CN1207673A - Endoparasiticidal agents - Google Patents

Endoparasiticidal agents Download PDF

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CN1207673A
CN1207673A CN96199748A CN96199748A CN1207673A CN 1207673 A CN1207673 A CN 1207673A CN 96199748 A CN96199748 A CN 96199748A CN 96199748 A CN96199748 A CN 96199748A CN 1207673 A CN1207673 A CN 1207673A
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chmech
alkyl
chme
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J·卡尔贝
R·勒尔
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Bayer AG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/15—Depsipeptides; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents

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  • Tropical Medicine & Parasitology (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Hydrogenated Pyridines (AREA)
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Abstract

The invention relates to orally administered endoparasiticidal agents which contain cyclic and open-chain depsipeptides comprising amino acids and hydroxycarboxylic acids as structural components and 6 to 30 ring atoms or chain atoms.

Description

The pharmaceutical composition of Endoparasiticidal
The present invention relates to a kind of combination of oral medication that contains ring-type and open chain ester peptide (depsipeptide).
EP-OS (European prospectus)-382 173 discloses a kind of cyclic ester peptide PF1022 and antibody endoparasite activity thereof.
German patent application DE-A 4 317 432.9,4 317 457.4 and 4 317 458.2 also discloses a kind of goal of the invention product and Endoparasiticidal active function thereof of cyclic ester peptide.
The present invention relates to a kind of Endoparasiticidal pharmaceutical composition of oral administration, this pharmaceutical composition contains ring-type and open chain ester peptide, ester peptide wherein be with aminoacid and hydroxy carboxylic acid be construction unit and by 6-30 the ring or chain atom form.
Ester peptide in the compositions of the present invention is that water is sl. sol..Will be when preparing its oral administration by means of suitable cosolvent with solution.
In order to guarantee that reactive compound of the present invention has good bioavailability; Ideal administering mode is that active compounds solution is encapsulated in administration in the gelatine capsule.At this moment; This solution must neither produce destruction to gelatine capsule; And solvent can not slowly be diffused into outside the gelatine capsule.This just means a kind of dicyandiamide solution of needs exploitation; Makes the sl. sol. ester peptide of above-mentioned water can keep sufficiently high concentration for a long time in this solution; The gelatine capsule of sealing each dosage is not produced destruction again simultaneously.The present invention relates to:1. separately or the ring-type and/or the open chain ester peptide combinations of the oral administration of forming with form of mixtures with other reactive compounds; It is characterized in that:these reactive compounds are dissolved in the solvent mixture, and this solvent mixture is by the fatty acid ester of-propylene glycol-polyhydric alcohol (oil)-emulsifying agent.2. be characterised in that its active compounds solution is encapsulated in the compositions in the gelatin soft capsule.3. is characterised in that the pharmaceutical composition that its solvent mixture is comprised of following component :-propane diols 5-20%-oil 50-70%-emulsifying agent 1-10%4. is characterised in that its gelatin soft capsule contains the pharmaceutical composition of following composition system :-reactive compound 0.1-20%-propane diols 5-20%-oil 50-70%-emulsifying agent 1-8%
But the invention still further relates to the preparation method of the Endoparasiticidal medicine Unctuous compositions of the administration that contains the ester peptide, wherein this ester peptide is to be the ring structure list and to be made up of 6-30 annular atoms with amino and hydroxy carboxylic acid.
Preferred cyclic ester peptide is those ester peptides that contain 18-24 annular atoms.
The ester peptide that contains 18 annular atomses comprises the chemical compound shown in the general formula (I):
Figure A9619974800041
R wherein 1, R 3And R 5Independently of one another; represented hydrogen respectively; the straight or branched alkyl that contains 8 carbon atoms at most; hydroxy alkyl; the alkanoyloxy alkyl; alkoxyalkyl; aryloxy alkyl; mercaptoalkyl; alkylthio alkyl; the alkyl sulphinyl alkyl; the alkyl sulphonyl alkyl; carboxyalkyl; alkoxy carbonyl alkyl; the aryl-alkoxy carbonyl alkyl; the carbamoyl alkyl; aminoalkyl; the alkyl amino alkyl; dialkyl aminoalkyl; guanidine alkylation; above-mentioned group can be by 1 or 2 benzyloxycarbonyl or 1; 2; 3 or 4 alkyl; the alkoxycarbonyl amino alkyl; 9-fluorenyl methoxy carbonyl (Fmoc) aminoalkyl; alkenyl; cycloalkyl; cycloalkyl-alkyl replaces arbitrarily; with the aryl alkyl of any replacement, wherein halogen; hydroxyl; alkyl; alkoxyl can be used as substituent group.R 2, R 4And R 6Independently of one another; represented hydrogen respectively; the straight or branched alkyl that contains 8 carbon atoms at most; hydroxy alkyl; mercaptoalkyl; the alkanoyloxy alkyl; alkoxyalkyl; aryloxy alkyl; alkylthio alkyl; the alkyl sulphinyl alkyl; the alkyl sulphonyl alkyl; carboxyalkyl; alkoxy carbonyl alkyl; the aryl-alkoxy carbonyl alkyl; the carbamoyl alkyl; aminoalkyl; the alkyl amino alkyl; dialkyl aminoalkyl; the alkoxycarbonyl amino alkyl; alkenyl; cycloalkyl; cycloalkyl-alkyl; any substituted aryl or aryl alkyl, wherein halogen; hydroxyl; alkyl; alkoxyl can be mentioned as substituent group.
And the optical isomer of above-claimed cpd and racemate.
Figure A9619974800051
Chemical compound is those shown in the preferred construction formula (I): R wherein 1, R 3And R 5Independently of one another, represented straight or branched C respectively 1-C 8-alkyl, especially methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, isopentyl, sec-amyl, hexyl, isohesyl, Sec-Hexyl, heptyl, different heptyl, Zhong Gengji, uncle's heptyl, octyl group, iso-octyl, secondary octyl; Hydroxyl-C 1-C 6-alkyl, especially methylol, 1-ethoxy; C 1-C 4-alkanoyloxy-C 1-C 6-alkyl, preferred acetoxy-methyl, 1-acetoxyl group ethyl; C 1-C 4-alkoxy-C 1-C 6-alkyl, preferred methoxy, 1-methoxy ethyl; Aryl-C 1-C 4-alkoxy-C 1-C 6-alkyl, preferred benzyloxymethyl, 1-benzyl oxygen base-ethyl; Sulfydryl-C 1-C 6-alkyl, preferred thiopurine methyltransferase; C 1-C 4-alkyl sulfenyl-C 1-C 6-alkyl, preferred methylmercaptoethyl; C 1-C 4-alkyl sulphinyl-C 1-C 6-alkyl, preferable methyl sulfinyl ethyl; C 1-C 4-alkyl sulphonyl-C 1-C 6-alkyl, preferable methyl sulfonyl ethyl; Carboxyl-C 1-C 6-alkyl, preferred carboxymethyl, carboxyethyl; C 1-C 4-alkoxy carbonyl-C 1-C 6-alkyl, preferred methoxycarbonyl methyl, ethoxy carbonyl ethyl; C 1-C 4-aryl-alkoxy carbonyl-C 1-C 6-alkyl, preferred benzyloxycarbonyl methyl; Carbamoyl-C 