CN104788519A - Novel sixteen-membered ring triamine lactone derivative and application thereof - Google Patents

Novel sixteen-membered ring triamine lactone derivative and application thereof Download PDF

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CN104788519A
CN104788519A CN201410030016.7A CN201410030016A CN104788519A CN 104788519 A CN104788519 A CN 104788519A CN 201410030016 A CN201410030016 A CN 201410030016A CN 104788519 A CN104788519 A CN 104788519A
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ethyl
methyl
base
hydroxyl
pyrans
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CN104788519B (en
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黄文江
袁海卿
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CHENGDU VICTOR PHARMACEUTICALS Ltd
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CHENGDU VICTOR PHARMACEUTICALS Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives

Abstract

The invention discloses a novel sixteen-membered ring triamine lactone derivative and application thereof. The novel sixteen-membered ring triamine lactone derivative is a compound as shown in a general formula (I) or (II) which is described in the specification or a pharmaceutically acceptable salt thereof. In the formula, R1 is arbitrarily substituted C1-6 alkyl group or C3-8 cycloalkyl group and R2 is hydrogen or arbitrarily substituted C1-6 alkyl group or C3-8 cycloalkyl group, or R1 and R2 is connected through a chemical bond so as to allow R1-N-R2 group to compose arbitrarily substituted 3-to-5-membered or 7-to-9-membered heterocyclic group; and R3 and R4 are independently selected from the group consisting of hydrogen or C1-3 alkyl group. The compound or the pharmaceutically acceptable salt thereof has excellent antibacterial activity, is applied to treatment and prevention of animal bacterial infection and mycoplasma infection and provides a novel approach for treatment or prevention of animal bacterial infection and mycoplasma infection.

Description

Novel sixteen-ring triamine lactone derivatives and application thereof
Technical field
The invention belongs to pharmacy field, relate to a kind of new microbiotic.Specifically, the present invention relates to a class 16-ring take off 20,23 new derivatives modified of the safe happy lactone of mycaminose, this analog derivative can be medicinal salt, prepare the method for this analog derivative and the application of this analog derivative.
Background technology
Since the mankind find penicillin in generation nineteen twenty, since the 1940's discovery Streptomycin sulphate, various compound with anti-microbial activity newly is constantly found and as antibiotic usage, thus has saved thousands of life and greatly facilitated the development of Modern Animal Husbandry.But As time goes on, bacterium can, to existing drug resistant, make infection be difficult to healing even uncontrollable.At present, the bacterium having a resistance to microbiotic has become a day by day serious public health and has threatened, and there is the concentrated reflection that drug-resistant bacteria the MRSA for a long time and superbacteria NDM-1 that occurs recently is this kind of serious threat.In fact, the Clinical practice of nearly all antibiotics, finally all can cause appearance and the existence of drug-resistant bacteria, such as: the persister of gram positive bacterium, as methicillin-resistant Staphylococcus, suis, faecalis of penicillin resistant and vancomycin resistance etc.These drug-resistant bacterias may cause serious even fatal consequence to the patient infected by it or animal.In drug research field, developing new microbiotic is the important means solving resistant organism problem.
Macrocyclic lactone is the microbiotic that a class contains the cyclosubstituted 14-16 ring of one or more 6 yuan of sugar, comprises erythromycin, tylosin, tilmicosin, Roxithromycin, dirithromycin, Azythromycin, clarithromycin, Spiramycin Base, Tulathromycin, romicil, Magnamycin A, Flurithromycin etc.The mechanism of action of macrolide antibiotics is combined with procaryotic rrna 50S subunit, and its binding site is closely related or identical with the action site of lincosamides with paraxin.The transposition of transfer ribonucleic acid can be stoped after macrolide is combined with rrna, and then destroy the synthesis of bacterioprotein.Macrocyclolactone lactone kind medicine is optionally only combined with procaryotic rrna 50S, does not then have avidity to mammiferous rrna.
To macrolide antibiotics, there is drug-fast bacterium also to occur.Its resistance mechanism mainly contains: (1) reduces medicine in intracellular accumulation by the permeability or acquired outer row's mechanism reducing bacteria cell wall; (2) methylating thus greatly reducing the avidity of antibacterials and ribosome bind site by the ribosomal binding site of the 50S of ermA, ermB and ermC gene mediated; (3) bacterium produces ester hydrolase by induction thus makes drug inactivation.
Tylosin and relevant 16 member cyclic macrolide derivatives (see formula one) thereof be proved to be already effectively can resist some gram-positive microorganism and Gram-negative bacteria and cause poultry, the animal such as ox and pig infection.(people such as Ke Site (Kirst), U.S. Patent number 4468511,4920103; The people such as pottery (Tao), U.S. Patent number 4921947; The people such as Georg Lukacs (Lukacs), U.S. Patent number 5032581).But its shortcoming is relatively low bioavailability, gastrointestinal side effect, and limited anti-microbial activity spectrum.Tilmicosin is 20 desugar derivatives modified of tylosin, and the advantage of tilmicosin is mainly its pharmacokinetics, the particularly longer transformation period (U.S. Patent number 5545624).Its shortcoming is cardiac toxic, especially during drug administration by injection.Formula one:
Another macrolide derivatives Zuprevo relevant to tylosin is then on the basis of 20 piperidine structures remaining tilmicosin, the further substituting group having modified 23, and instead of 6-deoxidation-D-allose with piperidyl equally, obtain new antimicrobial agent (US 6514946 B1 having greater activity for pasteurellosis bacillus; Chinese invention patent, publication number CN 101506220 A).Zuprevo and Tulathromycin all contain three alkaline amino, and there are close relationship this feature and their enrichments in lung tissue and segmental bronchus liquid and longer transformation period.But, although two piperidine structure is improving the combined coefficient of this medicine and helpful in reducing costs, might not be best pharmacophoric group.In fact, the Si Difen people such as scholar Witter (Stephen Douthwaite) just shows 16 membered macrolide derivatives of tylosin class and the interactional the study of computer simulation of bacterial ribosome combining site recently, the contact internal walls of the piperidyl that Zuprevo molecule is 23 and bacterial ribosome combining site, and on the interaction at this position and piperidyl, the protonation state of amino nitrogen has substantial connection.（ACS Chem.Biol.2012,7,1351-1355。）
The structure of modification of tylosin class macrolide more report.The people such as such as nearest Hong Fu transform 9 of the happy lactone of Thailand and 20, obtain certain success (Bioorganic & Medicinal Chemistry Letters16 (2006) 1259 – 1266).Find with like ketolide, to the streptococcus pneumoniae of resistance to macrolides medicine and the activated derivative of the staphylococcus aureus strains of inducible phenotype in test in vitro.
