CN102260252A - Novel oxazolidinone used for treating bacterial infection - Google Patents

Abstract

The invention provides novel substituted B ring oxazolidinone which can be taken as an antibacterial drug as shown in the following formula I, or a pharmaceutically acceptable salt thereof, a precursor, or an oxazolidinone-containing pharmaceutical composition, an application method and a preparation method.

Description

Can be used for treating infectation of bacteria De Xin oxazolidone

Technical field

The invention provides Xin De oxazolidone compound, these compounds have effective bacterial-infection resisting activity.The present invention also comprises its using method, and preparation technology.

Background technology

Because the increase of antibiotic resistant presses for the new antimicrobial compounds with new binding mode of exploitation, to be used for the treatment of infectation of bacteria.， oxazolidone Zhong the antiseptic-germicide of new research and development is because its unique binding mode, thus not can with other treatment agent generation crossed resistance.Up to the present, this class antiseptic-germicide has only linezolid (Zyvox ^R) be used for the treatment of the Gram-positive infection by the USFDA approval.But its anti-microbial activity is still not high enough, and its severe side effect has limited its application; Wherein, monoamine oxidase inhibition, bone marrow depression and bone marrow toxicity are the principal elements that the restriction Linezolid is used.Therefore, need to study and produce to have better curative effect and safer novel oxazolidinone antibiotics medicine urgently.

Summary of the invention

The invention provides new substituted B Huan oxazolidone compounds.This compounds has the how stronger bacterial-infection resisting activity of oxazolone of Billy, can be applied to treatment of infection, includes, but are not limited to skin infections, soft tissue infection, microbemia, respiratory tract infection, urinary tract infections, infection of bone and eye infections.

The invention provides formula I compound or its various crystalline forms, its pharmacy acceptable salt, prodrug, hydrate or solvate and synthetic method thereof and its treatment application:

R wherein ₁Be CH ₂OH, CH ₂NHC (=O) C _1-5Alkyl, CH ₂NHC (=O) OC _1-5Alkyl, CH ₂NH-Het ¹, CH ₂O-Het ¹, CH ₂Het ¹, CH ₂Het ², CH ₂OPO ₃H ₂, CH ₂OC (=O) CH ₂(CH ₂) _mOPO ₃H ₂Or CH ₂OC (=O) CH (NH ₂) C _1-4Alkyl, m are 1,2, or 3;

R ₂, R ₃, R ₄Be H, OH, CH independently of one another ₃, CN, Cl or F;

R ₅Be CH ₃, CF ₃Or Cl;

X and Y are CH, CF, N or N independently of one another ⁺-O ^-

Z is H, NH ₂, OH, CN, halogen, Het ¹, Het ²Or 4 to 7 element heterocycle;

Each Het ¹Be the tetrazolium that C-connects independently of one another, 1,2,3-triazoles, 1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazoles, 1,2,4-oxadiazole, 1,2,4-thiadiazoles, 1,2,5-oxadiazole ， oxazole, thiazole ， isoxazole, isothiazole ， isoxazoline, or pyrazoles;

Each Het ²Be the tetrazolium that C-connects independently of one another, 1,2,3-triazoles, 1,2,4-triazole ， oxazolidone, 2-Pyrrolidone, 2-imidazolidone, pyrazoles or imidazoles.

In some respects, R ₁Be CH ₂OH.

Aspect other, R ₁Be (5-R ₆-isoxazole-3-bases) amino methyl or (4-R ₆-1,2,3-triazoles-1-yl) methyl, wherein R ₆Be H, Me, F or CN.

Aspect other, R ₅Be Me.

Aspect other, Z is CN, Het ¹Or Het ²

Aspect other, R ₂Be H, and R _{3 Hes}R ₄Be selected from H and F independently of one another.

Aspect other, formula I compound is selected from the compound of formula II:

In above various situations, each alkyl, thiazolinyl or cycloalkyl can be randomly by one, two or three substituting groups replacements, and described substituting group is selected from halogen atom, aryl, Het ¹Or Het ²In various situations, Het ¹The tetrazolium that connects for C-independently, 1,2,3-triazoles, 1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazoles, 1,2,4-oxadiazole, oxazole, thiazole, isoxazole, isothiazole, isoxazoline, or pyrazoles. in various situations, Het ²The tetrazolium that connects for C-independently, 1,2,3-triazoles, 1,2,4-triazole ， oxazolidone, 2-Pyrrolidone, 2-imidazolidone, pyrazoles or imidazoles.

In another preference, described compound is a synthetic compound among the embodiment 1-8.

On the other hand, the invention provides a kind of pharmaceutical composition, described composition comprises any compound in formula I-II, or its pharmacy acceptable salt, and pharmaceutically acceptable carrier.

On the other hand, the invention provides a kind of any compound or its pharmacy acceptable salt in the formula I-II for the treatment of significant quantity of taking by the Mammals of giving needs, the treatment Mammals is because of the method for bacterial infection.

In some respects, because of being meant Gram-positive, bacterial infection infects.

In some respects, formula I-II compound is to be used for Mammals with described compound or the form that contains the formula of medicine of described compound in the following manner: oral, parenterai administration, transdermal administration, topical, rectal administration or intranasal administration or pass through inhalation.

In some respects, formula I-II compound is the significant quantity that can award the Mammals treatment, is used for the treatment of because of bacterial infection.This infection includes, but are not limited to skin infections, soft tissue infection, microbemia, respiratory tract infection, urinary tract infections, infection of bone and eye infections.

In some respects, formula I-II compound is administered once every day, and dosage is about 1 to 75 milligram of per kilogram of body weight every day.

In some respects, the invention provides the formula I-II compound that is used for the treatment of.

In some respects, the invention provides formula I-II compound is treated infectation of bacteria in the Mammals of needs purposes.

In some respects, the invention provides the purposes of formula I-II compound in the preparation medicine.

In some respects, the invention provides the pharmaceutical composition that contains formula I-II compound, said composition comprises any formula I-II compound and pharmaceutically acceptable carrier, vehicle or the thinner for the treatment of significant quantity.

In some respects, the invention provides formula I-II compound is used for the Mammals of needs is treated the medicine of infectation of bacteria in preparation purposes.On the other hand, formula I-II compound can be used in combination with other biological promoting agent (for example: anti-infective or antiphlogiston).For example, in order to reach best result of treatment (as the wide spectrum effect), the Gram-positive pathogenic agent is had active formula I-II compound can be used with following combinations of substances: gram negative bacterium is had active antiseptic-germicide (quinolone for example, beta-lactam, aminoglycoside, colistin (colistin), macrolide medicine etc.), fungi or yeast had active medicament (allylamine for example, special pyrene naphthols, pyrroles etc.), perhaps antiviral agent (for example enters retarding agent (entry-blocker), virus protease (viralprotease) or DNA inhibitor, anti-reverse transcription enzymophathy toxic agent (antiretroviral agent) etc.).

