] oneself-the 1-yl)-(2.5g 5.7mmol), synthesizes according to the method for embodiment 102 4-(3-furyl methylthio group)-2-aza-oxo-cyclobutane-1-yl acetamide.Thick product obtains containing the sample (0.6g) of about 98% diastereomer 1 from the ethyl acetate crystallization, fusing point 162-163 ℃.
1H?NMRδ(CDCl 3)1.30-1.34(4H，m)，
1.49-1.59(4H，m)，2.55(2H，t)，3.04(1H，dd)，3.20-3.26(2H，m)，3.55(1H，dd)，
3.74-3.78(2H，m)，3.86(1H，d)，4.13(1H，d)，4.59(1H，dd)，6.37-6.38(1H，m)，6.60
(1H，br.triplet)，7.08-7.10(1H，m)，7.21-7.26(2H，m)，7.46-7.47(2H，m).n c＝o?1792
cm -1
Found：??????????????????????????C，58.52；H，5.94；N，6.20％
C 22H 27ClN 2O 4S requires:C, 58.59; H, 6.03; N, 6.21% embodiment 122 (+/-)-N-(the 6-[4-chloro-phenyl-] oneself-the 1-yl)-4-(3-furyl methyl sulfinyl)-2-aza-oxo-cyclobutane-1-yl acetamide (diastereomer 2)
The mother liquor of evaporation embodiment 121 and with ether development, crystallization obtains containing the sample (0.7g) of about 98% diastereomer 2, fusing point 95-96 ℃ from ethyl acetate.
1H NMR δ (CDCl 3) 1.32-1.34 (4H, m), 1.50-1.60 (4H, m), 2.56 (2H, t), 3.03 (1H, dd), 3.20-3.32 (3H, m), 3.86-3.98 (3H, m), 4.24 (1H, d), 4.66 (1H, dd), 6.38-6.39 (1H, m), 7.08-7.10 (2H, m), 7.14 (1H, br.triplet), 7.21-7.26 (2H, m), 7.46-7.48 (2H, m) .n C=o1794 cm -1Found:C, 58.53; H, 5.94; N, 6.20%C 22H 27ClN 2O 4S requires:C, 58.59; H, 6.03; N, 6.21% embodiment 123 (+/-)-N-(the 6-[4-chloro-phenyl-] oneself-the 1-yl)-4-(3-furyl methyl alkylsulfonyl)-2-aza-oxo-cyclobutane-1-yl acetamide
With N-(6-(4-chloro-phenyl-) oneself-1-yl)-4-(3-furyl methyl sulfinyl)-2-aza-oxo-cyclobutane-1-yl acetamide, synthesize according to embodiment 107 methods.Develop thick product with ether and obtain title compound, fusing point 95-6 ℃.
1H?NMRδ(CDCl 3)1.31-
1.35(4H，m)，1.48-1.61(4H，m)，2.56(2H，t)，3.20-3.27(4H，m)，3.87(1H，d)，4.02
(1H，d)，4.18(1H，d)，4.25(1H，d)，4.91(1H，dd)，5.98(1H，br.triplet)，6.53-6.54
(1H，m)，7.08-7.11(2H，m)，7.21-7.26(2H，m)，7.47-7.48(1H，m)，7.57(1H，d).n c＝o
1795?cm -1
Found：???????????????????????????????C，55.41；H，5.61；N，5.83％
C 22H 27ClN 2O 5S.0.5H 2O requires:C, 55.51; H, 5.93; N, 5.89% embodiment 124 (+/-)-N-[6-(4-chloro-phenyl-hexyl)]-a) (+/-)-4-(2-thienyl methylthio group) azetidine-2-ketone of 4-(2-thienyl methylthio group)-2-aza-oxo-cyclobutane-1-yl acetamide
With 2-(ethanoyl sulfenyl methyl) thiophene (71mmol) and 4-acetoxyl group nitrogen heterocyclic din-2-ketone (71mmol); synthesize according to embodiment 101a method; chromatography (silica gel, the 50-70% EtOAc in sherwood oil) obtains the title compound (9.1g) into oil.
1H?NMRδ(CDCl 3)
2.88(1H，m)，3.35(1H，m)，4.06(2H，m)，4.75(1H，m)，5.82(1H，m)，6.96(2H，m)，
(7.24 1H, m) b) (+/-)-N-[6-(4-chloro-phenyl-hexyl)]-4-(2-thienyl methylthio group)-2-aza-oxo-cyclobutane-1-yl acetamide
Be used for (+/-)-4-(2-thienyl methylthio group)-azetidine-2-ketone (5mmol), N-(6-(4-chloro-phenyl-) oneself-1-yl)-2-bromo ethanamide (5.5mmol), Tetrabutylammonium bromide (0.5mmol) and the powdery KOH (5.25mmol) of anhydrous THF (25ml), synthesize according to embodiment 101b method.Chromatography (silica gel, the 30-80%EtOAc in sherwood oil) also obtains the title compound (0.66g) into oil, fusing point 55-7 ℃ with ether/sherwood oil development.
1HNMR δ (CDCl 3) 1.33 (4H, m), 1.55 (4H, m); 2.56 (2H, t), 2.97 (1H, dd); 3.23 (2H, m), 3.41 (1H, dd); 3.63 (1H, d), 3.79 (1H, d); 4.05 (2H, m), 4.88 (1H, m); 6.05 (1H, m), 6.89-7.26 (7H, m). embodiment 125 (+/-)-N-[6-(4-chloro-phenyl-hexyl)]-4-(2-thienyl methyl sulfinyl)-2-aza-oxo-cyclobutane-1-yl acetamide (diastereomer 1)
With (+/-)-N-(6-(4-chloro-phenyl-) oneself-1-yl)-(3.0g 6.65mmol), synthesizes according to the method for embodiment 102 4-(2-thienyl methylthio group)-2-aza-oxo-cyclobutane-1-yl acetamide.Thick product from the ethyl acetate crystallization and from acetonitrile recrystallization obtain containing the sample (0.73g) of about 97% diastereomer 1, fusing point 161-2 ℃.
1H?NMRδ(CDCl 3)1.33(4H，m)，1.51-1.61(4H，m)，2.56(2H，t)，3.01(1H，dd)，
3.23(2H，m)，3.48(1H，dd)，3.74(1H，d)，4.13(1H，d)，4.13(1H，dd)，4.25(1H，dd)，
4.57(1H，dd)，6.59(1H，m)，7.03-7.35(7H，m).n c＝o?1791?cm -1
Found：???????????????????????????C，56.51；H，5.71；N，6.06％
C 22H 27ClN 2O 3S 2Requires:C, 56.58; H, 5.83; N, 6.00% embodiment 126 (+/-)-N-[6-(4-chloro-phenyl-hexyl)]-4-(2-thienyl methyl sulfinyl)-2-aza-oxo-cyclobutane-1-yl acetamide (diastereomer 2)
Obtain crystal by further placement of the ethyl acetate mother liquor of embodiment 125, contain about 98% diastereomer 2 (0.57g), fusing point 93-5 ℃.
1H?NMRδ(CDCl 3)
1.34(4H，m)，1.55(4H，m)，2.56(2H，t)，2.98(1H，dd)，3.25(3H，m)，3.89(1H，d)，
4.25(1H，d)，4.25(1H，d)，4.33(1H，d)，4.65(1H，dd)，7.04-7.35(7H，m).n c＝o?1793
cm -1
Found：????????????????????????????C，56.41；H，5.72；N，5.99％
C 22H 27ClN 2O 3S 2Requires:C, 56.58; H, 5.83; N, 6.00% embodiment 127 (+/-)-N-[6-(4-chloro-phenyl-hexyl)]-4-(2-thienyl methyl alkylsulfonyl)-2-aza-oxo-cyclobutane-1-yl acetamide
With N-(6-(4-chloro-phenyl-) oneself-1-yl)-4-(2-thienyl methyl sulfinyl)-2-aza-oxo-cyclobutane-1-yl acetamide (1.1g), synthesize according to embodiment 107 methods.Crystallization obtains title compound (0.9g) from ethyl acetate/petroleum ether, fusing point 108-110 ℃.
1HNMR δ (CDCl 3) 1.33 (4H, m), 1.55 (4H, m), 2.57 (2H, t), 3.09-3.28 (4H, m), 3.88 (1H, d), 3.97 (1H, d), 4.53 (1H, d), 4.60 (1H, d), 4.91 (1H, dd), 5.98 (1H, m), 7.05-7.41 (7H, m) .n C=o1795 cm -1Found:C, 54.59; H, 5.52; N, 5.80%C 22H 27ClN 2O 4S 2Requires:C, 54.70; H, 5.63; N, 5.80% embodiment 128 (+/-)-N-[6-(4-chloro-phenyl-hexyl)]-a) (+/-)-4-(3-thienyl methylthio group) azetidine-2-ketone of 4-(3-thienyl methylthio group)-2-aza-oxo-cyclobutane-1-yl acetamide
With 3-(ethanoyl sulfenyl methyl) thiophene (85mmol) and 4-acetoxyl group nitrogen heterocyclic din-2-ketone (85mmol); synthesize according to embodiment 101a method; chromatography (silica gel; 50-70% EtOAc in sherwood oil) and with sherwood oil development obtain title compound (8.65g), fusing point 41-45 ℃ into oil.
1H NMR δ (CDCl 3) 2.85 (1H, m), 3.32 (1H, m), 3.88 (2H, m), 4.68 (1H, m), 5.72 (1H, s), 7.01-7.15 (2H, m), 7.33 (1H, m) b) (+/-)-N-[6-(4-chloro-phenyl-hexyl)]-4-(3-thienyl methylthio group)-2-aza-oxo-cyclobutane-1-yl acetamide
Be used for (+/-)-4-(3-thienyl methylthio group)-azetidine-2-ketone (5mmol), N-(6-(4-chloro-phenyl-) oneself-1-yl)-2-bromo ethanamide (5.5mmol), Tetrabutylammonium bromide (0.5mmol) and the powdery KOH (5.25mmol) of anhydrous THF (25ml), synthesize according to embodiment 101b method.Chromatography (silica gel, the 40-90% EtOAc in sherwood oil) also obtains title compound (0.85g) into oil, fusing point 54-57 ℃ with sherwood oil development.
1H?NMRδ
(CDCl 3)1.32(4H，m)，1.53(4H，m)，2.56(2H，t)，2.93(1H，dd)，3.22(2H，m)，3.38
(1H，dd)，3.56(1H，d)，3.76(1H，d)，3.84(2H，m)，4.81(1H，m)，6.07(1H，m)，7.04-
7.82 (7H, m) embodiment 129 (+/-)-N-[6-(4-chloro-phenyl-hexyl)]-4-(3-thienyl methyl sulfinyl)-2-aza-oxo-cyclobutane-1-yl acetamide (diastereomer 1)
With (+/-)-N-(6-(4-chloro-phenyl-) oneself-1-yl)-(4.12g 9.1mmol), synthesizes according to the method for embodiment 102 4-(3-thienyl methylthio group)-2-aza-oxo-cyclobutane-1-yl acetamide.Thick product from the ethyl acetate crystallization and from acetonitrile recrystallization obtain the sample (0.57g) of diastereomer 1, fusing point 158-9 ℃.
1H?NMRδ
(CDCl 3)1.33(4H，m)，1.55(4H，m)，2.56(2H，t)，2.94(1H，dd)，3.23(2H，m)，3.44
(1H，dd)，3.73(1H，d)，3.98(1H，d)，4.11(1H，d)，4.06(1H，d)，4.51(1H，dd)，6.61
(1H，m)，7.01-7.41(7H，m).n c＝o?1791?cm -1
Found：????????????????????????????C，56.45；H，5.62；N，6.02％
C 22H 27ClN 2O 3S 2Requires:C, 56.58; H, 5.83; N, 6.00% embodiment 130 (+/-)-N-[6-(4-chloro-phenyl-hexyl)]-4-(3-thienyl methyl sulfinyl)-2-aza-oxo-cyclobutane-1-yl acetamide (diastereomer 2)
Carry out obtaining containing the sample (1.42g) of about 80% diastereomer 2 successively by the mother liquor of embodiment 129, fusing point 109-111 ℃ by the recrystallization in ethyl acetate, acetonitrile and the ethyl acetate.
1H?NMRδ(CDCl 3)1.34(4H，m)，1.55
(4H，m)，2.56(2H，t)，2.93(1H，dd)，3.24(3H，m)，3.89(1H，d)，4.09(1H，d)，4.18
(1H，d)，4.23(1H，d)，4.59(1H，dd)，7.02-7.42(7H，m).n c＝o?1793?cm -1
Found：????????????????????????????C，56.55；H，5.65；N，6.03％
C 22H 27ClN 2O 3S 2Requires:C, 56.58; H, 5.83; N, 6.00% embodiment 131 (+/-)-N-[6-(4-chloro-phenyl-hexyl)]-4-(3-thienyl methyl alkylsulfonyl)-2-aza-oxo-cyclobutane-1-yl acetamide
With N-(6-(4-chloro-phenyl-) oneself-1-yl)-4-(3-thienyl methyl sulfinyl)-2-aza-oxo-cyclobutane-1-yl acetamide (0.81g), synthesize according to embodiment 107 methods.Crystallization obtains title compound (0.67g) from ethyl acetate/petroleum ether, fusing point 114-116 ℃.
1H
NMRδ(CDCl 3)1.33(4H，m)，1.55(4H，m)，2.57(2H，t)，3.05(1H，dd)，3.15(1H，
dd)，3.25(2H，m)，3.84(1H，d)，3.94(1H，d)，4.38(1H，d)，4.43(1H，d)，4.83(1H，
dd)，5.96(1H，m)，7.08-7.43(7H，m).n c＝o?1794?cm -1
Found：????????????????????????????C，54.62；H，5.44；N，5.83％
C 22H 27ClN 2O 4S 2Requires:C, 54.70; H, 5.63; N, 5.80% embodiment 132 (+/-)-N-[6-(4-chloro-phenyl-hexyl)]-a) (+/-)-4-(2-thiazolyl methylthio group) azetidine-2-ketone of 4-(thiazol-2-yl methylthio group)-2-aza-oxo-cyclobutane-1-yl acetamide
With 2-(ethanoyl sulfenyl methyl) thiazole (23mmol) and 4-acetoxyl group nitrogen heterocyclic din-2-ketone (23mmol), synthesize according to embodiment 101a method, obtain title compound (1.48g), fusing point 89-92 ℃ with the ether development.
1H?NMRδ(CDCl 3)2.76(1H，m)，2.30(1H，
M), 4.26 (2H, s), 4.85 (1H, m), 7.68 (1H, d), 7.73 (1H, d), 8.63 (1H, br s) .b) (+/-)-N-[6-(4-chloro-phenyl-hexyl)]-4-(thiazol-2-yl methylthio group)-2-aza-oxo-cyclobutane-1-yl acetamide
Be used for (+/-)-4-(2-thiazolyl methylthio group)-azetidine-2-ketone (6.9mmol), N-(6-(4-chloro-phenyl-) oneself-1-yl)-2-bromo ethanamide (6.9mmol), Tetrabutylammonium bromide (0.69mmol) and the powdery KOH (6.9mmol) of anhydrous THF (40ml), synthesize according to embodiment 101b method.(silica gel is in CH to repeat chromatography 2Cl 2In 2-6%MeOH; Silica gel BuOMe) obtains title compound (0.04g) into oil.
1H NMR δ (CDCl 3) 1.33 (4H, m), 1.55 (4H, m), 2.56 (2H; t), 2.99 (1H, dd), 3.23 (2H, m); 3.44 (1H, dd), 3.73 (1H, d), 3.90 (1H; d), 4.12 (1H, d), 4.21 (1H, d); 5.02 (1H, dd), 6.19 (1H, m), 7.07-7.26 (4H; m), 7.31 (1H, d), 7.69 (1H, d). embodiment 133 (+/-)-N-[6-(4-chloro-phenyl-hexyl)]-4-(thiazol-2-yl methylsulfinyl)-2-aza-oxo-cyclobutane-1-yl acetamide (diastereomer 1)
With (+/-)-N-(6-(4-chloro-phenyl-) oneself-1-yl)-(1.03g 2.28mmol), synthesizes according to the method for embodiment 102 4-(2-thiazolyl methylthio group)-2-aza-oxo-cyclobutane-1-yl acetamide.Thick product is developed the sample (0.35g) that obtains containing 96% diastereomer 1, fusing point 154-7 ℃ with ethyl acetate.
1H NMR (CDCl 3) 1.33 (4H, m), 1.55 (4H, m), 2.56 (2H, t), 3.02 (1H, dd), 3.23 (2H, m), 3.36 (1H, dd), 3.80 (1H, d), 4.14 (1H, d), 4.35 (1H, d), 4.42 (1H, d), 4.92 (1H, dd), 6.46 (1H, m), 7.09 (2H, m), 7.23 (2H, m), 7.43 (1H, d), 7.84 (1H, d) .n C=o1760,1791 cm -1Found:C, 53.91; H, 5.55; N, 8.94%C 21H 26ClN 3O 3S 2Requires:C, 53.89; H, 5.60; N, 8.98% embodiment 134 (+/-)-N-[6-(4-chloro-phenyl-hexyl)]-4-(thiazol-2-yl methylsulfinyl)-2-aza-oxo-cyclobutane-1-yl acetamide (diastereomer 2)
The mother liquor of embodiment 133 concentrated and then induce the crystallization (0.49g) of the sample that contains 94% diastereomer 2 with the sherwood oil dilution, fusing point 103-104 ℃.