Summary of the invention
The object of the invention is on the basis of existing technology, provide a class to relate to 20,23 novel triamine lactone derivative compounds and salt thereof modified of the safe happy lactone of 16-ring microbiotic.
Another object of the present invention is to provide a kind of preparation method of above-claimed cpd.
3rd object of the present invention is to provide the application of a kind of above-claimed cpd in treatment and prevention human or animal's bacteriological infection and mycoplasma infection.
Object of the present invention can be reached by following measures:
Compound representated by general formula (I) or general formula (II) or its pharmacy acceptable salt,
Wherein,
R 1the C replaced arbitrarily 1-6alkyl or C 3-8cycloalkyl, its substituting group is selected from aryl or hydroxyl;
R 2the C be hydrogen, replacing arbitrarily 1-6alkyl or C 3-8cycloalkyl, its substituting group is selected from aryl or hydroxyl;
Or R 1with R 2be connected with chemical bond and make R 1-N-R 2group forms the 3-5 unit or the first heterocyclic group of 7-9 that replace arbitrarily, and its substituting group is selected from C 1- 3alkyl or hydroxyl;
R 3and R 4separately be selected from hydrogen or C 1-3alkyl.
In the present invention, a kind of preferred scheme is R 1the C replaced arbitrarily 1-4alkyl or C 3-8cycloalkyl, its substituting group is selected from benzene, pyridine or hydroxyl.
In the present invention, a kind of preferred scheme is R 1the C replaced arbitrarily 1-2alkyl, its substituting group is selected from benzene, pyridine or hydroxyl.
In the present invention, a kind of preferred scheme is R 1ethyl, n-propyl, sec.-propyl, butyl, benzyl, 2-hydroxyethyl, 2-picolyl, 3-picolyl, 4-picolyl or cyclohexyl.
In the present invention, a kind of preferred scheme is R 2the C being hydrogen or replacing arbitrarily 1-4alkyl, its substituting group is selected from benzene, pyridine or hydroxyl.
In the present invention, a kind of preferred scheme is R 2the C being hydrogen or replacing arbitrarily 1-2alkyl, its substituting group is selected from benzene, pyridine or hydroxyl.
In the present invention, a kind of preferred scheme is R 2hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl or 2-hydroxyethyl.
In the present invention, a kind of preferred scheme is R 1with R 2be connected with chemical bond and make R 1-N-R 2group forms 5 yuan or 9 yuan of heterocyclic groups, and its substituting group is selected from methyl, ethyl, n-propyl, sec.-propyl or hydroxyl.
In the present invention, a kind of preferred scheme is R 1with R 2be connected with chemical bond and make R 1-N-R 2group forms Pyrrolidine base, 3-hydroxypyrrole alkyl, 3,5-lupetidine bases or isoindoline base.
In the present invention, a kind of preferred scheme is R 3and R 4separately be selected from hydrogen or methyl.
Unless otherwise indicated, the following term used in the specification and in the claims has implication discussed below:
" alkyl " represents the saturated aliphatic radical of 1-20 carbon atom, comprises straight chain and branched group (digital scope mentioned in the application's book, such as " 1-6 ", refer to this group, be now alkyl, can 1 carbon atom, 2 carbon atoms, 3 carbon atoms etc. be contained, until comprise 6 carbon atoms).Alkyl containing 1-4 carbon atom is called low alkyl group.When low alkyl group does not have substituting group, be called unsubstituted low alkyl group.It is further preferred that alkyl is the alkyl having 1-4 carbon atom, such as methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-, the tertiary butyl etc., further preferably alkyl is the alkyl having 1-2 carbon atom.
" cycloalkyl " represents to be all the monocycle of carbon or ring (" condensing " ring means that each ring in system and other ring in system the share a pair carbon atom adjoined) group that condenses, wherein one or more rings do not have the π-electron system connected completely, and the example (being not limited to) of cycloalkyl is cyclopropane, tetramethylene, pentamethylene, cyclopentenes, hexanaphthene, diamantane, cyclohexadiene, suberane and cycloheptatriene.Cycloalkyl can be replacement with unsubstituted.The digital scope mentioned in the application's book, such as " 3-8 ", referring to can containing 3 carbon atoms, 4 carbon atoms, 5 carbon atom etc. in this group, until comprise 8 carbon atoms, the cycloalkyl in the application preferably adopts C 5-6cycloalkyl.
" aryl " represents the full carbon of 1 to 12 carbon atom or contains heteroatomic monocycle or fused polycycle group, has the π-electron system of total conjugated.Wherein heteroatoms is generally N, O and S, and heteroatomic number can be one, two, three or four.The limiting examples of aryl has phenyl, pyridyl, pyrryl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyrimidyl, quinolyl, isoquinolyl, purine radicals, tetrazyl, triazinyl, naphthyl and anthryl etc.Aryl can be replacement or unsubstituted.Aryl in the present invention is preferably phenyl or pyridyl.
" heterocyclic radical " represents monocycle or fused ring group, has 3 to 9 annular atomses in ring, and wherein one or two annular atoms is selected from N, O or S (O) mthe heteroatoms of (wherein m is the integer of 0 to 2), all the other annular atomses are C.These rings can have one or more double bond, but these rings do not have the π-electron system of total conjugated.The limiting examples of unsubstituted heteroalicyclyl has pyrrolidyl, piperidino-(1-position only), Piperazino, morpholino base, thiomorpholine for base, homopiperazino, indoline base, isoindoline base etc.Heterocyclic radical in the present invention is preferably pyrrolidyl, piperidyl or isoindoline base.
" hydroxyl " represents-OH group.
" substituting group is selected from " refers to that the one or more concrete group that aforesaid each group can be lifted by listed thereafter replaced.Such as " substituting group is selected from aryl or hydroxyl " refer to aforementioned group can by one or more aryl or hydroxyl replace.
" replace arbitrarily " expression " to be substituted " or " not being substituted " two kinds of situations, the alkyl such as replaced arbitrarily refers to " alkyl be substituted " or " unsubstituted alkyl ".
" pharmacy acceptable salt " represents the reservation biological effectiveness of parent compound and those salt of character.This kind of salt comprises:
(1) with sour salify, react by the free alkali of parent compound and mineral acid or organic acid and obtain, mineral acid comprises hydrochloric acid, Hydrogen bromide, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid and perchloric acid etc., organic acid comprises acetic acid, trifluoroacetic acid, propionic acid, vinylformic acid, caproic acid, pentamethylene propionic acid, hydroxyethanoic acid, pyruvic acid, oxalic acid, or (L) oxysuccinic acid (D), fumaric acid, toxilic acid, phenylformic acid, hydroxy-benzoic acid, gamma-hydroxybutyric acid, methoxybenzoic acid, phthalic acid, methylsulfonic acid, ethyl sulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, tosic acid, Whitfield's ointment, tartrate, citric acid, lactic acid, styracin, dodecyl sulphate, glyconic acid, L-glutamic acid, aspartic acid, stearic acid, amygdalic acid, succsinic acid or propanedioic acid etc.
