CN106632133A - Novel thiazole derivatives, and preparation method and application thereof - Google Patents

Abstract

The invention relates to a structure of novel thiazole derivatives, a preparation method of the thiazole derivatives and application of the thiazole derivatives in the aspect of bioactivities. The invention also relates to pharmaceutically acceptable salts, a solvate or prodrug, and a pharmaceutical composition of the derivatives. Thiazolyl, uramido, thioureido and other active groups are introduced to obtain the series thiazole derivatives (I) and (II). The test on the activities of the compounds for some representative pathogenic bacteria and parasites shows that the series compounds have parasite resisting activities; and the CC50/IC50 of partial compounds for Toxoplasma gondii is greater than 1 or even higher, so the partial compounds have favorable inhibiting activities. Besides, the compounds XQH-2-97, XQH-3-13 and XQH-3-14 have obvious inhibitory effects on Streptococcus mutans, have obviously higher bactericidal capacities than nitazoxanide in the positive control group, and thus, are hopeful to be developed into new antibacterial compounds.

Description

Novel thiazole analog derivative and preparation method and application

Technical field

The invention discloses a class new compound and its application, are specifically related to the knot of novel thiazole analog derivative The application of structure, preparation method and biological activity.The invention further relates to the derivant, its pharmaceutically acceptable salt, solvent The pharmaceutical composition of compound or prodrug and the above-mentioned type, belongs to field of pharmaceutical chemistry technology.

Background technology

One of microorganism impact most important on the mankind is the prevalence for causing infectious disease.Having in human diseasess about 50% is Caused by microorganism infection.Microorganism causes the history of human diseasess, that is, the history that the mankind constantly resist therewith. Although prevention and treatment of diseases aspect, the mankind have been achieved for the progress for attracting people's attention, but emerging, or produce resistance to The microorganism infection of medicine is all present always, the increasingly serious antibiotics resistance problem that such as people face at present, in the urgent need to The development of novel drugs.

In recent decades, although have many antimicrobial agents to be applied to clinic, but microbial infectious diseases are always It is growing on and on.For example, although new antibacterials are continued to bring out so that most infectious disease is efficiently controlled And treatment, but reality is that people maintain an equal level before being come out with sulphonamidess by the disease general mortality rate that bacterium infection causes.This aspect Because the pathogen for causing infection constantly constantly produces variation due to drug resistance, on the other hand, new infectious disease not pregnancy ceased Raw, such as the generation of the superbacteria that present people feel simply helpless makes diagnosis and treatment become increasingly complex and difficulty.

Pathogenic microorganism is referred to can invade human body, cause the infection even microorganism of infectious disease, also known as pathogen.Cause of disease Body includes parasite (such as protozoon, anthelmintic, medical insect, toxoplasma), funguses, antibacterial, spirillum, mycoplasma, rickettsia, clothing Substance, virus etc..

Bacterium infection is that pathogenic bacterium or conditioned pathogen invade growth and breeding in blood circulation, the toxin of generation, antibacterial and Other metabolites, from wound or In vivo infection focus the acute systemic infection that blood causes is invaded.Clinically patient Chang Biao It is now the symptom such as irritated, extreme cold of the limbs and cyanosis, pulse thin speed, tachypnea, blood pressure drops.Especially in old man, child, have slow Sexually transmitted disease (STD) or immunologic hypofunction person, treatment not in time and have in complication patient, can develop into septicemia or pyemia.

Human parasitic diseases are the infectious disease that the class caused by parasite endangers severe human's health, in the torrid zone, sub- heat Sickness rate is higher in the country of band.Common parasite has protozoon, whipworm, Schistosoma japonicum, thread nematicide, gutstring worm and silk ribbon Worm, toxoplasma etc..There are about 50% people infection superparasitization worm in the world, China mean parasitized insect infection rate also up to 20%～ 30%.

Toxoplasma, in the single celled eukaryotic protista of the multiple door in top, is a kind of special sexual cell endoparasitism protozoon, can be infected Most of host including people is more in stealthy infection in the normal body of immunologic function.If body's immunity is damaged, Stealthy infection acute attack can be made and threat to life.Infection of pregnant women toxoplasma can cause congenital toxoplasmosis, cause the dead of fetus Die, anemia of pregnant woman miscarriage etc. serious consequence.Male's toxoplasma gondii infection can then cause infertility.And treat toxoplasmosiss medicine exist it is optional The difficult problem such as medicine is few, treatment cycle length, high recurrence rate, poisonous side effect of medicine are big, particularly there is no the medicine for killing cyst of toxoplasma gonndii Thing.At present, clinical treatment toxoplasmosiss are still based on traditional sulfadiazine and pyrimethamine drug combination.Both medicines There is treatment course length, the shortcomings of untoward reaction is more, it is unsatisfactory in overall therapeutic curative effect.In view of still to no effect good at present In the case of good Toxoplasma gondii vaccine, find is with little, the inexpensive resisting toxoplasmosis medicine of good insecticidal effect and toxic and side effects The important directions of Chinese scholars effort for it.

Ester of Harden Young aldolase (Fructose 1,6-Bisphosphate Aldolase, FBA) is glycolysiss The key enzyme of approach, is responsible for reversibly cracking Fructose 1, and 6- diphosphonic acid (FBP) is glyceraldehyde 3-phosphate (GAP) and di(2-ethylhexyl)phosphate hydroxypropyl Ketone (DHAP).

Fructose-1,6-diphosphonic acid aldolase (FBA) the catalysis sugar 1,6- diphosphonic acid cracking process reaction equations are as follows：

This step enzymatic reaction is in the approach such as glycolysis, Calvin cycle (reduced form phosphopentose pathway) and glyconeogenesis An important reaction.

FBA in nature is broadly divided into I types and II types.Wherein, I types are primarily present in vertebratess, such as people and other Superior being.And II types are primarily present in invertebratess, such as antibacterial and protozoacide.The main distinction of I types and II types exists In：Both catalytic mechanisms are different, shown in following reaction equation.

When I types ester of Harden Young aldolase (FBA) is catalyzed, by the lysine residue (Lys) at activity itself position The carbonyl condensation of amino and substrate form a Schiff base intermediate.And II classes fructose-1,6-diphosphonic acid aldolase (FBA) sends out During raw catalytic reaction, it is impossible to form stable intermediate, need using as Zn²⁺Such bivalent cation promotees as cofactor It is set to play catalysis activity.The ester of Harden Young aldolase (FBA) of antibacterial and toxoplasma belongs to II types, and it is urged Change effect needs to have two conditions：1) Zn is needed²⁺Promote its active as cofactor, and play catalytic action；2) Hydrogen bonded is formed by its key amino acid and substrate ester of Harden Young, so as to prevent the combination of the enzyme-to-substrate, most The activity of whole inhibitory enzyme.Based on the characteristic of above two type FBA, if certain inhibitor be selectively acting in II types FBA, Rather than for I types FBA of mammal, then will not give people body and bring any toxic and side effects.Therefore, novel specific effect is developed In the inhibitor of II types FBA so as to act only on antibacterial and protozoacide and not to mammal toxic side effect, be expected to become A very promising class antibacterial and anti-parasite medicine.

The content of the invention

Present invention aims to the deficiencies in the prior art, there is provided a class has the thiophene of antibacterial and Antiparasitic Activity Azole derivative, its pharmaceutically acceptable salt, solvate or prodrug, pharmaceutical composition so as to be likely to become treatment The index higher antibacterial and anti-parasite medicine that can be used for clinic, the research and development for follow-up clinical medicine provide foundation and reference.

Thiazolyl, urea groups, ghiourea group are important pharmacophore, and the compound containing thiazole and urea groups (or ghiourea group) is reported Road has multiple biological activities, such as antibacterial, anticancer, antiinflammatory, antiviral biological activity.The present invention is by introducing thiazole, urea groups With ghiourea group isoreactivity group, serial thiazole derivative (I) and (II) are obtained, and for some representational malignant bacterias, And the toxoplasma in parasite, active testing has been carried out to synthesized compound.

The design considerationss that technical solution of the present invention is taken are：

Based on following reaction：

As shown in above-mentioned reaction equation, compound 1 is the quinoline derivatives of Carlos et al. design synthesis, with significant The antibacterial activity of protozoacide (parasite) and wide spectrum.Compound 2 (nitazoxanide, NTZ) is a kind of traditional wide spectrum, efficiently Parasiticide and antibacterials, have listed using for many years, and biological target of its effect exactly acts only on antibacterial and primary dynamic The II type fructose-1,6-diphosphonic acid aldolases of thing.Construction featuress of the present invention based on compound 1 and 2, comprehensively utilize drug design In molecular hybridization, cyclization, bioisostere, pharmacophore move the strategies such as jump, devise and selectively targeted act on II types fruit The novel thiazole analog derivative of sugar -1,6- bisphosphate aldolases, formula (I) and formula (II) of its chemical constitution as shown in reaction equation. The purpose of urea groups (or ghiourea group) is introduced in noval chemical compound two：On the one hand can be with the water solublity of modulating compound, raisingization The bioavailability of compound；On the other hand, chemical combination can be strengthened by increasing the donor (NH) and receptor (C=O) of hydrogen bond Thing and the adhesion of receptor protein II type ester of Harden Young aldolases, improve the potential antibacterial of target compound and resist and post Infested activity.

Thiazole derivative containing urea groups or ghiourea group of the present invention, with the knot shown in logical formula (I) or (II) Structure：

Wherein：

N is 0～8 positive integer；

X is O or S；

Y is CH or N；

R¹Selected from hydrogen, halogen (F, Cl, Br, I), hydroxyl, cyano group, nitro, amino, carboxyl, different hydroxyl valeric acid base, carbamyl Base, sulfoamido, C1-8 straight or branched alkanoyls, C1-8 straight or branched alkane sulfonyls, C1-8 straight or branched alkyls, C_2-8Straight or branched thiazolinyl, C_2-8Straight or branched alkynyl, miscellaneous alkyl, C3-12 cycloalkyl, halo C1-8 straight or branched alkane Base, C_1-8Straight or branched alkoxyl, C1-8 straight or branched alkylthio groups, C1-8 acyl groups, R⁸-O、R⁹SC(O)-、R¹⁰SO₂-、 (R¹¹)NH-C(O)-、(R¹²)(R¹³) amino that N- can be substituted, can be substituted C3-12 cycloalkyl, C1-8 aliphatic acyloxies, 4 Heterocyclic radical, 5- or 6- unit nitrogen atom aromatic heterocyclic radical to 7 yuan of nitrogen atoms.Optionally taken by one or more following groups Generation：Halogen, nitro, aryl, heteroaryl, hydroxyl, aryloxy, heteroaryl epoxide, miscellaneous alkoxyl, amino, C1-8 straight chains are propped up Chain amino, dialkyl amido, arylamino, heteroaryl amino, C1-8 alkyl aryl aminos, miscellaneous alkyl amino, sulfydryl, C1-8 alkane Base sulfydryl, aryl thiol, heteroaryl sulfydryl, miscellaneous alkyl sulfydryl, C1-8 alkyl sulphonyls, aryl sulfonyl, heteroarylsulfonyl, C1-8 alkane sulfoxide groups, aryl sulfoxid es base, heteroaryl sulfoxide group, cyano group, C1-8 alkyl-carbonyls, aryl carbonyl, Heteroarylcarbonyl, C1-8 alkoxyls, C1-8 haloalkyls；

