CN103772376B - Substituted benzo-1,3-miscellaneous azole compound and preparation method and application thereof - Google Patents
Substituted benzo-1,3-miscellaneous azole compound and preparation method and application thereof Download PDFInfo
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- CN103772376B CN103772376B CN201310505300.0A CN201310505300A CN103772376B CN 103772376 B CN103772376 B CN 103772376B CN 201310505300 A CN201310505300 A CN 201310505300A CN 103772376 B CN103772376 B CN 103772376B
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- 0 */C(/N)=C(/C(O)=O)\S[N+] Chemical compound */C(/N)=C(/C(O)=O)\S[N+] 0.000 description 1
- NHHQOYLPBUYHQU-UHFFFAOYSA-N Cc1c(C(O)=O)[s]nn1 Chemical compound Cc1c(C(O)=O)[s]nn1 NHHQOYLPBUYHQU-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D277/82—Nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention relates to a substituted benzo-1, 3-miscellaneous azole compound shown in the general formula I, and further relates to a preparation method of the compound and application to the preparation of antituberculosis drugs. The compound provided by the invention has effect not only on mycobacterium tuberculosis sensitive strains, but also on resistant strains which have drug resistance to isoniazid, rifampicin, and other traditional frontline antituberculosis drugs, and is a novel antimycobacterium tuberculosis compound.
Description
Technical field
The present invention relates to substituted phendioxin, the miscellaneous azole compounds of 3-, the invention still further relates to the preparation side of described compound
Method and for preparing the purposes of antituberculotics.
Background technology
The chronic infectious disease that tuberculosis is a kind of people, animal and fowl suffers from altogether.In history, it was once widely current in the whole world, took by force
Take the life of several hundred million people, be referred to as " white pestilence " by people.1882, section is conspicuous found that tuberculosis is by mycobacterium tuberculosis
The infectious disease that (Mycobacterium tuberculosis is called for short tubercule bacillus) causes.Since the 1950's,
Owing to various effective chemotherapeutics are constantly found and are applied to clinic, lungy popular the most once it was under control.But
It is that in recent years, the tuberculosis being once effectively controlled has the most greatly the equal rebound significantly of the gesture staged a comeback, sickness rate and case fatality rate,
Become and acquired immune deficiency syndrome (AIDS), malaria the big killer of infectious disease three claimed.The population of the most global 1/3rd has infected tuberculosis and has divided
Branch bacillus, every AIR is 1%, has about 65,000,000 people to be infected the most every year.A lot of countries and regions report in the world in 2011
Lead serious multi-drug resistance tuberculosis, especially even more serious in the pandemic country of HIV.World Health Organization (WHO) estimates, the whole world
50,000,000 people are had to infect drug-resistant tuberculosis.
The revivable reason of tuberculosis is a lot, a most critically important aspect be exactly multi-drug resistant bacteria (MDR-TB) and
The extensively increase of Resistance Mycobacterium Tuberculosis (XDR-TB).The line that isoniazid and rifampicin etc. are traditional is resisted by this two paratuberculosiss mycobacteria
Tubercular drugs all has stronger drug resistance.But, between decades since rifampicin the is found nineteen sixty-five, only one of which two virtue
Base quinoline (diarylquinoline) TMC207 develops as treatment multi-drug resistance tuberculosis (MDR-TB).Therefore, find newly
Effective antituberculotics extremely urgent.
Summary of the invention
Inventor passes through unremitting effort, searches out a class through substantial amounts of experiment and has the Antitubercular of development potentiality
Compound, it is not only effective to tubercule bacillus sensitive strain, but also to a traditional line, two wires resistive connections such as resistance to isoniazid and rifampicin
The extensive Resistant strain of nuclear pharmaceuticals or multiple antibiotic resistant strain are effective.In particular it relates to the following aspects:
First aspect present invention relates to the compound shown in formula I, or its pharmaceutically acceptable salt, stereoisomer or molten
Agent compound,
Wherein, R1For on diverse location on phenyl ring replace, it is monosubstituted or polysubstituted, its be each independently selected from hydrogen,
Halogen, phenyl, nitro, carboxylic acid, hydroxyl, amino, cyano group, alkoxy carbonyl group, alkoxyl, alkylamino, C1～C6 alkyl；
R2For hydrogen, C1～C6 alkyl；
R3For substituted or unsubstituted five-membered unsaturated heterocycle group or hexa-atomic aromatic rings, wherein said substituent group is halogen
Element, hydroxyl or C1～C6 alkyl；
X is O, S or N；
Y is O or S.
Preferably, wherein said five-membered unsaturated heterocycle group selected from furan, thiophene, thiazole, pyrroles, pyrrolin, imidazoles,
Azoles, isoxazole, 1,2,3-thiadiazoles, pyrazoles.
Preferably, wherein said hexa-atomic aromatic rings is selected from benzene, naphthalene, pyridine, quinoline, pyrazine.
In embodiments of the invention, described five-membered unsaturated heterocycle group is selected from
In embodiments of the invention, described hexa-atomic aromatic rings is selected from
Preferably, it is selected from following compound:
2'-N-(5'-chlorobenzene also-1', 3'-azoles)-4-methyl isophthalic acid, 2,3-thiadiazoles-5-Methanamide；
2'-N-(6'-chlorobenzene also-1', 3'-azoles)-4-methyl isophthalic acid, 2,3-thiadiazoles-5-Methanamide;
2'-N-(5'-fluorobenzene also-1', 3'-azoles)-4-methyl isophthalic acid, 2,3-thiadiazoles-5-Methanamide;
2'-N-(5'-bromobenzene also-1', 3'-azoles)-4-methyl isophthalic acid, 2,3-thiadiazoles-5-Methanamide;
2'-N-(phendioxin ', 3'-thiazole) furan-2-Methanamide；
2'-N-(phendioxin ', 3'-thiazole) thiophene-2-carboxamide derivatives；
2'-N-(phendioxin ', 3'-imidazoles) furan-2-Methanamide；
2'-N-(5'-methyl benzo-1', 3'-azoles)-4-methyl isophthalic acid, 2,3-thiadiazoles-5-Methanamide；
2'-N-phendioxin ', 3'-azoles-4-methyl isophthalic acid, 2,3-thiadiazoles-5-Methanamide；
2'-N-phendioxin ', 3'-thiazole-3 methyl thiophene-2-Methanamide；
2'-N-phendioxin ', 3'-thiazole-Benzoylamide；
2'-N-phendioxin ', 3'-thiazole-4-fluorobenzamide；
2'-N-phendioxin ', 3'-thiazole-pyridine-3-carboxamide.
A second aspect of the present invention relates to pharmaceutical composition, its comprise the compound of any one of first aspect present invention or its
Pharmaceutically acceptable salt, stereoisomer or solvate, and optional pharmaceutically acceptable adjuvant, carrier or excipient.