(2) acid proton be present in parent compound replaced by metal ion or with organic bases ligand compound the salt that generates, metal ion is alkalimetal ion, alkaline-earth metal ions or aluminum ion such as, and organic bases is as thanomin, diethanolamine, trolamine, Trometamol, N-METHYL-ALPHA-L-GLUCOSAMINE, quinine etc.
" pharmaceutical composition " refers to such as, by one or more or its pharmacy acceptable salt, solvate, hydrate or the prodrug in the compound in the present invention and other chemical composition, pharmaceutically acceptable carrier, mixing.The object of pharmaceutical composition promotes that administration is to the process of animal.
In compound of the present invention or its pharmacy acceptable salt, described compound specifically can be selected from:
(4R, 5S, 6S; 7R, 9R, 11E; 13E, 15R, 16R)-15-((diethylamino) methyl)-6-(((2R; 3R, 4S, 5S; 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-16-ethyl-4-hydroxyl-5,9; 13-trimethylammonium-7-(2-(piperidin-1-yl) ethyl) oxa-16 ring-11,13-diene-2,10-diketone;
(4R, 5S, 6S; 7R, 9R, 11E; 13E, 15R, 16R)-6-(((2R; 3R, 4S, 5S; 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-15-((dipropylamino) methyl)-16-ethyl-4-hydroxyl-5,9; 13-trimethylammonium-7-(2-(piperidin-1-yl) ethyl) oxa-16 ring-11,13-diene-2,10-diketone;
(4R, 5S, 6S; 7R, 9R, 11E; 13E, 15R, 16R)-15-((butyl is amino) methyl)-6-(((2R; 3R, 4S, 5S; 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-16-ethyl-4-hydroxyl-5,9; 13-trimethylammonium-7-(2-(piperidin-1-yl) ethyl) oxa-16 ring-11,13-diene-2,10-diketone;
(4R, 5S, 6S; 7R, 9R, 11E; 13E, 15R, 16R)-6-(((2R; 3R, 4S, 5S; 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-16-ethyl-4-hydroxyl-5,9; 13-trimethylammonium-7-(2-(piperidin-1-yl) ethyl)-15-(pyrrolidin-1-yl methyl) oxa-16 ring-11,13-diene-2,10-diketone;
(4R, 5S, 6S; 7R, 9R, 11E; 13E, 15R, 16R)-15-((benzylamino) methyl)-6-(((2R; 3R, 4S, 5S; 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-16-ethyl-4-hydroxyl-5,9; 13-trimethylammonium-7-(2-(piperidin-1-yl) ethyl) oxa-16 ring-11,13-diene-2,10-diketone;
(4R; 5S; 6S; 7R, 9R, 11E; 13E; 15R, 16R)-15-((benzyl (methyl) is amino) methyl)-6-(((2R, 3R; 4S; 5S, 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-16-ethyl-4-hydroxyl-5; 9; 13-trimethylammonium-7-(2-(piperidin-1-yl) ethyl) oxa-16 ring-11,13-diene-2,10-diketone;
(4R; 5S; 6S; 7R, 9R, 11E; 13E; 15R, 16R)-15-((two (2-hydroxyethyl) is amino) methyl)-6-(((2R, 3R; 4S; 5S, 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-16-ethyl-4-hydroxyl-5; 9; 13-trimethylammonium-7-(2-(piperidin-1-yl) ethyl) oxa-16 ring-11,13-diene-2,10-diketone;
(4R, 5S, 6S; 7R, 9R, 11E; 13E, 15R, 16R)-15-((Cyclohexylamino) methyl)-6-(((2R; 3R, 4S, 5S; 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-16-ethyl-4-hydroxyl-5,9; 13-trimethylammonium-7-(2-(piperidin-1-yl) ethyl) oxa-16 ring-11,13-diene-2,10-diketone;
(4R; 5S; 6S; 7R, 9R, 11E; 13E; 15R, 16R)-15-((benzyl (ethyl) is amino) methyl)-6-(((2R, 3R; 4S; 5S, 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-16-ethyl-4-hydroxyl-5; 9; 13-trimethylammonium-7-(2-(piperidin-1-yl) ethyl) oxa-16 ring-11,13-diene-2,10-diketone;
(4R; 5S; 6S; 7R, 9R, 11E; 13E; 15R, 16R)-15-((benzyl (sec.-propyl) is amino) methyl)-6-(((2R, 3R; 4S; 5S, 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-16-ethyl-4-hydroxyl-5; 9; 13-trimethylammonium-7-(2-(piperidin-1-yl) ethyl) oxa-16 ring-11,13-diene-2,10-diketone;
(4R; 5S; 6S; 7R, 9R, 11E; 13E; 15R, 16R)-6-(((2R, 3R; 4S; 5S, 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-16-ethyl-4-hydroxyl-5; 9; 13-trimethylammonium-15-((methyl (pyridin-3-yl methyl) is amino) methyl)-7-(2-(piperidin-1-yl) ethyl) oxa-16 ring-11,13-diene-2,10-diketone;
(4R, 5S, 6S; 7R, 9R, 11E; 13E, 15R, 16R)-6-(((2R; 3R, 4S, 5S; 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-16-ethyl-4-hydroxyl-15-(isoindoline-2-ylmethyl)-5,9; 13-trimethylammonium-7-(2-(piperidin-1-yl) ethyl) oxa-16 ring-11,13-diene-2,10-diketone;
(4R; 5S; 6S, 7R, 9R; 11E; 13E, 15R, 16R)-15-((benzyl (sec.-propyl) is amino) methyl)-6-(((2R; 3R; 4S, 5S, 6R)-4-(dimethylamino)-3; 5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-7-(2-(3; 5-lupetidine-1-base) ethyl)-16-ethyl-4-hydroxyl-5,9,13-trimethylammonium oxa-16 ring-11; 13-diene-2,10-diketone;
(4R; 5S; 6S, 7R, 9R; 11E; 13E, 15R, 16R)-6-(((2R; 3R; 4S, 5S, 6R)-4-(dimethylamino)-3; 5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-7-(2-(3; 5-lupetidine-1-base) ethyl)-16-ethyl-4-hydroxyl-5,9,13-trimethylammonium-15-((methyl (pyridin-3-yl methyl) is amino) methyl) oxa-16 ring-11; 13-diene-2,10-diketone;
(4R, 5S, 6S, 7R; 9R, 11E, 13E; 15R, 16R)-6-(((2R, 3R; 4S, 5S, 6R)-4-(dimethylamino)-3; 5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-7-(2-(3,5-lupetidine-1-base) ethyl)-16-ethyl-4-hydroxyl-15-(isoindoline-2-ylmethyl)-5,9; 13-trimethylammonium oxa-16 ring-11,13-diene-2,10-diketone;
(4R; 5S; 6S; 7R, 9R, 11E; 13E; 15R, 16R)-15-((benzyl (methyl) is amino) methyl)-6-(((2R, 3R; 4S; 5S, 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-16-ethyl-4-hydroxyl-7-(2-(isoindoline-2-base) ethyl)-5; 9; 13-trimethylammonium oxa-16 ring-11,13-diene-2,10-diketone;
(4R, 5S, 6S; 7R, 9R, 11E; 13E, 15R, 16R)-6-(((2R; 3R, 4S, 5S; 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-16-ethyl-4-hydroxyl-7-(2-(isoindoline-2-base) ethyl)-5,9; 13-trimethylammonium-15-(piperazine heavy stone used as an anchor-1-ylmethyl) oxa-16 ring-11,13-diene-2,10-diketone;