R²For pharmaceutically acceptable mineral acid or organic acid；

R³、R⁴、R⁵、R⁶、R⁷It is hydrogen, halogen (F, Cl, Br, I), hydroxyl, cyanogen for identical or different and independent substituent groups Base, nitro, amino, carboxyl, hydrazide group, C_1～8Straight or branched alkyl, C_2-8Straight or branched thiazolinyl, C_2-8Straight or branched alkynes Base, miscellaneous alkyl, C_3-12Cycloalkyl, haloalkyl, alkoxyl, alkylthio group, alkanoyl, aroyl, 4-hetaroylpyrazol, aryl C_1-8Alkane Acyl group, heteroaryl C_1-8Straight or branched alkanoyl, arylsulfonyl, miscellaneous sulfonyl, aryl C_1-8It is straight or branched alkane sulfonyl, miscellaneous Aryl C_1-8Straight or branched alkane sulfonyl, C_1-8Aliphatic acyloxy, aryl, heteroaryl, Heterocyclylalkyl, miscellaneous alkoxyl, 4 to 7 yuan The heterocyclic radical of nitrogen atom, 5- or 6- units nitrogen atom aromatic heterocyclic radical, each optionally by one or more selected from following Substituent group replaces：Hydroxyl, halogen, nitro, amino, carboxyl, alkyl, cycloalkyl, aryl, heteroaryl, Heterocyclylalkyl, alkoxyl, Alkoxy-alkyl-, alkoxy carbonyl, aryl, heteroaryl, aryloxy, heteroaryl epoxide, miscellaneous alkoxyl, C_1-8Straight chain is propped up The amino of chain, dialkyl amido, arylamino, heteroaryl amino, C_1-8Straight or branched alkyl arylamino, miscellaneous alkyl amino, Sulfydryl, C_1-8Straight or branched alkyl sulfydryl, aryl thiol, heteroaryl sulfydryl, miscellaneous alkyl sulfydryl, C1-8 straight or branched alkyls Sulfonyl, aryl sulfonyl, heteroarylsulfonyl, C1-8 straight or branched alkane sulfoxide groups, aryl sulfoxid es base, heteroaryl sulfoxide Base, cyano group, C1-8 straight or branched alkyl carbonyls, aryl carbonyl, Heteroarylcarbonyl, C1-8 straight or branched alkoxyls, C1-8 Haloalkyl, R⁸SC(O)-、R⁹SO₂-、(R¹⁰)NH-C(O)-、(R¹¹)(R¹²)N-、R¹³- O-, HC (O)-, aryloxy group.

The above-mentioned thiazole derivative containing urea groups or ghiourea group is preferred embodiment：The R¹、R³、R⁴、R⁵、R⁶、 R⁷It is independently C_1～8Straight or branched alkyl, aryl, Heterocyclylalkyl, halogen, C_1-8Straight or branched alkoxyl, hydroxyl, dioxane Base amino, alkyl sulphonyl, aryloxy group, heteroaryl, it is each optionally replaced by 1～5 selected from following substituent group：C_1-8 Straight or branched alkyl, halogen, hydroxyl, C_1-8Straight or branched alkoxyl, hydroxyl, nitro, amino, carboxyl, HC=O-, fragrant oxygen Base；R²It is hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, weight sulphuric acid, phosphoric acid, diphosphonic acid, acetic acid, propanoic acid, hydroxyacetic acid, 2- hydroxyls third Acid, Acetylformic acid, oxalic acid, malonic acid, fumaric acid, the acid of 2- hydroxyls -1,2,3- the third three, lactic acid, tartaric acid, tannic acid, citric acid, Trifluoroacetic acid, malic acid, succinic acid, salicylic acid, Fumaric acid, gluconic acid, saccharic acid, benzoic acid, phenylacetic acid, ferulic acid, 2 hydroxybenzoic acid, 4- amino-2-hydroxybenzoic acids, methanesulfonic acid, ethyl sulfonic acid, cyclohexyl sulfinic acid, benzenesulfonic acid, to toluene sulphur Acid, citric acid, maleic acid, caffeic acid, gallic acid or bar be not sour.

Pharmaceutically acceptable salt containing above-claimed cpd, solvate or prodrug, or pharmaceutical composition, its feature exists In：Described solvate, the water of crystallization containing one or more molecules；Described prodrug includes C_1～8Straight or branched alkane Base ester, aryl ester, C_1～8Straight or branched alkyl amide, aryl amide；Described pharmaceutical composition is except containing one or more medicine On outside acceptable carrier or excipient, also at least it is similar to containing the thiazole described in a kind of claim 1 or 2 of therapeutic dose Thing, its pharmaceutically acceptable salt, solvate or prodrug.

Wherein：Described solvate is preferably containing the water of crystallization of 1～3 molecule；The ester that described prodrug contains also includes Cycloalkyl ester and alkyl aryl.

A class thiazole derivative with antibacterial and resisting toxoplasmosis activity of the present invention, it is characterised in that：It is selected from down One of row compound：

4- (2- ((5- nitrothiazole -2- bases) amino) -2- oxoethyls)-N- phenylpiperazine -1- Methanamides；

N- (4- fluorophenyls) -4- (2- ((5- nitrothiazole -2- bases) amino) -2- oxoethyls) piperazine -1- Methanamides；

N- (4- chlorphenyls) -4- (2- ((5- nitrothiazole -2- bases) amino) -2- oxoethyls) piperazine -1- Methanamides；

N- (4- bromophenyls) -4- (2- ((5- nitrothiazole -2- bases) amino) -2- oxoethyls) piperazine -1- Methanamides；

N- (5- nitrothiazole -2- bases) amino) -2- (4- benzene first sulfonyls) piperazine -1- bases) acetamide；

N- (3,4 Dimethoxyphenyl) -4- (2- ((5- nitrothiazole -2- bases) amino) -2- oxoethyls) piperazine -1- first Amide；

N- (4- bromophenyls) -4- (2- ((5- nitrothiazole -2- bases) amino) -2- oxoethyls) piperazine -1- Methanamides；

N- (4- tolyls) -4- (2- ((5- nitrothiazole -2- bases) amino) -2- oxoethyls) piperazine -1- Methanamides；

N- (2- methoxyphenyls) -4- (2- ((5- nitrothiazole -2- bases) amino) -2- oxoethyls) piperazine -1- formyls Amine；

N- (2- methoxyphenyls) -4- (3- ((5- nitrothiazole -2- bases) amino) -2- oxopropyls) piperazine -1- formyls；

N- (4- tolyls) -4- (2- ((5- nitrothiazole -2- bases) amino) ethyl of -2- oxygen third) piperazine -1- Methanamides；

N- (4- fluorophenyls) -4- (2- ((5- nitrothiazole -2- bases) amino) -2- oxoethyls) piperazine -1- Methanamides；

N¹- (3- chlorphenyl-N⁴- (5- nitrothiazole -2- bases) piperidines -1,4- diformamides；

N¹- (4- tolyls)-N⁴- (5- nitrothiazole -2- bases) piperidines -1,4- diformamides；

N¹- (4- methoxyphenyls)-N⁴- (5- nitrothiazole -2- bases) piperidines -1,4- diformamides；

N¹- (3- methoxyphenyls)-N⁴- (5- nitrothiazole -2- bases) piperidines -1,4- diformamides；

N⁴- (5- nitrothiazole -2- bases)-N¹- Phenylpiperidine) -1,4- diformamides；

N¹- (4- chlorphenyls)-N4- (5- nitrothiazole -2- bases) piperidines -1,4- diformamides；

N- (5- nitrothiazole -2- bases)-(4- (3- phenylthioureas) piperidin-1-yl) acetamide；

2- (4- (3- (4- chlorphenyls) urea) piperidin-1-yl)-N- (5- nitrothiazole -2- bases)) acetamide；

2- (4- (3- (4- fluorophenyls) urea) piperidin-1-yl)-N- (5- nitrothiazole -2- bases)) acetamide；

2- (4- (3- (4- bromophenyls) urea groups) piperidin-1-yl)-N- (5- nitrothiazole -2- bases)) acetamide；

2- (4- (3- (3- bromophenyls) urea) piperidin-1-yl)-N- (5- nitrothiazole -2- bases)) acetamide；

2- (4- (3- (4- methoxyphenyls) urea) piperidin-1-yl)-N- (5- nitrothiazole -2- bases)) acetamide；

2- (4- (3- (4- tolyls) urea) piperidin-1-yl)-N- (5- nitrothiazole -2- bases)) acetamide；

2- (4- (3- (3,4- xylyls) urea) piperidin-1-yl)-N- (5- nitrothiazole -2- bases)) acetamide.

Above-mentioned thiazole derivative concrete structure formula is as follows：

One of thiazole derivative listed by formula (I)：

One of thiazole derivative listed by formula (II)：

The invention provides the compound of formula (I) and (II), has with the pharmaceutical composition containing such compound and part There is the preferred compound of notable antibacterial and Antiparasitic Activity.It is applicable defined below for the purpose of this specification is explained, And it is any it is suitable in the case of, the term for using in the singular also includes plural form, and vice versa.

Unless otherwise stated, term " halogen " used herein refers to fluorine, chlorine, bromine and iodine.

Term " alkyl " is the fully saturated hydrocarbon chain of straight or branched with 1～20 carbon atom.Alkyl preferably comprise 1 to 8 carbon atoms, the representative example of alkyl include but is not limited to methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl, Isobutyl group, the tert-butyl group, n-pentyl, isopentyl, neopentyl, n-hexyl, 3- methylhexyls, 2,2- dimethyl amyl groups, 2,3- diformazans Base amyl group, n-heptyl, n-octyl, n-nonyl, positive decyl.

Term " aryl " refers to 6～14 carbon atoms and up to aromatic systems of 3 rings, the ring can be condense or It is directly connected to.The representative illustration of the aryl includes but is not limited to phenyl, biphenyl, phenanthryl, Herba Alii fistulosi base.Aryl can also include one The ring of individual or multiple non-fully aromatics, the system example is dihydrofuran.

Term " thiazolinyl " refer to comprising at least one double bond (having cis or trans) and preferably have 2～20 carbon atoms point Prop up or non-limbed unsaturated alkyl.Thiazolinyl example includes vinyl, 2- acrylic and isopropenyl.

Term " alkynyl " refers to comprising at least one 3 keys and preferably has the branch of 2～20 carbon atoms or non-limbed insatiable hunger And alkyl.Alkynyl example includes acetenyl, 2-propynyl and isopropynyl.

Term " cycloalkyl " refers to the nonaromatic cyclic group with 3～20 ring carbon atoms and forms 1-3 ring and optional include One or more ethylene linkages.Polycyclic system can be volution, condensed ring or bridged ring etc..Cycloalkyl includes such as cyclopropyl, cyclobutyl, ring It is amyl group, cyclohexyl, suberyl, cyclooctyl, cyclopentenyl, cyclohexenyl group, adamantyl, bicyclic [2.2.1] heptane, bicyclic [2.2.2] octane, three rings [3.3.1.1] decane etc..

Term " miscellaneous alkyl " refers to saturation or undersaturated, side chain or straight chain, substituted or unsubstituted at least contain One heteroatomic alkyl, wherein any one hetero atom are non-conterminous.Contain 2～15 carbon atoms in miscellaneous alkyl, preferably comprise 2 ～10 atoms.

Term " Heterocyclylalkyl " or " heterocycle " refer to optionally substituted fully saturated, fractional saturation or undersaturated Aromatics or non-aromatic heterocycle.For example, it is 4 to 7 unit monocycles, 7 to 12 yuan of bicyclo- ring systems, its can be condense, spiral, And with least one hetero atom in the ring containing at least one carbon atom.Each ring containing heteroatomic heterocyclic radical can be with Containing 1,2 or 3 hetero atoms selected from nitrogen-atoms, oxygen atom and the sulphur atom ,-CH on its medium ring₂- can be by-C (O)-group Substitute, and sulfur heteroatom can also optionally be oxidized to S (O) or S (O)₂Group.In fused ring system, ring can be with It is non-aromatic heterocyclic, and other rings can be cycloalkyl, aryl or heteroaryl.Additionally, heterocyclic radical can with hetero atom or It is connected at carbon atom.