On the other hand, the invention provides the purposes of above-claimed cpd of the present invention, it is characterized in that, be used for the medicine of the bacterial infection of (a) preparation, perhaps (b) will treat significant quantity described compound administration in Mammals, be used for the treatment of because of bacterial infection.

Preferably, this infection includes, but are not limited to skin infections, soft tissue infection, microbemia, respiratory tract infection, urinary tract infections, infection of bone and eye infections.

In another preference, when being used for bacterial infection, described compound is administered once every day, and dosage is about 1 to 75 milligram of per kilogram of body weight every day; And/or

Be used for Mammals with described compound or the form that contains the formula of medicine of described compound in the following manner: oral, parenterai administration, transdermal administration, topical, rectal administration or intranasal administration.

Detailed Description Of The Invention

Except as otherwise noted, the following term implication of using in this specification sheets and claims is as follows.

The carbonatoms of various hydrocarbonaceous parts is represented with the prefix that indicates minimum and maximum carbonatoms of this part, i.e. prefix C _I-jThe carbonatoms of representing this part be integer " i " to " j ", comprise i and j.For example, C _1-7Alkyl is meant the alkyl of (comprising 1 and the 7) carbon atom that has 1 to 7.

Radicals R ^#With R _#Or the implication of R# is identical: R ¹With R ₁Or the implication of R1 is identical, or the like.

T-Alk is identical with the implication of tert-Alk or tert-Alk: the implication of t-Bu and tert-Bu or tert-Bu is identical.

Term " alkyl ", " thiazolinyl " etc. are meant straight chain and branched group, but then only refer to straight chain group for single group (as " propyl group "), then particularly point out for branched chain isomer (as " sec.-propyl ").Group such as alkyl, thiazolinyl can be randomly replaced by one, two or three substituting groups, and described substituting group is selected from halogen atom, aryl, Het ¹Or Het ₂Representational example includes, but is not limited to: difluoromethyl, 2-fluoro ethyl, trifluoroethyl ,-the CH=CH-aryl ,-CH=CH-Het ¹,-CH ₂-phenyl, 1-phenyl-1,1-two (tertiary butyl) methyl or the like.

Term " cycloalkyl " is meant the three saturated univalence hydrocarbyls of ring-type to six carbon atom, for example cyclopropyl, cyclohexyl or the like.Described cycloalkyl can be randomly replaced by one, two or three substituting groups, and described substituting group is selected from halogen atom, aryl, Het ¹Or Het ²

Term " assorted alkyl " is meant to have to contain and is selected from N, O or S (O) _nHeteroatomic substituent alkyl or cycloalkyl as defined above, wherein n is 0 to 2 integer, comprises hydroxyl (OH), C _1-4Alkoxyl group, amino, sulfydryl (SH) or the like.Representational substituting group comprises-NR _aR _b,-OR _aOr-S (O) _nR _c, R wherein _aBe hydrogen, C _1-4Alkyl, C _3-6Cycloalkyl, the optional aryl that replaces, the optional heterocyclic radical that replaces or-(wherein R is C to COR _1-4Alkyl); R _bBe hydrogen, C _1-4Alkyl ,-SO ₂(wherein R is C to R _1-4Alkyl or C _1-4Hydroxyalkyl) ,-SO ₂(wherein R and R ' are hydrogen or C to NRR ' independently of one another _1-4Alkyl) ,-CONR ' R " (wherein R ' and R " be hydrogen or C independently of one another _1-4Alkyl); N is 0 to 2 integer; R _cBe hydrogen, C _1-4Alkyl, C _3-6Cycloalkyl, optional aryl or the NR that replaces _aR _b, R wherein _aAnd R _bDefinition as mentioned above.Representational example includes, but is not limited to: 2-methoxy ethyl (CH ₂CH ₂OCH ₃), 2-hydroxyethyl (CH ₂CH ₂OH), methylol (CH ₂OH), 2-amino-ethyl (CH ₂CH ₂NH ₂), 2-methylamino ethyl (CH ₂CH ₂NHCH ₃), benzyl oxo methyl, thiophene-2-base thiopurine methyltransferase or the like.

Term " halogen atom " is meant fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

Term " aryl " is meant aromatic base, comprises by N, O or S (O) _nDeng the aromatic base that heteroatoms replaces, wherein n is 0 to 2 integer, as pyridine, and piperidines, pyrimidine, triazine, Het ¹, Het ²Deng.Aryl " also comprise phenyl, xenyl or naphthyl.These aromatic bases can be randomly replaced by 1 to 3 substituting group, described substituting group be independently selected from halogen atom (as various fluorobenzenes) ,-C _1-4Alkyl ,-OH ,-OC _1-4Alkyl ,-S (O) _nC _1-4Alkyl (wherein n is 0,1 or 2) ,-C _1-4Alkyl NH ₂,-NHC _1-4Alkyl ,-C (=O) H or-C=N-OR _d(R wherein _dBe hydrogen or-C _1-4Alkyl).Equally, the term phenyl is meant the phenyl that can randomly be replaced by above-mentioned substituting group.

Term " heterocycle " is meant aromatic ring or saturated or undersaturatedly has 3 to 10 carbon atoms and 1 to 4 heteroatomic non-aromatic ring that described heteroatoms is selected from oxygen, nitrogen or S (O) _n, wherein the definition of n as mentioned above.Described heterocycle can randomly be replaced by following group: halogen atom ,-C _1-4Alkyl ,-OH ,-OC _1-4Alkyl ,-S (O) _nC _1-4Alkyl (wherein n is 0,1 or 2) ,-C _1-4Alkyl NH ₂,-NHC _1-4Alkyl ,-C (=O) H or-C=N-OR _d(R wherein _dBe hydrogen or C _1-4Alkyl).

The heterocyclic example includes, but is not limited to: azetidine, the pyrroles, imidazoles, pyrazoles, pyrimidine (pyridine), pyrazine, pyrimidine (pyrimidine), pyridazine, indolizine (indolizine), different benzazole (isoindole), indoles, dihydroindole, indazole, purine, quinolizine, isoquinoline 99.9, quinoline, phthalazines, naphthyl pyridine (naphthylpyridine), quinoxaline, quinazoline, cinnolines, pteridine, carbazole, carboline, phenanthridines, acridine, phenanthrolene, isothiazole, azophenlyene isoxazole isoxazolidinone phenoxazine, thiodiphenylamine, imidazoles alkene, tetrahydroglyoxaline, piperidines, piperazine, indoline, phthalic imidine, 1,2,3,4-tetrahydrochysene-isoquinoline 99.9,4,5,6,7-tetrahydro benzo [b] thiophene, thiazole, thiadiazole tetrazolium (thiadiazole tetrazole), thiazolidine, thiophene, benzo [b] thiophene, morpholinyl, thio-morpholinyl (thiomorpholinyl, also can be described as thiamorpholinyl), piperidines, tetramethyleneimine, tetrahydrofuran base (tetrahydrofuranyl), l, the 3-benzoxazine, 1,4-oxazine-3-ketone (1,4-oxazine-3-one), 1,3-benzoxazine-4-ketone (1,3-benzoxazine-4-one), tetramethyleneimine, pyrrolidin-2-one (pyrrolidine-2-one) oxazolidine-2-ketone (oxazolidine-2-one), azepines (azepine), perhydro-azepines (perhydroazepine), perhydro-azepines-2-ketone (perhydroazepine-2-one), perhydro--carotene 1,4-Evil azepines (perhydro-1,4-oxazepine), perhydro--carotene 1,4-Evil azepines-2-ketone (perhydro-1,4-oxazepine-2-one), perhydro--carotene 1,4-Evil azepines-3-ketone (perhydro-1,4-oxazepine-3-one), perhydro--carotene 1,3-Evil azepines-2-ketone (perhydro-1,3-oxazepine-2-one) or the like.Heterocycle comprises ring unsubstituted and that replace.