(4R, 5S, 6S; 7R, 9R, 11E; 13E, 15R, 16R)-15-((diethylamino) methyl)-6-(((2R; 3R, 4S, 5S; 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-16-ethyl-4-hydroxyl-7-(2-(isoindoline-2-base) ethyl)-5,9; 13-trimethylammonium oxa-16 ring-11,13-diene-2,10-diketone;
(4R, 5S, 6S, 7R, 9R, 11E, 13E, 15R, 16R)-6-(((2R, 3R, 4S, 5S, 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-15-((3,5-dimethyl piperazine heavy stone used as an anchor-1-base) methyl)-16-ethyl-4-hydroxyl-7-(2-(isoindoline-2-base) ethyl)-5,9,13-trimethylammonium oxa-16 rings-11,13-diene-2,10-diketone.
The invention provides the preparation method of the compound of a kind of general formula I or general formula I I, specifically comprise the steps:
Step one, tylosin take off red mould sugared reduction amination condensation: the hexahydropyridine of tylosin and corresponding replacement or isoindoline are reacted, and generate de-red mould sugared reduction amination intermediate 1a or 1b;
Step 2, de-6-deoxidation-D-allose: intermediate 1a or 1b is under mineral acid effect, and de-6-deoxidation-D-allose generates intermediate 2a or 2b;
Step 3, activation: intermediate 2a or 2b and iodine react under the effect of triphenyl phosphorus and pyridine, generate iodide 3a or 3b;
Step 4, amination: intermediate 3a or 3b reacts with organic amine in the basic conditions, generate product 4a or 4b;
Above-mentioned various in group definition described above.Wherein preferred, carry out at 70 ~ 85 DEG C in toluene or dioxane under formic acid effect in the reaction of step one; Mineral acid in step 2 is Hydrogen bromide, and temperature of reaction is 50 DEG C ~ 60 DEG C; In step 3, reaction solvent is methylene dichloride, and temperature of reaction is 0 ~ 20 DEG C; In step 4, alkali used is selected from salt of wormwood, sodium carbonate or triethylamine, and adopt or do not adopt reaction solvent, temperature of reaction is 25 ~ 140 DEG C.
Another embodiment of the present invention relates to a kind of pharmaceutical composition, it for activeconstituents with each new compound involved in specification sheets of the present invention or its salt (compound particularly according to any one of claim 1 ~ 6 or its pharmacy acceptable salt), and is aided with pharmaceutical excipient and makes pharmaceutical preparation.
Compound or its salt (compound particularly according to any one of claim 1 ~ 6 or its pharmacy acceptable salt) in the present invention can be applicable to preparation treatment or prevents animal or human bacterium or mycoplasma infection medicine aspect, mycoplasma infection aspect, such as animal or human's bacteriological infection aspect, or animal or human.Concrete, the disease of the animal (comprising Mammals, fish and birds) caused by bacterium and mycoplasma in the present invention includes but are not limited to: Pasteurella haemolytica, the ox respiratory system disease that pasteurellosis bacillus and Haemophilus somnus cause; The pig that pasteurella multocida causes, goat, the Bacillus pasteurii disease of sheep and poultry; The porcine contagious pleuropneumonia that actinobacillus causes, streptococcus suis infection; And ox, pig, goat, the mycoplasma infection of sheep and poultry.
Compound of the present invention or its pharmacy acceptable salt have excellent anti-microbial activity, are applied to treatment and prevention animal bacterial infection and mycoplasma infection, for the treatment of such disease or prevention provide new approach.
Embodiment
The present invention is illustrated by following examples.But the present invention is not limited to the detail of following examples.
The reagent solvent needed for compou nd synthesis preparation that the present invention relates to etc., apart from outside special indicating, are commercially available prod.The separation and purification of compound can be completed by chromatography.Material therefor as tlc silica gel, HG/T2354-92, GF254, chemical pure, Qingdao Marine Chemical Co., Ltd.; Xylo-Mucine, 300-800mPaS, chemical pure, 30036328, Chemical Reagent Co., Ltd., Sinopharm Group, plate prepared by 300-400 order silica gel.The compound structure qualification that the present invention relates to can be completed by nucleus magnetic resonance and mass spectrum etc.As 300-Bruker nuclear magnetic resonance analyser; SHIMADZU LCMS-2020, ESI source.
Embodiment 1. (4R, 5S, 6S, 7R, 9R, 11E, 13E, 15R, 16R)-6-(((2R, 3R, 4S, 5S, 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-16-ethyl-4-hydroxyl-15-((((2R, 3R, 4R, 5R, 6R)-5-hydroxyl-3,4-dimethoxy-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen) methyl)-5,9,13-trimethylammonium-7-(2-(piperidin-1-yl) ethyl) oxa-16 ring-11,13-diene-2,10-diketone (compound 1)
Tylosin (9.2 grams, 0.01 mole), hexahydropyridine (2.55 grams, 0.03 mole), toluene (30 milliliters) adds there-necked flask together, stirs and is warming up to 75 DEG C, slowly drip formic acid (2.5 grams, 0.05 mole), temperature control, at about 75 DEG C, drips off formic acid, and 75-80 DEG C is reacted 2 hours.After reaction terminates, add 15% dilute hydrochloric acid and lower floor's dope is dissolved, point water-yielding stratum.Benzene layer 90 milliliters of dilute hydrochloric acid wash twice, combining water layer.Be neutralized to pH with 30% aqueous sodium hydroxide solution and be about about 10, separate out white solid product, washing once, is dried, is obtained thick product (compound 1) about 10 grams, close to theoretical yield.Mass spectrum theoretical value: 840.53, measured value: 841.45(M+H +).