Exemplary preferred monocyclic heterocycles base includes：Pyrrolidinyl, pyrrole radicals, oxetanyl, imidazole radicals, imidazoline Base, imidazolidinyl, triazolyl, oxazolyl, oxazolidinyl, isoxazoline-3-yl, isoxazolyls, thiazolyl, thiadiazolyl group, Thiazolidine Base, isothiazolyl, isothiazole alkyl, furyl, tetrahydrofuran base, thienyl, pyridine radicals, pyrazinyl, pyrimidine radicals, pyridazinyl, THP trtrahydropyranyl, morpholinyl, tetrahydro-1,4-thiazine base, tetrahydro-1,4-thiazine base Asia vitriol；Exemplary preferred bicyclic heterocycles base includes：Indyl, two Hydrogen indoles base, benzothiazolyl, benzoxazinyl, benzoxazolyl, benzothienyl, benzothiazine base, quininuclidinyl, quinoline Base, tetrahydric quinoline group, decahydroquinolyl, isoquinolyl, tetrahydro isoquinolyl, Decahydroisoquinolinpreparation base, benzimidazolyl, benzo pyrrole Mutter base, benzofuranyl, coumarin；Exemplary tricyclic heterocyclic base includes：Carbazyl, phenothiazinyl, carbolinyl etc..

Term " heteroaryl " is referred in aromatic ring comprising the aryl of at least one of sulfur, oxygen and nitrogen.Preferably, the heteroaryl Base is 5～10 yuan of aromatic ring systems.The nonrestrictive example is pyranose, furyl, pyridine radicals, pyrimidine radicals, thienyl, different Thiazolyl, imidazole radicals, tetrazole base, triazole, pyrazinyl, quinolyl (quinolyl), isoquinolyl (isoquinolyl), Benzothienyl, isobenzofuran-base, pyrazolyl, indyl, piperazinyl, tetrahydrochysene piperazinyl etc..

Term " carbamoyl " refers to H₂NC (O)-, alkyl-NHC (O)-, (alkyl)₂NC (O)-, aryl-NHC (O)-, Alkyl (aryl)-NC (O)-, heteroaryl-NHC (O)-, alkyl (heteroaryl)-NC (O)-, aryl-alkyl-NHC (O)-, alkyl (aryl-alkyl)-NC (O)-etc..

Term " sulfonamido " refers to alkyl-S (O)₂- NH-, aryl-S (O)₂- NH-, aryl-alkyl-S (O)₂It is-NH-, miscellaneous Aryl-S (O)₂- NH-, heteroaryl-alkyl-S (O)₂- NH-, alkyl-S (O)₂- (alkyl)-, aryl-S (O)₂- N (alkyl)-, virtue Base-alkyl-S (O)₂- N (alkyl)-, heteroaryl-S (O)₂- N (alkyl)-, heteroaryl-alkyl-S (O)₂- N (alkyl)-etc..

Term " acyl group " refers to the group R-C of straight chain, side chain or the cyclic configuration of 1 to 10 carbon atom or its combination configuration (O)-, it passes through carbonyl functional group and is connected with precursor structure.This kind of group can be saturated or unsaturated, and can be It is aliphatic series or aromatics.Preferably, the R in acyl group is alkyl or alkoxyl or aryl or heteroaryl.The example includes but does not limit In acetyl group, benzoyl, propiono, isobutyryl, tert-butoxycarbonyl, section Epoxide carbonyl etc..Lower acyl is referred to containing 1 To the acyl group of 4 carbon.

Term " alkoxyl " refers to group：- O- (replacement alkyl), wherein alkyl alkoxyl exemplary as previously mentioned be- OCH₃、-OCH₂CH₃、-OCH(CH₃)₂、OCH₂CH₂CH₃。

Term " cycloalkyloxy " refers to substituted or unsubstituted, saturation or undersaturated cyclic alkoxy, and it is former that it contains carbon Son and/or one or more hetero atoms.The ring can be the system of monocyclic or condensed ring, bridged ring or volution.It is monocyclic generally to have 3～9 Individual atom, preferably 4～7 atoms are multi-ring to usually contain 7～17 atoms, preferably 7～13 atoms.

Term " aryloxy group " refers to aromatic carbocyclic epoxide, and preferred aromatic ring contains 6～10 carbon atoms.

Term " alkylthio group " refers to hydrogen by alkyl-substituted sulfydryl, such as methyl mercapto, ethylmercapto group, rosickyite base, tert-butyl group sulfur Base, cyclopropylsulfanyl etc..

Term " sulfonyl " refers to R-SO₂-.Wherein R is hydrogen, alkyl, aryl, heteroaryl, aryl-alkyl, heteroaryl-alkane Base, aryl-O-, heteroaryl-O-, alkoxyl, aryloxy group, cycloalkyl or Heterocyclylalkyl.

Term " aryl amine " refers to aromatic carbocyclic amido, and preferred aromatic ring contains 6～10 carbon atoms.

Term " heteroaryloxy " refers to aromatic heterocycle epoxide, can be monocyclic or bicyclic radicals.

Term " heteroaryl amido " refers to aromatic heterocycle amido, can be monocyclic or bicyclic radicals.

" aroyl " refers to that aromatic carbon ring end is connected with the group of carbonyl to term.Preferred aromatic ring has 6～10 carbon originals Son.

Term " 4-hetaroylpyrazol " refers to that heteroaromatic end is connected with the group of carbonyl, can be monocyclic or bicyclic radicals. Preferred heteroaryl includes：Thiophene, furan, pyrroles, pyridine, piperidines, piperazine, N methyl piperazine, pyrazine, thiazole, pyrimidine, quinoline Quinoline, tetrazole, triazole, benzothiazole, benzofuran, indole etc..

Term " cycloalkanoyl " refers to saturation or unsaturation, and substituted or unsubstituted annular termination is connected with the group ring of carbonyl System, can be monocyclic or bicyclic radicals.Preferably comprise 7～13 atoms.

Term " pharmaceutically-acceptable salts ", the term includes the salt of hydroxy-acid group, can be by making compound with appropriate alkali React to provide corresponding base addition salts.The example of this alkali is：Alkali metal hydroxide, including potassium hydroxide, sodium hydroxide And Lithium hydrate；Alkaline earth metal hydroxide, such as magnesium hydroxide and calcium hydroxide.Additionally, also including the salt of organic base, it is described Organic base lysine, arginine, ethanolamine, choline etc.；The salt of inorganic base, the inorganic basis such as ammonium or substituted ammonium salt. In due course, the compounds of this invention can also be by with pharmaceutically acceptable organic acid and mineral acid, such as halogen acids, salt Acid, hydrogen are smelt acid, hydroiodic acid etc. and process the compound and form acid-addition salts；The corresponding salt of other mineral acids, such as sulfate, Nitrate, phosphate etc.；And alkylsulfonate and single arylsulphonate, such as ethane sulfonate, toluene fulfonate and benzene sulphur Hydrochlorate；And the corresponding salt of other organic acid, such as acetate, tartrate, maleate, citrate lactate, winestone Hydrochlorate, tannate, citrate, trifluoroacetate, malate, succinate, salicylate, fumarate, glucose Hydrochlorate, saccharate, benzoate, phenylacetate, ferulate etc..

Term " pharmaceutically acceptable solvate " refers to water (i.e. hydrate) or pharmaceutically acceptable solvent is molten Agent compound, such as with the solvate of ethanol etc..

Term " prodrug " refers to that in vivo (generally promptly) conversion obtains the compound of the parent compound of above formula.Example Such as, hydrolyzed in blood by compound.General example including but not limited to has the activity form with carboxylic moiety The active ester of compound and the form of amide.For example, the front medicinal ester of compound of the present invention includes but is not limited to Arrcostab (such as with the Arrcostab of 1 to 6 carbon atoms), wherein alkyl include straight or branched.Acceptable ester also includes cycloalkyl Ester and alkyl aryl.

Term " pharmaceutical acceptable carrier " includes any and all of solvent, disperse medium, coatingss, surfactant, antioxygen Agent, preservative (such as antibacterial agent, antifungal), isotonic agent, absorption delaying agent, salt, preservative, medicine, drug substance stable The materials such as agent, binding agent, excipient, disintegrating agent, lubricant, sweeting agent, correctivess, dyestuff and its reasonable combination.

Term is " pharmaceutically acceptable " to be represented by administrative organization's approval of federal government or state government or according to U.S.'s medicine Allusion quotation or other generally acknowledged ancient books and records records can be used for animal especially people.

The present invention is provided has resisting pathogenic microbes, the thiazole especially with parasiticide (such as toxoplasma) and antibacterial activity Analog derivative, is proved to be respectively provided with good activity in antibacterial of the present invention and the test of resisting toxoplasmosis activity experiment.This Compound, its pharmaceutically acceptable salt, solvate or prodrug described in text, or pharmaceutical composition, can pass through Orally, local, rectum, intranasal or parental routes give animal for therapeutic purposes.Drug regimen disclosed herein Specifically described herein compound of the thing comprising pharmaceutical effective amount and one or more pharmaceutically acceptable carrier, excipient or dilute Release agent.

Medicament forms miscellaneous can be used when giving the compounds of this invention.For the solid preparation bag of oral administration Include：Capsule, tablet, pill, powder, granule.For solid preparation, reactive compound can be mixed with following adjuvant：One Kind or various inert pharmaceutically acceptable excipient or carrier (such as sodium citrate, calcium hydrogen phosphate) and/or filler or Extender (such as starch based, Lactose, sucrose, glucose, Mannitol, silicic acid or their mixture)；Binding agent, for example Shuttle methylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, arabic gum or their mixture；Disintegrate Agent, such as agar, Calcium Carbonate, potato starch, alginic acid, some silicate, sodium carbonate or their mixture；Absorb Accelerator, such as quaternary ammonium compound；Wetting agent, such as single hard acid acid glyceride or their mixture；Adsorbent, for example Kaolin；Lubricant, such as Talcum, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulphate or they Mixture.Buffer agent can be also included in capsule, tablet or pill.Can be by using one or more layers coating or shell (example Such as enteric-coating material or other coating materials well known by persons skilled in the art) preparing tablet, capsule, pill or granule Agent, to the release for adjusting active component.Liquid form preparation for oral administration includes：Pharmaceutically acceptable Emulsion, Solution, suspending agent, syrup.In this liquid form preparation, can be by reactive compound and water or one or more Nontoxic solvent, solubilizing agent or emulsifying agent (such as water, ethanol, isopropanol, ethylene are cruel, ethyl acetate, Propylene Glycol), oils (fatty acid that for example Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, Semen Maydis oil, germ oil, olive oil, Oleum Ricini and Oleum sesami, glycerol, Sorbitol are matched somebody with somebody, Or their mixture) mixing.Orally administered composition can also comprising one or more adjuvant (for example wetting agent, emulsifying agent, Suspending agent, sweeting agent, correctivess, aromatic or their mixture).

Can according to method known to those skilled in the art especially with one or more suitable dispersant or Wetting agent and suspending agent are allocating injection (such as sterile injectable preparation) and aqueous suspension agent.Adoptable acceptable excipient and Solvent includes one or more or their mixture in water, isotonic sodium chloride.For preparing the straight of the compounds of this invention Enteral administration suppository.The dosage form of local administration or percutaneous dosing for the compounds of this invention includes：Ointment, paste, emulsifiable paste, wash Agent, gel, powder, solution, spray, inhalant or patch.Can aseptically by reactive compound and one Plant or various pharmaceutically acceptable carriers, and mix with various preservative or buffer agent to washability as needed.Eye drop, Ear drop, eye ointment, powder and solution are also contained in the scope of the present invention.Pharmaceutical preparation can be in the form of unit dosage forms. In unit dosage forms, pharmaceutical preparation can be subdivided into the unit dose of the active component containing appropriate amount.Unit dosage forms can be with It is packaged preparation, ointment, capsule, pouch, tablet, gel containing detached capsule or powder in vial or ampulla bottle This packaging agent of agent, emulsifiable paste or combination in any and quantity.

Compounds as disclosed herein, its pharmaceutically acceptable salt, solvate or prodrug, or drug regimen Thing, can by organic synthesiss know and technology familiar to one skilled in the art of the present invention be prepared.Following reality Example is intended to illustrate the present invention, but is not to limit the present invention.In addition, methods described herein are not synthesis of the present inventionization The unique method of compound.Additionally, multiple synthesis steps described herein can be carried out so as to provide required compound with alternating sequence.

