CN102007130A - Antibiotic tetrahydro-beta-carboline derivatives - Google Patents

Abstract

Disclosed are compounds of Formula (I), pharmaceutical compositions comprising Formula (I) and methods of treating bacterial infections. The disclosed compounds are inhibitors of PPAT (phosphopantetheine adenyl transferase), and are useful in the treatment and prevention of diseases caused by bacteria, particularly bacteria dependent on PPAT, for example, species such Escherichia coli, Helicobacter pylori, Staphyloccocus aureus, and the like.

Description

Microbiotic tetrahydrochysene-beta-carboline derivatives

Related application

The application requires the right of priority of the U.S. Provisional Application that is entitled as " microbiotic tetrahydrochysene-beta-carboline derivatives " the 60/991st, No. 520 (file number NPZ-006-1) of submission on November 30th, 2007.The content of any patent, patent application and the reference of being quoted in this specification sheets is all included this paper by reference in.

Technical field

The present invention relates to as the composition of PPAT inhibitor and the preparation method and the application of said composition.

Background of invention

In eighties of last century, microbiotic is developed, causes mortality ratio obviously to descend thus.But, unfortunately, antibiotic being extensive use of causes tolerating antibiotic bacterium appearance, the staphylococcus of anti-methicillinum (Staphyloccocus aureus) (MRS A) for example, the faecalis of anti-vancocin (enterococci) (VRE) and penicillin-fast streptococcus pneumoniae (Streptococcus pneumonias) (PRSP).Some bacteriums all have resistance to the microbiotic in the certain limit, for example Mycobacterium tuberculosis (Mycobacterium tuberculosis) bacterial strain tolerance vazadrine, Rifampin, Tibutol, Streptomycin sulphate, ethionamide, kantlex and rifabutin.Except resistance, the bacterium that global Tourism development is unknown relatively with some again propagates into new population from area of isolation.In addition, also exist the bacterium of biological weapon to threaten.These bacteriums do not tackle with existing microbiotic so easily.

Infectious bacteria utilizes coenzyme A (CoA) biosynthetic pathway, particularly in the inferior last step of this approach, this step depends on pantetheinphosphate adenylyl transferase (PPAT), this transferring enzyme partly is converted into 4 '-phosphopantetheine with the adenosine of Triphosaden (ATP), forms dephosphorylation-CoA (dPCoA).Though PPAT is present in the mammalian cell, bacterium and Mammals PPAT enzyme are completely different aspect basic sequence (about 18% identification) and physical properties.Therefore, PPAT shows required selectivity target spot to new antibiotic.

Nearest research has realized that some suppress compound (Leslie etc., " the antibiotic anthranilic acid (Antibacterial Anthranilates with a Novel Mode of Action) with novel binding mode " of faecalis PPAT; Zhao etc., " inhibitor of pantetheinphosphate adenylyl transferase (Inhibitors of Phosphopantetheine Adenylyltransferase) "; Be published in the 42nd biocide and chemotherapeutic cross-cutting annual meeting (the 42ndInterscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) of San Diego, CA in 2002, San Diego, CA, 2002) on).But these compounds are not suitable for drug development.And in one case, their structure is a polypeptide, and in other situation, representational compound shows relatively poor activity to the PPAT of purifying.

Therefore, need the new antibiotic of a kind of target PPAT, can treat the bacterial infection that depends on PPAT with this microbiotic.

Summary of the invention

The present invention relates to some dicyclo PPAT inhibitor.The compound that is disclosed comprises that for bacterium drug tolerant bacteria has anti-microbial activity.Therefore, the invention provides compound, the method for the treatment of with the PPAT inhibitor that discloses, and the pharmaceutical composition that comprises the PPAT inhibitor that is disclosed as the PPAT inhibitor.

On the one hand, the invention provides a kind of method that the object that is subjected to infectation of bacteria is treated, comprise that the object that is subjected to infectation of bacteria to this treatment of needs gives the compound that the structural formula I of significant quantity represents:

And the pharmacy acceptable salt of this compound, solvate, hydrate, enantiomer, steric isomer, rotational isomer, tautomer, diastereomer or racemic modification.

The present invention can be used for treatment (therapeutic or preventative) infectation of bacteria, particularly by the bacterial infection that relies on the CoA biosynthetic pathway, especially by the bacterial infection of expressing the PPAT enzyme.In addition, the present invention can be used for resisting the bacterium that has had obvious antibiotic resistance, particularly resists the multidrug resistance bacterial strain, and this is because the mechanism of action of the present invention it is believed that different with existing widely used microbiotic.

Detailed Description Of The Invention

The present invention relates generally to be used for the treatment of and prevent method, compound and the pharmaceutical composition of infectation of bacteria.The invention particularly relates to tetrahydrochysene-beta-carboline derivatives as the PPAT inhibitor.

One preferred embodiment in, compound is represented with structural formula I:

And the pharmacy acceptable salt of this compound, solvate, hydrate, enantiomer, steric isomer, rotational isomer, tautomer, diastereomer or racemic modification;

In the formula:

Ring A is aryl or heteroaryl, and it is chosen wantonly at any commutable annular atoms place and is substituted;

J is-O-,-S-or-NR2-, wherein R2 is-H or the optional C1-C5 alkyl that replaces;

Perhaps, J is-NR2 '-, wherein R2 ' is optional aryl, aralkyl, heteroaryl, heteroaralkyl, C3-C7 alicyclic group or the C3-C7 cycloalkyl that replaces;

R3 is optional aryl, aralkyl, heteroaryl, heteroaralkyl, C3-C7 alicyclic group or the C3-C7 cycloalkyl that replaces;

L is-(CH ₂)-,-(CO)-,-(CS)-,-(SO)-or-(SO ₂)-;

R4 is aryl, dibenzyl, heteroaryl, connection heteroaryl, heteroaryl-aryl, aryl-heteroaryl, aralkyl, heteroaralkyl, C1-C8 aliphatic group, C3-C7 cycloalkyl, C5-C7 alicyclic group or 3-7 unit non-aromatic heterocycle;

Wherein R4 can by halogen ,-(CO) OR ^aThe O of ,-(CO) (CO) R ^aThe OR of ,-(CS) ^aThe OR of ,-(SO) ^a, SO ₃R ^a,-OSO ₃R ^a,-P (OR ^a) ₂(the OR of ,-(PO) ^a) ₂,-O (PO) (OR ^a) ₂,-B (OR ^a) ₂The NR of ,-(CO) ^b ₂,-NR ^c(CO) R ^a,-SO ₂NR ^b ₂Or-NR ^cSO ₂R ^aReplace;

R5 is-H ,-(CO) OR ^aThe O of ,-(CO) (CO) R ^aThe OR of ,-(CS) ^aThe OR of ,-(SO) ^a, SO ₃R ^a,-OSO ₃R ^a,-P (OR ^a) ₂(the OR of ,-(PO) ^a) ₂,-O (PO) (OR ^a) ₂,-B (OR ^a) ₂The NR of ,-(CO) ^b ₂,-NR ^c(CO) R ^a,-SO ₂NR ^b ₂Or-NR ^cSO ₂R ^a

R6 is-H ,-OH, halogen or optional C1-C3 alkyl or the alkoxyl group that replaces;

R ^aAnd R ^cIndependently be separately-H, C1-C5 alkyl, aryl or aralkyl;

R ^bIndependently be separately-H, C1-C5 alkyl, aryl or aralkyl, perhaps NR ^b ₂It is non-aromatic heterocycle.