Specifically, Het ¹(define same het ¹, Het ₁Or het ₁) be meant five-(5) or six-(6) first heterocycles that C-connects, comprise dicyclo." Het ¹" representational example includes, but is not limited to: pyridine (pyridine); thiophene; furans; pyrazoles; pyrimidine (pyrimidine); 2-pyridyl, the 3-pyridyl, the 4-pyridyl, the 2-pyrimidyl, the 4-pyrimidyl, the 5-pyrimidyl, the 3-pyridazinyl, the 4-pyridazinyl, the 3-pyrazinyl, 4-oxo-2-imidazolyl, the 2-imidazolyl, the 4-imidazolyl, the 3-isoxazolyl, the 4-isoxazolyl, the 5-isoxazolyl, the 3-pyrazolyl, the 4-pyrazolyl, the 5-pyrazolyl, the 2-oxazolyl, the 4-oxazolyl, 4-oxo-2-oxazolyl, the 5-oxazolyl, 1,2,3-Evil thiazole (1,2,3-oxathiazole), 1,2, the 3-oxadiazole, 1,2, the 4-oxadiazole, 1,2, the 5-oxadiazole, 1,3, the 4-oxadiazole, the 2-thiazolyl, the 4-thiazolyl, the 5-thiazolyl, 3-isothiazole, 4-isothiazole, 5-isothiazole, 2-furyl (2-furanyl), 3-furyl (3-furanyl), the 2-thienyl, the 3-thienyl, the 2-pyrryl, the 3-pyrryl, the different pyrryl of 3-, the different pyrryl of 4-, the different pyrryl of 5-, 1,2,3-Evil thiazole-1-oxide compound (1,2,3-oxathiazole-1-oxide), 1,2,4-oxadiazole-3-base, 1,2,4-oxadiazole-5-base, 5-oxo-1,2,4-oxadiazole-3-base, 1,2,4-thiadiazoles-3-base, 1,2,5-thiadiazoles-3-base, 1,2,4-thiadiazoles-5-base, 3-oxo-1,2,4-thiadiazoles-5-base, 1,3,4-thiadiazoles-5-base, 2-oxo-1,3,4-thiadiazoles-5-base, 1,2,4-triazole-3-base, 1,2,4-triazole-5-base, 1,2,3,4-tetrazolium-5-base, the 5-oxazolyl, the 3-isothiazolyl, 4-isothiazolyl and 5-isothiazolyl, 1,3,4,-oxadiazoles, 4-oxo-2-thiazolinyl or 5-methyl isophthalic acid, 3,4-thiadiazoles-2-base, thiazole diketone (thiazoledione), 1,2,3, the 4-thiatriazole, 1,2,4-dithiazole ketone (1,2,4-dithiazolone) or 3-azabicyclic [3.1.0] hexane-6-base (3-azabicyclo[3.1.0] hexan-6-yl).

Het ²(define same het ², Het ₂Or het ₂) be meant five-(5) or six-(6) first heterocycles that N-connects, (comprising two rings), it has 1 to 4 nitrogen-atoms, and can randomly have a Sauerstoffatom or sulphur atom.Het ²Representational example include, but is not limited to: pyrryl, imidazolyl, pyrazolyl, 1,2,3-triazoles base, 1,2,4-triazolyl, 1,2,3,4-tetrazyl, isoxazole dinonyl (isoxazolidinonyl group), 3-azabicyclic [3.1.0] hexane-3-base, 1,3,9,9a-four hydrogen oxazoles [3,4-a] indoles-1-base, 2-alkyl pyrroles [3,4-c] pyrazoles-5 (2H, 4H, 6H)-Ji and 5H-pyrroles's [3,4-b] pyridines-6 (7H)-Ji.

" optional " or " randomly " be meant that described incident or situation can take place but be not to take place, and described term comprises and described incident or the example of situation and the example that described incident or situation do not occur occur.For example, " randomly being replaced or dibasic aryl by the alkyl list " be meant that alkyl can exist but be not to exist, and comprise that aryl is replaced by the alkyl list or situation that dibasic situation and aryl are not replaced by alkyl.

Have the same molecular formula but between its character or its atom the order of connection or the different compound of atom spatial disposition be called " isomer ".The isomer that the atom spatial disposition is different is called " steric isomer ".The steric isomer that is not enantiomorph each other is called " diastereomer ", and is called " enantiomer " for the steric isomer of the enantiomorph of non-overlapped (non-superimposable) each other.When compound has asymmetric center, for example be connected with four different groups, just may become a pair of enantiomer.Enantiomer can characterize with the absolute configuration of its asymmetric center, represents with R-and the S-ordering rule of Cann and Pu Lailuoge, perhaps represents with the plane of molecule rotatory polarization light, is called dextrorotation or left-handed (promptly being called (+) or (-) isomer).Chipal compounds can single enantiomer exist or exist with mixture of enantiomers.The mixture that contains the enantiomorph of same ratio is called " racemic mixture ".

Compound of the present invention can have one or more asymmetric centers, so this compound can be used as single (R)-or (S)-steric isomer or its mixture prepares.Except as otherwise noted, in the application's specification sheets and claims, describe and the particular compound of name had both comprised single enantiomorph, also comprise its racemic mixture or other mixture.The method that is used for measuring stereochemistry and separation of stereoisomers is that prior art is well-known (referring to J.March, " Advanced Organic Chemistry " chapter 4 (" Advanced Organic Chemistry " that John Wiley and Sons (New York) published in 1992,4th edition J.March, John Wiley and Sons, New York, 1992) ").

For the hydrogen (H) of formula I compound or (C) replace any isotopic replacement comprise with relevant atom.Therefore, hydrogen (H) replacement comprises ¹H, ²H (deuterium) or ³H (tritium) isotropic substance replaces, and if necessary, for example for special treatment or diagnoses and treatment, perhaps metabolism research is used.Randomly, compound of the present invention can be introduced known isotropic substance of prior art or radio isotope, for example ³H, ¹⁵O, ¹³C or ¹³The N isotropic substance is to provide the formula I compound of corresponding labelled with radioisotope.