The preparation method of thiazole derivative of the present invention, specifically：

The preparation method of compound has following two lines shown in formula (I)：

When Y is the N atomic time, using the method shown in synthetic route 1；

Specifically, the thiazolamine (1eq) with 5 replacements is as initiation material, and chloro alkyl chloride compounds (1.2eq) it is condensed (such as triethylamine, 1.2eq) in the basic conditions, synthetic intermediate 1-1, intermediate 1-1 (1eq) and 4- The piperazine (1.2eq) that Boc replaces generates intermediate 1-2 under the catalysis of mineral acid (potassium carbonate), and intermediate 1-2 is in trifluoroacetic acid Boc protection groups are sloughed in solution, intermediate 1-3 (1eq) is generated, then 1- is generated with phenyl isocyanate (1eq) reaction for replacing 4, finally generate target compound with the saturation ethyl acetate solution of various organic or inorganic acids；

The chemical equation of synthetic route 1 is as follows：

Reagent used and reaction condition in said synthesis route 1：(a) triethylamine, anhydrous methylene chloride, 0 DEG C to room temperature； (b) potassium carbonate, anhydrous acetonitrile, 60 DEG C；(c) trifluoroacetic acid, 0 DEG C to room temperature, 3-4h；(d) triethylamine, anhydrous tetrahydro furan, 0 DEG C To room temperature；The ethyl acetate saturated solution of (e) mineral acid or organic acid, room temperature；Used various solvents are according to conventional mark Quasi- drying meanss are dried；

When Y is CH, using the method shown in synthetic route 2；

Specifically, with 5 thiazolamines (1eq) for replacing as initiation material, in HOBt (1.2eq) and EDCI condensing agents (1.2eq) and under the conditions of triethylamine (1.2eq), and 1-Boc-4- piperidine carboxylic acids (1eq) carry out condensation reaction, generate intermediate 2- 1, intermediate 2-1 slough Boc protection groups in trifluoroacetic acid solution, generate intermediate 2-2, and intermediate 2-2 (1eq) again and takes Phenyl isocyanate 2-3 (1eq) reaction in generation, generates 2-4, finally with the saturation ethyl acetate solution of various organic or inorganic acids Generate target compound；

The chemical equation of synthetic route 2 is as follows：

Reagent used and reaction condition in said synthesis route 2：(a) HOBT, EDCI, triethylamine, 0 DEG C to room temperature, 4h； (b) trifluoroacetic acid, 0 DEG C to room temperature, 3h；(c) triethylamine, anhydrous tetrahydro furan, 0 DEG C to room temperature；(d) mineral acid or organic acid Ethyl acetate saturated solution, room temperature.Used various solvents are dried according to conventional standard drying method；

The preparation of compound shown in formula (II) is using the method shown in synthetic route 3；

Specifically, the thiazolamine (1eq) with 5 replacements is as initiation material, and chloro alkyl chloride compounds (1.2eq) it is condensed under the conditions of alkalescence condition (triethylamine, 1.2eq), is generated intermediate 3-1；Intermediate 3-1 (1eq) Intermediate 3-2 is generated under the catalysis of mineral acid potassium carbonate (1eq) with 4-Boc- amino piperidines (1eq)；Intermediate 3-2 is in trifluoro Slough Boc protection groups in acetic acid, generate intermediate 3-3, then with phenyl isocyanate (1eq) reaction for replacing, finally with it is various The saturation ethyl acetate solution of organic or inorganic acid generates target compound (II)；

The chemical equation of synthetic route 3 is as follows：

Reagent and reaction condition in said synthesis route 3：(a) triethylamine, anhydrous methylene chloride, 0 DEG C to room temperature；(b) Potassium carbonate, anhydrous acetonitrile, 60 DEG C；(c) trifluoroacetic acid, 0 DEG C to room temperature, 3-5h；(d) triethylamine, anhydrous tetrahydro furan, 0 DEG C is extremely Room temperature；The ethyl acetate saturated solution of (e) mineral acid or organic acid, room temperature；Used various solvents are according to conventional standard Drying meanss are dried.

The thiazole derivative containing urea groups or ghiourea group that the present invention is provided has resisting pathogenic microbes, especially with anti- Parasite (such as toxoplasma) and antibacterial activity, experimental result shows that the part of compounds of the series compound is to toxoplasma The even more highs of CC50/IC50 ＞ 1, present preferable inhibitory activity.In addition, numbering be XQH-2-97, XQH-3-13 and Three compounds of XQH-3-14 are notable to the inhibition of Streptococcus mutans, and compared with the nitazoxanide of positive controls The sterilizing ability of above three compound is obviously improved, and is expected to develop into new antimicrobial compound.The present invention for therapeutic index compared with The high antibacterial and anti-parasite medicine that can be used for clinic, the research and development for follow-up clinical medicine provide foundation and reference.Using front Scape is wide.

Specific embodiment

With reference to following instance, the invention will be further described, but the scope of the present invention is by no means limited to these realities Example, the content is explanation of the invention rather than restriction.

The synthesis of formula I preferred compound：

Embodiment 1：4- (2- ((5- nitrothiazole -2- bases) amino) -2- oxoethyls)-N- phenylpiperazine -1- Methanamides The preparation method of (compound I-1, code name XQH-3-13)

The chloro- N- of the ＞ intermediate 2- of ＜ 1 (5- nitrothiazole -2- bases) preparations (1-1)

During 5- nitro thiazolamines (1eq) and triethylamine (1.2eq) are dissolved in into dichloromethane, dropwise drip at 0 DEG C Plus chloracetyl chloride (1.2eq), certainly intensification continues to react 5h completion of dropping, and with TLC detection reactions, raw material is without residue, stopped reaction. The distilled water of 100ml, water is added to extract three times (3 × 100ml), the organic layer saturation of merging with dichloromethane in reactant liquor Sodium chloride solution is washed twice (2 × 100ml), and anhydrous magnesium sulfate is dried, and then evaporation and concentration obtains crude product.Crude product Jing silicagel columns are pure Change and separate (dichloromethane:Methanol=150:1) yellow solid target compound, yield 72% are obtained.

The ＞ intermediate 4- tert-butyl groups of ＜ 2-(2- ((5- nitrothiazole-2- bases) amino)-2- oxoethyls) piperazine-1- carboxylic acids (1-2) preparation

By previous step intermediate 1-1 (1eq), 4-Boc- piperazines (1.2eq) and K₂CO₃(1.2eq) it is dissolved in anhydrous CH₃CN In, 8h is reacted at 60 DEG C, reacted with TLC detections, raw material is without residue, stopped reaction.Steam CH₃CN, adds in reactant liquor The distilled water of 100ml, water is mutually extracted with ethyl acetate three times (3 × 100ml), merges organic faciess, and with saturation NaCl twice (2 are washed × 100ml), anhydrous magnesium sulfate is dried, and then vacuum evaporation obtains crude product.Crude product Jing silica gel chromatographic columns column purification separates (two Chloromethanes:Methanol=100:1) yellow solid, yield 78% are obtained.

The preparation of the ＞ intermediate Ns of ＜ 3 (5- nitrothiazole -2- bases) -2- (piperazine -1- bases) acetamide (1-3)

Method 1：Under ice bath, the intermediate 1-2 of previous step is dissolved in minimal amount of anhydrous methylene chloride solution, once Property add trifluoroacetic acid solution (2eq), temperature is warmed to room temperature reaction, to TLC monitorings reaction completely.Reactant liquor concentrated in vacuo, uses Dichloromethane takes away unnecessary trifluoroacetic acid, and the product 1-3 for being generated can be directly used in the reaction of next step without process.

Method 2：Chloroacetic chloride is slowly instilled (V in dehydrated alcohol:V=4:5), the HCl of generation is passed directly into ethyl acetate In make saturated solution, then previous step intermediate 3 is dissolved in wherein, stir 15 minutes at normal temperatures, reacted with TLC detections Entirely, solvent evaporated, obtains yellow solid, and crude product yield 100% is unprocessed directly to carry out next step.

The ＞ 4- of ＜ 4 (2- ((5- nitrothiazole -2- bases) amino) -2- oxoethyls)-N- phenylpiperazine -1- Methanamides (I-1, Code name is XQH-3-13) preparation

During intermediate 1-3 (1eq) and triethylamine (1.2eq) are dissolved in into anhydrous tetrahydro furan at 0 DEG C, benzene is added dropwise Based isocyanate (1.2eq), stirs 3h, reacted completely to raw material with TLC monitorings reaction.Tetrahydrofuran is steamed, to reaction Add the distilled water of 50ml, water to be mutually extracted with ethyl acetate three times (3 × 50ml) in liquid, merge organic faciess, it is molten with saturated sodium-chloride Liquid is washed (2 × 50ml) twice, anhydrous magnesium sulfate drying 30 minutes, and then Jing vacuum evaporations obtain crude product.Crude product Jing silica gel colors Spectrum post (200-300 mesh) purifies and separates, dichloromethane:Methanol=60:1 used as eluant, obtains off-white powder, yield 73%.¹H NMR(400MHz,DMSO-d₆)：δ 8.63 (s, 1H), 8.54 (s, 1H), 7.47-7.42 (m, 2H), 7.23 (t, J= 7.9Hz, 2H), 6.93 (t, J=7.3Hz, 1H), 3.54 (s, 2H), 3.53-3.50 (m, 4H), 2.64-2.61 (m, 4H) ppm； ESI-MS:388.9[M-H]^-。

Embodiment 2：N- (4- fluorophenyls) -4- (2- ((5- nitrothiazole -2- bases) amino) -2- oxoethyls) piperazine -1- The preparation method of Methanamide (I-2, code name is XQH-2-78)

The same I-1 of preparation method, yield 72%.¹H NMR(400MHz,DMSO-d₆)：δ8.63(s,1H),8.57(s,1H), 7.48-.42 (m, 2H), 7.07 (t, J=8.9Hz, 2H), 3.53 (s, 2H), 3.52-3.48 (m, 5H), 2.67-2.62 (m, 4H) ppm；ESI-MS:408.1[M-H]^-.

Embodiment 3：N- (4- chlorphenyls) -4- (2- ((5- nitrothiazole -2- bases) amino) -2- oxoethyls) piperazine -1- The preparation method of Methanamide (I-3, code name is XQH-2-80)

The same I-1 of preparation method, yield 70%,¹H NMR(400MHz,DMSO-d₆)：δ8.67(s,1H),8.63(s,1H), (s, the 4H) .ESI-MS of 7.49 (d, J=8.6Hz, 2H), 7.28 (d, J=8.6Hz, 2H), 3.52 (m, 6H), 2.64:423.0[M- H]^-.

Embodiment 4：N- (4- bromophenyls) -4- (2- ((5- nitrothiazole -2- bases) amino) -2- oxoethyls) piperazine -1- The preparation method of Methanamide (I-4, code name is XQH-2-85)

The same I-1 of preparation method, yield 78%.¹H NMR(400MHz,DMSO-d₆)：δ8.68(s,1H),8.64(s,1H), (s, the 4H) .ppm of 7.49 (d, J=8.6Hz, 2H), 7.30 (d, J=8.6Hz, 2H), 3.53 (m, 6H), 2.65；ESI-MS: 469.1[M+H]⁺.

Embodiment 5：N- (5- nitrothiazole -2- bases) amino) -2- (4- benzene first sulfonyls) piperazine -1- bases) acetamide (I- 5, code name is XQH-2-73) preparation method

The same I-1 of preparation method, yield 69%.¹H NMR(400MHz,DMSO-d₆)：δ8.62(s,1H),8.54(s,1H,), 7.47-7.44 (m, 2H), 7.23 (t, J=7.9Hz, 2H), 6.94 (t, J=7.3Hz, 1H), 3.54 (s, 2H), 3.53-3.50 (m,4H),2.64-2.62(m,4H)ppm；ESI-MS:405.4[M-H]-.