In one embodiment, the ring A among the structural formula I is the optional heteroaryl that replaces, for example optional pyrazolyl (pyrazyl), furyl, pyrryl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or the imidazolyl that replaces.

Describe hereinafter the suitable optional substituting group in commutable annular atoms place in ring A is provided in the substituent paragraph of aryl and heteroaryl.More preferably, the ring A randomly, independently any desirable generation the annular atoms place replaced by R1.R1 independently be separately halogen ,-CN ,-NO ₂,-CF ₃,-OCF ₃,-OR ^dThe R of ,-(CO) ^dThe OR of ,-(CO) ^d,-O (CO) R ^dThe O of ,-(CO) (CO) R ^dThe OR of ,-(CS) ^dThe OR of ,-(SO) ^d,-SO ₃R ^d,-CONR ^e ₂,-O (CO) NR ^e ₂,-NR ^f(CO) NR ^e ₂,-NR ^f(CO) OR ^d,-NR ^fCOR ^d,-(SO ₂) NR ^e ₂,-NR ^fSO ₂R ^d,-(CH ₂) _sNR ^d ₂Or optional aryl, aralkyl or the C1-C5 alkyl that replaces.Hereinbefore, s is 0-5, R ^dAnd R ^fIndependently be separately-H, aryl, aralkyl, C1-C5 alkyl or C1-C5 haloalkyl, R ^cIndependently be separately-H, aryl, aralkyl or C1-C5 alkyl, NR ^e ₂Be non-aromatic heterocycle, for example piperidyl, morpholinyl etc.More preferably, R1 be halogen ,-CN ,-NO ₂,-CF ₃,-OCF ₃,-OR ^dThe R of ,-(CO) ^dThe OR of ,-(CO) ^d,-O (CO) R ^d,-CONR ^e ₂,-O (CO) NR ^e ₂,-NR ^f(CO) OR ^d,-NR ^fCOR ^d,-(SO ₂) NR ^e ₂,-NR ^fSO ₂R ^d,-(CH ₂) _sNR ^d ₂Or optional aryl, aralkyl or the C1-C5 alkyl that replaces.More preferably, R1 be-H ,-OH ,-F ,-CH ₃,-CF ₃,-OCH ₃Or-OCF ₃Best, R1 is-H.

In one embodiment, R3 among the structural formula I is the optional phenyl that replaces, pyridyl, benzo [1,3] dioxa cyclopentenyl (dioxolyl), 2,3-dihydro-benzo [1,4] dioxin base (dioxinyl), pyrimidyl, pyrazolyl, furyl, pyrryl, thienyl oxazolyl isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, naphthyl, quinolyl, xenyl, the benzo pyrimidyl, the benzopyrazoles base, benzofuryl, indyl, benzothienyl benzoxazolyl, the benzoisoxazole base, benzothiazolyl, benzisothiazole base or benzimidazolyl-.The suitable optional substituting group of the group that R3 is represented sees below.More preferably, the R3 among the structural formula I is shown in a kind of among the formula R 3-i to R3-v:

In formula R 3-i to R3-v, Y is-N-,-CH-or-CR11-; Z is-NR ^z-,-S-or-O-, wherein R ^zBe-H or C1-C3 alkyl, be more preferably-H or methyl, most preferably be-H; Variable w is 0,1,2 or 3; R11 independently be separately halogen ,-CN ,-NO ₂,-CF ₃,-OCF ₃,-OR ¹The R of ,-(CO) ¹The OR of ,-(CO) ¹,-O (CO) R ¹The O of ,-(CO) (CO) R ¹The OR of ,-(CS) ¹The OR of ,-(SO) ¹,-SO ₃R ¹,-CONR ^m ₂,-O (CO) NR ^m ₂,-NR ⁿ(CO) NR ^m ₂,-NR ⁿ(CO) OR ¹,-NR ⁿCOR ¹,-(SO ₂) NR ^m ₂) ,-NR ⁿSO ₂R ¹,-(CH ₂) _uNR ¹ ₂Or optional aryl, aralkyl or the C1-C5 alkyl that replaces.Hereinbefore, u is 0-5, R ¹And R ⁿIndependently be separately-H, aryl or aralkyl, C1-C5 alkyl or C1-C5 haloalkyl, R ^mIndependently be separately-H, aryl, aralkyl or C1-C5 alkyl, perhaps NR ^m ₂It is non-aromatic heterocycle.

More preferably, a kind of expression of the R3 possible constructions formula R3-i ' among the structural formula I to the R3-v ':

To R3-v ', w is 0,1,2 or 3 at formula R 3-i ', R11 independently is separately-OH ,-NO ₂,-F ,-Cl ,-Br, C1-C4 alkyl, C1-C4 alkoxyl group ,-CF ₃Or-OCF ₃

More preferably, R11 is shown in a kind of among the formula R 11-i to R11-xxiii:

Wherein, R independently is-H, aryl or aralkyl, C1-C5 alkyl or C1-C5 haloalkyl.

More preferably, R3 such as formula R 3 ^aTo R3 ^rIn a kind of shown in:

Best, R3 such as formula R 3 ^eShown in, perhaps R3 is perfluorophenyl or tetrazolium (tretrazole).

Described in the paragraph of the suitable substituent of aryl, heteroaryl, aliphatic group and cycloalkyl, the R4 among the structural formula I randomly further is substituted as described below.More preferably, R4 is phenyl, pyridyl, pyrimidyl, pyrazolyl, naphthyl, xenyl, phenyl-pyridyl, quinolyl, benzo pyrimidyl, benzopyrazoles base, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl or the C2-C8 thiazolinyl that replaces.

More preferably, R4 is shown in a kind of among the formula R 4-i to R4-vii:

In formula R 4-i to R4-vii, m independently is 0,1,2 or 3 separately, X is-N-,-CH-or-CR10-; Ring B is C3-C6 cycloalkyl or C3-C6 cycloalkenyl group; Ring C and D independently are aryl or heteroaryl separately; R8 is-OR ^qOr-NR ^r ₂R9 is-H, aryl, aralkyl or C1-C6 aliphatic group; R10 independently be separately halogen ,-CN ,-NO ₂,-CF ₃,-OCF ₃,-OR ⁱThe R of ,-(CO) ⁱThe OR of ,-(CO) ⁱ,-O (CO) R ⁱThe O of ,-(CO) (CO) R ⁱThe R of ,-(CS) ⁱThe OR of ,-(SO) ⁱ,-SO ₃R ⁱ,-CONR ^j ₂,-O (CO) NR ^j ₂,-NR ^k(CO) NR ^j ₂,-NR ^k(CO) OR ⁱ,-NR ^kCOR ⁱ,-(SO ₂) NR ^j ₂,-NR ^kSO ₂R ⁱ,-(CH ₂) _tNR ^j ₂Or optional aryl, aralkyl or the C1-C5 alkyl that replaces; Variable t is 0-5, R ⁱAnd R ^kIndependently be separately-H, aryl, aralkyl, C1-C5 alkyl or C1-C5 haloalkyl; R ^jAnd R ^rIndependently be separately-H, aryl, aralkyl or C1-C5 alkyl, perhaps NR ^j ₂And NR ^r ₂Independently be non-aromatic heterocycle separately; R ^qBe-H or optional aryl, aroyl, aralkyl, aralkanoyl (aralkanoyl), C1-C5 alkyl or the C1-C5 alkyloyl that replaces.