A third aspect of the present invention relates to the preparation method of the compound of first aspect present invention, and it comprises the following steps:
(1) respectively there to be R on phenyl ring1Substituted o-aminophenol, adjacent iodo aniline and ortho-diaminobenzene are raw material, close
Become to have R1The substituted 2-amino miscellaneous azoles of benzo-1,3-；
(2) with R3The formic acid of five-membered unsaturated heterocycle represented, or the formic acid of hexa-atomic aromatic rings is that Material synthesis is unsaturated
Five-ring heterocycles formyl chloride, or hexa-atomic aromatic rings formyl chloride；
(3) step (1) there is R1The formyl chloride reaction that substituted 2-amino phendioxin, the miscellaneous azoles of 3-and step (2) synthesize, raw
Become and have the substituted phendioxin of acyl group, the miscellaneous azole compounds of 3-on amino；
(4) product above-mentioned (3) synthesized reacts through chloralkane, obtains R on the amino of first aspect present invention2Replace
Product；
(5) by the product of (4) respectively with Lawesson reagent reacting, obtain the corresponding sulfur of first aspect present invention for acyl
Aminated compounds；
The same first aspect present invention of definition of the most each substituent group.
Specifically, the concrete synthetic route of the compound of first aspect present invention is as follows:
Wherein a is HCl, NH4SCN；B is PbO, MeOH；C is CuI；D is 1) HCl, NH2CN, 2) NaOH；
Preferably, concrete reaction condition be a be 1.5mol/LHCl, NH4SCN, 110 DEG C；B is PbO, MeOH, backflow；C is
CuI, 50 DEG C；D is 1) HCl, 50%NH2CN solution, backflow；2) 50%NaOH solution, backflow；
Wherein a be DCM, b be CH3I；
Preferably, concrete reaction condition be a be DCM, dropping, 0 DEG C, b is CH3I；
Wherein a is Lawesson reagent；
Wherein, intermediate 4-methyl (hydrogen)-1, the synthetic route of 2,3-thiadiazoles-5-formic acid is as follows:
Wherein, a is room temperature, and b is SOCl2, c is NaOH/H2O;
Preferably, concrete reaction condition be a be room temperature, 6h, b are SOCl2, room temperature, 24h, c are NaOH/H2O, room temperature, 3h.
The compound that a fourth aspect of the present invention relates to described in any one of first aspect present invention in preparation prevention and/or is controlled
Treat the purposes in tuberculosis.
Purposes according to a fourth aspect of the present invention, wherein said tuberculosis is pulmonary tuberculosis or outer tuberculosis (the such as lymph of lung
Tuberculosis, tuberculous meningitis, tuberculous peritonitis, tuberculosis of intestine, renal tuberculosis, tuberculosis of epididymis, female reproduction tuberculosis (include defeated ovum
Pipe, endometrium, ovarian tuberculosis), tuberculosis of bone and joint etc.).
The compound that a fifth aspect of the present invention relates to described in any one of first aspect present invention in preparation prevention and/or is controlled
Treat the purposes in the medicine of the disease that mycobacterial infections causes.
Purposes according to a fifth aspect of the present invention, wherein said mycobacteria is mycobacterium tuberculosis.The present invention's
In one embodiment, described mycobacterium tuberculosis is mycobacterium tuberculosis type strain H37Rv, or to isoniazid and rifampicin
The Mycobacterium tuberculosis H37Rv of drug resistance.
In the present invention, described halogen refers to fluorine, chlorine, bromine, iodine.
In the present invention, described C1-C6Alkyl refers to comprise the saturated hydrocarbyl of straight chain and the side chain specifying number carbon atom,
The most e.g. methyl, ethyl, and isopropyl, normal-butyl, amyl group, hexyl etc..Term " alkyl " also includes cycloalkyl, i.e. ring
Shape C3-C6Alkyl, such as cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl.Preferably, term used herein " alkyl " refers to
Specify number the straight chain of carbon atom and the chain-like alkyl of side chain.
In the present invention, described alkoxy carbonyl group refers to alkyl-O-CO-group, wherein said alkyl for example, C1-C6Alkane
Base, its definition is as described herein.Exemplary alkoxycarbonyl groups includes methoxycarbonyl and ethoxy carbonyl.
The various raw materials reacting used in the present invention are that those skilled in the art can prepare according to existing knowledge
, or can be by what method known to document prepared, or can be by commercially available.In above reaction scheme
Used intermediate, raw material, reagent, reaction condition etc. all can be able to be made suitably according to the existing knowledge of those skilled in the art
Change.Or, those skilled in the art can also prepare that the inventive method fails to contain according to the teachings of the present invention other
Type I compound.
Type I compound of the present invention can exist with stereoisomer form.The present invention includes all possible stereoisomerism
Body, i.e. along or anti-single stereoisomers or the mixture of the two any required ratio.The present invention considers all this isomeries
The purified form of body (such as enantiomer and diastereomer) and mixed form, including racemic mixture.Enol shape
Formula is also included within the scope of the present invention.
Type I compound of the present invention i.e. can also the form of its pharmaceutically acceptable salt or solvate can make with itself
With.The pharmaceutically acceptable salt of type I compound include with pharmaceutically acceptable mineral acid or organic acid or inorganic base or
The conventional salt that organic base is formed.The suitably example of acid-addition salts includes and hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, nitric acid, high chlorine
Acid, fumaric acid, acetic acid, propanoic acid, succinic acid, hydroxyacetic acid, formic acid, lactic acid, maleic acid, tartaric acid, citric acid, flutter acid, the third two
Acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, benzene
The salt that sulfonic acid, hydroxynaphthoic acid, hydroiodic acid, malic acid, tannic acid etc. are formed.Pharmaceutical salts includes its inorganic or acylate, wherein
Include but not limited to: hydriodate, disulfate, hydrophosphate, butyrate, oxalates, pivalate, adipate,
Alginate, picrate, aspartate, gluconate, esilate, tosilate, embonate, acetone acid
Salt, glycollate, trifluoroacetate, para-aminosalicylic acid salt, embonate, pyruvate, glycollate, trifluoroacetic acid
Salt, para-aminosalicylic acid salt, pamoate and Ascorbate etc..Suitably the example of base addition salts include with sodium, lithium, potassium, magnesium,
Aluminum, calcium, zinc, N, N`-dibenzyl-ethylenediamin, chloroprocaine, choline, diethanolamine, ethylenediamine, N-METHYL-ALPHA-L-GLUCOSAMINE and general
The salt that Shandong caine etc. are formed.Referred to herein to the compounds of this invention time, including formula I, formula II and formula III compound and pharmacy thereof
Acceptable salt or solvate.The salt form of the compounds of this invention free alkali form and each of which is in some physical property
(dissolubility as in polar solvent) is upper slightly different, but for the object of the invention, each acid salt and each of which free alkali
Form is suitable.See for example S.M.Berge, et al., " Pharmaceutical Salts, " J.Pharm.Sci., 66:1-19
(1977), it is incorporated herein by.
Term used herein " compositions " means to include to comprise each product specifying composition of specified amount, and directly or
Any product indirectly produced from each combination specifying composition of specified amount, those skilled in the art can be similar to bright according to this explanation
The implication that " pharmaceutical composition " is had, and " compositions " can exchange with " pharmaceutical composition " and to make in some cases
With.According to the difference of administering mode, the present composition can contain weight ratio 0.1%, or more suitably weight ratio 10-60%
Active component.But when comprising unit dose in component, each unit preferably comprises 1-500 milligram active component.
