CN1355794A - Cyclo-imino depsipeptides and their utilization in controlling endoparasites - Google Patents

Cyclo-imino depsipeptides and their utilization in controlling endoparasites Download PDF

Info

Publication number
CN1355794A
CN1355794A CN00808822A CN00808822A CN1355794A CN 1355794 A CN1355794 A CN 1355794A CN 00808822 A CN00808822 A CN 00808822A CN 00808822 A CN00808822 A CN 00808822A CN 1355794 A CN1355794 A CN 1355794A
Authority
CN
China
Prior art keywords
alkyl
group
carbonyl
represent
optional
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN00808822A
Other languages
Chinese (zh)
Inventor
P·杰施克
A·哈德
G·冯萨姆森－希梅尔斯特杰纳
G·邦泽
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer AG
Original Assignee
Bayer AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer AG filed Critical Bayer AG
Publication of CN1355794A publication Critical patent/CN1355794A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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

The invention relates to cyclo-imino depsipeptides of formula (I), especially 24-membered cyclo-imino depsipeptides. The invention also relates to methods for their preparation and to their utilization in controlling endoparasites.

Description

Cyclo-imino depsipeptides and the application in the control volume entozoa thereof
The present invention relates to cyclo-imino depsipeptides (depsipeptide), particularly 24-unit cyclo-imino depsipeptides, its preparation method and the application in the control volume entozoa thereof.
In order particularly to alleviate the backbone modifications of its peptide that merits attention that unstable of enzymic hydrolysis is carried out, except comprising amide oxygen is changed into the sulphur, undoubtedly also comprise changing the oxygen on the acid amides into the optional imino-that replaces.
The native peptides that has imino-peptide bond or amidino groups in molecule is considerably less.The example that can mention have bottromycin-a kind of be derived from streptomyces bottropensis (Streptomyces bottropensis) peptide antibiotics, myxoviromycin and T-1384 (people such as J.M.Waiswisz, J.Am.Chem.Soc.79,1957, p.4520; S.Nakamura Chem.Pharm.Bull.9,1961, p.641; People such as S.Nakamura, J.Antibiot.17A, 1964, p.220).
The method that the optional imino-functional group that replaces is incorporated in the synthetic peptide is known in the document.The example that can mention have synthetic chenotactic peptide amidoxim, cyanogen amidine and amidrazone analogue (people such as G.Sauve, Can.J.Chem.61,1985, p.3089).N-formyl radical-methionyl-leucyl-phenylalanine (f-Met-Leu-Phe-OR) type chemotactic Toplink is advantageously used for that the biological regulator prototype of immunocyte-they are for example induced from human neutrophils and discharge N,O-Diacetylmuramidase (people such as S.V.Rao, Spectroscopy (Ottawa) 4 (3), 1985, p.153; People such as B.Belleau, Int.J.Immunopharmacol.11 (5), 1989, p.467; People such as E.Schiffmann, Proc.Natl.Acad.Sci.U.S.A.72,1975, p.1059; People such as R.J.Freer, Biochemistry 21,1982, p.257).People such as H.A.Moynihan have described N ω-hydroxy-n ω(J.Chem.Soc.PerkinTrans.I 1994, p.769) for preparation method's modification of the NO synthetase inhibitors that-methyl-L-arginine-a kind of is new.According to people such as people such as G.Sauve or H.A.Moynihan, the suitable raw material that is used to prepare above-mentioned imino-peptide be preferably corresponding in the sulfo-peptide.
It is also known that by the synthetic imino-peptide of corresponding alpha-aminonitriles (referring to N-benzyloxycarbonyl-imino-dipeptides: people Chem.Ber.95 such as W.Ried, 1962, p.728; Ann.Chem.661,1963, p.76; People such as T.Yamada, Bull.Chem.Soc.Jpn.50 (5), 1977, p.1088; N-phthaloyl (imino-glycyl)-(S)-Xie Ansuan analogue: people such as E.Vargha, Studia Univ.Babes-Bolyai, Ser.Chem.11,1966, p.85, ref.Chem.Abstr.66,1967,2757).
(referring to people such as A.Eschenmoser, Helv.Chim.Acta 69,1986, p.1224) as the comparison product of alpha-aminonitriles oligomerization by imines nitrogen alternate poly-(dipeptides amidine) for the ketonic oxygen that has prepared each second peptide amide group wherein.
The method of the imino-peptide that replaces with the various N-of the preparation of having mentioned is opposite, not disclose any about preparing the document by amino acid, oxyimino carboxylic acid and optional hydroxycarboxylic acid, cyclo-imino depsipeptides that the hydroxyl thiocarboxylic acid constitutes.
Particularly, do not disclose up to now any about with corresponding epithio for depsipeptides preparation document by the cyclo-imino depsipeptides that constitutes as the unitary amino acid of ring structure, oxyimino carboxylic acid and optional hydroxycarboxylic acid, hydroxyl thiocarboxylic acid and 24 annular atomses.
Cyclic depsipeptide and preparation thereof and be the theme of a lot of publications as the application of Endoparasiticidal agent.
For example, the name is called the cyclic depsipeptide of PF 1022A and the effect of antibody endoparasite is known (EP-OS 382 173 and EP-OS 503 538).
(cyclooctadepsipeptides: WO 98,/55 469 for other cyclic depsipeptide; WO 98,/43 965; WO98/15 523; WO 98,/37 088; WO 97,/02 256; WO 97,/09 331; WO 96/11945; WO 95,/07 272; WO 94,/19 334; WO 93,/19 053; EP-OS 634 408; EP-OS 626 375; EP-OS 626 376; EP-OS 664 297; EP-OS 634 408; EP-OS 718 298; WO 97,/09 331; Encircle six depsipeptides: WO 93,/25 543; WO 95/27498; EP-OS 658 551; Encircle four depsipeptides: EP-OS 664 297; Dioxo morpholine: WO96/38 165; JP 08 225 552) and the open chain depsipeptides (EP-OS 657 171; EP-OS 657172; EP-OS 657 173; WO 97,/07 093) and the Endoparasiticidal effect disclosed.
Is the theme of the application's patent application early (WO 98,/43 965) by the epithio that constitutes as the unitary amino acid of ring structure, hydroxyl thiocarboxylic acid and optional hydroxycarboxylic acid and 24 annular atomses for depsipeptides, its preparation and the application in the control volume entozoa thereof.
Except new cyclo-imino depsipeptides, the invention provides preparation cyclo-imino depsipeptides, particularly by the method for the cyclo-imino depsipeptides that constitutes as the unitary amino acid of ring structure, oxyimino carboxylic acid and optional hydroxycarboxylic acid, hydroxyl thiocarboxylic acid and 24 annular atomses.
The present invention also provides the cyclo-imino depsipeptides, particularly is used for the application of the entozoal composition of control volume in preparation by the cyclo-imino depsipeptides that constitutes as the unitary amino acid of ring structure, oxyimino carboxylic acid and optional hydroxycarboxylic acid, hydroxyl thiocarboxylic acid and 24 annular atomses.
The present invention be more particularly directed to: 1. be used at medical treatment and the entozoal formula of animal doctor's control volume (I) cyclo-imino depsipeptides and its pure optically active isomer, racemic modification and physiological acceptable salt R wherein 1, R 4, R 7And R 10Represent hydrogen, straight or branched alkyl independently of one another, R 2, R 5, R 8And R 11Represent hydrogen, optional straight or branched alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl and aryl or the heteroaryl that replaces independently of one another, R 10And R 11Represent optional 5-unit that replaces or 6-unit ring with the atom that they connected, described ring can be chosen wantonly by oxygen, sulphur, sulfoxide group (Sulfoxy) or alkylsulfonyl and be interrupted R 6And R 12Represent hydrogen, the optional alkyl or aryl alkyl that replaces and the optional cycloalkylalkyl that replaces independently of one another, R 3And R 9Represent hydrogen, optional straight or branched alkyl, alkenyl, cycloalkyl, alkoxy carbonyl alkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, aryl or the heteroaryl that replaces independently of one another, and C=X 1, C=X 2, C=X 3And C=X 4Respectively represent group C=O, a C=S or CH independently of one another 2Or group C=N-A, wherein C=X 1, C=X 2, C=X 3And C=X 4In the middle of have at least one to represent C=N-A, wherein A represent hydrogen, optional alkyl, alkenyl, alkynyl group, alkyl-carbonyl, alkyl sulphonyl and the cyano group that replaces, nitro, formamyl, alkoxy carbonyl, formyl radical ,-(C=NH)-NH 2,-P (O)-O-alkyl ,-P (S)-O-alkyl or the optional group A that represents 1
-Y-R 13(A 1) wherein Y represent oxygen, sulphur or-N-R 14, R 13And R 14Represent hydrogen, optional straight or branched alkyl, alkenyl, alkynyl group, cycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, aryl or the heteroaryl that replaces independently of one another and represent formyl radical, alkoxyl group dicarbapentaborane, alkyl sulphonyl, halogenated alkoxy alkyl alkylsulfonyl, alkoxy carbonyl, alkyl amino-carbonyl, alkenyloxy carbonyl, chain oxy-acetylene carbonyl, aryloxy alkyl, heteroaryl carbonyl, alkyl-carbonyl or optional representative to be selected from B 1, B 2, B 3And B 4Group,
Figure A0080882200201
Wherein the straight or branched alkyl that replaces is chosen in the Q representative wantonly, alkenyl, alkynyl group, cycloalkyl, alkoxyl group, alkenyloxy, chain oxy-acetylene, cycloalkyloxy, aryloxy, alkoxy aryl, heteroaryloxy, the heteroaryl alkoxyl group, alkylthio, alkenyl thio, sulfur-based chain acetylene, cycloalkylthio, arylthio, alkylthio-aryl, heteroarylthio, the heteroaryl alkylthio, alkylamino, alkenyl amino, chain alkynyl amino, cycloalkyl amino, arylamino, aryl-alkyl amino, heteroaryl amino, heteroarylalkyl amino, dialkyl amido, two alkenyl aminos, aryl, arylalkyl, heteroaryl or heteroarylalkyl, cyano group, the cyclic amino of optional replacement amino or that connect via nitrogen
Figure A0080882200202
Representation carboxy, thiocarboxyl group, sulfoxide group, alkylsulfonyl ,-P (O)-O-alkyl ,-P (S)-O-alkyl or-C=N-R 15, R 15Represent hydrogen, hydroxyl, alkoxyl group, alkyl-carbonyl, alkoxy carbonyl, halogenated alkyl carbonyl, alkyl sulphonyl, nitro or cyano group, R 16Represent hydrogen or alkyl, n represents 0,1 or 2, Y 1Represent oxygen, sulphur or-N-R 17If, Y 1Represent nitrogen, then R 18Can represent the cyclic amino that connects via nitrogen-atoms, R 17And R 18Represent hydrogen, optional straight or branched alkyl, alkenyl, alkynyl group, cycloalkyl, cycloalkylalkyl, alkoxy carbonyl, aryl, arylalkyl, heteroaryl or the heteroarylalkyl that replaces, perhaps R independently of one another 17And R 18Represent the optional heterocycle 4-unit that replaces, 5-unit, 6-unit or 7-unit's ring system or the optional 7-unit that replaces of representative-bicyclic ring system of 10-unit with adjacent nitrogen-atoms, described ring system also can choose wantonly by oxygen, sulphur, sulfoxide group, alkylsulfonyl, carbonyl ,-N-O ,-N=,-NR 22Or quaternary nitrogen is interrupted R 19And R 20Represent hydrogen, straight or branched alkyl, alkenyl, cycloalkyl and optional aryl, arylalkyl, heteroaryl, the heteroarylalkyl that replaces, perhaps R independently of one another 19And R 20The volution that replaces, R are chosen in representative wantonly together 20And R 21Represent the optional 5-unit that replaces, 6-unit or 7-unit ring with the atom that they connected, described ring can be chosen wantonly by oxygen, sulphur, sulfoxide group or alkylsulfonyl and be interrupted R 21Represent hydrogen, optional straight or branched alkyl, cycloalkyl, arylalkyl, heteroarylalkyl and aryl or the heteroaryl that replaces, R 22Represent hydrogen, optional straight or branched alkyl, alkenyl, alkynyl group, cycloalkyl, cycloalkylalkyl, alkoxy carbonyl, alkyl-carbonyl, naphthene base carbonyl, cyano group, arylalkyl, heteroarylalkyl and aryl or the heteroaryl that replaces, R 13Can also represent the protecting group that optionally is removed or close group (Ankergruppe) and be connected polymeric carrier on the Y via the anchor that optionally is removed.
According to substituent character, general formula (I) compound can be used as geometry and/or mixture of optical isomers and has the different regional isomer intermixtures of forming and exists.The present invention relates to pure isomer and isomer mixture.
Be preferred by the cyclo-imino depsipeptides and optically active isomer, racemic modification and the physiological acceptable salt that constitute as the unitary amino acid of ring structure, oxyimino carboxylic acid and optional hydroxycarboxylic acid, hydroxyl thiocarboxylic acid and 24 annular atomses shown in the general formula (I) R wherein 1, R 4, R 7And R 10Represent straight or branched C 1-4-alkyl, particularly methyl, R 2, R 5, R 8And R 11Represent C independently of one another 1-4-alkyl, particularly isobutyl-, R 6And R 12The C that replaces is chosen in representative wantonly independently of one another 1-4-alkyl or aryl-C 1-2-alkyl, the particularly optional benzyl that replaces, R 3And R 9Represent C independently of one another 1-4-alkyl, heteroaryl-C 1-2-alkyl, C 1-C 4-alkoxy carbonyl methyl, aryl-C 1-2-alkyl, the particularly optional benzyl that replaces, wherein, the substituting group that can mention is hydrogen, halogen, cyano group, formamyl, C 1-4-alkyl, the hydroxyl that carries protecting group or unprotected hydroxyl, C 1-8-alkoxyl group, C 1-4-alkoxy-C 1-4-alkoxyl group, C 2-4-alkenyloxy, wherein heterocyclic moiety can substituted again heteroaryl-C 1-4-alkoxyl group, nitro, or be selected from R 23R 24N-C 1-C 6-alkoxyl group, R 23R 24N-C 1-C 8-alkyl, NR 23R 24With-SO 2-NR 23R 24Group, R wherein 23And R 24Respectively represent hydrogen, C independently of one another 1-C 6-alkyl, C 1-C 6-alkoxy-C 1-C 6-alkyl, C 3-C 7-cycloalkyl, C 3-C 7-cycloalkyl amino-C 1-C 6-alkyl, the one or more carbon atoms on the wherein said cycloalkyl ring can be substituted heteroaryl-C by nitrogen, oxygen or sulphur atom 1-C 4-alkyl or protecting group, perhaps R 23And R 24Represent heteroaryl or Heterocyclylalkyl with the nitrogen-atoms that they connected, particularly N-pyrrolidyl, N-piperazinyl, N-morpholinyl, N-thio-morpholinyl, N-piperidyl, TMSIM N imidazole base, 2-oxo-pyrrolidine base, phthalimido or tetrahydrochysene phthalimido, and (i) C=X 1Represent group C=N-A, C=X 2, C=X 3And C=X 4Represent C=O, C=S or CH 2, or (iii) C=X 3Represent group C=N-A, C=X 1, C=X 2And C=X 4Represent C=O, C=S or CH 2, or (iv) C=X 1And C=X 3Represent group C=N-A, C=X 2And C=X 4Represent C=O, C=S or CH 2, wherein A represents hydrogen, the optional C that replaces 1-4-alkyl, C 2-4-alkenyl, C 2-4-alkynyl group, C 1-C 4-alkyl-carbonyl, C 1-6-alkyl sulphonyl and cyano group, nitro, formamyl, C 2-6-alkoxy carbonyl, formyl radical ,-(C=NH)-NH 2,-P (O)-O-C 1-3-alkyl ,-P (S)-O-C 1-3-alkyl or the optional A that represents 1
-Y-R 13(A 1), wherein Y represent oxygen or-N-R 14, R 13And R 14Represent hydrogen, the optional straight or branched C that replaces independently of one another 1-8-alkyl, C 2-8-alkenyl, C 2-8-alkynyl group, C 3-7-cycloalkyl, C 3-7-cycloalkyl-C 1-2-alkyl, aryl-C 1-2-alkyl, heteroaryl-C 1-2-alkyl, aryl or heteroaryl and formyl radical, C 1-C 8-alkyl sulphonyl, C 1-C 2-halogenated alkoxy-C 1-2-alkyl sulphonyl, C 1-C 8-alkyl-carbonyl, C 1-C 8-alkoxy carbonyl, C 1-C 8-alkyl amino-carbonyl, C 2-C 8-alkenyloxy carbonyl, C 2-C 8-chain oxy-acetylene carbonyl, aryloxy-C 1-C 2-alkyl, heteroaryl carbonyl, C 1-4-alkoxyl group dicarbapentaborane or optional representative are selected from B 1, B 2, B 3And B 4Group
Figure A0080882200231
Wherein the straight or branched C that replaces is chosen in the Q representative wantonly 1-8-alkyl, C 2-8-alkenyl, C 2-8-alkynyl group, C 3-7-cycloalkyl, C 1-6-alkoxyl group, C 2-6-alkenyloxy, C 2-6-chain oxy-acetylene, C 3-7-cycloalkyloxy, aryloxy, aryl-C 1-2-alkoxyl group, heteroaryloxy, heteroaryl-C 1-2-alkoxyl group, C 1-6-alkylthio, C 2-6-alkenyl thio, C 2-6-sulfur-based chain acetylene, C 3-7-cycloalkylthio, arylthio, aryl-C 1-2-alkylthio, heteroarylthio, heteroaryl-C 1-2-alkylthio, C 1-6-alkylamino, C 2-6-alkenyl amino, C 2-6-chain alkynyl amino, C 3-6-cycloalkyl amino, arylamino, aryl-C 1-2-alkylamino, heteroaryl amino, heteroaryl-C 1-2-alkylamino, two-C 1-4-alkylamino, two-C 2-4-alkenyl amino, aryl, aryl-C 1-2-alkyl, heteroaryl, heteroaryl-C 1-C 2The cyclic amino of-alkyl and cyano group, amino or the optional replacement that connects via nitrogen, Represent thiocarboxyl group or carboxyl, R 15Represent hydrogen, hydroxyl, C 1-4-alkoxyl group, C 1-4-alkyl-carbonyl, C 1-4-alkoxy carbonyl, halo-C 1-4-alkyl-carbonyl, C 1-4-alkyl sulphonyl, nitro or cyano group, R 16Represent hydrogen or C 1-4-alkyl, n represent 0,1 or 2, Y 1Represent oxygen, sulphur or-N-R 17If, Y 1Represent nitrogen, then R 18The cyclic amino that representative connects via nitrogen-atoms, R 17And R 18Represent hydrogen, the optional straight or branched C that replaces independently of one another 1-6Alkyl, C 2-6-alkenyl, C 2-6-alkynyl group, C 3-7-cycloalkyl, C 3-7-cycloalkyl-C 1-6-alkyl, C 1-6-alkoxy carbonyl, aryl, aryl-C 1-2-alkyl, heteroaryl, heteroaryl-C 1-2-alkyl, perhaps R 17And R 18Represent the optional heterocycle 4-unit that replaces, 5-unit, 6-unit or 7-unit's ring system or the optional 7-unit-bicyclic ring system of 10-unit of representative with adjacent nitrogen-atoms, described ring system also can choose wantonly by oxygen, sulphur, sulfoxide group, alkylsulfonyl, carbonyl ,-N-O ,-N=,-NR 22Or quaternary nitrogen is interrupted R 19And R 20Represent hydrogen, the optional straight or branched C that replaces independently of one another 1-6-alkyl, C 2-6-alkenyl, C 3-7-cycloalkyl and optional aryl, the aryl-C that replaces 1-2-alkyl, heteroaryl, heteroaryl-C 1-2-alkyl, perhaps R 19And R 20The volution that replaces, R are chosen in representative wantonly together 20And R 21Represent the optional 5-unit that replaces, 6-unit or 7-unit ring with the atom that they connected, described ring can be chosen wantonly by oxygen, sulphur, sulfoxide group or alkylsulfonyl and be interrupted R 21Represent hydrogen, the optional straight or branched C that replaces 1-6-alkyl, C 3-7-cycloalkyl, aryl-C 1-2-alkyl, heteroaryl-C 1-2-alkyl and aryl or heteroaryl, R 22Represent hydrogen, the optional straight or branched C that replaces 1-6-alkyl, C 2-6-alkenyl, C 2-6-alkynyl group, C 3-7-cycloalkyl, C 3-7-cycloalkyl-C 1-6-alkyl, C 1-6-alkoxy carbonyl, C 1-6-alkyl-carbonyl, C 3-7-naphthene base carbonyl, cyano group, aryl-C 1-2-alkyl, heteroaryl-C 1-2-alkyl and aryl or heteroaryl, R 13Also represent the protecting group that optionally is removed; for example allyl group, allyloxy carbonyl (Alloc), benzyl (Bn), benzyloxycarbonyl (Z), tert-butoxycarbonyl (Boc), tetrahydropyrans-2-base (THP) or fluorenyl methoxy carbonyl (Fmoc), and representative is closed group via the anchor that optionally is removed and is connected polymeric carrier on the Y.
General formula (I) provides the General Definition of cyclo-imino depsipeptides of the present invention and salt thereof.
Cyclo-imino depsipeptides of the present invention and acid salt thereof and metal salt complex have good Endoparasiticidal, particularly anthelmintic effect, and can be preferred for veterinary applications.2. the method 1 for preparing new cyclo-imino depsipeptides of general formula (I) and salt thereof R wherein 1-R 12And group C=X 1-C=X 4Has given implication in the 1st title above, it is characterized in that, at suitable metal-salt or metal oxide, particularly mercuric acetate (II), mercury chloride (II) or red precipitate (II) exist down, in the presence of the alkali reaction auxiliary, and in the presence of suitable diluent, with general formula (I) epithio for depsipeptides and salt thereof
Figure A0080882200261
R 1-R 12Have the implication that in the 1st title above, provides, and C=X 1, C=X 2, C=X 3And C=X 4Represent C=O, C=S or CH independently of one another 2, group C=X wherein 1, C=X 2, C=X 3And C=X 4In the middle of have at least one must represent C=S, react with general formula (II) aminocompound
H 2N-A (II) wherein A has the implication that provides in the 1st title above.
The inventive method especially preferably relates to new cyclo-imino depsipeptides and the salt thereof of preparation general formula (Ia) Wherein A and R 1-R 12Has the implication that in the 1st title above, provides.
Be used to prepare new and the inventive method 2 preferred general formula (Ia) cyclo-imino depsipeptides and salt thereof is characterised in that a) at suitable metal-salt or metal oxide, particularly mercuric acetate (II), mercury chloride (II) and red precipitate (II) exist down, in the presence of the alkali reaction auxiliary, and in the presence of suitable diluent, with general formula (Ib) epithio for depsipeptides or its salt
Figure A0080882200271
R wherein 1-R 12Have the implication that in the 1st title above, provides, react with general formula (II) aminocompound
H 2N-A (II) wherein A has the implication that provides in the 1st title above, or b) in order to prepare general formula (Ia) new cyclo-imino depsipeptides and salt thereof
Figure A0080882200272
R wherein 1-R 12Have the implication that provides in the 1st title above, A represents group-Y-R 13(A 1), wherein Y has the implication that provides, R in the 1st title above 13Representative is selected from B 1-B 3Group,
Figure A0080882200281
Wherein
Figure A0080882200282
Q, Y 1, n, R 16, and R 18-R 20Have the implication that in the 1st title above, provides, will be by the inventive method 2a) and the new cyclo-imino depsipeptides and the salt thereof of 3 general formulas (Ic) that obtain
Figure A0080882200283
Wherein Y and R 1-R 12Have the implication that in the 1st title above, provides, react with general formula (IIIa-c) compound Wherein
Figure A0080882200292
Q, Y 1, n, R 16, and R 18-R 20Has the implication that in the 1st title above, provides, W represents for example halogen of suitable leavings group, if suitably this is reflected at the catalyzer existence down, if suitably in the presence of the alkali reaction auxiliary, if with suitably in the presence of thinner, carry out perhaps c) for prepare new cyclo-imino depsipeptides of general formula (Ia) and salt thereof wherein A represent group-Y-R 13(A 1) wherein Y have the implication that in the 1st title above, provides, R 13Representative is selected from B 1And B 3Group
Figure A0080882200293
Wherein Q, Y 1, n, R 18-R 20Have the implication that provides in the 1st title above, n represents 0, and group Representation carboxy is with general formula (Ic) compound and salt thereof
Figure A0080882200301
Wherein Y and R 1-R 12Have the implication that in the 1st title above, provides, react with general formula (IV) carboxylic acid anhydride
(Q-CO) 2O (IV) wherein Q has the implication that provides in the 1st title above, or represents group
Figure A0080882200302
Y wherein 1, R 18-R 20Has the implication that in the 1st title above, provides, if suitably this is reflected at the catalyzer existence down, if suitably in the presence of the alkali reaction auxiliary, if with suitably in the presence of thinner, carry out perhaps e) with general formula (Ic) compound α) and with logical formula V amino acid derivative reaction
Figure A0080882200303
Wherein
Figure A0080882200311
Q and R 19-R 21Has the implication that in the 1st title above, provides, if suitably this is reflected at the coupling agent existence down, if if suitably in the presence of thinner, carrying out in the presence of the alkali reaction auxiliary and suitably, perhaps β) with general formula (VI) and (VII) compound react R 15-N=C=Y (VI) Wherein
Figure A0080882200313