More preferably, R4 is shown in a kind of to the R4-vii ' of formula R 4-i ':

To R4-vii ', m independently is 0,1,2 or 3 separately at formula R 4-i '; R8 is-OH, C1-C5 alkoxyl group or C1-C5 alkanoyloxy; R9 is-H or C1-C6 aliphatic group; R10 independently is separately-OH ,-NO ₂,-F ,-Cl ,-Br, C1-C4 alkyl, C1-C4 alkoxyl group ,-CF ₃Or-OCF ₃

More preferably, R4 is by the aryl of a kind of replacement among the formula R 10-i to R10-xix (for example phenyl):

More preferably, R4 such as formula R 4 ^aTo R4 ^qIn a kind of shown in:

Best, R4 such as formula R 4 ^aOr R4 ^bShown in, the perhaps phenyl that replaced by tetrazolium of R4.

At R4 ^aTo R4 ^qIn, R8 is-NR ^y ₂,-OH, C1-C5 alkoxyl group or C1-C5 alkanoyloxy, wherein R ^yIndependently be separately-H or C1-C3 alkyl.More preferably, R8 is-OH or C1-C4 alkoxyl group, perhaps be more preferably-OH ,-OCH ₃Or-OCH ₂CH ₃Best, R8 is OCH ₃Or-OCH ₂CH ₃

One preferred embodiment in, R5 is:

In a most preferred embodiment, R ⁵Be-H or-CO ₂H.

In preferred embodiment, in structural formula I, R8 is-OH, OCH ₃Or-OCH ₂CH ₃

In structural formula I, R3 is with a kind of expression the among the formula R 3-i to R3-v, and perhaps R4 is with a kind of expression the among the formula R 4-i to R4-vii.More preferably, R3 is with a kind of expression the among the formula R 3-i to R3-v, and R4 is with a kind of expression the among the formula R 4-i to R4-vii.In another embodiment, in structural formula I, R3 is with a kind of represent of formula R 3-i ' to the R3-v ', and perhaps R4 is with a kind of represent of formula R 4-i ' to the R4-vii '.More preferably, R3 is with a kind of represent of formula R 3-i ' to the R3-v ', and R4 is with a kind of represent of formula R 4-i ' to the R4-vii '.Another preferred embodiment in, for structural formula I, R3 is with formula R 3 ^aTo R3 ^rIn a kind of expression, perhaps R4 is with formula R 4 ^aTo R4 ^qIn a kind of expression.Preferably, R3 formula R 3 ^aTo R3 ^rIn a kind of expression, and R4 is with formula R 4 ^aTo R4 ^qIn a kind of expression.More preferably, R3 formula R 3 ^d, R3 ^eOr R3 ^fExpression, perhaps R4 formula R 4 ^a, R4 ^cOr R4 ^eExpression.More preferably, R3 formula R 3 ^d, R3 ^eOr R3 ^fExpression, R4 formula R 4 ^a, R4 ^cOr R4 ^eExpression.

In another embodiment of general formula I, ring A is a phenyl moiety; J is N (H); R3 is optional by the phenyl of halogen or tetrazolium replacement one or many; L is (CO) or (CH ₂); R4 be randomly, independently by halogen, CO ₂H or tetrazolium replace the phenyl of one or many; R5 is H.

In another embodiment, the compound of general formula I is shown in general formula 5:

In the formula, J and R ₃Define as mentioned, A is diazole, dioxolane, diox or phenyl ring, R ' and R " independently be hydrogen, halogen, carboxylic acid, alkyl, heterocycle, nitrile or oxyamide separately.

In another embodiment, the compound of general formula I is shown in general formula 6:

In the formula, J, R ₃And R ₅Define as mentioned, Y is C=O or CH ₂, A is diazole, dioxolane, diox or phenyl ring, R ' and R " independently be hydrogen, halogen, carboxylic acid, alkyl, heterocycle, nitrile or oxyamide.

In another embodiment, this compound is shown in general formula I, and wherein encircling A is aryl moiety; J is N (H); R3 is optional by the aryl of halogen or heteroaryl replacement one or many; L is (CO) or (CH ₂); R4 be randomly, independently by halogen, CO ₂H or heteroaryl replace the phenyl of one or many; R5 is H, alkyl, alkoxyl group, CO ₂H or CO ₂Alkyl; R6 is H, alkyl or alkoxyl group.

In another embodiment, this compound is shown in general formula I, and wherein encircling A is phenyl moiety; J is N (H); R3 is optional by the phenyl of halogen or tetrazolium replacement one or many; L is (CO) or (CH ₂); R4 be randomly, independently by halogen, CO ₂H or heteroaryl replace the phenyl of one or many; R5 is H or CO ₂H; R6 is H.

In another embodiment, this compound is shown in general formula I, and wherein encircling A is phenyl moiety: J is N (H); R3 is the optional phenyl that is replaced by tetrazolium; L is CH ₂R4 is the phenyl that is replaced one or many randomly, independently by halogen.

In other embodiments, each compound shown in the compound in compound, the method, each personal table 1 of the compound in the pesticide composition is represented:

Table

In a concrete embodiment, the compound of table 1 can be used for the object of needs is carried out the infectation of bacteria treatment.

In another embodiment, compound 4,13,22,32,49,67,71 and 72 can be used for the object of needs is carried out the infectation of bacteria treatment.

Term " object " used in the literary composition comprises Mammals, people for example, companion animals (for example dog, cat, bird, aquarium fish, reptile etc.), farming animals (for example cow, sheep, pig, horse, poultry, agriculture feeding fish etc.) and laboratory animal (for example, rat, mouse, guinea pig, bird, aquarium fish, reptile etc.).Perhaps, to liking warm-blooded animal.More preferably to liking Mammals.Most preferably to liking the people.

Need the object of treatment to be subjected to infectation of bacteria (perhaps being exposed in the easy infection environment that has bacterium, for example in hospital), the symptom of this infectation of bacteria can be alleviated by the bicyclic derivatives that is disclosed that gives significant quantity.For example, the object that needs to treat may be infected, treats for the bicyclic derivatives that this infection can disclose.In another example, need the object of treatment to have open wound or burn, perhaps have the immunity system of immunity degradation, the PPAT inhibitor that can give this to be disclosed is as preventive.Therefore, object can obtaining medical treatment property or preventative treatment.More preferably, the treatment of obtaining medical treatment property of object.