Embodiment 6：N- (3,4 Dimethoxyphenyl) -4- (2- ((5- nitrothiazole -2- bases) amino) -2- oxoethyls) The preparation method of piperazine -1- Methanamides (I-6, code name is XQH-2-88)

The same I-1 of preparation method, yield 74%.¹H NMR(400MHz,DMSO-d₆)：δ8.62(s,1H),8.37(s,1H), 7.14 (s, 1H), 6.96 (d, J=7.8Hz, 1H), 6.82 (d, J=8.7Hz, 1H), 3.70 (s, 3H, OCH3), 3.69 (s, 3H, ), OCH3 3.53 (s, 2H), 3.50 (d, J=3.9Hz, 4H), 2.68-2.61 (m, 4H) .ppm；ESI-MS:449.6[M-H]^-.

Embodiment 7：N- (4- bromophenyls) -4- (2- ((5- nitrothiazole -2- bases) amino) -2- oxoethyls) piperazine -1- The preparation method of Methanamide (I-7, code name is XQH-2-94)

The same I-1 of preparation method, yield 75%.¹H NMR(400MHz,DMSO-d₆)：8.63(s,1H),8.37(s,1H), 7.33 (d, J=8.7Hz, 2H), 6.82 (d, J=8.7Hz, 2H), 3.70 (s, 3H), 3.53 (s, 2H), 3.49 (s, 4H), 2.65 (s,4H)ppm；ESI-MS:408.1[M-H]^-.

Embodiment 8：N- (4- methoxyphenyls) -4- (2- ((5- nitrothiazole -2- bases) amino) -2- oxygen propyl group) piperazine - The preparation method of 1- Methanamides (I-8, XQH-2-100)

The same I-1 of preparation method, yield 74%.¹H NMR(400MHz,DMSO-d₆)：δ8.62(s,1H),8.34(s,1H), 7.32 (d, J=9.0Hz, 2H), 6.81 (d, J=9.1Hz, 2H), 3.70 (s, 3H), 3.41 (d, J=9.3Hz, 4H), 2.74 (s,4H),2.49-2.42(m,4H)ppm；ESI-MS:434.9[M+H]⁺.

Embodiment 9：N- (4- tolyls) -4- (2- ((5- nitrothiazole -2- bases) amino) -2- oxoethyls) piperazine -1- The preparation method of Methanamide (I-9, code name is XQH-2-83)

The same I-1 of preparation method, yield 66%.¹H NMR(400MHz,DMSO-d₆)：δ8.63(s,1H),8.43(s,1H), 7.32 (d, J=8.4Hz, 2H), 7.03 (d, J=8.3Hz, 2H), 3.53 (s, 2H), 3.52-3.47 (m, 4H), 2.66-2.63 (m,4H),2.22(s,3H,CH₃)ppm；ESI-MS:403.1[M-H]^-.

Embodiment 10：N- (2- methoxyphenyls) -4- (2- ((5- nitrothiazole -2- bases) amino) -2- oxoethyls) piperazine The preparation method of piperazine -1- Methanamides (I-10, code name is XQH-2-96)

The same I-1 of preparation method, yield 67%.¹H NMR(400MHz,DMSO-d₆)：δ 8.63 (s, 1H), 7.67 (d, J= 8.4Hz, 1H), 7.63 (d, J=7.6Hz, 1H), 7.01-6.98 (m, 2H), 6.89-6.84 (m, 1H), 3.85 (d, J= 9.5Hz,1H),3.80(s,3H),3.53(s,2H),3.5-3.47(m,4H),2.67-2.63(m,4H).ppm；ESI-MS: 419.6[M-H]^-.

Embodiment 11：N- (2- methoxyphenyls) -4- (3- ((5- nitrothiazole -2- bases) amino) -2- oxopropyls) piperazine The preparation method of piperazine -1- formyls (I-11, code name is XQH-2-98)

The same I-1 of preparation method, yield 62%.¹H NMR(400MHz,DMSO-d₆)：δ 8.62 (s, 1H), 7.63 (d, J= 8.8Hz, 2H), 7.00 (d, J=6.0Hz, 2H), 6.86 (t, J=8.3Hz, 1H), 3.80 (s, 3H), 3.41 (s, 4H), 2.74 (s,4H),2.50(s,2H),2.46(s,4H)ppm；ESI-MS:434.0[M-H]^-.

Embodiment 12：N- (4- tolyls) -4- (2- ((5- nitrothiazole -2- bases) amino) -2- oxygen propyl group) piperazine -1- first The preparation method of amide (I-12, code name is XQH-3-2)

The same I-1 of preparation method, yield 71%.¹H NMR(400MHz,DMSO-d₆)：δ8.62(s,1H),8.41(s,1H), 7.32 (d, J=8.4Hz, 2H), 7.02 (d, J=8.3Hz, 2H), 3.41 (d, J=4.3Hz, 4H), 2.74 (s, 4H), 2.49- 2.40(m,4H),2.22(s,3H)ppm；ESI-MS:417.0[M-H]^-.

Embodiment 13：N¹- (3- chlorphenyl-N⁴- (5- nitrothiazole -2- bases) piperidines-Isosorbide-5-Nitrae-diformamide (I-13, code name For XQH-3-5) preparation method

The ＞ intermediate 4- tert-butyl groups of the ＜ 1-(preparation of (5- nitrothiazole-2- bases) carbamyl-1- carboxylic acids (2-1).

1-Boc-4- piperidine carboxylic acids (1eq) are dissolved in into DMF, then be separately added into HOBt (1.2eq) and EDCI (1.2eq), Deca triethylamine (1.2eq).Completion of dropping, adds 5- nitro thiazolamines (1.2eq), at normal temperatures Reaction overnight, adds the distilled water of 200ml, water to be mutually extracted with ethyl acetate three times (3 × 200ml) in reactant liquor, merges organic Washed (2 × 100ml) twice with saturation NaCl, anhydrous magnesium sulfate is dried, and then obtains crude product with Rotary Evaporators evaporation and concentration.Slightly Product Jing silica gel chromatographic columns column purification separates (dichloromethane:Methanol=200:1) yellow solid, yield 75% are obtained.

The preparation of the ＞ intermediate 2- of ＜ 2 (4- amino -1- bases)-N- (5- nitrothiazole -2- bases) piperidines -4- Methanamides (2-2)

Chloroacetic chloride is slowly instilled (V in dehydrated alcohol:V=4:5), the HCl of generation is passed through in ethyl acetate and makes HCl's Ethyl acetate saturated solution, then previous step intermediate is dissolved in wherein, stir 15 minutes at normal temperatures, reacted with TLC detections Entirely, solvent evaporated, obtains yellow solid, and crude product yield 100% is unprocessed directly to carry out next step.

〈3〉N¹- (4- chlorphenyl-N⁴- (5- nitrothiazole -2- bases) (I-13, code name is XQH- to piperidines-Isosorbide-5-Nitrae-diformamide Preparation 3-5)

During intermediate 3 (1eq) and triethylamine (1.2eq) are dissolved in into anhydrous tetrahydro furan at 0 DEG C, 4- chlorine is added dropwise Phenyl isocyanate (1.2eq), stirs 3h, is reacted with TLC detections, steams tetrahydrofuran, and the distillation of 50ml is added in reactant liquor Water, water is mutually extracted with ethyl acetate three times (3 × 50ml), merges organic faciess saturated nacl aqueous solution and washes (2 × 50ml) twice, Anhydrous magnesium sulfate be dried 30 minutes, then Jing vacuum evaporations obtain crude product.Crude product Jing silica gel chromatographic columns (200-300 mesh) purification Separate, dichloromethane:Methanol=50:1 used as eluant, obtains off-white powder, yield 55%.¹H NMR(400MHz, DMSO-d₆)：δ 9.41 (s, 1H), 8.55 (s, 1H), 7.82 (d, J=7.1Hz, 1H), 7.44 (d, J=7.7Hz, 2H), 7.31 (t, J=7.9Hz, 2H), 7.09 (t, J=7.4Hz, 1H), 4.25 (s, 1H), 3.75 (s, 2H), 2.81 (t, J=11.0Hz, 2H), 2.04 (d, J=11.0Hz, 2H), 1.72 (d, J=10.2Hz, 2H) ppm；ESI-MS:409.9[M+H]⁺.

Embodiment 14：N¹- (4- tolyls)-N⁴- (5- nitrothiazole -2- bases) piperidines -1,4- diformamides (compound I- 14, code name is XQH-3-1) preparation method

The same I-13 of preparation method, yield 64%.¹H NMR(400MHz,DMSO-d₆)：δ8.63(s,1H),8.44(s,1H), 7.33 (d, J=8.3Hz, 2H), 7.03 (d, J=8.2Hz, 2H), 4.15 (d, J=13.2Hz, 2H), 2.85 (t, J= 11.9Hz, 3H), 2.22 (s, 3H), 1.89 (d, J=12.0Hz, 2H), 1.57 (m, 2H) ppm；ESI-MS:388.1[M-H]^-.

Embodiment 15：N¹- (4- methoxyphenyls)-N⁴- (5- nitrothiazole -2- bases) piperidines -1,4- diformamide (chemical combination The preparation method of thing (I-15, code name is XQH-2-99)

The same I-13 of preparation method, yield 67%.¹H NMR(400MHz,DMSO-d₆)：δ9.41(s,1H),8.55(s,1H), 7.82 (d, J=7.1Hz, 1H), 7.44 (d, J=7.7Hz, 2H), 7.31 (t, J=7.9Hz, 2H), 7.09 (t, J=7.4Hz, 1H), 4.25 (s, 1H), 3.75 (s, 2H), 3.22 (d, J=12.1Hz, 3H), 2.81 (t, J=11.0Hz, 2H), 2.04 (d, J =11.0Hz, 2H), 1.72 (d, J=10.2Hz, 2H) ppm；ESI-MS:405.1[M-H]^-.

Embodiment 16：N¹- (3- methoxyphenyls)-N⁴- (5- nitrothiazole -2- bases) piperidines -1,4- diformamide (chemical combination Thing I-16, code name is XQH-2-97) preparation method

The same I-13 of preparation method, yield 62%.¹H NMR(400MHz,DMSO-d₆)：δ13.14(s,1H),8.64(s, 1H), 7.69 (s, 1H), 7.62 (d, J=7.3Hz, 1H), 7.01 (d, J=6.4Hz, 2H), 6.87 (dd, J=11.1,3.0Hz, 1H), 4.10 (d, J=13.4Hz, 2H), 3.81 (s, 3H), 2.89 (t, J=11.6Hz, 2H), 2.81 (d, J=7.3Hz, 1H), 1.90 (d, J=12.8Hz, 2H), 1.64-1.52 (m, 2H) ppm；ESI-MS:406.0[M+H]⁺.

Embodiment 17：N⁴- (5- nitrothiazole -2- bases)-N¹- Phenylpiperidine)-Isosorbide-5-Nitrae-diformamide (compound I-17, generation Number be XQH-3-14) preparation method

The same I-13 of preparation method, yield 57%.¹H NMR(400MHz,DMSO-d₆)：δ13.14(s,1H),8.63(s, 1H), 8.52 (s, 1H), 7.45 (d, J=7.8Hz, 2H), 7.23 (t, J=7.6Hz, 2H), 6.93 (t, J=7.1Hz, 1H), (m, the 2H) ppm of 4.17 (d, J=13.1Hz, 2H), 2.91-2.76 (m, 3H), 1.90 (d, J=11.5Hz, 2H), 1.58；ESI- MS:375.0[M-H]^-.

The synthesis of formula II preferred compound

Embodiment 18：N- (5- nitrothiazole -2- bases)-(4- (3- phenylthioureas) piperidin-1-yl) acetamide (compound II-1, code name is XQH-2-39) preparation method

The preparation of the chloro- N- of the ＞ intermediate 2- of ＜ 1 (5- nitrothiazole -2- bases) acetamide (3-1)

During 5- nitro thiazolamines (1eq) and triethylamine (1.2eq) are dissolved in into dichloromethane, dropwise drip at 0 DEG C Plus chloracetyl chloride (1.2eq), certainly intensification continues to react 5h completion of dropping, and with TLC detection reactions, raw material is without residue, stopped reaction. The distilled water of 100ml, water is added to extract three times (3 × 100ml), the organic layer saturation of merging with dichloromethane in reactant liquor Sodium chloride solution is washed twice (2 × 100ml), and anhydrous magnesium sulfate is dried, and then evaporation and concentration obtains crude product.Crude product Jing silicagel columns are pure Change and separate (dichloromethane:Methanol=150:1) yellow solid target compound, yield 72% are obtained.