Y and R 15Has the implication that in the 1st title above, provides, if suitably this is reflected at the alkali reaction auxiliary or catalyzer exists down, if suitably in the presence of thinner, carry out.
The invention still further relates to 3. methods 3 that are used to prepare general formula (Ic) cyclo-imino depsipeptides and salt thereof
Figure A0080882200314
Wherein Y and R 1-R 12Have the implication that in the 1st title above, provides, it is characterized in that general formula (Ia) the cyclo-imino depsipeptides and the salt thereof that a) obtain by foundation method 2a
Figure A0080882200321
R wherein 1-R 12Have the implication that provides in the 1st title above, A represents group-Y-R 13(A 1), wherein Y represent oxygen or-N-H, R 13The protecting group that representative optionally is removed is allyl group, allyloxy carbonyl (Alloc), benzyl (Bn), benzyloxycarbonyl (Z), tert-butoxycarbonyl (Boc), tetrahydropyrans-2-base (THP) or fluorenyl methoxy carbonyl (Fmoc) for example; according to the protecting group that can be removed; or in the presence of the hydrogenation catalyst, in the presence of protonic acid or alkali reaction auxiliary and in the presence of thinner, with radicals R 13Optionally remove, perhaps b) by being connected general formula (Ia) cyclo-imino depsipeptides and salt thereof on the polymeric carrier by what method 2a obtained
Figure A0080882200331
R wherein 1-R 12Have the implication that provides in the 1st title above, A represents group-Y-R 13(A 1) wherein Y represent oxygen or-N-H, R 13The anchor that optionally be removed of representative on polymeric carrier closes group,
In the presence of the appropriate catalyst or, by anchor being closed group from polymeric carrier R in the presence of the protonic acid and in the presence of thinner 13On optionally remove and discharge general formula (Ic) compound.
General formula (I) provides the General Definition of cyclo-imino depsipeptides of the present invention and salt thereof.
Cyclo-imino depsipeptides of the present invention and acid salt thereof and metal salt complex have good Endoparasiticidal, particularly anthelmintic effect, and can be preferred for veterinary applications.
The definition of following term is applicable to above or general formula of hereinafter mentioning and description.
Preferably have 1-6, the straight or branched alkyl of 1-4 carbon atom particularly separately or as the alkyl represent of the optional replacement of the part of group in the general formula.The example that can mention is the optional methyl that replaces, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, the 1-methyl butyl, the 2-methyl butyl, the 3-methyl butyl, 1, the 2-dimethyl propyl, 1, the 1-dimethyl propyl, 2, the 2-dimethyl propyl, the 1-ethyl propyl, hexyl, the 1-methyl amyl, the 2-methyl amyl, the 3-methyl amyl, the 4-methyl amyl, 1, the 2-dimethylbutyl, 1, the 3-dimethylbutyl, 2, the 3-dimethylbutyl, 1, the 1-dimethylbutyl, 2, the 2-dimethylbutyl, 3, the 3-dimethylbutyl, 1,1,2-trimethylammonium propyl group, 1,2,2-trimethylammonium propyl group, 1,2,2-trimethylammonium propyl group, 1-ethyl-butyl and ethyl-butyl.
Methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl and the tertiary butyl are preferred.
Preferably have 1-6, the straight or branched alkenyl of 1-4 carbon atom particularly separately or as the alkenyl representative of the optional replacement of the part of group in the general formula.The example that can mention has the optional vinyl that replaces, the 2-propenyl, crotyl, the 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, pentenyl, the 3-pentenyl, the 4-pentenyl, 1-methyl-2-butene base, 2-methyl-2-butene base, 3-methyl-2-butene base, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl, the 2-hexenyl, the 3-hexenyl, the 4-hexenyl, the 5-hexenyl, 1-methyl-pentenyl, 2-methyl-pentenyl, 3-methyl-pentenyl, 4-methyl-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-crotyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-crotyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-crotyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-crotyl, 2,3-dimethyl-3-butenyl, 1-ethyl-crotyl, 1-ethyl-3-butenyl, 2-ethyl-crotyl, 2-ethyl-3-butenyl, 1,1,2-trimethylammonium-2-propenyl, 1-ethyl-1-methyl-2-propenyl and 1-ethyl-2-methyl-2-propenyl.
Optional vinyl, 2-propenyl, crotyl or the 1-methyl-2-propenyl that replaces is preferred.
Preferably have 1-6, the straight or branched alkynyl group of 1-4 carbon atom particularly separately or as the alkynyl group representative of the optional replacement of the part of group in the general formula.The example that can mention has the optional ethynyl that replaces, 2-propynyl, the 2-butyne base, the 3-butynyl, 1-methyl-2-propynyl, the valerylene base, the 3-pentynyl, the 4-pentynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-methyl-2-butyne base, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexin base, 3-hexin base, 4-hexin base, 5-hexin base, 1-methyl-valerylene base, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-valerylene base, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl and 1-ethyl-1-methyl-2-propynyl.
Optional ethynyl, 2-propynyl or the 2-butyne base that replaces is preferred.
Preferably has the monocyclic, bicyclic or tricyclic cycloalkyl of 3-10, particularly 3,5 or 7 carbon atoms separately or as the cycloalkyl representative of the optional replacement of the part of group in the general formula.The example that can mention has the optional cyclopropyl that replaces, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, two ring [2.2.1] heptyl, two ring [2.2.2] octyl group and adamantyls.
Contain 1-4, particularly 1 or 2 carbon atom separately or as the haloalkyl of the part of group in the general formula, and preferably have 1-9,1-5 identical or different halogen atom particularly, preferred fluorine, chlorine or bromine, particularly fluorine or chlorine.The example that can mention has trifluoromethyl, trichloromethyl, chlorodifluoramethyl-, dichlorofluoromethyl, chloromethyl, brooethyl, 1-fluoro ethyl, 2-fluoro ethyl, 2,2-two fluoro ethyls, 2,2,2-trifluoroethyl, 2,2,2-three chloroethyls, 2-chloro-2,2-two fluoro ethyls, pentafluoroethyl group and the five fluorine tertiary butyls.
Preferably have 1-6, the straight or branched alkoxyl group of 1-4 carbon atom particularly separately or as the alkoxyl group representative of the optional replacement of the part of group in the general formula.The example that can mention is optional methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and the tert.-butoxy that replaces.
Represent be connected to each other together 2 aforesaid alkoxyl groups of C-O-wherein separately or as the alkoxyl group alkoxyl group of the optional replacement of the part of group in the general formula.The example that can mention has optional methoxymethoxy, methoxy ethoxy, methoxyl group positive propoxy and the oxyethyl group isopropoxy that replaces.
Separately or as the alkoxyl group alkoxyl group alkoxyl group representative of the optional replacement of the part of group in the general formula be connected to each other together 3 aforesaid alkoxyl groups of each C-O-wherein.The example that can mention has optional methoxymethoxy oxyethyl group, methoxy ethoxy oxyethyl group and the methoxy ethoxy positive propoxy that replaces.
Preferably have 1-6, the straight or branched halogenated alkoxy of 1-4 carbon atom particularly separately or as the halogenated alkoxy representative of the optional replacement of the part of group in the general formula.The example that can mention has optional difluoro-methoxy, trifluoromethoxy, trichlorine methoxyl group, chlorine difluoro-methoxy, 1-fluorine oxyethyl group, the 2-fluorine oxyethyl group, 2 that replaces, 2-difluoroethoxy, 1,1,2,2-tetrafluoro oxyethyl group, 2,2,2-trifluoro ethoxy and 2-chloro-1,1, the 2-trifluoro ethoxy.
Preferably have 1-6, the straight or branched alkylthio of 1-4 carbon atom particularly separately or as the alkylthio representative of the optional replacement of the part of group in the general formula.The example that can mention has the optional methylthio group that replaces, ethylmercapto group, positive rosickyite base, iprotiazem base, positive butylthio, isobutyl sulfenyl, secondary butylthio and uncle's butylthio.
Preferably have 1-6, the straight or branched halogenated alkylthio of 1-4 carbon atom particularly separately or as the halogenated alkylthio representative of the optional replacement of the part of group in the general formula.The example that can mention has optional difluoro methylthio group, trifluoromethylthio, trichloro-methylthio, chlorine difluoro methylthio group, 1-fluorine ethylmercapto group, the 2-fluorine ethylmercapto group, 2 that replaces, 2-difluoro ethylmercapto group, 1,1,2,2-tetrafluoro ethylmercapto group, 2,2,2-trifluoro ethylmercapto group and 2-chloro-1,1,2-trifluoro ethylmercapto group.
Preferably have 1-6, the straight or branched alkyl-carbonyl of 1-4 carbon atom particularly separately or as the alkyl-carbonyl representative of the optional replacement of the part of group in the general formula.The example that can mention has optional methyl carbonyl, ethyl carbonyl, n-propyl carbonyl, sec.-propyl carbonyl, sec-butyl carbonyl and the tertiary butyl carbonyl that replaces.
Separately or preferably have monocycle, two ring and tricyclic naphthenes base carbonyls of 3-10, particularly 3,5 or 7 carbon atoms as the naphthene base carbonyl representative of the optional replacement of the part of group in the general formula.The example that can mention has the optional cyclopropyl carbonyl that replaces, cyclobutyl carbonyl, cyclopentylcarbonyl, cyclohexyl-carbonyl, suberyl carbonyl, ring octyl group carbonyl, two ring [2.2.1] heptyl carbonyls, two ring [2.2.2] octyl group carbonyl and adamantyl carbonyls.
Preferably have 2-7, the straight or branched alkoxy carbonyl of 2-5 carbon atom particularly separately or as the alkoxy carbonyl representative of the optional replacement of the part of group in the general formula.The example that can mention has optional methoxycarbonyl, ethoxy carbonyl, positive propoxy carbonyl, isopropoxy carbonyl, n-butoxy carbonyl, isobutoxy carbonyl, sec-butoxy carbonyl and the tert-butoxycarbonyl that replaces.
Aryl is for example monocycle, two ring or polycyclic aromatic groups, for example phenyl, naphthyl, tetralyl, indanyl, fluorenyl etc., but preferred phenyl or naphthyl.
The optional aryl that replaces is preferably represented optional phenyl or naphthyl, the particularly phenyl that replaces in the general formula.
In the general formula the optional arylalkyl that replaces preferably represent choose wantonly on aryl moiety and/or alkyl substituted, and preferably have 6 or 10,6 carbon atoms particularly at aryl moiety (preferred phenyl or naphthyl, particularly phenyl), and preferably having preferred 1-4, the particularly arylalkyl of 1 or 2 carbon atoms at moieties, wherein said alkyl can be a straight or branched.For example preferred optional benzyl and the 1-phenylethyl that replaces.
Optional group portability one or more, preferred 1-3, the particularly 1-2 that replace an identical or different substituting group in the general formula.The substituent preferred embodiment that can mention is:
Preferably have 1-4, the particularly alkyl of 1-2 carbon atom, for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl and the tertiary butyl; Preferably have 1-4, the particularly alkoxyl group of 1-2 carbon atom, for example methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert.-butoxy; Alkylthio, for example methylthio group, ethylmercapto group, positive rosickyite base, iprotiazem base, positive butylthio, isobutyl sulfenyl, secondary butylthio; Preferably have 1-5, the particularly haloalkyl of 1-3 halogen atom, wherein halogen atom is identical or different, and halogen atom preferably represents fluorine, chlorine or bromine, particularly fluorine or chlorine, for example difluoromethyl, trifluoromethyl, trichloromethyl; Hydroxyl; Halogen, preferred fluorine, chlorine, bromine and iodine, particularly fluorine and chlorine; Cyano group; Nitro; Amino; On each alkyl, preferably has 1-4, particularly an alkyl of 1 or 2 carbon atom-and dialkyl amido, for example methylamino, methylethyl amino, dimethylamino, n-propyl amino, sec.-propyl amino, methyl normal-butyl amino; Alkyl-carbonyl, for example methyl carbonyl; Preferably have 2-4, the particularly alkoxy carbonyl of 2-3 carbon atom, for example methoxycarbonyl and ethoxy carbonyl; Have 1-4, the particularly alkyl sulphinyl of 1-2 carbon atom; Haloalkyl sulfinyl with 1-4, particularly 1-2 carbon atom and 1-5 halogen atom, for example trifluoromethyl sulphinyl base; Halogenated alkyl sulfonyl with 1-4, particularly 1-2 carbon atom and 1-5 halogen atom, for example trifluoromethyl sulfonyl, perfluor normal-butyl alkylsulfonyl, perfluor isobutyl-alkylsulfonyl; The aryl sulfonyl that preferably has 6 or 10 aryl carbon atoms, for example phenyl sulfonyl; Itself can carry acyl group, aryl, the aryloxy of an above-mentioned substituting group and formimino (HC=N-O-alkyl).
These substituent numbers are hard-core, and it is preferably 1-4 identical or different substituting group.Also having two identical or different substituting groups is present on the atom of same atom or cyclic amino.
Separately or as one of the optional replacement of the part of group in the general formula-or the dialkyl amido representative preferably have 1-6, the straight or branched alkyl of 1-4 carbon atom particularly.Replace one-or the example of dialkyl amido methylamino, ethylamino, dimethylamino, diethylamino, di amino, diisopropylaminoethyl or dibutylamino are arranged.
Separately or as one of the optional replacement of the part of group in the general formula-or the representative of dialkoxy alkylamino preferably have 1-6, the straight or branched alkoxyalkyl of 1-4 carbon atom particularly.One of replacement-or the example of dialkoxy alkylamino has methoxymethyl amino, methoxy ethyl amino, two (methoxymethyl) is amino or two (methoxy ethyl) amino.
Suitable cyclic amino is to have one or more nitrogen-atoms as heteroatomic heteroaromatic or aliphatic ring system, wherein heterocycle can be saturated or undersaturated, can be monocycle system or a plurality of ring system that condenses, and can choose wantonly and comprise other heteroatoms for example one or two nitrogen, oxygen and sulphur etc.In addition, cyclic amino can also be represented volution or bridged ring system.The atom number that forms cyclic amino is hard-core, and for example for monocycle system, they are by 3-8 atomic building, and for three ring systems, group is by 7-11 atomic building.
Have saturated and unsaturated monocyclic groups and the monocyclic groups that can mention have nitrogen-atoms and as the example of heteroatomic cyclic amino 1-azetidinyl, pyrrolidyl, 2-pyrroline-1-base, 1-pyrryl, piperidyl, 1 are arranged, 4-dihydro pyrazine-1-base, 1,2,5,6-tetrahydrochysene pyrazine-1-base, 1,4-dihydropyridine-1-base, 1,2,5,6-tetrahydropyridine-1-base, homopiperidinyl (Homopiperidinyl); Have saturated and unsaturated monocyclic groups and the monocyclic groups that can mention have two or more nitrogen-atoms and as the example of heteroatomic cyclic amino 1-imidazolidyl, 1-imidazolyl, 1-pyrazolyl, 1-triazolyl, 1-tetrazyl, 1-piperazinyl, the high piperazinyl of 1-, 1 are arranged, 2-dihydrogen dazin-1-base, 1,2-dihydro-pyrimidin-1-base, perhydro pyrimidine-1-base, 1,4-Diazesuberane-1-base; Having saturated and unsaturated monocyclic groups and monocyclic groups has 1 or 2 Sauerstoffatom and 1-3 nitrogen-atoms and as the example of heteroatomic cyclic amino Li such as oxazolidine-3-base, 2 is arranged, 3-dihydro-isoxazole-2-base, isoxazole-2-base, 1,2,3-oxadiazine-2-base, morpholinyl, have saturated and unsaturated monocyclic groups and the monocyclic groups that can mention have 1-3 nitrogen-atoms and 1-2 sulphur atom and as the example of heteroatomic cyclic amino thiazolidine-3-base, isothiazoline-2-base, thio-morpholinyl or dioxo thio-morpholinyl are arranged; Saturated and the unsaturated example that condenses the cyclic amino of cyclic group that has that can mention has indoles-1-base, 1,2-dihydrobenzo imidazoles-1-base, perhydro pyrrolo-[1,2-a] pyrazine-2-base; The example of the cyclic amino with volution group that can mention has 2-azaspiro [4,5] decane-2-base; The example of the cyclic amino with bridge heterocyclic group that can mention has 2-azabicyclic [2,2,1] heptane-7-base.
Suitable unit price amino protecting group is preferably to have 1-6; the acyl group of 1-4 carbon atom formyl radical for example particularly; ethanoyl; propionyl; valeryl; caproyl; or the acyl group that contains (or two or three) halogen 2-chloro-for example; the 2-bromo-; the 2-iodo-; 2; the 2-dichloro-acetyl; 2; 2; 2-trifluoroacetyl group or 2; 2; 2-tribromo-acetyl base; preferably have 1-14; the alkoxy carbonyl of 1-4 carbon atom methoxycarbonyl for example particularly; ethoxy carbonyl; propoxycarbonyl; tert-butoxycarbonyl (Boc); tert-pentyloxy carbonyl (Aoc); hexyloxy carbonyl; the methyl sulphonyl ethoxy carbonyl; adamantyl oxygen base carbonyl (Adoc) and 1-[1-adamantyl]-1-methyl ethoxy carbonyl (Adpoc); formamyl; aroyl is phenyl acetyl and phenyl propionyl for example; aryloxycarbonyl is phenyloxycarbonyl and naphthyloxy carbonyl for example; the aryloxy alkanoyl is the phenoxy group ethanoyl for example; with the phenoxy group propionyl; the glyoxyl-based for example phenyl of aryl is glyoxyl-based and naphthyl is glyoxyl-based; have for example benzyloxycarbonyl (Cbo-or Cbz of conventional substituent alkoxy carbonyl; Z); 4-methoxyl group benzyloxy base carbonyl; 3; 5-dimethoxy benzyloxycarbonyl; 4-phenylazo benzyloxycarbonyl; the benzene ethoxy carbonyl; the nitro benzyloxycarbonyl; the chlorine benzyloxycarbonyl; α; alpha-alpha-dimethyl-3; 5-dimethoxy benzyloxycarbonyl; 2-nitro-4; 5-dimethoxy benzyloxycarbonyl (Nvoc); fluorenyl-9-methoxycarbonyl (Fmoc), replacement or unsubstituted alkylidene group be benzylidene for example; the hydroxyl benzylidene; the alkyl that contains (or two or three a) phenylalkyl is benzyl for example; styroyl; diphenyl-methyl or trityl group (trityl) etc.Suitable divalence amino protecting group can be one-or dibasic methylene radical, and 1-lower alkoxy (for example methoxy or ethoxy)-low-grade alkylidene (for example inferior normal-butyl of ethylidene or 1-) for example, for example=C (CH 3) (O-C 2H 5), in addition for example=C (CH 3) 2Or=CH-phenyl, particularly diacyl, phthaloyl for example, phthaloyl forms 1H-isoindole-1,3 (2H)-diketone (phthalimide-based group) with protected nitrogen-atoms.
Amino protecting group and introducing thereof and to remove be known, and be described in for example J.F.W.McOmie, " protecting group in the organic chemistry ", Plenum Press; London, New York, 1973, and T.W.Greene; " protecting group in the organic synthesis ", Wiley, New York is in 1984.
Suitable hydroxyl protecting group is the alkyl for example tertiary butyl, methylthiomethyl and the trimethyl silyl that preferably has 1-6, a particularly optional replacement of 1-4 carbon atom; the alkyl that comprises phenylalkyl is benzyl or diphenyl methyl for example, and heterocyclic group is THP trtrahydropyranyl etc. for example.
Suitable thiol protecting group is alkyl for example acetylamino methyl and the chloro-acetyl chloride ylmethyl that preferably has 1-6, a particularly optional replacement of 1-4 carbon atom, and the alkyl that contains arylalkyl is benzyl, 4-methoxy-benzyl, diphenyl methyl, trityl group and pyridyl diphenyl methyl etc. for example.
The above-mentioned protecting group of further mentioning has in the chemistry of peptides known function with temporary protection amino, hydroxyl or thiol.
The suitable synthetic resins that is used as polymer support in the solid phase synthesis of cyclic depsipeptide of the present invention is suitable functionalized base polymer (in most of the cases being to form to obtain on the polystyrene of chloromethylation), for example functionalized Merrifield type resin of amino oxygen base or diazanyl.Specially suitable is the commercially available DHP HM resin that originates from Novabiochem, and such resin allows that by using hydroxyl amino or diazanyl functional group simple anchor closes, and makes thus cyclic depsipeptide of the present invention can be provided.
General formula (Ia) compound and optically active isomer, racemic modification and physiological acceptable salt are particularly preferred R wherein 1, R 4, R 7And R 10Represent methylidene, R 2, R 5, R 8And R 11Represent isobutyl-, R 6And R 12Represent methylidene, R 3And R 9The benzyl that replaces is chosen in representative wantonly independently of one another, and wherein the substituting group that can mention has hydrogen, halogen, particularly bromine, fluorine, chlorine or iodine, and cyano group, formamyl carries the hydroxyl or the unprotected hydroxyl of protecting group, C 1-8-alkoxyl group, particularly methoxyl group, tert.-butoxy, C 1-4-alkoxy-C 1-4-alkoxyl group, particularly methoxymethoxy, 2-methoxy ethoxy, C 2-4-alkenyloxy, particularly allyloxy, heteroaryl-C 1-4-alkoxyl group, particularly furans-2-base-methoxyl group, tetrahydrofuran (THF)-2-base-methoxyl group, N-Boc-tetramethyleneimine-2-base-methoxyl group, tetramethyleneimine-2-base-methoxyl group, 5-sec-butyl-1,2,4-oxadiazole-3-base-methoxyl group, 5-cyclopropyl-1,2,4-oxadiazole-3-base-methoxyl group, imidazoles-5-base-methoxyl group, thiazolyl methoxyl group, tetrazolium-5-base-methoxyl group, thienyl methoxyl group, nitro, or be selected from-O-CH 2-CH 2-NR 23R 24,-CH 2-NR 23R 24,-NR 23R 24With-SO 2-NR 23R 24Group, R 23And R 24Respectively represent hydrogen, C independently of one another 1-4-alkyl, particularly methyl, ethyl, heteroaryl-C 1-4-alkyl, particularly furans-2-base-methyl, tetrahydrofuran (THF)-2-base-methyl, tetramethyleneimine-2-base-, R 23And R 24Represent heteroaryl with the nitrogen-atoms that they connected, particularly N-pyrrolidyl, N-piperazinyl, N-morpholinyl, N-thio-morpholinyl, N-piperidyl, TMSIM N imidazole base, 2-oxo-pyrrolidine base, phthalimido or tetrahydrochysene phthalimido, A are represented hydrogen, cyano group or the optional group A that represents 1
-Y-R 13A 1) wherein Y represent oxygen or or-N-R 14, R wherein 13And R 14Represent hydrogen independently of one another, straight or branched C 1-4-alkyl, particularly methyl, ethyl, propyl group, sec.-propyl, isobutyl-, sec-butyl, the tertiary butyl, C 1-C 4-alkyl-carbonyl, particularly methyl carbonyl, ethyl carbonyl, cyano group-C 1-C 4-alkyl, amino-C 1-C 4-alkyl, hydroxyl-C 1-C 4-alkyl, C 1-4-alkyl sulphonyl, particularly methyl sulphonyl, C 1-2-halogenated alkoxy-C 1-2-alkyl sulphonyl, particularly 1,1,1-trifluoro ethoxy ethylsulfonyl, straight or branched C 1-4-alkoxy carbonyl, particularly methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, isobutoxy carbonyl, sec-butoxy carbonyl, tert-butoxycarbonyl, straight or branched C 1-4-alkyl amino-carbonyl, particularly methylamino carbonyl, ethylamino carbonyl, C 2-4-alkenyl, particularly vinyl, 2-propenyl, crotyl, C 2-4-alkenyloxy carbonyl, particularly ethylene oxy carbonyl, 2-propenyloxy group carbonyl, 2-butylene oxygen base carbonyl, C 2-4-halo alkenyloxy carbonyl, particularly 1,1,2-trifluoro but-1-ene-4-base oxygen base carbonyl, C 2-4-alkenyl amino carbonyl, particularly 2-propenyl aminocarboxyl, C 2-4-alkynyl group, particularly 2-propynyl, C 2-4-chain oxy-acetylene carbonyl, particularly the 2-third alkynyloxy group carbonyl, cyano methyl, hydroxyethyl, amino-ethyl, aryl-C 1-2-alkyl, the particularly optional benzyl that replaces, heteroaryl-C 1-2-alkyl, the particularly optional heteroaryl methyl that replaces, particularly optional tetrahydrofuran (THF) ylmethyl, furyl methyl, thienyl methyl, thiadiazolyl group methyl, tetrazyl methyl, the pyridylmethyl that replaces, aryloxy-C 1-2-alkyl, the particularly optional phenoxy group ethyl that replaces, the optional heteroaryl carbonyl that replaces, wherein the substituting group that can mention is a hydrogen, nitro, amino, halogen, particularly bromine, chlorine or fluorine, C 1-4-alkyl, particularly methyl, C 1-4-haloalkyl, particularly trifluoromethyl, phenyl, C 1-4-alkoxyl group, particularly methoxyl group, C 1-4-alkoxy carbonyl, particularly methoxycarbonyl, N-morpholinyl, or heteroaryl carbonyl methyl, particularly N-morpholinyl carbonyl methyl, N-pyrrolidyl carbonyl methyl, or the optional group B of representing 4,