Embodiment 2. (4R, 5S, 6S, 7R, 9R, 11E, 13E, 15R, 16R)-6-(((2R, 3R, 4S, 5S, 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-16-ethyl-4-hydroxyl-15-(hydroxymethyl)-5,9,13-trimethylammonium-7-(2-(piperidin-1-yl) ethyl) oxa-16 ring-11,13-diene-2,10-diketone (compound 2)
Compound 1(9.0 gram, 0.01 mole) add in there-necked flask, then add Hydrogen bromide 30 milliliters and 30 milliliters, water, 57 DEG C are reacted 5 hours.Cold filtration, the sodium hydroxide solution of filtrate 30%-40% is neutralized to pH and is about 10, and precipitation product is solid, can filter.If separating out product is that dope needs dehydration, dry to obtain crude product 4.7 grams, productive rate is 70%.Mass spectrum theoretical value: 666.45, measured value: 667.40(M+H +).
Embodiment 3. (4R, 5S, 6S, 7R, 9R, 11E, 13E, 15S, 16R)-6-(((2R, 3R, 4S, 5S, 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-16-ethyl-4-hydroxyl-15-(iodomethyl)-5,9,13-trimethylammonium-7-(2-(piperidin-1-yl) ethyl) oxa-16 ring-11,13-diene-2,10-diketone (compound 3)
In there-necked flask, add compound 2(12.4 gram, 0.02 mole) methylene dichloride (40 milliliters), triphenyl phosphorus (8 grams, 0.03 mole), pyridine (2 grams, 0.022 mole), ice bath, makes temperature lower than 13 DEG C.Add iodine (8 grams, 0.03 mole) in batches, add iodine temperature control at 15 ± 3 DEG C, and stir 3 hours.Cold filtration, filtrate is with 30 milliliter of 15% dilute hydrochloric acid extraction twice, and united extraction liquid, being neutralized to pH with 30% sodium hydroxide solution is 9-10, separates out pale solid product, filters out product.Product is dissolved in a small amount of methylene dichloride, dry concentrated, drip the sherwood oil of boiling range 60-90 DEG C, make its crystallize out.Filter to obtain iodide crude product 8.7 grams, productive rate is 55%.Mass spectrum theoretical value: 776.35, measured value: 777.70(M+H +).
The safe happy lactone organic amine series derivatives compound 4a-4l of embodiment 4.
Organic amine, toluene, Isosorbide-5-Nitrae-dioxane all uses anhydrous sodium sulfate drying in advance; Triethylamine after drying re-distillation obtains.
method A: get 0.5 gram of iodide (compound 3), 1 milliliter of organic amine, 2 milliliters of toluene, 1 milliliter of triethylamine, under nitrogen protection reflux 24-48 hour, be cooled to room temperature, with the separation and purification of preparative chromatography plate after underpressure distillation.Developping agent is ethyl acetate: chloroform: methyl alcohol=1:1:1(v/v/v), productive rate 50%-60%.
method B: get 1.0 grams of iodide, 0.2 gram of Anhydrous potassium carbonate, 2-10 milliliter organic amine, under nitrogen protection stirring reaction at 25-140 DEG C of temperature, to iodide raw material disappears substantially (TLC detection).Reaction terminates the excessive organic amine of rear pressure reducing and steaming, adds sherwood oil and washes away residual organic amine, obtain thick product.Sterling preparative chromatography plate is purified.
method C: get 0.5 gram of iodide, 0.1 gram of Anhydrous potassium carbonate, the organic amine of 5 equivalents, 10 milliliters of Isosorbide-5-Nitrae-dioxane, stirring reaction at 110 DEG C of temperature, to iodide raw material disappears substantially (TLC detection).Reaction terminates rear pressure reducing and steaming solvent, adds sherwood oil and washes away residual organic amine, obtain thick product.Sterling preparative chromatography plate is purified.
Embodiment 5. (4R, 5S, 6S, 7R, 9R, 11E, 13E, 15R, 16R)-6-(((2R, 3R, 4S, 5S, 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-7-(2-(3,5-lupetidine-1-base) ethyl)-16-ethyl-4-hydroxyl-15-((((2R, 3R, 4R, 5R, 6R)-5-hydroxyl-3,4-dimethoxy-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen) methyl)-5,9,13-trimethylammonium oxa-16 ring-11,13-diene-2,10-diketone (compound 5)
Tylosin (19 grams, 0.021 mole), 3,5-lupetidine (6.8 grams, 0.060 mole), toluene (60 milliliters) adds there-necked flask together, stirs and is warming up to 75 DEG C, slowly drip (4.6 grams, formic acid, 0.10 mole), temperature control, at about 75 DEG C, drips off formic acid, and 75-80 DEG C is reacted 2 hours.After reaction terminates, add 15% dilute hydrochloric acid and lower floor's dope is dissolved, point water-yielding stratum.Benzene layer 180 milliliters of dilute hydrochloric acid wash twice, combining water layer.Be neutralized to pH with 30% aqueous sodium hydroxide solution and be about about 10, separate out white solid product, washing once, is dried, is obtained faint yellow solid 22.5 grams.Mass spectrum theoretical value: 868.57, measured value: 869.55(M+H +).
Embodiment 6. (4R, 5S, 6S, 7R, 9R, 11E, 13E, 15R, 16R)-6-(((2R, 3R, 4S, 5S, 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-7-(2-(3,5-lupetidine-1-base) ethyl)-16-ethyl-4-hydroxyl-15-(hydroxymethyl)-5,9,13-trimethylammonium oxa-16 ring-11,13-diene-2,10-diketone (compound 6)
Compound 5(22.5 gram, crude product) add in there-necked flask, then add 30 milliliters, water and Hydrogen bromide 30 milliliters, 57 DEG C of reactions 4 hours.Cold filtration, the sodium hydroxide solution of filtrate 30%-40% is neutralized to pH and is about 10, and precipitation product is dope, and water dissolution after taking out, then adds sodium-chlor and saltout, fully stir and filter, dry to obtain crude product 15 grams.Mass spectrum theoretical value: 694.48, measured value: 695.45(M+H +).