The compound of the present invention can use with the form of the pharmaceutically acceptable salt derived from mineral acid or organic acid.Word
Language " pharmaceutically acceptable salt " refers in the range of reliable medical judgment, is suitable for and the mankind and zootic contact tissue
And occur without excessive toxicity, stimulation, anaphylaxis etc., and the salt matched with rational effect/Hazard ratio.Pharmaceutically acceptable
Salt is well known in the art.Such as, S.M.Berge, et al., " Pharmaceutical Salts, " J.Pharm.Sci.,
66:1-19 (1977), has wherein been described in detail pharmaceutically acceptable salt.Described salt can be by the trip of the compounds of this invention
From alkali degree of functionality and suitable organic acid reaction, in the final separation and purge process of the compounds of this invention, in situ preparation or
Person is manufactured separately.Representational acid-addition salts includes but not limited to acetate, adipate, alginate, citrate, Radix Asparagi
Propylhomoserin salt, benzoate, benzene sulfonate, disulfate, butyrate, Camphora hydrochlorate, camsilate, digluconate, glycerol
Phosphate, Hemisulphate, enanthate, caproate, fumarate, hydrochlorate, hydrobromate, hydriodate, 2-ethylenehydrinsulfonic acid
Salt (different thiosulfate, isothionate), lactate, maleate, mesylate, nicotinate, 2-naphthalene sulfonate, oxalic acid
Salt, palmitate, pectate, persulfate, 3-phenylpropionic acid salt, picrate, Pivalate, propionate, succinate,
Tartrate, rhodanate, phosphate, glutamate, Glu, bicarbonate, tosilate and hendecane hydrochlorate.Equally, alkalescence
It is quaternized that nitrogen-containing group may be used to lower material；The elementary alkyl halide such as chloride of methyl, ethyl, propyl group and butyl, bromination
Thing and iodide；Dialkyl sulfate such as dimethyl sulfate, diethylester, dibutyl ester and diamyl ester；Long chain halide such as decyl, ten
The chloride of dialkyl group, myristyl and octadecyl, bromide and iodide；Arylalkyl halide such as benzyl bromide a-bromotoluene and benzene second
Bromide and other.Therefore dissolved in or be scattered in the product of water or oil.Can be used to form pharmaceutically acceptable acid-addition salts
Sour example include mineral acid example hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid, and organic acid such as oxalic acid, maleic acid, succinic acid and lemon
Lemon acid.
Base addition salts can by make the compounds of this invention containing carboxylic moiety and suitable alkali reaction, at the compounds of this invention
Final separation and purge process situ prepare, the hydroxide of the most pharmaceutically acceptable metal cation of described alkali,
Carbonate and bicarbonate, or ammonia or organic primary amine, secondary amine or tertiary amine.
Pharmaceutically acceptable salt include but not limited to cation based on alkali metal or alkaline-earth metal such as lithium, sodium, potassium, calcium,
Magnesium and aluminium salt etc., and nontoxic quaternary amine and amine cation, including ammonium, tetramethyl-ammonium, tetraethyl ammonium, ammonium methyl, Dimethyl Ammonium,
Trimethyl ammonium, triethyl ammonium, diethyl ammonium and ethyl ammonium etc..Other the representative organic amines that can be used for being formed base addition salts include
Ethylenediamine, ethanolamine, diethanolamine, piperidines, piperazine etc..
Type I compound of the present invention or its pharmaceutically acceptable salt can also form solvate, such as hydrate, alcohol adduct
Deng.Above-claimed cpd can also is that prodrug or can discharge the form of described active component in vivo after metabolic alterations.Select and
Preparing suitable front derivant is technology as well known to those skilled in the art.Generally, for the purpose of the present invention, can with pharmacy
The solvate form thereof of the solvent such as water, the ethanol etc. that accept is suitable with non solvate form.
Powder, spray, ointment and inhalant is included for administering locally to the dosage form of the compounds of this invention.Aseptic
Under the conditions of by reactive compound and pharmaceutically acceptable carrier and any preservative, buffer agent or propellants.Ophthalmic preparation,
Eye ointments, powder and solution are contemplated within the scope of the present invention.
When for above-mentioned treatment or other treatment, a kind of the compounds of this invention of therapeutically effective amount can be answered in a pure form
With, or with pharmaceutically acceptable salt, ester or prodrug forms (in the case of there are these forms) application.Or, describedization
Compound can be administered with the pharmaceutical composition containing this purpose compound with one or more pharmaceutically acceptable excipient.Word
The compounds of this invention of " therapeutically effective amount " refers to be applicable to the foot of the reasonable effect/Hazard ratio treatment obstacle of any therapeutic treatment
The compound of enough amounts.It is to be understood that total consumption per day of the compounds of this invention and compositions must be by attending physician doctor reliably
Make decision in learning determination range.For any concrete patient, concrete treatment effective dose level must be according to many factors
Depending on, described factor includes the order of severity of treated obstacle and this obstacle；The activity of the particular compound used；Adopted
Concrete compositions；The age of patient, body weight, general health, sex and diet；The particular compound used to
Medicine time, route of administration and excretion rate；The treatment persistent period；It is applied in combination with the particular compound used or uses simultaneously
Medicine；And similar factor known to medical field.Such as, the way of this area is, the dosage of compound is from less than obtaining institute
The level needing therapeutic effect and require starts, and is gradually increased dosage, until required effect.It is, in general, that the compounds of this invention
For mammal particularly people dosage can between 0.0001～1000mg/kg body weight/day, such as between 0.001～
100mg/kg body weight/day, such as between 0.01～100mg/kg body weight/day, such as between 0.01～10mg/kg body weight/day.
The present invention also provide for comprising optionally diluent acceptable with one or more non-toxic pharmaceutical, carrier, excipient,
Adjuvant or the pharmaceutical composition of vehicle the compounds of this invention formulated together.Described pharmaceutical composition can particular formulation especially
Become for oral administration with solid or liquid form, for parental injection or for rectally.
The pharmaceutical composition of the present invention can by oral, rectum, parenteral, pond, intravaginal, intraperitoneal, locally (as led to
Cross powder, ointment or drop), buccal give the mankind and other mammals, or as oral spray or nasal spray
Agent gives.Terms used herein " parenteral " refers to include intravenous, intramuscular, intraperitoneal, breastbone interior, subcutaneous and intra-articular injection
Administering mode with transfusion.
In yet another aspect, the present invention provides and includes present component and the pharmaceutical composition of physiologically tolerable diluent.
Include one or more above-claimed cpds in invention, its with one or more nontoxic physiologically tolerable or acceptable diluent,
Carrier, adjuvant or vehicle (herein they being referred to as diluent) are configured to compositions, together for parental injection, intranasal
Transmit, with solid or liquid form oral administration, rectum or topical etc..
The compositions being suitable for parental injection can include physiologically acceptable sterile, aqueous or non-aqueous liquor, dispersion
Agent, suspensoid or Emulsion, and for reconstructing the sterile powders of sterile injectable solution agent or dispersant.The most aqueous or non-aqueous
The example of carrier, diluent, solvent or vehicle includes water, ethanol, polyhydric alcohol (propylene glycol, Polyethylene Glycol, glycerol etc.), plant
Oil (such as olive oil), injectable organic ester such as ethyl oleate and their suitable mixture.
These compositionss also can contain adjuvant, such as preservative, wetting agent, emulsifying agent and dispersant.By various antibacteriums
Agent and antifungal, such as parabens, chlorobutanol, phenol, sorbic acid etc., it may be determined that prevent the effect of microorganism.Also
Expect to include isotonic agent, such as saccharide, sodium chloride etc..By using the material that can postpone absorption, such as aluminum monostearate and bright
Glue, the prolongation that can reach injectable drug form absorbs.