Figure A0080882200411
Wherein
Figure A0080882200421
The protecting group that optionally is removed of representative, for example ethanoyl (Ac), allyloxy carbonyl (Alloc), benzyloxycarbonyl (Z) or tert-butoxycarbonyl (Boc), R 19Represent hydrogen, R 20Represent hydrogen, propyl group, sec.-propyl, isobutyl-, benzyl, 4-hydroxybenzyl, imidazol-4 yl methyl, indol-3-yl methyl, phenyl, 2-hydroxyethyl, 1-hydroxyethyl, 2-methylmercaptoethyl, 2-formamyl ethyl, R 21Represent hydrogen or C 1-C 4-alkyl.
Following general formula (Ia) compound and optically active isomer, racemic modification and physiological acceptable salt are very particularly preferred
Figure A0080882200422
R wherein 1, R 4, R 7And R 10Represent methylidene, R 2, R 5, R 8And R 11Represent isobutyl-, R 6And R 12Represent methylidene, R 3And R 9Represent benzyl, A representative-NHMe or group A 1
-Y-R 13(A 1) wherein Y represent oxygen, R 13Represent hydrogen, straight or branched C 1-4-alkyl, particularly methyl, ethyl, propyl group, the tertiary butyl, C 1-4-alkyl sulphonyl, particularly methyl sulphonyl, C 1-C 4-alkyl-carbonyl, particularly methyl carbonyl, cyano group-C 1-C 4-alkyl, hydroxyl-C 1-C 4-alkyl, amino-C 1-C 4-alkyl, C 1-2-halogenated alkoxy-C 1-2-alkyl sulphonyl, particularly 1,1,1-trifluoro ethoxy ethylsulfonyl, straight or branched C 1-4-alkoxy carbonyl, particularly methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, isobutoxy carbonyl, sec-butoxy carbonyl, tert-butoxycarbonyl, C 2-4-alkenyl, 2-propenyl, C 2-4-alkenyloxy carbonyl, particularly ethylene oxy carbonyl, 2-propenyloxy group carbonyl, C 2-4-halo alkenyloxy carbonyl, particularly 1,1,2-trifluoro but-1-ene-4-base oxygen base carbonyl, C 2-4-alkenyl amino carbonyl, particularly 2-propenyl aminocarboxyl, C 2-4-chain oxy-acetylene carbonyl, particularly the 2-third alkynyloxy group carbonyl, aryl-C 1-2-alkyl, the particularly optional benzyl that replaces, N-morpholinyl carbonyl methyl, N-pyrrolidyl carbonyl methyl, heteroaryl-C 1-2-alkyl, particularly optional tetrahydrofuran (THF) ylmethyl, furyl methyl, 5-diuril diazole-4-ylmethyl, N-methyl tetrazolium-5-ylmethyl, pyridylmethyl, the 2-chloropyridine-5-ylmethyl that replaces, aryloxy-C 1-2-alkyl, particularly optional phenoxy group ethyl, the 4-trifluoromethylphenopendant ethyl that replaces, the optional heteroaryl carbonyl that replaces, particularly optional furyl carbonyl, the pyridyl carbonyl that replaces, wherein the substituting group that can mention is a hydrogen, nitro, amino, halogen, particularly bromine, chlorine or fluorine, methyl, trifluoromethyl, phenyl, methoxyl group, methoxycarbonyl, N-morpholinyl, or the optional group B of representing 4,
Figure A0080882200431
Wherein The protecting group that optionally is removed of representative, for example ethanoyl (Ac), allyloxy carbonyl (Alloc), benzyloxycarbonyl (Z) or tert-butoxycarbonyl (Boc), R 19Represent hydrogen, R 20Represent hydrogen, methyl, propyl group, sec.-propyl, isobutyl-, R 21Hydrogen or methyl.
But general or preferred group definition or above-mentionedly illustrate combination with one another together promptly comprises the combination of each scope and preferable range.They are applicable to end product, and correspondingly are applicable to precursor and intermediate.
General formula (I) the cyclo-imino depsipeptides and the salt thereof that use according to the present invention also comprise one or more chiral centres, therefore and can be used as that pure steric isomer exists or exist with the form of various enantiomorphs and non-enantiomer mixture, if necessary, they can separate or use the pure raw material of stereochemistry to make by the stereoselectivity reaction by himself known method.
Yet,, preferably use the optically-active stereoisomeric forms in any ratio of general formula (I) compound and salt thereof according to the present invention.Preferred especially the use by cyclic depsipeptide as unitary (the S)-configuration of ring structure amino acid (L-type) and D-form hydroxycarboxylic acid (D-type) formation.
Therefore, the present invention relates to be used for the control volume entozoa, particularly the entozoal pure enantiomorph of control volume and diastereomer and composition thereof in medical treatment and veterinary applications.
The suitable salt of the general formula that can mention (I) cyclo-imino depsipeptides is conventional non-toxic salt, i.e. salt and the acid salt that forms with Different Alkali.The preferably salt that can mention has: with the salt of mineral alkali formation, for example an alkali metal salt such as sodium salt, sylvite or cesium salt, alkaline earth salt is calcium salt or magnesium salts for example, ammonium salt, with organic bases and the salt that forms with inorganic amine, triethylammonium salts for example, the dicyclohexyl ammonium salt, N, N '-dibenzyl second di-ammonium salts, pyridinium salt, picoline salt or alcohol salt, the salt that forms with mineral acid is hydrochloride for example, hydrobromate, dihydro vitriol, three hydrosulphuric acid salt, or phosphoric acid salt, salt with organic carboxyl acid or organic sulfonic acid formation, formate for example, acetate, trifluoroacetate, maleate, tartrate, mesylate, benzene sulfonate or tosilate are with amino acids formed salt arginic acid salt for example, aspartate or glutaminate etc.
The optional imino-that replaces is incorporated into synthetic polypeptide or the method in the pharmaceutical use heterocycle is arranged is known in the document.
What be suitable for use as raw material is corresponding interior sulfo-peptide or heterocycle thio lactam.That for example, can mention has amidoxim, cyanogen amidine and an amidrazone analogue from the synthetic chenotactic peptide of interior sulfo-peptide people such as (, Can.J.Chem.61,1985,3089 pages) G.Sauve.People such as H.A.Moynihan have described by N α-tert-butoxycarbonyl-δ-(N-methylthiourea base)-(R)-norvaline tert-butyl ester prepares N ω-hydroxy-n ω-methyl-(R)-arginine modification (1994,769 pages of J.Chem.Soc.Perkin Trans.I).Equally, the heterocycle thio lactam can be changed into amidine (pyrrolo-[2,1-c] [1,4] benzodiazepine -5,11-diketone: people such as M.Robba, Tetrahedron Lett.33 (20), 1992,2803 pages), or without difficulty azetidine-2-thioketones is changed into azetidine-2-imines (beta-lactam: people such as L.Ghosez, J.Chem.Soc., Chem.Commun.1983,818 pages).
Surprisingly, have been found that now general formula of the present invention (I) cyclo-imino depsipeptides can also make like this: use general formula (II) aminocompound, make for depsipeptides by corresponding epithio by reacting one or more thioamides groups.According to the present invention, special thioamides group of preferred reaction.
General formula (I) compound is new, and they can make by for example method in above title 2 and 3 times descriptions.
Hereinafter illustrate the inventive method (also referring to preparation embodiment) by selected embodiment.
If, in the inventive method 2a of the new cyclo-imino depsipeptides of preparation general formula (Ia), general formula (Ib) compound that uses be epithio for depsipeptides ring (N-methyl-L-leucyl-D-sulfo-lactoyl-N-methyl-L-leucyl-D-phenyl-lactoyl-N-methyl-L-leucyl-D-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-), general formula (II) aminocompound is O-methyl oxyamine (A:-O-Me; Referring to approach A) or N-methyl hydrazine (A:-NH-Me; Referring to approach B), described method can be by following reaction scheme I representative: reaction scheme I
Figure A0080882200451
Cis/trans isomer mixture A): H 2N-O-MeHCl, Hg (O-Ac) 2, alkali B): H 2N-NH-Me, Hg (O-Ac) 2, alkali
In the inventive method 2a, if use is general formula (II) aminocompound, then general formula (I) compound can be used as cis and the formation of trans-isomer(ide) mixture.
Formula (Ib) provides carries out the General Definition of the required epithio of the inventive method 2a for the depsipeptides raw material.
In formula (Ib), R 1-R 12Preferred representative is mentioned when describing general formula of the present invention (I) compound to be preferred those groups for these substituting groups.
For disclose in the former patent application of depsipeptides, and correspondingly can the cyclic depsipeptide sulfuration be made (referring to WO 98/43965, and see prepare embodiment) as the epithio of raw material by using suitable vulcanizing agent.
General formula (II) provides and has carried out the inventive method 2a also as the definition of the used aminocompound of starting raw material.
In formula (II), it is preferred implication for this substituting group that A has mentioned when describing general formula of the present invention (I) compound.
The commercially available acquisition of general formula (II) aminocompound part, some is known, and can obtain by currently known methods (referring to, heteroaryl methoxamine (methoxamine) for example: US-Pat.5 489 680; DE-OS 2119012, alkoxylamine: EP-OS 495 750; DE-OS2206890; People Farmaco such as D.Favara, Ed.Sci.42 (10), 1987,697 pages).
Preparation formula (II) aminooxy compound (A=A 1:-Y-R 13, general way Y:-O-) comprises, the hydroxy amine derivatives (for example R ' and R " be together: phthaloyl, isopropylidene, Alpha-hydroxy benzylidene) and the compound R of protecting group for example will be arranged on nitrogen 13-E (O-alkylation) reacts in thinner, removes the corresponding protection base then.At compound R 13Among-the E, R 13Has implication same as described above, and E represents the freestone leavings group, the for example sulfonyloxy that replaces of aliphatic series or aromatics such as mesyloxy, sulfonate, tolysulfonyl oxygen base (tosyloxy) and for example halogen, particularly bromine, chlorine or iodine (referring to the O-alkylation).In following scheme II, shown formula (II) aminocompound (A=A 1:-Y-R 13, preparation Y:-O-): scheme II
Figure A0080882200471
Perhaps, if use oxy-compound (R 13-OH), can carry out for example intermolecular dehydration reaction.Particularly suitable be that [Synthesis 1976 for the modification of Mitsunobu reaction; 682 pages]; wherein be with the hydroxy amine derivatives of oxy-compound and N-protected for example N-hydroxyphthalimide, N-hydroxyl-5-norbornylene-2; 3-dicarboximide or ethanoyl hydroxamic acid ethyl ester and for example triphenylphosphine and N, N '-diethyl azodiformate reaction.
Can formula (II) compound be discharged easily by following method: hydrazinolysis can preferably for example carry out in boiling point in the alcohol at thinner.Hydrolysis can preferably be undertaken by heating a plurality of hours in water, water-alcohol or alcoholic solution.If R ' and R " represent isopropylidene together, then can use acid hydrolysis, if R ' and R " represent Alpha-hydroxy benzylidene or R together " and represent ethoxycarbonyl, then both can use basic hydrolysis also can use acid hydrolysis (referring to DE-OS 2119012; People Farmaco such as D.Favara, Ed.Sci.42 (10), (1987) 697 pages).
In order to prepare salt, preferably in ethanol or aqueous isopropanol, use mineral acid for example hydrochloric acid or sulfuric acid.
General formula (Ib) sulfo-depsipeptides and general formula (II) are if the reaction of aminocompound preferably in the presence of metal-salt or the metal oxide and is suitably using thinner to carry out in the presence of the alkali reaction auxiliary.
Be applicable to that metal-salt or the metal oxide of implementing the inventive method are the salt of all metals of periodic table of elements I and II transition group.The example that can mention has acetate, muriate, bromide, iodide, fluorochemical, nitrate, vitriol, carbonate, three fluoroborates, the fluoroform sulphonate of copper, silver, gold, zinc, cadmium or mercury.
But, preferably use carbonate, three fluoroborates and fluoroform sulphonate and II magnesium-yttrium-transition metal particularly acetate, oxide compound, the halogenide of mercury of I magnesium-yttrium-transition metal, particularly silver.
The material that is suitable for use as the alkali reaction auxiliary of implementing the inventive method 2a is all suitable acid binding agents, for example amine, particularly tertiary amine and basic metal and alkaline earth metal compound.
The example that can mention has lithium, sodium, potassium, magnesium, the oxyhydroxide of calcium and barium, oxide compound and carbonate, and other basic cpd for example amidine alkali or guanidine alkali, 7-methyl isophthalic acid for example, 5,7-three azabicyclics (4.4.0) last of the ten Heavenly stems-5-alkene (MTBD), diazabicylo (4.3.0) nonene (DBN), diazabicylo (2.2.2) octane (DABCO), 1,8-diazabicylo (5.4.0) undecylene (DBU), cyclohexyl tetrabutyl guanidine (CyTBG), cyclohexyl tetramethyl guanidine (CyTMG), N, N, N, N-tetramethyl--1, the 8-naphthylene diamine, the pentamethyl-piperidines, tertiary amine is triethylamine for example, Trimethylamine, tribenzyl amine, triisopropylamine, tributylamine, tribenzyl amine, thricyclohexyl amine, three amylamines, three hexyl amines, N, accelerine, N, N-dimethyl methyl aniline, N, the N-dimethyl is to aminopyridine, the N-crassitude, the N-methyl piperidine, the N-Methylimidazole, the N-methylpyrrole, N-methylmorpholine, N-methyl hexamethylene imine, pyridine, 4-pyrrolidyl pyridine, 4-dimethylaminopyridine, quinoline, α-Jia Jibiding, beta-picoline, isoquinoline 99.9, pyrimidine, acridine, N, N, N ', N '-tetramethylene-diamine, N, N ', N '-four ethylene diamine, quinoxaline, N-propyl group diisopropylamine, the N-ethyl diisopropyl amine, N, N '-dimethylcyclohexylam,ne, 2, the 6-lutidine, 2,4-lutidine or triethylenediamine.
Preferred tertiary amine, particularly trialkylamine for example triethylamine, N, N-diisopropyl ethyl amine, N-propyl group diisopropylamine, N, N '-dimethylcyclohexylam,ne or the N-methylmorpholine of using.
For the purpose of favourable, generally be in the presence of thinner, to carry out the inventive method 2a.Thinner is preferably can make reaction mixture keep the amount use that is easy to whipped state during whole.The thinner that is suitable for carrying out the inventive method 2a is all inert organic solvents.
The example that can mention has: halohydrocarbon, hydrochloric ether particularly, for example zellon, tetrachloroethane, propylene dichloride, methylene dichloride, dichlorobutane, chloroform, tetracol phenixin, trichloroethane, trieline, pentaline, two fluorobenzene, 1,2-ethylene dichloride, chlorobenzene, bromobenzene, dichlorobenzene, toluene(mono)chloride, trichlorobenzene; Alcohol, for example methyl alcohol, ethanol, Virahol, butanols; Ether, for example polyethers of ethyl propyl ether, methyl tertiary butyl ether, n-butyl ether, methyl-phenoxide, phenyl ethyl ether, cyclohexyl methyl ether, dimethyl ether, ether, dipropyl ether, Di Iso Propyl Ether, di-n-butyl ether, diisobutyl ether, diisoamyl ether, ethylene glycol dimethyl ether, tetrahydrofuran (THF), dioxane, Dichlorodiethyl ether and oxyethane and/or propylene oxide; Amine, for example Trimethylamine, triethylamine, tripropylamine, tributylamine, N-methylmorpholine, pyridine and tetramethylene-diamine; Nitro-hydrocarbon is Nitromethane 99Min., nitroethane, nitropropane, oil of mirbane, chloronitrobenzene, Ortho Nitro Toluene for example; Nitrile, for example acetonitrile, propionitrile, butyronitrile, isopropyl cyanide, phenyl cyanide, m-chloro phenyl cyanide, and compound for example tetramethylene sulfide dioxide and methyl-sulphoxide, tetramethylene sulfoxide, dipropyl sulfoxide, benzyl methyl sulfoxide, diisobutyl sulfoxide, dibutyl sulfoxide, diisoamyl sulfoxide; Sulfone, for example dimethyl sulfone, diethyl sulfone, dipropyl sulfone, dibutyl sulfone, sulfobenzide, dihexyl sulfone, methylethyl sulfone, ethyl propyl sulfone, ethyl isobutyl-sulfone and pentamethylene sulfone; Aliphatic, alicyclic or aromatic hydrocarbon, for example pentane, hexane, heptane, octane, nonane, with industrial hydrocarbon, for example have boiling point and be for example 40-250 ℃ the petroleum solvent of component, isopropyl toluene, boiling point is 70 ℃-190 ℃ a gasoline fraction, hexanaphthene, methylcyclohexane, sherwood oil, V.M.. naphtha, octane, benzene, toluene, chlorobenzene, bromobenzene, oil of mirbane, dimethylbenzene; Ester, for example methyl acetate, ethyl acetate, butylacetate, isobutyl acetate, and methylcarbonate, dibutyl carbonate, ethylene carbonate; Acid amides is hexa-methylene phosphoryl triamide, methane amide, N-methylformamide, N for example, dinethylformamide, N, N-dipropyl methane amide, N, N-dibutyl formamide, N-crassitude, N-methyl caprolactam, 1,3-dimethyl-3,4,5,6-tetrahydrochysene-2 (1H)-pyrimidine, octylpyrrolidone, octyl group hexanolactam, 1,3-dimethyl-2-imidazolinedione, N-formyl piperidine, N, N '-1,4-diformyl piperazine; Ketone is acetone, methyl phenyl ketone, methyl ethyl ketone, methyl butyl ketone for example.
Certainly, for the inventive method, also can use the mentioned solvent and the mixture of thinner.
Yet, the preferable absorbent that is used to carry out the inventive method is a nitrile, acetonitrile for example, propionitrile, butyronitrile, isopropyl cyanide, phenyl cyanide or m-chloro phenyl cyanide, acetonitrile particularly, propionitrile or butyronitrile, ether is ethyl propyl ether for example, methyl tertiary butyl ether, n-butyl ether, cyclohexyl methyl ether, dimethyl ether, Anaesthetie Ether, dipropyl ether, Di Iso Propyl Ether, di-n-butyl ether, diisobutyl ether, diisoamyl ether, ethylene glycol dimethyl ether, tetrahydrofuran (THF) or dioxane, particularly tetrahydrofuran (THF) or dioxane, halohydrocarbon, hydrochloric ether particularly, zellon for example, tetrachloroethane, propylene dichloride, methylene dichloride, dichlorobutane, chloroform, tetracol phenixin, trichloroethane, trieline or pentaline, particularly methylene dichloride, chloroform or tetracol phenixin.
According to method 2a, the reaction of general formula (II) aminocompound is performed such: in the presence of general formula (II) aminocompound, in the presence of a kind of mentioned periodic table of elements I and II magnesium-yttrium-transition metal salt or metal oxide, if and suitably in the presence of a kind of mentioned alkali reaction auxiliary, in a kind of mentioned thinner, general formula (Ib) epithio is reacted for depsipeptides.
Reaction times is 10 minutes-48 hours.This be reflected at-10 ℃-+200 ℃, preferred+10 ℃-+180 ℃, carry out particularly preferably in room temperature.This reaction generally is to carry out under normal pressure.Preferably normal pressure or be up to 15 the crust pressure under carry out, if suitably under the atmosphere of shielding gas (nitrogen or helium), carry out.
In order to carry out the inventive method 2a, generally be that every mole of thioamides group that exists in for depsipeptides at general formula (Ib) epithio uses 0.5-7.0Mol, preferred 1.0-5.0Mol, preferred especially 2.0-3.0Mol general formula (II) aminocompound.
In addition, in order to carry out the inventive method 2a, generally be that every mole of thioamides group that exists in general formula (Ib) compound uses 0.5-6.0Mol, preferred 1.0-4.0Mol, preferred especially 1.5-2.5Mol metal-salt or metal oxide.
After reaction finishes, entire reaction mixture and the metallic sulfide that is precipitated out are separated, if suitably washing.Can pass through recrystallization, underpressure distillation or column chromatography purifying products therefrom (also referring to preparation embodiment) in a usual manner.
At the inventive method 2b and the 2c that are used for preparing the new cyclo-imino depsipeptides of general formula (Ia); if used formula (Ic) compound be for example cyclo-imino depsipeptides ring [N-methyl-L-leucyl-D-(oxyimino)-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-N-methyl-L-leucyl-D-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl); and used general formula (III) compound is chloroformic acid vinyl acetate (referring to approach C); used general formula (IV) compound is diacetyl oxide (referring to approach D), and then described method can be by following synthetic schemes III representative.Synthetic schemes III
Figure A0080882200501
Cis/trans isomer mixture C): Cl-CO-O-CH=CH 2, alkali D): (CH 3-CO) 2O
Formula (Ic) provides carries out the inventive method 2b and 2c is particularly useful as the required cyclo-imino depsipeptides of raw material and the General Definition of salt thereof.
In formula (Ic), R 1-R 12Preferred representative is mentioned when describing general formula of the present invention (I) compound to be preferred those groups for these substituting groups.
General formula (Ic) cyclo-imino depsipeptides (Y:-O-) as raw material is new, and can obtain by aforesaid method 2a or following method 3.
According to method 2a, general formula (Ic) cyclo-imino depsipeptides (Y:-OH) can make (referring to reaction scheme IV) for depsipeptides with as the oxyamine of general formula (II) compound by general formula (Ib) epithio.Reaction scheme IV
Figure A0080882200511
Formula (III) and the General Definition of the starting compound that also is used to carry out the inventive method 2b and 2c (IV) is provided.
In formula (III) with (IV),
Figure A0080882200512
W, Q and Y have when describing general formula of the present invention (I) compound mentioned about these substituent implications.
Formula (III) compound is the known compound in the organic chemistry normally, or some commercially available acquisitions in them or obtain (Houben Weyl for example by the currently known methods in the document, Methoden der organischen Chemie[organic chemistry method], Volume E4).
Cyclo-imino depsipeptides (Ic) preferably uses thinner to carry out in the presence of the alkali reaction auxiliary with the reaction of general formula (III) compound.
The alkali reaction auxiliary that is suitable for carrying out the inventive method 2b is all acid binding agents of mentioning in method 2a, for example amine, particularly tertiary amine.
In method 2b, preferably use tertiary amine, particularly trialkylamine for example triethylamine, N, N-diisopropyl ethyl amine, n-propyl diisopropylamine, N, N '-dimethylcyclohexylam,ne or N-methylmorpholine and pyridine derivate, particularly pyridine.
In the inventive method 2b, can certainly use the mixture of mentioned acid binding agent.
The thinner that is suitable for carrying out the inventive method 2b is the inertia aprotonic solvent of mentioning in method 2a, for example dioxane, acetonitrile or tetrahydrofuran (THF), and halohydrocarbon, particularly hydrochloric ether such as methylene dichloride or chloroform.