1H NMR δ (CDCl 3) 1.33 (4H, m), 1.55 (4H, m), 2.57 (2H, t), 3.11 (1H, dd), 3.25 (2H, m), 3.33 (1H, dd), 4.08 (1H, d), 4.29 (1H, d), 4.44 (1H, d), 4.50 (1H, d), 4.98 (1H, dd), 7.09 (2H, m), 7.24 (2H, m), 7.34 (1H, m), 7.42 (1H, d), 7.84 (1H, d) n C=o1793 cm -1Found:C, 54.12; H, 5.56; N, 8.87%C 21H 26ClN 3O 3S 2Requires:C, 53.89; H, 5.60; N, 8.98% embodiment 135 (+/-)-N-[6-(4-chloro-phenyl-hexyl)]-a) 5-(ethanoyl sulfenyl methyl) furans-5-carboxylate methyl ester of 4-(5-methoxycarbonyl-2-furyl methylthio group)-2-aza-oxo-cyclobutane-1-yl acetamide
Will (15.7g, (68g be in ice-cold solution 0.39mol) 0.4mol) to join 5-(chloromethyl) furans-5-carboxylate methyl ester in dry DMF (30mL) in the thioacetic acid potassium in the dry DMF (100ml).After cooling is removed,, pour in the water then and use extracted with diethyl ether this mixture restir 30 minutes.Organic extract liquid is separated the title compound (42.7g) that obtains to oil with chromatography (silica gel, the 0-30% ether in sherwood oil).
1H?NMRδ(CDCl 3)2.36(3H，s)，3.88(3H，s)，4.16(2H，s)，6.35(1H，d)，7.08
(1H, d) .b) 4-(5-methoxycarbonyl)-2-furyl methylthio group) azetidine-2-ketone
Sodium methylate with 5-(ethanoyl sulfenyl methyl) furans-5-carboxylate methyl ester (47mmol), 4-acetoxyl group nitrogen heterocyclic din-2-ketone (47mmol) and replacement sodium ethylate synthesizes according to embodiment 101a method.Develop thick product with ether and obtain title compound (8.7g), fusing point 102-103 ℃.
1H?NMRδ
(CDCl 3)2.85(1H，dd)，3.43(1H，dd)，3.88-3.92(5H，m)，4.92(1H，dd)，6.33(1H，
M), 6.78 (1H, br.singlet), 7.09-7.11 (1H, m) .c) (+/-)-N-[6-(4-chloro-phenyl-hexyl)]-4-(5-methoxycarbonyl)-2-furyl methylthio group)-2-aza-oxo-cyclobutane-1-yl acetamide
Be used for anhydrous THF (+/-)-4-(5-(methoxycarbonyl)-2-furyl methylthio group)-azetidine-2-ketone (21mmol), N-(6-phenyl) oneself-the 1-yl)-2-bromo ethanamide (21mmol), Tetrabutylammonium bromide (3mmol) and powdery KOH (211mmol), synthesize according to embodiment 101b method.Chromatography (silica gel, EtOA/ sherwood oil) obtains the title compound (5.0g) into oil.
1H?NMRδ(CDCl 3)1.29-1.35(4H，m)，1.43-1.63
(4H，m)，2.55(2H，t)，2.94(1H，dd)，3.19-3.27(2H，m)，3.24(1H，dd)，3.78(1H，d)，
3.88-3.90(3H，m)，3.95-3.97(1H，m)，4.04-4.17(2H，m)，5.01(1H，dd)，6.25(1H，br
Triplet), and 6.33-6.35 (1H, m); 7.06-7.10 (3H; m), 7.20-7.26 (3H, m). embodiment 136 (+/-)-N-[6-(4-chloro-phenyl-hexyl)]-4-(5-methoxycarbonyl-2-furyl methyl sulfinyl)-2-aza-oxo-cyclobutane-1-yl acetamide (diastereomer 1)
With (+/-)-N-(6-phenyl oneself-1-yl)-4-(5-methoxycarbonyl-2-furyl methylthio group)-(4.0g 8mmol), synthesizes according to the method for embodiment 102 2-aza-oxo-cyclobutane-1-yl acetamide.Thick product obtains the sample (0.8g) of diastereomer 1 from re-crystallizing in ethyl acetate, fusing point 141-2 ℃.
1H?NMR(CDCl 3)1.20-1.35(4H，m)，1.40-1.65(4H，
m)，2.55(2H，t)，3.05(1H，dd)，3.19-3.33(3H，m)，3.83(1H，d)，3.90(3H，s)，4.09-
4.16(3H，m)，4.71(1H，dd)，6.46(1H，br.triplet)，6.55-6.56(1H，m)，7.07-7.26(5H，
m).n c＝o?1792?cm -1
Found：???????????????????????????C，56.65；H，5.68；N，5.55％
C 24H 29ClN 2O 6S requires:C, 56.63; H, 5.74; N, 5.50% embodiment 137 (+/-)-N-[6-(4-chloro-phenyl-hexyl)]-4-(5-methoxycarbonyl-2-furyl methyl sulfinyl)-2-aza-oxo-cyclobutane-1-yl acetamide (diastereomer 2)
Obtain the sample (1.5g) of diastereomer 2, fusing point 113-114 ℃ with the mother liquid evaporation of embodiment 136 and from re-crystallizing in ethyl acetate.
1H?NMRδ
(CDCl 3)1.29-1.40(4H，m)，1.50-1.64(4H，m)，2.56(2H，t)，3.00(1H，dd)，3.23-3.40
(3H，m)，3.90(3H，s)，4.03(1H，d)，4.19-4.29(3H，m)，4.72(1H，dd)，6.53-6.55(1H，
m)，7.00(1H，br.triplet)，7.07-7.26(5H，m).n c＝o?1795?cm -1
Found：???????????????????????????C，56.73；H，5.69；N，5.57％
C 24H 29ClN 2O 6S requires:C, 56.63; H, 5.74; N, 5.50% embodiment 138 (+/-)-4-(2-furyl methylthio group)-1-(9-phenyl nonyl) nitrogen heterocyclic din-2-ketone
Will be in ice/salt in the cooling of sodium hydride (3.65mmol) suspension among the anhydrous THF (10ml), dropping under being lower than 5 ℃ (+/-)-4-(2-furyl methylthio group) nitrogen heterocyclic din-2-ketone (0.61g, 3.32mmol).The solution of gained is chilled to-10 ℃ again, in 1 hour, slowly be incorporated in (10ml) among the THF 9-phenyl nonyl-1-trifluoromethanesulfonic acid ester solution (1.17g, 3.32mmol).In 0 ℃ of restir after 5 minutes, pour into this reaction mixture in the salt solution and use extracted with diethyl ether.Chromatography separation organic extract liquid (silica gel, the 10-25% EtOAc in sherwood oil) obtains the title compound (0.38g) into oil.
1H?NMRδ(CDCl 3)1.2-1.7(14H，m)，2.60(2H，t，
J＝8Hz)，2.9(2H，m)，3.3(2H，m)，4.78(2H，s)，4.68(1H，m)，6.20，6.32(each?1H，
M), 7.15-7.3 (5H, m), 7.36 (1H, m). embodiment 139 (+/-)-4-(2-furyl methyl sulfinyl)-1-(9-phenyl nonyl) nitrogen heterocyclic din-2-ketone
With (+/-)-(0.37g 0.97mmol), carries out the synthetic of embodiment 102 to 4-(2-furyl methylthio group)-1-(9-phenyl nonyl) nitrogen heterocyclic din-2-ketone.Chromatography (silica gel, the 50-70% EtOAc in sherwood oil) obtains the title compound (0.28g) into oil, contains about 63% diastereomer 1,37% diastereomer 2.
1H?NMRδ(CDCl 3)1.2-1.7(14H，m)，
2.55(3H，m)，2.90，(1H，dd，J＝5，15Hz)，3.10(1H，dd，J＝5，15Hz)，3.15-3.5(3H，
m)，3.95-4.15(2H，m)，4.42(1H，m)，6.42(2H，m)，7.1-7.3(5H，m)，7.43(1H，m).
n c＝o?1776?cm -1
Found：??????????????????????C，68.5；H，7.8；N，3.3％
C 23H 31NO 3S requires:C, 68.8; H, 7.8; N, 3.5% embodiment 140 (+/-)-4-(2-furyl methylthio group)-1-(9-(4-fluorophenyl) nonyl) nitrogen heterocyclic din-2-ketone
With (+/-)-(1.5g, 8.2mmol) (2.9g, 7.8mmol carry out the synthetic of embodiment 138 to 4-(2-furyl methylthio group) nitrogen heterocyclic din-2-ketone with (9-(4-fluorophenyl) nonyl)-1-triflate.Chromatography (silica gel, the 10-25% EtOAc in sherwood oil) obtains the title compound (0.56g) into oil.
1H?NMRδ(CDCl 3)1.2-1.7(14H，m)，2.56(2H，t，J＝7.7Hz)，2.90
(2H，m)，3.29(2H，m)，3.77(2H，s)，4.68(1H，m)，6.20(1H，m)，6.31(1H，m)，6.95
(2H, m), 7.10 (2H, m), 7.36 (1H, m). embodiment 141 (+/-)-4-(2-furyl methyl sulfinyl)-1-(9-(4-fluorophenyl) nonyl) nitrogen heterocyclic din-2-ketone
With (+/-)-(0.52g 1.28mmol), carries out the synthetic of embodiment 102 to 4-(2-furyl methylthio group)-1-(9-(4-fluorophenyl) nonyl) nitrogen heterocyclic din-2-ketone.Chromatography (silica gel, the 50-70% EtOAc in sherwood oil) obtains the title compound (0.42g) into oil, contains about 65% diastereomer 1,35% diastereomer 2.
1H NMR δ (CDCl 3) 1.2-1.7 (14H, m), 2.55 (3H, m), 2.90, (1H, dd, J=5,15Hz), 3.10 (1H, dd, J=5,15Hz), 3.15-3.5 (2H, m) 3.95-4.15 (2H, m), 4.42 (1H, m), 6.42 (2H, m), 6.95,7.10 (each 2H, m), 7.43 (1H, m) .n C=o1776 cm -1Found:C, 65.7; H, 7.2; N, 3.2%C 23H 30FNO 3S requires:C, 65.8; H, 7.2; N, 3.3% embodiment 142 (+/-)-4-(2-furyl methyl alkylsulfonyl)-1-(9-(4-fluorophenyl) nonyl) nitrogen heterocyclic din-2-ketone
With (+/-)-4-(2-furyl methyl sulfinyl)-1-(9-(4-fluorophenyl) nonyl) nitrogen heterocyclic din-2-ketone (88mg), carry out the synthetic of embodiment 107.Chromatography (silica gel, EtOAc/ sherwood oil 2: 1) obtains the title compound (56mg) into oil.
1H NMR δ (CDCl 3) 1.2-1.7 (14H, m), 2.56 (2H, t, J=8Hz), 2.99 (1H, dd, J=2,15Hz), 3.15 (2H, m), 3.45 (1H, m), 4.37 (2H, s), 4.57 (1H, m), 6.45,6.55 (each 1H, m), 6.95,7.10 (each 2H, m), 7.47 (1H, m). embodiment 143 N-[6-(4-fluorophenyl) oneself-the 1-yl]-4-(5-allyloxy carbonyl furyl-2-methylthio group)-2-aza-oxo-cyclobutane-1-yl acetamide
Will be in the 4-in the anhydrous tetrahydro furan (150ml) (5-allyloxy carbonyl furyl-2-methyl) thio-aza ring fourth-2-ketone (4g, 0.015mol) and N-(4-fluoro phenyl oneself-1-yl) bromo ethanamide (4.73g, 0.0015mol) solution be cooled to-30 ℃, in 15 minutes, drip potassium tert.-butoxide in anhydrous tetrahydro furan (80ml) (1.85g, 0.0165mol).In 2 hours temperature is risen to 10 ℃, water is also used ethyl acetate extraction with mixture diluted then, elimination and discarded any insolubles.With extraction liquid drying (MgSO 4), evaporation obtains being yellow oil (2.54g, 33% productive rate) by flash chromatography (thin silica gel, ethyl acetate/gasoline) this product of purifying.
1H?NMRδ(CDCl 3)1.32(4H，m，N(CH 2) 2(CH 2) 2)，1.52(4H，m，
NCH 2CH 2+FPhCH 2CH 2)，2.55(2H，t，FPhCH 2)，2.96(1H，dd，H 3a)，3.24(2H，m，
NCH 2)，3.49(1H，dd，H 3b)，3.76-4.06(4H，CH 2CO+CH 2S)，4.79(2H，m，OCH 2)，
5.03(1H，dd，H 4)，5.36(2H，m，CH 2CH)，5.99(1H，m，CHCH 2)，6.30(1H，m，NH)，
6.35,7.12 (each 1H, d; furan-H); 6.92-7.12 (4H, m, FPh-H) embodiment 144 N-[6-(4-fluorophenyl) oneself-the 1-yl]-4-(5-allyloxy carbonyl furyl-2-methylsulfinyl)-2-aza-oxo-cyclobutane-1-yl acetamide (diastereomer 1)
The mCPBA that is used for methylene dichloride at low temperatures handle N-[6-(4-fluorophenyl) oneself-the 1-yl]-4-(5-allyloxy carbonyl furyl-2-methylthio group)-2-aza-oxo-cyclobutane-1-yl acetamide, according to the method for embodiment 102 carry out and recrystallization after obtain title compound into white crystal, fusing point 122-125 ℃, 16% productive rate.
1H NMR δ (CDCl 3) 1.32 (4H, m, N (CH 2) 2(CH 2) 2), 1.54 (4H, m, NCH 2CH 2+ FPhCH 2CH 2), 2.56 (2H, t, FPhCH 2), 3.08 (1H, dd, H 3a), 3.23 (2H, m, NCH 2), 3.30 (1H, dd, H 3b), 3.55,3.73 (each 1H, d, SCH 2), 3.84,4.13 (each 1H, d, CH 2CO), 4.73 (1H, dd, H 4), 4.80 (2H, m, OCH 2), 5.38 (2H, m, CH 2CH), 5.97 (1H, m, CHCH 2), 6.56,7.18 (each 1H; d, furan-H), 6.91-7.14 (4H; m, FPh-H) embodiment 145 N-[6-(4-fluorophenyl) oneself-the 1-yl]-4-(5-allyloxy carbonyl furyl-2-methylsulfinyl)-2-aza-oxo-cyclobutane-1-yl acetamide (diastereomer 2)
The mother liquor recrystallization of embodiment 144 is obtained title compound (diastereomer 2: 1 about 83: 17) into white crystal, fusing point 79-82 ℃, 29%.v C=o1793 -1Actual measurement: C, 59.82; H, 5.93; N, 5.40%.C 26H 31FN 2O 6S calculated value: C, 60.22; H, 6.03; N5.40% embodiment 146 N-[6-(4-fluorophenyl) oneself-the 1-yl]-4-(5-carbonyl furyl-2-methylsulfinyl)-2-aza-oxo-cyclobutane-1-yl acetamide (diastereomer 2)
With tetra-triphenylphosphine palladium (0) (10.7mg; 0.0093mmol) handle the triphenylphosphine (0.81g in methylene dichloride (10ml); 0.31mmol), tetramethyleneimine (0.027ml; 0.31mmol) and N-[6-(4-fluorophenyl) oneself-the 1-yl]-4-(5-allyloxy carbonyl furyl-2-methylsulfinyl)-2-aza-oxo-cyclobutane-1-yl acetamide (diastereomer 2; 0.16g; 0.31mmol) solution, and stirred 2 hours.Evaporating solvent is with flash chromatography (silica gel, methylene dichloride/acetone/acetate) this resistates of purifying.Should be dissolved in the methylene dichloride (10ml) by thick product, use the salt water washing, dry (MG), and evaporation obtains oil, and it is obtained being the solid title compound with methylene dichloride and ether processing.(46mg, 31% productive rate), fusing point 124-7 ℃.
1H?NMRδ(CDCl 3)1.31(4H，m，N(CH 2) 2(CH 2) 2)，)1.53(4H，m，
NCH 2CH 2+FPhCH 2CH 2)，2.56(2H，t，FPhCH 2)，3.07(1H，dd，H 3a)，3.26(2H，m，
NCH 2)，3.40(1H，dd，H 3b)，4.21-4.34(4H，m，SCH 2+CH 2CO)，4.76(1H，dd，H 4)，
6.55,7.10 (each 1H, d, furan-H), 6.92-7.16 (4H, m, FPh-H), 7.60 (1H, NH) embodiment 147 N-(6-(4-chloro-phenyl-) oneself-1-yl)-4-(5-allyloxy carbonyl furyl-2-methylthio group-2-aza-oxo-cyclobutane-1-yl) ethanamides
In 4-(5-allyloxy carbonyl furyl-2-methyl) thio-aza ring fourth-2-ketone (2.4g) and N-(4-chlorophenyl oneself-1-yl) the bromo ethanamide of-40 ℃ of potassium tert.-butoxide (1.03g) solution-treated that are used for anhydrous tetrahydro furan (50ml) in anhydrous tetrahydro furan (170ml) ★(2.99g), the step of carrying out embodiment 143 subsequently obtains the title compound into yellow oil, 37% productive rate.
1H?NMRδ(CDCl 3)1.30-1.60(8H，m，4xCH 2)，2.55(2H，t，
J＝7.6Hz，CH 2Ph)，2.92，2.98(1H，dd，J＝2.2，15.4Hz，H 3)，3.24(2H，m，NHCH 2)，
3.46，3.52(1H，dd，J＝5.2，15.4Hz，H 3)，3.94(4H，m，NCH 2，SCH 2)，4.79(2H，m，
CO 2CH 2)，5.02(1H，m，H 4)5.35(2H，m，CH 2＝CH)，6.0(1H，m，CH 2＝CH)，6.26(1H，
M, NH), 6.34 (1H, d, J=3.4Hz, furan-H), 7.06-7.26 (5H, m, furan-H, Ph-H) ★ ★6-(4-chloro-phenyl-) hexanamide (2.0g) and Hunig ' the s alkali (1.33g) handled in anhydrous methylene chloride (25ml) by the bromo acetyl bromide (2.07g) that is used for methylene dichloride (10ml) in 0-5 ℃ obtain.Embodiment 148 N-(6-(4-chloro-phenyl-) oneself-1-yl)-4-(5-allyloxy carbonyl furyl-2-methylsulfinyl-2-aza-oxo-cyclobutane-1-yl) ethanamide (diastereomer 1)
Anhydrous solid, fusing point 135-136 ℃, 15% productive rate.
