CN104788519B - Sixteen-ring triamine lactone derivatives and its application - Google Patents
Sixteen-ring triamine lactone derivatives and its application Download PDFInfo
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- CN104788519B CN104788519B CN201410030016.7A CN201410030016A CN104788519B CN 104788519 B CN104788519 B CN 104788519B CN 201410030016 A CN201410030016 A CN 201410030016A CN 104788519 B CN104788519 B CN 104788519B
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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
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- 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 kind of novel sixteen-ring triamine lactone derivatives and its applications, for the compound or its pharmaceutically acceptable salt representated by logical formula (I) or logical formula (II), wherein R1It is arbitrary substituted C1‑6Alkyl or C3‑8Naphthenic base, R2It is hydrogen, the C arbitrarily replaced1‑6Alkyl or C3‑8Naphthenic base or R1With R2Being connected with chemical bond makes R1‑N‑R2Group constitutes arbitrary substituted 35 yuan or 79 circle heterocyclic ring groups, R3And R4Separately it is selected from hydrogen or C1‑3Alkyl.The compound of the present invention or its pharmaceutically acceptable salt have excellent antibacterial activity, are applied to treat and prevent animal bacterial infection and mycoplasma infection, new approach is provided for the treatment or prevention of such disease.
Description
Technical field
The invention belongs to pharmaceutical fields, are related to a kind of new antibiotic.Specifically, the present invention relates to a kind of 16- membered rings
The new derivatives of 20,23 modifications of the safe happy lactone of de- mycaminose, the salt that can be medicinal of the analog derivative prepare such and spread out
The method of biology and the application of the analog derivative.
Background technology
Since the mankind are since generation nineteen twenty finds that penicillin, the 1940's find streptomysin, various new has
The compound of antibacterial activity is constantly found and as antibiotic usage, to save thousands of life and greatly promote
Into the development of Modern Animal Husbandry.But over time, bacterium can keep infection difficult existing drug resistant
It is even unable to control with curing.It is defended currently, there is the bacterium of drug resistance to have become the public of getting worse antibiotic
Raw to threaten, the superbacteria NDM-1 that there is drug-resistant bacteria MRSA for a long time and occur recently is this kind of concentration seriously threatened
Reflection.In fact, the Clinical practice of almost all of antibiotics, it finally can all lead to the appearance of drug-resistant bacteria and deposit
, such as：The persister of gram-positive bacterium, such as methicillin-resistant Staphylococcus, streptococcus, penicillin resistant and resistance to mould through the ages
The enterococcus etc. of element.These drug-resistant bacterias may to by its infection patient or animal cause it is serious or even fatal after
Fruit.In drug research field, it is the important means for solving the problems, such as drug-fast bacteria to develop new antibiotic.
Macrocyclic lactone is a kind of antibiotic containing the cyclosubstituted 14-16 membered rings of one or more 6 yuan of sugar, including red mould
Element, tylosin, Tilmicosin, roxithromycin, Dirithromycin, azithromycin, clarithromycin, spiramvcin, Tulathromycin, bamboo
Taocin, carbomycin, Flurithromycin etc..The mechanism of action of macrolide antibiotics is the ribosomes 50S with prokaryotes
Subunit combines, and binding site is closely related or identical with the action site of chloramphenicol and lincosamides.In big ring
Ester can prevent the transposition of transfer ribonucleic acid after being combined with ribosomes, and then destroy the synthesis of bacterio protein.Macrolide
Only combined with the ribosomes 50S of prokaryotes to class drug selectivity, and to the ribosomes of mammal then without affinity.
There is the bacterium of drug resistance also to have occurred macrolide antibiotics.Its resistance mechanism mainly has：（1）Pass through
The permeability or acquired outer row's mechanism for reducing bacteria cell wall reduce the accumulation of drug in the cell；（2）By ermA, ermB
It thus greatly reduces antibacterials with methylating for the ribosomal binding sites of 50S of ermC gene mediateds and is combined with ribosomes
The affinity in site；（3）Bacterium is generated ester hydrolase to make drug inactivation by induction.
Tylosin and its relevant 16 member cyclic macrolide derivative（See formula one）It is demonstrated to be effective against already
The infection of the animals such as the certain gram-positive bacterias and microbial poultry of Gram-negative, ox and pig.（Ke Site（Kirst）Deng
People, U.S. Patent number 4468511,4920103；Pottery（Tao）Et al., U.S. Patent number 4921947；Georg Lukacs（Lukacs）Deng
People, U.S. Patent number 5032581）.But its shortcomings that is relatively low bioavilability, gastrointestinal side effect and limited anti-
Bacterium activity profile.Tilmicosin is the desugar derivative of 20 modifications of tylosin, and the advantage of Tilmicosin essentially consists in its medicine
Object dynamics, especially longer half-life period（U.S. Patent number 5545624）.Its shortcomings that is cardiac toxic, is especially injected
When administration.Formula one：
Another is with the relevant macrolide derivatives Zuprevo of tylosin then in 20 piperazines for remaining Tilmicosin
On the basis of pyridine structure, 23 substituent groups have further been modified, and equally with piperidyl instead of 6- deoxidation-D- alloses,
Obtain the new antimicrobial agent for having greater activity for Pasteurella（US 6514946 B1；Chinese invention patent, publication number CN
101506220 A）.Zuprevo and Tulathromycin all contain there are three the amino of alkalinity, this feature with them in lung tissue and
Enrichment and longer half-life period in bronchus liquid have close relationship.However, bipiperidine structure is in the conjunction for improving the drug
Although helpful, not necessarily best pharmacophoric group at efficiency and in terms of reducing cost.In fact, Stefan is all
Scholar Witter（Stephen Douthwaite）Et al. recently to 16 membered macrolide derivatives of tylosin class and bacterium ribose
The study of computer simulation of the interaction of body binding site indicates that, the piperidyl that Zuprevo molecules are 23 and bacterium ribose
The inner wall of body binding site contacts, and the interaction at the position and the protonation state of ammonia nitrogen on piperidyl have close pass
System.（ACS Chem.Biol.2012,7,1351-1355.）
The structure of modification of tylosin class macrolide more to be had been reported that.Such as nearest Hong Fu et al. are to safe happy lactone
9 and 20 be transformed, obtain certain success（Bioorganic&Medicinal Chemistry
Letters16 (2006)1259–1266）.In vitro test in be found that with as ketolide, to resistance to macrolides medicine
Streptococcus pneumonia and inducible phenotype the active derivative of staphylococcus aureus strains.