1-C 6-alkyl, preferred carbamyl ylmethyl, carbamoyl ethyl; Amino-C 1-C 6-alkyl, preferred aminopropyl, amino butyl; C 1-C 4-alkyl amino-C 1-C 6-alkyl, preferable methyl aminopropyl, methylamino butyl; C 1-C 4-dialkyl amido-C 1-C 6-alkyl, preferred dimethylaminopropyl, dimethylamino butyl; Guanidine radicals-C 1-C 6-alkyl, preferred guanidine radicals propyl group; C 1-C 6-alkoxycarbonyl amino-C 1-C 6-alkyl, preferred tertiary butoxy carbonyl aminopropyl, the amino butyl of tert-butoxycarbonyl; 9-fluorenyl-methoxycarbonyl (Fmoc) amino-C 1-C 6-alkyl, preferred 9-fluorenyl-methoxycarbonyl (Fmoc) aminopropyl, the amino butyl of 9-fluorenyl methoxy carbonyl (Fmoc); C 2-C 8-alkenyl, preferred vinyl, pi-allyl, cyclobutenyl; C 3-C 7-cycloalkyl, preferred cyclopenta, cyclohexyl, suberyl; C 3-C 7-cycloalkyl-C 1-C 4-alkyl, preferred cyclopentyl-methyl, cyclohexyl methyl, suberyl methyl; Phenyl-C 1-C 4-alkyl, preferred benzyl, this benzyl can be by serial halogen group institute any replacement, especially fluorine, chlorine, bromine or iodine; Hydroxyl; C 1-C 4-alkoxyl, preferred methoxy or ethoxy; C 1-C 4-alkyl, preferable methyl.R 2, R 4And R 6Independently of one another, represented straight or branched C respectively 1-C 8-alkyl, especially methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, isopentyl, sec-amyl, hexyl, isohesyl, Sec-Hexyl, heptyl, different heptyl, Zhong Gengji, uncle's heptyl, octyl group, iso-octyl, secondary octyl; Hydroxyl-C 1-C 6-alkyl, especially methylol, 1-ethoxy; C 1-C 4-alkanoyloxy-C 1-C 6-alkyl, preferred acetoxy-methyl, 1-acetoxyl group ethyl; C 1-C 4-alkoxy-C 1-C 6-alkyl, preferred methoxy, 1-methoxy ethyl; Aryl-C 1-C 4-alkoxy-C 1-C 6-alkyl, preferred benzyl oxygen ylmethyl, 1-benzyl oxygen base-ethyl; Sulfydryl-C 1-C 6-alkyl, preferred thiopurine methyltransferase; C 1-C 4-alkylthio group-C 1-C 6-alkyl, preferred methylmercaptoethyl; C 1-C 4-alkyl sulphinyl-C 1-C 6-alkyl, preferable methyl sulfinyl ethyl; C 1-C 4-alkyl sulphonyl-C 1-C 6-alkyl, preferable methyl sulfonyl ethyl; Carboxyl-C 1-C 6-alkyl, preferred carboxymethyl, carboxyethyl; C 1-C 4-alkoxy carbonyl-C 1-C 6-alkyl, preferred methoxycarbonyl methyl, ethoxy carbonyl ethyl; C 1-C 4-aryl-alkoxy carbonyl-C 1-C 6-alkyl, preferred benzyloxycarbonyl methyl; Carbamoyl-C 1-C 6-alkyl, preferred carbamyl ylmethyl, carbamoyl ethyl; Amino-C 1-C 6-alkyl, preferred aminopropyl, ammonia butyl; C 1-C 4-alkyl amino C 1-C 6-alkyl, preferable methyl aminopropyl, methylamino butyl; C 1-C 4-dialkyl amido-C 1-C 6-alkyl, preferred dimethylaminopropyl, dimethylamino butyl; C 2-C 8-alkenyl, preferred vinyl, pi-allyl, cyclobutenyl; C 3-C 7-cycloalkyl, preferred cyclopenta, cyclohexyl, suberyl; C 3-C 7-cycloalkyl-C 1-C 4-alkyl, preferred cyclopentyl-methyl, cyclohexyl methyl, suberyl methyl; Phenyl; Phenyl-C 1-C 4-alkyl, preferred benzyl, this benzyl can be by serial halogen group institute any replacement, especially fluorine, chlorine, bromine or iodine; Hydroxyl; C 1-C 4-alkoxyl, preferred methoxy or ethoxy; C 1-C 4-alkyl, preferable methyl.
And their optical isomer and racemate.
Preferred structural formula (I) chemical compound is those: R wherein 1, R 3And R 5Independently of one another, represented straight or branched C respectively 1-C 8-alkyl, especially methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, isopentyl, sec-amyl, hexyl, isohesyl, Sec-Hexyl, heptyl, different heptyl, Zhong Gengji, uncle's heptyl, octyl group, iso-octyl, secondary octyl; Hydroxyl-C 1-C 6-alkyl, especially methylol, 1-ethoxy; C 1-C 4-alkanoyloxy-C 1-C 6-alkyl, preferred acetoxy-methyl, 1-acetoxyl group ethyl; C 1-C 4-alkoxy-C 1-C 6-alkyl, preferred methoxy, 1-methoxy ethyl; Aryl-C 1-C 4-alkoxy-C 1-C 6-alkyl, preferred benzyloxymethyl, 1-benzyl oxygen base-ethyl; C 1-C 4-alkoxycarbonyl amino-C 1-C 6-alkyl, preferred tertiary butoxy carbonyl aminopropyl, the amino butyl of tert-butoxycarbonyl; C 2-C 8-alkenyl, preferred vinyl, pi-allyl, C 3-C 7-cycloalkyl, preferred cyclopenta, cyclohexyl, suberyl; C 3-C 7-cycloalkyl-C 1-C 4-alkyl, preferred cyclopentyl-methyl, cyclohexyl methyl, suberyl methyl; Phenyl-C 1-C 4-alkyl, preferred benzyl, this benzyl can be replaced arbitrarily by one or more identical or different above-mentioned substituted radicals.R 2, R 4And R 6Independently of one another, represented straight or branched C respectively 1-C 8-alkyl, especially methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, isopentyl, sec-amyl, hexyl, isohesyl, Sec-Hexyl, heptyl, different heptyl, Zhong Gengji, uncle's heptyl, octyl group, iso-octyl, secondary octyl; Hydroxyl-C 1-C 6-alkyl, especially methylol; Aryl-C 1-C 4-alkoxy-C 1-C 6-alkyl, preferred benzyl oxygen ylmethyl, 1-benzyl oxygen base-ethyl; Carboxyl-C 1-C 6-alkyl, preferred carboxymethyl, carboxyethyl; C 1-C 4-alkoxy carbonyl-C 1-C 6-alkyl, preferred methoxycarbonyl methyl, ethoxy carbonyl ethyl; C 1-C 4-aryl-alkoxy carbonyl-C 1-C 6-alkyl, preferred benzyloxycarbonyl methyl; C 1-C 4-alkyl amino-C 1-C 6-alkyl, preferable methyl aminopropyl, methylamino butyl; C 1-C 4-dialkyl amido-C 1-C 6-alkyl, preferred dimethylaminopropyl, dimethylamino butyl; C 2-C 8-alkenyl, preferred vinyl, pi-allyl, cyclobutenyl; C 3-C 7-cycloalkyl, preferred cyclopenta, cyclohexyl, suberyl; C 3-C 7-cycloalkyl-C 1-C 4-alkyl, preferred cyclopentyl-methyl, cyclohexyl methyl, suberyl methyl; Phenyl; Phenyl-C 1-C 4-alkyl, preferred benzyl, this benzyl can be replaced arbitrarily by one or more identical or different above-mentioned substituted radicals.
And their optical isomer and racemate.
Chemical compound is those shown in the most preferred structural formula (I): R wherein 1, R 3And R 5Independently of one another, represented straight or branched C respectively 1-C 8-alkyl, especially methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, amyl group, isopentyl, sec-amyl, hexyl, isohesyl, Sec-Hexyl, heptyl, different heptyl, Zhong Gengji, octyl group, iso-octyl, secondary octyl; C 2-C 8-alkenyl, preferred pi-allyl; C 3-C 7-cycloalkyl-C 1-C 4-alkyl, preferred cyclohexyl methyl; Phenyl-C 1-C 4-alkyl, preferred benzyl; R 2, R 4And R 6Independently of one another, represented straight or branched C respectively 1-C 8-alkyl, especially methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, amyl group, isopentyl, sec-amyl, hexyl, isohesyl, Sec-Hexyl, heptyl, different heptyl, Zhong Gengji, octyl group, iso-octyl, secondary octyl; C 2-C 8-alkenyl, preferred vinyl, pi-allyl; C 3-C 7-cycloalkyl-C 1-C 4-alkyl, preferred cyclohexyl methyl; Phenyl-C 1-C 4-alkyl, preferred benzyl, this benzyl can be replaced arbitrarily by one or more identical or different above-mentioned substituted radicals.
And their optical isomer and racemate.
Optical active matter, stereoisomer or the racemic mixture of chemical compound shown in all general formulas (I) all belong to the material in the category of the present invention.Yet what preferably adopt is the optical active matter and the stereoisomer of chemical compound shown in the general formula (I).