Method 2b is performed such: in the presence of the alkali reaction auxiliary, if suitably in a kind of mentioned thinner, with general formula (Ic) compound and the reaction of general formula (III) compound.
Perhaps and preferably, method 2b can not use thinner and directly carries out in suitable alkali reaction auxiliary.
General formula (IV) provides the General Definition of the carboxylic acid anhydride raw material that is used to carry out the inventive method 2c.
Reaction times is 4-72 hour.Be reflected at-10 ℃-+150 ℃, preferred-5 ℃-+80 ℃, particularly 0 ℃-room temperature is carried out.Be reflected under the normal pressure and carry out.
In order to carry out the inventive method 2b, general every mole of formula (Ic) compound uses 2.0-8.0Mol, preferred 2.0-4.0Mol acetylizing agent.
In order to carry out the inventive method 2c, general every mole of formula (Ic) compound uses 1.0-3.0Mol, preferred 1.0-1.5Mol carboxylic acid anhydride.
Perhaps, method 2c can not use thinner yet and uses excessive formula (IV) carboxylic acid anhydride to carry out, as long as reaction mixture keeps being easy to stir.
After reaction finishes,, and isolate organic phase, dry and concentrating under reduced pressure with the reaction soln washing.Can pass through recrystallization, underpressure distillation or column chromatography purifying products therefrom (also referring to preparation embodiment) in a usual manner.
At the method 2d α that is used for preparing the new cyclo-imino depsipeptides of general formula (Ia)) and β), if used formula (Ic) compound is a cyclo-imino depsipeptides ring [N-methyl-L-leucyl-D-(oxyimino)-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-N-methyl-L-leucyl-D-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-) for example, used logical formula V compound is (S)-N-tert-butoxycarbonyl-methylphenylamine ((S)-Boc-MeAla-OH; Referring to approach E), used general formula (VI) compound is allyl isocyanate (referring to approach F), then described method can be by following reaction scheme V representative.Reaction scheme V
Figure A0080882200531
Cis/trans isomer mixture E): (S)-Boc-MeAla-OH, BOP, alkali F): O=C=N-CH 2-CH=CH 2, alkali
Formula (Ic) provides and has been used to carry out the inventive method 2d α) and the β) General Definition of required cyclo-imino depsipeptides raw material.
In these formulas (Ic), R 1-R 12Preferred representative is mentioned when describing general formula of the present invention (I) compound to be preferred those groups for these substituting groups.
Formula V provides as being particularly useful for carrying out the inventive method 2d α) the General Definition of compound of raw material.
In formula V,
Figure A0080882200532
Q 1, R 16, R 17And R 18Have when describing general formula of the present invention (I) compound mentioned about these substituent implications.
, can exist if chirality as the natural or synthesizing amino acid of raw material with (S)-or (R)-form (or L-or D-form).
The example that can mention has: Aad, Abu, γ Abu, Abz, 2Abz, ε Aca, Acp, Adpd, Ahb, Aib, β Aib, Ala, β Ala, Δ Ala, Alg, All, Ama, Amt, Ape, Apm, Apr, Arg, Asn, Asp, Asu, Aze, Azi, Bai, Bph, Can, Cit, Cys, (Cys) 2, Cyta, Daad, Dab, Dadd, Dap, Dapm, Dasu, Djen, Dpa, Dtc, Fel, Gln, Glu, Gly, Guv, hAla, hArg, hCys, hGln, hGlu, His, hIle, hLeu, hLys, hMet, hPhe, Pro, hSer, hThr, hTrp, hTyr, HyI, Hyp, 3Hyp, Ile, Ise, Iva, Kyn, Lant, Lcn, Leu, Lsg, Lys, β Lys, Δ Lys, Met, Mim, Min, nArg, Nle, Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg, Pic, Pro, Δ Pro, Pse, Pya, Pyr, Pza, Qin, Ros, Sar, Sec, Sem, Ser, Thi, β Thi, Thr, Thy, Thx, Tia, Tle, Tly, Trp, Trta, Tyr, Val, Nal, Tbg, Npg, Chg, Thia
(referring to for example Houben-Weyl, Methoden der Organischen Chemie, Band XV/1 and 2 Stuttgart, 1974)
The commercially available acquisition of some logical formula V compound, perhaps by the currently known methods in the document obtain (referring to for example, N-methylamino acid: people such as R.Bowmann, J.Chem.Soc.1950,1346 pages; People such as J.R.McDermott, Can J.Chem.51 (1973), 1915 pages; People such as H.Wurziger, Kontakte (Merck, Darmstadt) 3 (1987), 8 pages).
The reaction of general formula (Ic) cyclo-imino depsipeptides and formula V amino acid derivative is preferably using thinner to carry out in the presence of the coupling agent and in the presence of the alkali reaction auxiliary.
Be applicable to that the coupling agent that carries out method 2d α is that all coupling agents of being suitable for forming amido linkage are [referring to for example: Houben-Weyl, Methoden der organischen Chemie, Band15/2; People such as Bodanszky, Peptide Synthesis 2nd ed. (Wiley ﹠amp; Sons, New York 1976) or Gross, Meienhofer, The Peptides:AnalysisSynthesis, Biology (Academic Press, New York 1979)].The following method of preferred use: Acibenzolar method; wherein use pentachlorophenol (Pcp) and Pentafluorophenol (Pfp); N-hydroxy-succinamide (HOSu); N-hydroxyl-5-norbornylene-2; 3-diformamide (HONB); 1-hydroxyl-benzotriazole (HOBt) or 3-hydroxyl-4-oxo-3; 4-dihydro-1; 2; the 3-phentriazine is as alkoxide component; according to the DCC additive process with for example dicyclohexylcarbodiimide (DCCI) coupling of carbodiimide; or use n-propane phosphonic acid anhydride (PPA) and mixed acid anhydride method; wherein use valeryl chlorine; Vinyl chloroformate (EEDQ) and isobutyl chlorocarbonate (IIDQ), perhaps Yong Phosphonium reagent benzotriazole-1-base oxygen base three (Er Jia base An Ji Phosphonium) hexafluoro phosphonate (BOP) for example; two (2-oxos-3-oxazolidinyl) Phosphonium acyl chlorides (BOP-Cl); benzotriazole-1-base tripyrrole alkyl phosphorus hexafluoro phosphonate (PyBOB ), benzotriazole-1-base-tripyrrole Wan Ji Phosphonium hexafluoro phosphonate (PyBOB ), bromine tripyrrole Wan Ji Phosphonium hexafluoro phosphonate (PyBroP ) or use for example diethyl phosphorocyanidate (DEPC) and diphenyl phosphoryl azide (DPPA) or urea (Uronium) reagent 2-(1H-benzotriazole-1-yl)-1 for example of phosphonate reagent; 1; 3; 3-tetramethyl-urea a tetrafluoro borate (TBTU); 2-(5-norbornylene-2; 3-two formamido groups)-1; 1; 3; 3-tetramethyl-urea a tetrafluoro borate (TNTU); 2-(2-oxo-1 (2H)-pyridyl-1,1,3; 3-two-pentamethylene-tetramethyl-urea a tetrafluoro borate (TSTU) or 2-(1H-benzotriazole-1-yl)-1 for example; 1,3,3-tetramethyl-urea hexafluoro phosphonate (HBTU) coupling.
Preferred Shi Yong Phosphonium reagent is two (2-oxo-3-oxazolidinyl) Phosphonium acyl chlorides (BOP-Cl), benzotriazole-1-base oxygen base three (Er Jia base An Ji Phosphonium) hexafluoro phosphonate (BOP), benzotriazoles-1-base tripyrrole Wan Ji Phosphonium hexafluoro phosphonate (PyBOB for example ), bromine tripyrrole Wan Ji Phosphonium hexafluoro phosphonate (PyBroP ) and phosphonate reagent for example diethyl phosphorocyanidate (DEPC) and diphenyl phosphoryl azide (DPPA) carry out coupling.
Be applicable to and carry out the inventive method 2d α) the alkali reaction auxiliary be all acid binding agents that are applicable to method 2a equally.
Preferred what be suitable for is tertiary amine, for example triethylamine, N of trialkylamine particularly, N-diisopropylamine, N-propyl group diisopropylamine, N, N '-dimethylcyclohexylam,ne or N-methylmorpholine.
Be applicable to and carry out method 2d α) thinner be the solvent of in method 2a, mentioning, for example halohydrocarbon, particularly hydrochloric ether, for example methylene dichloride, chloroform or 1, the mixture of 2-ethylene dichloride and they and other mentioned solvent.
This method generally is performed such: in the presence of a kind of mentioned alkali reaction auxiliary, in a kind of mentioned solvent, with general formula (Ic) compound and the reaction of logical formula V compound.
Reaction times is 4-72 hour.Be reflected at-10 ℃-+120 ℃, preferred-5 ℃-+50 ℃, particularly 0 ℃-room temperature is carried out.Be reflected under the normal pressure and carry out.
In order to carry out the inventive method 2d, general every mole of formula (Ic) compound uses 1.0-3.0Mol, preferred 1.0-1.5Mol coupling agent.
Formula (VI) or (VII) provide as being particularly useful for carrying out the inventive method 2d β) the General Definition of compound of raw material.In these formulas (VI) or (VII),
Figure A0080882200561
Y and R 15Having mentioned when describing general formula of the present invention (I) compound is preferred implications for these substituting groups.
Some general formula (VI) or (VII) the commercially available acquisition of compound perhaps make (referring to for example Houben-Weyl, Methoden der OrganischenChemie, Band E4) by the currently known methods in the document.
General formula (Ic) cyclo-imino depsipeptides and general formula (VI) if or (VII) reaction of compound preferably in the presence of thinner, suitably in the presence of the alkali reaction auxiliary, carry out.
Be applicable to and carry out the inventive method 2d β) thinner be the solvent of in method 2a, mentioning, halohydrocarbon for example, hydrochloric ether particularly, methylene dichloride for example, chloroform or 1, the 2-ethylene dichloride, nitrile is acetonitrile for example, propionitrile, butyronitrile, acetonitrile particularly, ether is ethyl propyl ether for example, n-butyl ether, ether, dipropyl ether, Di Iso Propyl Ether, tetrahydrofuran (THF) or dioxane, particularly tetrahydrofuran (THF) or dioxane, aliphatic series or aromatic hydrocarbon be normal hexane for example, normal heptane, benzene, the mixture of toluene or dimethylbenzene and these thinners and other mentioned thinner.
Method 2d β) also can in the presence of the alkali reaction auxiliary, carry out.The alkali reaction auxiliary that is suitable for carrying out the inventive method 2e is all above-mentioned acid binding agents, but be preferably tertiary amine, for example triethylamine, N of trialkylamine particularly, N-diisopropylethylamine or N-methylmorpholine, with amidine alkali or guanidine alkali for example diazabicylo (4.3.0) nonene (DBN), diazabicylo (2.2.2) octane (DABCO), 1,8-diazabicylo (5.4.0) undecylene (DBU), particularly 1,8-diazabicylo (5.4.0) undecylene (DBU).
Method 2d β) generally is performed such: if suitably in the presence of a kind of mentioned alkali reaction auxiliary, in a kind of mentioned thinner, with general formula (Ic) compound and general formula (VI) or (VII) compound reaction.
Reaction times is 4-72 hour.Be reflected at-10 ℃-+180 ℃, preferred-5 ℃-+120 ℃, preferably under the boiling temperature of 0 ℃-used thinner, carry out especially.This reaction is generally carried out under normal pressure; Yet, also can boost or pressure-lowering condition under carry out.Preferably normal pressure or be up to 15 the crust pressure under carry out.
In order to carry out the inventive method 2d β), general every mole of formula (Ic) compound uses 1.0-3.0Mol, preferred 1.0-1.5Mol general formula (VI) or (VII) compound.
The invention still further relates to the novel method of preparation general formula (Ic) cyclo-imino depsipeptides.
General formula (Ic) cyclo-imino depsipeptides (Y:-O-) can make by general formula (Ib) sulfo-depsipeptides with as the oxyamine of general formula (II) compound according to method 2a, perhaps can be obtained by suitable general formula (Ia) cyclo-imino depsipeptides according to method 3.
For example; in method 3a, if use new cyclo-imino depsipeptides ring [N-methyl-L-leucyl-D-(benzyloxy imino-)-lactoyl-N-methyl-L-leucyl-D-phenyl-lactoyl-N-methyl-L-leucyl-D-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-) as general formula (Ia) compound (A=A 1=-Y-R 13:-O-CH 2-phenyl); and carry out hydrogenation; then can form corresponding cyclo-imino depsipeptides ring [N-methyl-L-leucyl-D-(oxyimino)-lactoyl-N-methyl-L-leucyl-D-phenyl-lactoyl-N-methyl-L-leucyl-D-lactoyl-N-methyl-L-leucyl-D-phenyl-lactoyl-) (referring to reaction scheme VI, approach G).
Formula (Ia) provides the General Definition of carrying out the required cyclo-imino depsipeptides raw material of the inventive method 3a.In these formulas (Ia), A, R 1-R 12Preferred representative is mentioned when describing general formula (I) compound to be preferred those groups for these substituting groups.
General formula (Ia) cyclo-imino depsipeptides can be made by general formula (Ib) sulfo-depsipeptides and general formula (II) compound according to aforesaid method 2a, and wherein the A representative has the O protecting group R that optionally is removed 13Group-Y-R 13(A 1), described protecting group be for example benzyl-, benzyloxycarbonyl-, allyl group-, tert-butoxycarbonyl-, the THP trtrahydropyranyl oxyamine.
According to the protecting group R in general formula (Ia) compound 13, this group can be by in hydrogenolysis in the presence of the suitable hydrogenation catalyst or hydrolysis and optionally being removed in the presence of protonic acid.
According to the present invention, if particularly preferably be in the presence of the hydrogenation catalyst, in the presence of the thinner and suitably in the presence of the acid-respons auxiliary with general formula (Ia) cyclo-imino depsipeptides hydrogenolysis (reaction scheme VI, approach G, H, I).Reaction scheme VI
The cis/trans isomer mixture
G:H 2, 10%Pd (OH)-carbon, H +/ Me-OH (R 13:-benzyl)
H:H +(R 13The THP=of :-THP) THP trtrahydropyranyl
I: pyridine-right-toluenesulphonic acids (R 13=-THP-CH 2-O-CH 2-C 6H 4-polymkeric substance)
The catalyzer that is applicable to this catalytic hydrogenation is all hydrogenation catalyst commonly used, for example platinum catalyst (platinum foils, the platinum silk floss, platinum black, colloidal state platinum, platinum oxide, platinum filament etc.), palladium catalyst (palladium silk floss for example, palladium black, palladous oxide, palladium/carbon, pallamine, palladium/barium sulfate, palladium/barium carbonate, palladium hydroxide etc.), nickel catalyzator (reductive nickel for example, nickel oxide, Raney Ni etc.), ruthenium catalyst, cobalt catalyst (reductive cobalt for example, blue Buddhist nun's cobalt etc.), iron catalyst (reductive iron for example, Lan Nitie etc.), copper catalyst (reductive copper for example, Lan Nitong, Ullmann copper etc.).Yet, preferably use noble metal catalyst, platinum and palladium or the ruthenium catalyst of for example suitable words on suitable carriers such as carbon or silicon.
For hydrogenation general formula (Ia) cyclo-imino depsipeptides, use the inert organic solvents of in method 2a, mentioning, for example alcohol, particularly methyl alcohol or ethanol.
The acid-respons auxiliary that can mention has for example mineral acid.Mineral acid preferably includes haloid acid for example hydrofluoric acid, Hydrogen bromide, hydrochloric acid or hydroiodic acid HI, and sulfuric acid, phosphoric acid (Phosphors  ure), phosphoric acid (Phosphorige S  ure) and nitric acid.
According to the present invention, in order to carry out hydrogenation, if in the presence of suitable hydrogenation catalyst and suitably in the presence of the acid-respons auxiliary, with the alcoholic solution reaction of general formula (Ia) ring-type benzyloxy imino-depsipeptides.
The preferred hydrogenation catalyst that uses is a palladium catalyst, particularly palladium or palladium hydroxide/carbon.
The preferred acid-respons auxiliary that uses is a mineral acid, particularly haloid acid hydrochloric acid for example.
Reaction times is 5 minutes-20 hours.Hydrogenation is carried out under-5 ℃-+100 ℃, preferred 0 ℃ of-+30 ℃ of temperature.
Perhaps, general formula (Ic) ring-type oxyimino depsipeptides (Y:-O-) also can be by carrying out the catalytic scission reaction of acid chloride (II) by general formula (Ia) ring-type allyloxy imino-depsipeptides (A:-O-CH in the presence of triethylammonium formate and triphenylphosphine 2-CH=CH 2) make (people such as T.Yamada, Tetrahedron Lett.28,1987,4557 pages).
Certainly and according to the present invention, general formula (Ic) cyclo-imino depsipeptides (Y:-O-) also can be removed THP trtrahydropyranyl oxygen base (A:-O-THP is referring to approach H) or by anchor is closed radicals R by acid catalysis 13From the cyclo-imino depsipeptides of general formula (Ia) polymkeric substance-O-bonding (A=A for example 1=Y-R 13=-O-has the anchor of optionally removing and closes group) on remove and make (referring to reaction scheme VI, approach I).
If for example use the cyclo-imino depsipeptides ring [N-methyl-L-leucyl-D-(polymkeric substance-THP-oxygen base-imino-)-lactoyl-N-methyl-L-leucyl-D-phenyl-lactoyl-N-methyl-L-leucyl-D-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-) of polymer-bound as general formula (Ia) compound (A=A being used for the method 3a that selectivity removes 1=-Y-R 13=-O-has the anchor of optionally removing and closes group); then formed corresponding cyclo-imino depsipeptides ring [N-methyl-L-leucyl-D-(hydroxyl-imino-)-lactoyl-N-methyl-L-leucyl-D-phenyl-lactoyl-N-methyl-L-leucyl-D-lactoyl-N-methyl-L-leucyl-D-phenyl-lactoyl-) (referring to reaction scheme VI, approach I).
Formula (Ia) provides the General Definition of carrying out the required cyclo-imino depsipeptides raw material of the inventive method 3b.
In these formulas (Ia), A and R 1-R 12Preferred representative is mentioned when describing general formula (I) compound to be preferred those groups for these substituting groups.
The cyclo-imino depsipeptides of general formula (Ia) polymer-bound can be according to aforesaid method 2a by general formula (Ib) epithio for depsipeptides with have A=-Y-R for general formula (II) 13(A 1) anchor removed of the alternative polymeric carrier that closes group makes (referring to reaction scheme VII).Reaction scheme VII
Figure A0080882200601
As raw material and have A=-Y-R for general formula (II) 13(A 1) anchor removed of alternative some polymeric carrier of closing group is known in the document (referring to for example synthetic hydroxamic acid: the Mitsunobu reaction of using the N-hydroxyphthalimide to carry out on the Wang resin: people Tetrahedron Lett.37 (44) such as D.Floyd, 1996,8045 pages; The reaction of trityl chloride resin and N-hydroxyphthalimide: people Tetrahedron Lett.38 (41) such as U.Bauer, 1997,7233 pages), perhaps can obtain (synthetic referring to ketone: by the currently known methods in the document with DHP HM resin reaction: O.B.WallaceTetrahedron Lett.38 (28), 1997,4939 pages; Alcohol coupling: people J.Org.Chem.60 such as J.A.Ellmann, 1995,7712 pages; People Tetrahedron Lett.35 (50) such as J.A.Ellmann, 9333 pages) (referring to reaction scheme VIII).Reaction scheme VIII
Figure A0080882200602
In order to carry out the inventive method 3a, the preferred 6-(amino oxygen base)-3,4,5 that obtains according to reaction scheme VIII that uses, 6-tetrahydrochysene-2H-pyrans-2-base-methoxymethyl-polystyrene resin (referring to preparation embodiment).
By ordinary method, for example handle the ring-type oxyimino depsipeptides (also referring to preparation embodiment) that forms in this mode by chromatogram purification.Yet they can be directly according to method 2b reaction (not being further purified).
General formula (I) the compound imino-depsipeptides that obtains by the inventive method 2 can be used as cis and trans-isomer(ide) existence; Yet, under the given reaction conditions of method 2, be preferably formed this two kinds of mixture of isomers.
" inert solvent " mentioned in the method modification 2 is meant in all cases and is being inertia under the reaction conditions separately but is not all to be the inert solvent under any reaction conditions in front.
The pathogenic agent entozoa that active compound of the present invention is suitable for being controlled at people and livestock industry and cattle breeding, takes place in productivity livestock, raise livestock, zoo animal, laboratory animal, animal for research and pet, and very little to toxicity homoiothermous.They can tackle resistance and usually responsive insect effectively, and can resist the insect of all or some etap.By control cause of disease parasite, it can palliate a disease, mortality ratio and the output value (for example at meat, milk, wool, fur, egg, honey etc.) that constantly descends, so the application of the invention active compound can be realized the more economical and simpler animal output value.The pathogenic agent entozoa comprises tapeworm, fluke and nematode, particularly
Pseudophyllidea (Pseudophyllidea), for example Diphyllobothrium (diphyllobothriumspp.), Spirometra (Spirometra spp.), Bothriocephalus (Schistocephalus spp.), Ligula (Ligula spp.), bothridium tapeworm belong to (Bothridium spp.), diplogonorus spp..
Cyclophyllidea (Cyclophyllidea), for example Mesocestoides (Mesocestoidesspp.), Anaplocephala (Anoplocephala spp.), Paranoplocephala (Paranoplocephala spp.), cover the Buddhist nun tapeworm and belong to (Moniezia spp.), Thysanosma spp., Thysaniezia (Thysaniezia spp.), Avitellina (Avitellina spp.), Stilezia (Stilesia spp.), Cittotaenia (Cittotaenia spp.), Anhyra spp., Bertiella (Bertiella spp.), Taenia spp., Echinococcus (Echinococcus spp.), Hydatigera (Hydatigeraspp.), Davainea (Davainea spp.), Raillietina (Raillietinaspp.), Hymenolepis (Hymenolepis spp.), Echinolepis (Echinolepisspp.), Echinocotyle spp., the anorchism tapeworm belongs to (diorchis spp.), Diplopylidium (dipylidium spp.), Joyeuxiella (Joyeuxiella spp.), Diplopylidium (diplopylidium spp.).
Helerocolylea (Monogenea), for example Cyrtodactylus (Gyrodactylus spp.), Dactylogyrus (Dactylogyrus spp.), Polystoma (Polystoma spp.).
Digenea (Digenea), for example Diplostomum (Diplostomum spp.), Posthodiplostomum (Posthodiplostomum spp.), Schistosoma (Schistosomaspp.), Trichobillharzia (trichobilharzia spp.), Ornithobilharzia (Ornithobilharzia spp.), Austrobilharzia (Austrobilharzia spp.), Gigantobilharzia (Gigantobilharzia spp.), Leucochloridium (Leucochloridium spp.), Brachylaimus (Brachylaima spp.), Echinostoma (Echinostoma spp.), Echinoparyphium (Echinoparyphium spp.), Echinochasmus (Echinochasmus spp.), low stem fluke belongs to (Hypoderaeumspp.), Fasciola (Fasciola spp.), Fasciolides spp., Fasciolopsis (Fasciolopsis spp.), the ring cavity fluke belongs to (cyclocoelum spp.), Typhlocoelum (Typhloccelum spp.), Paramphistomum (Paramphistomun spp.), Calicophoron (Calicophoron spp.), Cotylophoron (Cotylophoronspp.), Gigantocotyle (Gigantocotyle spp.), Fischoederius spp., Gastrothylacus spp., Notocotylus (Notocotylus spp.), Calotropis (Catatropis spp.), Plagiorchis (Plagiorchis spp.), Prosthogonismus spp., Dicrocoelium (Dicrocoelium spp.), Collyriculum (Collyriclum spp.), Nanophyetus (Nanophyetus spp.), Opisthorchis (Opisthorchis spp.), Clon (Clonorchis spp.), Meotrchis (Metorchis spp.), Heterophyes(Heterophyes) (Heterophyes spp.), Metagonimus (Metagonimus spp.).
Enoplida, for example Trichocephalus (Trichuris spp.), Hepaticola (Capillaria spp.), Trichlomosoides spp., Trichinella (Trichinellaspp.).
Rhabditida, for example Micronema spp., Strongyloides (Strongyloidesspp.).