Usually, treatment target causes infection by the bacterium that is selected from following Pseudomonas: different Chromatium (Allochromatium), acinetobacter (Acinetobacter), Bacillaceae (Bacillus), campylobacter (Campylobacter), chlamydozoan (Chlamydia), criticize Chlamydobacteria (Chlamydophila), fusobacterium (Clostridium), Citrobacter (Citrobacter), escherichia (Escherichia), intestinal bacteria belongs to (Enterobacter), enterococcus spp (Enterococcus), Frances Bordetella (Francisella), hemophilus (Haemophilus), Helicobacter (Helicobacter), klebsiella (Klebsiella), listeria (Listeria), Moraxella (Moraxella), Mycobacterium (Mycobacterium), eisseria (Neisseria), proteus (Proteus), Rhodopseudomonas (Pseudomonas), salmonella (Salmonella), Serratia (erratia), Shigella (Shigella), oligotrophy zygosaccharomyces (Stenotrophomonas), Staphylococcus (Staphyloccocus), strep belongs to (Streptococcus), poly-ball cyanobacteria belongs to (Synechococcus), Vibrio (Vibrio) and yersinia's genus (Yersina).

More preferably, treatment target causes infection by following bacterium: the different chomophoric bacterium of wine and women-sensual pursuits (Allochromatium vinosum), Acinetobacter bauamnnii (Acinetobacter baumanii), anthrax bacillus (Bacillus anthracis), campylobacter jejuni (Campylobacter jejuni), sand holes Rickettsiae (Chlamydia trachomatis), Chlamydia pneumoniae (Chlamydia pneumoniae), fusobacterium (Clostridium spp.), Citrobacter (Citrobacter spp.), intestinal bacteria (Escherichia coli), enterobacter (Enterobacter spp.), enterococcus faecalis (Enterococcusfaecalis.), faecium (Enterococcus faecium), soil draws hot pasteurella (Francisella tularensis), popular influenzae (Haemophilus influenzas), Hp (Helicobacterpylori), Klebsiella (Klebsiella spp.), increasing property of monocyte listeria bacteria (Listeria moiwcytogenes), Moraxella catarrhalis (Moraxella catarrhalis), mycobacterium tuberculosis (Mycobacterium tuberculosis), Neisseria meningitidis (Neisseria meningitidis), gonococcus (Neisseria gonorrhoeae), proteus mirabilis (Proteus mirabilis), proteus vulgaris (Proteus vulgaris), Pseudomonas aeruginosa (Pseudomonas aeruginosa), salmonella (Salmonella spp.), Serratia (Serratia spp.), shigella (Shigella spp.), have a liking for maltose oligotrophy Zymomonas mobilis (Stenotrophomonas maltophilia), streptococcus aureus (Staphyloccocus aureus), staphylococcus epidermidis (Staphyloccocus epidermidis), streptococcus pneumoniae (Streptococcus pneumoniae), streptococcus pyogenes (Streptococcus pyogenes), streptococcus agalactiae (Streptococcus agalactiae), yersinia pestis (Yersinapestis) and Yersinia enterocolitica (Yersina enterocolitica) etc.

Preferably, treatment target causes infection by expressing the proteic bacterium of PPAT." the PPAT albumen " that uses in the literary composition is the phosphopantetheine adenosyl transferase, be systematic name ATP: pantetheine-4 '-the adenosine phosphate acyltransferase, the classification EC 2.7.7.3 of IUBMB system, (referring to biological chemistry and molecular biology League of Nations (International Union ofBiochemistry and Molecular Biology) Www.chem.qmul.ac.uk/iubmb/).

In one embodiment, the also fungi infestation of treatment target simultaneously, for example by following fungus-caused fungi infestation: skin moss bacterium, for example Trichophyton (Trichophyton), moss (Tinea), microsporum (Microspormn), Epidermophyton (Epidermophyton) etc. cause a disease; Or pathogenic filamentous fungus, for example aspergillus (Aspergillus), Histoplasma (Histoplasma), genera cryptococcus (Cryptococcus), microsporum (Microspormn) etc.; Or the non-filamentous fungus of causing a disease, for example yeast, for example Candida (Candida), Malassezia (Malassezia), trichosporon (Trichosporon), Rhodotorula (Rhodotorula), Torulopsis (Torulopsis), Blastomyces (Blastomyces), Paracoccidioides (Paracoccidioides), Coccidioides (Coccidioides) etc.Preferably, simultaneously treatment target by aspergillus or send out the fungi infestation that the moss Pseudomonas causes.The species of sending out the moss Pseudomonas comprise for example trichophyton mentagrophytes (T.Mentagrophytes), dark red Trichophyton (T.Rubrum), trichophyton schonenleini (T.Schoenleinii), trichophyton tonsurans (T.Tonsurans), trichophyton verrucosum (T.Verrucosum) and trichophyton violaceum (T.Violaceum).The aspergillar species comprise for example Aspergillus fumigatus (A.fumigatus), flavus (A.flavus), aspergillus niger (A.Niger), Amsterdam aspergillus (A.Amstelodami), Aspergillus candidus (A.Candidus), Aspergillus carneus (A.carneus), Aspergillus nidulans (A.Nidulans), aspergillus oryzae (A oryzae), Aspergillus restrictus (A.restrictus), aspergillus sydowii (A.sydowi), terreus (A.terreus), Aspergillus ustus (A.ustus), aspergillus versicolor (A.versicolor), the grey aspergillus of shallow orchid (A.caesiellus), rod aspergillus (A.clavatus), oat aspergillus (A.avenaceus) and Aspergillus deflectus (A.deflectus).More preferably, simultaneously treatment target by being selected from down the fungi infestation that the Aspergillus species organized cause: Aspergillus fumigatus (A.fumigatus), flavus (A.flavits), aspergillus niger (A.niger), Amsterdam aspergillus (A.canstelodami), Aspergillus candidus (A.candidus), Aspergillus carneus (A.carneus), Aspergillus nidulans (A.nidulans), aspergillus oryzae (A oryzae), Aspergillus restrictus (A.restrictus), aspergillus sydowii (A.sydowi), terreus (A.terreus), Aspergillus ustus (A.ustus), aspergillus versicolor (A.versicolor), the grey aspergillus of shallow orchid (A.caesiellus), rod aspergillus (A.clavatus), oat aspergillus (A.avenaceus) and Aspergillus deflectus (A.deflectus).More preferably, treatment target most preferably is used for the treatment of the fungi infestation that is caused by Aspergillus fumigatus (Aspergillus fumigatus) by the fungi infestation that Aspergillus fumigatus (Aspergillus fumigatus) or aspergillus niger (Aspergillus niger) cause simultaneously.