More specifically, the following compounds shown in the general formula (I), wherein R 1-R 6Group is as shown in the table:
Figure A9619974800091
??R 1 R 2 R 3 R 4 R 5 R 6
??-CHMeCH 2Me Cyclohexane extraction -CHMeCH 2Me -Me -CHMeCH 2Me -Me
??-CHMeCH 2Me -cyclohexyl -CHMeCH 2Me -Me -CHMeCH 2Me Cyclohexane extraction
??-CHMeCH 2Me -CH 2-Phe -CHMeCH 2Me -Me -CHMeCH 2Me -Me
??-CHMeCH 2Me -CH 2-Phe -CHMeCH 2Me -Me -CHMeCH 2Me -CH 2-Phe
??-CHMeCH 2Me -(CH 2) 3-Me -CHMeCH 2Me -Me -CHMeCH 2Me -Me
??-CHMeCH 2Me -(CH 2) 3-Me -CHMeCH 2Me -Me -CHMeCH 2Me -(CH 2) 3-Me
??-CHMe 2 -CH 2-Phe -CHMeCH 2Me -Me -CHMeCH 2Me -Me
??-CH 2-Phe -CHMe 2 -CH 2-Phe -CHMe 2 -CHMeCH 2Me -CHMe 2
??-CH 2CHMe 2 -CH 2-Phe -CH 2CHMe 2 -Me -CH 2CHMe 2 -CH 2-Phe
??-(CH 2) 3-Me -Me -CHMeCH 2Me -Me -CHMeCH 2Me -Me
??-CHMe 2 -Me -CHMe 2 -Me -CHMe 2 -Me
??-CH 2-Me -Me -CH 2-Me -Me -CH 2-Me -Me
??-(CH 2) 2-Me -Me -(CH 2) 2-Me -Me -(CH 2) 2-Me -Me
??-(CH 2) 3-Me -Me -(CH 2) 3-Me -Me -(CH 2) 3-Me -Me
??-CH 2-CH＝CH 2 -Me -CH 2-CH＝CH 2 -Me -(CH 2)-CH＝CH 2 -Me
??-CHMeCH 2Me -Me -CHMeCH 2Me -Me -CHMeCH 2Me -CH 2-Me
??-CHMeCH 2Me -Me -CHMeCH 2Me -Me -CHMeCH 2Me -(CH 2) 2-Me
??-CHMeCH 2Me -Me -CHMeCH 2Me -Me -CHMeCH 2Me -(CH 2) 3-Me
??-CHMeCH 2Me -Me -CHMeCH 2Me -Me -CH 2Me -Me
??-CHMeCH 2Me -Me -CHMeCH 2Me -Me -(CH 2) 2-Me -Me
Cyclohexane extraction -Me -cyclohexyl -Me -cyclohexyl -Me
??-CH 2CHMe 2 Cyclohexane extraction -CH 2CHMe 2 -Me -CH 2CHMe 2 Cyclohexane extraction
??-CH 2CHMe 2 -cyclohexyl -CH 2CHMe 2 -Me -CH 2CHMe 2 -Me
??-CHMeCH 2Me -CHMe 2 -CHMeCH 2Me -CHMe 2 -CHMeCH 2Me -Me
??-CH 2-Phe -Me -CH 2-Phe -Me -CH 2-Phe -Me
Cyclohexane extraction -Me Cyclohexane extraction -Me Cyclohexane extraction -Me
??-CHMe 2 -CHMe 2 -CHMe -Me -CHMe 2 -Me
??-CHMe 2 -CHMe 2 -CHMe 2 -CHMe 2 -CHMe 2 -Me
??-CH 2-Me -CHMe 2 -CH 2Me -Me -CH 2-Me -Me
??-CH 2-Me -CHMe 2 -CHMe 2 -CHMe 2 -CH 2-Me -Me
??-(CH 2) 2-Me -CHMe 2 -(CH 2) 2-Me -Me -(CH 2) 2-Me -Me
??-(CH 2) 2-Me -CHMe 2 -(CH 2) 2-Me -CHMe 2 -(CH 2) 2-Me -Me
??-(CH 2) 2-Me -CHMe 2 -(CH 2) 2-Me -Me -(CH 2) 2-Me -Me
??R 1 ??R 2 ??R 3 ??R 4 ??R 5 ??R 6
??-(CH 2) 3-Me ??-CHMe 2 ??-(CH 2) 3-Me ??-CHMe 2 ??-(CH 2) 3-Me ??-Me
??-CH 2-CH＝CH 2 ??-CHMe 2 ??-CH 2-CH＝CH 2 ??-Me ??-CH 2-CH＝CH 2 ??-Me
??-CH 2-CH＝CH 2 ??-CHMe 2 ??-CH 2-CH＝CH 2 ??-CHMe 2 ??-CH 2-CH＝CH 2 ??-Me
??-Me ??-Me ??-CHMeCH 2Me ??-Me ??-CH 2-Me ??-Me
??-Me ??-Me ??-CHMeCH 2Me ??-Me ??-(CH 2) 3-Me ??-Me
The Me=methyl, the Phe=phenyl
In addition, disclosed Compound P F1022 with following structural formula also is regarded as an ester peptide in EP-OS (the European prospectus) 382 173: Also have, disclosed chemical compound also can be used as the ester peptides among the PCT patent application WO 93/19053.
What especially should be mentioned in that is PCT patent application WO 93/19053 chemical compound with following structural: Wherein Z has represented N-morpholinyl, amino, list-or dimethylamino.
In addition, this list have below the chemical compound of structural formula:
Figure A9619974800122
R wherein 1, R 2, R 3, R 4Independently of one another, hydrogen, C have been represented respectively 1-C 10-alkyl or aryl, especially phenyl, abovementioned alkyl or aryl can also be by hydroxyl, C 1-C 10-alkoxy or halogen replaces arbitrarily.
Chemical compound is a compound known shown in the general formula (I) under certain conditions; They can be by for example following method preparation: a) cyclisation has the open chain six ester peptide compounds shown in the general formula (II-a) of activated carboxyl Wherein A represents an amido protecting group, for example benzyl, benzyloxycarbonyl, and this blocking group is compared with the Acibenzolar blocking group by the removing of selectivity, and R 1, R 2, R 3, R 4, R 5And R 6Identical with above-mentioned definition, can adopt hydrogenation catalyst, alkaline reaction auxiliary agent and diluent in the reaction, or b) the open chain six ester peptide compounds shown in the cyclisation general formula (II-b)
Figure A9619974800132
Wherein
R 1, R 2, R 3, R 4, R 5And R 6Definition as indicated above,
Can adopt coupling agent, alkaline reaction auxiliary agent and diluent in the reaction.
If adopting a), method prepares new ring-type six ester peptides (enniatin) (I), then with pentafluorophenyl group N-benzyloxycarbonyl-N-methyl-L-isoleucyl--D-lactoyl-N-methyl-L-isoleucyl--D-lactoyl-N-methyl-L-isoleucyl--D-lactate as the compound of reaction shown in the structural formula (II), this preparation method can be represented with following reacting flow chart:
Figure A9619974800141
Being one and containing activated carboxyl and in carrying out a) preparation method, need general structure of structural formula (II) expression as the open chain six ester peptide derivants of initial reactant.In this structural formula, preferred A and R 1-R 6Those groups of when describing structural formula of the present invention (I) compound substituent, having mentioned have been represented.
Be used as the pentafluorophenyl group ester that contains activated carboxyl shown in the structural formula (II-a) of initiation material and can adopt in the document that disclosed method makes (list of references: people such as L. Kisfaludy, the 3563rd page of J.Org.Chem.35 (1970); People such as L.Kisfaludy, J.Org.Chem.44 (1979) 654-655 pages or leaves).
Specifically, should be mentioned that the chemical compound shown in the following general formula (IIa), wherein group A and R 1-R 6Represented following groups respectively:
A ?R 1 R 2 R 3 R 4 R 5 ?R 6
Z Bn Bn Bn Z Z Bn Bn Z Bn Bn Z Bn Bn Z Z Z Z Z Bn Z Z Z Bn Bn Z Z Bn Bn Bn Bn Bn Bn Bn Bn -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CHMe 2-CH 2-Phe -CH 2CHMe 2-CH 2-Me -(CH 2) 2-Me -(CH 2) 2-Me -CH 2-CH＝CH 2-CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2e -cyclohexyl -CH 2CHMe 2-CH 2CHMe 2-CHMeCH 2Me -CH 2-Phe cyclohexyl-CHMe 2-CHMe 2-CH 2-Me -CH 2-Me -(CH 2) 2-Me -(CH 2) 2-Me -(CH 2) 3-Me -(CH 2) 3-Me -CH 2-CH＝CH 2-CH 2-CH＝CH 2 Cyclohexyl ring hexyl-CH 2-Phe -CH 2-Phe -(CH 2) 3-Me -(CH 2) 3-Me -(CH 2) 3-Me -CH 2-Phe -CHMe 2-CH 2-Phe-Me-Me-Me-Me-Me-Me-Me-Me-Me-Me cyclohexyl ring hexyl-CHMe2-Me -Me -CHMe 2-CHMe 2-CHMe 2-CHMe 2-CHMe 2-CHMe 2-CHMe 2-CHMe 2-CHMe 2-CHMe 2 -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CH 2-Phe -CH 2CHMe 2-CH 2-Me -(CH 2) 2-Me -(CH 2) 3-Me -CH 2-CH＝CH 2-CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me cyclohexyl-CH 2CHMe 2-CH 2CHMe 2-CHMeCH 2Me -CH 2-Phe cyclohexyl-CHMe 2-CHMe 2-CH 2-Me -CH 2-Me -(CH 2) 2-Me -(CH 2) 2-Me -(CH 2) 2-Me -(CH 2) 3-Me -CH 2-CH＝CH 2-CH 2-CH＝CH 2 -Me -Me -Me -Me -Me -Me -Me -Me -CHMe 2-Me -Me -Me -Me -Me -Me -Me -Me -Me -Me -Me -Me -Me -CHMe 2-Me -Me -Me -CHMe 2-Me -CHMe 2-Me -CHMe 2-Me -CHMe 2-Me -CHMe 2 -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CH 2CHMe 2-CH 2-Me -(CH 2) 2-Me -(CH 2) 3-Me -CH 2-CH＝CH 2-CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CH 2Me -(CH 2) 2-Me cyclohexyl-CH 2CHMe 2-CH 2CHMe 2-CHMeCH 2Me -CH 2-Phe cyclohexyl-CHMe 2-CHMe 2-CH 2-Me -CH 2-Me -(CH 2) 2-Me -(CH 2) 2-Me -(CH 2) 3-Me -(CH 2) 3-Me -CH 2-CH＝CH 2-CH 2-CH＝CH 2 -Me cyclohexyl-Me-CH 2-Phe -Me -Me -(CH 2) 3-Me -Me -CHMe 2-CH 2-Phe -Me -Me -Me -Me -CH 2-Me -(CH 2) 2-Me -(CH 2) 3-Me-Me-Me-Me cyclohexyl-Me-Me-Me-Me-Me-Me-Me-Me-Me-Me-Me-Me-Me-Me
Bn;-CH 2-phenyl; Z:-CO-O-CH 2-phenyl; The Me=methyl; The Phe=phenyl
The cyclization of chemical compound shown in the structural formula (II) preferably carries out having under suitable hydrogenation catalyst and alkaline reaction auxiliary agent and the simultaneous reaction condition of diluent.