Ⅰ

In some cases, the R in the formula I compound ₂Be H; X and Y are CF or N independently of one another.

In some cases, the R in the formula I compound ₅Be Me.

In some cases, the R in the formula I compound ₁Be CH ₂OH.

On the one hand, the invention provides synthetic compound among the embodiment 1-8, comprise the antimicrobial compounds that is selected from following structural formula:

Term " Mammals " is meant all Mammalss that comprise the mankind, domestic animal and pet.

" salt " of compound is meant pharmacy acceptable salt, and it has the pharmacologically active of parent compound.This class salt comprises:

Additive salt that (1) form or that form with organic acid with mineral acid.Described mineral acid comprises hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid or the like; Described organic acid comprises acetate, propionic acid, caproic acid, pentamethylene propionic acid (cyclopentanepropionic acid), oxyacetic acid, pyruvic acid, lactic acid, propanedioic acid, succsinic acid, oxysuccinic acid, toxilic acid, fumaric acid, tartrate, citric acid, phenylformic acid, 3-(4-hydroxy benzoyl) phenylformic acid, styracin, phenylglycollic acid, methylsulfonic acid, ethyl sulfonic acid (ethanesulfonic acid), 1, the 2-ethionic acid, the 2-ethylenehydrinsulfonic acid, Phenylsulfonic acid, the 4-chlorobenzenesulfonic acid, the 2-naphthene sulfonic acid, the 4-toluenesulphonic acids, camphorsulfonic acid, 4-methyl bicyclic [2.2.2] oct-2-ene-1-carboxylic acid (4-methylbicyclo[2.2.2] oct-2-ene-1-carboxylicacid), glucose enanthic acid (glucoheptonic acid), 4,4 '-methylene radical two-(3-hydroxyl-2-alkene-1-carboxylic acid), the 3-phenylpropionic acid, trimethylacetic acid, tert.-butylacetic acid (tertiary butylacetic acid), lauryl sulfonic acid, glyconic acid, L-glutamic acid, carbonaphthoic acid, Whitfield's ointment, stearic acid, muconic acid or the like; Perhaps

(2) acid proton that exists in the parent compound replaced by metal ion (as alkalimetal ion, alkaline-earth metal ions or aluminum ion) or with organic bases (as thanomin, diethanolamine, trolamine, tromethane, N-methyl glucoside amine or the like) the formed salt of coordination.

" prodrug (prodrug) " is meant when taking described prodrug to mammalian object, discharges any compound of the active parent drug of The compounds of this invention in vivo.Narration to various prodrugs is arranged: people such as Alexander, J.Med.Chem.1988, the 318th page in such as following publication; People such as Alexander, J.Med.Chem., 1991, the 78 pages; People such as Murdock, J.Med.Chem., 1993, the 2098 pages; People such as Davidsen, J.Med.Chem., 1994, the 4423 pages; People such as Robinson, J.Med.Chem., 1996, the 10 pages; People such as Keyes, J.Med.Chem., 1996, the 508 pages; People such as Krise, J.Med.Chem., 1999, the 3094 pages; People such as Rahmathullah, J.Med.Chem., 1999, the 3994 pages; People such as Zhu, Bioorg.Med.Chem.Lett., 2000, the 1121 pages; People such as Sun, J.Med.Chem., 2001, the 2671 pages; People such as Ochwada, Bioorg.Med.Chem.Lett., 2003, the 191 pages; People such as Sohma, Med.Chem., 2003, the 4124 pages; People such as Ettmayer, J.Med.Chem., 2004, the 2393 pages; People such as Stella, Adv.Drug Delivery Rev., 2007, the 677 pages, people such as Josyula, International Patent Publication No. .WO 2005/028473; People such as Rhee, International Patent Publication No. .WO 2005/058886, and EP 1,683,803.According to the method described in these publications and the reference wherein quoted, can prepare the corresponding prodrug of The compounds of this invention equally.Therefore, the prodrug of formula I compound is prepared by the functional group that changes (modification) The compounds of this invention, can be to be removed in vivo to discharge parent compound thereby modify part.Described prodrug can be used to improve water-soluble, oral, transdermal or through the bioavailability of eye, is used to realize the controlled release (as: prolong and discharge) of drug molecule, and is used to improve tolerance or the like.Prodrug comprises such The compounds of this invention, wherein the hydroxyl in the compound, sulfydryl, amido (amido) thereby or amino being connected in anyly can be removed the group that produces free hydroxyl, amido, amino or sulfydryl again respectively in vivo.The example of prodrug includes, but is not limited to: ester class (for example acetic ester, manthanoate, benzoic ether, phosphoric acid ester or phosphate derivatives), amino formate (N for example, the N-carbonyl dimethyl ammonium), the N-phosphamide, they have from the hydroxyl of compound of the present invention or amine deutero-functional group.Prodrug derivatives both can be used as the form (for example acid or amine) of neutral prodrug and had used, the form that also can be used as its corresponding salt [is for example used, the sodium salt of phosphoric acid prodrug, or for the prodrug that has amido, as amine salt (example hydrochloric acid salt, Citrate trianion etc.)], also can be used as zwitterionic form and use, if having positively charged and negative electricity or ionogenic functional group simultaneously.The prodrug group can be introduced at each different sites of formula I compound.

Compound of the present invention is generally named by IUPAC or CAS nomenclature.Can use the abbreviated form that those of ordinary skill in the art knows (" Ph " expression phenyl for example, " Me " represent methyl, " Et " represents ethyl, " h " represents hour, " r.t. " represents room temperature).

General synthetic method

Be provided for preparing or producing the universal method of this new substituted B Huan oxazolidone at this.The synthetic of Gai oxazolidone can be partly according to the more known synthetic method that is generally used for synthetic some Hete rocyclic derivatives in the heterocyclic chemistry method.

On the one hand, the synthetic of The compounds of this invention can be used generalized flowsheet 1 explanation.In the step (c) of flow process 1, be used for the similar agents of He Cheng oxazolidone, at Org.Proc.Res.﹠amp; Development has summary in 2003, the 533 pages.If described blocking group is not the tert-butoxycarbonyl described in the flow process 1 (Boc) group, the extension of these methods can comprise the new operation processing method of removing other possible blocking group.In the generalized flowsheet 1, B has the heterocyclic front body structure, can become the oxazolidone derivative by suitable linked reaction life.

The universal synthesis method of generalized flowsheet 1. Xin oxazolidone derivatives

A) reductive agent: H for example ₂, Pd/C, Fe/NH ₄Cl or SnCl ₂Deng; B) reagent of synthesis of carbamates: AlkOC (=O) Cl, A1kOCOC for example ₆F ₅Or analogue; Alkali: NaOH, NaH, Py, triethylamine (TEA) or analogue; C the reagent of) He Cheng oxazolidone: (S)-3-chloro-2-hydroxypropyl t-butyl carbamate for example, or (S) epoxy-2-ylmethyl t-butyl carbamate ((S)-tert-butyloxiran-2-ylmethylcarbamate); Alkali: LiOBu-t, KOBu-t, NaH or analogue; D) coupling agents useful for same: PdCl for example ₂(dppf) DCM, Pd (PPh ₃) ₄Alkali: NaHCO ₃, Cs ₂CO ₃, K ₂CO ₃Or analogue; B is a heterocycle.