Strongylid order (Strongylida), Strongylus (Stronylus spp.) for example, Ternidens (Triodontophorus spp.), Oesophagodontus (Oesophagodontus spp.), Trichonema spp., Gyalocephalus (Gyalocephalus spp.), Cylindropharynx spp., Poteriostromumspp., Cyclococercus spp., cup Stephanurus (Cylicostephanus spp.), oesophagostomum (Oesophagostomum spp.), Chabertia belongs to (Chabertiaspp.), Stephanurus (Stephanurus spp.), Ancylostoma (Ancylostomaspp.), Ancylostoma (Uncinaria spp.), Bunostomum (Bunostomum spp.), Globocephalus (Globocephalus spp.), Syngamus (Syngamus spp.), Cyathostomum spp., Metastrongylus (Metastrongylus spp.), Dictyocaulus (dictyocaulus spp.), Miao Shi Turbatrix (Muellerius spp.), former strongylid (Protostrongylus spp.), Neostrongylus (Neostrongylus spp.), the capsule tail belongs to (Cystocaulus spp.), Pneumostrongylus (Pneumostrongylusspp.), Spicocaulus spp., Elaphostrongylus (Elaphostrongylus spp.), Parelaphostrongylus (Parelaphostrongylus spp.), Crenosoma (Crenosoma spp.), Paracrenosoma spp., Angiostrongylus (Angiostrongylus spp.), Aelurostrongylus (Aelurostrongylus spp.), Filaroides (Filaroides spp., Parafilaroides spp.), trichostrongylus (Trichostrongylus spp.), Haemonchus (Haemonchus spp.), Ostertagia (Ostertagia spp.), Marshallagla (Marshallagia spp.), Cooperia spp., Nematodirus (Nematodirus spp.), pig garden molded lines Eimeria (Hyostrongylus spp.), Obeliscoides (Obeliscoides spp.), Amidostomum (Amidostomum spp.), Ollulanus (Ollulanus spp.), cup ring [nematode] belongs to (Cylicocyclus spp.), double comb belongs to (Cylicodontophorus spp.).
Fine stern order (Oxyurida), for example Oxyuris (Oxyuris spp.), Enterobius (Enterobius spp.), Passalurus (Passalurus spp.), Syphacia (Syphacia spp.), Aspiculuris (Aspiculuris spp.), Heterakis (Heterakis spp.).
Ascaridina (Ascaridia), for example Ascaris (Ascaris spp.), Toxascaris (Toxascaris spp.), Belascaris (Toxocara spp.), parascris (Parascaris spp.), Anisakis spp., Ascaridia (Ascaridia spp.).
Spirurata (Spirurida), for example the jaw mouth nematode belongs to (Gnathostoma spp.), physaloptera (Physaloptera spp.), Thelazia (Thelazia spp.), Gongylonema (Gongylonema spp.), Habronema (Habronema spp.), Parabronema spp., Draschia spp., Dracunculus (Dracunculus spp.).
Filarioidea (Filariida), for example Stephanofilaria (Stephanofilaria spp.), Parafilaria (Parafilaria spp.), Setaria (Setaria spp.), Loa (Loa spp.), Dirofilaria (dirofilaria spp.), mouse Filaria (Litomosoides spp.), cloth Shandong Filaria (Brugia spp.), Wuchereria (Wuchereria spp.), Onchocerca (Onchocerca spp.).
Acanthocephala order (Gigantohynchida), for example Filicollis (Filicollisspp.), beads Acanthocephalus (Moniliformis spp.), Gigantorhynchus (Macracanthorhynchus spp.), Prosthenorchis (Prosthenorchisspp.).
Productivity livestock and raising property livestock comprise Mammals, for example ox, horse, sheep, pig, goat, camel, buffalo, donkey, rabbit, brown deer, reinder, fur output animal is ermine, squirrel or racoon for example, bird, for example chicken, goose, turkey or duck, fresh water and saltwater fish be trout, carp, eel for example, and Reptilia, insect be honeybee and silkworm for example.
Laboratory and animal for research comprise mouse, rat, cavy, golden hamster, dog and cat.
Pet comprises dog and cat.
Its application can be preventative and curative.
Active compound of the present invention can be directly or with the appropriate formulation form through intestines, parenteral route give, through skin, nasal administration, wherein be by handling site or for example grinding belt, plate, belt, neck ring, ear tag, limb wing cringle and labelling apparatus are used by means of the goods that contain active compound.
It is by for example realizing with pulvis, suppository, tablet, capsule, paste, the form oral administration of drinking agent, granula, drencs, bolus, dosing food or tap water that active compound is used through intestines.Applied dermally is for example to carry out to flood, to spray, to take a shower, to wash, to pour into a mould (topple over and put with) and the form of powdering.It is for example to carry out with the form of injection (intramuscular, subcutaneous, intravenously or intraperitoneal) or by implanting that parenteral route is used.
Appropriate formulation comprises: solution, for example injection solution, oral liquid, be used for diluting the back oral administration enriched material, be used on skin or solution, cast preparation, gelifying agent that body cavity uses; Oral or transdermal administration and injection emulsion and suspension; Semi-solid preparation; Wherein active ingredient is incorporated into the preparation in paste substrate or oil-in-water or the water-in-oil emulsion matrix; Solid preparation, for example pulvis, premixture or enriched material, granula, pill, tablet, bolus, capsule; Aerosol and inhalation, contain the goods of active compound.
Injection solution is intravenously, intramuscular and subcutaneous administration.
Injection solution is by active compound being dissolved in suitable solvent, and for example solubility promoter, acid, alkali, buffering salt, antioxidant or sanitas make to add additive if necessary.With such solution sterile filtration or pour in the container.
Suitable solvent comprises: the physiology acceptable solvent, for example water is pure as ethanol, butanols, phenylcarbinol, glycerine, hydrocarbon, propylene glycol, polyoxyethylene glycol and N-Methyl pyrrolidone and composition thereof.
If necessary, but also active compound can be dissolved in the physiology recipient plant or synthetic oil that is suitable for injecting.
Suitable solubility promoter comprises: promote dissolving or the prevention active compound sedimentary solvent of active compound in primary solvent.The example of solubility promoter has polyvinylpyrrolidone, polyoxyethylated castor oil and polyoxy ethylization Isosorbide Dinitrate.
Sanitas is: phenylcarbinol, trichlorine methyl alcohol, p-Hydroxybenzoate, propyl carbinol.
Oral liquid is direct administration.At first enriched material is diluted to administration concentration, then oral administration.Prepare oral liquid and enriched material according to the method for preparing injection solution as mentioned above, but disinfecting action is optional.
The solution that on skin, uses by drop by drop, be coated with, wipe, sprinkle or spraying is used, perhaps by soaking, bathe or washing and use.These solution are to prepare according to the method for preparing injection solution as mentioned above.
It may be favourable adding thickening material in preparation process.
Thickening material is: inorganic thickening agent is wilkinite, colloidal silica, monostearate aluminium for example, or inorganic thickening agent for example derivatived cellulose, polyvinyl alcohol and multipolymer thereof, acrylate and methacrylic acid ester.
Gelifying agent is to be applied on the skin or to be coated in or to be added in the body cavity.Gelifying agent makes like this: a certain amount of thickening material is added in the solution for preparing according to the method for preparing injection solution as mentioned above, has in the clarification composition of paste shape denseness to form thus.Used thickening material is the thickening material that above further describes.
Cast and point with preparation be water or sprinkle on the limited area at skin, active compound transdermal and whole body work or are distributed on the body surface.
Cast and point can tolerate in solvent or the solvent mixture and make by active compound being dissolved, suspends or being emulsified in suitable skin with preparation.If suitably, add other auxiliary material for example tinting material, bio-absorbable promotor, antioxidant, photostabilizer or tackifier.
Suitable solvent comprises: water, alkanol, glycol, polyoxyethylene glycol, polypropylene glycol, glycerine, aromatic alcohol be phenylcarbinol, phenylethyl alcohol or phenoxyethyl alcohol for example, ester is ethyl acetate, butylacetate or peruscabin for example, ether, for example alkane glycol alkyl ether such as dipropylene glycol monomethyl ether or butylcarbitol, ketone is acetone or methyl ethyl ketone for example, aromatics and/or aliphatic hydrocrbon, vegetables oil or synthetic oil, DMF, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, 2,2-dimethyl-4-oxygen methylene radical-1, the 3-dioxolane.
Tinting material is that solubilized or suspension and being allowed to can be used for all tinting materials in the animal.
The example of bio-absorbable promotor has DMSO, dope for example Isopropyl myristate, dipropylene glycol pelargonate, silicone oil, fatty acid ester, triglyceride level or Fatty Alcohol(C12-C14 and C12-C18).
Antioxidant is: for example inclined to one side Potassium hydrogen sulfite of sulphite or metabisulphite, xitix, butylhydroxy toluene, butylated hydroxy anisole or tocopherol.
The example of photostabilizer is to be selected from benzophenone or Novantisols  ure.
Tackifier are for example alginate or gelatin of derivatived cellulose, starch derivative, polyacrylic ester or natural polymer for example.
Emulsion can be oral, transdermal or as the injection administration.
Emulsion is water-in-oil-type or oil-in-water-type.
They make like this: active compound is dissolved in hydrophobic phase or the aqueous favoring, and by means of suitable emulsifying agent with the solvent of another phase with this phase homogenizing, if suitably, also use for example material of tinting material, bio-absorbable promotor, sanitas, antioxidant, photostabilizer, increase viscosity of other auxiliary material.
Suitable hydrophobic phase (oil) comprising: paraffin oil, and silicone oil, crude vegetal is sesame oil, Prunus amygdalus oil or Viscotrol C for example, and synthetic glycerine three esters are the caprylic/capric triglyceride for example, has chain length C 8-12Vegetable fatty acid or the triglyceride mixture of other concrete natural acid of selecting, also contain the mixture of partial glyceride of the saturated or unsaturated fatty acids of hydroxyl, C 8/ C 10The monoglyceride of-lipid acid and triglyceride.
Fatty acid ester, for example Stearic ethyl stearate, Di-n-butyl Adipate, lauric acid hexyl ester, dipropylene glycol pelargonate, branched chain fatty acid and chain length C with medium chain 16-C 18The ester of saturated fatty alcohol, Isopropyl myristate, Wickenol 111, chain length C 12-C 18Octanoate/the decylate of saturated fatty alcohol, isopropyl stearate, oleic acid oleic alcohol ester, decyl oleate, ethyl oleate, ethyl lactate, wax shape fatty acid ester for example artificial duck glandula uropygialis fat, dibutyl phthalate, Wickenol 116, relate to the latter's ester mixture etc.
Fatty Alcohol(C12-C14 and C12-C18), for example different tridecyl alcohol, 2-Standamul G, cetyl stearyl alcohol, oleyl alcohol.
Lipid acid is oleic acid and composition thereof for example.
Suitable aqueous favoring comprises: water, alcohol is propylene glycol, glycerine, sorbyl alcohol and composition thereof for example.
Suitable emulsifying agent comprises: nonionogenic tenside, for example polyoxyethylated castor oil, polyoxy ethylization anhydro sorbitol monooleate, anhydro sorbitol monostearate, monostearin, polyoxy ethyl stearate or alkyl phenol polyethylene glycol ethers; Amphoterics, for example N-lauryl-β-imino-disodium beclomethasone or Yelkin TTS; Anion surfactant, for example the Monoethanolamine MEA BASF salt of sodium lauryl sulphate, fatty alcohol ether sulphate and one/dialkyl group polyglycol ether ortho-phosphoric acid ester; Cats product is chlorination hexadecyl TMA (TriMethylAmine) for example.
Other proper supplementary material comprises: the material that increases viscosity and stable emulsion, for example carboxymethyl cellulose, methylcellulose gum and other Mierocrystalline cellulose and starch derivative, the mixture of polyacrylic ester, alginate, gelatin, gum arabic, polyvinylpyrrolidone, polyvinyl alcohol, methylvinylether/copolymer-maleic anhydride, polyoxyethylene glycol, wax, colloidal silica or above-mentioned substance.
Suspension can be oral, transdermal or as the injection administration.They make like this: active compound is suspended in the liquid vehicle, if suitably, add other auxiliary material for example wetting agent, tinting material, bio-absorbable promotor, sanitas, antioxidant, photostabilizer.
Suitable liquid vehicle comprises all even solvent and solvent mixtures.
Suitable wetting agent (dispersion agent) comprises above-mentioned tensio-active agent.Other proper supplementary material comprises those that above further describe.
Oral or the transdermal administration of semi-solid preparation.They only make a distinction by its viscosity higher and above-mentioned suspension and emulsion.
In order to prepare solid preparation, active compound is mixed with suitable carriers, if suitably add auxiliary material, and prepare this mixture as required and become desired form.
Suitable carriers comprises that all physiology can accept the solid, inert material.They are inorganic or organic substance.Inorganic substance are for example lime carbonate, supercarbonate, aluminum oxide, silicon-dioxide, clay, precipitation or colloidal state carbonic acid gas and phosphoric acid salt of salt, carbonate for example.
Organic substance is for example sugar, Mierocrystalline cellulose, food and animal-feed, for example milk powder, animal powder, cereal powder, cereal meal and starch.
Auxiliary material is foregoing preservatives, antioxidant and tinting material.
Other proper auxiliary agent is lubricant and glidant, for example Magnesium Stearate, stearic acid, talcum powder, wilkinite, disintegrating agent is starch or cross-linked polyvinylpyrrolidone for example, and tackiness agent is starch, gelatin or straight linear polyethylene pyrrolidone and dry adhesive Microcrystalline Cellulose for example for example.
Active compound of the present invention can be used as with other active compound for example the mixture of sterilant, disinfectant (Sterilantien), sterilant, miticide, nematocides or mycocide be present in preparation and its type of service with these formulation preparation.These sterilants for example comprise phosphoric acid ester, carbamate, carboxylicesters, hydrochloric ether, phenylurea, nicotine (Nicotinyle), neonicotine and by the material of microorganisms particularly.
：：Aldimorph；Ampropylfos；Ampropylfos-Kalium；Andoprim；；；Azoxystrobin；；；；Benzamacril；Benzamacry1-；；；；；-S；；；；；；；；；；Carvon；；Chlobenthiazon；Chlorofenazol；；；；；Clozylacon；Cufraneb；；；；；；；；Diclofluanid；；；；；；；；-M；；；；；；；；；；；；；；Famoxadon；；；；；；；；；；；；；；Flumetover；；；；；；；；；；；Fthalid；；；Furametpyr；；；；Furmecyclox；；；；；；；；albesilate；；Iodocarb；； （IBP）；；Irumamycin；；isovaledione；；Kresoxim-；；；；；；；；；；Meferimzone；；；；；；；Metiram；Metomeclam；；；；；；；；；；Oxamocarb；；；Oxyfenthiin；；；；；；；；；；；；；；Propanosine-；；；；；；；Pyroxyfur；Quinconazol； （PCNB）；；；；；Tetcyclacis；；；；；；；Tioxymid；；；；；Triazbutil；；；；；；；；；A；；Viniconazol；；；Dagger G；OK-8705；OK-8801；α-（1；1-）-β-（2-）-1H-1；2；4--1-；α-（2；4-）-β--b--1H-1；2；4--1-；α-（2；4-）-β--a--1H-1；2；4--1-；α-（5--1；3--5-）-β-4-[[ （）]]-1H-1；2；4--1-； （5RS；6RS）-6--2；2；7；7--5-（1H-1；2；4--1-）-3-； （E）-a-（）-N--2-；{2--1-[[[1-（4-）]]]}-1-；1-（2；4-）-2-（1H-1，2，4--1-）--O-（）；1-（2--1-）-1H--2；5-；1-（3；5-）-3-（2-）-2，5-；1-[ （）]-4-；1-[[2-（2，4-）-1；3--2-]]-1H-；1-[[2-（4-）-3-]]-1H-1；2，4-；1-[1-[2-[ （2，4-）]]]-1H-；1--5--2-（）-3-；2’；6’--2--4’--4’--1；3--5-；2，2--N-[1-（4-）-]-1--3--；2，6--5-（）-4-2；6--N-（4-）；2；6--N-[[4-（）]]；2-（2，3，3--2-）-2H-；2-[ （1-）]-5-（）-1；3；4-；2-[[6--4-O-（4-O--β-D-）-a-D-]-4--1H-[2，3-d]-5-；2-；2--2-（）；2--N-（2，3--1；1；3--1H--4-）-3-；2--N-（2，6-）-N-（）；2- （OPP）；3，4--1-[4-（）]-1H--2；5-；3；5--N-[ （1--2-）]]；3-（1，1--1--1H--2-；3-[2-（4-）-5--3-]；4--2--N，N--5-（4-）-1H--1-；4-[1；5-a]-5 （4H）-；8-（1；1-）-N--N--1，4-[4.5]-2-；8-；9H--2-[ （）]-9-；-（1-）-3--4-[ （3-）]-2，5-；-1-（4-）-2-（1H-1；2；4--1-）-；-4-[3-[4-（1，1-）-2-]-2，6-；[ （4-）]；；；1-（2；3--2；2--1H--1-）-1H--5-；N-（2，6-）-N-（5-）-DL-；N-（）-N-（2，6-）-DL-；N-（2；3--4-）-1--；N-（2；6-）-2--N-（-2--3-）；N-（2，6-）-2--N-（-2--3-）；N-（2--4-）-4--3-；N-（4-）-1，4；5；6--2-；N-（4-）-1，4，5；6--2-；N-（5--2-）-2--N-（2--3-）；N-（6-）-3-）；N-[2；2，2--1-[ （）]]；N-[3--4，5--（2-）]-N’- （methanimidamid）；N--N--DL-；O；O-[2-（）-2-]；O-S-；S-1；2，3--7-；[2H]-1--2，1’ （3’H）-]-3’-。Sterilant: bronopol, dichlorophen, nitrapyrin, nickel dimethyldithiocarbamate, kasugamycin, octhilinone, furancarboxylic acid, terramycin, probenazole, Streptomycin sulphate, tecloftalam, copper sulfate and other copper agent, quinolone is Ciprofloxacin for example, Danofloxacin, difloxacin, Enrofloxacin, flumequine, Ibafloxacin, Marbofloxacin, Norxin, Ofloxacine USP 23, Orbifloxacin, Premafloxacin, Sarafloxacin.／／：；；；；；；；α-；；；；AZ 60541；；；A；M；；；；；；；；Beauveria tenella；；；；；；Bifenazate；；Bioethanomethrin；；BPMC；A；；；Butathiofos；；；；；；；；；Chlorethocarb；；chlorfenapyr；；；；；M；Chlovaporthrin；Cis-Resmethrin；Cispermethrin；Clocythrin；；；；；Cycloprene；；；；；；；；Chlothianidin；；M；S；；；；；Dicyclanil；；；；；；；Dofenapyn；Dinotefuran；Eflusilanate；Emamectin；；；Eprinometin；S-；；；Ethiprole；；；Etoxazole；；；；；；；Fenoxacrim；；；Fenpyrad；Fenpyrithrin；；；；；；；Flubrocythrinate；；；；；Flutenzine；；；；；Fubfenprox；；Flupyrazofos；；Halofenozide；HCH；；；；；；Indoxacarb；；；；；；λ-；；；；；；Metharhiziumanisopliae；Metharhizium flavoviride；；；；；Methoxyfenozide；Metolcarb；；Metrifonat；；Milbemectin；；Moxidectin；；；Nithiazine；Novaluron；NEEM；；；M；Paecilomyces fumosoroseus；A；M；；；；；；；；；A；M；；；；；；；；Pyresmethrin；；Pyridaben；Pyridathion；；；Protrifenbute；；；；Sebufos；；Spinosad；；；；；；Tebupirimiphos；；；；Temivinphos；；；Thetacypermethrin；Thiamethoxam；；Thiatriphos；；；；Thuringiensin；；；；；；Triazuron；Trichlophenidine；；；；Thiacloprid；；Vaniliprole；Verticillium lecanii；YI 5302；ζ-；Zolaprofos； （1R-）-[5-（）-3-]-3-[ （-2--3 （2H）-）]-2；2-； （3-）2；2；3；3-；1-[ （2--5-）]-3；5--N--1；3；5--2 （1H）-；2-（2--6-）-4-[4-（1；1-）]-4；5-；2-（）-3--1；4-2--N-[[[4-（1-）]]]；2--N-[[[4-（2；2--1；1-）]]]；3-4-[4-（4-）-4-]-1--2-；4--2-（1；1-）-5-[[2-（2；6--4-）]]-3 （2H）-；4--2-（2--2-）-5-[ （6--3-）]-3 （2H）-；4--5-[ （6--3-）]-2-（3；4-）-3 （2H）-；EG-2348；[2--1-（1；1-）-；2；2--3-（2；4-）-2--1-[4.5]-3--4-；[3-[ （6--3-）]-2-]；-2-（）-2H-1；3--3 （4H）-；[2-[[1；6--6--1-（）-4-]]]；N-（3；4；4--1--3-）；N-（4-）-3-[4-（）]-4；5--4--1H--1-；N-[ （2--5-）]-N’--N"-；N--N’-（1--2-）-1；2-；N--N’-2--1；2-；O，O-[2-（）-2-]。
The compounds of this invention can also be present in its commercial preparation and its type of service with these formulation preparation as the mixture with synergist.Synergist is the compound that can improve the active compound effect, and the synergist that is added self need not activity.
Immediately use (Anwendungsfertig/e) preparation to comprise the active compound of concentration as 10ppm-20% weight, preferred 0.1-10% weight.
Xi Shi preparation comprises the active compound that concentration is 0.5-90% weight, preferred 5-50% weight before use.
It is found that in order to obtain effective result, the amount of using about 1-100mg active compound/kg body weight every day is favourable.Preparation EXAMPLE Example 1 ring [N-methyl-L-leucyl-D-(hydroxyl-imino-)-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-N-methyl-L-leucyl-D-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-]
Figure A0080882200751
A) use mercuric acetate (II) according to method 2a
To use 43.6mg (0.62mmol) hydroxy amine hydrochloric acid salt, 145.0mg (0.45mmol) mercuric acetate (II) and 162.2mg (1.25mmol) ethyl diisopropyl amine (" H ü nig ' s alkali ") processing successively at the 200.0mg in the 5ml acetonitrile (0.20mmol) ring (N-methyl-L-leucyl-D-sulfo-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-N-methyl-L-leucyl-D-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-) (referring to WO 98,/43 965), and with this mixture stirring at room 18 hours.Carry out fully in order to make reaction, add 21.8mg (0.31mmol) hydroxy amine hydrochloric acid salt, 72.5mg (0.45mmol) mercuric acetate (II) and 107.4mg (1.25mmol) ethyl diisopropyl amine (" H ü nig ' s alkali ") again, and with this mixture room temperature restir 6 hours.Then the entire reaction mixture is stirred to about 20ml NH 4In the Cl aqueous solution, and with 15ml chloroform extraction 4 times.(silica gel 60-Merck, particle diameter: 0.04-0.063mm) will remain crude product and carry out chromatogram purification, use hexanaphthene: acetone (4: 1) is as moving phase to use silicagel column.Obtained 70.4mg (productive rate 35%) ring [N-methyl-L-leucyl-D-(oxyimino)-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-N-methyl-L-leucyl-D-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-], for trans-/cis-isomer mixture.B) use mercury chloride (II)/mercuric acetate (II) according to method 2a
With this reaction of hydroxy amine hydrochloric acid salt be according to the reaction method that is similar to embodiment 1; (modification a) uses following reagent to carry out: 500.0mg; (0.52mmol) ring; (N-methyl-L-leucyl-D-sulfo-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-N-methyl-L-leucyl-D-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-) 107.9mg; (1.55mmol) hydroxy amine hydrochloric acid salt 422.0mg; (1.55mmol) mercury chloride; (II) 230.2mg; (1.81mmol) ethyl diisopropyl amine; (" H ü nig ' s alkali ") 30ml tetrahydrofuran (THF)
After 20 hours, add 180.0mg (0.56mmol) mercuric acetate (II) 50 ℃ of stirrings again, 50 ℃ are continued to stir 24 hours again.Then the entire reaction mixture is filtered, and (modification a) as carrying out aftertreatment as described in the embodiment.Output: 250mg (theoretical yield 50%).B) according to 3a hydrogenated derivatives 17
[N-methyl-L-leucyl-D-(benzyloxy imino-)-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-N-methyl-L-leucyl-D-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-] 17 (referring to table 1) of 400.0mg (0.37mmol) ring are stirred in 40ml methyl alcohol, and in the presence of 200mg Pd/ carbon [palladium content is 10%] and 0.7ml concentrated hydrochloric acid, stop (about 20 minutes) until absorption of hydrogen in room temperature hydrogenation.Filter out catalyzer, then the entire reaction solution decompression is concentrated, will remain crude product with the RP-18 post and carry out chromatogram purification, use acetonitrile: water is as moving phase.Output: 110mg (theoretical yield 30%).C) according to method 3b deblocking from the fluoropolymer resin carrier
100mg is contained polystyrene resin, 3.0ml propyl carbinol and the 3.0ml1 of cyclodepsipeptide, and the mixture of 2-ethylene dichloride is handled with 8.5mg pyridine tosic acid, and stirs 1 hour at 60 ℃.Filter out polystyrene resin then, and with washed with dichloromethane 5 times.Concentrating under reduced pressure has obtained the 9.4mg crude product, can confirm that it is embodiment 1 product by APCI-MS.LC-MS (acidity) m/z (%): 964 (M +, 100).C 52H 77N 5O 12(964.2) R t-value (HPLC post: 125 * 2.1 Kromasil , C-18): 17.54; 17.66 minute; Trans-/cis-isomer mixture (20: 80).Embodiment 2 rings [N-methyl-L-leucyl-D-(O-methyl-imino-)-lactoyl-N-methyl-L-leucyl-D-phenyl-lactoyl-N-methyl-L-leucyl-D-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-]
Figure A0080882200771
This reaction of the amine component that replaces with O-is to use following reagent to carry out according to the reaction method that is similar to embodiment 1: 200.0mg; (0.20mmol); (N-methyl-L-leucyl-D-sulfo-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-N-methyl-L-leucyl-D-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-) 52.4mg; (0.62mmol) O-methyl-hydroxy amine hydrochloric acid salt 145.0mg; (0.45mmol) mercuric acetate; (II) 162.2mg; (1.25mmol) ethyl diisopropyl amine; (" H ü nig ' s alkali ") 5ml acetonitrile
(silica gel 60-Merck, particle diameter: 0.04-0.063mm) the residue crude product is carried out chromatogram purification, at first use hexanaphthene: acetone (4: 1) is as moving phase to use silicagel column.Obtained 170mg (theoretical yield 83%) ring [N-methyl-L-leucyl-D-(O-methyl-imino-)-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-N-methyl-L-leucyl-D-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-]. 1H-NMR (600MHz, CDCl 3, δ): 2.85; 2.87; 2.90; 3.04 (4xN-CH 3); 3.65[-O-CH 3, oxime) and ppm. 13C-NMR (100 MHz, CDCl 3, δ): 29.3; 30.2; 30.9; 31.0 (4xN-CH 3); 61.3 (O-CH 3, oxime); 66.9; 68.1; 69.7; 71.1; (4x-CH-O-); 56.9; 53.9; 53.9; 59.5 (4x-CH-N-); 170.3; 170.3; 172.5; (3x-N-C=O); (152.9 1x-C=N-O, oxime); 170.2; 170.7; 171.1; 172.5 (4x-O-C=O) ppm.LC-MS (acidity) m/z (%): 978 (M +, 100) and .C 53H 79N 5O 12(978.2) R t-value (HPLC-post: 125 * 2.1 Kromasil , C-18): 18.34 minutes embodiment 3 rings [N-methyl-L-leucyl-D-(O-ethanoyl-imino-)-lactoyl-N-methyl-L-leucyl-D-phenyl-lactoyl-N-methyl-L-leucyl-D-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-]