Invention content
The purpose of the present invention is on the basis of existing technology, provide one kind to be related to the safe happy lactone of 16- membered rings antibiotic
The novel triamine lactone derivative compound and its salt of 20,23 modifications.
It is a further object of the present invention to provide a kind of preparation methods of above compound.
Third object of the present invention is to provide a kind of above compound treat and prevent human or animal's bacterium infection and
Application in terms of mycoplasma infection.
The purpose of the present invention can be achieved by the following measures：
As led to compound or its pharmaceutically acceptable salt representated by formula (I) or logical formula (II),
Wherein,
R1It is arbitrary substituted C1-6Alkyl or C3-8Naphthenic base, substituent group be selected from aryl or hydroxyl；
R2It is hydrogen, the C arbitrarily replaced1-6Alkyl or C3-8Naphthenic base, substituent group be selected from aryl or hydroxyl；
Or R1With R2Being connected with chemical bond makes R1-N-R2Group constitutes arbitrary substituted 3-5 members or 7-9 circle heterocyclic ring groups,
Its substituent group is selected from C1-3Alkyl or hydroxyl；
R3And R4Separately it is selected from hydrogen or C1-3Alkyl.
In the present invention, a kind of preferred scheme is R1It is arbitrary substituted C1-4Alkyl or C3-8Naphthenic base, take
Dai Ji is selected from benzene, pyridine or hydroxyl.
In the present invention, a kind of preferred scheme is R1It is arbitrary substituted C1-2Alkyl, substituent group be selected from benzene, pyrrole
Pyridine or hydroxyl.
In the present invention, a kind of preferred scheme is R1It is ethyl, n-propyl, isopropyl, butyl, benzyl, 2- hydroxyl second
Base, 2- picolyls, 3- picolyls, 4- picolyls or cyclohexyl.
In the present invention, a kind of preferred scheme is R2It is hydrogen or the C arbitrarily replaced1-4Alkyl, substituent group is selected from
Benzene, pyridine or hydroxyl.
In the present invention, a kind of preferred scheme is R2It is hydrogen or the C arbitrarily replaced1-2Alkyl, substituent group is selected from
Benzene, pyridine or hydroxyl.
In the present invention, a kind of preferred scheme is R2It is hydrogen, methyl, ethyl, n-propyl, isopropyl, normal-butyl or 2-
Hydroxyethyl.
In the present invention, a kind of preferred scheme is R1With R2Being connected with chemical bond makes R1-N-R2Group constitutes 5 yuan or 9
Circle heterocyclic ring group, substituent group are selected from methyl, ethyl, n-propyl, isopropyl or hydroxyl.
In the present invention, a kind of preferred scheme is R1With R2Being connected with chemical bond makes R1-N-R2Group constitutes nafoxidine
Base, 3- hydroxypyrroles alkyl, 3,5- lupetidines base or isoindoline base.
In the present invention, a kind of preferred scheme is R3And R4Separately it is selected from hydrogen or methyl.
Unless otherwise stated, the following term used in the specification and in the claims has meaning discussed below：
" alkyl " indicates the aliphatic group of the saturation of 1-20 carbon atom, including straight chain and branched group（It is carried in this specification
The digital scope arrived, such as " 1-6 " refer to the group, are at this time alkyl, can contain 1 carbon atom, 2 carbon atoms, 3 carbon
Atom etc., until including 6 carbon atoms）.Alkyl containing 1-4 carbon atom is known as low alkyl group.When low alkyl group does not replace
When base, it is called unsubstituted low alkyl group.It is further preferred that alkyl is the alkyl for having 1-4 carbon atom, such as methyl, second
Base, propyl, 2- propyl, normal-butyl, isobutyl group, tertiary butyl etc., it is further preferred that alkyl is the alkane for having 1-2 carbon atom
Base.
" naphthenic base " indicates the monocycle of all carbon or condensed ring（" condensed " ring means each ring in system and is
Shared a pair of of the carbon atom adjoined of other rings in system）Group, wherein one or more rings do not have the pi-electron system being fully connected
System, the example of naphthenic base（It is not limited to）For cyclopropane, cyclobutane, pentamethylene, cyclopentene, hexamethylene, adamantane, hexamethylene two
Alkene, cycloheptane and cycloheptatriene.Naphthenic base can be substitution and unsubstituted.The digital scope mentioned in this specification, such as
" 3-8 " refers to that can contain 3 carbon atoms, 4 carbon atoms, 5 carbon atoms etc. in the group, until include 8 carbon atoms, this
Naphthenic base in application preferably uses C5-6Naphthenic base.
The full carbon of 1 to 12 carbon atom of " aryl " expression contains heteroatomic monocycle or fused polycycle group, has complete
The pi-electron system of conjugation.Wherein hetero atom is generally N, O and S, and heteroatomic number can be one, two, three or four
It is a.The non-limiting examples of aryl have phenyl, pyridyl group, pyrrole radicals, furyl, thienyl, imidazole radicals, oxazolyls, thiazolyl,
Pyrazolyl, pyrimidine radicals, quinolyl, isoquinolyl, purine radicals, tetrazole radical, triazine radical, naphthalene and anthryl etc..Aryl can be taken
It is generation or unsubstituted.Aryl in the present invention is preferably phenyl or pyridyl group.
" heterocycle " indicates monocycle or fused ring group, has 3 to 9 annular atoms, wherein one or two ring in ring
Atom is to be selected from N, O or S (O)m（Wherein m is 0 to 2 integer）Hetero atom, remaining annular atom is C.These rings can have
One or more double bond, but these rings do not have the pi-electron system of total conjugated.The non-limiting reality of unsubstituted heteroalicyclyl
Example has pyrrolidinyl, piperidino, Piperazino, morpholino base, thiomorpholine for base, homopiperazino, indoline base, different Yin
Diindyl quinoline base etc..Heterocycle in the present invention is preferably pyrrolidinyl, piperidyl or isoindoline base.