Contain the (isoxazole-3-base among the present invention) amino compound synthetic shown in generalized flowsheet 2.

The general of generalized flowsheet 2. (isoxazole-3-base) An oxazolidinone derivatives synthesized

A) 3-(N-Boc-amino)-5-R-isoxazole; Alkali: as NaH, potassium tert.-butoxide, trimethyl carbinol lithium, tetramethyl guanidine and analogue; B) acid: the solution that trifluoroacetic acid or hydrochloric acid and organic solvent such as THF or dioxane form; Then add alkali such as NaHCO ₃, TEA etc.

Be understandable that, within the scope of the invention, can come preparation formula I and other compound by the multiple nonessential version of above-mentioned flow process.

By the method described in the following embodiment, specify the synthesis flow of compound of the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise umber and per-cent are weight part and weight percent.

Embodiment

In the following embodiments specific embodiments of the present invention is described in detail.These are that the present invention will be described, rather than scope of the present invention is limited.The abbreviation commonly used of wherein having used those of ordinary skills to know.Except as otherwise noted, ¹(δ is at CDCl ppm) to H NMR spectrum ₃Middle record, mass-spectrometric data obtains with the cationization method.Chromatography is meant silica gel chromatography.TLC is meant tlc.All reagent is from the market to be buied, and perhaps makes by the ordinary method described in the existing documents and materials.

The structural formula of embodiment 1 compound is as follows:

The compound of embodiment 1 synthesizes route:

The compound of intermediate 1 salt of wormwood embodiment 1

The compound of embodiment 1. with reaction intermediate 1 (300mg 1.05mmol) places the flask of 15mL, then to wherein add intermediate 17 (363mg, 1.26mmol), K ₂CO ₃(290mg, 2.0eq.) and catalyzer (79mg, 0.1eq.).Under nitrogen protection to wherein adding mixed solvent (2mL water and 8mL 1,4-dioxane).The compound that obtains is removed oxygen (1 hour) be heated to 70 ℃ and under this temperature, stirred one hour then.Mixture is diluted through diatomite filtration with ethyl acetate, after diatomite layer is washed with ethyl acetate ethyl acetate is concentrated, merge organic phase and wash with saturated common salt.Organic phase concentrates behind anhydrous sodium sulfate drying.Residuum is washed with sherwood oil and is just obtained target product, gray solid (285mg, 74%). ¹H?NMR(400MHz，DMSO-d ₆)：8.83(d，J＝1.2Hz，1H)，8.31(d，J＝7.6Hz，1H)，8.11(dd，J＝8.0，2.0Hz，1H)，7.61(d，J＝8.8Hz，，1H)，7.58(s，1H)，7.38(d，J＝8.8Hz，1H)，5.25(t，J＝5.8Hz，1H)，4.66～4.74(m，1H)，4.47(s，3H)，4.15(t，J＝9.0Hz，1H)，3.91(dd，J＝8.6，6.6Hz，1H)，3.70(m，1H)，3.61(m，1H)，2.34(s，3H).MS(m/z)：367[M+H].

The structural formula of embodiment 2 compounds is as follows:

The synthetic route of embodiment 2 compounds:

(285mg 0.78mmol) is dissolved in the methylene dichloride of 5mL and places 0 ℃ intermediate 2. with the compound among the embodiment 1.Successively add triethylamine (421 μ L, 3.0eq.) and methylsulfonyl chloride (121 μ L, 2.0eq.).Mixture stirred 1 hour down at 0 ℃, added saturated aqueous ammonium chloride and carried out cancellation.Use dichloromethane extraction, organic layer is washed back anhydrous sodium sulfate drying, filtration, is concentrated with saturated common salt.(ethyl acetate: methyl alcohol=20: 1) get target product is fluffy white solid (340mg, 98%) to residuum through column chromatography purification.

Intermediate 3. with potassium tert.-butoxide (206mg, 2.4eq.) and DMF (2mL) place the flask of 10mL and be cooled to 0 ℃, then to wherein adding tert-butyl isoxazol-3-ylcarbamate (310mg, DMF 2.2eq.) (3mL) solution.This reaction mixture is risen to stirring at room to join intermediate 2 (340mg, in DMF 0.77mmol) (3mL) solution, this mixed solution is heated to 40 ℃ of stirrings and spends the night after 1 hour.Add saturated ammonium chloride and carry out cancellation, extract with ethyl acetate, merge organic layer and wash, with anhydrous sodium sulfate drying, filtration, concentrated after column chromatography purification (ethyl acetate: must target product be yellow spumescence solid (300mg, 74%) methyl alcohol=20: 1) with saturated common salt.

(200mg 0.37mmol) is dissolved in (2mL ethyl acetate and 2mL ethanol) in the mixed solvent, slowly drips concentrated hydrochloric acid (3mL) then with intermediate 3 under the compound .0 of embodiment 2 ℃.Add afterreaction liquid and rose to stirring at room 1 hour, slowly add 10% aqueous sodium hydroxide solution then and neutralize, have precipitation to produce, collecting precipitation washes the back with water and carry out recrystallization in the mixed solvent of ethanol (3mL) and water (2mL), get target product, white solid (150mg, 92%). ¹H?NMR(400MHz，DMSO-d ₆)：8.83(d，J＝2.0Hz，1H)，8.42(d，J＝1.6Hz，1H)，8.31(d，J＝8.4Hz，1H)，8.11-8.13(dd，J＝8.0，2.0Hz，1H)，7.59-7.61(dd，J＝8.4，2.4Hz，1H)，7.55(d，J＝2.0Hz，，1H)，7.39(d，J＝8.4Hz，1H)，6.61(t，J＝6.2Hz，1H)，6.02(d，J＝1.6Hz，1H)，4.92(m，1H)，4.47(s，3H)，4.22(t，J＝9.0Hz，1H)，3.88(dd，J＝9.0，6.2Hz，1H)，3.47(m，2H)，2.34(s，3H).MS(m/z)：433[M+H].

The structural formula of embodiment 3 compounds is as follows:

The synthetic route of embodiment 3 compounds:

((340mg is in tetrahydrofuran solution 1.06mmol) 1.38mmol) to join intermediate 4 for 1.0M in THF, 1.4mL with hexamethyl two silica-based amido lithiums under-78 ℃ for intermediate 1..Be reflected at-78 ℃ and stirred 1 hour down, be warming up to-30 ℃ and continue to stir 0.5 hour, (307mg rises to room temperature after 2.13mmol), and stirring is spent the night down and to wherein slowly adding (R)-Racemic glycidol butyl ester to be cooled to-78 ℃ then.Reaction adds entry after finishing and extracts with ethyl acetate, after organic layer concentrates residuum is dissolved in the mixed solvent of first alcohol and water, add salt of wormwood, this mixture at room temperature stirred 10 minutes, add entry, obtain solid after the filtration, obtain target product, white solid after water and ethyl acetate are washed.MS(m/z)：286，288[M+H].