" significant quantity " of disclosed compound is meant such amount, when measuring the object administration that needs are treated with this, can improve the prognosis of object, for example postpone outbreak and/or alleviate one or multinomial severity in all symptoms of the object relevant with infectation of bacteria.The amount that gives the compound that discloses of object depends on concrete disease, administering mode, gives the characteristics of drug compound (if existence) and object, for example general health situation, other disease, age, sex, genotype, body weight and resistance altogether.Those skilled in the art can determine proper dosage according to these and other factor.The significant quantity of the compound that is disclosed is generally about 0.01 mg/kg/day to about 100 mg/kg/day, is preferably 0.1 mg/kg/day to about 10 mg/kg/day.See with the technology of disclosed compound administration and to be set forth in Lei Mingdun: pharmaceutical science with put into practice (Remington:the Science and Practice of Pharmacy), the 19th edition, Mei Ke publishing company (Mack Publishing Co.), Easton, PA (1995), its full content is included this paper by reference in.

" pharmacy acceptable salt " of the compound that discloses is the product that contains ionic linkage by announcement compound and acid or alkali reaction generation that is applicable to the object administration.

For example, the hydrochlorate that contains the compound of amine or other basic group can make by this compound and suitable organic or inorganic acid-respons, and the example of described organic acid or mineral acid comprises hydrochloric acid, Hydrogen bromide, acetate, perchloric acid etc.Compound with quaternary ammonium group also contains counter ion, for example chlorion, bromide anion, iodide ion, acetate moiety, perchlorate etc.Other example of these salt comprises hydrochloride, hydrobromate, vitriol, mesylate, nitrate, maleate, acetate, Citrate trianion, fumarate, tartrate (for example (+)-tartrate, (-)-tartrate or their mixture comprise racemic mixture), succinate, benzoate and the salt that forms with amino acid such as L-glutamic acid.

The salt that contains the compound of carboxylic acid or other acidic functionality can make by this compound and suitable alkali reaction.This pharmacy acceptable salt utilizable energy gives pharmaceutically acceptable cationic alkali and makes, comprise an alkali metal salt (particularly sodium salt and sylvite), alkaline earth salt (particularly calcium salt and magnesium salts), aluminium salt and ammonium salt, and the salt that makes by acceptable organic bases on the physiology, Trimethylamine 99 for example, triethylamine, morpholine, pyridine, piperidines, picoline, dicyclohexyl amine, N, N '-dibenzyl-ethylenediamin, 2 hydroxy ethylamine, two-(2-hydroxyethyl) amine, three-(2-hydroxyethyl) amine, PROCAINE HCL, PHARMA GRADE, the dibenzyl piperidines, N-benzyl-3-styroyl amine, dehydroabietylamine, N, N '-two dehydroabietylamines, glycosamine, the N-methylglucosamine, collidine, quinine, quinoline and basic aminoacids such as Methionin and arginine.

Some compound and salt thereof also can exist with the form of solvate, and for example hydrate the present invention includes various solvates and their mixture.

" pharmaceutical composition " that uses in the literary composition is the preparation that discloses compound to some extent that contains to be applicable to that form to the object administration exists.Pharmaceutical composition can be formulation in bulk or unit dosage.Unit dosage can be various forms, comprises single pump or bottle on for example capsule, IV bag, tablet, the aerosol sucker.The amount of active ingredient in the units dosage composition (i.e. the preparation of the compound or its salt that discloses) is a significant quantity, can change according to relevant concrete treatment.Should be realized that, may carry out some conventional variations to dosage by needs according to the age and the situation of sufferer.Dosage also depends on the approach of administration.Multiple route of administration be can consider, part, oral cavity, lung, rectum, intravaginal, parenteral comprised, in skin, subcutaneous, intravenously, intramuscular, intraperitoneal and nose.

Compound described in the literary composition and pharmacy acceptable salt thereof can be used for pharmaceutical preparation with pharmaceutically acceptable carrier or thinner combination.Suitable pharmaceutically acceptable carrier comprises inert solid fillers or thinner and sterile aqueous or organic solution.The amount that compound described in this pharmaceutical composition exists should be enough to the required dosage in the scope described in the literary composition that is provided at.The preparation of disclosed compound and medicine-feeding technology are referring to above-mentioned Lei Mingdun: pharmaceutical science with put into practice (Remington:the Science andPractice of Pharmacy).

For oral administration, disclosed compound or its salt can with suitable solid or liquid vehicle or thinner combination, form capsule, tablet, pill, powder, syrup, solution, suspension etc.

Tablet, pill and capsule etc. contain active ingredient and the following component of the 1-99 weight % that has an appointment: tackiness agent, for example tragakanta, gum arabic, W-Gum or gelatin; Vehicle, for example Lin Suanergai; Disintegrating agent, for example W-Gum, yam starch or Lalgine; Lubricant, for example Magnesium Stearate; And/or sweeting agent, for example sucrose, lactose or asccharin.When unit dosage was capsule, except the mentioned kind material, capsule also can comprise liquid vehicle, for example fatty oil.

Can exist various other materials as dressing, or improve the physical form of dose unit.For example, available shellac, sugar or both coated tablets.Except the active ingredient beyond the region of objective existence, syrup or elixir also can comprise sucrose as sweeting agent, and Tegosept M and propylben be as sanitas, dyestuff and seasonings such as cherry or orange seasonings, or the like.

For parenteral admin, the compound or its salt that is disclosed, solvate or hydrate can be combined to form injectable solution or suspension with sterile aqueous or organic medium.For example can use the solution of sesame oil or peanut oil, aqueous propylene glycol etc., and the aqueous solution of the pharmaceutically acceptable water-soluble salt of described compound.The dispersion that can also in oil, prepare glycerol, liquid macrogol and their mixture.Under routine storage and working conditions, these goods contain sanitas to prevent microorganism growth.

Except described preparation before, compound can also be mixed with long-acting goods.This suitable based article comprises the polyalcohol hydrogel preparation with biocompatibility and biodegradability that uses crosslinked or water-insoluble polysaccharide formulation, polymerisable polyethylene oxide preparation, impregnated membranes etc.The preparation of this long term can carry out administration by implantation or transdermal delivery (for example subcutaneous or intramuscular), intramuscularly or transdermal patch.Preferably, they are implanted or be administered in the microenvironment of infected organ or tissue, for example, the film that has flooded the compound that discloses are administered to open wound or burn site.Therefore, for example, available suitable polymers or hydrophobic material preparation compound, for example as in the emulsion that can accept in the oil, or ion exchange resin, perhaps as the microsolubility derivative, for example as slightly soluble salt.

For topical, suitable reagent can comprise biocompatibility oil, wax, gel, powder, polymkeric substance or other liquid or solid carrier.This preparation can carry out administration by directly being applied to infected tissue, for example is used for the treatment of the eyes that mode that liquid preparation that conjunctival tissue infects can drip gives object, and cream formulation can give the wound, perhaps floods bandage with preparation, or the like.

For rectal administration, suitable pharmaceutical compositions is for example local with goods, suppository or enema.

For intravaginal administration, suitable pharmaceutical compositions is for example local with goods, vaginal suppository, tampon, emulsifiable paste, gel, paste, foaming agent or sprays.

In addition, compound can also be formulated as by the pulmonary administration active agent delivery, the aerosol that for example contains promoting agent is by for example manually pump spray, spraying gun or pressurised metered dose inhalers administration.This suitable class preparation also can comprise other reagent such as static inhibitor, is effective aerosol form with the compound that keeps being disclosed.