Suspensoid the most also can contain suspending agent, such as ethoxylation i-octadecanol, polyoxyethylene mountain
Pears alcohol and polyoxyethylene sorbitan ester, microcrystalline Cellulose, inclined aluminium hydroxide, bentonite, agar and yellow write glue or these
The mixture etc. of material.
In some cases, for extending the action time of medicine, it is desirable to slow down and subcutaneously or intramuscularly inject the absorption of medicine.This
Can be realized by the liquid suspension of the crystal of use poorly water-soluble or amorphous substance.So, the infiltration rate of medicine takes
Certainly in its dissolution velocity, and dissolution velocity can be depending on crystal size and crystal formation.Or, the medicament forms of parenteral
Postpone absorb by by this medicine dissolution in or be suspended in oil vehicle in realize.
Injectable depot formulations can be by biodegradable polymer such as polylactide-polyglycolide (polylatide-
Prepared by the microcapsule matrix forming medicine in polyglycolide).Can be according to the ratio of medicine and polymer and the tool used
The character of body polymer, is controlled by drug releasing rate.The example of other biological degradable polymer also includes poly-ortho acid
Esters (poly (orthoesters)) and polyanhydrides (poly (anhydrides)).Injectable depot formulations also can be by by medicine
Thing is embedded in can be prepared in the liposome compatible with bodily tissue or microemulsion.
Injectable agent can be such as by filtering with bacteriological filtration bacteria filter or by mixing the sterilizing of aseptic solid composite form
Agent carrys out sterilizing, and described solid composite can be dissolved or dispersed in sterilized water or other sterile injectable medium before use.
Capsule, tablet, pill, powder and granule is included for the solid dosage forms of administration can be taken.In this type of solid dosage forms
In, reactive compound can be with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate
And/or the mixing of following material: a) filler or extender such as starch, lactose, sucrose, glucose, mannitol and silica gel；B) viscous
Mixture such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and Radix Acaciae senegalis；C) heat preserving agent is the sweetest
Oil；D) disintegrating agent such as agar, calcium carbonate, Rhizoma Solani tuber osi or tapioca, alginic acid, some silicate and sodium carbonate；E) solution resistance
Stagnant dose such as paraffin；F) accelerator such as quaternary ammonium compound is absorbed；G) wetting agent such as spermol and glyceryl monostearate；H) adsorbent
Such as Kaolin and bentonite and i) lubricant such as Pulvis Talci, calcium stearate, magnesium stearate, solid polyethylene glycol, dodecyl
Sodium sulfate and their mixture.In the case of capsule, tablet and pill, described dosage form also can comprise buffer agent.
The solid composite of similar type uses excipients such as lactose and high molecular weight polyethylene glycol etc., it is possible to as soft
Implant in capsule and hard capsule.
The solid dosage forms of tablet, dragee (dragees), capsule, pill and granule can with bag and and shell material such as
Prepare together with enteric coating material other clothing materials known with pharmaceutical preparation.These solid dosage formss can optionally contain opacifier, and its group
One-tenth can make its simply or preferentially at certain position of intestinal optionally with delayed mode release of active ingredients.The embedding that can use
The example of compositions includes polymer substance and wax class.If be suitable for, reactive compound also can be with one or more above-mentioned figurations
Agent is made into microencapsulated form.
Liquid dosage form for oral administration includes pharmaceutically acceptable Emulsion, solution, suspensoid, syrup and elixir.
Liquid dosage form also can be containing inert diluent commonly used in the art except containing active ingredient beyond the region of objective existence, and such as water or other solution increase
Solvent and emulsifying agent such as ethanol, isopropanol, ethyl carbonate, EtOAc, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-fourth two
Alcohol, dimethylformamide, oils (particularly Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, Semen Maydis oil, germ oil, olive oil, Oleum Ricini and Semen Sesami
Oil), glycerol, tetrahydrofurfuryl alcohol (tetrahydrofurfuryl alcochol), Polyethylene Glycol and the fat of glue sorbitol and acid esters
And their mixture.Orally administered composition also can comprise adjuvant in addition to including inert diluent, such as wetting agent, emulsifying agent and outstanding
Floating agent, sweeting agent, correctives and flavouring agent.
Compositions for rectum or vagina administration is preferably suppository.Suppository can by by the compounds of this invention with the most non-
Prepared by the mixing of zest excipient or carrier such as cocoa butter, Polyethylene Glycol or suppository wax, they are at room temperature solid, but
Be the most then liquid, therefore can rectal cavity or intravaginal fusing and discharge reactive compound.
The compounds of this invention can also be administered by liposomal form.It is known in the art, liposome generally with phospholipid or other
Lipid material prepares.Liposome is formed by the single or multiple lift water liquid crystal being scattered in water-bearing media.Any can form fat
Plastid nontoxic, physiologically acceptable and metabolizable lipid all can use.The present composition of liposomal form is except containing
Outside the compounds of this invention, also can contain stabilizer, preservative, excipient etc..Preferably lipid be natural and the phospholipid of synthesis and
Phosphatidylcholine (lecithin), they can use individually or together.The method forming liposome is well known in the art.See
Such as Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York,
N.Y.(1976),p.33。
Accompanying drawing explanation
Fig. 1: male SD rat gives 50 through gavage, 100, drug-time curve figure after the T097 of 150mg/kg
Detailed description of the invention
Below in conjunction with embodiment, embodiment of the present invention are described in detail, but those skilled in the art will
Understanding, the following example is merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.In embodiment unreceipted specifically
Condition person, the condition advised according to normal condition or manufacturer is carried out.Agents useful for same or instrument unreceipted production firm person, be
Can by city available from conventional products.
Embodiment 1: synthesis 3-(methoxycarbonyl hydrazone)-ethyl n-butyrate.
Take ethyl acetoacetate 7.28g(0.055mol) in 100ml there-necked flask, add 35ml ethanol and dissolve, room temperature
Lower dropping methyl hydrazinocarboxylate 5.02g(0.055mol) ethanol solution 15ml.Finish, be stirred at room temperature 6 hours, remove under reduced pressure molten
Agent 10.51g, yield 94.5%.
Embodiment 2: synthesis 4-methyl isophthalic acid, 2,3-tri-thiazole-5-Ethyl formate
By thionyl chloride 13ml(0.18mol) it is added to be connected with in the 100ml there-necked flask of drying tube, device for absorbing tail gas,
Cryosel bath under the conditions of be slowly added dropwise 3-(methoxycarbonyl hydrazone)-ethyl n-butyrate. 11.80g(0.06mol) and dichloromethane 50ml.Instead
Remove thionyl chloride and the dichloromethane of excess after answering 24 hours under reduced pressure, obtain brown solid.Post separates, petroleum ether-ethyl acetate:
10:1 (V/V) eluting, obtains yellow oil 6.72g, yield 65.1%.