200.0mg (0.20mmol) 1 (seeing embodiment 1) is handled in the 1ml diacetyl oxide, and 70 ℃ of stir abouts 30 minutes.Then with the saturated NaHCO of entire reaction mixture 3Solution-treated, and with 15ml ethyl acetate extraction 3 times.Isolate organic phase, use dried over mgso, and concentrating under reduced pressure.(silica gel 60-Merck, particle diameter: 0.04-0.063mm) the residue crude product is carried out chromatogram purification, use hexanaphthene: acetone (10: 1) is as moving phase to use silicagel column.Obtained 125.8mg (theoretical yield 60%) crude product; behind preparation HPLC (RP-18) purifying; obtained the pure ring [N-methyl-L-leucyl-D-(O-ethanoyl-imino-)-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-N-methyl-L-leucyl-D-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-] of 80mg (theoretical yield 38%), for trans-/cis-isomer mixture (purity: 98.7%).LC-MS (acidity) m/z (%): 1006 (M +, 100) and .C 54H 79N 5O 13(1006.2) R t-value (HPLC post: 125 * 2.1 Kromasil , C-18): 7.35 minutes.Embodiment 4 rings [N-methyl-L-leucyl-D-(O-ethylene oxy carbonyl-imino-)-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-N-methyl-L-leucyl-D-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-]
Figure A0080882200791
At 0 ℃, 300.0mg (0.31mmol) 1 (seeing embodiment 1) is stirred in the 10ml anhydrous pyridine, and handle with 99.4mg (0.93mmol) chloroformic acid vinyl acetate.Continue then to stir 6 hours at 0 ℃.With entire reaction mixture concentrating under reduced pressure, resistates is placed chloroform afterwards, and, use NaHCO with 1N HCl washing 1 time 3Solution washing 2 times.Isolate organic phase, use dried over mgso, concentrating under reduced pressure then, (silica gel 60-Merck, particle diameter: 0.04-0.063mm) the residue crude product is carried out chromatogram purification, use hexanaphthene: ethyl acetate (2: 1) is as moving phase to use silicagel column.Obtained 188.7mg (theoretical yield 58.7%) ring [N-methyl-L-leucyl-D-(O-ethylene oxy carbonyl-imino-)-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-N-methyl-L-leucyl-D-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-], for trans-/cis-isomer mixture.LC-MS (acidity) m/z (%): 1037 (MH +, 100) and .C 55H 81N 5O 14(1036.2) R t-value (HPLC post: 125 * 2.1 Kromasil , C-18): 17.82 minutes embodiment 5 rings [N-methyl-L-leucyl-D-(O-methyl sulphonyl-imino-)-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-N-methyl-L-leucyl-D-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-]
Figure A0080882200801
With this reaction of methylsulfonyl chloride be to use following reagent to carry out according to the reaction method that is similar to embodiment 4: 200.0mg (0.20mmol) ring [N-methyl-L-leucyl-D-(hydroxyl-imino-)-lactoyl-N-methyl-L-leucyl-D-phenyl-lactoyl-N-methyl-L-leucyl-D-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-] (embodiment 1) 71.3mg (0.62mmol) methylsulfonyl chloride 8ml anhydrous pyridine
(silica gel 60-Merck, particle diameter: 0.04-0.063mm) the residue crude product is carried out chromatogram purification, at first use hexanaphthene: ethyl acetate (3: 2) is as moving phase to use silicagel column.Obtained 81.8mg (theoretical yield 38%) ring [N-methyl-L-leucyl-D-(O-methyl sulphonyl-imino-)-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-N-methyl-L-leucyl-D-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-], for trans-/cis-isomer mixture.LC-MS (acidity) m/z (%): 1042 (MH +, 100) and .C 53H 79N 5O 14S (1042.3) R t-value (HPLC post: 125 * 2.1 Kromasil , C-18): 17.18 minutes embodiment 6 rings [N-methyl-L-leucyl-D-(O-allyl amino carbonyl-imino-)-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-N-methyl-L-leucyl-D-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-]
To use 30.4mg (0.36mmol) allyl isocyanate and 21 successively in the 300.0mg in the 10ml dry toluene (0.31mmol) ring [N-methyl-L-leucyl-D-(hydroxyl-imino-)-lactoyl-N-methyl-L-leucyl-D-phenyl-lactoyl-N-methyl-L-leucyl-D-lactoyl-N-methyl-L-leucyl-D-phenyl-lactoyl-] (embodiment 1); 8-diazabicylo [5.4.0] 11 carbon-7-alkene (" DBU ") are handled, and stirring at room 33 hours.Then with entire reaction mixture concentrating under reduced pressure.At first use silicagel column (silica gel 60-Merck, particle diameter: 0.04-0.063mm) the residue crude product is carried out chromatogram purification, use hexanaphthene: acetone (3: 1) is as moving phase, and then with second silicagel column (silica gel 60-Merck, particle diameter: 0.04-0.063mm) carry out chromatogram purification, use hexanaphthene: ethyl acetate (2: 1-1: 1) as moving phase.Obtained 52.4mg (theoretical yield 16.1%) ring [N-methyl-L-leucyl-D-(O-allyl amino carbonyl-imino-)-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-N-methyl-L-leucyl-D-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-], for trans-/cis-isomer mixture.LC-MS (acidity) m/z (%): 1047 (M +, 100) and .C 56H 82N 6O 13(1047.3) R t-value (HPLC post: 125 * 2.1 Kromasil , C-18, pH2.3): 17.09; 17.39 minute.Embodiment 7 rings [N-methyl-L-leucyl-D-(O-N-tert-butoxycarbonyl-N-methyl-alanyl-imino-)-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-N-methyl-L-leucyl-D-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-]
At 0 ℃; with 184.0mg (4.1mmol) benzotriazole-1-base oxygen base-three (Er Jia base An Ji Phosphonium) hexafluorophosphate (BOP) and 124.0mg (0.95mmol) N; N-diisopropyl ethyl amine (" H ü nigs alkali ") is added in 300.0mg (0.31mmol) ring [N-methyl-L-leucyl-D-(hydroxyl-imino-)-lactoyl-N-methyl-L-leucyl-D-phenyl-lactoyl-N-methyl-L-leucyl-D-lactoyl-N-methyl-L-leucyl-D-phenyl-lactoyl-] (embodiment 1) and 75.7mg (0.37mmol) N-tert-butoxycarbonyl-solution of N-methylalanine in the 10ml anhydrous acetonitrile; this mixture was stirred 30 minutes at 0 ℃, then stirring at room 24 hours.With entire reaction mixture concentrating under reduced pressure, resistates is placed chloroform afterwards, and, isolate organic phase, use dried over sodium sulfate, then concentrating under reduced pressure with water extraction 2 times.By the remaining crude product of preparation HPLC purifying.Obtained 15.6mg (theoretical yield 4.4%) ring [N-methyl-L-leucyl-D-(O-N-tert-butoxycarbonyl-N-methyl-alanyl-imino-)-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-N-methyl-L-leucyl-D-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-], for trans-/cis-isomer mixture.LC-MS (acidity) m/z (%): 1150 (MH +, 100) and .C 61H 92N 6O 15(1149.4) R t-value (HPLC post: 125 * 2.1 Kromasil , C-18): 7.69; 7.76 minute.
The formula of in table 1, listing (Ia) compound (R 1, R 3, R 4, R 7, R 9, R 10:-Me; R 2, R 5, R 8, R 11:-isobutyl-; X 2:=N-A; X 2-X 4:=O) can make by similar approach.Table 1
The embodiment numbering -A R’ R” Physical data a)
? 8 ? -O-CH 2-Me ? -H ? -H 993(MH +，100)；R t：20.05 ? C 54H 81N 5O 12(992.2)
? 9 ? -O-CH 2-CH＝CH 2 ? -H ? -H 1005(MH +，100)；R t: 20.21; (20.31 trans/cis isomer mixture) C 55H 81N 5O 12(1048.3)
? 10 ? -O-CH 2-CH 2-Me ? -H ? -H 1006(MH +，100)；R t：13.75 ? C 55H 83N 5O 12(1006.3)
? 11 ? -O-CHMe 2 ? -H ? -H 1006(MH +，100)；R t：13.54 ? C 55H 83N 5O 12(1006.3)
Table 1 (continuing)
The embodiment numbering -A R’ R” Physical data a)
? 12 ? -O-CMe 3 ? -H ? -H 1006(MH +，100)；R t: 22.52; (22.85 trans/cis isomer mixture) C 56H 85N 5O 12(1006.3)
? 13 ? -O-CH 2-CN ? -H ? -H 1003(M +，100)；R t：7.49 ? C 54H 78N 6O 12(1003.2)
? 14 ? -O-CH 2-CH 2-OH ? -H ? -H 1008(M +，100)；R t：17.58 ? C 54H 81N 5O 13(1008.2)
? 15 ? -O-CH 2-CH 2-NH 2 ? -H ? -H 1008(MH +，100) ? C 54H 82N 6O 12(1007.3)
? 16 ? -NHMe ? -H ? -H 978(MH +，100)；R t：18.33 ? C 53H 80N 6O 11(977.2)
? 17 ? -O-CH 2-phenyl ? -H ? -H 1055(MH +，100)；R t: 21.23; (21.50 trans/cis isomer mixture) C 59H 83N 5O 12(1054.3)
? 18 ? -O-CH 2-(4-NO 2-phenyl) ? -H ? -H 1100(MH +，100)；R t：20.50 ? C 59H 82N 6O 14(1099.3)
Table 1 (continuing)
The embodiment numbering -A R’ R” Physical data a)
19 -O-CH 2-(2-NO 2-phenyl) -H -H 1099(M +，100)；R t：19.06 C 59H 82N 6O 14(1099.3)
20 -O-CH 2-(3-CF 3-phenyl) -H -H 1123(MH +，100)； R t: 19.50; (19.68 trans/cis isomer mixture) C 60H 82N 5O 12(1122.3)
21 -O-CH 2-(4-CF 3-phenyl) -H -H 1123(MH +，100)；R t：19.43 C 60H 82N 5O 12(1122.3)
22 -O-CH 2-(2-Cl-phenyl) -H -H 1088(MH +，100) R t: 19.65; (20.07 trans/cis isomer mixture) C 59H 82ClN 5O 12(1088.7)
23 -O-CH 2-(3-Cl-phenyl) -H -H 1088(MH +，100) R t：19.61；19.78 C 59H 82ClN 5O 12(1088.7)
24 -O-CH 2-(4-Cl-phenyl) -H -H 1088(MH +，100)； R t: 19.65; (19.82 trans/cis isomer mixture) C 59H 82ClN 5O 12(1088.7)
25 -O-CH 2-(3，4-Cl 2-phenyl) -H -H 1124(MH +，100)； R t: 20.14; (20.40 trans/cis isomer mixture) C 59H 81Cl 2N 5O 12(1123.2)
Table 1 (continuing)
The embodiment numbering -A R’ R” Physical data a)
26 -O-CH 2-(2，6-Cl 2-phenyl) -H -H 1124(MH +，100)； R t: 19.82; (20.12 trans/cis isomer mixture) C 59H 81Cl 2N 5O 12(1123.2)
27 -O-CH 2-(2，4-Cl 2-phenyl) -H -H 1124(MH +，100)； R t: 20.68; (21.16 trans/cis isomer mixture) C 59H 81Cl 2N 5O 12(1123.2)
28 -O-CH 2-(2，3-Cl 2-phenyl) -H -H 1124(MH +，100)； R t: 20.32; (20.79 trans/cis isomer mixture) C 59H 81Cl 2N 5O 12(1123.2)
29 -O-CH 2-(2-Cl, 6-F-phenyl) -H -H 1106(M +，100)； R t: 19.24; (19.44 trans/cis isomer mixture) C 59H 81ClFN 5O 12(1106.8)
30 -O-CH 2-(4-MeO-phenyl) -H -H 1084(MH +，100)；R t：18.97 C 60H 85N 5O 13(1084.3)
31 -O-CH 2-(4-MeOOC-phenyl) -H -H 1112(MH +，100)；R t：18.89 C 60H 85N 5O 13(1112.3)
32 -O-CH 2-(4-F-phenyl) -H -H 1072(MH +，100)；R t：19.48 C 59H 82FN 5O 12(1072.3)
Table 1 (continuing)
The embodiment numbering -A R’ R” Physical data a)
33 -O-CH 2-(4-Me-phenyl) -H -H 1068(M +，100)；R t：19.95 C 60H 85N 5O 12(1068.3)
34 -NH 2 -H -H 964(MH +，100)；R t：16.24 C 52H 78N 6O 11(963.2)
35 -O-CO-O-Me -H -H 1022(MH +，100)；R t：7.32 C 54H 79N 5O 14(1022.2)
36 -O-CO-O-CH 2-Me -H -H 1036(MH +，100)；R t：17.69 C 55H 81N 5O 14(1036.2)
37 -O-CO-O-CH 2-CH＝CH 2 -H -H 1048(MH +，100)；R t：17.83 C 56H 81N 5O 14(1048.3)
38 -O-CO-O-CH 2-C≡CH -H -H 1046(M +，38)；R t：7.32 C 56H 79N 5O 14(1046.3)
39 -O-CO-O-CHMe-CH 2-Me -H -H 1064(MH +，100)；R t：18.28 C 57H 85N 5O 14(1064.3)
40 -O-CO-O-CH 2-CHMe 2 -H -H 1064(MH +，100)；R t：18.33 C 57H 85N 5O 14(1064.3)
Table 1 (continuing)
Figure A0080882200881
Table 1 (continuing) A) 1H-NMR (400 MHz, δ, ppm); 13C-NMR (100 MHz, δ, ppm); LC-MS (acidity)
M/z (%); R t-value (minute, HPLC post: 125 * 2.1 Kromasil , the C-18) reaction of the oxyamine of example I-56 polymkeric substance combination and ring [N-methyl-L-leucyl-sulfo-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-N-methyl-L-leucyl-D-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-]
(modification a) uses following reagent to carry out 6-(amino-oxy)-3 according to the reaction method that is similar to embodiment 1; 4; 5; 6-tetrahydrochysene-2H-pyrans-2-base-methoxy methyl base polystyrene and epithio are for the reaction of depsipeptides: 500.0mg (0.52mmol) ring (N-methyl-L-leucyl-D-sulfo-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-N-methyl-L-leucyl-D-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-) 200.0mg 6-(amino-oxy)-3; 4; 5,6-tetrahydrochysene-2H-pyrans-2-base-methoxyl group-methyl-polystyrene 181.0mg (1.55mmol) mercuric acetate (II) 15ml methylene dichloride
At first with 6-(amino-oxy)-3,4,5,6-tetrahydrochysene-2H-pyrans-2-base-methoxymethyl-polystyrene in stirring at room 30 minutes, uses epithio to handle for depsipeptides and mercuric acetate (II) in methylene dichloride then.Isolate polystyrene afterwards, and respectively use methylene dichloride, dimethyl formamide/water (1: 1), dimethyl formamide respectively to wash successively 3 times, and dry under high vacuum.Output: 180mg polystyrene IR (KBr): 1730cm -1(ν C=OCyclodepsipeptide) formula (Ib) raw material embodiment (Ib-1) ring [N-methyl-L-leucyl-D-sulfo-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-N-methyl-L-leucyl-D-sulfo-lactoyl-N-methyl-L-leucyl-D-phenyl sulfo-lactoyl-)
Will be at the 1.0g in the 20ml toluene (1.05mmol) ring (N-methyl-L-leucyl-D-lactoyl-N-methyl-L-leucyl-D-phenyl-lactoyl-N-methyl-L-leucyl-D-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-) PF 1022A (referring to EP-OS 382173; US patent 5116815) with 1.4g (3.5mmol) 2; 4-two (4-p-methoxy-phenyl)-2; 4-dithio-1; 3; 2; 4-dithia two phospholanes (dithiadiphosphetan) (" Lawesson ' s reagent ") handle, and under reflux temperature, stirred 3.5 hours.Then the entire reaction mixture is cooled to 0 ℃, filters, and the gained filtrate decompression is concentrated.(silica gel 60-Merck, particle diameter: 0.04-0.063mm) the residue crude product is carried out chromatogram purification, at first use methylene dichloride as moving phase, use hexanaphthene then: acetone (3: 1) is as moving phase with silicagel column.Obtained 0.46g (theoretical yield 43.6%) ring (N-methyl-L-leucyl-D-sulfo-lactoyl-N-methyl-L-leucyl-D-phenyl sulfo-lactoyl-N-methyl-L-leucyl-D-sulfo-lactoyl-N-methyl-L-leucyl-D-phenyl sulfo-lactoyl-). 1H-NMR (CDCl 3, δ): 2,99,3.06,3.26,3.42 (4x-N-Me); 4.86,6.42,6.61 (4x-N-CH 2-); 5.31,5.55,5.81,5.89 (4x-O-CH 2-); 7.26 (ppm.LC-MS (acidity) m/z (%) of phenyl-H): 1013 (M +, 100); 310 (21); 274 (30); 198 (42) .C 52H 76N 4O 8S 4(1013.4) embodiment (Ib-2) ring (N-methyl-L-leucyl-D-sulfo-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-N-methyl-L-leucyl-D-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-)
Figure A0080882200921
At 0 ℃; will be at the 1.0g in the 15ml tetrahydrofuran (THF) (1.05mmol) ring (N-methyl-L-leucyl-D-lactoyl-N-methyl-L-leucyl-D-phenyl-lactoyl-N-methyl-L-leucyl-D-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-) PF 1022A (referring to EP-OS 382173; US patent 5116815) with 0.26g (0.05mmol) 2; 4-two (4-Phenoxyphenyl)-2; 4-dithio-1; 3; 2; 4-dithia two phospholanes (" Belleau ' s reagent ") are handled, and stirring at room 18 hours.With entire reaction mixture concentrating under reduced pressure, (silica gel 60-Merck, particle diameter: 0.04-0.063mm) the residue crude product is carried out chromatogram purification twice, use hexanaphthene: acetone (3: 1) is as moving phase with silicagel column then.Obtained 0.12g (theoretical yield 11.8%) ring (N-methyl-L-leucyl-D-sulfo-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-N-methyl-L-leucyl-D-lactoyl-N-methyl-L-leucyl-D-phenyl lactoyl-).LC-MS (acidity) m/z (%): 965 (M +, 100); 200 (45) .C 52H 76N 4O 11S (965.2)
The formula of in following table 2, listing (Ib) compound (R 1, R 3, R 4, R 7, R 9, R 10:-Me; R 2, R 5, R 8, R 11:-isobutyl-) can make by similar approach.Table 2 Table 2 (continuing)
Figure A0080882200941
Table 2 (continuing)
Figure A0080882200951
A) 1H-NMR (400 MHz, δ, ppm); 13C-NMR (100 MHz, δ, ppm); LC-MS (acidity) m/z (%) formula (II) raw material embodiment (II-1) is (S)-N-[(tetrahydrofuran (THF)-2-yl a)) methoxyl group] phthalic imidine (referring to people such as S.Bailey, J.Med.Chem.34,1991,57-65 page or leaf)
Figure A0080882200961
With 1.5g (14.7mmol) (S)-tetrahydrofuran (THF)-2-base methyl alcohol (people such as A.Mravik; Tetrahedron:Asymmetry 7 (5); 1996; the 1477-1484 page or leaf), 2.4g (14.7mmol) N-hydroxyphthalimide and 3.85 (14.7mmol) triphenylphosphine stir in 50ml THF; and handle with 3.4g (19.5mmol) diethyl azodiformate at 0 ℃ (under protective atmosphere), stirring at room 18 hours.With entire reaction mixture concentrating under reduced pressure, resistates is placed ether then, and water extracts 2 times.(silica gel 60-Merck, particle diameter: 0.04-0.063mm) the residue crude product is carried out chromatogram purification, use hexanaphthene: acetone (6: 1) is as moving phase with silicagel column.Obtained 1.7g (theoretical yield 46.8%) (S)-N-[(tetrahydrofuran (THF)-2-yl) methoxyl group] phthalic imidine.LC-MS-LOOP m/z (%): 248 (MH +, 100); C 13H 13NO 4(247.2) R t-value (HPLC post: 125 * 2.1 Kromasil , C-18): 7.56 minutes b) (S)-tetrahydrofuran (THF)-2-ylmethoxy amine
Figure A0080882200962
With 1.6g (6.47mmol) (S)-[N-(tetrahydrofuran (THF)-2-yl) methoxyl group] phthalic imidine in the 30ml methylene dichloride, stir, add 0.6g (12.9mmol) N-methyl hydrazine at 0 ℃, and with this mixture stirring at room 18 hours.Then the entire reaction mixture is filtered, and filtrate decompression is concentrated.With silicagel column (silica gel 60-Merck, particle diameter: 0.04-0.063mm) the residue crude product is carried out chromatogram purification, use ethyl acetate as moving phase.Obtained 130mg (theoretical yield 17.2%) (S)-tetrahydrofuran (THF)-2-ylmethoxy amine.LC-MS (acidity) m/z (%): 118 (MH +, 100) and .C 52H 76N 4O 11S (117.1) embodiment (II-2) is N-tert-butoxycarbonyl amino oxygen base ethanoyl morpholine a)
Figure A0080882200971
2.0g (10.5mmol) N-tert-butoxycarbonyl amino oxygen guanidine-acetic acid (Novabiochem:01-63-0060) is stirred in the 75ml methylene dichloride, and at 0 ℃ with 3.1g (24.0mmol) N, (2-oxo-3-oxazolidine base) Phosphonium acyl chlorides (BOP-Cl) is handled, and stirs 30 minutes for N-diisopropylethylamine (H ü nig ' s alkali), 3.1g (12.0mmol) two.Add 1.05g (12.0mmol) morpholine then, continue to stir 6 hours at 0 ℃.With this reaction soln water extraction 2 times, isolate organic phase, use dried over sodium sulfate, then concentrating under reduced pressure.(silica gel 60-Merck, particle diameter: 0.04-0.063mm) the residue crude product is carried out chromatogram purification, use hexanaphthene: acetone (3: 1) is as moving phase with silicagel column.Obtained 1.0g (theoretical yield 37%) N-tert-butoxycarbonyl amino oxygen base ethanoyl morpholine. 1H-NMR (CDCl 3, δ): 1.47 (s, 9H, C (CH 3) 3); 3.37-3.72 (3m, 8H, 2x-N-CH 2-; 2x-O-CH 2-; ); 4.54 (s, 2H ,-O-CH 2-); 8.06 (s, 1H, N-H) ppm.LC-MS (acidity) m/z (%): 205 (M +-H 2C=CMe 2, 12), 161 (100) .C 11H 20N 2O 5(260.3) R t-value (HPLC-post: 125 * 2.1 Kromasil , C-18): the hydrochloride of amino oxygen base ethanoyl morpholine 5.22 minutes b)
Figure A0080882200972
Feed 30 minutes anhydrous hydrogen chloride gas in 0 ℃ the solution to 0.65g (2.5mmol) N-tert-butoxycarbonyl amino oxygen base ethanoyl morpholine being cooled in the 220ml anhydrous methylene chloride.Then with this mixture about 16 hours, and with this entire reaction mixture concentrating under reduced pressure in stirring at room.Obtained the hydrochloride of 380mg (theoretical yield 77%) amino oxygen base ethanoyl morpholine.LC-MS (acidity) m/z (%): 161 (MH +-HCl, 100), 146 (12), 129 (45) .C 6H 13ClN 2O 3(196.6) a) 6-(N-succinimido oxygen base)-3,4,5 of embodiment (II-3), 6-tetrahydrochysene-2H-pyrans-2-ylmethoxy methyl-polystyrene resin
Figure A0080882200981
1.0g (0.51mmol) DHP HM resin (Novabiochem:01-64-0192) at 8.0ml 1, was expanded about 30 minutes in the 2-ethylene dichloride.Add 293.5mg (2.5mmol) N-hydroxy-succinamide and 261.4mg (1.0mmol) pyridine tosilate (PPTS) then, and this mixture was stirred 16 hours at 80 ℃.Isolate resin then, and with washed with dichloromethane 1 time, with dimethyl formamide/water (1: 1) washing 4 times, with dimethyl formamide washing 3 times, with washed with dichloromethane 3 times.With the 6-(N-succinimido oxygen base)-3,4,5 of purifying, 6-tetrahydrochysene-2H-pyrans-2-base-methoxymethyl-polystyrene resin is dry under high vacuum, and can be used for the subsequent reaction step.IR (KBr): 1730cm -1(ν C=OSuccinimido) 6-(amino oxygen base)-3,4,5 b), 6-tetrahydrochysene-2H-pyrans-2-ylmethoxy methylated polystyrene
Figure A0080882200982
Under protective atmosphere (under the argon atmospher); with 1.0g 6-(N-succinimido oxygen base)-3,4,5; 6-tetrahydrochysene-2H-pyrans-2-ylmethoxy methyl-polystyrene resin is handled with 127.7mg (2.55mmol) hydrazine hydrate in 20ml benzene, and under refluxad stirs 20 hours.Isolate resin then, use washed with dichloromethane 5 times, and dry under high vacuum.IR (KBr): 1630cm -1(ν The N-H distortion-O-NH 2); 3300cm -1(ν The N-H distortion-O-NH 2)
The formula of in following table 3, listing (II) compound (A=-Y-R 13) can make by the method that is similar to example II-1 and II-2.Table 3
Figure A0080882200991
Figure A0080882200992
Figure A0080882201001
A) 1H-NMR (400 MHz, δ, ppm); 13C-NMR (100 MHz, δ, ppm); Nematode test Heterakis spumosa (Heterakis spumosa)/mouse in LC-MS (acidity) m/z (%) the biological Examples embodiment A body
With Heterakis spumosa kind nematode with the mouse infection that experimentizes.For infecting mouse, that Heterakis spumosa is Orally administered as 90 embryonated eggs.
After finishing latent period, the 46th day intraperitoneal used the active compound of suspension after infection.Determine active:
The 54th day selection mouse after infection.With the ripe parasite in microscopic counting colon and the caecum.Compare administration group and the successful treatment of not treating in the control group.
The active compound and the effective dose (effective dose) of test are as shown in the table.
Active compound embodiment sequence number Effective dose [mg/kg] Minimizing ratio [%]
Ring (MeLeu-D-Lac-MeLeu-D-PhLac-MeLeu-D-Lac-MeLeu-D-PhLac) PF1022A is known a)Ring (MeLeu-D-Lact-MeLeu-D-PhLac-MeLeu-D-Lac-MeLeu-D-PhLac) is known b) 25 ? ? 25 0 ? ? 0
The embodiment of the invention 1 25 75-90
A)Referring to EP-OS 382173, EP-OS 503538; B)Referring to WO 98/43965MeLeu=N-methyl-L-leucine, D-Lac=D-lactic acid, nematode test Nematospiroides dubius/ mouse in the D-PhLac=D-phenyl-lactic acid, D-Lact=D-sulfo-lactoyl Embodiment B body
With Nematospiroides dubius kind nematode with the mouse infection that experimentizes.For infecting mouse, that Nematospiroides dubius is Orally administered as 90 embryonated eggs.
After finishing latent period, the 46th day intraperitoneal used the active compound of suspension after infection.Determine active:
The 54th day selection mouse after infection.With the ripe parasite in microscopic counting colon and the caecum.Compare administration group and the successful treatment of not treating in the control group.
The active compound and the effective dose (effective dose) of test are as shown in the table.
Active compound embodiment sequence number Effective dose [mg/kg] Minimizing ratio [%]
Ring (MeLeu-D-Lac-MeLeu-D-PhLac-MeLeu-D-Lac-MeLeu-D-PhLac) PF1022A is known a)Ring (MeLeu-D-Lac-MeLeu-D-PhLac-MeLeu-D-Lac-MeLeu-D-PhLac) is known b) 25 ? ? 25 0 ? ? 0
The embodiment of the invention 1 25 100
A)Referring to EP-OS 382173, EP-OS 503538; B)Referring to WO 98/43965MeLeu=N-methyl-L-leucine, D-Lac=D-lactic acid, the nematode trial point changes blood thatch nematode (Haemonchus contortus)/sheep in the D-PhLac=D-phenyl-lactic acid, D-Lact=D-sulfo-lactoyl Embodiment C body
Finish the back to the sheep infection that experimentizes with haemonchus contortus in this parasitic latent period.With active compound as pure oral administration of active compounds and/or intravenous administration.
By determining to render a service with the worm egg of ight soil discharge afterwards before the quantitative counting treatment.
Stop fully being meant that worm has been evicted from or seriously damaged them no longer can produce any ovum (effective dose) to such an extent as to treatment back ovum is discharged
The active compound and the effective dose (effective dose) of test are as shown in the table.
Active compound embodiment sequence number Effective dose [mg/kg] Minimizing ratio [%]
Ring (MeLeu-D-Lac-MeLeu-D-PhLac-MeLeu-D-Lac-MeLeu-D-PhLac) PF1022A is known a) 0.25 0.01 100 0
The embodiment of the invention 8 embodiment of the invention 36 embodiment of the invention 46 0.01 0.01 0.10 100 100 100
A)Referring to EP-OS 382173, EP-OS 503538; MeLeu=N-methyl-L-leucine, D-Lac=D-lactic acid, D-PhLac=D-phenyl-lactic acid