The term that uses in the literary composition " lung " refers in patient's body that major function is that to carry out gaseous interchange with outside atmosphere (be O ₂/ CO ₂Exchange) any part, tissue or organ." lung " is often referred to the tissue of respiratory tract.Therefore, term " pulmonary administration " refers to that giving major function with the preparation described in the literary composition is any part, tissue or the organ (for example, mouth, nose, pharynx, oropharynx, laryngopharynx, larynx, tracheae, protuberantia, segmental bronchus, bronchiole, alveolar) that carries out gaseous interchange with outside atmosphere.In the present invention, " lung " also comprises organ related with respiratory tract or cavity, particularly hole.

The drug delivery device that is used to send aerosol comprises the suitable aerosol jar that comprises described medicinal aerosol formulation with metering valve and is suitable for holding this aerosol jar and allows the actuator housings that medicine is sent.The aerosol jar of drug delivery device leaves about 15% space above this aerosol jar cumulative volume at the top.Usually, be used for pulmonary administration polymer dissolution, suspend or be emulsified in the mixture of solvent, tensio-active agent and propelling agent.This mixture remains on under the certain pressure in the aerosol jar of metering valve sealing.

For intranasal administration, can use solid or liquid vehicle.Solid carrier comprises the coarse meal of granularity in about 20-500 micrometer range for example, and this preparation is by sucking and administration fast through nasal meatus.In the situation of using liquid vehicle, preparation can be used as nasal spray or drop administration, can comprise the oiliness or the aqueous solution of active ingredient.

Except above-mentioned preparation, preparation can randomly comprise one or more other medicines or be total to administration with them, and the example of these other medicines has other microbiotic, anti-inflammatory agent, anti-mycotic agent (antirungals), antiviral agent, immunomodulator, antiprotozoan agent, steroid, separates congested agent, bronchodilator etc.For example, the compound that is disclosed can be total to administration with the following medicine that exemplifies: Ibuprofen BP/EP, prednisone (reflunomide) pentoxifylline, amphotericin B, fluconazole, KETOKONAZOL, itraconazole, penicillin, Ampicillin Trihydrate, amoxycilline Trihydrate bp etc.Said preparation also can comprise sanitas, solubilizing agent, chemical buffer, tensio-active agent, emulsifying agent, tinting material, reodorant and sweeting agent.

Term " derivative " (for example in the term " bicyclic derivatives ") refers to have the compound that identical mother nucleus structure is still replaced by the different groups described in the literary composition.For example, all compounds that structural formula I represents are tetrahydrochysene-beta-carboline derivatives, and they have structural formula I as the common parent nucleus.

In the described in the text structural formula, dotted line is represented a key, is connected with the rest part of molecule by described part of this key or group.For example, the dotted line among the R4-i represents to connect the key of described group and other structural formula.Across the dotted line or the solid line of a key in the ring, for example the solid line that stretches out from R11 among the R4-i represents that the key of its representative can be connected with any commutable atom in the ring.The zigzag meander line is represented each substituent cis of key or the trans position with respect to this dotted line representative.

Term " aryl " expression carbocyclic aromatic base, for example phenyl, naphthyl and anthryl (anthracyl).Term " heteroaryl " expression heteroaromatic base, for example imidazolyl, different imidazolyl, thienyl, furyl, pyridyl, pyrimidyl, pyranyl, pyrazolyl, pyrryl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl and tetrazyl." heteroaryl " that uses in the literary composition is to contain 5 yuan of carbocyclic rings of at least one N, S or O atom and two two keys or contain at least one N, S or 6 yuan of carbocyclic rings of O atom and three two keys.

Term " non-aromatic heterocyclic " refers to 4-8 unit, the non-aromatics member ring systems of preferred 5-6 unit, wherein one or more, preferred 1-4 ring carbon atom replaced by heteroatomss such as N, O or S.The example of non-aromatic heterocyclic comprises the 3-tetrahydrofuran base, the 2-THP trtrahydropyranyl, the 3-THP trtrahydropyranyl, the 4-THP trtrahydropyranyl, [1,3]-dioxolane base (dioxalanyl), [1,3]-dithiolane base (dithiolanyl), [1,3]-alkyl dioxins (dioxanyl), the 2-tetrahydro-thienyl, the 3-tetrahydro-thienyl, the 2-morpholinyl, morpholinyl, 4-morpholinyl (raorpholinyl), the 2-thio-morpholinyl, the 3-thio-morpholinyl, the 4-thio-morpholinyl, the 1-pyrrolidyl, the 2-pyrrolidyl, 3-pyrrolidyl (pyrorolidinyl), the 1-piperazinyl, the 2-piperazinyl, piperidino, the 2-piperidyl, the 3-piperidyl, the 4-piperidyl, the 4-thiazolidyl, 5-diazonium alkyl (diazolonyl), diazonium alkyl (diazolonyl) and 1-o-benzoyl imido grpup that N-replaces.

The compound that is disclosed can contain one or more chiral centres.Exist chiral centre can cause steric isomer in the molecule.For example, there is a pair of optical isomer, is called " enantiomer " for each chiral centre in the molecule.There is a pair of diastereomer in each chiral centre in the compound with two or more chiral centres.When structural formula does not conclusively show stereochemical structure, for example in structural formula I, should understand these structural formulas and comprise the enantiomer that does not contain corresponding optical isomer, racemic mixture, be rich in the mixture of this enantiomer with respect to the corresponding optical isomer of a kind of enantiomer, the diastereomer that does not contain other diastereomer, do not contain the right a pair of diastereomer of other diastereomer, the mixture of diastereomer, the mixture that diastereomer is right, be rich in a kind of mixture of diastereomer with respect to other diastereomer, with respect to other diastereomer to being rich in the right mixture of the right diastereomer of a kind of diastereomer.

Term " alkyl " uses separately or as a more most part (for example aralkyl, alkoxyl group, alkylamino, alkyl amino-carbonyl, haloalkyl), is meant the saturated non-aromatic hydrocarbon of straight or branched fully.Except as otherwise noted, otherwise usually the straight or branched alkyl has about 1-10 carbon atom, preferably about 1-5 carbon atom.The example of suitable straight or branched alkyl comprises methyl, ethyl, n-propyl, 2-propyl group, w-butyl, sec-butyl, the tertiary butyl, amyl group, hexyl, heptyl or octyl group.C1-C10 straight or branched alkyl or C3-C8 cycloalkyl are also referred to as " low alkyl group "." alkoxyl group " refers to the alkyl by the Sauerstoffatom connection of inserting, for example methoxyl group, oxyethyl group, 2-propoxy-, tert.-butoxy, 2-butoxy, 3-pentyloxy etc.

The term that uses in the literary composition " optional halogenated alkyl " and " optional halogenated alkoxyl group " comprise by one or more-F ,-Cl ,-Br or-each group of I replacement.

Each group that expression such as the term that uses in the literary composition " alkyloyl ", " aroyl " connects by the carbonyl that inserts, for example-(CO) CH ₂CH ₃, benzoyl etc.Expressions such as the term that uses in the literary composition " alkanoyloxy ", " aryl acyloxy " connect each group by the carboxyl that inserts, for example-and O (CO) CH ₂CH ₃,-O (CO) C ₆H ₅Deng.