The compound of embodiment 3.

With 5-(4,4,5,5-tetramethyl--1,3,2-dioxy borolon-2-yl) (5-(4 for the nicotinoyl nitrile, 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) nicotinonitrile) (69mg, 0.3mmol), intermediate 1 (87mg, 0.3mmol), salt of wormwood (124mg, 0.9mmol) and PdCl ₂(dppf) (34mg 0.05mmol) is dissolved in 1 to DCM, in the 4-dioxane (2mL), mixture is replaced three post-heating to 70 ℃ stirrings of argon gas spend the night.The reaction solution cool to room temperature, through diatomite filtration, diatomite layer is successively washed with ethyl acetate and methylene dichloride, filtrate is water and saturated common salt washing successively, organic layer is through anhydrous sodium sulfate drying, filtration, concentrated, (methylene dichloride: methyl alcohol=30: 1) purifying gets target compound to residuum, light yellow solid through column chromatography. ¹H?NMR(400MHz，DMSO-d ₆)：9.03(d，J＝2.0Hz，1H)，8.87(d，J＝1.6Hz，1H)，8.39(d，J＝2.0Hz，1H)，7.54(m，2H)，7.34(d，J＝8.4Hz，1H)，5.24(t，J＝5.6Hz，1H)，4.73(m，1H)，4.13(t，J＝9.2Hz，1H)，3.88(dd，J＝8.4，6.0Hz，1H)，3.69(m，1H)，3.58(m，1H)，2.29(s，3H).MS(m/z)：310[M+H].

The structural formula of embodiment 4 compounds is as follows:

The synthetic route of embodiment 4 compounds:

The compound of example 4. the compound of the compound of embodiment 4 and embodiment 3 is similar.Use reagent: intermediate 13 (74mg, 0.36mmol), intermediate 1 (105mg, 0.36mmol), salt of wormwood (150mg, 1.08mmol), PdCl ₂(dppf) DCM (40mg, 0.05mmol) and dioxane (2mL). ¹H NMR (400MHz, DMSO): 8.58 (m, 2H), 7.79 (m, 1H), 7.53 (m, 3H), 7.28 (d, J=8.4Hz, 1H), 5.26 (t, J=5.6Hz, 1H), 4.73 (m, 1H), 4.13 (t, J=9.2Hz, 1H), 3.88 (dd, J=8.4,6.0Hz, 1H), 3.69 (m, 1H), 3.58 (m, 1H), 2.27 (s, 3H) .MS (m/z): 285[M+H].

The structural formula of embodiment 5 compounds is as follows:

The synthetic route of embodiment 5 compounds:

Intermediate 6. with 2-chloroethyl chloro-formic ester (10mL, 0.10mol), lime carbonate (7.5g, 0.08mol) and 5-bromo-2-aminopyridine (5.2g 0.03mol) is dissolved in the dioxane (50mL), and reaction mixture spends the night 80 ℃ of stirrings.Be cooled to room temperature, use ethyl acetate extraction after adding water.Organic layer is washed with salt, and anhydrous magnesium sulfate drying, pressure reducing and steaming solvent obtain white solid (5.8g, 70%).

(1.3g 4.65mmol) is scattered in the methanol solution (10mL) of ammonia intermediate 7., is heated to 120 ℃ of reactions 3 hours with intermediate 6.The pressure reducing and steaming solvent, product is dissolved in ethyl acetate, uses saturated aqueous ammonium chloride successively, the salt water washing, anhydrous magnesium sulfate drying obtains white solid product (0.9g, 80%) behind the pressure reducing and steaming solvent.

Intermediate 8. will join boric acid pinacol ester (1.5g, 5.9mmol), intermediate 7 (730mg, 3.0mmol), Potassium ethanoate (882mg, 9.0mmol), and PdCl ₂(dppf) (240mg 0.3mmol) is dissolved in the methyl-sulphoxide (10mL) DCM, is heated to 80 ℃ of reactions under the argon shield and spends the night.Reaction mixture is cooled to room temperature, filters, and washes with ethyl acetate.Filtrate is water and salt water washing successively again, anhydrous sodium sulfate drying.Obtain yellow solid product (522mg, 80%) with column chromatography purification (methylene chloride=50: 1) behind the pressure reducing and steaming solvent.

The compound of embodiment 5. the compound of the compound of example 5 and embodiment 3 is similar.The reagent that uses: (R)-3-(4-bromo-3-aminomethyl phenyl)-5-(hydroxymethyl) oxazolidine-2-ketone (50mg, 0.17mmol), intermediate 8 (60mg, 0.21mmol), salt of wormwood (72mg, 0.52mmol) and PdCl ₂(dppf) DCM (13mg, 0.01mmol). ¹H NMR (400MHz, DMSO-d ₆): 8.36 (d, J=2.4Hz, 1H), 8.16 (d, J=8.8Hz, 1H), 7.86 (dd, J=8.4,2.4Hz, 1H), 7.53 (m, 2H), 7.26 (d, J=8.4Hz, 1H), 5.22 (t, J=5.6Hz, 1H), 4.73 (m, 1H), 4.49 (t, J=8.0Hz, 2H), 4.22 (t, J=8.0Hz, 2H), 4.12 (t, J=9.0Hz, 1H), 3.88 (dd, J=8.8,6.4Hz, 1H), 3.69 (m, 1H), 3.58 (m, 1H), 2.28 (s, 3H) .MS (m/z): 370[M+H].

The structural formula of embodiment 6 compounds is as follows:

The synthetic route of embodiment 6 compounds:

Intermediate 9. with sodium azide (2.2g, 0.03mol) and 5-bromo-2-aminopyridine (5.0g 0.03mol) is dissolved in the triethyl orthoformate (30mL), is warming up to 80 ℃ of stirring reactions 6 hours after adding acetic acid (20mL) again.Reaction mixture cooling back adds frozen water, uses ethyl acetate extraction.Organic layer is washed with salt, anhydrous magnesium sulfate drying.Obtain white solid product (5.7g, 84%) .MS (m/z) behind the pressure reducing and steaming solvent: 226,228[M+H].

The preparation of intermediate 8 is similar among the preparation of intermediate 10. intermediates 3 and the embodiment 5.The reagent that uses: connection boric acid pinacol ester (5.08g, 20mmol), intermediate 9 (2.26g, 10mmol), Potassium ethanoate (2.94g, 30mmol) and PdCl ₂(dppf) DCM (375mg, 0.5mmol). ¹H NMR (400MHz, DMSO-d ₆): 9.61 (s, 1H), 8.87 (d, J=0.8Hz, 1H), 8.35 (d, J=8.0Hz, 1H), 7.90 (dd, J=8.0,0.8Hz, 1H), 1.41 (s, 12H).