" hydroxyl " expression-OH groups.
" substituent group is selected from " refers to that the specific group of one or more that each group above-mentioned can be lifted by listed thereafter is taken
Generation.Such as " substituent group be selected from aryl or hydroxyl " to refer to aforementioned group can be replaced by one or more aryl or hydroxyl.
" arbitrary substitution " expression " substituted " or " unsubstituted " two kinds of situations, such as the alkyl arbitrarily replaced refers to " quilt
Substituted alkyl " or " unsubstituted alkyl ".
" pharmaceutically acceptable salt " indicates to retain those of biological effectiveness and the property of parent compound salt.This kind of salt
Including：
（1）With acid at salt, obtained with inorganic acid or reacting for organic acid by the free alkali of parent compound, inorganic acid packet
Include hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid and perchloric acid etc., organic acid include acetic acid, trifluoroacetic acid,
Propionic acid, acrylic acid, caproic acid, pentamethylene propionic acid, oxyacetic acid, pyruvic acid, oxalic acid,（D）Or（L）Malic acid, fumaric acid, maleic acid,
Benzoic acid, hydroxybenzoic acid, gamma-hydroxybutyric acid, methoxy benzoic acid, phthalic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene -1- sulphurs
Acid, naphthalene-2-sulfonic acid, p-methyl benzenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, cinnamic acid, dodecyl sulphate, gluconic acid,
Glutamic acid, aspartic acid, stearic acid, mandelic acid, succinic acid or malonic acid etc..
（2）The acid proton being present in parent compound is replaced or given birth to organic base ligand compound by metal ion
At salt, metal ion such as alkali metal ion, alkaline-earth metal ions or aluminium ion, organic bases for example ethanol amine, diethanol amine,
Triethanolamine, tromethamine, N-METHYL-ALPHA-L-GLUCOSAMINE, quinine etc..
" pharmaceutical composition " refers to one or more of compound in the present invention or its pharmaceutically acceptable salt, molten
Agent compound, hydrate or prodrug and other chemical composition, such as pharmaceutically acceptable carrier, mixing.The mesh of pharmaceutical composition
Be promote administration to animal process.
In the compound of the present invention or its pharmaceutically acceptable salt, the compound can be specifically selected from：
(4R, 5S, 6S, 7R, 9R, 11E, 13E, 15R, 16R) -15- ((diethylamino) methyl) -6- (((2R, 3R, 4S,
5S, 6R) -4- (dimethylamino) -3,5- dihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -16- ethyl -4- hydroxyls -
16 ring -11,13- diene -2,10- diketone of 5,9,13- trimethyls -7- (2- (piperidin-1-yl) ethyl) oxa-;
(4R, 5S, 6S, 7R, 9R, 11E, 13E, 15R, 16R) -6- (((2R, 3R, 4S, 5S, 6R) -4- (dimethylamino) -
3,5- dihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -15- ((dipropylamino) methyl) -16- ethyl -4- hydroxyls -
16 ring -11,13- diene -2,10- diketone of 5,9,13- trimethyls -7- (2- (piperidin-1-yl) ethyl) oxa-;
(4R, 5S, 6S, 7R, 9R, 11E, 13E, 15R, 16R) -15- ((butylamino) methyl) -6- (((2R, 3R, 4S,
5S, 6R) -4- (dimethylamino) -3,5- dihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -16- ethyl -4- hydroxyls -
16 ring -11,13- diene -2,10- diketone of 5,9,13- trimethyls -7- (2- (piperidin-1-yl) ethyl) oxa-;
(4R, 5S, 6S, 7R, 9R, 11E, 13E, 15R, 16R) -6- (((2R, 3R, 4S, 5S, 6R) -4- (dimethylamino) -
3,5- dihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -16- ethyl -4- hydroxyl -5,9,13- trimethyls -7- (2- (piperazines
Pyridine -1- bases) ethyl) 16 ring -11,13- diene -2,10- diketone of -15- (pyrrolidin-1-yl methyl) oxa-;
(4R, 5S, 6S, 7R, 9R, 11E, 13E, 15R, 16R) -15- ((benzylamino) methyl) -6- (((2R, 3R, 4S,
5S, 6R) -4- (dimethylamino) -3,5- dihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -16- ethyl -4- hydroxyls -
16 ring -11,13- diene -2,10- diketone of 5,9,13- trimethyls -7- (2- (piperidin-1-yl) ethyl) oxa-;
(4R, 5S, 6S, 7R, 9R, 11E, 13E, 15R, 16R) -15- ((benzyl (methyl) amino) methyl) -6- (((2R,
3R, 4S, 5S, 6R) -4- (dimethylamino) -3,5- dihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -16- ethyls -4-
16 ring -11,13- diene -2,10- diketone of hydroxyl -5,9,13- trimethyls -7- (2- (piperidin-1-yl) ethyl) oxa-;
(4R, 5S, 6S, 7R, 9R, 11E, 13E, 15R, 16R) -15- ((two (2- hydroxyethyls) amino) methyl) -6-
(((2R, 3R, 4S, 5S, 6R) -4- (dimethylamino) -3,5- dihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -16-
16 ring -11,13- diene -2,10- two of ethyl -4- hydroxyl -5,9,13- trimethyls -7- (2- (piperidin-1-yl) ethyl) oxa-
Ketone;
(4R, 5S, 6S, 7R, 9R, 11E, 13E, 15R, 16R) -15- ((Cyclohexylamino) methyl) -6- (((2R, 3R, 4S,
5S, 6R) -4- (dimethylamino) -3,5- dihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -16- ethyl -4- hydroxyls -
16 ring -11,13- diene -2,10- diketone of 5,9,13- trimethyls -7- (2- (piperidin-1-yl) ethyl) oxa-;
(4R, 5S, 6S, 7R, 9R, 11E, 13E, 15R, 16R) -15- ((benzyl (ethyl) amino) methyl) -6- (((2R,