Embodiment 7. (4R, 5S, 6S, 7R, 9R, 11E, 13E, 15S, 16R)-6-(((2R, 3R, 4S, 5S, 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-7-(2-(3,5-lupetidine-1-base) ethyl)-16-ethyl-4-hydroxyl-15-(iodomethyl)-5,9,13-trimethylammonium oxa-16 ring-11,13-diene-2,10-diketone (compound 7)
Compound 6(15 gram, about 0.021 mole) add in methylene dichloride (60 milliliters) and dissolve, and add anhydrous sodium sulfate drying, add after filtering out siccative in there-necked flask, add triphenyl phosphorus (13 grams, 0.050 mole), pyridine (3.2 grams, 0.042 mole) again, ice bath, makes temperature lower than 13 DEG C.Add iodine (13 grams, 0.051 mole) in batches, add iodine temperature control at 15 ± 3 DEG C, and stir 4 hours.Cold filtration, filtrate is poured in separating funnel, extracts three times, separate lower floor with 15 milliliters of concentrated hydrochloric acids, merges No. three extracting solutions, and being neutralized to pH with 30% sodium hydroxide solution is 9-10, separates out pale solid product, filters out product.Be dissolved in by product in 20 ml waters, make it fully dissolve, add sodium-chlor and saltout, if be still dope, continue to add 20 ml waters after filtrate and dissolve, adding sodium-chlor saltouts, and filters, after drying, drips the sherwood oil of boiling range 60-90 DEG C, make its crystallize out.Filter to obtain product 7.3 grams.Mass spectrum theoretical value: 804.38, measured value: 805.35(M+H +).
The safe happy lactone organic amine series derivatives compound 8a-8c of embodiment 8.
Compound 8a-8c is prepared by the method B in compound 7 Application Example 4.
Embodiment 9. (4R, 5S, 6S, 7R, 9R, 11E, 13E, 15R, 16R)-6-(((2R, 3R, 4S, 5S, 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-16-ethyl-4-hydroxyl-15-((((2R, 3R, 4R, 5R, 6R)-5-hydroxyl-3,4-dimethoxy-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen) methyl)-7-(2-(isoindoline-2-base) ethyl)-5,9,13-trimethylammonium oxa-16 rings-11,13-diene-2,10-diketone (compound 9)
Tylosin (9.5 grams, 0.011 mole), formic acid (2.7 grams, 0.059 mole), isoindoline (3.7 grams, 0.031 mole), Isosorbide-5-Nitrae-dioxane (10 milliliters) adds there-necked flask together, is warming up to 70 DEG C of stirring reactions 2 hours.After reaction terminates, pressure reducing and steaming solvent, thick product is dissolved in 30 ml waters, be neutralized to pH9-10 with 20% diluted sodium hydroxide solution, solution becomes oyster white, takes out solid, solid anhydrous diethyl ether is washed away green surface, clean solid with sherwood oil again, porphyrize in mortar, filtration drying obtains pressed powder.Mass spectrum theoretical value: 874.52, measured value: 893.50(M+H 3o +).Embodiment 10. (4R, 5S, 6S, 7R, 9R, 11E, 13E, 15R, 16R)-6-(((2R, 3R, 4S, 5S, 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-16-ethyl-4-hydroxyl-15-(hydroxymethyl)-7-(2-(isoindoline-2-base) ethyl)-5,9,13-trimethylammonium oxa-16 ring-11,13-diene-2,10-diketone (compound 10)
Compound 9(9.8 gram, crude product) add in there-necked flask, then add 50 milliliters, water and Hydrogen bromide 45 milliliters, 58 DEG C of reactions 3.5 hours.Cold filtration, filtrate is neutralized to pH is about 9-10 with the sodium hydroxide solution of 30%, filters out solid, washes once, porphyrize by solid sherwood oil, and be dissolved in 30 milliliters of methylene dichloride, add anhydrous sodium sulphate, each 10 grams of dry filters of anhydrous magnesium sulfate.Filtrate is directly used in next step reaction.Mass spectrum theoretical value: 700.43, measured value: 719.40(M+H 3o +).
Embodiment 11. (4R, 5S, 6S, 7R, 9R, 11E, 13E, 15S, 16R)-6-(((2R, 3R, 4S, 5S, 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-16-ethyl-4-hydroxyl-15-(iodomethyl)-7-(2-(isoindoline-2-base) ethyl)-5,9,13-trimethylammonium oxa-16 ring-11,13-diene-2,10-diketone (compound 11)
The dichloromethane solution (30 milliliters) of the compound 10 in embodiment 10 adds in there-necked flask, then adds triphenyl phosphorus (4.2 grams, 0.016 mole), pyridine (2.5 grams, 0.033 mole), and ice bath, makes temperature lower than 15 DEG C.Add iodine (4.4 grams, 0.017 mole) in batches, add iodine and stir 3.5 hours at 20 DEG C.Cold filtration, filtrate is poured in separating funnel, extracts secondary, separate lower floor with 25 milliliters of concentrated hydrochloric acids, and merge secondary raffinate, being neutralized to pH with 30% sodium hydroxide solution is 9-10, separates out pale solid product, filters out product.If any oily product, be dissolved in 20 ml waters, make it fully dissolve, add sodium-chlor and saltout, after filtration drying, obtained product.Mass spectrum theoretical value: 810.33, measured value: 811.20(M+H +).
The safe happy lactone organic amine series derivatives compound 12a-12d of embodiment 12.
Compound 12a-12d is prepared by the method B in compound 11 Application Example 4.
In Vitro Bacteriostatic is tested
(1) bacterial strain
Quality Control bacterium: the other C25922 of intestinal bacteria, streptococcus aureus 29213.The 's, C83543(80 of swine escherichia coli are separated); Swine escherichia coli 0039(2011 is separated).Salmonella gallinarum 533, C79-13; Salmonella gallinarum 0008(2011 is separated).Pig streptococcus aureus 546, C56023(1989 is separated); Pig streptococcus aureus 5-1(2011 is separated).The strain of fowl many Sha Shi pasteurellosis bacillus 2.Streptococcus pneumoniae 2 strain.Klebsiella Pneumoniae 2 strain.Pig pleuropneumonia actinomycetes 2 strain.Mycoplasma strains etc.
(2) substratum
With Ca, the M-H substratum (large intestine, sramana, golden Portugal, Pasteur) that Mg regulates, the martin's bouillon (suis) adding 5% Sheep Blood that Ca, Mg regulate, the TSB(pancreas peptone soybean broth adding 1/100000NAD with Ca, Mg regulate) (pleuropneumonia actinomycetes).
(3) method
The preparation of medicine: accurately take 5120 micrograms (5.12 milligrams), add 1 milliliter of volumetric flask, after dripping dissolving, adds tri-distilled water to 1 milliliter with 95% alcohol.Content is 5120 mcg/ml.