What carry out can be used as catalyst in a method all is conventional hydrogenation catalyst.The preferred noble metal catalyst that adopts, for example platinum, platinum oxide, palladium or ruthenium, and if need, these noble metal catalysts can combine with appropriate carriers, as carbon or silicon.
Adoptable alkaline reaction auxiliary agent all is the acid binding agent that suits, amine for example, preferred tertiary amine; Also have alkali metal and alkaline earth metal compound.
What can exemplify in these chemical compounds has: the hydroxide of lithium, sodium, potassium, magnesium, calcium and barium, oxide and carbonate; And other alkali compoundss, triethylamine for example, trimethylamine, tribenzyl amine, triisopropylamine, tri-butylamine, tribenzyl amine, thricyclohexyl amine, three amylamines, three hexyl amines, N, accelerine, N, N-dimethyl-toluidines, N, N-dimethyl-p-aminopyridine, N-methyl-pyrrolidine, N-methyl-piperidines, N-methyl-imidazoles, N-methyl-pyrroles, N-methyl-morpholine, N-methyl-hexamethylene imine, pyridine, 4-pyrrolidine generation (pyrrolidino)-pyridine, 4-dimethylamino-pyridine, quinoline, α-Jia Jibiding, beta-picoline, isoquinolin, pyrimidine, acridine, N, N, N ', N '-tetramethylene-diamidogen, N, N, N ', N '-four ethylidene-diamidogen, quinoxaline, N-propyl group-diisopropylamine, N-ethyl-diisopropylamine, N, N '-two-methyl-cyclohexyl base amine, 2, the 6-lutidines, 2, the 4-lutidines, triethylenediamine, diazabicyclooctane (DABCO), Diazabicyclononene (DBN) or diazabicylo endecatylene (DBU).
Preferred heteroaromatics, for example pyridine, N-methyl-imidazoles or the 4-pyrrolidine generation-pyridine of adopting.
Carrying out in a preparation method all to be inert organic solvents as the material of diluent.
The example that can exemplify has: halogenated hydrocarbon.Preferred chlorinated hydrocarbon, for example tetrachloroethylene, sym-tetrachloroethane, dichloropropane, dichloromethane, dichloroetane, chloroform, carbon tetrachloride, trichloroethane, trichloroethylene, Pentalin., two fluorobenzene, 1,2-dichloroethanes, monochloro-benzene, dichloro-benzenes, chlorotoluene, trichloro-benzenes; Alcohol, for example methanol, ethanol, isopropyl alcohol, butanols; Ether, for example ethyl propyl ether, methyl tertiary butyl ether(MTBE), n-butyl ether, di-n-butyl ether, diisobutyl ether, diisoamyl ether, Di Iso Propyl Ether, methyl phenyl ethers anisole, ethyl phenyl ether, cyclohexyl methyl ether, diethyl ether, glycol dimethyl ether, oxolane, diox, Dichlorodiethyl ether; Nitro Hydrocarbon, for example Nitrocarbol., nitroethane, Nitrobenzol, chloronitrobenzene, o-Methylnitrobenzene; Nitrile, for example acetonitrile, butyronitrile, isopropyl cyanide, benzonitrile, m-benzyl chloride nitrile; Aliphatic, alicyclic or aromatic hydrocarbon, for example gasoline fraction, cyclohexane extraction, hexahydrotoluene, petroleum ether, ligroin, octane, the benzene,toluene,xylene in heptane, hexane, nonane, cymol, the 70-190 ℃ boiling spread; Ester, for example ethyl acetate, isobutyl acetate; Amide, for example Methanamide, N-methylformamide, N, dinethylformamide, N-methyl-ketopyrrolidine; Ketone, for example acetone, methyl ethyl ketone.The mixture of above-mentioned solvent and diluent also is suitable for.
Preferred ether, the mixture of for example diox, and pure and mild ether of using in the reaction.
The method a of being prepared will heat chemical compound shown in the structural formula (IIa), and reaction is to comprise alkaline reaction auxiliary agent, suitable hydrogenation catalyst, atmosphere of hydrogen and carrying out under diluent high dilution condition.
The time of reacting required approximately is 4-20 hour.Being reflected at+carry out in 20 ℃-+200 ℃ the temperature range, preferred temperature range is+70 ℃-155 ℃.Simultaneously, reaction is preferably carried out under atmosphere of inert gases and pressure, and this pressure is owing to produce being heated under the reaction condition of desired reaction temperature.
In carrying out preparation method 3a of the present invention, in 2-10 hour process, feed hydrogen continuously and under 95 ℃ of conditions, the mistake that the dioxane solution of the pentafluorophenyl group N-benzyloxycarbonyl-N-methyl-L-isoleucyl--D-lactoyl-N-methyl-L-isoleucyl--D-lactoyl-N-methyl-L-isoleucyl--D-lactate of structural formula (IIa) is added drop-wise to the mole hydrogenation catalyst such as suitable that is stirred is fast measured in the two Evil solution, and hydrogenation catalyst can for example be palladium/carbon.As catalyst, contain 4-pyrrolidine generation-pyridine and alcohol in its solution usually, wherein contained 4-pyrrolidine generation-pyridine is 0.5-2.5mol, preferred 1.0-2.0mol, contained alcohol is 0.5-10%, preferred 2-5% (for solvent).
Perhaps, except the PFBBR ester of N-benzyloxycarbonyl-replacement, also can utilize the N-benzyl shown in the structural formula (IIa)-and the PFBBR ester of uncle N--butoxy carbonyl-replacement; Carry out in the two-phase system that the latter can adopt U.Schmidt to describe cyclization (list of references, for example: people such as U.Schmidt, Synthesis (1991) 294-300 pages or leaves, [didemninA, B﹠amp; C]).
After reaction finished, with the compound of reaction cooling, the reactant of all each batches is concentrated under vacuum condition, and residue carried out post processing with organic solvent extraction and with extract by known method.Product also adopts conventional method wax purification, for example recrystallization, vacuum distilling or chromatogram column technique.
If employing b) method prepares new ring-type six ester peptides (enniatin) (I), then use N-methyl-L-isoleucyl--D-lactoyl-N-methyl-L-isoleucyl--D-lactoyl-N-methyl-L-isoleucyl--D-lactic acid as the chemical compound shown in the structural formula (IIb), this preparation method can be represented with following reacting flow chart:
Figure A9619974800181
Structural formula (II) expression be to carry out b) need general structure in the preparation method as the open chain six ester peptide derivants of initial reactant.In this structural formula, preferred R 1-R 6The preferred group of having represented those in describing structural formula of the present invention (I) chemical compound, to mention during substituent group.
Can be used as that six ester peptides can also make by following method shown in the structural formula (II) of start material.