3R, 4S, 5S, 6R) -4- (dimethylamino) -3,5- dihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -16- ethyls -4-
16 ring -11,13- diene -2,10- diketone of hydroxyl -5,9,13- trimethyls -7- (2- (piperidin-1-yl) ethyl) oxa-;
(4R, 5S, 6S, 7R, 9R, 11E, 13E, 15R, 16R) -15- ((benzyl (isopropyl) amino) methyl) -6- (((2R,
3R, 4S, 5S, 6R) -4- (dimethylamino) -3,5- dihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -16- ethyls -4-
16 ring -11,13- diene -2,10- diketone of hydroxyl -5,9,13- trimethyls -7- (2- (piperidin-1-yl) ethyl) oxa-;
(4R, 5S, 6S, 7R, 9R, 11E, 13E, 15R, 16R) -6- (((2R, 3R, 4S, 5S, 6R) -4- (dimethylamino) -
3,5- dihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -16- ethyl -4- hydroxyl -5,9,13- trimethyl -15- ((first
Base (pyridin-3-yl methyl) amino) methyl) 16 ring -11,13- diene -2,10- of -7- (2- (piperidin-1-yl) ethyl) oxa-
Diketone;
(4R, 5S, 6S, 7R, 9R, 11E, 13E, 15R, 16R) -6- (((2R, 3R, 4S, 5S, 6R) -4- (dimethylamino) -
3,5- dihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -16- ethyl -4- hydroxyls -15- (isoindoline -2- Ji Jia
Base) 16 ring -11,13- diene -2,10- diketone of -5,9,13- trimethyls -7- (2- (piperidin-1-yl) ethyl) oxa-;
(4R, 5S, 6S, 7R, 9R, 11E, 13E, 15R, 16R) -15- ((benzyl (isopropyl) amino) methyl) -6- (((2R,
3R, 4S, 5S, 6R) -4- (dimethylamino) -3,5- dihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -7- (2- (3,
5- lupetidine -1- bases) ethyl) 16 diene -2 ring -11,13- of -16- ethyl -4- hydroxyl -5,9,13- trimethyls oxa-,
10- diketone;
(4R, 5S, 6S, 7R, 9R, 11E, 13E, 15R, 16R) -6- (((2R, 3R, 4S, 5S, 6R) -4- (dimethylamino) -
3,5- dihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -7- (2- (3,5- lupetidine -1- bases) ethyl) -16- second
16 ring -11,13- two of base -4- hydroxyl -5,9,13- trimethyls -15- ((methyl (pyridin-3-yl methyl) amino) methyl) oxa-
Alkene -2,10- diketone;
(4R, 5S, 6S, 7R, 9R, 11E, 13E, 15R, 16R) -6- (((2R, 3R, 4S, 5S, 6R) -4- (dimethylamino) -
3,5- dihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -7- (2- (3,5- lupetidine -1- bases) ethyl) -16- second
16 ring -11,13- diene -2,10- two of base -4- hydroxyls -15- (isoindoline -2- ylmethyls) -5,9,13- trimethyls oxa-
Ketone;
(4R, 5S, 6S, 7R, 9R, 11E, 13E, 15R, 16R) -15- ((benzyl (methyl) amino) methyl) -6- (((2R,
3R, 4S, 5S, 6R) -4- (dimethylamino) -3,5- dihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -16- ethyls -4-
16 ring -11,13- diene -2,10- diketone of hydroxyl -7- (2- (isoindoline -2- bases) ethyl) -5,9,13- trimethyls oxa-;
(4R, 5S, 6S, 7R, 9R, 11E, 13E, 15R, 16R) -6- (((2R, 3R, 4S, 5S, 6R) -4- (dimethylamino) -
3,5- dihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -16- ethyl -4- hydroxyls -7- (2- (isoindoline -2- bases) second
Base) 16 ring -11,13- diene -2,10- diketone of -5,9,13- trimethyls -15- (piperazine heavy stone used as an anchor -1- ylmethyls) oxa-;
(4R, 5S, 6S, 7R, 9R, 11E, 13E, 15R, 16R) -15- ((diethylamino) methyl) -6- (((2R, 3R, 4S,
5S, 6R) -4- (dimethylamino) -3,5- dihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -16- ethyl -4- hydroxyls -
16 ring -11,13- diene -2,10- diketone of 7- (2- (isoindoline -2- bases) ethyl) -5,9,13- trimethyls oxa-;
(4R, 5S, 6S, 7R, 9R, 11E, 13E, 15R, 16R) -6- (((2R, 3R, 4S, 5S, 6R) -4- (dimethylamino) -
3,5- dihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -15- ((3,5- dimethyl piperazine heavy stone used as an anchor -1- bases) methyl) -16- second
16 ring -11,13- diene -2,10- of base -4- hydroxyls -7- (2- (isoindoline -2- bases) ethyl) -5,9,13- trimethyls oxa-
Diketone.
The present invention provides a kind of general formula I or the preparation methods of compounds of formula II, specifically comprise the following steps：
Step 1: tylosin takes off red mould sugared reduction amination condensation：By tylosin and the hexahydropyridine accordingly replaced or
Isoindoline reacts, and generates de- red mould sugared reduction amination intermediate 1a or 1b；
Step 2: de- 6- deoxidation-D- alloses：Intermediate 1a or 1b takes off 6- deoxidation-D- alloses under inorganic acid effect
Generate intermediate 2a or 2b；
Step 3: activation：Intermediate 2a or 2b is reacted with iodine under the action of triphenyl phosphorus and pyridine, generates iodide 3a
Or 3b；
Step 4: amination：Intermediate 3a or 3b are reacted with organic amine under alkaline condition, generate product 4a or 4b；
Group definition in the above formulas is as described above.It is wherein preferred, step 1 reaction under formic acid effect
It is carried out at 70~85 DEG C in toluene or dioxane；Inorganic acid in step 2 is hydrobromic acid, and reaction temperature is 50 DEG C~60
℃；In step 3, reaction dissolvent is dichloromethane, and reaction temperature is 0~20 DEG C；Alkali used is selected from potassium carbonate, carbon in step 4
Sour sodium or triethylamine, are used with or without reaction dissolvent, and reaction temperature is 25~140 DEG C.