Claims (10)

1. the compound of formula (I) and its pure optically active isomer, racemic modification and physiological acceptable salt R wherein 1, R 4, R 7And R 10Represent hydrogen, straight or branched alkyl independently of one another, R 2, R 5, R 8And R 11Represent hydrogen, optional straight or branched alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl and aryl or the heteroaryl that replaces independently of one another, R 10And R 11Represent optional 5-unit that replaces or 6-unit ring with the atom that they connected, described ring can be chosen wantonly by oxygen, sulphur, sulfoxide group or alkylsulfonyl and be interrupted R 6And R 12Represent hydrogen, the optional alkyl or aryl alkyl that replaces and the optional cycloalkylalkyl that replaces independently of one another, R 3And R 9Represent hydrogen, optional straight or branched alkyl, alkenyl, cycloalkyl, alkoxy carbonyl alkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, aryl or the heteroaryl that replaces independently of one another, and C=X 1, C=X 2, C=X 3And C=X 4Represent group C=O, a C=S or CH independently of one another 2Or group C=N-A, wherein C=X 1, C=X 2, C=X 3And C=X 4In the middle of have at least one to represent C=N-A, wherein A represent hydrogen, optional alkyl, alkenyl, alkynyl group, alkyl-carbonyl, alkyl sulphonyl and the cyano group that replaces, nitro, formamyl, alkoxy carbonyl, formyl radical ,-(C=NH)-NH 2,-P (O)-O-alkyl ,-P (S)-O-alkyl or the optional group A that represents 1
-Y-R 13(A 1) wherein Y represent oxygen, sulphur or-N-R 14, R 13And R 14Represent hydrogen, optional straight or branched alkyl, alkenyl, alkynyl group, cycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, aryl or the heteroaryl that replaces independently of one another and represent formyl radical, alkoxyl group dicarbapentaborane, alkyl sulphonyl, halogenated alkoxy alkyl alkylsulfonyl, alkoxy carbonyl, alkyl amino-carbonyl, alkenyloxy carbonyl, chain oxy-acetylene carbonyl, aryloxy alkyl, heteroaryl carbonyl, alkyl-carbonyl or optional representative to be selected from B 1, B 2, B 3And B 4Group,
Figure A0080882200031
Wherein the straight or branched alkyl that replaces is chosen in the Q representative wantonly, alkenyl, alkynyl group, cycloalkyl, alkoxyl group, alkenyloxy, chain oxy-acetylene, cycloalkyloxy, aryloxy, alkoxy aryl, heteroaryloxy, the heteroaryl alkoxyl group, alkylthio, alkenyl thio, sulfur-based chain acetylene, cycloalkylthio, arylthio, alkylthio-aryl, heteroarylthio, the heteroaryl alkylthio, alkylamino, alkenyl amino, chain alkynyl amino, cycloalkyl amino, arylamino, aryl-alkyl amino, heteroaryl amino, heteroarylalkyl amino, dialkyl amido, two alkenyl aminos, aryl, arylalkyl, heteroaryl or heteroarylalkyl, cyano group, the cyclic amino of optional replacement amino or that connect via nitrogen
Figure A0080882200032
Representation carboxy, thiocarboxyl group, sulfoxide group, alkylsulfonyl ,-P (O)-O-alkyl ,-P (S)-O-alkyl or-C=N-R 15, R 15Represent hydrogen, hydroxyl, alkoxyl group, alkyl-carbonyl, alkoxy carbonyl, halogenated alkyl carbonyl, alkyl sulphonyl, nitro or cyano group, R 16Represent hydrogen or alkyl, n represents 0,1 or 2, Y 1Represent oxygen, sulphur or-N-R 17If, Y 1Represent nitrogen, then R 18The cyclic amino that representative connects via nitrogen-atoms, R 17And R 18Represent hydrogen, optional straight or branched alkyl, alkenyl, alkynyl group, cycloalkyl, cycloalkylalkyl, alkoxy carbonyl, aryl, arylalkyl, heteroaryl or the heteroarylalkyl that replaces, perhaps R independently of one another 17And R 18Represent the optional heterocycle 4-unit that replaces, 5-unit, 6-unit or 7-unit's ring system or the optional 7-unit that replaces of representative-bicyclic ring system of 10-unit with adjacent nitrogen-atoms, described ring system also can choose wantonly by oxygen, sulphur, sulfoxide group, alkylsulfonyl, carbonyl ,-N-O ,-N=,-NR 22Or quaternary nitrogen is interrupted R 19And R 20Represent hydrogen, straight or branched alkyl, alkenyl, cycloalkyl and optional aryl, arylalkyl, heteroaryl, the heteroarylalkyl that replaces, perhaps R independently of one another 19And R 20The volution that replaces, R are chosen in representative wantonly together 20And R 21Represent the optional 5-unit that replaces, 6-unit or 7-unit ring with the atom that they connected, described ring can be chosen wantonly by oxygen, sulphur, sulfoxide group or alkylsulfonyl and be interrupted R 21Represent hydrogen, optional straight or branched alkyl, cycloalkyl, arylalkyl, heteroarylalkyl and aryl or the heteroaryl that replaces, R 22Represent hydrogen, optional straight or branched alkyl, alkenyl, alkynyl group, cycloalkyl, cycloalkylalkyl, alkoxy carbonyl, alkyl-carbonyl, naphthene base carbonyl, cyano group, arylalkyl, heteroarylalkyl and aryl or the heteroaryl that replaces, R 13Can also represent the protecting group that optionally is removed or close group and be connected polymer support on the Y via the anchor that optionally is removed.
2. the general formula of claim 1 (I) cyclo-imino depsipeptides and optically active isomer, racemic modification and physiological acceptable salt
Figure A0080882200051
R wherein 1, R 4, R 7And R 10Represent straight or branched C 1-4-alkyl, particularly methyl, R 2, R 5, R 8And R 11Represent C independently of one another 1-4-alkyl, particularly isobutyl-, R 6And R 12The C that replaces is chosen in representative wantonly independently of one another 1-4-alkyl or aryl-C 1-2-alkyl, the particularly optional benzyl that replaces, R 3And R 9Represent optional C independently of one another 1-4-alkyl, heteroaryl-C 1-2-alkyl, C 1-C 4-alkoxy carbonyl methyl, aryl-C 1-2-alkyl, the particularly optional benzyl that replaces, wherein, the substituting group that can mention is hydrogen, halogen, cyano group, formamyl, C 1-4-alkyl, the hydroxyl that carries protecting group or unprotected hydroxyl, C 1-8-alkoxyl group, C 1-4-alkoxy-C 1-4-alkoxyl group, C 2-4-alkenyloxy, wherein heterocyclic moiety can substituted again heteroaryl-C 1-4-alkoxyl group, nitro, or be selected from R 23R 24N-C 1-C 6-alkoxyl group, R 23R 24N-C 1-C 8-alkyl, NR 23R 24With-SO 2-NR 23R 24Group, R wherein 23And R 24Respectively represent hydrogen, C independently of one another 1-C 6-alkyl, C 1-C 6-alkoxy-C 1-C 6-alkyl, C 3-C 7-cycloalkyl, C 3-C 7-cycloalkyl amino-C 1-C 6-alkyl, the one or more carbon atoms on the wherein said cycloalkyl ring can be substituted heteroaryl-C by nitrogen, oxygen or sulphur atom 1-C 4-alkyl or protecting group, perhaps R 23And R 24Represent heteroaryl or Heterocyclylalkyl with the nitrogen-atoms that they connected, particularly N-pyrrolidyl, N-piperazinyl, N-morpholinyl, N-thio-morpholinyl, N-piperidyl, TMSIM N imidazole base, 2-oxo-pyrrolidine base, phthalimido or tetrahydrochysene phthalimido, and (i) C=X 1Represent group C=N-A, C=X 2, C=X 3And C=X 4Represent C=O, C=S or CH 2, or (iii) C=X 3Represent group C=N-A, C=X 1, C=X 2And C=X 4Represent C=O, C=S or CH 2, or (iv) C=X 1And C=X 3Represent group C=N-A, C=X 2And C=X 4Represent C=O, C=S or CH 2, wherein A represents hydrogen, the optional C that replaces 1-4-alkyl, C 2-4-alkenyl, C 2-4-alkynyl group, C 1-C 4-alkyl-carbonyl, C 1-6-alkyl sulphonyl and cyano group, nitro, formamyl, C 2-6-alkoxy carbonyl, formyl radical ,-(C=NH)-NH 2,-P (O)-O-C 1-3-alkyl ,-P (S)-O-C 1-3-alkyl or the optional A that represents 1
-Y-R 13(A 1), wherein Y represent oxygen or-N-R 14, R 13And R 14Represent hydrogen, the optional straight or branched C that replaces independently of one another 1-8-alkyl, C 2-8-alkenyl, C 2-8-alkynyl group, C 3-7-cycloalkyl, C 3-7-cycloalkyl-C 1-2-alkyl, aryl-C 1-2-alkyl, heteroaryl-C 1-2-alkyl, aryl or heteroaryl and formyl radical, C 1-C 8-alkyl sulphonyl, C 1-C 2-halogenated alkoxy-C 1-2-alkyl sulphonyl, C 1-C 8-alkyl-carbonyl, C 1-C 8-alkoxy carbonyl, C 1-C 8-alkyl amino-carbonyl, C 2-C 8-alkenyloxy carbonyl, C 2-C 8-chain oxy-acetylene carbonyl, aryloxy-C 1-C 2-alkyl, heteroaryl carbonyl, C 1-4-alkoxyl group dicarbapentaborane or optional representative are selected from B 1, B 2, B 3And B 4Group Wherein the straight or branched C that replaces is chosen in the Q representative wantonly 1-8-alkyl, C 2-8-alkenyl, C 2-8-alkynyl group, C 3-7-cycloalkyl, C 1-6-alkoxyl group, C 2-6-alkenyloxy, C 2-6-chain oxy-acetylene, C 3-7-cycloalkyloxy, aryloxy, aryl-C 1-2-alkoxyl group, heteroaryloxy, heteroaryl-C 1-2-alkoxyl group, C 1-6-alkylthio, C 2-6-alkenyl thio, C 2-6-sulfur-based chain acetylene, C 3-7-cycloalkylthio, arylthio, aryl-C 1-2-alkylthio, heteroarylthio, heteroaryl-C 1-2-alkylthio, C 1-6-alkylamino, C 2-6-alkenyl amino, C 2-6-chain alkynyl amino, C 3-6-cycloalkyl amino, arylamino, aryl-C 1-2-alkylamino, heteroaryl amino, heteroaryl-C 1-2-alkylamino, two-C 1-4-alkylamino, two-C 2-4-alkenyl amino, aryl, aryl-C 1-2-alkyl, heteroaryl, heteroaryl-C 1-C 2The cyclic amino of-alkyl and cyano group, amino or the optional replacement that connects via nitrogen,
Figure A0080882200071
Represent thiocarboxyl group or carboxyl, R 15Represent hydrogen, hydroxyl, C 1-4-alkoxyl group, C 1-4-alkyl-carbonyl, C 1-4-alkoxy carbonyl, halo-C 1-4-alkyl-carbonyl, C 1-4-alkyl sulphonyl, nitro or cyano group, R 16Represent hydrogen or C 1-4-alkyl, n represent 0,1 or 2, Y 1Represent oxygen, sulphur or-N-R 17If, Y 1Represent nitrogen, then R 18The cyclic amino that representative connects via nitrogen-atoms, R 17And R 18Represent hydrogen, the optional straight or branched C that replaces independently of one another 1-6-alkyl, C 2-6-alkenyl, C 2-6-alkynyl group, C 3-7-cycloalkyl, C 3-7-cycloalkyl-C 1-6-alkyl, C 1-6-alkoxy carbonyl, aryl, aryl-C 1-2-alkyl, heteroaryl, heteroaryl-C 1-2-alkyl, perhaps R 17And R 18Represent the optional heterocycle 4-unit that replaces, 5-unit, 6-unit or 7-unit's ring system or the optional 7-unit that replaces of representative-bicyclic ring system of 10-unit with adjacent nitrogen-atoms, described ring system also can choose wantonly by oxygen, sulphur, sulfoxide group, alkylsulfonyl, carbonyl ,-N-O ,-N=,-NR 22Or quaternary nitrogen is interrupted R 19And R 20Represent hydrogen, the optional straight or branched C that replaces independently of one another 1-6-alkyl, C 2-6-alkenyl, C 3-7-cycloalkyl and optional aryl, the aryl-C that replaces 1-2-alkyl, heteroaryl, heteroaryl-C 1-2-alkyl, perhaps R 19And R 20The volution that replaces, R are chosen in representative wantonly together 20And R 21Represent the optional 5-unit that replaces, 6-unit or 7-unit ring with the atom that they connected, described ring can be chosen wantonly by oxygen, sulphur, sulfoxide group or alkylsulfonyl and be interrupted R 21Represent hydrogen, the optional straight or branched C that replaces 1-6-alkyl, C 3-7-cycloalkyl, aryl-C 1-2-alkyl, heteroaryl-C 1-2-alkyl and aryl or heteroaryl, R 22Represent hydrogen, the optional straight or branched C that replaces 1-6-alkyl, C 2-6-alkenyl, C 2-6-alkynyl group, C 3-7-cycloalkyl, C 3-7-cycloalkyl-C 1-6-alkyl, C 1-6-alkoxy carbonyl, C 1-6-alkyl-carbonyl, C 3-7-naphthene base carbonyl, cyano group, aryl-C 1-2-alkyl, heteroaryl-C 1-2-alkyl and aryl or heteroaryl, R 13The protecting group that representative optionally is removed; for example allyl group, allyloxy carbonyl (Alloc), benzyl (Bn), benzyloxycarbonyl (Z), tert-butoxycarbonyl (Boc), tetrahydropyrans-2-base (THP) or fluorenyl methoxy carbonyl (Fmoc), and representative is closed group via the anchor that optionally is removed and is connected polymer support on the Y.
3. the method for preparing general formula (I) new compound of claim 1
Figure A0080882200081
R wherein 1-R 12And group C=X 1-C=X 4Has the implication that in claim 1, provides, it is characterized in that, at suitable metal-salt or metal oxide, particularly mercuric acetate (II), mercury chloride (II) and red precipitate (II) exist down, in the presence of the alkali reaction auxiliary, and in the presence of suitable diluent, with general formula (I) epithio for depsipeptides and salt thereof
Figure A0080882200091
R wherein 1-R 12Have the implication that in claim 1, provides, and C=X 1, C=X 2, C=X 3And C=X 4Represent C=O, C=S or CH independently of one another 2, group C=X wherein 1, C=X 2, C=X 3And C=X 4In the middle of have at least one must represent C=S, react with general formula (II) aminocompound
H 2N-A (II) wherein A has the implication that provides in claim 1.
4. the method for preparing general formula (Ia) compound and salt thereof, and be characterised in that a) at suitable metal-salt or metal oxide, particularly mercuric acetate (II), mercury chloride (II) and red precipitate (II) exist down, in the presence of the alkali reaction auxiliary, and in the presence of suitable diluent, with general formula (Ib) epithio for depsipeptides or its salt R wherein 1-R 12Have the implication that in claim 1, provides, react with general formula (II) aminocompound
H 2N-A (II) wherein A has the implication that provides in claim 1, or b) in order to prepare general formula (Ia) new cyclo-imino depsipeptides and salt thereof R wherein 1-R 12Have the implication that provides in claim 1, A represents group-Y-R 13(A 1), wherein Y has the implication that provides, R in claim 1 13Representative is selected from B 1-B 3Group,
Figure A0080882200102
Wherein
Figure A0080882200103
Q, Y 1, n, R 16, and R 18-R 20Has the implication that in claim 1, provides, with general formula (Ic) compound and its salt
Figure A0080882200111
Wherein Y and R 1-R 12Have the implication that in claim 1, provides, react with general formula (IIIa-c) compound Wherein
Figure A0080882200113
Q, Y 1, n, R 16, and R 18-R 20Has the implication that in claim 1, provides, W represents for example halogen of suitable leavings group, if suitably this is reflected at the catalyzer existence down, if suitably in the presence of the alkali reaction auxiliary, if with suitably in the presence of thinner, carry out perhaps c) for prepare general formula (Ia) compound and salt thereof wherein A represent group-Y-R 13(A 1) wherein Y have the implication that in claim 1, provides, R 13Representative is selected from B 1And B 3Group
Figure A0080882200121
Wherein Q, Y 1, n, R 18-R 20Have the implication that provides in claim 1, n represents 0, and group
Figure A0080882200122
Representation carboxy is with general formula (Ic) compound and salt thereof
Figure A0080882200123
Wherein Y and R 1-R 12Have the implication that in claim 1, provides, react with general formula (IV) carboxylic acid anhydride
(Q-CO) 2O (IV) wherein Q has the implication that provides in claim 1, or represents group
Figure A0080882200131
Y wherein 1, R 18-R 20Has the implication that in claim 1, provides, if suitably this is reflected at the catalyzer existence down, if suitably in the presence of the alkali reaction auxiliary, if with suitably in the presence of thinner, carry out perhaps d) with general formula (Ic) compound α) and with logical formula V amino acid derivative reaction Wherein
Figure A0080882200133
Q and R 19-R 21Has the implication that in claim 1, provides, if suitably this is reflected at the coupling agent existence down, if if suitably in the presence of thinner, carrying out in the presence of the alkali reaction auxiliary and suitably, perhaps β) with general formula (VI) and (VII) compound react R 15-N=C=Y (VI) Wherein
Figure A0080882200141
Y and R 15Has the implication that in claim 1, provides, if suitably this is reflected under alkali reaction auxiliary or the catalyzer existence, if suitably carry out in the presence of thinner.
5. the method for preparing general formula (Ic) compound and salt thereof Wherein Y and R 1-R 12Have the implication that in claim 1, provides, it is characterized in that a) by general formula (Ia) compound and salt thereof
Figure A0080882200143
R wherein 1-R 12Have the implication that provides in claim 1, A represents group-Y-R 13(A 1), wherein Y represent oxygen or-N-H, R 13The protecting group that representative optionally is removed is allyl group, allyloxy carbonyl (Alloc), benzyl (Bn), benzyloxycarbonyl (Z), tert-butoxycarbonyl (Boc), tetrahydropyrans-2-base (THP) or fluorenyl methoxy carbonyl (Fmoc) for example; according to the protecting group that can be removed; or in the presence of the hydrogenation catalyst, in the presence of protonic acid or alkali reaction auxiliary and in the presence of thinner, with radicals R 13Optionally remove, perhaps b) by general formula (Ia) compound and the salt thereof that are connected on the polymer support
Figure A0080882200151
R wherein 1-R 12Have the implication that provides in claim 1, A represents group-Y-R 13(A 1) wherein Y represent oxygen or-N-H, R 13The anchor that optionally be removed of representative on polymer support closes group,
In the presence of the appropriate catalyst or, by anchor being closed group from polymeric carrier R in the presence of the protonic acid and in the presence of thinner 13On optionally remove and discharge general formula (Ic) compound.
6. composition is characterized in that, it comprises formula (I) compound of at least a claim 1.
7. the application of the formula of claim 1 (I) compound in the control volume entozoa.
8. the entozoal method of control volume is characterized in that, with formula (I) compound effects of claim 1 in endoparasite and/or its site.
9. the method for compositions of preparation antibody endoparasite is characterized in that, formula (I) compound of claim 1 is mixed with spreading agent and/or tensio-active agent.
10. the application of the formula of claim 1 (I) compound in preparation antibody endoparasite composition.
CN00808822A 1999-06-11 2000-05-30 Cyclo-imino depsipeptides and their utilization in controlling endoparasites Pending CN1355794A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19926620.4 1999-06-11
DE19926620A DE19926620A1 (en) 1999-06-11 1999-06-11 New cycloiminodepsipeptides, processes for their preparation and their use in combating endoparasites