Embodiment 3: synthesis 4-methyl isophthalic acid, 2,3-tri-thiazole-5-formic acid
In 100ml round-bottomed flask, add the aqueous solution of 20ml3mol/L, 10ml ethanol, be gradually added into 4-methyl isophthalic acid, 2,
3-tri-thiazole-5-Ethyl formate 5.14g(0.03mol), it is stirred at room temperature 3 hours.Remove solvent under reduced pressure, obtain solid ether and wash
Wash, then solid is dissolved in 40ml water, under stirring condition, be added dropwise over concentrated sulphuric acid acidifying water liquid to pH～3.Sucking filtration is consolidated
Body, ether washs, finally gives white powder, 3.67g, yield 85.0%.1H NMR(400MHz,CD3OD):2.848(s,3H,-
CH3)。
Embodiment 4: synthesis 2'-N-(5'-chlorobenzene also-1', 3'-azoles)-4-methyl isophthalic acid, 2,3-thiadiazoles-5-Methanamide
(i.e. compound T097)
Take 4-methyl isophthalic acid, 2,3-thiadiazoles-5-formic acid 1.04g(0.0072mol), 10ml oxalyl chloride is in 10ml round-bottomed flask
In, in 70 DEG C of 7h that reflux, remove the oxalyl chloride of excess under reduced pressure, obtain 4-methyl isophthalic acid, 2,3-thiadiazoles-5-formyl chlorides, non-purification
Process direct plunges into next step reaction.2-amino-5-chlorine phendioxin, 3-azoles, 10ml tetrahydrochysene is added in 50ml there-necked flask
Furan dissolves, 5ml triethylamine.Then the oxolane being dried with 10ml dissolves above-mentioned acyl chlorides, under conditions of being less than-5 DEG C slowly
Dropping, stirring reaction 4h under room temperature.Add 40ml saturated sodium-chloride water solution, respectively by 25ml dichloromethane aqueous phase extracted three
Secondary, merge organic facies.Post separates, petroleum ether-ethyl acetate: 8:1(V/V) eluting, yellow solid 1.48g, m.p.247～249
DEG C, yield: 69.7%:1H NMR (400MHz, DMSO): 13.334 (brs, 1H), 7.321～7.619(m, 3H, Ph-H),
2.914(s, 3H ,-CH3), MS (ESI): m/z [M+H]+295.0。
Embodiment 5: synthesis 2'-N-(phendioxin ', 3'-thiazole) furan-2-Methanamide
Take furan-2-formic acid 0.90g(0.00812mol), 2-amino benzo-1,3-thiazoles 1.20g(0.00812mol) in
In 100ml round-bottomed flask, add 20ml DMF and dissolve.It is subsequently adding EDCI3.10g(0.01624mol), DMAP2.48g
(0.0203mol).Finish, reaction 15 hour is stirred at room temperature.
Being poured into by reactant liquor in 150ml ethyl acetate, wash twice with the aqueous hydrochloric acid solution of 50ml10%, 50ml is saturated
Sodium bicarbonate aqueous solution washes twice.Organic facies anhydrous sodium sulfate is dried.It is spin-dried for solvent, obtains faint yellow solid 0.65g,
M.p.152～154 DEG C, yield 32.8%,1H NMR (400MHz, DMSO): 12.844 (s, 1H), 8.039 (m, 1H), 7.986
(m, 1H), 7.745 (m, 1H), 7.455 (m, 1H), 7.322(m, 1H), 6.758 (m, 1H), MS (ESI): m/z [M+H]+
245.11。
Embodiment 6: synthesis 2'-N-(phendioxin ', 3'-thiazole) thiophene-2-carboxamide derivatives
Take thiophene-2-carboxylic acid 1.04g(0.00812mol), 2-amino benzo-1,3-thiazoles 1.20g(0.00812mol) in
In 100ml round-bottomed flask, add 20ml DMF and dissolve.It is subsequently adding EDCI3.10g(0.01624mol), DMAP2.48g
(0.0203mol).Finish, reaction 15 hour is stirred at room temperature.
Being poured into by reactant liquor in 150ml ethyl acetate, wash twice with the aqueous hydrochloric acid solution of 50ml10%, 50ml is saturated
Sodium bicarbonate aqueous solution washes twice.Organic facies anhydrous sodium sulfate is dried.It is spin-dried for solvent, obtains faint yellow solid 0.781g,
M.p.193～194 DEG C, yield 37.0%.1H NMR (400MHz, DMSO): 7.299 (m, 2H), 7.458(m, 1H), 7.801 (m,
1H), 8.014 (m, 2H), 8.329 (s, 1H), 12.983 (s, 1H), MS (ESI): m/z [M+H]+261.09。
Embodiment 7: synthesis 2'-N-(phendioxin ', 3'-imidazoles) furan-2-carboxamide hydrochloride
Take furan-2-formic acid 0.90g(0.00812mol), 2-amino phendioxin, 3-imidazoles 1.08g(0.00812mol) in
In 100ml round-bottomed flask, add 20ml DMF and dissolve.It is subsequently adding EDCI3.10g(0.01624mol), DMAP2.48g
(0.0203mol).Finish, reaction 15 hour is stirred at room temperature.
Reactant liquor is poured in 150ml ethyl acetate, wash twice with the aqueous hydrochloric acid solution of 50ml10%, collect aqueous phase, put
Put precipitation solid.Cross elimination solvent, obtain off-white color solid, use methanol-diethyl ether recrystallization, obtain white solid 0.858g,
M.p. ＞ 300 DEG C, yield 40.1%.1H NMR (400MHz, DMSO): 6.836 (m, 1H), 7.379(m, 2H), 7.699 (m,
3H), 8.138 (s, 1H), MS (ESI): m/z [M-HCl+H]+228.10。
Embodiment 8:2'-N-(5'-methyl benzo-1', 3'-azoles)-4-methyl isophthalic acid, 2,3-thiadiazoles-5-Methanamide
The synthesis of 5-methyl benzothiazole-2-amine: take 40ml1.5mol/L HCl and be placed in 250ml round-bottomed flask, successively
Add 4-methyl-2 amino-phenol 5.0g(0.04mol), ammonium thiocyanate 4.57g(0.06mol), in 100 DEG C of uncovered reactions of water-bath 6
Hour.Let cool, separate out solid, use ethyl acetate dissolution, solvent is evaporated off, obtain faint yellow solid.Re-crystallizing in ethyl acetate, obtains
White crystal 1.23g, m.p.149～151 DEG C, yield 17.5%.MS(ESI):m/z[M+H]+:183.0。
Take above-mentioned solid 1.23g(0.007mol), it is dissolved in the round-bottomed flask of 50ml with 20ml methanol, adds lead oxide
1.57g(0.007mol), backflow 8h.Sucking filtration while hot, obtains black liquor.Recycling design, post separates, dichloromethane: methanol=
30:1 eluting, obtains khaki solid 0.69g, m.p.140～141 DEG C, yield 66.3%.MS(ESI):m/z[M+H]+:149.03。
4-methyl isophthalic acid, the preparation of 2,3-thiadiazoles-5-formyl chloride is with embodiment 4.
Adding 5-methyl benzothiazole-2-amine in 50ml there-necked flask, 10ml oxolane dissolves, 5ml triethylamine.So
The oxolane being dried with 10ml afterwards dissolves above-mentioned acyl chlorides, is slowly added dropwise under conditions of being less than-5 DEG C, stirring reaction 4h under room temperature.