Another embodiment of the present invention is related to a kind of pharmaceutical composition, with involved each in description of the invention
Noval chemical compound or its salt（Compound especially according to any one of claims 1 to 6 or its pharmaceutically acceptable salt）For
Active constituent, and be aided with pharmaceutic adjuvant and pharmaceutical preparation is made.
Compound or its salt in the present invention（Compound or its pharmacy especially according to any one of claims 1 to 6
Upper acceptable salt）It can be applied to prepare and treat or prevent animal or people bacterium or mycoplasma infection drug aspect, such as animal
Or in terms of people's bacterium infection or in terms of animal or mycoplasma hominis's infection.Specifically, being caused by bacterium and mycoplasma in the present invention
Animal（Including mammal, fish and birds）Disease include but are not limited to：Pasteurella haemolytica, Pasteurella and
Ox respiratory disease caused by Haemophilus somnus；The Pasteur of pig caused by pasteurella multocida, goat, sheep and poultry
Bacillosis；Porcine contagious pleuropneumonia caused by Actinobacillus, streptococcus suis infection；And ox, pig, goat, sheep and poultry
Mycoplasma infection.
The compound of the present invention or its pharmaceutically acceptable salt have excellent antibacterial activity, are applied to treat and prevent
Animal bacterial infection and mycoplasma infection provide new approach for the treatment or prevention of such disease.
Specific implementation mode
The present invention is illustrated by the following examples.But the present invention is not limited to the details of following embodiment.
Compound synthesis of the present invention prepares required reagent solvent etc. in addition to having special indicate, is commercially available production
Product.Isolating and purifying for compound can be completed by chromatography.Material therefor such as tlc silica gel, HG/T2354-92,
GF254, chemical pure, Qingdao Marine Chemical Co., Ltd.；Sodium carboxymethylcellulose, 300-800mPaS, chemistry is pure,
30036328, Sinopharm Chemical Reagent Co., Ltd., 300-400 mesh silica gel prepares plate.Compound structure of the present invention
Identification can be by completions such as nuclear magnetic resonance and mass spectrums.Such as 300-Bruker Nuclear Magnetic Resonance；SHIMADZU LCMS-2020, ESI
Source.
Embodiment 1. (4R, 5S, 6S, 7R, 9R, 11E, 13E, 15R, 16R) -6- (((2R, 3R, 4S, 5S, 6R) -4- (diformazans
Base amino) -3,5- dihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -16- ethyl -4- hydroxyls -15- ((((2R, 3R,
4R, 5R, 6R) -5- hydroxyl -3,4- dimethoxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) methyl) -5,9,13- trimethyls -
16 ring -11,13- diene -2,10- diketone of 7- (2- (piperidin-1-yl) ethyl) oxa-（Compound 1）
Tylosin（9.2 grams, 0.01 mole）, hexahydropyridine（2.55 grams, 0.03 mole）, toluene（30 milliliters）Together plus
Enter there-necked flask, stirring is warming up to 75 DEG C, formic acid is slowly added dropwise（2.5 grams, 0.05 mole）, temperature control drips off formic acid at 75 DEG C or so,
75-80 DEG C is reacted 2 hours.After reaction, add 15% dilute hydrochloric acid that lower layer's dope is made to dissolve, separate water layer.Benzene layer is with 90 milliliters
Dilute hydrochloric acid is washed twice, combining water layer.It is about 10 or so to be neutralized to pH with 30% sodium hydrate aqueous solution, and white solid production is precipitated
Object, washing is primary, and drying obtains crude product（Compound 1）About 10 grams, close to theoretical yield.Mass spectrum theoretical value：840.53, actual measurement
Value：841.45（M+H+）.
Embodiment 2. (4R, 5S, 6S, 7R, 9R, 11E, 13E, 15R, 16R) -6- (((2R, 3R, 4S, 5S, 6R) -4- (diformazans
Base amino) -3,5- dihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -16- ethyl -4- hydroxyls -15- (hydroxymethyl) -
16 ring -11,13- diene -2,10- diketone of 5,9,13- trimethyls -7- (2- (piperidin-1-yl) ethyl) oxa-（Compound 2）
Compound 1（9.0 grams, 0.01 mole）It is added in there-necked flask, adds 30 milliliters of 30 milliliters of hydrobromic acid and water, 57
DEG C reaction 5 hours.Cold filtration, it is about 10 that filtrate is neutralized to pH with the sodium hydroxide solution of 30%-40%, and it is solid that product, which is precipitated,
Body may filter that.If product is precipitated to be needed to be dehydrated for dope, 4.7 grams of crude product, yield 70% are dried to obtain.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- (diformazans
Base amino) -3,5- dihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -16- ethyl -4- hydroxyls -15- (iodomethyl) -5,
16 ring -11,13- diene -2,10- diketone of 9,13- trimethyls -7- (2- (piperidin-1-yl) ethyl) oxa-（Compound 3）
Compound 2 is added in there-necked flask（12.4 grams, 0.02 mole）Dichloromethane（40 milliliters）, triphenyl phosphorus（8 grams,
0.03 mole）, pyridine（2 grams, 0.022 mole）, ice bath, make temperature be less than 13 DEG C.Iodine is added portionwise（8 grams, 0.03 mole）,
Iodine temperature control is added at 15 ± 3 DEG C, and is stirred 3 hours.Cold filtration, twice with 30 milliliter of 15% dilute hydrochloric acid extraction, merging carries filtrate
Liquid is taken, it is 9-10 to be neutralized to pH with 30% sodium hydroxide solution, and pale solid product is precipitated, filters out product.Product is dissolved in
In a small amount of dichloromethane, dry concentration is added dropwise the petroleum ether of 60-90 DEG C of boiling range, it is made to precipitate crystal.Filter to obtain iodide crude product
8.7 grams, yield 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 are dried with anhydrous sodium sulfate in advance；Triethylamine re-distillation after drying
It is made.