1H?NMRδ(CDCl 3)1.3023-1.60(8H，
m，4xCH 2)，2.56(2H，t，J＝7.6Hz，CH 2Ph)，3.03，3.09(1H，dd，J＝4.7，15Hz，H 3)，
3.24(2H，m，NHCH 2)，3.28，3.34(1H，dd，J＝5.4，15Hz，H 3)，3.81，4.13(each?1H，d，
J＝17.2Hz，NCH 2)4.09(2H，s，SOCH 2)，4.70(1H，m，H 4)，4.80(2H，d，J＝5.8Hz，
CO 2CH 2)，5.37(2H，m，CH 2＝CH)，6.0(1H，m，CH 2＝CH)，6.44(1H，m，NH)，6.56
(1H，d，J＝3.5Hz，furan-H)，7.07-7.26(5H，m，furan-H，Ph-H).v c＝o?1792?cm -1.
Found:C, 58.2; H, 5.8; N, 5.3%.C 26H 31ClN 2O 6S requires:C, 58.4; H, 5.8; N, 5.2% embodiment, 149 N-(6-(4-chloro-phenyl-) oneself-1-yl)-4-(5-allyloxy carbonyl furyl-2-methylsulfinyl-2-aza-oxo-cyclobutane-1-yl) ethanamide (diastereomer 2)
Anhydrous solid, fusing point 89-92 ℃, 13% productive rate.
1H NMR δ (CDCl 3) 1.30-1.60 (8H, m, 4xCH 2), 2.56 (2H, t, J=7.6Hz, CH 2Ph), 2.99,3.05 (1H, dd, J=2.4,15.4Hz, H 3), 3.24 (2H, m, NHCH 2), 3.32,3.39 (1H, dd, J=5.4,15.4Hz, H 3), 4.03,4.25 (each 1H, d, J=17.2Hz, NCH 2), 4.20 (2H, m, SOCH 2), 4.72 (1H, m, H 4), 4.79 (2H, d, J=5.8Hz, CO 2CH 2), 5.37 (2H, m, CH 2=CH), 6.0 (1H, m, CH 2=CH), 6.55 (1H, d, J=3.5Hz, furan-H), 7.02 (1H, m, NH), 7.07-7.26 (5H, m, furan-H, Ph-H) .v C=o1795 cm -1.Found:C, 58.2; H, 5.8; N, 5.3%.C 26H 31ClN 2O 6S requires:C, 58.4; H, 5.8; N, 5.2% embodiment, 150 N-(6-(4-chloro-phenyl-) oneself-1-yl)-4-(5-carbonyl furyl-2-methylsulfinyl-2-aza-oxo-cyclobutane-1-yl) ethanamide (diastereomer 2)
With tetra-triphenylphosphine palladium (0) (6.5mg; 0.0093mmol) handle in methylene dichloride (4ml) triphenylphosphine (53.3g), tetramethyleneimine (14.3mg) and N-[6-(4-chloro-phenyl-) oneself-the 1-yl]-4-(5-allyloxy carbonyl furyl-2-methylsulfinyl)-2-aza-oxo-cyclobutane-1-yl acetamide (diastereomer 2; 10.5mg) solution; and the step of carrying out embodiment 146 obtains being paste solid title compound; fusing point 166-7 ℃, 49% productive rate. 1H?NMRδ(DMSO)1.26(4H，m，2xCH 2)，1.37(2H，m，CH 2)，1.52(2H，m，CH 2)，
2.50(2H，m，CH 2Ph)，2.95，2.99(1H，dd，H 3)，3.05(2H，m，NHCH 2)，3.83，4.07
(each?1H，d，J＝17.2Hz，NCH 2)，4.29，4.42(each?1H，d，J＝14Hz，SOCH 2)，4.86
(1H，m，H 4)，6.60(1H，d，J＝3.2Hz，furan-H)，7.15-7.32(5H，m，furan-H，Ph-H)，8.08
(1H，m，NH)，Found：C，54.5；H，5.3；N，5.6％，C 23H 27ClN 2O 6S?requires：C，55.8；
H, 5.5; N, 5.7% embodiment, 151 N-(6-(4-chloro-phenyl-) oneself-1-yl)-4-(5-methoxycarbonyl furyl-2-methylthio group-2-aza-oxo-cyclobutane-1-yl) ethanamide
Handle 4-(5-methoxycarbonyl furyl-2-methyl) thio-aza ring fourth-2-ketone (embodiment 135b) in anhydrous tetrahydro furan and N-(4-fluoro phenyl oneself-1-yl) bromo ethanamide in-30 ℃ of potassium tert.-butoxides that are used for anhydrous tetrahydro furan, the step of carrying out embodiment 143 subsequently obtains the title compound into light yellow oil, 55% productive rate.
1H?NMRδ(CDCl 3)1.32(4H，m，N(CH 2) 2(CH 2) 2)，1.54(4H，m，NCH 2CH 2+
FPhCH 2CH 2)，2.56(2H，t，FPhCH 2)，2.95(1H，dd，H 3a)，3.24
(2H，m，NCH 2)，3.48(1H，dd，H 3b)，3.88(3H，s，OCH 3)，3.75-4.05(4H，m，SCH 2+
CH 2CO)，5.02(1H，dd，H 4)，6.30(1H，m，NH)，6.35，7.12(each?1H，d，furan-H)，
6.90-7.13(4H，m，FPh-H)
Handle N-(6-(4-fluorophenyl) oneself-1-yl)-4-(5-methoxycarbonyl furyl-2-methylthio group-2-aza-oxo-cyclobutane-1-yl) ethanamide according to the method for embodiment 102 and embodiment 103 with mCPBA, obtain embodiment 152 and 153 behind the method recrystallization according to embodiment 102 and embodiment 103.Embodiment 152 N-(6-(4-chloro-phenyl-) oneself-1-yl)-4-(5-methoxycarbonyl furyl-2-methylsulfinyl-2-aza-oxo-cyclobutane-1-yl) ethanamide (diastereomer 1)
White crystal, fusing point 137-8 ℃
1H NMR δ (DMSO) 1.27 (4H, m, N (CH 2) 2(CH 2) 2) 1.39 (2H, m, FPhCH 2CH 2), 1.53, (2H, m, NCH 2CH 2), 2.55 (2H, t, FPhCH 2), 3.04 (4H, m, NCH 2+ H 3a+ H 3b), 3.68,4.03 (each 1H, d, SCH 2), 4.13,4.39 (each 1H, d, CH 2CO), 4.99 (1H, m, H 4), 6.64,7.30 (each 1H; d, furan-H), 7.04-7.24 (4H; m, FPh-H) embodiment 153 N-(6-(4-chloro-phenyl-) oneself-1-yl)-4-(5-methoxycarbonyl furyl-2-methylsulfinyl-2-aza-oxo-cyclobutane-1-yl) ethanamide (diastereomer 2)
White crystal, fusing point 100-2 ℃, v C=o1795 -1Actual measurement: C, 58.53; H, 5.90; N, 5.68%.C 24H 29FN 2O 6S calculated value: C, 58.52; H, 5.93; N5.69% embodiment 201 N-(6-(phenyl) hexyl)-(4-(2-fluorinated phenoxy)-2-aza-oxo-cyclobutane-1-yl) ethanamide
Will be in the 4-among the anhydrous THF (20ml) (2-fluorinated phenoxy) nitrogen heterocyclic din-2-ketone (0.5g, 3mmol), N-(6-phenyl hexyl) bromo ethanamide (0.9g, 3mmol) be chilled to-30 ℃, and (0.3g handles 3mmol) with potassium tert.-butoxide with 118-crown ether-6 (5mg) solution.Stir the gained mixture 90 minutes, and be warming up to 0 ℃, use the salt water washing, paste (Na 2SO 4) and evaporation.Obtain title compound (0.33g, 28%) with the purified by flash chromatography resistates into water white oil.Actual measurement: C, 59.8; H, 5.9; N, 5.5%; C 23H 27FN 2O 3.0.97CH 2C 12Calculated value: C, 59.9; H, 6.1; N, 5.8%
Make following compounds with required azetidinone and bromo ethanamide according to the method for embodiment 201.Embodiment 202 N-(6-(chloro-phenyl-) hexyl)-(4-(2-fluorinated phenoxy)-2-aza-oxo-cyclobutane-1-yl) ethanamide
Colorless solid, fusing point 79-80 ℃, 31% productive rate.Actual measurement: C, 63.6; H, 6.0; N, 6.5%; C 23H 26ClFN 2O 3Calculated value: C, 63.8; H, 6.1; N, 6.5% embodiment, 203 N-(6-(4-phenyl) hexyl)-(4-(2-methylphenoxy)-2-aza-oxo-cyclobutane-1-yl) ethanamide
White solid, fusing point 53-4 ℃, 55% productive rate.Actual measurement: C, 72.6; H, 7.5; N, 7.2%; C 24H 30N 2O 3.0.04CH 2C 12Calculated value: C, 72.5; H, 7.5; N, 7.1% embodiment, 204 N-(6-(4-phenyl) hexyl)-(4-(2-benzyloxy phenoxy group)-2-aza-oxo-cyclobutane-1-yl) ethanamide
White solid, fusing point 87-8 ℃, 38% productive rate.Actual measurement: C, 74.0; H, 7.1; N, 5.8%; C 30H 34N 2O 3Calculated value: C, 74.1; H, 7.1; N, 5.8% embodiment, 205 N-(6-(4-phenyl) hexyl)-(4-(2-methylthio group phenoxy group)-2-aza-oxo-cyclobutane-1-yl) ethanamide
White solid, fusing point 79-80 ℃, 32% productive rate.Actual measurement: C, 67.0; H, 7.0; N, 6.8%; C 24H 30N 2O 3S calculated value: C, 67.6; H, 7.1; N, 6.6% embodiment, 206 N-(6-(4-phenyl) hexyl)-(4-(4-chloro phenoxy group)-2-aza-oxo-cyclobutane-1-yl) ethanamide
Water white oil, 32% productive rate.Actual measurement: C, 64.5; H, 6.4; N, 6.5%; C 23H 27ClFN 2O 3.0.21CH 2C 12Calculated value: C, 64.4; H, 6.4; N, 6.5% embodiment, 207 N-(6-(4-phenyl) hexyl)-(4-(4-methoxyl group phenoxy group)-2-aza-oxo-cyclobutane-1-yl) ethanamide
Light yellow solid, fusing point 43-45 ℃, 30% productive rate.Actual measurement: C, 70.3; H, 7.5; N, 7.1%; C 24H 30N 2O 4Calculated value: C, 70.2; H, 7.4; N, 6.8% embodiment, 208 N-(6-(4-phenyl) hexyl) ((4-methylthio group phenoxy group)-2-aza-oxo-cyclobutane-1-yl) ethanamide
Water white oil, 15.5% productive rate.Actual measurement: C, 67.0; H, 6.9; N, 6.6%; C 24H 30N 2O 3S calculated value: C, 67.0; H, 7.0; N, 6.5% embodiment, 209 N-(6-(4-chloro-phenyl-) hexyl)-(4-(4-allyloxy carbonyl methylphenoxy)-2-aza-oxo-cyclobutane-1-yl) ethanamide
Colorless solid, fusing point 79-80 ℃, 31% productive rate. 1H NMR δ (CDCl 3) 1.37 (m, 4H), 1.53 (m, 4H), 2.55 (t, 2H, 7.6Hz), 3.21 (dd, 1H, J=16.1Hz), 3.24 (m, 2H), 3.39 (dd, 1H, J=1.6Hz), 3.59 (s, 2H), 3.99,3.94,3.99 (each 1H, d, J=17.1Hz), 5.59 (m, 2H), 5.25 (m, 1H), 5.72 (m, 1H), 5.86 (m, 1H), 6.34 (bm, 1H), 6.81-7.26 (m, 8H) embodiment 210 N-(6-(4-phenyl) hexyl)-(4-phenoxy group-2-aza-oxo-cyclobutane-1-yl) ethanamide
Light yellow solid, fusing point 45-48 ℃, 41% productive rate.Actual measurement: C, 72.3; H, 7.3; N, 7.7%; C 23H 28N 2O 3Calculated value: C, 72.6; H, 7.4; N, 7.4% embodiment, 211 N-(6-(4-phenyl) hexyl)-(4-benzyloxy-2-aza-oxo-cyclobutane-1-yl) ethanamide
Light yellow oil, 46% productive rate.Actual measurement: C, 71.56; H, 7.9; N, 6.7%; C 24H 30N 2O 3.0.5C 4H 8O 2Calculated value: C, 71.4; H, 7.7; N, 6.4% embodiment, 212 N-(6-(4-phenyl) hexyl)-(4-(4-methylsulfinyl phenoxy group)-2-aza-oxo-cyclobutane-1-yl) ethanamide
Handle N-(6-(4-phenyl) hexyl)-(4-(4-methylthio group phenoxy group)-2-aza-oxo-cyclobutane-1-yl) ethanamide in-70 ℃ of mCPBA (1.1 equivalent) that are used for methylene dichloride, obtain title compound after the chromatography, 92% productive rate into water white oil.Actual measurement: C, 61.6; H, 6.5; N, 6.0%; C 24H 30N 2O 4S.0.4CH 2Cl 2Calculated value: C, 61.5; H, 6.5; N, 5.9% embodiment, 213 N-(6-(4-phenyl) hexyl)-(4-(4-sulfonyloxy methyl phenoxyl)-2-aza-oxo-cyclobutane-1-yl) ethanamide
Handle N-(6-(4-phenyl) hexyl)-(4-(4-methylthio group phenoxy group)-2-aza-oxo-cyclobutane-1-yl) ethanamide in 20 ℃ of mCPBA (4 equivalent) that are used for methylene dichloride, obtain title compound after the chromatography into colorless solid, fusing point 101-2 ℃, 92% productive rate.Actual measurement: C, 62.3; H, 6.5; N, 6.1%; C 24H 30N 2O 5S calculated value: C, 62.8; H, 6.6; N, 6.1% embodiment, 214 N-(6-(4-phenyl) hexyl)-(4-(2-methylsulfinyl phenoxy group)-2-aza-oxo-cyclobutane-1-yl) ethanamide
Handle N-(6-(4-phenyl) hexyl)-(4-(2-methylthio group phenoxy group)-2-aza-oxo-cyclobutane-1-yl) ethanamide in-30 ℃ of mCPBA (1.2 equivalent) that are used for methylene dichloride, obtain title compound after the chromatography, 75% productive rate into water white oil.Actual measurement: C, 62.9; H, 6.5; N, 6.1%; C 24H 30N 2O 4S.0.25CH 2Cl 2Calculated value: C, 62.8; H, 6.6; N, 6.0% embodiment, 215 N-(6-(4-phenyl) hexyl)-(4-(2-sulfonyloxy methyl phenoxyl)-2-aza-oxo-cyclobutane-1-yl) ethanamide
Handle N-(6-(4-phenyl) hexyl)-(4-(2-methylthio group phenoxy group)-2-aza-oxo-cyclobutane-1-yl) ethanamide in 20 ℃ of mCPBA (3 equivalent) that are used for methylene dichloride, obtain title compound after the chromatography into colorless solid, fusing point 127-8 ℃, 75% productive rate.Actual measurement: C, 62.6; H, 6.5; N, 6.1%; C 24H 30N 2O 5S calculated value: C, 62.8; H, 6.6; N, 6.1% embodiment, 216 N-(6-(4-phenyl) hexyl)-(4-(2-hydroxyphenoxy)-2-aza-oxo-cyclobutane-1-yl) ethanamide
Be used for THF in room temperature and handled N-(6-(4-phenyl) hexyl)-(4-(2-benzyloxy phenoxy group)-2-aza-oxo-cyclobutane-1-yl) ethanamide 1 hour, obtain title compound after the chromatography, 71% productive rate into water white oil with hydrogen/10% palladium on carbon.Actual measurement: C, 64.4; H, 6.6; N, 6.4%; C 23H 28N 2O 4.0.5CH 2Cl 2Calculated value: C, 64.3; H, 6.7; N, 6.4% embodiment, 217 N-(6-(4-chloro-phenyl-) hexyl)-(4-(2-carbonyl methylphenoxy)-2-aza-oxo-cyclobutane-1-yl) ethanamide
Four (triphenylphosphinyl) palladium, triphenylphosphine and tetramethyleneimine processing N-(6-(4-chloro-phenyl-) hexyl)-(4-(4-allyloxy carbonyl methylphenoxy)-2-aza-oxo-cyclobutane-1-yl) ethanamide of being used for methylene dichloride in room temperature spend the night, obtain title compound after the flash chromatography, 38% productive rate into glue.