Term " cycloalkyl " is to have about 3-10 carbon atom, the preferred cycloalkyl of about 3-7 carbon atom.The example of suitable cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group." cycloalkyloxy " refers to the cycloalkyl by the Sauerstoffatom connection of inserting, for example cyclopentyloxy, cyclohexyloxy etc.

Term " aliphatic group " comprises that containing one or more carbon carbon unsaturated units is carbon-carbon double bond or triple-linked branched-chain or straight-chain alkyl.Alicyclic group is the cyclic aliphatic base, for example cyclohexenyl or cyclopentenyl.

Term " aralkyl ", " heteroaralkyl ", " cycloalkylalkyl ", " alicyclic group alkyl " and " non-aromatic heterocyclic alkyl " refer to the aryl, heteroaryl, cycloalkyl, alicyclic group and the non-aromatic heterocycle that are connected by alkyl chain respectively, for example benzyl ,-CH ₂-CH ₂-pyridine, (3-cyclohexyl) propyl group etc.

Two aryl that the term dibenzyl of using in the literary composition, connection heteroaryl, aryl-heteroaryl and heteroaryl-aryl are represented respectively to be connected by a covalent linkage, two heteroaryls that connect by a covalent linkage, the aryl and the heteroaryl that connect by a covalent linkage, and heteroaryl and aryl by a covalent linkage connection.The example of dibenzyl, connection heteroaryl, heteroaryl-aryl and aryl-heteroaryl comprises xenyl, bipyridyl, pyrimidyl-phenyl and phenyl-pyridyl respectively.The definition of R4 in as structural formula I, when dibenzyl, connection heteroaryl, heteroaryl-aryl or aryl-heteroaryl were substituting group, described first group was connected with rest part (being " L " among the structural formula I) in the molecule.For example, when the R4 among the structural formula I was phenyl-pyridyl, the phenyl in phenyl-pyridyl was connected with L.

" acyclic " base is the substituting group that does not contain ring." monocycle " base only contains a ring, for example, and not with other ring condensed phenyl ring." many rings " base is the group that contains a plurality of fused rings, for example naphthyl.

" commutable atom " is any atom of the nitrogen that is connected with hydrogen atom by a covalent linkage or carbon and so on, and wherein hydrogen atom can be replaced by other group." commutable annular atoms " in the aromatic ring is any annular atoms of the carbon that is connected with hydrogen atom by a covalent linkage or nitrogen and so on, and wherein hydrogen atom can be replaced by other group.

Suitable substituents is those substituting groups that can not disturb the pharmaceutical activity of the compound that discloses substantially.Compound or group can have one or more identical or different substituting groups.The example that is used for the suitable substituent of alkyl, aliphatic group, cycloalkyl, alicyclic group, non-aromatic heterocycle, aryl or heteroaryl substitutable carbon atom comprises-OH, halogen (Br ,-Cl ,-I and-F) ,-R ,-OR ,-CH ₂R ,-CH ₂CH ₂R ,-OCH ₂R ,-CH ₂OR ,-CH ₂CH ₂OR ,-CH ₂OC (O) R ,-O-COR ,-COR ,-SR ,-SCH ₂R ,-CH ₂SR ,-SOR ,-SO ₂R ,-CN ,-NO ₂,-COOH ,-SO ₃H ,-NH ₂,-NHR ,-N (R) ₂,-COOR ,-CH ₂COOR ,-CH ₂CH ₂COOR ,-CHO ,-CONH ₂,-CONHR ,-CON (R) ₂,-NHCOR ,-NRCOR ,-NHCONH ₂,-NHCONRH ,-NHCON (R) ₂,-NRCONH ₂,-NRCONRH ,-NRCON (R) ₂,-C (=NH)-NH ₂,-C (=NH)-NHR ,-C (=NH)-N (R) ₂,-C (=NR)-NH ₂,-C (=NR)-NHR ,-C (=NR)-N (R) ₂,-NH-C (=NH)-NH ₂,-NH-C (=NH)-NHR ,-NH-C (=NH)-N (R) ₂,-NH-C (=NR)-NH ₂,-NH-C (=NR)-NHR ,-NH-C (=NR)-N (R) ₂,-NRH-C (=NH)-NH ₂,-NR-C (=NH)-NHR ,-NR-C (=NH)-N (R) ₂,-NR-C (=NR)-NH ₂,-NR-C (=NR)-NHR ,-NR-C (=NR)-N (R) ₂,-SO ₂NH ₂,-SO ₂NHR ,-SO ₂NR ₂,-SH ,-SO _kR (k is 0,1 or 2) and-NH-C (=NH)-NH ₂Each R independently is optional alkyl, cycloalkyl, benzyl, aromatic group, heteroaromatic base or the N-anilino that replaces.Preferably, R is unsubstituted.In addition ,-N (R) ₂Can also form together and replace or unsubstituted heterocyclic, for example pyrrolidyl, piperidyl, morpholinyl and thio-morpholinyl.Substituent example on the group that R represents comprises amino, alkylamino, dialkyl amido, aminocarboxyl, halogen, alkyl, alkyl amino-carbonyl, dialkyl amido carbonyl oxygen base, alkoxyl group, nitro, cyano group, carboxyl, alkoxy carbonyl, alkyl-carbonyl, hydroxyl, halogenated alkoxy or haloalkyl.

Suitable substituent on the nitrogen-atoms of heterocyclic radical or heteroaryl comprises-R ' ,-N (R ') ₂,-C (O) R ' ,-CO ₂R ,-C (O) C (O) R ' ,-C (O) CH ₂C (O) R ' ,-SO ₂R ' ,-SO ₂N (R ') ₂,-C (=S) N (R ') ₂,-C (=NH)-N (R ') ₂With-NR ' SO ₂R ', wherein R ' is optional hydrogen, alkyl, alkoxyl group, cycloalkyl, cycloalkyloxy, phenyl, phenoxy group, benzyl, benzyloxy, heteroaryl or the heterocyclic radical that replaces.Substituent example on the group of R ' expression comprises amino, alkylamino, dialkyl amido, aminocarboxyl, halogen, alkyl, alkyl amino-carbonyl, dialkyl amido carbonyl oxygen base, alkoxyl group, nitro, cyano group, carboxyl, alkoxy carbonyl, alkyl-carbonyl, hydroxyl, halogenated alkoxy or haloalkyl.Preferably, R ' is unsubstituted.

Advantageously, the present invention also provides the medicine box that is used for the treatment of disease for the human consumer.This medicine box comprises the pharmaceutical composition that a) comprises microbiotic and pharmaceutically acceptable carrier, vehicle or thinner; With optional b) specification sheets of the method for using this medicine composite for curing specified disease described.This specification sheets can point out that also this medicine box can be used for treating disease, the side effect relevant with the microbiotic administration that simultaneously obvious reduction may be followed.