Publications (1)

Publication Number Publication Date
CN1355794A true CN1355794A (en) 2002-06-26

Family

ID=7910898

Family Applications (1)

Application Number Title Priority Date Filing Date
CN00808822A Pending CN1355794A (en) 1999-06-11 2000-05-30 Cyclo-imino depsipeptides and their utilization in controlling endoparasites

Country Status (11)

Country Link
EP (1) EP1192142A1 (en)
JP (1) JP2003502318A (en)
CN (1) CN1355794A (en)
AU (1) AU768501B2 (en)
BR (1) BR0011498A (en)
CA (1) CA2374632A1 (en)
DE (1) DE19926620A1 (en)
HK (1) HK1047589A1 (en)
HU (1) HUP0201592A2 (en)
WO (1) WO2000076985A1 (en)
ZA (1) ZA200109179B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114891070A (en) * 2015-05-20 2022-08-12 勃林格殷格翰动物保健美国公司 Anthelmintic depsipeptide compounds

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4902519B2 (en) * 2007-12-21 2012-03-21 大塚化学株式会社 Immobilized catalyst

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4317432A1 (en) * 1993-05-26 1994-12-01 Bayer Ag Octacyclodepsipeptides with endoparasiticidal activity
DE4317457A1 (en) * 1993-05-26 1994-12-01 Bayer Ag Octacyclodepsipeptides with endoparasiticidal activity
DE19713626A1 (en) * 1997-04-02 1998-10-08 Bayer Ag New thiodepsipeptides to control endoparasites and a simple process for their preparation

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114891070A (en) * 2015-05-20 2022-08-12 勃林格殷格翰动物保健美国公司 Anthelmintic depsipeptide compounds

Also Published As

Publication number Publication date
BR0011498A (en) 2002-04-02
DE19926620A1 (en) 2000-12-14
AU768501B2 (en) 2003-12-11
EP1192142A1 (en) 2002-04-03
HK1047589A1 (en) 2003-02-28
WO2000076985A1 (en) 2000-12-21
JP2003502318A (en) 2003-01-21
HUP0201592A2 (en) 2002-08-28
AU5218000A (en) 2001-01-02
ZA200109179B (en) 2003-01-29
CA2374632A1 (en) 2000-12-21

Similar Documents

Publication Publication Date Title
CN1070481C (en) Use of dioxomorpholines to combat endopharasites, novel dioxomorpholines and process for their production
AU679724B2 (en) Octacyclodepsipeptides having an endoparasiticidal action
SK151594A3 (en) Enniatines and enniatine derivatives used to control endoparasites
CN1165338C (en) Endoparasiticidal compositions
CN1082051C (en) Novel cyclic depsipeptide PF1022 derivatives
CN1083445C (en) Thiodepsipeptides for combating endoparasites and a method for producing the same
JP3626233B2 (en) Use of cyclic depsipeptides having 12 ring atoms for the control of endoparasites, novel cyclic depsipeptides having 12 ring atoms and methods for their production
CN1076349C (en) Desoxycyclodepsipeptides and their use for combatting endoparasites
JP3600287B2 (en) New cyclic depsipeptides having 18 ring atoms and their use for controlling endoparasites
JPH0649045A (en) Use of 3-amino-substituted isoxazole derivative to control endoparasite, new 3-amino-substituted isoxazole derivative, and its production
CN1355794A (en) Cyclo-imino depsipeptides and their utilization in controlling endoparasites
EP1109794A1 (en) Aza-cyclodepsipeptides and their use as antiparasitics
AU2004308593B2 (en) 18-membered nitrobenzyl-substituted and aminobenzyl-substituted cyclohexadepsipeptides for controlling endoparasites, and method for the production thereof
CN1111535C (en) 4a,5a,8a,8b-tetrahydro-6H-pyrrolo [3',4' : 4,5] furo (3,2-b] pyridine-6,8 [7H]-dione derivatives for use in controlling endoparasites and method
CN1255923A (en) 6-substituted 1,2,4a,51,8a,8b hexahydro- and 1,2,3,4,4a,5a,8a,8b-octahydro-6h-pyrrolo [3',4': 4,5] furo [3,2-b] pyrid-8(7h)-on derivatives and their use in combatting encoparasites

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
AD01 Patent right deemed abandoned
C20 Patent right or utility model deemed to be abandoned or is abandoned
REG Reference to a national code

Ref country code: HK

Ref legal event code: WD

Ref document number: 1047589

Country of ref document: HK