The ＞ intermediate tert-butyl groups of ＜ 2-(1- (2- ((5- nitrothiazole-2- bases) the amino)-2- oxoethyls) base of piperidines-4)-ammonia The preparation of carbamate (3-2)

By previous step intermediate 1 (1eq), 4-Boc- amino-piperadines (1.2eq) and K₂CO₃(1.2eq) it is dissolved in CH₃CN In, 8h is reacted at 60 DEG C, reacted with TLC detections, raw material is without residue, stopped reaction.Steam CH₃CN, adds in reactant liquor The distilled water of 100ml, water is mutually extracted with ethyl acetate three times (3 × 100ml), merge organic faciess saturation NaCl wash twice (2 × 100ml), anhydrous magnesium sulfate is dried, and then vacuum evaporation obtains crude product.Crude product Jing silica gel chromatographic columns column purification separates (dichloro Methane:Methanol=80:1) yellow solid, yield 73% are obtained.

The preparation of the ＞ intermediate 2- of ＜ 3 (4- amino piperidine -1- bases)-N- (5- nitrothiazole -2- bases) acetamide (3-3)

Chloroacetic chloride is slowly instilled (V in dehydrated alcohol:V=4:5), the HCl of generation is passed through in ethyl acetate and makes HCl's Ethyl acetate saturated solution, then previous step intermediate 2 is dissolved in wherein, stir 15 minutes at normal temperatures, reacted with TLC detections Entirely, solvent evaporated, obtains yellow solid, and crude product yield 100% is unprocessed directly to carry out next step.

The ＞ N- of ＜ 4 (5- nitrothiazole -2- bases)-(4- (3- phenylthioureas) piperidin-1-yl) acetamide (compound II-1, generation Number be XQH-2-39) preparation method

At 0 DEG C, during intermediate 3 (1eq) and triethylamine (1.2eq) are dissolved in into anhydrous tetrahydro furan, add dropwise PITC (1.2eq), stirs 3h, is reacted with TLC detections, steams tetrahydrofuran, and the steaming of 50ml is added in reactant liquor Distilled water, water is mutually extracted with ethyl acetate three times (3 × 50ml), merge organic faciess saturated nacl aqueous solution wash twice (2 × 50ml), anhydrous magnesium sulfate be dried 30 minutes, then Jing vacuum evaporations obtain crude product.Crude product Jing silica gel chromatographic column (200-300 Mesh) purifies and separates, dichloromethane:Methanol=60:1(v:V) as eluant, off-white powder, yield 68% are obtained.¹H NMR (400MHz,DMSO-d₆)：δ 9.41 (s, 1H), 8.55 (s, 1H), 7.82 (d, J=7.1Hz, 1H), 7.44 (d, J=7.7Hz, 2H), 7.31 (t, J=7.9Hz, 2H), 7.09 (t, J=7.4Hz, 1H), 4.25 (s, 1H), 3.75 (s, 2H), 3.22 (d, J= 12.1Hz, 3H), 2.81 (t, J=11.0Hz, 2H), 2.04 (d, J=11.0Hz, 2H), 1.72 (d, J=10.2Hz, 2H) ppm； ESI-MS:419.2[M-H]^-.

Embodiment 19：2- (4- (3- (4- chlorphenyls) urea) piperidin-1-yl)-N- (5- nitrothiazole -2- bases)) acetamide The preparation method of (compound II-2, code name is XQH-2-76)

The same II-1 of preparation method, yield 66%.¹H NMR(400MHz,DMSO-d₆)：δ8.54(s,1H),8.46(s,1H), 7.40 (d, J=8.9Hz, 2H), 7.26 (d, J=8.9Hz, 2H), 6.30 (s, 1H), 3.75 (s, 2H), 3.65-3.58 (m, 1H), 3.19 (d, J=17.7Hz, 3H), 2.80 (d, J=9.9Hz, 2H), 1.94 (d, J=10.7Hz, 2H), 1.64 (d, J= 10.7Hz,2H)ppm；ESI-MS:439.3[M+H]⁺.

Embodiment 20：2- (4- (3- (4- fluorophenyls) urea) piperidin-1-yl)-N- (5- nitrothiazole -2- bases)) acetamide The preparation method of (compound II-3, code name is XQH-2-79)

The same II-1 of preparation method, yield 65%.¹H NMR(400MHz,DMSO-d₆)：δ8.55(s,1H),8.38(s,1H), 7.38(dd,J₁=10.5, J₂=3.5Hz, 2H), 7.06 (t, J=8.9Hz, 2H), 6.29 (d, J=6.7Hz, 1H), 3.80 (s, 2H), 3.64 (s, 2H), 3.24 (d, J=12.3Hz, 3H), 2.87 (t, J=10.8Hz, 2H), 1.95 (d, J=12.6Hz, 2H),1.65(m,2H)ppm；ESI-MS:421.0[M-H]^-.

Embodiment 21：2- (4- (3- (4- bromophenyls) urea groups) piperidin-1-yl)-N- (5- nitrothiazole -2- bases)) acetamide The preparation method of (compound II-4, XQH-2-86)

The same II-1 of preparation method, yield 76%.¹H NMR(400MHz,DMSO-d₆)：8.55(s,1H),8.38(s,1H), 7.38(dd,J₁=10.5, J₂=3.5Hz, 2H), 7.06 (t, J=8.9Hz, 2H), 6.29 (d, J=6.7Hz, 1H), 3.80 (s, 2H), 3.64 (s, 2H), 3.24 (d, J=12.3Hz, 3H), 2.87 (t, J=10.8Hz, 2H), 1.95 (d, J=12.6Hz, 2H),1.65(m,2H)ppm；ESI-MS:480.09[M-H]^-.

Embodiment 22：2- (4- (3- (3- bromophenyls) urea) piperidin-1-yl)-N- (5- nitrothiazole -2- bases)) acetamide The preparation method of (compound II-5, code name is XQH-2-91)

The same II-1 of preparation method, yield 61%.¹H NMR(400MHz,DMSO-d₆)：δ8.55(s,2H),7.81(s,1H), 7.19 (d, J=11.1Hz, 2H), 7.07 (d, J=7.2Hz, 1H), 6.39 (d, J=7.2Hz, 1H), 3.77 (s, 2H), 3.62 (s, 2H), 3.22 (d, J=11.2Hz, 2H), 2.84 (t, J=10.8Hz, 2H), 1.95 (d, J=11.5Hz, 2H), 1.65 (d, J=10.7Hz, 2H), 1.97-1.64 (m, 1H) ppm；ESI-MS:482.9[M-H]^-.

Embodiment 23：2- (4- (3- (4- methoxyphenyls) urea) piperidin-1-yl)-N- (5- nitrothiazole -2- bases)) acetyl The preparation method of amine (compound II-6, XQH-2-95)

The same II-1 of preparation method, yield 54%.¹H NMR(400MHz,DMSO-d₆)：δ8.54(s,1H),8.12(s,1H), 7.27 (d, J=8.6Hz, 2H), 6.81 (d, J=8.6Hz, 2H), 6.17 (d, J=6.9Hz, 1H), 3.78 (s, 2H), 3.69 (s, 3H), 3.23 (d, J=11.3Hz, 2H), 2.86 (t, J=11.0Hz, 2H), 1.95 (d, J=11.4Hz, 2H), 1.64 (d, J=10.9Hz, 2H), 1.18 (s, 2H) ppm；ESI-MS:435.8[M+H]⁺.

Embodiment 24：2- (4- (3- (4- tolyls) urea) piperidin-1-yl)-N- (5- nitrothiazole -2- bases)) acetamide The preparation method of (compound II-7, code name is XQH-2-84)

The same II-1 of preparation method, yield 62%.¹H NMR(400MHz,DMSO-d₆)：δ8.54(s,1H),8.20(s,1H), 7.25 (d, J=8.3Hz, 2H), 7.02 (d, J=8.3Hz, 2H), 6.22 (d, J=7.3Hz, 1H), 3.78 (s, 2H), 3.61 (s, 3H), 3.23 (d, J=10.7Hz, 2H), 2.86 (t, J=10.7Hz, 2H), 2.21 (s, 3H), 1.95 (m, 2H), 1.73- 1.52(m,2H)ppm；ESI-MS:419.9[M+H]⁺.

Embodiment 25：2- (4- (3- (3,4- Dimethoxyphenyls) urea) piperidin-1-yl)-N- (5- nitrothiazole -2- bases)) The preparation method of acetamide (compound II-8, code name is XQH-2-89)

The same II-1 of preparation method, yield 58%.¹H NMR(400MHz,DMSO-d₆)：δ9.41(s,1H),8.55(s,1H), 7.82 (d, J=7.1Hz, 1H), 7.44 (d, J=7.1Hz, 2H), 7.31 (t, J=7.9Hz, 2H), 7.09 (t, J=7.9Hz, 1H), 4.25 (s, 1H), 3.75 (s, 2H), 3.22 (d, J=12.1Hz, 3H), 2.81 (t, J=11.0Hz, 2H), 2.04 (d, J =11.0Hz, 2H), 1.72 (d, J=10.2Hz, 2H) ppm；ESI-MS:464.1[M-H]^-.

Antibacterial and parasiticide (the being primarily referred to as toxoplasma) activity of the compounds of this invention, but this are illustrated with reference to following instance The active range of application of invention compound is never limited to these examples.The present invention illustrates the present inventionization by taking Streptococcus mutans as an example Activity of the compound to all kinds of antibacterials.

Embodiment 26：The antibacterial activity test experiments of compound involved in the present invention and test result

1. the preparation of Streptococcus mutans UA159 bacterial strains and compound

Streptococcus mutans UA159 bacterial strains used in the present invention are type strain, in ncbi database (http:// Www.ncbi.nlm.nih.gov/ the reference gene group # in) is NC_004350.Streptococcus mutans used in the present invention UA246 bacterial strains are to be isolated from the clinical strains in the middle of the oral cavity with dental caries patient.Its preferred brain heart infusion of most suitable culture medium (Brain Heart Infusion) culture medium (Brain infusion solids 12.5g/L, Beef heart Infusion solids 5.0g/L, Proteose peptone 10.0g/L, Glucose 2.0g/L, Sodium Chloride 5.0g/L, Di-sodium phosphate 2.5g/L, pH 7.4 ± 0.2), at 37 DEG C, Anaerobic culturel it is most suitable Quiescent culture under the conditions of preferably.

(1) culture medium for cultivating Streptococcus mutans is brain heart infusion (Brain Heart Infusion) culture medium (brand OXOID, article No. CM1135), culture medium main component is Brain infusion solids 12.5g/L, Beef heart Infusion solids 5.0g/L, Proteose peptone 10.0g/L, Glucose 2.0g/L, Sodium Chloride 5.0g/L, Di-sodium phosphate 2.5g/L, pH 7.4 ± 0.2.Solid need to be such as configured to, needs to add Plus agar powder 15g/L.115 DEG C of sterilizing 30min, it is stand-by after cooling.

(2) Streptococcus mutans type strain UA159 is being contained into brain heart infusion agar solid medium with aseptic inoculation ring Flat board on rule, be inverted in 37 DEG C of anaerobic culture box culture until there is obvious single bacterium colony.

(3) with aseptic inoculation shovel scraping Streptococcus mutans UA159, it is transferred to respectively equipped with brain heart infusion fluid medium Test tube in, stand in 37 DEG C of anaerobic culture box, cultivate muddy to liquid.

(4) absorbance (OD of the Streptococcus mutans under 600nm is detected with ultraviolet-uisible spectrophotometer_600nm)。

(6) with analytical balance accurate weighing compound, add DMSO to be dissolved, be then 0.22 μm aseptic with aperture Filter filtration sterilization, is made into the stock solution of final concentration of 1024mg/L, deposit in -20 DEG C it is stand-by

2. experimental technique

(1) the Streptococcus mutans UA159 (OD of logarithmic (log) phase processed will be cultivated_600nm=0.8～1.0) dilute with brain-heart infusion medium Release to final concentration of 5 × 10⁵Cfu/ml is stand-by.