Add 40ml saturated sodium-chloride water solution, use 25ml dichloromethane aqueous phase extracted three times respectively, merge organic facies.Post separates, and two
Chloromethanes: methanol 60:1 eluting, obtains white solid 1.39g, m.p.174～176 DEG C, yield: 70.6%.1H NMR(400MHz,
DMSO): 11.68 (s, 1H ,-NH-), 8.02～7.06(m, 3H, Ph-H), 2.96 (s, 3H ,-CH3),2.62(s,3H,-CH3)。
MS(ESI):m/z[M+H]+: 275.02, [M+Na]+: 297.22, [M-H]-:273.12。
Embodiment 9:2'-N-phendioxin ', 3'-azoles-4-methyl isophthalic acid, 2,3-thiadiazoles-5-Methanamide
The synthesis of benzothiazole-2-amine: take Ortho-Aminophenol 4.25g (0.039mol), ammonium thiocyanate 4.45g
(0.059mol), adding in 100ml round-bottomed flask, be subsequently adding the hydrochloric acid 30ml of 0.059mol, reflux 6h.Let cool.Acetic acid second
Ester 30ml × 3 extraction sour water phase, merges organic facies, and anhydrous sodium sulfate is dried 12h.
Dissolving with 40ml methanol after being evaporated by the said goods, add lead oxide 13.2g (0.059mol), reflux 8h, while hot
Sucking filtration, obtains black liquor.Recycling design, post separates, and dichloromethane: methanol=30:1 eluting obtains faint yellow solid, 3.60g,
Yield 45.6%.MS(ESI):m/z[M+H]+134.97, [M-H]-132.92。
4-methyl isophthalic acid, the preparation of 2,3-thiadiazoles-5-formyl chloride is with embodiment 4.
Adding benzothiazole-2-amine 1.34g (0.01mol) in 100ml there-necked flask, 30ml oxolane dissolves, 5ml
Triethylamine.Then the oxolane being dried with 20ml dissolves above-mentioned acyl chlorides, is slowly added dropwise, stirs under room temperature under conditions of being less than-5 DEG C
Mix reaction 4h.Add 40ml saturated sodium-chloride water solution, use 40ml dichloromethane aqueous phase extracted three times respectively, merge organic facies.
Post separates, dichloromethane: methanol 30:1 eluting, obtains white solid 1.88g, m.p.237～238 DEG C, yield: 72.3%.
Embodiment 10:2'-N-(6'-chlorobenzene also-1', 3'-azoles)-4-methyl isophthalic acid, 2,3-thiadiazoles-5-Methanamide
Preparation 6-chlorobenzene thiazole-2-amine: take 2-amino-5-chlorophenol 5.0g (0.035mol), ammonium thiocyanate 4.0g
(0.053mol), adding in 100ml round-bottomed flask, be subsequently adding the hydrochloric acid 30ml of 0.053mol, reflux 6h.Let cool.Acetic acid second
Ester 30ml × 3 extraction sour water phase, merges organic facies, and anhydrous sodium sulfate is dried 12h.
Dissolving with 40ml methanol after being evaporated by the said goods, add lead oxide 11.9g (0.053mol), reflux 8h, while hot
Sucking filtration, obtains black liquor.Recycling design, post separates, and dichloromethane: methanol=30:1 eluting obtains reddish brown solid, 1.89g,
M.p.176～178 DEG C, yield: 32.0%.MS(ESI):m/z[M+H]+: 169.04, [M-H]-:167.05。
4-methyl isophthalic acid, the preparation of 2,3-thiadiazoles-5-formyl chloride is with embodiment 4.
Adding 6-chlorobenzene thiazole-2-amine 1.68g (0.01mol) in 100ml there-necked flask, 30ml oxolane is molten
Solve, 5ml triethylamine.Then the oxolane being dried with 20ml dissolves above-mentioned acyl chlorides, is slowly added dropwise, room under conditions of being less than-5 DEG C
Temperature lower stirring reaction 4h.Add 40ml saturated sodium-chloride water solution, use 40ml dichloromethane aqueous phase extracted three times respectively, be associated with
Machine phase.Post separates, and dichloromethane: methanol 30:1 eluting obtains white solid 1.76g, yield: 59.9%.1H NMR(400MHz,
DMSO): 13.43 (brs, 1H ,-NH-), 7.87～7.43(m, 3H, Ph-H), 2.95 (s, 3H ,-CH3)。MS(ESI):m/z[M+
H]+: 295.03, [M-H]-:293.05。
Embodiment 11:2'-N-(5'-fluorobenzene also-1', 3'-azoles)-4-methyl isophthalic acid, 2,3-thiadiazoles-5-Methanamide
Preparation 5-fluorine benzothiazole-2-amine: taking 2-amino-4-fluorophenol 5.0g (0.039mol), 4.45g pressed by Hydrogen thiocyanate
(0.059mol), adding in 100ml round-bottomed flask, be subsequently adding the hydrochloric acid 30ml of 0.059mol, reflux 6h.Let cool.Acetic acid second
Ester 30ml × 3 extraction sour water phase, merges organic facies, and anhydrous sodium sulfate is dried 12h.
Dissolving with 40ml methanol after being evaporated by the said goods, add lead oxide 13.2g (0.059mol), reflux 8h, while hot
Sucking filtration, obtains black liquor.Recycling design, post separates, and dichloromethane: methanol=30:1 eluting obtains faint yellow solid, 1.96g,
M.p.144～146 DEG C, yield: 33.05%.MS(ESI):m/z[M+H]+:153.03。
4-methyl isophthalic acid, the preparation of 2,3-thiadiazoles-5-formyl chloride is with embodiment 4.
Adding 5-fluorine benzothiazole-2-amine 1.52g (0.01mol) in 100ml there-necked flask, 30ml oxolane is molten
Solve, 5ml triethylamine.Then the oxolane being dried with 20ml dissolves above-mentioned acyl chlorides, is slowly added dropwise, room under conditions of being less than-5 DEG C
Temperature lower stirring reaction 4h.Add 40ml saturated sodium-chloride water solution, use 40ml dichloromethane aqueous phase extracted three times respectively, be associated with
Machine phase.Post separates, and dichloromethane: methanol 20:1 eluting obtains white solid 1.86g, yield: 66.9%.
1H NMR (400MHz, DMSO): 13.39 (brs, 1H ,-NH-), 7.69～7.17(m, 3H, Ph-H), 2.95 (s,
3H,-CH3)。MS(ESI):m/z[M+H]+: 279.05, [M+Na]+: 301.03, [M-H]-:276.98。
Embodiment 12:2'-N-(5'-bromobenzene also-1', 3'-azoles)-4-methyl isophthalic acid, 2,3-thiadiazoles-5-Methanamide
Preparation 5-bromine benzothiazole-2-amine: taking 2-amino-4-bromophenol 5.0g (0.027mol), 3.1g pressed by Hydrogen thiocyanate
(0.040mol), adding in 100ml round-bottomed flask, be subsequently adding the hydrochloric acid 25ml of 0.040mol, reflux 6h.Let cool.Acetic acid second
Ester 30ml × 3 extraction sour water phase, merges organic facies, and anhydrous sodium sulfate is dried 12h.
Dissolving with 40ml methanol after being evaporated by the said goods, add lead oxide 8.9g (0.040mol), reflux 8h, takes out while hot
Filter, obtains black liquor.Recycling design, post separates, and dichloromethane: methanol=80:1 eluting obtains faint yellow solid, 1.72g,
M.p.144～146 DEG C, yield: 29.02%.1H NMR (400MHz, DMSO): 13.35 (brs, 1H ,-NH-), 7.62～7.48
(m, 3H, Ph-H), 2.94 (s, 3H ,-CH3)。MS(ESI):m/z[M+H]+: 212.97, [M-H]-:210.90。
4-methyl isophthalic acid, the preparation of 2,3-thiadiazoles-5-formyl chloride is with embodiment 4.