What specifically, mention is the chemical compound shown in the following general formula (IIb), wherein radicals R 1-R 6Represent following groups:
R 1 R 2 R 3 R 4 R 5 R 6
-CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CHMe 2-CH 2-Phe -CH 2CHMe 2-(CH 2) 3-Me -CHMe 2-CH 2-Me -(CH 2) 2-Me -(CH 2) 3-Me -CH 2-CH＝CH 2-CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me cyclohexyl-CH 2CHMe 2-CH 2CHMe 2-CHMeCH 2Me -CH 2-Phe cyclohexyl-CHMe 2-CHMe 2-CH 2-Me -CH 2-Me -(CH 2) 2-Me -(CH 2) 2-Me -(CH 2) 3-Me -(CH 2) 3-Me -CH 2-CH＝CH 2-CH 2-CH＝CH 2 Cyclohexyl ring hexyl-CH 2-Phe -CH 2-Phe -(CH 2) 3-Me -(CH 2) 3-Me -CH 2-Phe -CHMe 2-CH 2-Phe-Me-Me-Me-Me-Me-Me-Me-Me-Me-Me-Me-Me cyclohexyl ring hexyl-CHMe2-Me -Me -CHMe 2-CHMe 2-CHMe 2-CHMe 2-CHMe 2-CHMe 2-CHMe 2-CHMe 2-CHMe 2-CHMe 2 -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CH 2-Phe -CH 2CHMe 2-CHMeCH 2Me -CHMe 2-CH 2-Me -(CH 2) 2-Me -(CH 2) 3-Me -CH 2-CH＝CH 2-CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me cyclohexyl-CH 2CHMe 2-CH 2CHMe 2-CHMeCH 2Me -CH 2-Phe cyclohexyl-CHMe 2-CHMe 2-CH 2Me -CH 2Me -(CH 2) 2-Me -(CH 2) 2-Me -(CH 2) 3-Me -(CH 2) 3-Me -CH 2-CH＝CH 2-CH 2-CH＝CH 2 -Me -Me -Me -Me -Me -Me -Me -CHMe 2-Me -Me -Me -Me -Me -Me -Me -Me -Me -Me -Me -Me -Me -Me -Me -CHMe 2-Me -Me -Me -CHMe 2-Me -CHMe 2-Me -CHMe 2-Me -CHMe 2-Me -CHMe 2 -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CH 2CHMe 2-CHMeCH 2Me -CHMe 2-CH 2-Me -(CH 2) 2-Me -(CH 2) 3-Me -CH 2-CH＝CH 2-CHMeCH 2Me -CHMeCH 2Me -CHMeCH 2Me -CH 2Me -(CH 2) 2-Me cyclohexyl-CH 2CHMe 2-CH 2CHMe 2-CHMeCH 2Me -CH 2-Phe cyclohexyl-CHMe 2-CHMe 2-CH 2-Me -CH 2-Me -(CH 2) 2-Me -(CH 2) 2-Me -(CH 2) 3-Me -(CH 2) 3-Me -CH 2-CH＝CH 2-CH 2-CH＝CH 2 -Me cyclohexyl-Me-CH 2-Phe -Me -(CH 2) 3-Me -Me -CHMe 2-CH 2-Phe -Me -Me -Me -Me -Me -Me -CH 2-Me -(CH 2) 2-Me -(CH 2) 3-Me-Me-Me-Me cyclohexyl-Me-Me-Me-Me-Me-Me-Me-Me-Me-Me-Me-Me-Me-Me
R 1 R 2 R 3 R 4 R 5 R 6
-Me -Me -CHMeCH 2Me -Me -CHMeCH 2Me -Me
-H -Me -Me -Me -CHMeCH 2Me -Me
-CH 2Me -Me -Me -Me -CHMeCH 2Me -Me
-(CH 2) 2-Me -Me -Me -Me -CHMeCH 2Me -Me
-CHMe 2 -Me -Me -Me -CHMeCH 2Me -Me
-(CH 2) 3-Me -Me -Me -Me -CHMeCH 2Me -Me
-CH 2CHMe 2 -Me -Me -Me -CHMeCH 2Me -Me
The Me=methyl; The Phe=phenyl
Be prepared the coupling agent that adopts among the method b and be the preparation method that all that is suitable for preparing amido link (list of references, for example: Houben-Weyl, Methoden der organischenChemie[organic chemistry method], the 15/2nd volume; People such as Bodanszky, peptide synthesizes the 2nd edition (Wiley ﹠amp; Sons, NeW York 1978), or Gross, Meienhofer, peptide: analyze and synthesize biology (Academic Press New Yord 1979)).The following preparation method of preferred employing: active ester method, adopt pentachlorophenol (Pcp) and Pentafluorophenol (Pfp), N-hydroxy-succinamide, N-hydroxyl-5-norborene-2 in this method, 3-dicarboxyl imines (HONB), 1-hydroxyl-benzotriazole (HOBt) or 3-hydroxyl-4-oxo-3,4-dihydro-1,2,3-benzotriazole alkane is as alkoxide component; Adopted carbodiimides in the coupling, for example finished coupling by adding dicyclohexyl carbodiimide (DCC); Or adopt the method for n-propane phosphonic acid anhydrides (PPA) and mixed acid anhydride to carry out coupling, adopted pivalyl chloride, chloroformyl ethyl ester (EEDQ) and chloroformyl isobutyl ester (IIDQ) in this method; Or adopted the coupling method of phosphorus reagent; benzotriazole-1-base-oxygen-three (dimethyl-amino phosphorus) hexafluorophosphate (BOP), two (2-oxo-3-oxazolidinyl)-phosphoryl chloride phosphorus oxychloride (BOP-Cl) and use phosphonate reagent for example; as diethylcyanophosphonise (DEPC) and diphenyl phosphoryl azide (DPPA) or urea (uronium) reagent; 2-(1H-benzotriazole-1-base-1 for example; 1; 3,3-tetramethylurea tetrafluoroborate
(TBTU)。
Preferred coupling reagent is: Phosphorus reagent, for example two (2-oxo-3-oxazolidinyl)-phosphoryl chloride phosphorus oxychlorides (BOP-Cl), benzotriazole-1-base-oxo-three-(dimethylamino-phosphorus) hexafluorophosphate (BOP); And phosphonate reagent, for example diethylcyanophosphonise (DEPC) or diphenylphosphine acyl azide (DPPA).
Being prepared the alkaline reaction adjuvant that adopts among the method b is the tertiary amine compound of mentioning in preparation method a, especially trialkylamine, for example triethylamine, N, N-diisopropyl ethyl amine or N-methyl-morpholine.
Being prepared the diluent that adopts among the method b also is the halogenated hydrocarbon of mentioning in method a, preferred chlorinated hydrocarbon.
Be prepared among the method b, to the height diluted state, and there be coupling agent and the alkaline reaction adjuvant of having mentioned above a kind of in the chemical compound of structural formula (II) and mixing diluents.Response time is between 4-72 hour.Reaction be-5 ℃ and+carry out in the temperature range between 100 ℃, preferred temperature range is between-5 ℃ to+50 ℃, more preferably 0 ℃ of temperature conditions to room temperature.Reaction is to carry out under normal pressure.
In order to carry out preparation method b of the present invention, the N-methyl of common every mole of structural formula (II)-L-isoleucyl--D-lactoyl-N-methyl-L-isoleucyl--D-lactoyl-N-methyl-L-isoleucyl--D-lactic acid will use the coupling agent of 1.0-3.0 mole, preferably the 1.0-1.5 mole.
After reaction finished, washing reaction solution was isolated organic facies until alkalescence, was dried and vacuum concentration.Adopt conventional method purification products therefrom, for example recrystallization, vacuum distilling or chromatogram column technique.
Open chain ester peptide as initial compounds can prepare by those known methods, for example, and method (Tetrahedron Lett.26 (43) (1985) the 5257-5260 pages or leaves that H.-G.Lerchen and H.Kunz describe; 28 (17) (1987) 1873-1876 pages or leaves), use B.F.Gisin people's such as (56 (1973) the 1476th pages of Helv.Chim Acta) esterification process.
The cyclic ester peptide that contains 24 annular atomses has comprised the chemical compound of general formula (Ia):
Figure A9619974800211
R wherein 1a, R 2a, R 11aAnd R 12aIndependently of one another, represented C respectively 1-8-alkyl, C 1-8-haloalkyl, C 3-6-cycloalkyl, aralkyl, aryl, R 3a, R 5a, R 7aAnd R 9aIndependently of one another, represented the C of hydrogen, straight or branched respectively 1-8-alkyl, this alkyl can be unsubstituted groups or be replaced by following substituent group: hydroxyl, C 1-4-alkoxyl, carboxyl (COOH), carboxamide groups (O-C (O)-NH 2), imidazole radicals, indyl, guanidine radicals ,-SH or C 1-4-alkylthio group, and can be by halogen, hydroxyl, C 1-4-alkyl, C 1-4The aryl or aralkyl that-alkoxyl replaces.R 4a, R 6a, R 8aAnd R 10aIndependently of one another, represented the C of hydrogen, straight chain respectively 1-5-alkyl, C 2-6-alkenyl, C 3-7-cycloalkyl, these group branches can be unsubstituted groups or be replaced by following substituent group: hydroxyl, C 1-4-alkoxyl, carboxyl, carboxamide groups, imidazole radicals, indyl, guanidine radicals ,-SH or C 1-4-alkylthio group, and can be by halogen, hydroxyl, C 1-4-alkyl, C 1-4The aryl or aralkyl that-alkoxyl replaces.
And their optical isomer and racemate.