Use 96 orifice plates, the corresponding meat soup of different compounds is cooked doubling dilution, make its concentration be followed successively by 320,160,80,40,20,10,5,2.5,1.25,0.625,0.313,0.156 mcg/ml, or adjust its concentration gradient as required.By above-mentioned different strains 37 degree of cultivation 18-24 hour on fresh Nutrient agar, picking, suspend with M-H meat soup, adjustment concentration, is 0.5 Maxwell unit.
After the bacterium liquid of 0.5 Maxwell unit is diluted 100 times, from above-mentioned different dilution compound balanced mix, cultivate 18-24 hour, then take out sentence read result for 37 degree, the minimum compound concentration of energy bacteria growing inhibiting is minimum inhibitory concentration.
Bacteriostatic activity detected result (μ g/ml, mcg/ml)
A: pneumonia actinomycetes serum 1 type; B: pneumonia actinomycetes serum 7-type; C: pasteurellosis bacillus 8217; D: pasteurellosis bacillus 8229; E: intestinal bacteria IN-F6-7; F: intestinal bacteria 25922(Quality Control bacterium); G: S. aureus L-forms 5-1; H: S. aureus L-forms 29213(Quality Control bacterium); I: Salmonellas LD4-8; J: Klebsiella Pneumoniae 3753; K: Klebsiella Pneumoniae 3699; L: streptococcus pneumoniae 2349; M: streptococcus pneumoniae 49619(Quality Control bacterium).
Mycoplasma sensitivity Detection result

Claims (10)

1. general formula (I) or the compound representated by general formula (II) or its pharmacy acceptable salt,
Wherein,
R 1the C replaced arbitrarily 1-6alkyl or C 3-8cycloalkyl, its substituting group is selected from aryl or hydroxyl;
R 2the C be hydrogen, replacing arbitrarily 1-6alkyl or C 3-8cycloalkyl, its substituting group is selected from aryl or hydroxyl;
Or R 1with R 2be connected with chemical bond and make R 1-N-R 2group forms the 3-5 unit or the first heterocyclic group of 7-9 that replace arbitrarily, and its substituting group is selected from C 1-3alkyl or hydroxyl;
R 3and R 4separately be selected from hydrogen or C 1-3alkyl.
2. compound according to claim 1 or its pharmacy acceptable salt, is characterized in that R 1the C replaced arbitrarily 1-4alkyl or C 3-8cycloalkyl, its substituting group is selected from phenyl, pyridyl or hydroxyl; R 2the C being hydrogen or replacing arbitrarily 1-4alkyl, its substituting group is selected from phenyl, pyridyl or hydroxyl.
3. compound according to claim 2 or its pharmacy acceptable salt, is characterized in that R 1ethyl, n-propyl, sec.-propyl, butyl, benzyl, 2-hydroxyethyl, 2-picolyl, 3-picolyl, 4-picolyl or cyclohexyl; R 2hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl or 2-hydroxyethyl.
4. compound according to claim 1 or its pharmacy acceptable salt, is characterized in that R 1with R 2be connected with chemical bond and make R 1-N-R 2group forms 5 yuan or 9 yuan of heterocyclic groups, and its substituting group is selected from methyl, ethyl, n-propyl, sec.-propyl or hydroxyl; Further, R 1with R 2be connected with chemical bond and make R 1-N-R 2group forms Pyrrolidine base, 3-hydroxypyrrole alkyl, 3,5-lupetidine bases or isoindoline base.
5. compound according to claim 1 or its pharmacy acceptable salt, is characterized in that R 3and R 4separately be selected from hydrogen or methyl.
6. the compound according to any one of Claims 1 to 5 or its pharmacy acceptable salt, is characterized in that described compound is selected from:
(4R, 5S, 6S; 7R, 9R, 11E; 13E, 15R, 16R)-15-((diethylamino) methyl)-6-(((2R; 3R, 4S, 5S; 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-16-ethyl-4-hydroxyl-5,9; 13-trimethylammonium-7-(2-(piperidin-1-yl) ethyl) oxa-16 ring-11,13-diene-2,10-diketone;
(4R, 5S, 6S; 7R, 9R, 11E; 13E, 15R, 16R)-6-(((2R; 3R, 4S, 5S; 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-15-((dipropylamino) methyl)-16-ethyl-4-hydroxyl-5,9; 13-trimethylammonium-7-(2-(piperidin-1-yl) ethyl) oxa-16 ring-11,13-diene-2,10-diketone;
(4R, 5S, 6S; 7R, 9R, 11E; 13E, 15R, 16R)-15-((butyl is amino) methyl)-6-(((2R; 3R, 4S, 5S; 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-16-ethyl-4-hydroxyl-5,9; 13-trimethylammonium-7-(2-(piperidin-1-yl) ethyl) oxa-16 ring-11,13-diene-2,10-diketone;
(4R, 5S, 6S; 7R, 9R, 11E; 13E, 15R, 16R)-6-(((2R; 3R, 4S, 5S; 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-16-ethyl-4-hydroxyl-5,9; 13-trimethylammonium-7-(2-(piperidin-1-yl) ethyl)-15-(pyrrolidin-1-yl methyl) oxa-16 ring-11,13-diene-2,10-diketone;
(4R, 5S, 6S; 7R, 9R, 11E; 13E, 15R, 16R)-15-((benzylamino) methyl)-6-(((2R; 3R, 4S, 5S; 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-16-ethyl-4-hydroxyl-5,9; 13-trimethylammonium-7-(2-(piperidin-1-yl) ethyl) oxa-16 ring-11,13-diene-2,10-diketone;
(4R; 5S; 6S; 7R, 9R, 11E; 13E; 15R, 16R)-15-((benzyl (methyl) is amino) methyl)-6-(((2R, 3R; 4S; 5S, 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-16-ethyl-4-hydroxyl-5; 9; 13-trimethylammonium-7-(2-(piperidin-1-yl) ethyl) oxa-16 ring-11,13-diene-2,10-diketone;
(4R; 5S; 6S; 7R, 9R, 11E; 13E; 15R, 16R)-15-((two (2-hydroxyethyl) is amino) methyl)-6-(((2R, 3R; 4S; 5S, 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-16-ethyl-4-hydroxyl-5; 9; 13-trimethylammonium-7-(2-(piperidin-1-yl) ethyl) oxa-16 ring-11,13-diene-2,10-diketone;