The compound of embodiment 6. the compound of the compound of example 6 and embodiment 3 is similar.The reagent that uses: (R)-3-(4-bromo-3-aminomethyl phenyl)-5-(hydroxymethyl) oxazolidine-2-ketone (90mg, 0.31mmol), intermediate 10 (149mg, 0.47mmol), salt of wormwood (86mg, 0.62mmol) and PdCl ₂(dppf) DCM (23mg, 0.03mmol). ¹H NMR (400MHz, DMSO-d ₆): (s, 1H), (dd, J=2.4,1.2Hz, 1H), (dd, J=8.4,2.4Hz, 1H), 8.15 (dd, J=8.0,0.8Hz, 1H), (dd, J=8.4,2.4Hz, 1H), 7.57 (d, J=2.4Hz, 1H), 7.39 (d, J=8.0Hz, 1H), 5.28 (t, J=6.0Hz, 1H), 4.75 (m, 1H), 4.16 (t, J=9.6Hz, 1H), 3.91 (dd, J=8.8,6.0Hz, 1H), 3.70 (m, 1H), 3.61 (m, 1H), 2.33 (s, 3H) .MS (m/z): 353[M+H].

The structural formula of embodiment 7 compounds is as follows:

The synthetic route of embodiment 7 compounds:

The compound of embodiment 7. the synthetic compound with embodiment 3 of the compound of embodiment 7 is similar.Agents useful for same: intermediate 16 (0.10g, 0.35mmol), intermediate 1 (0.08,0.28mmol), K ₂CO ₃(0.15g, 1.00mmol) and Pd (dppf) Cl ₂(26mg, 0.03mmol). ¹H?NMR(400MHz，DMSO-d ₆)：8.73(d，J＝1.2Hz，1H)，8.20(d，J＝8.0Hz，1H)，8.02(m，1H)，7.58(m，2H)，7.37(d，J＝8.4Hz，1H)，4.72(m，1H)，4.47(s，3H)，4.13(t，J＝8.4Hz，1H)，3.89(m，1H)，3.70(m，1H)，3.58(m，1H)，2.32(s，3H).MS(m/z)：367[M+H].

The structural formula of embodiment 8 compounds is as follows:

The synthetic route of embodiment 8 compounds:

Intermediate 12. intermediates 11 (1.0g, 4.24mmol) and NH ₄Cl (6.0g 111mmol) is dissolved in methyl alcohol (20mL) and the water (20mL), stirs under the room temperature after 20 minutes, the adding iron powder (2.0g, 35.7mmol).The mixture stirring after 5 hours, is removed by filter iron powder.With ethyl acetate (20mL * 2) extraction filtrate, organic layer salt is washed dry (Na ₂SO ₄), obtain intermediate 12 (80%) after concentrating.

Intermediate 14. is with K ₂CO ₃(0.6g, aqueous solution 4.34mmol) (3mL) join intermediate 12 (0.7g, in DCM 3.40mmol) (20mL) solution, stirring at room is after 10 minutes, in 20 minutes, drip chloroformic acid benzyl ester (0.7g, 4.11mmol).After reaction solution at room temperature stirs 1 hour, use saturated NH ₄The Cl cancellation.Mixture extracts with DCM, and water (20mL) and saturated aqueous common salt (10mL) are washed behind the merging organic layer.With anhydrous sodium sulfate drying.After desolventizing, steaming obtains intermediate 14 (43%).

Intermediate 1 is synthetic similar among the synthetic and embodiment 3 of intermediate 15. intermediates 15.Agents useful for same: intermediate 14 (0.5g, 1.46mmol), hexamethyl two silica-based amido lithiums (the THF solution of 1.7M, 1.4mL, 2.33mmol), the Racemic glycidol butyl ester (0.4g, 2.84mmol).Productive rate: 0.2g, 45%.

The compound of embodiment 8. the compound of the synthetic and embodiment 3 of the compound of embodiment 8 synthetic similar.Agents useful for same: intermediate 16 (92mg, 0.32mmol), intermediate 15 (80mg, 0.26mmol), K ₂CO ₃(0.11g, 0.79mmol) and Pd (dppf) Cl ₂(26mg, 0.03mmol). ¹H NMR (400MHz, DMSO-d ₆) 8.82 (s, 1H), 8.22 (d, J=8.0Hz, 1H), 8.10～8.13 (m, 1H), 7.92 (d, J=2.0Hz, 1H), 7.59～7.67 (m, 2H), 4.76 (m, 1H), 4.48 (s, 3H), 4.17 (t, J=8.0Hz, 1H), 3.91 (m, 1H), 3.68～3.72 (m, 1H), 3.56～3.60 (m, 1H).MS(m/z)：387[M+H]。

Use and test

Compound of the present invention demonstrates effective activity for multiple different microorganisms, and described microorganism comprises gram positive bacterium.

The compounds of this invention can be evaluated by Standard test programme in external activity, for example at " standard method of approved; be used for the method for dilution antimicrobial susceptibility test of the bacterium of grow aerobically " (ApprovedStandard.Methods for Dilution Antimicrobial Susceptibility Tests forBacteria That Grow Aerobically), the 3rd edition, 1993 by the National Committeefor Clinical Laboratory Standards (Villanova, Pennsylvania USA) publishes " described in the agar dilution of passing through measure minimal inhibitory concentration (MIC).Minimal inhibitory concentration (MIC) is meant that medicine is used to suppress the minimum concentration (μ g/mL) of the visible growth of organism.The MIC value is low more, and then anti-microbial activity is high more.

The result shows: compound of the present invention has the useful effectiveness of resisting gram-positive pathogenic agent, its MIC value usually≤16 μ g/mL.

Instructions of taking and pharmaceutical preparation

In general, compound of the present invention can by any acceptable medicament take mode (these administering modes are used for similar purposes) with the treatment significant quantity take.For instance, compound of the present invention can be oral, parenterai administration, transdermal administration, topical, rectal administration or intranasal administration.The actual amount of The compounds of this invention (being active ingredient) depends on all multifactor, severity, the age of treatment target and effectiveness, route of administration and form and the other factors of relevant healthy state, compound used therefor of the disease that for example needs to treat (promptly infecting), all of these factors taken together is all within the scope that the doctor in charge considers.

The toxicity of these compounds and treatment validity can be used the standard pharmaceutical program, measure with cell cultures or laboratory animal, for example measure LD ₅₀(50% lethal dose) and ED ₅₀(50% effective dose).The ratio of the dosage of toxicity and result of treatment is a therapeutic index, can use LD ₅₀/ ED ₅₀Ratio represent.The compound that therapeutic index is big is preferred.