Adding 5-bromine benzothiazole-2-amine 0.59g (0.003mol) in 100ml there-necked flask, 20ml oxolane is molten
Solve, 5ml triethylamine.Then the oxolane being dried with 20ml dissolves above-mentioned acyl chlorides, is slowly added dropwise, room under conditions of being less than-5 DEG C
Temperature lower stirring reaction 4h.Add 40ml saturated sodium-chloride water solution, use 20ml dichloromethane aqueous phase extracted three times respectively, be associated with
Machine phase.Post separates, and dichloromethane: methanol 40:1 eluting obtains white solid 0.54g, yield: 53.5%.1H NMR(400MHz,
DMSO): 13.39 (brs, 1H ,-NH-), 7.69～7.17(m, 3H, Ph-H), 2.95 (s, 3H ,-CH3)。MS(ESI):m/z[M+
H]+: 279.05, [M+Na]+: 301.03, [M-H]-:276.98。
Embodiment 13:2'-N-phendioxin ', 3'-thiazole-3 methyl thiophene-2-Methanamide
The synthesis of 3 methyl thiophene-2-formyl chloride is with embodiment 4.
Adding benzothiazole-2-amine 1.50g (0.01mol) in 100ml there-necked flask, 30ml oxolane dissolves, 5ml
Triethylamine.Then the oxolane being dried with 20ml dissolves above-mentioned acyl chlorides, is slowly added dropwise, stirs under room temperature under conditions of being less than-5 DEG C
Mix reaction 4h.Add 40ml saturated sodium-chloride water solution, use 30ml dichloromethane aqueous phase extracted three times respectively, merge organic facies.
Post separates, and dichloromethane: methanol 20:1 eluting obtains white solid 1.13g, yield: 41.2%.1H NMR (400MHz, DMSO):
12.42 (brs, 1H ,-NH-), 7.94～7.06(m, 6H, aromatic-H), 1.91 (s, 3H ,-CH3)。MS(ESI):m/z[M+
H]+:275.03。
Embodiment 14:2'-N-phendioxin ', 3'-thiazole-Benzoylamide
Taking benzoic acid 5g (0.04mol), benzothiazole-2-amine 6g (0.04mol), EDCI10g (0.08mol), in 100ml
In round-bottomed flask, 30ml DMF makees solvent, and room temperature reaction is overnight.React complete, above-mentioned reactant liquor is poured into the 100ml sour water of 5%
In, ethyl acetate 30ml × 3 aqueous phase extracted, merge organic facies, anhydrous sodium sulfate is dried.Post separates, petroleum ether: ethyl acetate=
3:1 eluting, obtains white solid 4.29g, yield 42.9%.1H NMR (500MHz, DMSO): 12.91 (s, 1H ,-NH-), 8.17～
7.34(m, 9H, aromatic-H).MS(ESI):m/z[M+H]+: 255.13, [M+Na]+: 276.99.
Embodiment 15:2'-N-phendioxin ', 3'-thiazole-4-fluorobenzamide
Take parafluorobenzoic acid 5g (0.35mol), benzothiazole-2-amine 5.4g (0.35mol), EDCI10g (0.08mol),
In 100ml round-bottomed flask, 30ml DMF makees solvent, and room temperature reaction is overnight.React complete, pour above-mentioned reactant liquor into 5%
In 100ml sour water, ethyl acetate 30ml × 3 aqueous phase extracted, merge organic facies, anhydrous sodium sulfate is dried.Post separates, petroleum ether:
Ethyl acetate=3:1 eluting, obtains white solid 3.59g, m.p.220～222 DEG C, yield 37.7%.1H NMR(500MHz,
DMSO): 12.94 (s, 1H ,-NH-), 8.26～7.33(m, 8H, aromatic-H).MS(ESI):m/z[M+Na]+: 295.03,
[M-H]-:271.54。
Embodiment 16:2'-N-phendioxin ', 3'-thiazole-pyridine-3-carboxamide
Take Nicotinicum Acidum 4.3g (0.35mol), benzothiazole-2-amine 5.4g (0.35mol), EDCI10g
(0.08mol), in 100ml round-bottomed flask, 30ml DMF makees solvent, and room temperature reaction is overnight.React complete, DMF is evaporated off, obtains
Yellow solid, adds 50ml acetic acid ethyl dissolution, filters insoluble madam's solid, and the HCl of the 5% of solid layer 50ml washs 2 times,
Separate sour water phase, adjust pH to alkalescence, separate out white solid, dry 3.02g, m.p.256～257 DEG C, yield 33.7%.1H
NMR (500MHz, DMSO): 9.29 (s, 1H, 2-H), 8.67(dd, 1H, 6-H), 8.45 (dd, 1H, 4-H), 7.81 (d, 1H, 4'-
H),7.59(d,1H,7'-H),7.49(m,1H,5-H),7.31(t,1H,5'-H),7.14(t,1H,6'-H)。MS(ESI):m/z
[M+H]+: 257.44, [M+Na]+:279.15。
Embodiment 17: embodiment compound anti-tubercular measures
In following example, mycobacteria type strain: H37Rv, FJ05349, FJ05060；Extensively drug resistance tuberculosis branch bar
Bacterium clinical strain: FJ05436(is to INH, RMP, STR, CPM, OFX, TYPE drug resistance), FJ05195(to INH, RMP, EMB, STR,
OFX, KAN, TYPE drug resistance)；Multiple-drug resistance tuberculosis mycobacteria clinical strain: FJ05120(is to INH, RMP drug resistance) by China's disease
Prevention provides with control centre.
The preparation method of 7H9 culture medium: weigh DifcoTM Middlebrook7H9Broth solid 4.7g, be dissolved in 900ml
In water, add 2ml glycerol, dense NaOH adjust pH at 7.2-7.5,121 DEG C of sterilizing 15min, after cooling add Middlebrook ADC
Growth Supplement100ml, uses after mixing.
Quantitative microwell plate quick colour-developing method (MABA) optimized is used to measure compound to mycobacterium tuberculosis type strain
H37Rv and the sensitive and minimum inhibitory concentration (MIC) of Drug-Resistant Mycobacterium tuberculosis clinical strain.
Operational approach is as follows:
Aseptic 96 orifice plates, test-compound (embodiment compound) dissolves with DMSO, and making concentration is at the beginning of 128 μ g/ml
Solution, maximum concentration hole adds 198 μ l7H9 culture medium, and 2 μ l test-compounds just solution, after mix homogeneously, to remaining each Kong Yi
Secondary 2 times of dilutions, test-compound is final concentration of: 128,64,32,16,8,4,2,1,0.5,0.25 μ g/ml.Choose mycobacteria
The training in the cultivation 3-4 week of type strain, extensive Drug-Resistant Mycobacterium tuberculosis strain and multiple-drug resistance tuberculosis mycobacteria clinical separation strain
Foster thing makes bacteria suspension, is inoculated into containing 0.05% Tween 80,10%ADC(albumin dextrose catalase, public purchased from BD
Department) 7H9 culture medium in, in 37 DEG C of quiescent culture 1-2 week, growing to turbidity is that McFarland1 (is equivalent to 107CFU/ml) time,
After 1:20 dilution, add each hole 100 μ l, final concentration of the 10 of bacterium solution6CFU/ml.2 growths without antimicrobial drug are set on every plate
Control wells (the same experimental port of remaining condition), 96 orifice plates are hatched in 37 DEG C.Growth control hole 20 μ l10 × Alamar is added after 7 days
Blue and 5%Tween-8050 μ l mixed liquor, after 37 DEG C hatch 24h, observes the change of culture hole color.If color is from indigo plant
Complexion changed is pink colour, then add Alamar Blue and the Tween-80 mixed liquor of above-mentioned amount in the hole of Experimental agents, incubate for 37 DEG C again
Educating and 1-2 week record the color in each hole, MIC is defined as stoping the lowest concentration of drug of color change (becoming pink from blueness).