Method A：Take 0.5 gram of iodide（Compound 3）, 1 milliliter of organic amine, 2 milliliters of toluene, 1 milliliter of triethylamine, in nitrogen
It is heated to reflux 24-48 hours, is cooled to room temperature under protection, isolated and purified with preparative chromatography plate after vacuum distillation.Solvent is second
Acetoacetic ester：Chloroform：Methanol=1：1：1（v/v/v）, yield 50%-60%.
Method B：Take 1.0 grams of iodide, 0.2 gram of Anhydrous potassium carbonate, 2-10 milliliters of organic amines, under nitrogen protection in 25-
It is stirred to react at a temperature of 140 DEG C, until iodate raw material disappears substantially（TLC is detected）.Decompression boils off excess after reaction
Organic amine adds petroleum ether to wash away remaining organic amine, obtains crude product.Sterling is purified with preparative chromatography plate.
Method C：Take 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,
It is stirred to react at a temperature of 110 DEG C, until iodate raw material disappears substantially（TLC is detected）.Decompression boils off molten after reaction
Agent adds petroleum ether to wash away remaining organic amine, obtains crude product.Sterling is purified with preparative chromatography plate.
Embodiment 5. (4R, 5S, 6S, 7R, 9R, 11E, 13E, 15R, 16R) -6- (((2R, 3R, 4S, 5S, 6R) -4- (diformazans
Base amino) -3,5- dihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -7- (2- (3,5- lupetidine -1- bases) second
Base) -16- ethyl -4- hydroxyls -15- ((((2R, 3R, 4R, 5R, 6R) -5- hydroxyl -3,4- dimethoxy -6- methyl tetrahydrochysenes -2H-
Pyrans -2- bases) oxygen) methyl) 16 ring -11,13- diene -2,10- diketone of -5,9,13- trimethyls oxa-（Compound 5）
Tylosin（19 grams, 0.021 mole）, 3,5- lupetidines（6.8 grams, 0.060 mole）, toluene（60 milliliters）
There-necked flask is added together, stirring is warming up to 75 DEG C, formic acid is slowly added dropwise（4.6 grams, 0.10 mole）, temperature control is at 75 DEG C or so, drop
Complete formic acid, 75-80 DEG C is reacted 2 hours.After reaction, add 15% dilute hydrochloric acid that lower layer's dope is made to dissolve, separate water layer.Benzene layer
It is washed twice with 180 milliliters of dilute hydrochloric acid, combining water layer.It is about 10 or so to be neutralized to pH with 30% sodium hydrate aqueous solution, is precipitated white
Color solid product, washing is primary, and drying obtains 22.5 grams of faint yellow solid.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- (diformazans
Base amino) -3,5- dihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -7- (2- (3,5- lupetidine -1- bases) second
Base) 16 ring -11,13- diene -2,10- two of -16- ethyl -4- hydroxyls -15- (hydroxymethyl) -5,9,13- trimethyls oxa-
Ketone（Compound 6）
Compound 5（22.5 grams, crude product）It is added in there-necked flask, 30 milliliters of 30 milliliters of water and hydrobromic acid is added, at 57 DEG C
Reaction 4 hours.Cold filtration, it is about 10 that filtrate is neutralized to pH with the sodium hydroxide solution of 30%-40%, and it is sticky that product, which is precipitated,
Then object, water dissolution after taking-up are added sodium chloride and saltout, be sufficiently stirred and filter, dry to obtain 15 grams of crude product.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- (diformazans
Base amino) -3,5- dihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -7- (2- (3,5- lupetidine -1- bases) second
Base) 16 ring -11,13- diene -2,10- diketone of -16- ethyl -4- hydroxyls -15- (iodomethyl) -5,9,13- trimethyls oxa-
（Compound 7）
Compound 6（15 grams, about 0.021 mole）Dichloromethane is added（60 milliliters）Middle dissolving, and anhydrous sodium sulfate is added
It is dry, it is added in there-necked flask after filtering out drier, adds triphenyl phosphorus（13 grams, 0.050 mole）, pyridine（3.2 grams,
0.042 mole）, ice bath, make temperature be less than 13 DEG C.Iodine is added portionwise（13 grams, 0.051 mole）, iodine temperature control is added 15 ± 3
DEG C, and stir 4 hours.Cold filtration, filtrate are poured into separatory funnel, three times with 15 milliliters of concentrated hydrochloric acid extractions, are separated lower layer, are closed
And extracting solution three times, it is 9-10 to be neutralized to pH with 30% sodium hydroxide solution, and pale solid product is precipitated, filters out product.It will
Product is dissolved in 20 milliliters of water, it is made fully to dissolve, and sodium chloride is added and saltouts, continues after water is filtered out if remaining as dope
Add 20 milliliters of water dissolutions, sodium chloride is added and saltouts, filters, after dry, the petroleum ether of 60-90 DEG C of boiling range is added dropwise, so that it is precipitated brilliant
Body.Filter to obtain 7.3 grams of product.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 7 Application Example 4 of compound.