In the preferred chemical compound of structural formula (Ia):
R 1a, R 2a, R 11aAnd R 12aIndependently of one another, represented respectively methyl, ethyl, propyl group, isopropyl, just, secondary, the tert-butyl group or phenyl, this phenyl can be a substituted radical or replaced by following substituent group not: halogen, C 1-4-alkyl, OH, C 1-4-alkoxyl, and benzyl or phenylethyl, benzyl wherein and phenylethyl can be unsubstituted, and the substituent group that can also have been described in above-mentioned phenyl example replaces;
R 3aTo R 10aDefinition as mentioned above.
Shown in the preferred structural formula (Ia) in the chemical compound:
R 1a, R 2a, R 11aAnd R 12aIndependently of one another, represented respectively methyl, ethyl, propyl group, isopropyl, just, secondary, the tert-butyl group;
R 3a, R 5a, R 7aAnd R 9aRepresented the C of hydrogen, straight or branched respectively 1-8-alkyl, preferably this alkyl be methyl, ethyl, propyl group, isopropyl, just, secondary, the tert-butyl group, each alkyl can be unsubstituted group or be replaced by following substituent group: C 1-4-alkoxyl, preferred methoxyl group, ethyoxyl; Imidazole radicals, indyl; Or C 1-4-alkylthio group, preferred methyl mercapto, ethylmercapto group; And can be by halogen, the phenyl, benzyl or the phenethyl that replace arbitrarily of chlorine particularly;
R 4a, R 6a, R 8aAnd R 10aIndependently of one another, represented hydrogen, methyl, ethyl, n-pro-pyl, normal-butyl, vinyl, cyclohexyl respectively, above-mentioned each group can be unsubstituted or following groups replace: methoxyl group, ethyoxyl, imidazole radicals, indyl, methyl mercapto, ethylmercapto group and isopropyl, sec-butyl and can be replaced by halogen or unsubstituted phenyl, benzyl or phenethyl.
Structural formula (Ia) chemical compound is to carry out cyclisation by the open chain monooctyl ester peptide with structural formula (IIc) to make.
Wherein:
R 1a-R 12aImplication as mentioned above,
Reaction is to carry out in the presence of diluent and coupling agent.
Suitable coupling agents be all be applicable to chemical compounds of connecting amido link (list of references, for example: Houben-Weyl, Methoden der organischen Chemie[organic chemistry method], the 15/2nd volume; People such as Bodanszky, peptide is synthetic, the 2nd edition (Wiley, Sons New York1976)).
Following reagent and method are preferred: the Acibenzolar method that has adopted Pentafluorophenol (Pfp), N-hydroxy-succinamide, I-hydroxybenzotriazole, coupling agent is a Carbodiimides, for example dicyclohexyl carbodiimide or N ' (3-dimethylaminopropyl)-N-ethyl-carbodiimides (Ebc); And mixed acid anhydride method; Perhaps used coupling agent is a phosphorus reagent, for example benzotriazole-1-base-oxo-three (dimethylamino phosphorus) hexafluorophosphoric acid ester (BOP), two (2-oxo-3-oxazolidinyl) phosphoryl chloride phosphorus oxychloride (BOP-Cl); Or phosphonate reagent, for example diethylcyanophosphonise (DEPc) and diphenylphosphine acyl azide (DPPA) have been adopted.
Preferred coupling reagent is: two (2-oxo-3-the oxazolidinyl)-phosphoryl chloride phosphorus oxychlorides (BOP-Cl) and N '-(3-the dimethylaminopropyl)-N-ethyl carbodiimides (EDC) that contain 1-hydroxyl-benzotriazole (HOBt).
Be reflected between 0-150 ℃ and carry out, preferable range is 20-100 ℃, more preferably reaction at room temperature.
All inert organic solvents all can be used as diluent.Particularly including aliphatic compound and aromatic compound, also can select for use or not select for use and select halogenated hydrocarbon in them; For example pentane, hexane, heptane, cyclohexane extraction, petroleum ether, gasoline, ligroin, benzene, toluene, dichloromethane, dichloroethanes, chloroform, carbon tetrachloride, chlorobenzene and o-dichloro-benzenes; Can also be ether, as Anaesthetie Ether and dibutyl ethers, glycol dimethyl ether, tirethylene glycol dimethyl ether, oxolane, Er oxazole; Can also select ketone for use, for example acetone, methyl ethyl ketone, methyl isopropyl Ketone, methyl iso-butyl ketone (MIBK); Also have ester, for example methyl acetate, ethyl acetate; Also can be nitrile, as acetonitrile, propionitrile, benzonitrile, glutaronitrile; Can select amide for use, as N, dinethylformamide, N,N-dimethylacetamide and N-Methyl pyrrolidone; And dimethyl sulfoxide, tetramethylene sulfone and hexamethyl phosphoramide.
Chemical compound and coupling agent ratio are 1 shown in the general formula (IIc) that adopts: 1-1: 1.5.Ratio near equivalent is preferred.
Diluent was removed in distillation after reaction finished, and adopted conventional method, for example chemical compound shown in the chromatography purification general formula (Ia).
Compositions of the present invention has the toxicity of appropriateness to homoiothermic animal, and be suitable for controlling the pathogenicity endoparasite, these parasites can colonize in the human body, be present in animal feeding and the reproductive process, also can colonize in animal, laboratory animal, test animal and the pet body in domestic animal, raising property animal, zoo.At this moment, they to parasite growth each or all the stage all effective, effective to drug-fast and normal responsive kind.By enantiopathy originality endobiosis parasitosis, the minimizing of animal dead number or output object (as the output of meat, milk, Pilus Caprae seu Ovis, leather, egg, Mel etc.) will reduce, therefore, by adopting reactive compound of the present invention to make more economical and simpler animal feeding become possibility.Pathogenic endoparasite comprises cestode, trematodiasis, nematicide, pinworm, particularly:
The example that Pseudophyllidea is washed worm has: Bothriocephalus, Spirometra, schistocephalus cestode genus, Ligula, phyllidium cestode belong to, japanese double cord tapeworm belongs to.
Ring leaf purpose example has: Mesocestoides, Anaplocephala, Paranoplocephalaspp., Moniezia, satisfy body cestode genus Tassel body and wash Eimeria, no vitellarium is washed Eimeria, Si Tai washs Eimeria, the stannum band is washed Eimeria, iS-One is washed Eimeria, Bert is washed Eimeria, Hydatigena, Echinococcus, the reed cestode belongs to, Davainea, Raillietina, Hymenolepis, Echinolepis spp., Echinocotyle spp., two testis cestodes belong to, Diplopylidium, Joyeuxiella spp., the Dilepididae Diplopylidium ...
The example of Helerocolylea trematodiasis has: Gyrodactylus, Dactylogyrus, spiral Eimeria ...
Digenetic trematode purpose example has: the two-wire trematodiasis belongs to, two six trematodiasiss belong to stem, Schistosoma, Trichobillharzia, the blunt edge trematodiasis belongs to, Austrobilharzia, huge trematodiasis belongs to, adopting larva of a tapeworm or the cercaria of a schistosome trematodiasis belongs to, Brachylaimus, Echinostoma, Echinoparyphium., Echinochasmus, Hypoderaerum, Fasciola, Echinochasmus, a trematodiasis belongs to ring, blind gastral cavity trematodiasis belongs to, Paramphistomum, Calicophoron, Cotylophoron, huge dish trematodiasis belongs to, luxuriant and rich with fragrance plan trematodiasis belongs to, abdomen bag trematodiasis belongs to, ridge hole trematodiasis belongs to, Catatropis, Plagiorchis, Prosthogonimus, Dicrocoelium, Eurytrema, Troglotrema, Paragonimus, Collyriculum, Nanophyetus salmincola belongs to, Opisthorchis, clonorchis sinensis belongs to, Meotrchis, Heterophyes(Heterophyes), Metagonimus ...
The example of Enoplida nematicide has: Trichocephalus, Hepaticola, Trichomosoides spp., Trichinella ...
The Rhabditis order has: microneme belongs to, Strongyloides ...
Strongylid purpose example has: Strongylus, Ternidens, esophagus tooth trace Eimeria, Trichinella, Gyalicephalus spp., Cylindropharynx spp., Poteriostomum, Cyclococercus spp., Cylicostephanus spp., oesophagostomum, Chabertia, Stephanurus, Ancylostoma, Ancylostoma, Bunostomum spp..
The class Globocephalus., Syngamus, Poteriostomum, Metastrongylus, Dictyocaulus, Miu Shi Turbatrix Protostrongylus, the buttock line Eimeria, Pneumostrongylus, Oxyuris., Elaphostongylus spp, Parelaphostrongylus spp, Crenosoma spp, Paracrenosoma spp, Angiostrongylus, Aelurostrongylus spp, Filaria, Parafilaria, trichostrongylus, blood lance trematodiasis belongs to, Ostertagia, the Ma Shi Turbatrix, Cooperia, linear Eimeria, light red Strongylus, Obeliscoides, Amidostomum, tricuspid disc Turbatrix, Ollulanus spp.