(4R, 5S, 6S; 7R, 9R, 11E; 13E, 15R, 16R)-15-((Cyclohexylamino) methyl)-6-(((2R; 3R, 4S, 5S; 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-16-ethyl-4-hydroxyl-5,9; 13-trimethylammonium-7-(2-(piperidin-1-yl) ethyl) oxa-16 ring-11,13-diene-2,10-diketone;
(4R; 5S; 6S; 7R, 9R, 11E; 13E; 15R, 16R)-15-((benzyl (ethyl) is amino) methyl)-6-(((2R, 3R; 4S; 5S, 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-16-ethyl-4-hydroxyl-5; 9; 13-trimethylammonium-7-(2-(piperidin-1-yl) ethyl) oxa-16 ring-11,13-diene-2,10-diketone;
(4R; 5S; 6S; 7R, 9R, 11E; 13E; 15R, 16R)-15-((benzyl (sec.-propyl) is amino) methyl)-6-(((2R, 3R; 4S; 5S, 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-16-ethyl-4-hydroxyl-5; 9; 13-trimethylammonium-7-(2-(piperidin-1-yl) ethyl) oxa-16 ring-11,13-diene-2,10-diketone;
(4R; 5S; 6S; 7R, 9R, 11E; 13E; 15R, 16R)-6-(((2R, 3R; 4S; 5S, 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-16-ethyl-4-hydroxyl-5; 9; 13-trimethylammonium-15-((methyl (pyridin-3-yl methyl) is amino) methyl)-7-(2-(piperidin-1-yl) ethyl) oxa-16 ring-11,13-diene-2,10-diketone;
(4R, 5S, 6S; 7R, 9R, 11E; 13E, 15R, 16R)-6-(((2R; 3R, 4S, 5S; 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-16-ethyl-4-hydroxyl-15-(isoindoline-2-ylmethyl)-5,9; 13-trimethylammonium-7-(2-(piperidin-1-yl) ethyl) oxa-16 ring-11,13-diene-2,10-diketone;
(4R; 5S; 6S, 7R, 9R; 11E; 13E, 15R, 16R)-15-((benzyl (sec.-propyl) is amino) methyl)-6-(((2R; 3R; 4S, 5S, 6R)-4-(dimethylamino)-3; 5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-7-(2-(3; 5-lupetidine-1-base) ethyl)-16-ethyl-4-hydroxyl-5,9,13-trimethylammonium oxa-16 ring-11; 13-diene-2,10-diketone;
(4R; 5S; 6S, 7R, 9R; 11E; 13E, 15R, 16R)-6-(((2R; 3R; 4S, 5S, 6R)-4-(dimethylamino)-3; 5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-7-(2-(3; 5-lupetidine-1-base) ethyl)-16-ethyl-4-hydroxyl-5,9,13-trimethylammonium-15-((methyl (pyridin-3-yl methyl) is amino) methyl) oxa-16 ring-11; 13-diene-2,10-diketone;
(4R, 5S, 6S, 7R; 9R, 11E, 13E; 15R, 16R)-6-(((2R, 3R; 4S, 5S, 6R)-4-(dimethylamino)-3; 5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-7-(2-(3,5-lupetidine-1-base) ethyl)-16-ethyl-4-hydroxyl-15-(isoindoline-2-ylmethyl)-5,9; 13-trimethylammonium oxa-16 ring-11,13-diene-2,10-diketone;
(4R; 5S; 6S; 7R, 9R, 11E; 13E; 15R, 16R)-15-((benzyl (methyl) is amino) methyl)-6-(((2R, 3R; 4S; 5S, 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-16-ethyl-4-hydroxyl-7-(2-(isoindoline-2-base) ethyl)-5; 9; 13-trimethylammonium oxa-16 ring-11,13-diene-2,10-diketone;
(4R, 5S, 6S; 7R, 9R, 11E; 13E, 15R, 16R)-6-(((2R; 3R, 4S, 5S; 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-16-ethyl-4-hydroxyl-7-(2-(isoindoline-2-base) ethyl)-5,9; 13-trimethylammonium-15-(piperazine heavy stone used as an anchor-1-ylmethyl) oxa-16 ring-11,13-diene-2,10-diketone;
(4R, 5S, 6S; 7R, 9R, 11E; 13E, 15R, 16R)-15-((diethylamino) methyl)-6-(((2R; 3R, 4S, 5S; 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-16-ethyl-4-hydroxyl-7-(2-(isoindoline-2-base) ethyl)-5,9; 13-trimethylammonium oxa-16 ring-11,13-diene-2,10-diketone;
(4R, 5S, 6S, 7R, 9R, 11E, 13E, 15R, 16R)-6-(((2R, 3R, 4S, 5S, 6R)-4-(dimethylamino)-3,5-dihydroxyl-6-methyl tetrahydrochysene-2H-pyrans-2-base) oxygen)-15-((3,5-dimethyl piperazine heavy stone used as an anchor-1-base) methyl)-16-ethyl-4-hydroxyl-7-(2-(isoindoline-2-base) ethyl)-5,9,13-trimethylammonium oxa-16 rings-11,13-diene-2,10-diketone.
7. a preparation method for compound according to claim 1, is characterized in that comprising the steps:
Step one, tylosin take off red mould sugared reduction amination condensation: the hexahydropyridine of tylosin and corresponding replacement or isoindoline are reacted, and generate de-red mould sugared reduction amination intermediate 1a or 1b;
Step 2, de-6-deoxidation-D-allose: intermediate 1a or 1b is under mineral acid effect, and de-6-deoxidation-D-allose generates intermediate 2a or 2b;
Step 3, activation: intermediate 2a or 2b and iodine react under the effect of triphenyl phosphorus and pyridine, generate iodide 3a or 3b;
Step 4, amination: intermediate 3a or 3b reacts with organic amine in the basic conditions, generate product 4a or 4b;
8. method according to claim 7, is characterized in that carrying out at 70 ~ 85 DEG C in toluene or dioxane under formic acid effect in the reaction of step one; Mineral acid in step 2 is Hydrogen bromide, and temperature of reaction is 50 DEG C ~ 60 DEG C; In step 3, reaction solvent is methylene dichloride, and temperature of reaction is 0 ~ 20 DEG C; In step 4, alkali used is selected from salt of wormwood, sodium carbonate or triethylamine, and adopt or do not adopt reaction solvent, temperature of reaction is 25 ~ 140 DEG C.
9. a pharmaceutical composition, is characterized in that it with the compound according to any one of claim 1 ~ 6 or its pharmacy acceptable salt for activeconstituents, and is aided with pharmaceutical excipient and makes pharmaceutical preparation.
10. the compound according to any one of claim 1 ~ 6 or the application of its pharmacy acceptable salt in the bacterium of preparing treatment or prevention animal or human or mycoplasma infection medicine.
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