(2) minimal inhibitory concentration using micro broth dilution method detection compound to Streptococcus mutans UA159.Will be again It is added separately in 96 aseptic orifice plates than the compound solution of variable concentrations after dilution, the 1st to the 11st hole is the experiment for adding medicinal liquid Group, the 12nd hole is not dosing as growth control group, and in each hole Streptococcus mutans bacterium solution final concentration of 5 × 10⁵Cfu/ml, this When, the 1st hole to the 12nd hole drug level is respectively 256,128,64,32,16,8,4,2,1,0.5,0.25,0mg/L.With little Least concentration positioning minimal inhibitory concentration (MIC) of bacterial growth is completely inhibited in hole.

(3) by after on the bacterium solution even spread in aperture to brain heart infusion agar solid medium, in 37 DEG C of Anaerobic culturels Culture 24 hours is inverted in case, with least concentration positioning minimal bactericidal concentration (MBC) produced without antibacterial.

(4) absorbance in each aperture under 600nm is detected with microplate reader, calculates thin under the conditions of each drug level The suppression ratio of born of the same parents, computing formula is suppression ratio=(1- experimental grouies/growth control group) × 100%, and the data obtained is united using SPSS Meter computed in software half maximum suppression concentration (IC₅₀).Test result is shown in Table 1.

MIC value result (unit mg/L) of the compound of table 1. to selected antibacterial

As can be seen from the above results, the preferred compound is relatively preferable to the fungistatic effect of Streptococcus mutans.Especially These three compounds of XQH-2-97, XQH-3-13 and XQH-3-14 are notable to the fungistatic effect of Streptococcus mutans, and with the positive The nitazoxanide of matched group is compared its sterilizing ability and is obviously improved, and is expected to develop new antimicrobial compound.Experimental result is shown in Table 2.

Activity analysiss of the particularly preferred compound of table 2. to Streptococcus mutans UA159

Embodiment 27：The resisting toxoplasmosis active testing experiment of the compounds of this invention and test result

(1) preparation of toxoplasma

We carry out toxoplasma culturing in vivo model and in-vitro culture model are handed over from the strong poison RH strain polypides of Toxoplasma gondii Fork is used.

Culturing in vivo model：Certain worm strain is expelled to into mouse peritoneal, after culture certain hour worm strain is collected, carry out purification Process.The conservation process is simple and convenient, can meet great majority demands of the experiment to tachyzoite completely, but conservation in mice body Weak point be that cost is higher, need Long-term breeding mice and periodically (2-3 days) cutd open and kill mice, and may be because of mice Die unexpectedly and cause polypide sterilization；

In vitro culture pattern：Toxoplasma the specificity of host cell is required it is not high, can in various kinds of cell endoparasitism, We select RAW246.7 (mouse macrophage) cells as the host cell of toxoplasma tachyzoite In vitro culture, due to from place The polypide of separate out can be dead quickly under the conditions of 37 DEG C in chief cell, but can survive 1-2 days under the conditions of 25 DEG C, in order to Increase the yield of tachyzoite, first the cell after inoculation polypide is placed in into 37 DEG C, 5%CO₂Cultivate under conditions of incubator, treat polypide Continue to cultivate under the conditions of going to 25 DEG C again into after cell, now polypide can breed in a large number in the cell, without soon general Cytoclasises.Tachyzoite can be collected when polypide rises brokenly by most cells, purification process is carried out, it is stand-by.

(2) toxicity test of the compound to RAW246.7 cells

The toxicity test of RAW246.7 cells is carried out to the compound of the present invention, test method is using conventional mtt assay (such as Lv Qiujun chief editors《Developmental pharmacology research method》2007:242-243).With spiramycin and nitazoxanide as control, The external activity test for suppressing cell to breed is carried out, 3 are the results are shown in Table.

Material：RAW246.7 cell strains, Methyl thiazoly tetrazolium assay MTT (3- (4,5- dimethylthiazole -2- bases) -2,5- bis- Phenyltetrazole father-in-law's bromide), 10% hyclone, trypsin.

Using conventional culture methods.Exponential phase cell is used during experiment.Take the logarithm trophophase cell, be inoculated in 96 holes In culture plate, cell number is 5 × 10³/ hole, volume is 100 μ L/ holes, is placed in 37 DEG C, 5%CO₂12h is cultivated in incubator environment, Formed after cell monolayer for testing.The μ L of compound (200～6.25 μM) 100 of addition variable concentrations, final concentration (100～ 3.125 μM), while setting up DMSO (dimethyl sulfoxide) matched group (DMSO final concentration≤5%) and PBS zeroing groups.Each concentration If 5 multiple holes, put 37 DEG C, 5%CO₂48h is cultivated in incubator, 20 μM of MTT is added per hole, and (concentration is 5mg/mL, and PBS is prepared, and is needed 4 DEG C keep in dark place), continuation is incubated 4h in incubator.Careful suction abandons culture fluid in each hole at the end of experiment, and DMSO is added per hole, 150 μ l, low-speed oscillation 10min determine each hole OD values after microplate reader wavelength 490nm.Represent that cell breeds feelings with hole meansigma methodss Condition, calculates cell proliferation rate under each concentration, with each drug level of the rate of increase of cell more than 90% as safe concentration, for body Outer resisting toxoplasmosis tachyzoite proliferation experiment.

Cell proliferation rate computational methods:

According to formula:

Suppression ratio %=(OD_{Matched group}-OD_{Administration group}-OD_{Blank group})/(OD_{Matched group}-OD_{Blank group}) × l00%,

The data obtained calculates half maximum suppression concentration (IC using SPSS statistical softwares₅₀).It is shown in Table 3

(3) mtt assay determines Compound ira vitro suppression toxoplasma tachyzoite enrichment procedure

Digestion exponential phase RAW246.7 cells make individual cells suspension, and with 5000/hole density 96- holes are inoculated in In Tissue Culture Plate.5%CO₂, 8h is cultivated in 37 DEG C of environment, after forming cell monolayer, arch is inoculated with 50000/hole density Worm RH strains, inhale after 6h and abandon old culture fluid, to remove the tachyzoite being also introduced in cell, are washed 2 times with the μ L/ holes of PBS 100, then with 100 μ L/ holes add culture medium.The μ L of compound 100 of variable concentrations are added per hole, 37 DEG C is placed in, 5%CO₂Culture environment It is middle to continue to cultivate 48h.Set the matched group for being not added with polypide and the matched group for adding polypide, and blank group in experiment simultaneously, connect down The step come is the same.

RAW246.7 cell proliferation rate computational methods：

The rate of increase (%)=(OD_{Test group-}OD_{Plus worm matched group}-OD_{Blank group})/(OD_{Be not added with worm matched group-}OD_{Blank group}) × l00%, the data obtained is used SPSS statistical softwares calculate half maximum suppression concentration (IC₅₀)。

Work as CC₅₀/IC₅₀Show that the compound has resisting toxoplasmosis activity during ＞ 1.

As can be seen from the test results, the CC of part of compounds₅₀/IC₅₀The even more highs of ＞ 1, illustrate the compound to arch Worm has inhibitory action, and being expected to further research and development becomes the new compound with resisting toxoplasmosis activity.The results are shown in Table 3.

The compound of table 3. is to toxoplasma active testing result

Note：Numerical value is the meansigma methodss of three tests in table, and the numerical tabular after " ± " shows standard deviation.Nitazoxanide and spiral Mycin is positive controls.

Claims (10)

1. the thiazole derivative containing urea groups or ghiourea group, with the structure shown in logical formula (I) or (II)：

Wherein：

N is 0～8 positive integer；

X is O or S；

Y is CH or N；

R¹Selected from hydrogen, halogen (F, Cl, Br, I), hydroxyl, cyano group, nitro, amino, carboxyl, different hydroxyl valeric acid base, carbamoyl, sulphur Amide groups, C1-8 straight or branched alkanoyls, C1-8 straight or branched alkane sulfonyls, C1-8 straight or branched alkyls, C_2-8Straight chain Or branched-chain alkenyl, C_2-8Straight or branched alkynyl, miscellaneous alkyl, C3-12 cycloalkyl, halo C1-8 straight or branched alkyls, C_1-8Directly Chain or branched alkoxy, C1-8 straight or branched alkylthio groups, C1-8 acyl groups, R⁸-O、R⁹SC(O)-、R¹⁰SO₂-、(R¹¹)NH-C (O)-、(R¹²)(R¹³) amino that N- can be substituted, can be substituted C3-12 cycloalkyl, C1-8 aliphatic acyloxies, 4 to 7 yuan contain The heterocyclic radical of nitrogen-atoms, 5- or 6- units nitrogen atom aromatic heterocyclic radical.Optionally by one or more following substituent groups：Halogen, Nitro, aryl, heteroaryl, hydroxyl, aryloxy, heteroaryl epoxide, miscellaneous alkoxyl, amino, C1-8 straight or branched amino, two Alkyl amino, arylamino, heteroaryl amino, C1-8 alkyl aryl aminos, miscellaneous alkyl amino, sulfydryl, C1-8 alkyl thiols, virtue Base sulfydryl, heteroaryl sulfydryl, miscellaneous alkyl sulfydryl, C1-8 alkyl sulphonyls, aryl sulfonyl, heteroarylsulfonyl, C1-8 alkane are sub- Sulfuryl, aryl sulfoxid es base, heteroaryl sulfoxide group, cyano group, C1-8 alkyl-carbonyls, aryl carbonyl, Heteroarylcarbonyl, C1-8 alcoxyls Base, C1-8 haloalkyls；

R²For pharmaceutically acceptable mineral acid or organic acid；

R³、R⁴、R⁵、R⁶、R⁷For identical or different and independent substituent groups, be hydrogen, halogen (F, Cl, Br, I), hydroxyl, cyano group, Nitro, amino, carboxyl, hydrazide group, C_1～8Straight or branched alkyl, C_2-8Straight or branched thiazolinyl, C_2-8Straight or branched alkynyl, Miscellaneous alkyl, C_3-12Cycloalkyl, haloalkyl, alkoxyl, alkylthio group, alkanoyl, aroyl, 4-hetaroylpyrazol, aryl C_1-8Alkane acyl Base, heteroaryl C_1-8Straight or branched alkanoyl, arylsulfonyl, miscellaneous sulfonyl, aryl C_1-8Straight or branched alkane sulfonyl, heteroaryl Base C_1-8Straight or branched alkane sulfonyl, C_1-8Aliphatic acyloxy, aryl, heteroaryl, Heterocyclylalkyl, miscellaneous alkoxyl, 4 to 7 yuan contain The heterocyclic radical of nitrogen-atoms, 5- or 6- units nitrogen atom aromatic heterocyclic radical, are each optionally taken by one or more selected from following Replace for base：Hydroxyl, halogen, nitro, amino, carboxyl, alkyl, cycloalkyl, aryl, heteroaryl, Heterocyclylalkyl, alkoxyl, alkane Epoxide-alkyl-, alkoxy carbonyl, aryl, heteroaryl, aryloxy, heteroaryl epoxide, miscellaneous alkoxyl, C_1-8Straight or branched Amino, dialkyl amido, arylamino, heteroaryl amino, C_1-8Straight or branched alkyl arylamino, miscellaneous alkyl amino, mercapto Base, C_1-8Straight or branched alkyl sulfydryl, aryl thiol, heteroaryl sulfydryl, miscellaneous alkyl sulfydryl, C1-8 straight or branched alkyl sulphurs Acyl group, aryl sulfonyl, heteroarylsulfonyl, C1-8 straight or branched alkane sulfoxide groups, aryl sulfoxid es base, heteroaryl sulfoxide group, Cyano group, C1-8 straight or branched alkyl carbonyls, aryl carbonyl, Heteroarylcarbonyl, C1-8 straight or branched alkoxyls, C1-8 halos Alkyl, R⁸SC(O)-、R⁹SO₂-、(R¹⁰)NH-C(O)-、(R¹¹)(R¹²)N-、R¹³- O-, HC (O)-, aryloxy group.