Enterobius purpose example has: Enterobius, gutstring Eimeria, Passalurus, Syphacia, Aspiculuris, thorn Turbatrix, Heterakis ...
Ascaris purpose example has: Ascaris, Toxascaris, Belascaris, parascris, different sharp Ascaris, Ascaris ...
Spiruroidea Turbatrix purpose example has: jaw mouth nematode genus, physaloptera, Thelazia, Gongylonema, Habronema, secondary Habronema, Drascheia, Dracunculus ...
Filaria purpose example has: Stephanofilaria, Parafilaria, Setaria, Loa, Dirofilaria, Mus Filaria, Bu Luge Filaria, Wuchereria, Onchocerca ...
Huge kiss tartar purpose example is by Filicollis spp., Moniliformis, Gigantorhynchus, preceding huge testis Acanthocephalus ...
Domestic animal and letting animals feed comprise: mammal as, cattle, horse, sheep, pig, goat, camel, Babalus bubalis L., donkey, rabbit, subsides deer, reinder; Fur-bearing animal, for example mink, squirrel, brown bear; Birds, for example hen, goose, turkey, duck, Ostriches; Fresh-water fishes and saltwater fish, for example: Squaliobarbus ourriculus, Cyprinus carpio, anguilla japonica; Reptile; Insecticide, for example Apis, silkworm.
Laboratory animal and test animal comprise: mice, rat, Cavia porcellus, golden hamster, Canis familiaris L. and cat.
House pet comprises Canis familiaris L. and cat.
Carrying out administration can be preventative and treatment usefulness.
Suitable plant or synthesis of polyol fatty acid (oils) be fatty acid triglycercide, preferred in length chain fatty acid triglyceride.More preferably neutral oil, indeterminate plant oil for example, wherein preferred rectification cocos nucifera oil, cocos nucifera oil for example known and that sell with commodity Miglyol by name, these can be with reference to the Lexikon der Hilfsstoffe [adjuvant complete works] that Fiedler showed, the 3rd edition, the 808-809 page or leaf, (1989).These cocos nucifera oil products comprise: Miglyol 810: a kind ofly contain sad and rectification cocos nucifera oil tricaprin, molecular weight is about 520.Its fatty acid consists of: mostly be 2% C most 6Fatty acid, about 65%-75%C 8Fatty acid, the C of about 25%-35% 10Fatty acid mostly is 2% C most 12Fatty acid; Its acid number is about 0.1, and saponification number is about 340-360, and iodine value is up to 1.Miglyol 812: be a kind of sad and rectification cocos nucifera oil tricaprin of containing, molecular weight is about 520, and its fatty acid consists of: mostly be 3% C most 6Fatty acid, the C of about 50%-65% 8Fatty acid, the C of about 30%-45% 10Fatty acid mostly is 5% C most 12Fatty acid; Its acid number is about 0.1, and saponification number is about 330-345, and iodine value is up to 1; Miglyol 818: contain sad, capric acid and linolenic acid triglyceride, molecular weight is about 510.Its fatty acid consists of: mostly be 3% C most 6Fatty acid, the C of about 45%-60% 8Fatty acid, the C of about 25%-40% 10Fatty acid, the C of about 2%-5% 12Fatty acid, the C of about 4-6 18: 1Fatty acid; Its acid number is about 0.2, and saponification number is about 315-335, and iodine value is up to 10.Captet 355 (1): contain sad and triglyceride capric acid, the fatty acid in this triglyceride is formed and is: caproic acid is about 2%, sadly is about 55%, and capric acid is about 42%; Its acid number is up to 0.1, and saponification number is about 325-240 at the most, and iodine value is up to 0.5.In addition, sad and triglyceride capric acid also is suitable for, and trade mark Myritol commercially available prod by name as is known can be with reference to the Lexikon derHilfsstoffe[adjuvant complete works that Fiedler showed], the 3rd edition, 834 pages, (1989).Wherein, the acid number of Myritol 813 is up to 1, and saponification number is about 340-350, and iodine value is about 0.5.
Below be other suitable materials: monoglyceride, Diglyceride and single acid/Diglyceride, the esterification products that preferably octanoic acid and capric acid and glycerol form.The example of this type of preferred product has: contain the monoglyceride of sad and/or capric acid and the product of diglyceride, product basic or that all form by the monoglyceride and the diglyceride of sad and/or capric acid, the commercially available prod of their known trade marks Imwitor by name, can be with reference to the Lexikon der Hilfsstoffe[adjuvant complete works that Fiedler showed], the 3rd edition, 645 pages, (1989).Preferred this series products that uses is Imwitor742 in the present composition, and it is a kind of and the mixture of about 40 weight portion capric acid and esterification products of glycerol sad by about 60 weight portions (ppw).Generally Imwitor 742 is yellow crystalline material, becomes liquid when 26 ℃ of left and right sides.Its acid number is up to 2, and iodine value is at most 1, and saponification number is about 235-275, it contains nearly 40%-50% monoglyceride, and the content of dissociative glycerin mostly is 2% most, the about 24-26 of tool ℃ fusing point, the contained non-saponification composition of this product is at most 0.3%, and peroxide value is the highest to be 1.
Known kind difference is fatty acid esters of sorbitan greatly, for example, product with trade mark Span sale by name, comprising for example single dodecylic acid Isosorbide Dinitrate, single hexadecanoic acid Isosorbide Dinitrate, monostearate Isosorbide Dinitrate, three stearic acid Isosorbide Dinitrates, single oleic acid Isosorbide Dinitrate and three oleic acid Isosorbide Dinitrates, for have in these can be for reference document, the Lexikon der Hilfsstoffe[adjuvant complete works of Fiedler works for example], the 3rd edition, 1139-1140 page or leaf (1989).
Acid of tetramethylolmethane fat and polyalkylene glycol ethers class, for example two pentaerythritol oleates, distearyl acid pentaerythritol ester, mono laurate pentaerythritol ester; Pentaerythritol polyethylene glycol ether and monostearate pentaerythritol ester and pentaerythritol fatty ester, these chemical compounds can be referring to the Lexikon der Hilfsstoffe[adjuvant complete works of Fiedler works], the 3rd edition, 923-924 page or leaf (1989).
Monoglyceride, for example glyceryl monooleate, monopalmitin and glyceryl monostearate, those known and on market, sold chemical compounds for example, product as commodity Myvatex, Myvaplex by name and Myverol, these can be referring to the Lexikon derHilfsstoffe[adjuvant complete works of Fiedler works], the 3rd edition, the 836th page (1989); And acetylizad monoglyceride; acetylation can be monoacylated or diacetylation; those known and on market, sold chemical compounds for example; product as commodity Myvacet by name; these can be referring to the Lexikon der Hilfsstoffe[adjuvant complete works of Fiedler works]; the 3rd edition, the 835th page (1989).
The list of propylene glycol-and di fatty acid ester, for example two sad propylene glycol esters, two lauric acid propylene glycol esters, hydroxy stearic acid propylene glycol ester, isostearic acid propylene glycol ester, lauric acid propylene glycol ester, ricinoleic acid propylene glycol ester, propylene glycol stearate and similar compound, these can be referring to the Lexikon der Hilfsstoffe[adjuvant complete works of Fiedler works], the 3rd edition, the 1013rd page (1989).More preferably sad capric acid propylene glycol diesters, this is known and the chemical compound sold on market, and as the product of commodity Mlglyol 840 by name, these can be referring to the Lexikon der Hilfsstoffe[adjuvant complete works of Fiedler works], the 3rd edition, the 809th page (1989).Mlglol 840 contains fatty acid, and this fatty acid contains: maximum about 3% C 6The C of fatty acid, about 65-80% 8The C of fatty acid, about 10-30% 10Fatty acid, maximum about 3% C 12Fatty acid; Mlglol 840 also has the saponification number that is up to 0.1 acid number, nearly 320-240 and is 1 iodine value to the maximum.