1H?NMRδ(CDCl 3)1.13(4H，bm)，1.53(4H，m)，2.55(2H，t，J＝7.5Hz)，3.07(1H，d，
J＝15Hz)，3.23(2H，m)，3.39(1H，dd，J＝15.3Hz)，3.59(2H，s)，3.91?and?4.05(1H?each，
d，J＝17Hz)，5.71(m，1H)，6.36(1H，bs)，6.83(2H，d，J＝8Hz)，7.07(2H，d，J＝8Hz)，
7.24 (4H, m) embodiment 218 N-(6-(4-phenyl) hexyl)-(3-methyl-4-phenoxy group-2-aza-oxo-cyclobutane-1-yl) ethanamide
Prepare 3-methyl-4 phenoxy group nitrogen heterocyclic din-2-ketone according to above-mentioned Prep 1 usefulness 3-methyl-4 acetoxyl group nitrogen heterocyclic din-2-ketone, handle with N-(6-phenyl hexyl) bromo ethanamide according to the method for embodiment 201 subsequently, obtain title compound, 52.3% productive rate for light yellow oil.Actual measurement: C, 71.8; H, 7.4; N, 7.1%; C 24H 30N 2O 3.0.1CH 2Cl 2Calculated value: C, 71.8; H, 7.6; N, 6.9% embodiment, 219 4-benzyloxy-1-(4-phenyl-2-oxo-butyl)-nitrogen heterocyclic din-2-ketone
To 4-benzyloxy nitrogen heterocyclic din-2-ketone (2g, 11.0mmol), 1-bromo-2-oxygen-4-phenyl butane (2.9g, 12.0mmol), Tetrabutylammonium bromide (TBAB) (0.4g, add in solution 1.2mmol) potassium hydroxide (0.68g, 12.0mmol).Water is with its cancellation and use ethyl acetate extraction.Dry organic extract liquid and evaporation are surveyed with the title compound (1.7g, 47% productive rate) that this resistates of purified by flash chromatography obtains to light yellow oil: C, 73.7; H, 6.6; N, 4.4%; C 20H 21NO 3.0.15H 2O calculated value: C, 73.7; H, 6.6; N, 4.3% embodiment, 220 4-phenoxy group-1-(4-phenyl-2-oxygen-butyl)-nitrogen heterocyclic din-2-ketone
As above-mentioned with 4-phenoxy group nitrogen heterocyclic din-2-ketone (1g, 6.2mmol), 1-bromo-2-oxygen-4-phenyl butane (1.55g, 6.7mmol), TBAB (0.2g, 0.7mmol) and potassium hydroxide (0.4g, 6.7mmol) reaction, at flash chromatography with behind ether/normal hexane recrystallization, obtain title compound (0.65g into light yellow solid, 31% productive rate), fusing point 59-60 ℃.Actual measurement: C, 73.0; H, 6.2; N, 4.6%; C 19H 19NO 3.0.2H 2O calculated value: C, 72.9; H, 6.2; N, 4.5% embodiment, 301 N-[6-(naphthalene-1-yl)-5-hexin-1-yl]-4-benzylthio--2-aza-oxo-cyclobutane-1-yl acetamide
The mixture of 4-benzylthio--2-aza-oxo-cyclobutane-1-guanidine-acetic acid (3.4g), 6-(naphthalene-1-yl)-5-hexin-1-base acid amides (3.0g), I-hydroxybenzotriazole hydrate (1.82g) and dicyclohexyl carbodiimide (2.27g) is stirred in the colourless dimethyl formamide (100ml) together spends the night.Evaporating solvent also is dissolved into resistates in the ethyl acetate, filters, and the water extraction.With ethyl acetate extraction water liquid, also evaporate with organic solution, drying that the salt water washing merges.Obtain title compound (4.65g) into oil, 75% productive rate through flash chromatography (silica gel, ethyl acetate-hexane). 1H NMR δ (CDCl 3) 1.66-1.82 (4H, m), 2.58-2.63 (4H, m); 2.91 (1H, dd), 3.29-3.40 (3H, m); 3.55,3.72 (1H each, d), 3.78 (2H; s), 4.78 (1H, dd); 6.21 (1H, br.singlet), 7.22-7.85 (11H; m), 8.28-8.32 (1H, m) embodiment 302 N-[6-(naphthalene-1-yl)-5-hexin-1-yl]-4-benzyl sulfinyl-2-aza-oxo-cyclobutane-1-yl acetamide (diastereomer 1)
Will the m-CPBA drips of solution in methylene dichloride be added to the N-[6-in methylene dichloride (100ml) (naphthalene-1-the yl)-5-hexin-1-yl that is chilled to-60 ℃]-solution of 4-benzylthio--2-aza-oxo-cyclobutane-1-yl acetamide (2.6g) in.Under this temperature, stir this mixture 1 hour, pour in sodium bicarbonate and the S-WAT mixing solutions layering into.With dichloromethane extraction water liquid, with the organic solution of salt water washing merging.Dry and evaporation obtains oil with solution, and its crystallization from ethyl acetate is obtained title compound, and fusing point 138-9 ℃, 22% productive rate.Actual measurement: C, 70.7; H, 6.0; N, 6.0%; C 28H 28N 2O 3S.0.3H 2O calculated value: C, 70.4; H, 6.0; N, 5.9% embodiment, 303 N-[6-(naphthalene-1-yl)-5-hexin-1-yl]-4-benzyl sulfinyl-2-aza-oxo-cyclobutane-1-yl acetamide (diastereomer 2)
Obtain title compound (diastereomer 2) with mother liquid evaporation and with ether development into white crystal, fusing point 95-97 ℃, 55% productive rate.Actual measurement: C, 70.8; H, 6.0; N, 6.0%; C 28H 28N 2O 3S calculated value: C, 71.2; H, 6.0; N, 5.9%
Method with embodiment 301 makes following compounds (embodiment 304-8) by (4-benzylthio--2-aza-oxo-cyclobutane-1-yl) acetate and required amine.Embodiment 304 N-[6-(3-chloro-phenyl-) hexin-5-yl]-(4-benzylthio--2-aza-oxo-cyclobutane-1-yl) ethanamide water white oil, 67.8% productive rate
1H?NMRδ(CDCl 3)1.34-1.67(4H，m，2xCH 2)，2.44(2H，
t，J＝6.51Hz，ArCCCH 2)，2.94(1H，dd，2.43Hz，15.34Hz，H 3a)，3.31(2H，m，
NHCH 2)，3.37(1H，dd，J＝5.22Hz，15.43Hz，H 3b)，3.63?&?3.78(1H?each，J＝16.49Hz，
NCH 2)，3.87(2H，s，SCH 2Ph)，4.80(1H，dd，J＝2.46Hz，5.11Hz，H 4)，6.36(1H，m，
NHC=O), 7.15-7.46 (9H, m, 9xArH) embodiment 305 N-[6-(2-chloro-phenyl-) hexin-5-yl]-4-benzylthio--2-aza-oxo-cyclobutane-1-yl acetamide water white oil, 76.2% productive rate
1H NMR δ (CDCl 3) 1.47-1.81 (4H, m, 2xCH 2), 2.51 (2H, t, J=6.48Hz, ArCCCH 2), 2.94 (1H, dd, 2.43Hz, 15.38Hz, H 3a), 3.22 (2H, m, NHCH 2), 3.35 (1H, dd, J=5.13Hz, 15.38Hz, H 3b), 3.54 ﹠amp; 3.76 (1H each, J=16.79Hz, NCH 2), 3.81 (2H, s, SCH 2Ph), 4.80 (1H, dd, J=2.45Hz, 5.13Hz, H 4), 6.10 (1H, m, NHC=O), 7.17-7.44 (9H, m, 9xArH) embodiment 306 N-[6-phenyl-3-hexin base]-(4-benzylthio--2-aza-oxo-cyclobutane-1-yl) ethanamide colorless solid, fusing point 96-97 ℃, 78% productive rate 1H NMR δ (CDCl 3) 2.34 (2H, m, CCCH 2), 2.46 (2H, m, CCCH 2), 2.80 (2H, t, J=7.4Hz, PhCH 2), 2.91,2.95 (1H, dd, J=2.4,15.3Hz, H 3), 3.34 (3H, m, NHCH 2, H 3), 3 44,3.73 (each 1H, d, J=16.8Hz, NCH 2), 3.80 (2H, s, SCH 2), 4.83 (1H, m, H 4), 6.0 (1H, m, NH), 7.20-7.33 (10H, m, 2Ph-H); v C=o1771 cm -1Found:C, 70.9; H, 6.5; N, 7.0%; C 24H 26N 2O 2S requires:C, 70.9; H, 6.5; N, 6.9% actual measurement: C, 70.9; H, 6.5; N, 7.0%; C 24H 26N 2O 2S calculated value: C, 70.9; H, 6.5; N, 6.9% embodiment, 307 Z-N-[6-phenyl-3-hexin base]-(4-benzylthio--2-aza-oxo-cyclobutane-1-yl) ethanamide water white oil, 65% productive rate
1H?NMRδ(CDCl 3)2.18(2H，m，C＝CCH 2)，2.35(2H，m，C＝CCH 2)，2.66(2H，t，
J＝7.6Hz，PhCH 2)，2.89，2.93(1H，dd，J＝2.4，15.3Hz，H 3)，3.20(2H，m，NHCH 2)，
3.31，3.37(1H，dd，J＝5.2，15.3Hz，H 3)，3.47，3.65(each?1H，d，J＝15.1Hz，NCH 2)，
3.75(2H，s，SCH 2)，4.80(1H，m，H 4)，5.35(1H，m，CH＝)，5.51(1H，m，CH＝)，5.93
(1H, m, NH), 7.16-7.41 (10H, m, 2Ph-H) embodiment 308 E-N-[6-phenyl-3-hexin base]-(4-benzylthio--2-aza-oxo-cyclobutane-1-yl) ethanamide colorless solid, fusing point 96-97 ℃, 78% productive rate
1H?NMRδ(CDCl 3)2.18(2H，m，C＝CCH 2)，2.33(2H，m，C＝CCH 2)，2.68(2H，t，
J＝7.7Hz，PhCH 2)，2.90，2.96(1H，dd，J＝2.4，15.3Hz，H 3)，3.24(2H，m，NHCH 2)，
3.33，3.39(1H，dd，J＝5.2，15.3Hz，H 3)，3.48，3.71(each?1H，d，J＝16.8Hz，NCH 2)，
3.81(2H，s，SCH 2)，4.81(1H，m，H 4)，5.34(1H，m，CH＝)，5.53(1H，m，CH＝)，5.87
(1H, m, NH), 7.15-7.36 (10H, m, 2Ph-H); v C=o1771 cm -1Actual measurement: C, 70.5; H, 6.9; N, 7.0%; C 24H 28N 2O 2S calculated value: C, 70.6; H, 6.9; N, 6.9% embodiment, 309 N-(5-phenoxy group amyl group)-4-benzylthio--2-aza-oxo-cyclobutane-1-yl acetamide yellow oil, 74% productive rate
1H?NMRδ(CDCl 3)1.4-1.9(6H，m，3xCH 2)，2.93(1H，dd，J＝2，15Hz，H 3)，3.3
(2H，m，NHCH 2)，3.36(1H，dd，J＝5，15Hz，H 3)，3.55，3.72(each?1H，d，J＝17Hz，
NCH 2)，3.81(2H，s，SCH 2)，3.95(2H，t，J＝6Hz，CH 2O)，4.81(1H，m，H 4)，6.13
(1H, br s, NH), 6.9 (3H, m, Ph-H), 7.3 (7H, m, Ph-H) embodiment 310 N-(2-(2-phenoxy group oxyethyl group) ethyl)-4-benzylthio--2-aza-oxo-cyclobutane-1-yl acetamide yellow oil, 84% productive rates
1H?NMRδ(CDCl 3)2.89(1H，dd，J＝2，15Hz，H 3)，3.31(1H，dd，J＝5，15Hz，H 3)，
3.50(3H，m，NHCH 2+NCH 2)，3.63(2H，m，CH 2O)，3.80(5H，m，CH 2O+SCH 2+
NCH 2)，4.10(2H，m，CH 2OPh)，4.82(1H，m，H 4)，6.38(1H，br?s，NH)，6.9(3H，m，
Ph-H), 7.3 (7H, m, Ph-H) embodiment 311 N-(2-(3--phenyl propoxy-) ethyl)-4-benzylthio--2-aza-oxo-cyclobutane-1-yl acetamide yellow oil, 77% productive rates
1H?NMRδ(CDCl 3)1.90(2H，m，CH 2)，2.68(2H，t，J＝8Hz，CH 2Ph)，2.93(1H，dd，
J＝2.15Hz，H 3)，3.36(1H，dd，J＝5.15Hz，H 3)，3.45(7H，m，NHCH 2+CH 2O+
NCH 2)，3.80(3H，m，SCH 2+NCH 2)，4.85(1H，m，H 4)，6.25(1H，br?s，NH)，7.3
(10H，m，Ph-H)
Method according to embodiment 2 and 3 prepares following sulfoxide (embodiment 312-327).Embodiment 312 N-[6-(3-chloro-phenyl-) hexin-5-yl]-4-benzyl sulfinyl-2-aza-oxo-cyclobutane-1-yl acetamide
White solid, fusing point 133-134 ℃, 15.5% productive rate.Actual measurement: C, 62.8; H, 5.4; N, 6.13%; C 24H 25ClN 2O 2S calculated value: C, 63.1; H, 5.5; N, 6.1% embodiment, 313 N-[6-(3-chloro-phenyl-) hexin-5-yl]-4-benzyl sulfinyl-2-aza-oxo-cyclobutane-1-yl acetamide
White solid, fusing point 68-70 ℃, 18.0% productive rate.Actual measurement: C, 62.8; H, 5.5; N, 6.2%; C 24H 25ClN 2O 2S calculated value: C, 63.1; H, 5.5; N, 6.1% embodiment, 314 N-[6-(2-chloro-phenyl-) hexin-5-yl]-4-benzyl sulfinyl-2-aza-oxo-cyclobutane-1-yl acetamide
White solid, fusing point 132-134 ℃, 48.1% productive rate.Actual measurement: C, 62.8; H, 5.5; N, 6.13%; C 24H 25ClN 2O 2S calculated value: C, 63.1; H, 5.5; N, 6.1% embodiment, 315 N-[6-(2-chloro-phenyl-) hexin-5-yl]-4-benzyl sulfinyl-2-aza-oxo-cyclobutane-1-yl acetamide
White solid, fusing point 91-92 ℃, 48.1% productive rate.Actual measurement: C, 62.9; H, 5.6; N, 6.2%; C 24H 25ClN 2O 2S calculated value: C, 63.1; H, 5.5; N, 6.1% embodiment, 316 N-(6-phenyl-3-hexin base)-(4-benzyl sulfinyl-2-aza-oxo-cyclobutane-1-yl) ethanamide (diastereomer 1)
Colorless solid, 186 ℃ of fusing points, 14% productive rate. 1H NMR δ (CDCl 3) 2.34 (2H, m, CCCH 2), 2.46 (2H, m, CCCH 2), 2.80 (2H, t, J=7.4Hz, PhCH 2), 2.91,2.95 (1H, dd, J=4.4,14.8Hz, H 3), 3.31 (2H, m, NHCH 2), 3.41,3.44 (1H, dd, J=2.0,14.8Hz, H 3), 3.78-4.01 (4H, m, NCH 2, SOCH 2), 4.59 (1H, m, H 4), 6.38 (1H, m, NH), 7.20-7.40 (10H, m, 2Ph-H); v C=o1791 cm -1Actual measurement: C, 68.0; H, 6.1; N, 6.6%; C 24H 26N 2O 3S calculated value: C, 68.2; H, 6.2; N, 6.6% embodiment, 317 N-(6-phenyl-3-hexin base)-(4-benzyl sulfinyl-2-aza-oxo-cyclobutane-1-yl) ethanamide (diastereomer 2)
Colorless solid, fusing point 127-128 ℃, 48% productive rate.
1H?NMRδ(CDCl 3)2.34(2H，m，CCCH 2)，2.46(2H，m，CCCH 2)，2.72-2.81(3H，m，
PhCH 2，H 3)，3.09，3.13(1H，dd，J＝5.6，15.2Hz，H 3)，3.34(2H，m，NHCH 2)，3.93-
4.19(4H，m，NCH 2，SOCH 2)，4.65(1H，m，H 4)，6.74(1H，m，NH)，7.20-7.40(10H，
M, 2Ph-H) embodiment 318 Z-N-(6-phenyl-3-hexin base)-(4-benzyl sulfinyl-2-aza-oxo-cyclobutane-1-yl) ethanamide (diastereomer 1)
Colorless solid, fusing point 145-146 ℃, 19% productive rate. 1H NMR δ (CDCl 3) 2.21 (2H, m, C=CCH 2), 2.35 (2H, m, C=CCH 2), 2.66 (2H, t, J=7.6Hz, PhCH 2), 2.91,2.95 (1H, dd, J=4.8,14.8Hz, H 3), 3.19 (2H, m, NHCH 2), 3.42,3.45 (1H, dd, J=2.0,14.8Hz, H 3), 3.73,4.02 (each 1H, d, J=17.6Hz, NCH 2), 3.87,4.01 (each 1H, d, J=13.2Hz, SOCH 2), 4.53 (1H, m, H 4), 6.47 (1H, m, NH), 7.16-7.41 (10H, m, 2Ph-H); v C=o1791 cm -1Actual measurement: C, 67.6; H, 6.6; N, 6.7%; C 24H 28N 2O 3S calculated value: C, 67.9; 6.7; N, 6.6% embodiment, 319 Z-N-(6-phenyl-3-hexin base)-(4-benzyl sulfinyl-2-aza-oxo-cyclobutane-1-yl) ethanamide (diastereomer 2)
Colorless solid, fusing point 105-106 ℃, 14% productive rate.
1H?NMRδ(CDCl 3)2.21(2H，m，C＝CCH 2)，2.37(2H，m，C＝CCH 2)，2.67(2H，t，
J＝7.6Hz，PhCH 2)，2.79，2.83(1H，dd，J＝2.4，15.6Hz，H 3)，3.12，3.16(1H，dd，J＝5.6，
15.6Hz，H 3)，3.22(2H，m，NHCH 2)，3.90，4.18(each?1H，d，J＝16.8Hz，NCH 2)，3.97，
4.16(each?1H，d，J＝12.8Hz，SOCH 2)，4.61(1H，m，H 4)，5.35(1H，m，CH＝)，5.51
(1H, m, CH=), 6.95 (1H, m, NH), 7.16-7.41 (10H, m, 2Ph-H); v C=o1793 cm -1Actual measurement: C, 67.4; H, 6.6; N, 6.7%; C 24H 28N 2O 3S calculated value: C, 67.9; H, 6.7; N, 6.6% embodiment, 320 E-N-(6-phenyl-3-hexin base)-(4-benzyl sulfinyl-2-aza-oxo-cyclobutane-1-yl) ethanamide (diastereomer 1)
Colorless solid, fusing point 182-183 ℃, 18% productive rate.