2. according to the thiazole derivative containing urea groups or ghiourea group described in claim 1, it is characterised in that：The R¹、R³、 R⁴、R⁵、R⁶、R⁷It is independently C_1～8Straight or branched alkyl, aryl, Heterocyclylalkyl, halogen, C_1-8Straight or branched alkoxyl, hydroxyl Base, dialkyl amido, alkyl sulphonyl, aryloxy group, heteroaryl, it is each optionally taken by 1～5 selected from following substituent group Generation：C_1-8Straight or branched alkyl, halogen, hydroxyl, C_1-8Straight or branched alkoxyl, hydroxyl, nitro, amino, carboxyl, HC= O-, aryloxy group；R²It is hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, weight sulphuric acid, phosphoric acid, diphosphonic acid, acetic acid, propanoic acid, hydroxyacetic acid, 2- The acid of hydracrylic acid, Acetylformic acid, oxalic acid, malonic acid, fumaric acid, 2- hydroxyls -1,2,3- the third three, lactic acid, tartaric acid, tannic acid, Citric acid, trifluoroacetic acid, malic acid, succinic acid, salicylic acid, Fumaric acid, gluconic acid, saccharic acid, benzoic acid, phenylacetic acid, It is ferulic acid, 2 hydroxybenzoic acid, 4- amino-2-hydroxybenzoic acids, methanesulfonic acid, ethyl sulfonic acid, cyclohexyl sulfinic acid, benzenesulfonic acid, right Toluenesulfonic acid, citric acid, maleic acid, caffeic acid, gallic acid or bar be not sour.

3. compound pharmaceutically acceptable salt, solvate or prodrug described in claim 1 or 2, or drug regimen are contained Thing, it is characterised in that：Described solvate, the water of crystallization containing one or more molecules；Described prodrug includes C_1～8Directly Chain or branched alkyl ester, aryl ester, C_1～8Straight or branched alkyl amide, aryl amide；Described pharmaceutical composition is removed and contains one Outside kind or various pharmaceutically acceptable carriers or excipient, also at least containing described in a kind of claim 1 or 2 of therapeutic dose Thiazole analog, its pharmaceutically acceptable salt, solvate or prodrug.

4. according to the solvate or prodrug described in claim 3, it is characterised in that：Described solvate, containing 1～3 The water of crystallization of molecule；The ester that described prodrug contains also includes cycloalkyl ester and alkyl aryl.

5. a class has the thiazole derivative of compound described in the active claim 1 or 2 of antibacterial and resisting toxoplasmosis, its feature It is：Selected from one of following compounds：

4- (2- ((5- nitrothiazole -2- bases) amino) -2- oxoethyls)-N- phenylpiperazine -1- Methanamides；

N- (4- fluorophenyls) -4- (2- ((5- nitrothiazole -2- bases) amino) -2- oxoethyls) piperazine -1- Methanamides；

N- (4- chlorphenyls) -4- (2- ((5- nitrothiazole -2- bases) amino) -2- oxoethyls) piperazine -1- Methanamides；

N- (4- bromophenyls) -4- (2- ((5- nitrothiazole -2- bases) amino) -2- oxoethyls) piperazine -1- Methanamides；

N- (5- nitrothiazole -2- bases) amino) -2- (4- benzene first sulfonyls) piperazine -1- bases) acetamide；

N- (3,4 Dimethoxyphenyl) -4- (2- ((5- nitrothiazole -2- bases) amino) -2- oxoethyls) piperazine -1- formyls Amine；

N- (4- bromophenyls) -4- (2- ((5- nitrothiazole -2- bases) amino) -2- oxoethyls) piperazine -1- Methanamides；

N- (4- tolyls) -4- (2- ((5- nitrothiazole -2- bases) amino) -2- oxoethyls) piperazine -1- Methanamides；

N- (2- methoxyphenyls) -4- (2- ((5- nitrothiazole -2- bases) amino) -2- oxoethyls) piperazine -1- Methanamides；

N- (2- methoxyphenyls) -4- (3- ((5- nitrothiazole -2- bases) amino) -2- oxopropyls) piperazine -1- formyls；

N- (4- tolyls) -4- (2- ((5- nitrothiazole -2- bases) amino) ethyl of -2- oxygen third) piperazine -1- Methanamides；

N- (4- fluorophenyls) -4- (2- ((5- nitrothiazole -2- bases) amino) -2- oxoethyls) piperazine -1- Methanamides；

N¹- (3- chlorphenyl-N⁴- (5- nitrothiazole -2- bases) piperidines -1,4- diformamides；

N¹- (4- tolyls)-N⁴- (5- nitrothiazole -2- bases) piperidines -1,4- diformamides；

N¹- (4- methoxyphenyls)-N⁴- (5- nitrothiazole -2- bases) piperidines -1,4- diformamides；

N¹- (3- methoxyphenyls)-N⁴- (5- nitrothiazole -2- bases) piperidines -1,4- diformamides；

N⁴- (5- nitrothiazole -2- bases)-N¹- Phenylpiperidine) -1,4- diformamides；

N¹- (4- chlorphenyls)-N4- (5- nitrothiazole -2- bases) piperidines -1,4- diformamides；

N- (5- nitrothiazole -2- bases)-(4- (3- phenylthioureas) piperidin-1-yl) acetamide；

2- (4- (3- (4- chlorphenyls) urea) piperidin-1-yl)-N- (5- nitrothiazole -2- bases)) acetamide；

2- (4- (3- (4- fluorophenyls) urea) piperidin-1-yl)-N- (5- nitrothiazole -2- bases)) acetamide；

2- (4- (3- (4- bromophenyls) urea groups) piperidin-1-yl)-N- (5- nitrothiazole -2- bases)) acetamide；

2- (4- (3- (3- bromophenyls) urea) piperidin-1-yl)-N- (5- nitrothiazole -2- bases)) acetamide；

2- (4- (3- (4- methoxyphenyls) urea) piperidin-1-yl)-N- (5- nitrothiazole -2- bases)) acetamide；

2- (4- (3- (4- tolyls) urea) piperidin-1-yl)-N- (5- nitrothiazole -2- bases)) acetamide；

2- (4- (3- (3,4- xylyls) urea) piperidin-1-yl)-N- (5- nitrothiazole -2- bases)) acetamide.

6. the preparation method of thiazole derivative described in claim 1 or 2, it is characterised in that：

The preparation method of compound has following two lines shown in formula (I)：

When Y is the N atomic time, using the method shown in synthetic route 1；

Specifically, the thiazolamine (1eq) with 5 replacements is as initiation material, and chloro alkyl chloride compounds (1.2eq) exists It is condensed (such as triethylamine, 1.2eq) under alkalescence condition, synthetic intermediate 1-1, what intermediate 1-1 (1eq) and 4-Boc replaced Piperazine (1.2eq) generates intermediate 1-2 under the catalysis of mineral acid (potassium carbonate), and intermediate 1-2 takes off in trifluoroacetic acid solution Go Boc protection groups, generate intermediate 1-3 (1eq), then 1-4 is generated with phenyl isocyanate (1eq) reaction for replacing, finally with The saturation ethyl acetate solution of various organic or inorganic acids generates target compound；

The chemical equation of synthetic route 1 is as follows：

Reagent used and reaction condition in said synthesis route 1：(a) triethylamine, anhydrous methylene chloride, 0 DEG C to room temperature；(b) Potassium carbonate, anhydrous acetonitrile, 60 DEG C；(c) trifluoroacetic acid, 0 DEG C to room temperature, 3-4h；(d) triethylamine, anhydrous tetrahydro furan, 0 DEG C is extremely Room temperature；The ethyl acetate saturated solution of (e) mineral acid or organic acid, room temperature；Used various solvents are according to conventional standard Drying meanss are dried；

When Y is CH, using the method shown in synthetic route 2；

Specifically, with 5 thiazolamines (1eq) for replacing as initiation material, in HOBt (1.2eq) and EDCI condensing agents (1.2eq) and under the conditions of triethylamine (1.2eq), and 1-Boc-4- piperidine carboxylic acids (1eq) carry out condensation reaction, generate intermediate 2- 1, intermediate 2-1 slough Boc protection groups in trifluoroacetic acid solution, generate intermediate 2-2, and intermediate 2-2 (1eq) again and takes Phenyl isocyanate 2-3 (1eq) reaction in generation, generates 2-4, finally with the saturation ethyl acetate solution of various organic or inorganic acids Generate target compound；

The chemical equation of synthetic route 2 is as follows：

Reagent used and reaction condition in said synthesis route 2：(a) HOBT, EDCI, triethylamine, 0 DEG C to room temperature, 4h；(b) Trifluoroacetic acid, 0 DEG C to room temperature, 3h；(c) triethylamine, anhydrous tetrahydro furan, 0 DEG C to room temperature；The second of (d) mineral acid or organic acid Acetoacetic ester saturated solution, room temperature.Used various solvents are dried according to conventional standard drying method；

The preparation of compound shown in formula (II) is using the method shown in synthetic route 3；

Specifically, the thiazolamine (1eq) with 5 replacements is as initiation material, and chloro alkyl chloride compounds (1.2eq) exists It is condensed under the conditions of alkalescence condition (triethylamine, 1.2eq), is generated intermediate 3-1；Intermediate 3-1 (1eq) and 4-Boc- ammonia Phenylpiperidines (1eq) generate intermediate 3-2 under the catalysis of mineral acid potassium carbonate (1eq)；Intermediate 3-2 is sloughed in trifluoroacetic acid Boc protection groups, generate intermediate 3-3, then react with the phenyl isocyanate (1eq) for replacing, finally with various organic or inorganics The saturation ethyl acetate solution of acid generates target compound (II)；

The chemical equation of synthetic route 3 is as follows：

Reagent and reaction condition in said synthesis route 3：(a) triethylamine, anhydrous methylene chloride, 0 DEG C to room temperature；(b) carbonic acid Potassium, anhydrous acetonitrile, 60 DEG C；(c) trifluoroacetic acid, 0 DEG C to room temperature, 3-5h；(d) triethylamine, anhydrous tetrahydro furan, 0 DEG C to room temperature； The ethyl acetate saturated solution of (e) mineral acid or organic acid, room temperature；Used various solvents are according to conventional standard drying side Method is dried.

7. the thiazole derivative containing urea groups or ghiourea group described in claim 1 or 2 is preparing antibacterials, parasiticide disease Application in medicine, treatment type ii diabetes medicine or anti-AIDS drug.

8. according to the application described in claim 7, it is characterised in that：The thiazole derivative for preparing antibacterials is N¹- (3- first Phenyl)-N⁴- (5- nitrothiazole -2- bases) piperidines -1,4- diformamides, 4- (2- ((5- nitrothiazole -2- bases) amino) - 2- oxoethyls)-N- phenylpiperazine -1- Methanamides or N⁴- (5- nitrothiazole -2- bases)-N¹- Phenylpiperidine) formyls of -1,4- two Amine；The thiazole derivative for preparing parasiticide especially toxoplasmosiss medicine is 2- (4- (3- (4- chlorphenyls) urea) piperidines -1- Base)-N- (5- nitrothiazole -2- bases)) acetamide, N- (3,4 Dimethoxyphenyl) -4- (2- ((5- nitrothiazole -2- bases) ammonia Base) -2- oxoethyls) piperazine -1- Methanamides or 2- (4- (3- (3,4- Dimethoxyphenyls) urea) piperidin-1-yl)-N- (5- nitre Base thiazol-2-yl)) acetamide.

9. a kind of pharmaceutical composition for being suitable to orally give mammal, containing thiazole derivative described in claim 1 or 2, Its pharmaceutically acceptable salt, solvate or prodrug, and one or more pharmaceutically acceptable carrier or excipient.

10. it is a kind of to be suitable to the pharmaceutical composition that parenteral gives mammal, it is derivative containing thiazoless described in claim 1 or 2 Thing, its pharmaceutically acceptable salt, solvate or prodrug, and one or more pharmaceutically acceptable carrier or excipient.