From the data that cell cultures is measured and zooscopy obtains, can be used for being designed for human dosage range.The dosage of these compounds preferably falls within such circulation composition (circulating concentrations) scope, and promptly described circulation composition comprises ED ₅₀But essentially no toxicity or totally nontoxic.Described dosage can change in this scope, and this depends on formulation and the route of administration that is adopted.For any compound used in the method for the present invention, can make preresearch estimates to the treatment effective dose by cell culture test.Can prepare dosage to animal model, to reach required circulating plasma concentration range, this circulating plasma concentration has comprised the IC that measures in cell cultures ₅₀(being the maximum concentration that suppresses to reach a half test compound of symptom).This information can be used for determining more accurately the useful dosage in human body.Can be by measure the levels of drugs in the blood plasma such as methods such as high performance liquid chromatography.

When the medicine, compound of the present invention is usually with the form administration of pharmaceutical composition.These compounds can be by multiple different approaches administrations such as oral, parenterai administration, transdermal administration, topical, rectal administration and intranasal administrations.

At this compound that provides, but the composition, oral compositions composition for inhalation or the Topically administrable compositions that can be used as injection all are effective.These compositions can be prepared with the method that the pharmacopedics field is known, and these compositions comprise at least a active compound.

Pharmaceutical composition is formulated in the dosage unit, and each dosage contains has an appointment 0.1 to about 2000mg active ingredient, is more preferably to contain 1 to the 900mg active ingredient of having an appointment.Term " dosage unit " is meant on the profile independently unit, is applicable to the single using dosage of human body or other animal body, and each unit contains the active substance and the appropriate drug auxiliary material of the predetermined amount that can produce required result of treatment as calculated.The content of above-claimed cpd of the present invention is not more than about 20 weight % of described pharmaceutical composition, be more preferably and be not more than about 15 weight %, and surplus is a pharmaceutical inert carriers.

Active compound all is effectively at very wide dosage range, usually with pharmaceutically or treatment go up the significant quantity administration.Yet, be understandable that, this compound in fact dosage can be decided according to relevant situation by the doctor, comprises illness to be treated, the severity that needs the infectation of bacteria of treatment, selected route of administration, the pragmatize compound of being used, age, body weight and the reaction of individual patient, severity of patient symptom or the like.

General preferred Indirection techniques generally includes compositions formulated, by hydrophilic medicament is converted into fat-soluble medicine, makes medicine have latentiation.Latentiation reaches usually by the following method: hydroxyl, carbonyl, sulfate radical and the primary amine group that exists in the drug molecule carried out end-blocking, and it is bigger fat-soluble that described medicine is had, and easier conveying is through hemato encephalic barrier.Perhaps, carry hydrophilic medicament also can inculcate hypertonic solution by intra-arterial and carried out better, described advanced pressure solution liquid can temporarily be opened hemato encephalic barrier.

Other is suitable for preparation of the present invention can be referring to Remington ' s Pharmaceutical Sciences, Mace Publishing Company, Philadelphia, PA, the 17th edition (1985).

The patent of quoting herein, patent application and publication (for example periodical, paper and/or textbook) are only for reference.Though at this present invention has been carried out brief description, those of ordinary skill in the art after having read above-mentioned explanation, can be at an easy rate to the present invention change, the of equal value replacement and the change of other type.Therefore above-mentioned description also can comprise or add these variations or all changes any or others.The present invention is not only limited to the concrete aspect described in the literary composition yet, and these concrete aspects just are used to illustrate indivedual aspects more of the present invention.Those of ordinary skill can be easy to the present invention is carried out multiple improvement and variation under the situation that does not break away from the spirit and scope of the present invention.For those skilled in the art, except those methods of enumerating in this article, method of equal value on the function within the scope of the present invention also will be conspicuous.Should be appreciated that the present invention is not only limited to concrete method, reagent, processing condition, material or the like, these all can change.Should be appreciated that also term used herein is just in order to narrate the purpose of concrete aspect, and be not limitation of the present invention.Therefore, specification sheets should be considered to exemplary.

Claims (10)

1. the compound that has following formula I comprises its steric isomer, or its pharmacy acceptable salt, or solvate, or pharmaceutical composition:

Wherein:

R ₁Be CH ₂OH, CH ₂NHC (=O) C _1-5Alkyl, CH ₂NHC (=O) OC _1-5Alkyl, CH ₂NH-Het ¹, CH ₂O-Het ¹, CH ₂Het ¹, CH ₂Het ², CH ₂OPO ₃H ₂, CH ₂OC (=O) CH ₂(CH ₂) _mOPO ₃H ₂Or CH ₂OC (=O) CH (NH ₂) C _1-4Alkyl, m are 1,2, or 3;

R ₂, R ₃, R ₄Be H, OH, CH independently of one another ₃, CN, Cl or F;

R ₅Be CH ₃, CF ₃Or Cl;

X and Y are CH, CF, N or N independently of one another ⁺-O ^-

Z is H, NH ₂, OH, CN, halogen, Het ¹, Het ²Or 4 to 7 element heterocycle;

Each Het ¹Be the tetrazolium that C-connects independently of one another, 1,2,3-triazoles, 1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazoles, 1,2,4-oxadiazole, 1,2,4-thiadiazoles, 1,2,5-oxadiazole ， oxazole, thiazole ， isoxazole, isothiazole ， isoxazoline, or pyrazoles;

Each Het ²Be the tetrazolium that C-connects independently of one another, 1,2,3-triazoles, 1,2,4-triazole ， oxazolidone, 2-Pyrrolidone, 2-imidazolidone, pyrazoles or imidazoles.

2. compound as claimed in claim 1, wherein R ₁Be CH ₂OH, (5-R ₆-isoxazole-3-bases) amino methyl or (4-R ₆-1,2,3-triazoles-1-yl) methyl, wherein R ₆Be H, Me, F or CN.

3. compound as claimed in claim 1, wherein R ₅Be Me.

4. compound as claimed in claim 1, wherein Z is CN, Het ¹Or Het ²

5. compound as claimed in claim 1, wherein R ₂Be H, and R _{3 Hes}R ₄Be selected from independently of one another and do H and F.

6. compound as claimed in claim 1 is selected from following structural formula II:

7. compound as claimed in claim 1 is characterized in that, described compound is a synthetic compound among the embodiment 1-8.

8. as the purposes of arbitrary described compound among the claim 1-7, it is characterized in that, be used for (a) preparation bacterial infection medicine, perhaps (b) will treat significant quantity described compound administration in Mammals, be used for the treatment of because of bacterial infection; Preferably, this infection includes, but are not limited to skin infections, soft tissue infection, microbemia, respiratory tract infection, urinary tract infections, infection of bone and eye infections.

9. as arbitrary described purposes in the claim 8, it is characterized in that when being used for bacterial infection, described compound is administered once every day, dosage is about 1 to 75 milligram of per kilogram of body weight every day; And/or

Be used for Mammals with described compound or the form that contains the formula of medicine of described compound in the following manner: oral, parenterai administration, transdermal administration, topical, rectal administration or intranasal administration.

10. pharmaceutical composition, said composition comprises any described compound of as above claim 1-7 and pharmaceutically acceptable carrier, vehicle or the thinner for the treatment of significant quantity.