1H?NMRδ(CDCl 3)2.19(2H，m，C＝CCH 2)，2.31(2H，m，C＝CCH 2).2.67(2H，t，
J＝7.7Hz，PhCH 2)，2.91，2.96(1H，dd，J＝4.7，14.8Hz，H 3)，3.24(2H，m，NHCH 2)，
3.41，3.47(1H，dd，J＝2.2，14.8Hz，H 3)，3.73，4.02(each?1H，d，J＝17.3Hz，NCH 2)，
3.88，4.01(each?1H，d，J＝13.1Hz，SOCH 2)，4.55(1H，m，H 4)，6.44(1H，m，NH)，
7.16-7.40 (10H, m, 2Ph-H); v C=o1790 cm -1Actual measurement: C, 67.5; H, 6.6; N, 6.6%; C 24H 28N 2O 3S calculated value: C, 67.9; H, 6.7; N, 6.6% embodiment, 321 E-N-(6-phenyl-3-hexin base)-(4-benzyl sulfinyl-2-aza-oxo-cyclobutane-1-yl) ethanamide (diastereomer 2)
Colorless solid, fusing point 111-112 ℃, 13% productive rate.
1H?NMRδ(CDCl 3)2.21(2H，m，C＝CCH 2)，2.34(2H，m，C＝CCH 2)，2.67(2H，t，
J＝7.6Hz，PhCH 2)，2.78，2.84(1H，dd，J＝2.5，15.3Hz，H 3)，3.11，3.17(1H，dd，J＝5.3，
15.3Hz，H 3)，3.28(2H，m，NHCH 2)，3.90，4.18(each?1H，d，J＝17.1Hz，NCH 2)，3.97，
4.16(each?1H，d，J＝12.9Hz，SOCH 2)，4.62(1H，m，H 4)，5.38(1H，m，＝CH)，5.53
(1H, m ,=CH), 6.86 (1H, m, NH), 7.16-7.42 (10H, m, 2Ph-H); v C=o1793 cm -1Actual measurement: C, 67.8; H, 6.6; N, 6.6%; C 24H 28N 2O 3S calculated value: C, 67.9; H, 6.7; N, 6.6% embodiment, 322 N-(5-phenoxy group amyl group)-(4-benzyl sulfinyl-2-aza-oxo-cyclobutane-1-yl) ethanamide
White solid, fusing point 132-135 ℃, 18% productive rate.
1H?nmrδ(CDCl 3)1.17-1.54(6H，m，CH 2CH 2CH 2)，2.94(1H，dd，J＝15.0，4.75Hz，
H 3b)，3.25(2H，m，NH-CH 2)，2.44(1H，dd，J＝15.0，2.25Hz，H 3a)，3.68-4.16(6H，m，
CH 2-OPh，N-CH 2，SOCH 2Ph)，4.52(1H，m，H 4)，6.74(1H，m，NH)，6.86-6.95，7.22-
7.35,7.37-7.40 (3H, 4H, 3H, m, O-Ph-H, SOCH 2Ph-H). embodiment 323 N-(5-phenoxy group amyl group)-(4-benzyl sulfinyl-2-aza-oxo-cyclobutane-1-yl) ethanamide
White solid, fusing point 116-118 ℃, 21% productive rate.
1H?nmrδ(CDCl 3)1.46-1.86(6H，m，CH 2CH 2CH 2)，2.87(1H，dd，J＝15.5，2.0Hz，
H 3a)，3.17(1H，dd，J＝15.5，50Hz，H 3b)，3.26-3.39(2H，m，NH-CH 2)，3.85-4.29
(6H，m，N-CH 2，CH 2-OPh，SOCH 2Ph)，4.60(1H，m，H 4)，6.86-6.94，7.22-7.43(3H，
8H, m, CH 2Ph-H, O-Ph-H, NH). actual measurement: C, 64.2; H, 6.4; N, 6.5%; C 23H 28N 2O 4S calculated value: C, 64.5; H, 6.6; N, 6.5% embodiment, 324 N-(2-(2-phenoxy group oxyethyl group) ethyl-(4-benzyl sulfinyl-2-aza-oxo-cyclobutane-1-yl) ethanamide (diastereomer 1)
Colorless solid, fusing point 135-5 ℃, 40% productive rate.
1H?NMRδ(CDCl 3)2.89(1H，dd，J＝5，15Hz，H 3)，3.39(1H，dd，J＝2.15Hz，H 3)
3.45(2H，m，NCH 2)，3.64(2H，m，OCH 2)，3.80(2H，m，OCH 2)，3.90(4H，m，NCH 2
+SOCH 2)，4.12(2H，m，CH 2OPh)，4.60(1H，m，H 4)，6.65(1H，br?s，NH)，6.95(3H，
M, Ph-H), 7.3 (7H, m, Ph-H); v C=o1789 cm -1Actual measurement: C, 61.1; H, 6.0; N, 6.6%; C 22H 26N 2O 5S calculated value: C, 61.4; H, 6.1; N, 6.5% embodiment, 325 N-(2-(2-phenoxy group oxyethyl group) ethyl-(4-benzyl sulfinyl-2-aza-oxo-cyclobutane-1-yl) ethanamide (diastereomer 2)
Colorless solid, fusing point 109-12 ℃, 47% productive rate.
1H?NMRδ(CDCl 3)2.67(1H，dd，J＝2，15Hz，H 3)，3.06(1H，dd，J＝5，15Hz，H 3)
3.5(2H，m，NCH 2)，3.65(2H，m，OCH 2)，3.82(2H，m，OCH 2)，4.0(6H，m，NCH 2+
SOCH 2+CH 2OPh)，4.65(1H，m，H 4)，7.06(1H，br?s，NH)，6.9(3H，m，Ph-H)，7.3
(7H, m, Ph-H); v C=o1790 cm -1Actual measurement: C, 61.0; H, 6.0; N, 6.5%; C 22H 26N 2O 5S calculated value: C, 61.4; H, 6.1; N, 6.5% embodiment, 326 N-2-(3-phenyl propoxy-) ethyl-(4-benzyl sulfinyl-2-aza-oxo-cyclobutane-1-yl) ethanamide (diastereomer 1)
Colorless solid, fusing point 124-5 ℃, 27% productive rate.
1H?NMRδ(CDCl 3)1.90(2H，m，CH 2)，2.68(2H，t，J＝8Hz，CH 2Ar)，2.91(1H，dd，
J＝5，15Hz，H 3)，3.4(7H，m，NCH 2+H 3+2xOCH 2)，3.85-4.0(4H，m，SOCH 2+
NCH 2)，4.62(1H，m，H 4)，6.61(1H，br?s，NH)，7.15-7.45(10H，m，2xPh-H)：v? c＝o
1789 cm -1Actual measurement: C, 64.2; H, 6.5; N, 6.6%; C 23H 28N 2O 4S calculated value: C, 64.5; H, 6.6; N, 6.5% embodiment, 327 N-2-(3-phenyl propoxy-) ethyl-(4-benzyl sulfinyl-2-aza-oxo-cyclobutane-1-yl) ethanamide (diastereomer 2)
Colorless solid, fusing point 82-4 ℃, 24% productive rate.
1H?NMRδ(CDCl 3)1.85(2H，m，CH 2)，2.7(3H，m，CH 2Ar+H 3)，3.09(1H，dd，
J＝5，15Hz，H 3)，3.45(6H，m，NCH 2+2xOCH 2)，3.9-4.2(4H，m，SOCH 2+
NCH 2)，4.67(1H，m，H 4)，6.97(1H，br?s，NH)，7.15-7.4(10H，m，2xPh-H)；v c＝o
1790 cm -1Actual measurement: C, 64.3; H, 6.5; N, 6.6%; C 23H 28N 2O 4S calculated value: C, 64.5; H, 6.6; N, 6.5% embodiment, 328 N-[6-(2-chloro-phenyl-) acetylene-5-yl]-4-benzyl alkylsulfonyl-2-aza-oxo-cyclobutane-1-yl) ethanamide
The mCPBA (1 equivalent) that is used for methylene dichloride in room temperature handles N-[6-(2-chloro-phenyl-) acetylene-5-yl]-4-benzyl alkylsulfonyl-2-aza-oxo-cyclobutane-1-yl) ethanamide (diastereomer 1) obtains the title compound into white solid; fusing point 114-117 ℃, 86.7% productive rate.Actual measurement: C, 60.4; H, 5.4; N, 5.8%; C 24H 25ClN 2O 4S calculated value: C, 60.9H, 5.3; N, 5.8%
When handling corresponding thioether with mCPBA, the method preparation that following sulfone (embodiment 329-331) can be identical is perhaps separated from formed mixture.Embodiment 329 N-[6-(3-chloro-phenyl-) acetylene-5-yl]-4-benzyl alkylsulfonyl-2-aza-oxo-cyclobutane-1-yl) the ethanamide white solid, fusing point 122-4 ℃, 5.6% productive rate.Actual measurement: C, 60.7; H, 5.3; N, 6.0%; C 24H 25ClN 2O 3S calculated value: C, 60.9; H, 5.3; N, 5.9% embodiment, 330 N-(6-phenyl-3-ethynyl)-(4-benzyl alkylsulfonyl-2-aza-oxo-cyclobutane-1-yl) ethanamide colorless solid, fusing point 135-6 ℃, 88% productive rate.
1H?NMRδ(CDCl 3)2.33(2H，m，CCCH 2)，2.47(2H，m，CCCH 2)，2.81(2H，t，
J＝7.4Hz，PhCH 2)，2.94，3.00(1H，dd，J＝2.4，15.3Hz，H 3)，3.07，3.13(1H，dd，J＝5.1，
15.3Hz，H 3)，3.30(2H，m，NHCH 2)，3.69，3.97(each?1H，d，J＝18.9Hz，NCH 2)，4.30，
4.37(each?1H，d，J＝14.2Hz，SO 2CH 2)，4.89(1H，m，H 4)，5.77(1H，m，NH)，7.20-
7.40 (10H, m, 2Ph-H); v C=o1792 cm -1Actual measurement: C, 65.4; H, 6.0; N, 6.4%; C 24H 26N 2O 4S calculated value: C, 65.7; H, 6.0; N, 6.4% embodiment, 331 E-N-(6-phenyl-3-ethynyl)-(4-benzyl alkylsulfonyl-2-aza-oxo-cyclobutane-1-yl) ethanamide colorless solid, fusing point 115-6 ℃, 39% productive rate.
1H?NMRδ(CDCl 3)2.17(2H，m，C＝CCH 2)，2.35(2H，m，CCCH 2)，2.69(2H，t，
J＝7.6Hz，PhCH 2)，2.94，3.00(1H，dd，J＝2.4，15.4Hz，H 3)，3.07，3.13(1H，dd，J＝5.1，
15.4Hz，H 3)，3.24(2H，m，NHCH 2)，3.74，3.95(each?1H，d，J＝16.9Hz，NCH 2)，4.30，
4.37(each?1H，d，J＝14.2Hz，SO 2CH 2)，4.87(1H，m，H 4)，5.33(1H，m，＝CH)，5.53
(1H, m ,=CH), 5.70 (1H, m, NH), 7.16-7.44 (10H, m, 2Ph-H); v C=o1794 cm -1Actual measurement: C, 65.1; H, 6.3; N, 6.4%; C 24H 28N 2O 4S calculated value: C, 65.4; H, 6.4; N, 6.4% embodiment, 332 1-(2-(6-phenyl hexyloxy) ethyl-4-benzylthio--2-aza-oxo-cyclobutane
Under nitrogen-10 ℃ with 60% (0.30g, 7.5mmol) sodium hydride in is suspended among the colourless THF (15ml), is incorporated in 4-(the benzylthio-)-2-azetidinone (1.35g) among the THF (10ml) under keeping＜0 ℃ in 10 minutes in mineral oil.Stir this mixture 15 minutes in 0 ℃, be chilled to-10 ℃, in 3 minutes, be incorporated in 2-(6-phenyl hexyloxy) the ethyl triflate (3.54g) among the THF (10ml) under keeping＜0 ℃.Under room temperature, stirred this mixture 30 minutes, and poured into then in the salt solution, separate and with extracted with diethyl ether water liquid.Organism drying (MG) and evaporation with merging obtain red oil.On silica gel, be purified 1-(2-(the 6-phenyl hexyloxy) ethyl-4-benzylthio--2-aza-oxo-cyclobutane (1.71g, 62%) that obtains to water white oil through chromatography (40-60 petrol ether/ethyl acetate).
1H?NMRδ(CDCl 3)1.3-1.7(8H，m，4xCH 2)，2.59(2H，t，J＝8Hz，CH 2Ph)，2.88
(1H，dd，J＝2，15Hz，H 3)，3.0(1H，m，NCH 2)，3.27(1H，dd，J＝5，15Hz，H 3)，3.4
(5H，m，NCH 2+CH 2OCH 2)，3.81(2H，s，SCH 2)，4.75(1H，m，H 4)，7.15-7.35(10H，
m，Ph-H).
According to the identical method of embodiment 332, prepare the following example (333-336) by 4-benzylthio--nitrogen heterocyclic din-2-ketone and corresponding triflate.Embodiment 333 1-(2-(6-(4-chloro-phenyl-) hexyloxy) ethyl-4-benzylthio--2-aza-oxo-cyclobutane
Water white oil, 62% productive rate
1H?NMRδ(CDCl 3)1.2-1.7(8H，m，4xCH 2)，2.55(2H，t，J＝8Hz，CH 2Ph)，2.88
(1H，dd，J＝2，15Hz，H 3)，3.0(1H，m，NCH 2)，3.28(1H，dd，J＝5，15Hz，H 3)，3.4
(5H，m，NCH 2+CH 2OCH 2)，3.81(2H，s，SCH 2)，4.75(1H，m，H 4)，7.07(2H，m，
ClPh-H), 7.35 (7H, m, Ph-H+ClPh-H) embodiment 334 1-(2-(6-(4-fluorophenyl) hexyloxy) ethyls-4-benzylthio--2-aza-oxo-cyclobutane
Water white oil, 22% productive rate
1H?NMRδ(CDCl 3)1.2-1.7(8H，m，4xCH 2)，2.55(2H，t，J＝8?Hz，CH 2Ph)，2.88
(1H，dd，J＝2，15Hz，H 3)，3.05(1H，m，NCH 2)，3.27(1H，dd，J＝5，15Hz，H 3)，3.4
(5H，m，NCH 2+CH 2OCH 2)，3.81(2H，s，SCH 2)，4.75(1H，m，H 4)，6.95，7.10(each
2H, m, FPh-H), 7.25 (5H, m, Ph-H) embodiment 335 N-3-(phenoxy propyl)-4-benzylthio--2-aza-oxo-cyclobutanes
Yellow oil, 82% productive rate
1H?NMRδ(CDCl 3)2.0(2H，m，CH 2)，2.89(1H，dd，J＝2，15Hz，H 3)，3.08，3.41
(each?1H，m，NCH 2)，3.26(1H，dd，J＝5，15Hz，H 3)，3.78(2H，s，SCH 2)，3.95(2H，
M, CH 2OPh), 4.63 (1H, m, H 4), 6.9 (3H, m, Ph-H), 7.3 (7H, m, Ph-H) embodiment 336 1-(2-benzyloxy ethyl)-4-benzylthio--2-oxo-azetidin-2-ketone
Water white oil, 74% productive rate
1H?NMRδ(CDCl 3)2.7(1H，dd，J＝2，15Hz，H 3)，3.0(1H，m，NCH 2)，3.26(1H，dd，
J＝5，15Hz，H 3)，3.5(3H，m，NCH 2+CH 2CH 2O)，3.76(2H，m，SCH 2Ph)，4.50(2H，
m，OCH 2Ph)，4.7(1H，m，H 4)，7.2-7.4(10H，m，2xPh-H).
According to the method for embodiment 302 and 303, prepare following sulfoxide (embodiment 337-345) by handle corresponding thioether with mCPBA.Embodiment 337 1-(2-(6-phenyl hexyloxy) ethyl-4-benzyl sulfinyl-2-aza-oxo-cyclobutane (80% diastereomer 2) colorless solid, fusing point 47-9 ℃, 37% productive rate.
1H?NMRδ(CDCl 3)1.2-1.7(8H，m，4xCH 2)，2.6(3H，m?CH 2Ph+H 3)，2.98(1H，
dd，J＝5，15Hz，H 3)，3.3-3.8(6H，m，NCH 2+CH 2OCH 2)，4.05(2H，d，J＝13Hz，
SCH 2), 4.52 (1H, m, H 4), 7.14-7.4 (10H, m, Ph-H); v C=o1776 cm -1Actual measurement: C, 69.7; H, 7.4; N, 3.5%; C 24H 31NO 3S calculated value: C, 69.7; H, 7.6; N, 3.4% embodiment, 338 1-(2-(6-(4-chloro-phenyl-) hexyloxy) ethyl)-4-benzyl sulfinyl-2-aza-oxo-cyclobutane (diastereomer 1) water white oil, 27% productive rate.
1H?NMRδ(CDCl 3)1.2-1.65(8H，m，4xCH 2)，2.58(2H，t，J＝8Hz，CH 2Ph)，2.87
(1H，dd，J＝5，15Hz，H 3)，3.25-3.7(7H，m，NCH 2+CH 2OCH 2+H 3)，3.84，3.98
(2H，2xd，J＝13Hz，SOCH 2)，4.51(1H，m，H 4)，7.09(2H，m，ClPh-H)，7.3(7H，m，
Ph-H+ClPh-H); v C=o1777 cm -1Actual measurement: C, 64.1; H, 6.6; N, 3.1%; C 24H 30ClNO 3S calculated value: C, 63.4; H, 6.8; N, 3.1% embodiment, 339 1-(2-(6-(4-chloro-phenyl-) hexyloxy) ethyl)-4-benzyl sulfinyl-2-aza-oxo-cyclobutane (diastereomer 2) colorless solid, fusing point 86-8 ℃, 37% productive rate.