Specific experiment result sees table 1.
Result shows, the compound of the present invention is not only effective to mycobacterium tuberculosis sensitive strain, but also to isoniazid
Good inhibiting effect is had with the Resistant strain of the tradition antituberculotics drug resistance such as rifampicin.
Embodiment 18: embodiment 4 compound acute toxicity testing in early days
Use 16 BALB/C mice, male and female half and half, carry out acute toxicity test (experimental technique reference: " toxicology is real
Proved recipe method and technology ", Wang Xinru edits, People's Health Publisher, and 2006).This test sets four dosage groups, often group four.
Result: LD50It is about 960mg/kg.
Embodiment 19: embodiment 4 compound pharmacokinetic evaluation is tested
Male SD rat, if 50,100, tri-dosage groups of 150mg/kg, often group three, CMC-Na suspendible gastric infusion.?
Under three dosage, animal is showed no any exception.Gather whole blood sample, separated plasma in different time points, process through heavy albumen
T097 concentration in rear employing liquid chromatography for measuring blood plasma.The results are shown in Table 2.Time front of blood concentration is shown in Fig. 1.Medicine is for power
Learn parametric results and be shown in Table 3.
Table 2 male SD rat gives 50 through gavage, 100, whole blood concentration (μ g/mL) after the T097 of 150mg/kg
Table 3 male SD rat gives 50 through gavage, 100, whole blood pharmacokinetic parameters after the T097 of 150mg/kg
Although the detailed description of the invention of the present invention has obtained detailed description, it will be understood to those of skill in the art that.Root
According to disclosed all teachings, those details can be carried out various amendment and replacement, these change all the guarantor of the present invention
Within the scope of protecting.The four corner of the present invention is given by claims and any equivalent thereof.
Claims (17)
1. the compound shown in formula I, or its pharmaceutically acceptable salt,
Wherein, R1For on diverse location on phenyl ring replace, it is monosubstituted or polysubstituted, its be each independently selected from hydrogen, halogen,
Phenyl, nitro, carboxylic acid, hydroxyl, amino, cyano group, C1～C6Alkoxy carbonyl group, C1～C6Alkoxyl, C1～C6Alkylamino, C1～C6Alkane
Base；
R2For hydrogen, C1～C6Alkyl；
R3For
X is O；
Y is O or S；
And described compound of Formula I does not comprise 2'-N-(5'-chlorobenzene also-1', 3'-azoles)-4-methyl isophthalic acid, 2,3-thiadiazoles-
5-Methanamide.
2. the compound of claim 1, wherein R3For
3. the compound of claim 1, it is selected from following compound:
2'-N-(6'-chlorobenzene also-1', 3'-azoles)-4-methyl isophthalic acid, 2,3-thiadiazoles-5-Methanamide；
2'-N-(5'-fluorobenzene also-1', 3'-azoles)-4-methyl isophthalic acid, 2,3-thiadiazoles-5-Methanamide；
2'-N-(5'-bromobenzene also-1', 3'-azoles)-4-methyl isophthalic acid, 2,3-thiadiazoles-5-Methanamide；
2'-N-(5'-methyl benzo-1', 3'-azoles)-4-methyl isophthalic acid, 2,3-thiadiazoles-5-Methanamide；
2'-N-phendioxin ', 3'-azoles-4-methyl isophthalic acid, 2,3-thiadiazoles-5-Methanamide.
4. pharmaceutical composition, its compound comprising any one of claim 1-3 or its pharmaceutically acceptable salt, and optional
Pharmaceutically acceptable adjuvant, carrier or excipient.
5. the preparation method of the compound of claim 1, it comprises the following steps:
(1) there to be R on phenyl ring1Substituted o-aminophenol is raw material, and synthesis has R1Substituted 2-amino benzo-1,3-azoles；
(2) with R3The formic acid of the five-membered unsaturated heterocycle represented is Material synthesis undersaturated five-ring heterocycles formyl chloride；
(3) step (1) there is R1The formyl chloride reaction that substituted 2-amino phendioxin, 3-azoles and step (2) synthesize, generates ammonia
The substituted phendioxin of acyl group, 3-azole compounds is had on base；
(4) product above-mentioned (3) synthesized reacts through chloralkane, obtains R on the amino of claim 12Substituted product；
(5) product of (4) is reacted with lawesson reagent respectively, obtain the corresponding thioamide analog compound of claim 1；
The definition of the most each substituent group is with claim 1.
6. the purposes in preparation prevention and/or treatment tuberculosis of the compound described in any one of claim 1-3.
7. the purposes of claim 6, wherein said tuberculosis is pulmonary tuberculosis or the outer tuberculosis of lung.
8. the purposes of claim 7, the outer tuberculosis of wherein said lung is selected from as lymphoid tuberculosis, tuberculous meningitis, Tuberculous peritoneum
Inflammation, tuberculosis of intestine, renal tuberculosis, tuberculosis of epididymis, female reproduction tuberculosis and tuberculosis of bone and joint.
9. the purposes of claim 8, wherein said female reproduction tuberculosis is selected from fallopian tube, endometrium, ovarian tuberculosis.
10. the disease that the compound described in any one of claim 1-3 causes in preparation prevention and/or treatment mycobacterial infections
Medicine in purposes.
The purposes of 11. claim 10, wherein said mycobacteria is mycobacterium tuberculosis.
12. compound 2'-N-(5'-chlorobenzene also-1', 3'-azoles)-4-methyl isophthalic acid, 2,3-thiadiazoles-5-Methanamide is pre-in preparation
Prevent and/or treat the purposes in tuberculosis.
The purposes of 13. claim 12, wherein said tuberculosis is pulmonary tuberculosis or the outer tuberculosis of lung.
The purposes of 14. claim 13, the outer tuberculosis of wherein said lung is selected from lymphoid tuberculosis, tuberculous meningitis, Tuberculous peritoneum
Inflammation, tuberculosis of intestine, renal tuberculosis, tuberculosis of epididymis, female reproduction tuberculosis and tuberculosis of bone and joint.
The purposes of 15. claim 14, wherein said female reproduction tuberculosis is selected from fallopian tube, endometrium, ovarian tuberculosis.
16. compound 2'-N-(5'-chlorobenzene also-1', 3'-azoles)-4-methyl isophthalic acid, 2,3-thiadiazoles-5-Methanamide is pre-in preparation
Purposes in the medicine of the disease that anti-and/or treatment mycobacterial infections causes.
The purposes of 17. claim 16, wherein said mycobacteria is mycobacterium tuberculosis.
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