Embodiment 9. (4R, 5S, 6S, 7R, 9R, 11E, 13E, 15R, 16R) -6- (((2R, 3R, 4S, 5S, 6R) -4- (diformazans
Base amino) -3,5- dihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -16- ethyl -4- hydroxyls -15- ((((2R, 3R,
4R, 5R, 6R) -5- hydroxyl -3,4- dimethoxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) methyl) -7- (2- (iso-indoles
Quinoline -2- bases) ethyl) 16 ring -11,13- diene -2,10- diketone of -5,9,13- trimethyls oxa-（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）There-necked flask is added together, is warming up to 70 DEG C and is stirred to react 2 hours.After reaction,
Decompression boils off solvent, and crude product is dissolved in 30 milliliters of water, is neutralized to pH9-10 with 20% diluted sodium hydroxide solution, solution becomes breast
White takes out solid, solid is washed away to the surface of green with anhydrous ether, then clean solid with petroleum ether, finely ground in mortar,
Filtration drying obtains solid powder.Mass spectrum theoretical value：874.52, measured value：893.50（M+H3O+）.Embodiment 10. (4R, 5S, 6S,
7R, 9R, 11E, 13E, 15R, 16R) -6- (((2R, 3R, 4S, 5S, 6R) -4- (dimethylamino) -3,5- dihydroxy -6- methyl
Tetrahydrochysene -2H- pyrans -2- bases) oxygen) -16- ethyl -4- hydroxyls -15- (hydroxymethyl) -7- (2- (isoindoline -2- bases) second
Base) 16 ring -11,13- diene -2,10- diketone of -5,9,13- trimethyls oxa-（Compound 10）
Compound 9（9.8 grams, crude product）It is added in there-necked flask, adds 45 milliliters of 50 milliliters of water and hydrobromic acid, it is anti-at 58 DEG C
It answers 3.5 hours.Cold filtration, it is about 9-10 that filtrate is neutralized to pH with 30% sodium hydroxide solution, filters out solid, by solid
It is washed once with petroleum ether, it is finely ground, and be dissolved in 30 milliliters of dichloromethane, add each 10 grams of anhydrous sodium sulfate, anhydrous magnesium sulfate dry
Dry filtering.Filtrate is directly used in be reacted in next step.Mass spectrum theoretical value：700.43, measured value：719.40 （M+H3O+）.
Embodiment 11. (4R, 5S, 6S, 7R, 9R, 11E, 13E, 15S, 16R) -6- (((2R, 3R, 4S, 5S, 6R) -4- (two
Methylamino) -3,5- dihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -16- ethyl -4- hydroxyls -15- (iodomethyl) -
16 ring -11,13- diene -2,10- diketone of 7- (2- (isoindoline -2- bases) ethyl) -5,9,13- trimethyls oxa-（Compound
11）
The dichloromethane solution of compound 10 in embodiment 10（30 milliliters）It is added in there-necked flask, adds triphenyl phosphorus
（4.2 grams, 0.016 mole）, pyridine（2.5 gram, 0.033 mole）, ice bath, make temperature be less than 15 DEG C.Iodine is added portionwise（4.4 grams,
0.017 mole）, add iodine and stirred 3.5 hours at 20 DEG C.Cold filtration, filtrate are poured into separatory funnel, with 25 milliliters of concentrated hydrochloric acids
It extracts secondary, separates lower layer, merge secondary raffinate, it is 9-10 to be neutralized to pH with 30% sodium hydroxide solution, and it is solid that canescence is precipitated
Body product, filters out product.It if any oily product, is dissolved in 20 milliliters of water, it is made fully to dissolve, sodium chloride salt is added
It analyses, product is obtained after filtration drying.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 11 Application Example 4 of compound.
In Vitro Bacteriostatic is tested
（1）Bacterial strain
Quality Control bacterium：The other C25922 of Escherichia coli, staphylococcus aureus 29213.Swine escherichia coli 1498, C83543（80
Age detaches）；Swine escherichia coli 0039（It detaches within 2011）.Salmonella gallinarum 533, C79-13；Salmonella gallinarum 0008
（It detaches within 2011）.Pig staphylococcus aureus 546, C56023（It detaches within 1989）；Pig staphylococcus aureus 5-1（2011
Year separation）.2 plants of the more Sha Shi Pasteurellas of fowl.2 plants of streptococcus pneumonia.2 plants of Klebsiella Pneumoniae.Pig pleuropneumonia actinomyces 2
Strain.Mycoplasma strains etc..
（2）Culture medium
The M-H culture mediums adjusted with Ca, Mg（Large intestine, sramana, golden Portugal, Pasteur）, that Ca, Mg are adjusted plus 5% Sheep Blood
Martin's bouillon（Streptococcus）, with Ca, TSB that Mg is adjusted plus 1/100000NAD（Pancreas peptone soybean broth）（Pleuropneumonia is put
Line bacterium）.
（3）Method
The preparation of drug：Accurately weigh 5120 micrograms（5.12 milligram）, 1 milliliter of volumetric flask is added, is added dropwise with 95% alcohol molten
Tri-distilled water is added to 1 milliliter in Xie Hou.Content is 5120 mcg/mls.
With 96 orifice plates, different compounds is done into doubling dilution with corresponding meat soup, so that its concentration is followed successively by 320,160,80,
40,20,10,5,2.5,1.25,0.625,0.313,0.156 mcg/ml, or its concentration gradient is adjusted as needed.It will be upper
It states different strains to cultivate 18-24 hours for 37 degree on fresh Nutrient agar, picking is suspended with M-H meat soups, is harmonized concentration, is made it
For 0.5 maxwell unit.
After the bacterium solution of 0.5 maxwell unit is diluted 100 times, and the compound mixed in equal amounts of above-mentioned different dilutions, 37 degree
Culture 18-24 hours, then takes out sentence read result, it is minimum antibacterial dense that can inhibit the minimum compound concentration of bacterial growth
Degree.
Bacteriostatic activity testing result（μ g/ml, mcg/ml）
A:Pneumonia actinomyces serum 1 type;B:Pneumonia actinomyces serum 7-type;C:Pasteurella 8217;D:Pasteurella
8229;E:Escherichia coli IN-F6-7;F:Escherichia coli 25922（Quality Control bacterium）;G:S. aureus L-forms 5-1;H:S. aureus L-forms 29213（Matter
Control bacterium）;I:Salmonella LD4-8; J:Klebsiella Pneumoniae 3753;K:Klebsiella Pneumoniae 3699;L:Streptococcus pneumonia
2349;M:Streptococcus pneumonia 49619（Quality Control bacterium）.