These type of other suitable product is Capmul MCT (1), Captex 300 (1), Captex800 (1), Neobee M5 (2)And Mazol1400 (3), Imwitor (4) (1)＝Capital?City?Products，P.O.Box?569，Columbus，OH，USA (2)＝Stepan，PVO?Dept.，100?West?Hunter?AVe.，Maywood，NJ?07607，USA (3)＝Mazer?Chemicals，3938?Porett?Drive，Gurnee，IL，USA (4)＝Hul?AG，14370?Marl，Germany
Imwitor 742 is as preferred fatty glyceride.Compositions of the present invention also contains pharmaceutically acceptable emulsifying agent.Here the nonionic surfactant of preferred hydrophilic and lipophilic non-ionic surface active agent are as emulsifying agent.The suitable example that can be used as the hydrophilic surfactant active of surface active agent composition has: the product of natural or hydrogenated vegetable oil and ethylene glycol, be called as the natural or hydrogenant vegetable oil of polyoxyethylene-ethylene glycolization, for example polyoxyethylene-ethylene glycolization is natural or castor oil hydrogenated.Adopt known method can make this product, for example: at first with natural or castor oil hydrogenated or its fraction according to certain molar ratio example and reacting ethylene oxide, for example their mol ratio is about 1: 35-1: 60, the free Polyethylene Glycol composition that is about in the product is removed then, in DE-B 1 182 388 and DE-B 1 518 819 said method is had description.Kinds of surface activating agent with trade (brand) name Cremophor name is particularly useful for the present invention.Wherein, particularly suitable is: the product of trade mark CremophorRH40 by name, this product have 50-60 saponification number, be lower than 1 acid number, be lower than 1 iodine value, be less than 2% water content (according to Fischer), the index of refraction n of about 1.453-1.457 D 20, about 14-16 HLB value (hydrophile-lipophile balance value); CremophorRH60, this material have 40-50 saponification number, be lower than 1 acid number, be lower than 1 iodine value, the water content (according to Fischer) that is less than 4.5-5.5%, the index of refraction n of about 1.453-1.457 D 20, about 15-17 HLB value (hydrophile-lipophile balance value); Cremophor EL, this material have about 1630 molecular weight (adopting the gas osmometry to measure), the saponification number of 65-70, about 2 acid number, the iodine value of about 28-32, about 1.471 index of refraction n D 20These can be referring to, the Lexikonder Hilfsstoffe[adjuvant complete works of Fiedler works for example], the 3rd edition, 326-327 page or leaf (1989).In addition, this series products that is suitable for also has the kinds of surface activating agent of those commodity Nikkol by name, for example Nikkol HCO-60.Product Nikkol HCO-60 is the product of castor oil hydrogenated and oxirane, the character of this product is: acid number=about 0.3, saponification number=about 47.4, hydroxyl value=about 42.5, pH (5%)=about 4.6, APHA (alpha pulse height analysic) color=about 40, fusing point=about 36.0 ℃, freezing point=about 32.4 ℃, water content (% content is according to KarlFischer)=about 0.03.
The fatty acid ester of polyethenoxy sorbitan, for example it is single-or trilaurin, single-and tripalmitate, single-and tristearate, and single-and trioleate; For example those are known and that sold on market and product commodity Tween by name, and these can be referring to the Lexikon der Hilfsstoffe[adjuvant complete works of Fiedler works], the 3rd edition, 1300-1340 page or leaf (1989). these products comprise, for example following products: Tween 20=polyoxyethylene (20) Arlacel-20 Tween 40=polyoxyethylene (20) Arlacel-40 Tween 60=polyoxyethylene (20) Arlacel-60 Tween 80=polyoxyethylene (20) Arlacel-80 Tween 65=polyoxyethylene (20) Arlacel-65 Tween 65=polyoxyethylene (20) sorbitan trioleate Tween 21=polyoxyethylene (4) Arlacel-20 Tween 61=polyoxyethylene (4) Arlacel-60 Tween 81=polyoxyethylene (5) Arlacel-80
Such product that more preferably adopts in the present composition is above-mentioned Tween40 that mentions and Tween 80.
Polyoxyethylene fatty acid ester, for example known Myrj 45 compounds, such material is those products of sale and commodity Myrj by name on market, these can be referring to the Lexikon der Hilfsstoffe[adjuvant complete works of Fiedler works], the 3rd edition, the 834th page (1989); And those have sold on market and the product of commodity Cetiol HE by name, and these can do [adjuvant complete works], the 3rd edition, the 284th page (1989) referring to the Lexikon der Hilfsstoffe of Fiedler works; Preferred especially this series products that adopts is product Myrj 52 in the present composition, and this product has about 1.1 index of refraction n D 20, the fusing point of about 40-44 ℃, about 16.9 HLB value, the acid number of about 0-1, the saponification number of about 25-35.
The copolymer of polyoxyethylene and polyoxypropylene, known example has: those are the product of sale and commodity Pluronic by name and Emkalyx on market, these can be referring to the Lexikon der Hilfsstoffe[adjuvant complete works of Fiedler works], the 3rd edition, 956-958 page or leaf (1989).Preferred especially this series products that adopts is Pluronic F68 in the present composition.
The block copolymer of polyoxyethylene and polyoxypropylene, known example has: those are the product of sale and commodity Poloxamer by name on market, these can be referring to the Lexikon der Hilfsstoffe[adjuvant complete works of Fiedler works], the 3rd edition, the 959th page (1989).Preferred especially this series products that adopts is Poloxamer 188 in the present composition.
Dioctyl succinate, dioctyl sodium sulphosuccinate, two-[2-ethylhexyl]-succinate or sodium lauryl sulphate.
Phospholipid, preferably lecithin especially, these can be referring to the Lexikon derHilfsstoffe[adjuvant complete works of Fiedler works], the 3rd edition, 731-733 page or leaf (1989).The lecithin that is suitable in the present composition adopting comprises, particularly soybean lecithin.
The suitable surfactant example that uses as emulsifying agent is the transesterification product of those crude vegetal glyceride and polyalkylene polyhydric alcohol.This class transesterification product is material well known in the art and is to prepare, and for example adopts disclosed method preparation among the US-A-3 288 824.They have comprised the transesterification products of multiple crude vegetal, crude vegetal wherein can for example be unhydrided vegetable oil, the mixture of Semen Maydis oil, kernel oil, almond oil, Oleum Arachidis hypogaeae semen, olive oil and Petiolus Trachycarpi oil and they and Polyethylene Glycol for example, wherein preferred mean molecule quantity is the Polyethylene Glycol of 200-800.Preferred those products by 2 moles of crude vegetal glyceride and 1 mole of Polyethylene Glycol generation transesterification, for example mean molecule quantity is the Polyethylene Glycol of 200-800.The various products of this type of transesterification are those products known and commodity of having sold on market Labrafil by name, and these can be referring to the Lexikon derHilfsstoffe[adjuvant complete works of Fiedler works], the 3rd edition, the 707th page (1989).Preferred this series products as component is in the present composition: Labraffl M 1944 CS, this product are the transesterification products of kernel oil and Polyethylene Glycol, and this product has the saponification number of about 2 acid number, about 145-175, the iodine value of about 60-90; Labrafil M 2130 CS, this product is C 12-C 18The transesterification products of glyceride and Polyethylene Glycol, this product have 35-40 ℃ fusing point, be lower than 2 acid number, about 185-200 saponification number, be lower than 3 iodine value.
It is very favourable containing thickening agent in the present composition.Thickening agent is: organic thickening agent, for example Bentonite, silica sol, aluminum monostearate; Organic thickening agent, for example cellulose derivative.Polyvinyl alcohol and their copolymer, acrylate and methacrylate.
The form of all right mixture of the reactive compound in the present composition and synergist or other reactive compounds exist, and these chemical compounds all have pathogenic parasite effect in the body of killing.These reactive compounds are, L-2 for example, 3,5,6-tetrahydrochysene-6-phenyl-Imidazothiazole, benzimidazole carbamate, for example febantel and pyrantel, praziquantel, ivermectin.
Contain the reactive compound that concentration is 10ppm-20% (weight) in the ready-made preparation, preferred concentration is 0.1-20% (weight).
Help the effect that obtains the effective treatment when usually, the The compounds of this invention dosage is about 1-100mg reactive compound/kg body weight/day.Preferred 1-10mg/kg/ days dosage.
Be to be used for explanation but not to be to limit embodiments of the invention below.Embodiment 18g reactive compound PF 10228g reactive compound praziquantel 6g Cremophor RH 40 (as emulsifying agent) 12g Polyethylene Glycol 66g Imvitor 742 (as oil)
Under the condition of slight fever (40 ℃), emulsifying agent, oil and Polyethylene Glycol are mixed, add reactive compound down in stirring then.Obtain clear solutions, this solution is packed in the gelatin soft capsule.

Claims (4)

1. the pro ore compositions of ring-type and/or open chain ester peptide, said composition is made up of aminoacid and hydroxy carboxylic acid as construction unit, they can mix separately or with other reactive compounds, it is characterized in that these reactive compounds are dissolved in the solvent mixture of being made up of following material: the fatty acid ester-emulsifying agent of-Polyethylene Glycol-plant or synthetic polyhydric alcohol (oils).
2. compositions according to claim 1 is characterized in that: this active compounds solution is encapsulated in the gelatin soft capsule.
3. compositions according to claim 1 is characterized in that: solvent mixture contains following compositions :-Polyethylene Glycol 5-20%-oil 50-70%-emulsifying agent 1-10%.
4. compositions according to claim 1 is characterized in that: closed following composition system in the gelatin soft capsule :-reactive compound 0.1-20% (weight)-Polyethylene Glycol 5-20% (weight)-oily 50-70% (weight)-emulsifying agent 1-8% (weight).
CN96199748A 1995-12-02 1996-11-20 Endoparasiticidal agents Pending CN1207673A (en)

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