1H?NMRδ(CDCl 3)1.2-1.7(8H，m，4xCH 2)，2.55(3H，m，CH 2Ph+H 3)，2.99(1H，
dd，J＝5，15Hz，H 3)，3.3-3.8(6H，m，NCH 2+CH 2OCH 2)，4.01，4.09(2H，2xd，
J＝13Hz，SOCH 2)，4.52(1H，m，H 4)，7.09(2H，m，ClPh-H)，7.3(7H，m，Ph-H+ClPh-H
); v C=o1777 cm -1Actual measurement: C, 64.2; H, 6.6; N, 3.3%; C 24H 30ClNO 3S calculated value: C, 63.4; H, 6.7; N, 3.1% embodiment, 340 1-(2-(6-(4-fluorophenyl) hexyloxy) ethyl)-4-benzyl sulfinyl-2-aza-oxo-cyclobutane (diastereomer 1) water white oil, 12% productive rate.
1H?NMRδ(CDCl 3)1.25-1.65(8H，m，4xCH 2)，2.58(2H，t，CH 2Ph)，2.87(1H，dd，
J＝5，15Hz，H 3)，3.25-3.7(7H，m，NCH 2+CH 2OCH 2+H 3)，3.84，3.98(2H，2xd，
J＝13Hz，SOCH 2)，4.52(1H，m，H 4)，6.95，7.10(each?2H，m，FPh-H)，7.3(5H，m，Ph-H
); v C=o1777 cm -1Embodiment 341 1-(2-(6-(4-fluorophenyl) hexyloxy) ethyl)-4-benzyl sulfinyl-2-aza-oxo-cyclobutane (diastereomer 2) colorless solid, fusing point 77-8 ℃, 37% productive rate.
1H?NMRδ(CDCl 3)1.25-1.65(8H，m，4xCH 2)，2.55(3H，m，CH 2Ph+H 3)，2.98
(1H，dd，J＝5，15Hz，H 3)，3.4-3.75(6H，m，NCH 2+CH 2OCH 2)，4.02，4.09(2H，2x
d，J＝13Hz，SOCH 2)，4.52(1H，m，H 4)，6.95，7.10(each?2H，m，FPh-H)，7.3(5H，m，
Ph-H); v C=o1777 cm -1Actual measurement: C, 66.5; H, 6.9; N, 3.2%; C 24H 30FNO 3S calculated value: C, 66.8; H, 7.0; N, 3.3% embodiment, 342 4-benzyl sulfinyl-1-(3-phenoxy propyl) nitrogen heterocyclic din-2-ketone (diastereomer 1) colorless solids, fusing point 93-7 ℃
1H?nmrδ(CDCl 3)2.05-2.17(2H，m，CH 2CH 2CH 2)，2.78(1H，dd，J＝14.75，4.75Hz，
H 3b)，3.34-3.57(3H，m，H 3a，N-CH 2)，3.82，3.92(2H，dd，J＝13.00，13.00Hz，
SOCH 2Ph)，3.95-4.06(2H，m，CH 2-OPh)，4.37(1H，m，H 4)，6.83-6.98(5H，m，OPh-H
), 7.19-7.37 (5H, m, CH 2Ph-H). actual measurement: C, 66.5; H, 6.2; N, 4.1%; C 19H 21NO 3S calculated value: C, 66.3; H, 6.2; N, 4.4% embodiment, 343 4-benzyl sulfinyl-1-(3-phenoxy propyl) nitrogen heterocyclic din-2-ketone (diastereomer 2) colorless solids, fusing point 62-65 ℃
1Hnmrδ(CDCl 3)2.12-2.19(2H，m，CH 2CH 2CH 2)，2.47(1H，dd，J＝15.0，2.25Hz，
H 3a)，2.91(1H，dd，J＝15.0，5.0Hz，H 3b)，3.51-3.67(2H，m，N-CH 2)，3.95-4.07(4H，
m，CH 2O，SOCH 2Ph)，4.42(1H，m，H 4)，6.83-6.97(5H，m，OPh-H)，7.22-7.39(5H，
M, SOCH 2Ph-H) actual measurement: C, 66.5; H, 6.2; N, 4.1%; C 19H 21NO 3S calculated value: C, 66.3; H, 6.3; N, 4.4% embodiment, 344 1-(2-benzyloxy ethyl)-4-benzyl sulfinyl-nitrogen heterocyclic din-2-ketone (diastereomer 1) water white oil, 49% productive rate.
1H?NMRδ(CDCl 3)2.78(1H，dd，J＝5，15Hz，H 3)，3.35(1H，d，J＝13?Hz?H 3)，3.4-
3.8(4H，m，NCH 2CH 2)，3.95，4.07(each?1H，d，J＝15Hz，SOCH 2)，4.5(3H，m，
OCH 2Ph+H 4), 7.2-7.4 (10H, m, Pb-H); v C=o1777 cm -1Embodiment 345 1-(2-benzyloxy ethyl)-4-benzyl sulfinyl-nitrogen heterocyclic din-2-ketone (diastereomer 2) water white oil, 26% productive rate.
1H?NMRδ(CDCl 3)2.49(1H，d，J＝15Hz?H 3)，2.93(1H，dd，J＝5，15Hz，H 3)，3.4-
3.8(4H，m，NCH 2CH 2)，3.95，4.07(each?1H，d，J＝13Hz，SOCH 2)，4.4-4.6(3H，m，
OCH 2Ph+H 4), 7.2-7.4 (10H, m, Ph-H); v C=o1777 cm -1Actual measurement: C, 66.4; H, 6.2; N, 4.3%; C 19H 21NO 3S calculated value: C, 66.5; H, 6.2; N, 4.1 embodiment, 346 4-methylthio group-1-(3-phenoxy propyl) nitrogen heterocyclic din-2-ketones (diastereomer 2)
Will (0.7g, 5.97mmol) solution be added drop-wise to NaH in anhydrous THF (5ml) (0.24g is 6.07mmol) in the suspension in 10 minutes in the 4-methyl nitrogen heterocyclic din-2-ketone among the anhydrous THF (10ml) under nitrogen in-20 ℃.In-55 ℃ of 3-iodo-1-phenoxypropane (1.56g, 5.97mmol) solution that in 10 minutes, drip in anhydrous FHF (10ml).This mixture stirring was spent the night in 18 hours, be poured on then on ice/water (50g), filter and the part evaporation.Handle this resistates with ethyl acetate, with salt solution (* 2) washing organic layer, dry (MG) and vapourisation under reduced pressure obtain yellow oil.This oil is obtained 4-methylthio group-1-(3-phenoxy propyl) nitrogen heterocyclic din-2-ketone (0.64g, 42%) into colorless solid by purified by flash chromatography on silica gel, fusing point 41-2 ℃.
1H?NMRδ(CDCl 3)2.04(3H，s，SCH 3)，2.10(2H，m，CH 2)，2.95(1H，dd，J＝2，15
Hz，H 3)，3.25(2H，m，H 3+NCH 2)，3.56(1H，m，NCH 2)，4.02(2H，m，CH 2OPh)，
4.66 (1H, m, H 4), 6.9 (3H, m, Ph-H), 7.3 (2H, m, Ph-H) embodiment 347 4-methylsulfinyl-1-(3-phenoxy propyl) nitrogen heterocyclic din-2-ketones
Method according to embodiment 302; handle 4-methylthio group-1-(3-phenoxy propyl) nitrogen heterocyclic din-2-ketone (0.59g with mCPBA; 2.34mmol) obtain 4-methylsulfinyl-1-(3-phenoxy propyl) nitrogen heterocyclic din-2-ketone (0.39g, 62%) into wax shape white solid.
1H?nmrδ(CDCl 3)2.12-2.23(4H，m，2xCH 2CH 2CH 2)，2.43(3H，s，SOCH 3)，2.56
(3H，s，SOCH 3)，2.78(1H，dd，J＝15.00，2.50Hz，H 3a)，3.07(1H，dd，J＝14.5，4.75Hz，
H 3b)，3.24(1H，dd，J＝15.00，5.25Hz，H 3b)，3.47-3.71(5H，m，2xN-CH 2，H 3a)，4.05-
4.20(4H，m，2xCH 2O)，4.40(1H，m，H 4)，4.50(1H，m，H 4)，6.8-7.0，7.2-7.33(6H，
4H, m, 2xAr-H). actual measurement: C, 58.4; H, 6.4; N, 5.2%; C 13H 17NO 3S calculated value: C, 58.1; H, 6.5; N, 5.3 embodiment, 348 1-(2-(6-(4-fluorophenyl) hexyloxy) ethyl)-4-(4-ethoxy carbonyl benzylthio-)-2-aza-oxo-cyclobutane
With powdered potassium hydroxide (0.47g, 0.00838mol) handle and to be chilled to 10 ℃ the 4-in anhydrous tetrahydro furan (40ml) (4-(ethoxy carbonyl) benzylthio-) nitrogen heterocyclic din-2-ketone (1.85g, 0.00697mol), 2-(6-(4-fluorophenyl) hexyloxy) ethyl) triflate (2.62g, 0.00704mol) and Tetrabutylammonium bromide (0.22g, 0.00068mol) solution.Remove cooling bath, should react 2 hours, be distributed in salt solution (70ml) and the ethyl acetate (70ml) in stirring at room.Dry (MG) organic layer and evaporation obtain oil (3.7g).By the flash column chromatography purifying on silica gel, with 2: 1 P.E40-60 ℃: eluent ethyl acetate, obtain 1-(2-(6-fluorophenyl) hexyloxy) ethyl for water white oil)-4-(4-ethoxy carbonyl benzylthio-)-2-aza-oxo-cyclobutane (1.15g, 34%).
1H?nmrδ(CDCl 3)1.42(11H，m，CH 2x4，CH 3)，2.55(2H，t，J＝7.6Hz，CH 2Ph)，2.84，
2.90(1H，dd，J＝1.9，15.2Hz，H 3)，3.03(1H，m，1?of?NCH 2)，3.26，3.32(1H，dd，J＝5，
15.2Hz，H 3)，3.40(5H，m，CH 2OCH 2，1?of?NCH 2)，3.85(2H，s，CH 2S)，4.36(2H，q，
CH 2O)，4.75(1H，m，H 4)，6.91-7.11(4H，m，p-F-Ar-H)，7.39，8.01(4H，2xd，
J=8.3Hz, Ar-H) embodiment 349 1-(2-(6-(4-fluorophenyl) hexyloxy) ethyl)-4-(4-ethoxy carbonyl benzyl sulfinyl)-2-aza-oxo-cyclobutane
Method according to embodiment 302 is handled 1-(2-(6-fluorophenyl) hexyloxy) ethyl in mCPBA (0.67g))-4-(4-ethoxy carbonyl phenyl sulfinyl)-2-aza-oxo-cyclobutane (1.05g); behind chromatography and recrystallization; obtain title compound for colorless solid; 2: 1 ratio of diastereomer is 96: 4; fusing point 75-75 ℃, 25% productive rate.
1H?nmrδ(CDCl 3)1.42(11H，m，CH 2x4，CH 3)，2.56(2H，t，J＝7.7Hz，CH 2Ph)，2.63，
2.69(1H，dd，J＝2.2，15.1Hz，H 3)，3.05，3.10(1H，dd，J＝5，15.1Hz，H 3)3.37-3.73(
6H，m，CH 2OCH 2，NCH 2)，4.08(2H，s，CH 2SO)，4.36(2H，q，CH 2O)，4.54(1H，
M, H 4), 6.91-7.11 (4H, m; p-F-Ar-H), 7.38,8.05 (4H; 2xd, J=8.3Hz, Ar-H) embodiment 350 1-(2-(6-(4-fluorophenyl) hexyloxy) ethyl)-4-(4-ethoxy carbonyl benzyl sulfinyl)-2-aza-oxo-cyclobutane (most diastereomer 1)
Embodiment 349 recrystallizations also obtain the title compound into colorless solid, are 68: 32 non-enantiomer mixture, and fusing point 53-55 ℃, 12.5% productive rate. 1H nmr (diastereoisomer 1) δ (CDCl 3) 1.42 (11H, m, CH 2X4, CH 3), 2.56 (2H, t, J=7.7Hz, CH 2Ph), 2.85,2.90 (1H, dd, J=4.6,14.6Hz, H 3), 3.30-3.7 (7H, m, H 3, CH 2OCH 2, NCH 2), 3.93 (2H, m, CH 2SO), 4.36 (2H, q, CH 2O), 4.53 (1H, m, H 4), 6.91-7.11 (4H, m, p-F-Ar-H), 7.33,8.05 (4H, 2xd, J=8.2Hz, Ar-H) biological data 1. examination Lp-PLA 2Restraining effect
Enzymic activity is containing 150mM NaCl by measuring artificial substrates (A) at 37 ℃, the upset speed in the 50mM HEPES of pH7.4 (the N-2-hydroxyethyl piperazine-N '-2-ethanesulfonic acid) damping fluid and measuring.
Figure A9619666101101
Test is carried out in 96 hole titer plates.
Lp-PLA 2Density gradient centrifugation partial purification by human plasma.With active part precipitation and be used as Lp-PLA 2The source.With enzyme and carrier or test compound at cumulative volume 180 μ l 37 ℃ of pre-cultivations 10 minutes.Start by adding 20 μ l, 10 * substrates (A) then and provide final concentration of substrate 20 μ M.Be reflected at 405nm and mix continuation down 20 minutes automatically with the plate reader.The change speed measurement of speed of reaction to absorb.
The result: compound of the present invention is found the IC that has in the 0.7-100000nM scope 50Value.

Claims (34)

1. a formula (I) compound:
Figure A9619666100021
Wherein: R 1And R 2, identical or different, be selected from hydrogen separately, halogen or C (1-8)Alkyl; R 4And R 5Can be identical or different, be selected from hydrogen separately, C (1-6)Alkyl, C (2-6)Thiazolinyl, aryl, aryl (C 1-4) alkyl and heteroaryl (C 1-4) alkyl, they can be substituted separately non-imposedly, or R 4And R 5Can be joined together to form (C 3-7) remainder of cycloalkyl ring; X connects base; Y is the aryl of non-imposed replacement; Z is oxygen and R 3Be C (1-8)Alkyl, C (3-8)Cycloalkyl, C (3-8)Cycloalkyl C (1-6)Alkyl, heteroaryl, heteroaryl (C 1-4) alkyl, aryl, aryl (C 1-4) alkyl, they can be replaced separately non-imposedly, or Z be S (O) n wherein n be 0,1 or 2, and R 3Be C (1-8)Alkyl, C (3-8)Cycloalkyl, C (3-8)Cycloalkyl C (1-6)Alkyl, aryl, aryl (C 1-4) alkyl, heteroaryl, or heteroaryl (C 1-4) alkyl, they can be replaced separately non-imposedly; And get rid of following compound wherein: X is direct key; Radicals X 1(CH 2) m X wherein 1Be CO, CONR 6, COO, CONR 6CO, or CONR 6O is R wherein 6Be hydrogen or C (1-6)Alkyl and m are 0 or 1 to 12 integers; Or it is non-imposed by X 1The C that inserts (1-12)Alkylidene chain; Z be S (O) n wherein n be 0,1 or 2 and R 3Be C (1-8)Alkyl, C (3-8)Cycloalkyl, C (3-8)Cycloalkyl C (1-6)Alkyl, aryl or aryl (C 1-4) alkyl, they can be replaced separately non-imposedly; And R 4And R 5Each is hydrogen naturally.
2. compound as claimed in claim 1, wherein X is: direct key; Radicals X 1(CH 2) m X wherein 1Be CO, CONR 6, COO, CONR 6CO, or CONR 6O is R wherein 6Be hydrogen or C (1-6)Alkyl and m are 0 or 1 to 12 integers; Group (X 1) aX 2Wherein a is 0 or 1 and X 2Be with the Y neighboring terminals by one or more O of being selected from, S (O) x, NR 6, the X of alkenyl or alkynyl 3The group of group inserts and/or terminated C (1-12)Alkylidene chain, wherein x is 0,1 or 2; Or it is non-imposed by X 1The C that inserts (1-12)Alkylidene chain.
3. as the compound of claim 1 or 2 wherein: X is direct key; X as claim 2 definition 1(CH 2) m; Group (X as claim 2 definition 1) aX 2Or it is non-imposed by X 1The C that inserts (1-12)Alkylidene chain; Z is oxygen and R 3Be C (1-8)Alkyl, C (3-8)Cycloalkyl, C (3-8)Cycloalkyl C (1-6)Alkyl, heteroaryl, heteroaryl (C 1-4) alkyl, aryl, aryl (C 1-4) alkyl, they can be replaced separately non-imposedly, or Z be S (O) n wherein n be 0,1 or 2, and R 3Be heteroaryl or heteroaryl (C 1-4) alkyl, they can be replaced separately non-imposedly.
4. compound as claimed in claim 3, wherein R 4And R 5Each hydrogen naturally, or one be hydrogen and another is a methyl.
5. as the compound of claim 3 or 4, wherein Z is oxygen and R 3It is the aryl of non-imposed replacement; Or S (O) n wherein n be 0,1 or 2, and R 3Be the heteroaryl (C of non-imposed replacement 1-4) alkyl.
6. compound as claimed in claim 5, wherein Z is oxygen and R 3It is the phenyl of non-imposed replacement.
7. compound as claimed in claim 5, wherein Z is S (O) n and R 3It is the heteroaryl methyl of non-imposed replacement.
8. compound as claimed in claim 7, wherein ZR 3It is the furans-2-ylmethyl of non-imposed replacement.
9. compound as claimed in claim 7, wherein ZR 3It is 5-carboxyl furans-2-ylmethyl.
10. as the compound of claim 1 or 2, wherein: X is direct key; Radicals X as claim 2 definition 1(CH 2) m; Group (X as claim 2 definition 1) aX 2Or it is non-imposed by X 1The C that inserts (1-12)Alkylidene chain; Z be S (O) n wherein n be 0,1 or 2, and R 3Be C (1-8)Alkyl, C (3-8)Cycloalkyl, C (3-8)Cycloalkyl C (1-6)Alkyl, aryl or aryl (C 1-4) alkyl, they can be replaced separately non-imposedly; R 4And R 5Can be identical or different, be selected from hydrogen separately, C (1-6)Alkyl, C (2-6)Thiazolinyl, aryl, aryl (C 1-4) alkyl and heteroaryl (C 1-4) alkyl, they can be substituted separately non-imposedly, or R 4And R 5Can be joined together to form (C 3-7) remainder of cycloalkyl ring, condition is R 4And R 5Be not hydrogen simultaneously.