Mycoplasma sensitivity Detection result
Claims (3)
1. compound or its pharmaceutically acceptable salt, it is characterised in that the 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- dihydroxy-6- methyl tetrahydrochysene-2H- pyrans-2- bases) oxygen) hydroxyl-5,9-16- ethyl-4-,
16 ring -11,13- diene -2,10- diketone of 13- trimethyls -7- (2- (piperidin-1-yl) ethyl) oxa-,
(4R, 5S, 6S, 7R, 9R, 11E, 13E, 15R, 16R) -6- (((2R, 3R, 4S, 5S, 6R) -4- (dimethylamino) -3,5-
Dihydroxy-6- methyl tetrahydrochysene-2H- pyrans-2- bases) oxygen) hydroxyl-5,9-15- ((dipropylamino) methyl)-16- ethyl-4-,
16 ring -11,13- diene -2,10- diketone of 13- trimethyls -7- (2- (piperidin-1-yl) ethyl) oxa-,
(4R, 5S, 6S, 7R, 9R, 11E, 13E, 15R, 16R) -15- ((butylamino) methyl) -6- (((2R, 3R, 4S, 5S,
6R)-4- (dimethylamino)-3,5- dihydroxy-6- methyl tetrahydrochysene-2H- pyrans-2- bases) oxygen) hydroxyl-5,9-16- ethyl-4-,
16 ring -11,13- diene -2,10- diketone of 13- trimethyls -7- (2- (piperidin-1-yl) ethyl) oxa-,
(4R, 5S, 6S, 7R, 9R, 11E, 13E, 15R, 16R) -15- ((benzyl (methyl) amino) methyl) -6- (((2R, 3R, 4S,
5S, 6R) -4- (dimethylamino) -3,5- dihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -16- ethyl -4- hydroxyls -
5,9,13- trimethyl -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 (isopropyl) amino) methyl) -6- (((2R, 3R,
4S, 5S, 6R) -4- (dimethylamino) -3,5- dihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -16- ethyl -4- hydroxyls
Base -5,9,16 ring -11,13- diene -2,10- diketone of 13- trimethyls -7- (2- (piperidin-1-yl) ethyl) oxa-,
(4R, 5S, 6S, 7R, 9R, 11E, 13E, 15R, 16R) -6- (((2R, 3R, 4S, 5S, 6R) -4- (dimethylamino) -3,5-
Dihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -16- ethyl -4- hydroxyl -5,9,13- trimethyls -15- ((methyl (pyrroles
Pyridine -3- ylmethyls) amino) methyl) 16 ring -11,13- diene -2,10- diketone of -7- (2- (piperidin-1-yl) ethyl) oxa-,
(4R, 5S, 6S, 7R, 9R, 11E, 13E, 15R, 16R) -6- (((2R, 3R, 4S, 5S, 6R) -4- (dimethylamino) -3,5-
Dihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -16- ethyl -4- hydroxyls -15- (isoindoline -2- ylmethyls) -5,9,
16 ring -11,13- diene -2,10- diketone of 13- trimethyls -7- (2- (piperidin-1-yl) ethyl) oxa-,
(4R, 5S, 6S, 7R, 9R, 11E, 13E, 15R, 16R) -15- ((benzyl (isopropyl) amino) methyl) -6- (((2R, 3R,
4S, 5S, 6R) -4- (dimethylamino) -3,5- dihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -7- (2- (3,5- bis-
Methyl piperidine -1- bases) ethyl) 16 ring -11,13- diene -2,10- two of -16- ethyl -4- hydroxyl -5,9,13- trimethyls oxa-
Ketone,
(4R, 5S, 6S, 7R, 9R, 11E, 13E, 15R, 16R) -15- ((benzyl (methyl) amino) methyl) -6- (((2R, 3R, 4S,
5S, 6R) -4- (dimethylamino) -3,5- dihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -16- ethyl -4- hydroxyls -
7- (2- (isoindoline -2- bases) ethyl) -5,9,13- trimethyl 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-
Dihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -16- ethyl -4- hydroxyls -7- (2- (isoindoline -2- bases) ethyl) -
5,9,13- trimethyl -15- (piperazine heavy stone used as an anchor -1- ylmethyls) 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- dihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -16- ethyl -4- hydroxyls -7-
(2- (isoindoline -2- bases) ethyl) -5,9,13- trimethyl 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-
Dihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -15- ((3,5- dimethyl piperazine heavy stone used as an anchor -1- bases) methyl) -16- ethyls -4-
16 ring -11,13- diene -2,10- diketone of hydroxyl -7- (2- (isoindoline -2- bases) ethyl) -5,9,13- trimethyls oxa-.
2. a kind of pharmaceutical composition, it is characterised in that it is with compound described in claim 1 or its pharmaceutically acceptable salt
For active constituent, and it is aided with pharmaceutic adjuvant and pharmaceutical preparation is made.
3. compound described in claim 1 or its pharmaceutically acceptable salt are preparing the bacterium for treating or preventing animal or people
Or the application in terms of mycoplasma infection drug.
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| CN1083068A (en) * | 1992-07-15 | 1994-03-02 | 美国辉瑞有限公司 | The derivative of the macrolide of 16 membered ring antibiotics |
| WO2003027250A2 (en) * | 2001-09-27 | 2003-04-03 | The United States Of America, As Represented By The Secretary Of Agriculture | Monoclonal antibodies to the drug tilmicosin and a method for detecting the same |
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| JPS59225199A (en) * | 1983-02-10 | 1984-12-18 | Microbial Chem Res Found | 20,23-dideoxy-23-alkyleneimino-20-substituted aminomycaminosyl relonolide |
| DE122011100013I1 (en) * | 1999-08-30 | 2011-09-15 | Zaidan Hojin Biseibutsu | Macrolide antibiotics and treatment of pasteurellosis. |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1083068A (en) * | 1992-07-15 | 1994-03-02 | 美国辉瑞有限公司 | The derivative of the macrolide of 16 membered ring antibiotics |
| WO2003027250A2 (en) * | 2001-09-27 | 2003-04-03 | The United States Of America, As Represented By The Secretary Of Agriculture | Monoclonal antibodies to the drug tilmicosin and a method for detecting the same |
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| CN108864228B (en) | 2021-02-02 |
| CN108864228A (en) | 2018-11-23 |
| CN104788519A (en) | 2015-07-22 |
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