11. as the compound of claim 10, wherein R 4And R 5One of be hydrogen and another is a methyl.
12., wherein work as R as the compound of the arbitrary claim in front 4And R 5One of another is a methyl when being hydrogen, at R 4And R 5Absolute configuration is S on the carbon that connects.
13. as each compound of claim 3 to 12, wherein X is CONH (CH 2) 6, CONR 6(CH 2) 4C ≡ C and (CH 2) O (CH 2) 6
14. as the compound of claim 1 or 2, wherein: X is the group (X as claim 2 definition 1) aX 2Z be S (O) n wherein n be 0,1 or 2, and R 3Be C (1-8)Alkyl, C (3-8)Cycloalkyl, C (3-8)Cycloalkyl C (1-6)Alkyl, aryl or aryl (C 1-4) alkyl, they can be replaced separately non-imposedly; R 4And R 5Each is hydrogen naturally.
15. as the compound of claim 14, wherein X is CONR 6(CH 2) 4C ≡ C or (CH 2) O (CH 2) 6
16. as each compound of claim 10 to 15, wherein ZR 3It is the benzyl sulfinyl of non-imposed replacement.
17. as the compound of claim 16, wherein ZR 3Be 4-carboxyl benzyl sulfinyl or its C (1-6)Alkyl or C (2-6)Alkenyl esters.
18. as claim 1 to 5 and 7 to 15 each compounds, wherein Z is S (O) n, n is 1.
19. as the compound of claim 18, wherein the absolute configuration in C-4 and SO part is respectively R and S.
20. as the compound of each claim of front, wherein Y is by the phenyl ring of 3 other non-imposed replacements of substituting group at the most.
21. as the compound of claim 20, wherein Y is by the phenyl of the non-imposed replacement of halogen.
22 of the formula (I) compound is selected from: N-[6 - (4 - chlorophenyl hexyl)] -2 - [4 - benzyl-thio-2 - oxo-azetidin-1 - yl] propanamide (non- Enantiomer b); N-[6 - (4 - chlorophenyl hexyl)] -2 - [4 - benzyl-thio-2 - oxo-azetidin-1 - yl] propanamide (non- Enantiomer a); N-[6 - (4 - chlorophenyl hexyl)] -2 - [4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl] propionic acid Amine (diastereomers b1 and b2); N-[6 - (4 - chlorophenyl hexyl)] -2 - [4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl] propionic acid Amine (isomer (-) b2); N-[6 - (4 - chlorophenyl hexyl)] -2 - [4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl] propionic acid Amine (isomer (+) b2); N-[6 - (4 - chlorophenyl hexyl)] -2 - [4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl] propionic acid Amine (isomer (+) b1); N-[6 - (4 - chlorophenyl hexyl)] -2 - [4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl] propionic acid Amine (isomer (-) b1); N-[6 - (4 - chlorophenyl hexyl)] -2 - [4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl] propionic acid Amine (diastereomer a1); N-[6 - (4 - chlorophenyl hexyl)] -2 - [4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl] propionic acid Amine (diastereomer a2); N-[6 - (4 - fluorophenyl hexyl)] -2 - [4 - benzyl-thio-2 - oxo-azetidin-1 - yl] propanamide (non- Enantiomer b); N-[6 - (4 - fluorophenyl hexyl)] -2 - [4 - benzyl-thio-2 - oxo-azetidin-1 - yl] propanamide (non- Enantiomer a); N-[6 - (4 - fluorophenyl hexyl)] -2 - [4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl] propionic acid Amine (diastereomer b1 + b2); N-[6 - (4 - fluorophenyl hexyl)] -2 - [4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl] propionic acid Amine (diastereomer (-) b2); N-[6 - (4 - fluorophenyl hexyl)] -2 - [4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl] propionic acid Amine (diastereomer (+) b2); N-[6 - (4 - fluorophenyl hexyl)] -2 - [4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl] propionic acid Amine (diastereomer a1); N-[6 - (4 - fluorophenyl hexyl)] -2 - [4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl] propionic acid Amine (diastereomer a2); N-[6 - (4 - fluorophenyl hexyl)] -2 - [4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl] propionic acid Amine (diastereomer a); N-[6 - (4 - fluorophenyl hexyl)] -2 - [4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl] propionic acid Amine (diastereomer b); N-(benzyl) -2 - [4 - benzyl-thio-2 - oxo-azetidin-1 - yl] propanamide (diastereomer a); N-(benzyl) -2 - [4 - benzyl-thio-2 - oxo-azetidin-1 - yl] propanamide (diastereomer b); N-[6 - (4 - fluorophenyl hexyl)] -2 - [4 - (allyloxycarbonyl benzylthio) -2 - oxo-azetidin- Adamantan-1 - yl] propanamide (diastereomer a); (+ / -)-N-[6 - (4 - fluorophenyl hexyl)] -2 - [4 - (allyloxycarbonyl benzylthio) -2 - oxo-aza- Cyclobutan - yl] propanamide (diastereomer b); (+ / -)-N-[6 - (4 - fluorophenyl hexyl)] -2 - [4 - (4 - allyloxycarbonyl) benzyl-sulfinyl-2 - O Substituting azetidin-1 - yl]-propionamide (diastereomeric b2 + b1); (+ / -)-N-[6 - (4 - fluorophenyl hexyl)] -2 - [4 - (4 - allyloxycarbonyl-sulfinyl benzyl) -2 - O Substituting azetidin-1 - yl] propanamide (diastereomer b2); (+ / -)-N-[6 - (4 - fluorophenyl hexyl)] -2 - [4 - (4 - allyloxycarbonyl-sulfinyl benzyl) -2 - O Substituting azetidin-1 - yl] propanamide (diastereomer b1); (+ / -)-N-[6 - (4 - fluorophenyl hexyl)] -2 - [4 - (4 - allyloxycarbonyl-sulfinyl benzyl) -2 - O Substituting azetidin-1 - yl] propanamide (diastereomer a1); (+ / -)-N-[6 - (4 - fluorophenyl hexyl)] -2 - [4 - (4 - allyloxycarbonyl-sulfinyl benzyl) -2 - O Substituting azetidin-1 - yl] propanamide (diastereomer a2); (+ / -)-N-[6 - (4 - fluorophenyl hexyl)] -2 - [4 - (4 - (carboxy) benzyl-sulfinyl)-2 - oxo-heterocyclic Butane-1 - yl]-propionamide (diastereomeric b2 + b1); (+ / -)-N-[6 - (4 - fluorophenyl hexyl)] -2 - (4 - benzyl-thio)-2 - oxo-azetidin-1 - yl -3 - (3 - Furyl)-propionamide (diastereomers a and b); (+ / -)-N-[6 - (4 - fluorophenyl hexyl)] -2 - (4 - benzyl-sulfinyl)-2 - oxo-azetidin-1 - yl - 3 - (3 - furyl)-propionamide; (+ / -)-N-[6 - (4 - fluorophenyl hexyl)] -2 - (4 - benzyl-sulfinyl)-2 - oxo-azetidin-1 - yl - 3 - (3 - furyl)-propionamide (diastereomer a2); (+ / -)-N-[6 - (4 - fluorophenyl hexyl)] -2 - (4 - benzyl-thio)-2 - oxo-azetidin-1 --3 - phenyl Propionamide (diastereomer a); (+ / -)-N-[6 - (4 - fluorophenyl hexyl)] -2 - (4 - benzyl-thio)-2 - oxo-azetidin-1 --3 - phenyl Propionamide (diastereomer b); N-[6 - (4 - fluorophenyl hexyl)] -2 - (4 - benzyl-sulfinyl)-2 - oxo-azetidin-1 --3 - phenyl Propionamide (diastereomer a2); N-[6 - (4 - fluorophenyl hexyl)] -2 - (4 - benzyl-sulfinyl)-2 - oxo-azetidin-1 --3 - phenyl Propionamide (diastereomer a1); (+ / -)-N-[6 - (4 - fluorophenyl hexyl)] -2 - (4 - benzyl-sulfinyl)-2 - oxo-azetidin-1 - yl - 3 - phenyl-propionamide (diastereomer b1); (+ / -)-N-[6 - (4 - fluorophenyl hexyl)] -2 - (4 - benzyl-sulfinyl)-2 - oxo-azetidin-1 - yl - 3 - phenyl-propionamide (diastereomer b2); (+)-N-[6 - (4 - fluorophenyl hexyl)] -2 - (4 - benzyl-sulfinyl)-2 - oxo-azetidin-1 - yl - 3 - phenyl-propionamide (diastereomeric (+)-b2); (-)-N-[6 - (4 - fluorophenyl hexyl)] -2 - (4 - benzyl-sulfinyl)-2 - oxo-azetidin-1 --3 - Phenyl-propionamide (diastereomer (-)-b2); (+ / -)-N-[6 - (4 - fluorophenyl hexyl)] -2 - (4 - benzyl-thio) -2 - fluoro-oxo-butane-1 heterocycle --2 - ene Propyl acetamide (diastereomer a); (+ / -)-N-[6 - (4 - fluorophenyl hexyl)] -2 - (4 - benzyl-thio)-2 - oxo-azetidin-1 --2 - ene Propyl acetamide (diastereomer b); (+ / -)-N-[6 - (4 - fluorophenyl hexyl)] -2 - (4 - benzyl-sulfinyl)-2 - oxo-azetidin-1 - yl - 2 - allyl acetamide (diastereomer a2 + a1); (+ / -)-N-[6 - (4 - fluorophenyl hexyl)] -2 - (4 - benzyl-sulfinyl)-2 - oxo-azetidin-1 - yl - 2 - allyl acetamide; (+ / -)-N-[6 - (4 - fluorophenyl hexyl)] -2 - [4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl] Butylamide; N-[6 - (4 - fluorophenyl hexyl)] -2 - [4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl] butanoic acid Amines; (+ / -)-N-[6 - (4 - fluorophenyl hexyl)] -2 - [4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl] Butylamide (isomer a1); (+ / -)-N-[6 - (4 - fluorophenyl hexyl)] -2 - [4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl] Butylamide (isomer b1 and b2); (+ / -)-N-[6 - (4 - fluorophenyl hexyl)] -2 - [4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl] Butylamide (isomer a2); (+ / -)-N-[6 - (4 - fluorophenyl hexyl)] -2 - [4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl] Pentanamide; (+ / -)-N-[6 - (4 - chlorophenyl hexyl)] -2 - [4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl] Propanamide; N-(benzyl) -2 - [4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl] propanamide (diastereomer b1 and b2); N-(benzyl) -2 - [4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl] propanamide (diastereomer a1); N-(benzyl) -2 - [4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl] propanamide (diastereomer a2); (Α-S ,4-R, SS)-N-[6 - (4 - fluorophenyl hexyl)] -2 - [4 - carboxy-benzyl-sulfinyl] -2 - oxo-N Heterocyclic butane-1 - yl-propionamide; (Α-S ,4-R, SS)-N-[6 - (4 - fluorophenyl hexyl)] -2 - [4 - allyloxy-benzyl-sulfinyl] -2 - Oxo-azetidin-1 - yl-propionamide; (+ / -) -4 - (Pyridin-2 - yl methylthio) -1 - (4 - phenyl - 2 - oxo-butyl) azetidin-2 - one; (+ / -) -4 - (Pyridin-2 - yl methylsulfinyl) -1 - (4 - phenyl - 2 - oxo-butyl) azetidin-2 - One (diastereomer 1); (+ / -) -4 - (Pyridin-2 - yl methylsulfinyl) -1 - (4 - phenyl - 2 - oxo-butyl) azetidin-2 - One (diastereomer 2); (+ / -)-N-(6 - phenyl-hex-1 - yl) -4 - (pyridin-4 - yl methylthio)-2 - oxo-azetidin-1 - yl acetate Amide; (+ / -)-N-(6 - phenyl-hex-1 - yl) -4 - (pyridin-4 - yl methylsulfinyl) -2 - oxo-azetidine - 1 - yl-acetamide (diastereomer 1); (+ / -)-N-(6 - phenyl-hex-1 - yl) -4 - (pyridin-4 - yl methylsulfinyl) -2 - oxo-azetidine - 1 - yl-acetamide (diastereomer 2); (+ / -)-N-(6 - phenyl-hex-1 - yl) -4 - (1 - oxo-4 - yl methylsulfinyl) -2 - oxo-aza- Ring butane-1 - yl-acetamide; (+ / -)-N-(6 - phenyl-hex-1 - yl) -4 - (2 - furyl-thio) -2 - oxo-azetidin-1 - yl acetate Amide; (+ / -)-N-(6 - phenyl-hex-1 - yl) -4 - (2 - furyl methylsulfinyl) -2 - oxo-azetidine - 1 - yl-acetamide (diastereomer 1); (+ / -)-N-(6 - phenyl-hex-1 - yl) -4 - (2 - furyl methylsulfinyl) -2 - oxo-azetidine - 1 - yl-acetamide (diastereomer 2); (+ / -)-N-(6 - phenyl-hex-1 - yl) -4 - (2 - furyl methylsulfinyl) -2 - oxo-azetidine - 1 - yl-acetamide; (+ / -)-N-(6 - [4 - fluorophenyl] hex-1 - yl) -4 - (2 - furyl-thio) -2 - oxo-azetidin-1 - Acetamide; (+ / -)-N-(6 - [4 - fluorophenyl] hex-1 - yl) -4 - (2 - furyl methylsulfinyl) -2 - oxo-heterocyclic Butane-1 - yl-acetamide (diastereomer 1); (+ / -)-N-(6 - [4 - fluorophenyl] hex-1 - yl) -4 - (2 - furyl methylsulfinyl) -2 - oxo-heterocyclic Butane-1 - yl-acetamide (diastereomer 2); (+ / -)-N-(6 - [4 - fluorophenyl] hex-1 - yl) -4 - (2 - furyl methylsulfinyl) -2 - oxo-heterocyclic Butane-1 - yl-acetamide; (+ / -)-N-(6 - [4 - chlorophenyl] hex-1 - yl) -4 - (2 - furyl-thio) -2 - oxo-azetidin-1 - Acetamide; (+ / -)-N-(6 - [4 - chlorophenyl] hex-1 - yl) -4 - (2 - furyl methylsulfinyl) -2 - oxo-heterocyclic Butane-1 - yl-acetamide (diastereomer 1); (+ / -)-N-(6 - [4 - chlorophenyl] hex-1 - yl) -4 - (2 - furyl methylsulfinyl) -2 - oxo-heterocyclic Butane-1 - yl-acetamide (diastereomer 2); (+ / -)-N-(6 - [4 - chlorophenyl] hex-1 - yl) -4 - (2 - furyl methylsulfinyl) -2 - oxo-heterocyclic Butane-1 - yl-acetamide; (+ / -)-N-(6 - [4 - chlorophenyl] hex-1 - yl) -4 - (3 - furyl-thio) -2 - oxo-azetidin-1 - Acetamide; (+ / -)-N-(6 - [4 - chlorophenyl] hex-1 - yl) -4 - (3 - furyl methylsulfinyl) -2 - oxo-heterocyclic Butane-1 - yl-acetamide (diastereomer 1); (+ / -)-N-(6 - [4 - chlorophenyl] hex-1 - yl) -4 - (3 - furyl methylsulfinyl) -2 - oxo-heterocyclic Butane-1 - yl-acetamide (diastereomer 2); (+ / -)-N-(6 - [4 - chlorophenyl] hex-1 - yl) -4 - (3 - furyl methylsulfinyl) -2 - oxo-heterocyclic Butane-1 - yl-acetamide; (+ / -)-N-[6 - (4 - chlorophenyl) hexyl] -4 - (2 - thienyl methylthio)-2 - oxo-azetidin-1 - yl Acetamide; (+ / -)-N-[6 - (4 - chlorophenyl) hexyl] -4 - (2 - methylsulfinyl-thienyl)-2 - oxo-azetidin- Adamantan-1 - yl-acetamide (diastereomer 1); (+ / -)-N-[6 - (4 - chlorophenyl)-hex-1 - yl] -4 - (2 - methylsulfinyl-thienyl)-2 - oxo-heterocyclic Butane-1 - yl-acetamide (diastereomer 2); (+ / -)-N-[6 - (4 - chlorophenyl) hexyl] -4 - (2 - thienyl methylsulfonyl) -2 - oxo-azetidine - 1 - yl-acetamide; (+ / -)-N-[6 - (4 - chlorophenyl) hexyl] -4 - (3 - methylthio-thienyl) -2 - oxo-azetidin-1 - yl Acetamide; (+ / -)-N-[6 - (4 - chlorophenyl) hexyl] -4 - (3 - thienyl methylsulfinyl)-2 - oxo-azetidin- Adamantan-1 - yl-acetamide (diastereomer 1); (+ / -)-N-[6 - (4 - chlorophenyl) hexyl] -4 - (3 - thienyl methylsulfinyl)-2 - oxo-azetidin- Adamantan-1 - yl-acetamide (diastereomer 2); (+ / -)-N-[6 - (4 - chlorophenyl) hexyl] -4 - (3 - thienyl methylsulfonyl) -2 - oxo-azetidine - 1 - yl-acetamide; (+ / -)-N-[6 - (4 - chlorophenyl) hexyl] -4 - (thiazol-2 - yl methylthio)-2 - oxo-azetidin-1 - yl Acetamide; (+ / -)-N-[6 - (4 - chlorophenyl) hexyl] -4 - (thiazol-2 - yl methylsulfinyl) -2 - oxo-azetidin- Adamantan-1 - yl-acetamide (diastereomer 1); (+ / -)-N-[6 - (4 - chlorophenyl) hexyl] -4 - (thiazol-2 - yl methylsulfinyl) -2 - oxo-azetidin- Adamantan-1 - yl-acetamide (diastereomer 2); (+ / -)-N-[6 - (4 - chlorophenyl hexyl)] -4 - (5 - methoxycarbonyl-2 - furyl-thio) -2 - oxo-N Heterocyclic butane-1 - yl-acetamide; (+ / -)-N-[6 - (4 - chlorophenyl hexyl)] -4 - (5 - methoxycarbonyl-2 - furyl methylsulfinyl) -2 - Oxo-azetidin-1 - yl-acetamide (diastereomer 1); (+ / -)-N-[6 - (4 - chlorophenyl hexyl)] -4 - (5 - methoxycarbonyl-2 - furyl methylsulfinyl) -2 - Oxo-azetidin-1 - yl-acetamide (diastereomer 2); (+ / -) -4 - (2 - furyl-thio) -1 - (9 - nonyl phenyl) azetidin-2 - one; (+ / -) -4 - (2 - furyl methylsulfinyl) -1 - (9 - nonyl phenyl) azetidin-2 - one; (+ / -) -4 - (2 - furyl-thio) -1 - (9 - (4 - fluorophenyl)-nonyl) azetidin-2 - one; (+ / -) -4 - (2 - furyl methylsulfinyl) -1 - (9 - (4 - fluorophenyl)-nonyl) azetidin-2 - one; (+ / -) -4 - (2 - furyl methylsulfonyl) -1 - (9 - (4 - fluorophenyl)-nonyl) azetidin-2 - one; N-[6 - (4 - fluorophenyl)-hex-1 - yl] -4 - (5 - allyloxy-carbonyl-furan-2 - methylthio)-2 - oxo-aza- Ring butane-1 - yl-acetamide; N-[6 - (4 - fluorophenyl)-hex-1 - yl] -4 - (5 - allyloxy-carbonyl-furan-2 - methylsulfinyl) -2 - O Substituting azetidin-1 - yl-acetamide (diastereomer 1); N-[6 - (4 - fluorophenyl)-hex-1 - yl] -4 - (5 - allyloxy-carbonyl-furan-2 - methylsulfinyl) -2 - O Generation azetidin-1 - yl acetamide (diastereomer 2); N-[6 - (4 - fluorophenyl)-hex-1 - yl] -4 - (5 - carboxy-furan-2 - methylsulfinyl) -2 - oxo-heterocyclic Butane-1 - yl-acetamide (diastereomer 2); N-(6 - {4 - Chlorophenyl} hexyl) -4 - (5 - allyloxy-carbonyl-furan-2 - methylthio)-2 - oxo-aza- Ring butane-1 - yl) acetamide; N-(6 - {4 - Chlorophenyl} hexyl) -4 - (5 - allyloxy-carbonyl-furan-2 - methylsulfinyl) -2 - O Substituting azetidin-1 - yl) acetamide (diastereomer 1); N-(6 - {4 - Chlorophenyl} hexyl) -4 - (5 - allyloxy-carbonyl-furan-2 - methylsulfinyl) -2 - O Generation azetidin-1 - yl) acetamide (diastereomer 2); N-(6 - {4 - Chlorophenyl} hexyl) -4 - (5 - carboxy-furan-2 - methylsulfinyl) -2 - oxo-azetidin- Adamantan-1 - yl) acetamide (diastereomer 2); N-[6 - (4 - fluorophenyl)-hex-1 - yl] -4 - (5 - methoxy-carbonyl-furan-2 - methylthio)-2 - oxo-azetidin- Adamantan-1 - yl-acetamide; N-[6 - (4 - fluorophenyl)-hex-1 - yl] -4 - (5 - methoxy-carbonyl-furan-2 - methylsulfinyl) -2 - oxo-N Heterocyclic butane-1 - yl-acetamide (diastereomer 1); N-[6 - (4 - fluorophenyl)-hex-1 - yl] -4 - (5 - methoxy-carbonyl-furan-2 - methylsulfinyl) -2 - oxo-N Heterocyclic butane-1 - yl-acetamide (diastereomer 2); N-[6 - (4 - chlorophenyl)-hex-1 - yl] -4 - (2 - fluorophenoxy 2 - oxo-azetidin-1 - yl) acetamide; N-(6 - (4 - phenyl) hexyl) - (4 - (2 - methyl-phenoxy) -2 - oxo-azetidin-1 - yl) acetamide; N-(6 - (4 - phenyl) hexyl) - (4 - (2 - benzyloxy-phenoxy) -2 - oxo-azetidin-1 - yl) acetamide; N-(6 - (4 - phenyl) hexyl) - (4 - (2 - (methylthio) phenyl) -2 - oxo-azetidin-1 - yl) acetamide; N-(6 - (4 - phenyl) hexyl) - (4 - (4 - chlorophenoxy)-2 - oxo-azetidin-1 - yl) acetamide; N-(6 - (4 - phenyl) hexyl) - (4 - (4 - methoxyphenoxy) -2 - oxo-azetidin-1 - yl) acetamide; N-(6 - (4 - phenyl) hexyl) (- (4 - (methylthio) phenyl) -2 - oxo-azetidin-1 - yl) acetamide; N-(6 - (4 - chlorophenyl) hexyl) - (4 - (4 - allyl-carbonyl phenoxy) -2 - oxo-azetidine - 1 - yl) acetamide; N-(6 - (4 - phenyl) hexyl) - (4 - phenoxy-2 - oxo-azetidin-1 - yl) acetamide; N-(6 - (4 - phenyl) hexyl) - (4 - benzyloxy) -2 - oxo-azetidin-1 - yl) acetamide; N-(6 - (4 - phenyl) hexyl) - (4 - (4 - methylsulfinyl-phenoxy) -2 - oxo-azetidin-1 - yl) Acetamide; N-(6 - (4 - phenyl) hexyl) - (4 - (4 - methylsulfonyl-phenoxy) -2 - oxo-azetidin-1-yl) - Amide; N-(6 - (4 - phenyl) hexyl) - (4 - (2 - methylsulfinyl-phenoxy) -2 - oxo-azetidin-1 - yl) Acetamide; N-(6 - (4 - phenyl) hexyl) - (4 - (2 - methylsulfonyl-phenoxy) -2 - oxo-azetidin-1-yl) - Amide; N-(6 - (4 - phenyl) hexyl) - (4 - (2 - hydroxyphenyl) -2 - oxo-azetidin-1 - yl) acetamide; N-[6 - (4 - chlorophenyl) hexyl] - [4 - (4 - carboxy-methyl-phenoxy) -2 - oxo-azetidin-1 - yl] acetic Amide; N-[6 - (4 - chlorophenyl) hexyl] - (3 - methyl - 4 - phenoxy-2 - oxo-azetidin-1 - yl) acetamide; 4 - benzyloxy-1 - (4 - phenyl - 2 - oxo-butyl) azetidin-2 - one; 4 - phenoxy-1 - (4 - phenyl - 2 - oxo-butyl) azetidin-2 - one; N-[6 - (naphthalen-1 - yl) -5 - hexyn-1 - yl] -4 - benzyl-thio-2 - oxo-azetidin-1 - yl-acetamide; N-[6 - (naphthalen-1 - yl) -5 - hexyn-1 - yl] -4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl acetate Amide (diastereomer 1); N-[6 - (naphthalen-1 - yl) -5 - hexyn-1 - yl] -4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl acetate Amide (diastereomer 2); N-[6 - (3 - chlorophenyl) hexyne -5 - yl] -4 - (benzyl-thio-2 - oxo-azetidin-1 - yl) acetamide; N-[6 - (2 - chlorophenyl) hexyne -5 - yl] -4 - (benzyl-thio-2 - oxo-azetidin-1 - yl) acetamide; N-[6 - phenyl-3 - hexynyl) - (4 - benzyl-thio-2 - oxo-azetidin-1 - yl) acetamide; ZN-[6 - phenyl-3 - hexenyl) - (4 - benzyl-thio-2 - oxo-azetidin-1 - yl) acetamide; EN-[6 - phenyl-3 - hexenyl) - (4 - benzyl-thio-2 - oxo-azetidin-1 - yl) acetamide; N-(5 - phenoxy-pentyl) -4 - benzyl-thio-2 - oxo-azetidin-1 - yl-acetamide; N-(2 - (2 - phenoxy-ethoxy)-ethyl) -4 - benzyl-thio-2 - oxo-azetidin-1 - yl-acetamide; N-(2 - (3 - propoxy-phenoxy) ethyl) -4 - benzyl-thio-2 - oxo-azetidin-1 - yl-acetamide; N-[6 - (3 - chlorophenyl) hexyne -5 - yl] -4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl acetyl Amines; N-[6 - (3 - chlorophenyl) hexyne -5 - yl] -4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl acetyl Amines; N-[6 - (2 - chlorophenyl) hexyne -5 - yl] -4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl acetyl Amines; N-[6 - (2 - chlorophenyl) hexyne -5 - yl] -4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl acetyl Amines; N-(6 - phenyl-3 - hexynyl) - (4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl) acetamide (Diastereomer 1); N-(6 - phenyl-3 - hexynyl) - (4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl) acetamide (Diastereomer 2); ZN-(6 - phenyl-3 - hexenyl) - (4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl) acetyl Amine (diastereomer 1); ZN-(6 - phenyl-3 - hexenyl) - (4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl) acetyl Amine (diastereomer 2); EN-(6 - phenyl-3 - hexenyl) - (4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl) acetyl Amine (diastereomer 1); EN-(6 - phenyl-3 - hexenyl) - (4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl) acetyl Amine (diastereomer 2); N-(5 - phenoxy-pentyl) - (4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl) acetamide; N-(5 - phenoxy-pentyl) - (4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl) acetamide; N-(2 - (2 - phenoxy-ethoxy)-ethyl) - (4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl) Acetamide (diastereomer 1); N-(2 - (2 - phenoxy-ethoxy)-ethyl) - (4 - benzyl-sulfinyl-2 - oxo-azetidin-1 - yl) Acetamide (diastereomer 2); N-2-(3 - phenyl-propoxy)-ethyl) - (4 - benzyl-sulfinyl-2 - oxo-azetidin-1-yl) - Amide (diastereomer 1); N-2-(3 - phenyl-propoxy)-ethyl) - (4 - benzyl-sulfinyl-2 - oxo-azetidin-1-yl) - Amide (diastereomer 2); N-[6 - (2 - chlorophenyl hexynyl -5 - yl] -4 - benzyl-sulfonyl-2 - oxo-azetidin-1 - yl-acetamide; N-[6 - (3 - chlorophenyl hexynyl -5 - yl] -4 - benzyl-sulfonyl-2 - oxo-azetidin-1 - yl-acetamide; N-(6 - phenyl-3 - hexynyl) - (4 - benzyl-sulfonyl-2 - oxo-azetidin-1 - yl) acetamide; EN-(6 - phenyl-3 - hexenyl) - (4 - benzyl-sulfonyl-2 - oxo-azetidin-1 - yl) acetamide; 1 - (2 - (6 - phenyl-hexyloxy) ethyl-4 - benzyl-thio-2 - oxo-azetidine; 1 - (2 - (6 - (4 - chlorophenyl) hexyloxy) ethyl) -4 - benzyl-thio-2 - oxo-azetidine; 1 - (2 - (6 - (4 - fluorophenyl) hexyloxy) ethyl) -4 - benzyl-thio-2 - oxo-azetidine; N-3-(phenoxy)-4 - benzyl-thio-2 - oxo-azetidine; 1 - (2 - benzyloxy-ethyl) -4 - benzyl-thio-2 - oxo-azetidin-2 - one; 1 - (2 - (6 - phenyl-hexyloxy) ethyl-4 - benzyl-sulfinyl-2 - oxo-azetidine (diastereomer 2); 1 - (2 - (6 - (4 - chlorophenyl) hexyloxy) ethyl) -4 - benzyl-sulfinyl-2 - oxo-azetidine (non- Enantiomer 1); 1 - (2 - (6 - (4 - chlorophenyl) hexyloxy) ethyl) -4 - benzyl-sulfinyl-2 - oxo-azetidine (non- Enantiomer 2); 1 - (2 - (6 - (4 - fluorophenyl) hexyloxy) ethyl) -4 - benzyl-sulfinyl-2 - oxo-azetidine (non- Enantiomer 1); 1 - (2 - (6 - (4 - fluorophenyl) hexyloxy) ethyl) -4 - benzyl-sulfinyl-2 - oxo-azetidine (non- Enantiomer 2); 4 - benzyl-sulfinyl-1 - (3 - benzyloxy-propyl) azetidin-2 - one (diastereomer 1); 4 - benzyl-sulfinyl-1 - (3 - benzyloxy-propyl) azetidin-2 - one (diastereomer 2); 1 - (2 - benzyloxy-ethyl) -4 - benzyl chloride heterocyclic sulfinyl group butan-2 - one (diastereomer 1); 1 - (2 - benzyloxy-ethyl) -4 - benzyl-sulfinyl azetidin-2 - one (diastereomer 2); 4 - (methylthio) -1 - (3 - phenoxy-propyl)-heterocycle butan-2 - one; 4 - methylsulfinyl -1 - (3 - phenoxy-propyl)-heterocycle butan-2 - one; 1 - (2 - (6 - (4 - fluorophenyl) hexyloxy) ethyl) -4 - (4 - ethoxycarbonyl-benzylthio) -2 - oxo-heterocyclic Butane; 1 - (2 - (6 - (4 - fluorophenyl) hexyloxy) ethyl) -4 - (4 - ethoxycarbonyl-benzyl-sulfinyl)-2 - oxo-N Oxetane (diastereomer 1); and 1 - (2 - (6 - (4 - fluorophenyl) hexyloxy) ethyl) -4 - (4 - ethoxycarbonyl-benzyl-sulfinyl)-2 - oxo-N Oxetane (diastereomer 2). ...
23. pharmaceutical composition that comprises formula (I) compound and pharmaceutical carrier.
24. formula (I) compound is used for the treatment of.
25. formula as claimed in claim 1 (I) compound is used for the treatment of purposes in the atherosclerotic medicine in production.
26. formula as claimed in claim 1 (I) compound is used for the treatment of diabetes in production, hypertension, after stenocardia and the local asphyxia, perfusion again, rheumatic arthritis, apoplexy, myocardial infarction, reperfusion injury, sepsis and acute and chronic inflammation, encephalitis disease such as Alzheimer ' s disease, the purposes in neuropsychopathy such as schizophrenia and the psoriasic medicine.
27. treatment and enzyme Lp-PLA 2The method of the illness that activity is relevant, this method comprise the patient who needs this class treatment with the ihibitors for treatment of treatment significant quantity.
28. as the method for claim 27, wherein illness and monocyte, involving of scavenger cell or lymphocytic increase is relevant.
29. as the method for claim 27, wherein illness is relevant with the formation of the free fatty acids of lyso-phosphatidylcholine and oxidation.
30. as the method for claim 27, wherein illness with and Lp-PLA 2The liposome peroxidation that activity is pulled together is relevant.
31. as the method for claim 27, wherein illness is relevant with endothelial dysfunction.
32. compound as claimed in claim 1 be selected from anti--hyperlipidemia agent, antiatherosclerotic, antidiabetic, the antianginal agent, the therapeutic activity medicament of anti-inflammatory agent or hypotensive agent is in conjunction with being used for the treatment of.
33. a method for preparing formula as claimed in claim 1 (I) compound, this method comprises: the alkylating agent of (A) using formula (III):
L 1CR 4R 5XY (III) wherein Z is suitable leaving group such as halogen; And R 4And R 5One of be hydrogen; And X and Y such as preceding definition; In the presence of suitable alkali such as sodium hydride or potassium hydroxide, in suitable alkylation solvent such as tetrahydrofuran (THF) (THF), handle the azetidinone of formula (II)-10 ℃ to 0 ℃ temperature ranges: N wherein, R 1, R 2And R 3As preceding definition; (B) alkylating agent of usefulness formula (IX):
R 3Z (IX) is R wherein 3With Z such as preceding definition; Under suitable alkylation conditions, the compound of processing formula (VIII) about 25 ℃;
Figure A9619666100152
R wherein 1, R 2, R 3, R 4And R 5As preceding definition; (C) refer to group CONR as X 6(CH 2) m, CONR 6X 2, CONR 6O (CH 2) m, or CONR 6OX 2The time, in the presence of activator such as chloro ethyl formate or dicyclohexylcarbodiimide (DCC), in suitable solvent such as chloroform or dimethyl formamide,, use the amine of formula V-10 to 20 ℃ temperature range:
NHR 6X 5The azanol of Y (V) or formula (VI):
NH 2OX 5Y (VI) is X wherein 5Be (CH 2) m or X 2, m, R 6, Y and X 2As preceding definition, the acid of processing formula (IV): Z wherein, R 1, R 2, R 3, R 4And R 5As preceding definition; (D) refer to group COO (CH as X 2) m or COOX 2The time, the methyl ester of usefulness formula (VII):
Figure A9619666100161
Wherein: Z, R 1, R 2, R 3, R 4And R 5As preceding definition; Use for this class and react this professional known condition, for example the transesterification that in the presence of the sodium methylate of catalytic amount and alcohol, in toluene, heats and preparing; (E) X refers to group COO (CH 2) m or COOX 2The time, use pure YX 5OH or its activatory derivative, for example tosylate is handled formula (IV) compound and is prepared; (F) when the basic X of connection contains ether functional group, use formula (IX) compound:
L 3(CH 2) qY (IX) processing formula (VIII) compound under the ether formation condition of standard: Z wherein, R 1, R 2, R 3, R 4, R 5And X 2As preceding definition; L wherein 2And L 3One of be halogen or other suitable leaving group such as trifluoromethanesulfonic acid base or toluenesulphonic acids base, and another is OH or its suitable salt, and p and q such as preceding definition.
34. basically as this paper embodiment 1 to 350 any described formula (I) compound.
CN96196661A 1995-07-01 1996-06-20 Azetidinone derivatives for treatment of atherosclerosis Pending CN1197452A (en)

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