" medicine box " that use among the application comprises the container that is used to hold the constituent parts formulation, for example independently bottle or independently paper tinsel bag (foil packet).This container can be the shape or the form of any routine as known in the art, can make by pharmaceutically acceptable material, for example carton or cardboard case, vial or Plastic Bottle or glass pot or plastics pot, reclosable bag (for example, hold " refilling " tablet, be put in another container), or can be with the Blister Package of indivedual dosage extrusion bags according to treatment plan.Use which kind of container to depend on related concrete formulation, for example Chang Yong cardboard case is not used in the loading liquid suspension usually.In order to sell a kind of formulation, it also is feasible using more than a kind of container in a packing.For example, in the bottle of tablet can being packed into, and then bottle packed in the box.

An example of this medicine box is a so-called blister packages.Blister Package is well-known in packaging industry, is widely used in the packing of pharmaceutical unit dosage forms (tablet, capsule etc.).Blister Package is made of the harder material piece of the plastic material paper tinsel that has covered preferably transparent usually.In wrapping process, in plastic foil, form depression.This depression has single tablet to be packaged or capsular size and dimension, perhaps can have to hold a plurality of tablets to be packaged and/or capsular size and dimension.Then, tablet or capsule are put into depression, will harder material piece be sealed on the opposite face of the direction with forming depression of plastic foil.Thus, according to hope like that, tablet or capsule are sealed in separately or collectively in the depression between plastic foil and the material piece.Preferably, the intensity of material piece should make and can take out tablet or capsule from Blister Package, and concrete way is with hand recess to be exerted pressure, and forms opening thus in the material piece of recess, and tablet or capsule can take out by described opening then.

Be desirable to provide a kind of written memory aids, the type of this written memory aids is to contain information and/or the directions for use that promising doctor, pharmacist or object provide, for example in tablet or the other numeral of capsule, this numeral perhaps comprises the card of same type information corresponding to the fate that tablet described in the therapeutic regimen or capsule should be ingested.Another example of this memory aids is the calendar that is printed on the card, for example " first week, Monday, Tuesday, " ... etc.. " second week, Monday, Tuesday ... " etc.The memory aids of other form is conspicuous." per daily dose " can be single tablet or capsule or a plurality of tablet or the capsule that will take in the appointed date.

Another embodiment of medicine box be designed for distribute per daily dose divider (whenever next).Preferably, divider is mixed memory aids, so more helps the matching medication scheme.The example of this memory aids is a mechanical counter, and this counter shows the number of times of the per daily dose that has distributed.Another example of this memory aids is battery-driven microchip stores device, this device has liquid crystal reader or sound equipment alerting signal, the date that for example shows the last per daily dose absorbed, and/or in the time need advancing medicine next time reminding object.

Embodiment

Embodiment 1: the PPAT inhibitor of composite structure formula I:

R ' and R " independently are for example hydrogen, carboxylic acid, halogen, alkyl, heterocycle, nitrile or oxyamide separately;

R ₃It is for example optional aryl that replaces.

To the amine that is stirring 1CH ₂Cl ₂Add aldehyde in the solution 2, add TFA then.With gained solution heated overnight under refluxing.After concentrating, filter the solid that forms, use hexane wash, drying obtains product 3With product 3At ambient temperature in bottle with DMF, phenyl aldehyde 4Stir together with AcOH, add NaBH (OAc) then ₃With gained solution 50 ℃ of heated overnight.Add excessive phenyl aldehyde so that react completely.With EtOAc abstraction reaction mixture, use saturated NaHCO ₃, the salt water washing, dry (Na ₂SO ₄), obtain product 5, this product 5Further use purification by flash chromatography.

Embodiment 2: synthetic PPAT inhibitor 2-(4-(2H-tetrazolium-5-yl) benzyl)-1-(2, the 3-dichlorophenyl)-2,3,4, and 9-tetrahydrochysene-1H-pyrido [3,4-b] indoles:

Reagent and condition: a) 2,3 dichloro benzaldehyde, TFA, DCE, heating; B) 3-cyanobenzaldehyde, AcOH, DCE, NaBH (OAc) then ₃C) NaN ₃, ZnBr ₂, heating

In ethylene dichloride (100 milliliters) solution of the tryptamines that stirs (3.2 grams, 20 mmoles), add 2,3 dichloro benzaldehyde (3.5 grams, 20 mmoles), add TFA (0.5 milliliter) then.With gained solution heated overnight under refluxing.After concentrating, filter the solid that forms, use hexane wash, drying obtains light yellow solid product 1 with quantitative yield.

At ambient temperature, in 15 milliliters of bottles that have screw cap, add 1 (316 milligrams, 1.0 mmoles), DMF (5 milliliters), 4-cyanobenzaldehyde (300 milligrams, 2.3 mmoles) and AcOH (200 microlitre).In this solution, add NaBH (OAc) ₃(640 milligrams, 3 mmoles).With gained solution 50 ℃ of heated overnight.In this solution, add 4-cyanobenzaldehyde (200 milligrams, 1.5 mmoles) and NaBH (OAc) again ₃(210 milligrams, 1 mmole).After 50 ℃ of heated overnight, extract solution with EtOAc (50 milliliters).Use saturated NaHCO ₃(25 milliliters), salt solution (10 milliliters) washing organic solution, dry (Na ₂SO ₄), by purification by flash chromatography (acetone: obtain white solid product 3 (260 milligrams, 60%) hexane=20: 80). ¹HNMR (400MHz, CDCl ₃) δ 2.70 (m, 1H), 2.83 (m, 2H), 3.05 (dt, 1H), 3.60 and 3.86 (two d, 2H, J=14Hz), 5.37 (s, 1H), 7.1-7.6 (multiplet group (set ofm), 11H); LC/MSES-430 (M-1); Purity＞95%.

In 15 milliliters of bottles that have a screw cap, add 2 (140 milligrams, 0.32 mmole), add MeOH (5 milliliters) then.To wherein adding NaN ₃(150 milligrams, 2.5 mmoles) add ZnBr then ₂(225 milligrams, 1 mmole).With this suspension 100 ℃ of heated overnight.Add some NaN again ₃(150 milligrams, 2.5 mmoles) are then 100 ℃ of heated overnight.After concentrating, use 1N HCl and CHCl successively ₃The development resistates, drying obtains solid, and this solid obtains yellow solid 3 (100 milligrams, 70%) after purification by flash chromatography (EtOAc). ¹H NMR (400MHz, DMSO-d ₆) δ 2.61 and 2.85 (two m, 2H+2H), 3.64 and 3.80 (two d, 2H J=13.6Hz), 5.31 (s, 1H), 6.9-8.0 (the multiplet group, 11H): LC/MS ES-473 (M-1), ES+475 (M+1), purity＞95%.

Embodiment 3: synthetic PPAT inhibitor 1-(3-(1H-tetrazolium-5-yl) phenyl)-2-(2, the 3-dichloro benzyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles

Reagent and condition: a) 3-cyanobenzaldehyde, TFA, DCE, heating; B) NaN ₃, ZnBr ₂, heating; C) 2,3 dichloro benzaldehyde, AcOH, DCE, NaBH (OAc) then ₃

In ethylene dichloride (50 milliliters) solution of the tryptamines that stirs (1.60 grams, 10 mmoles), add 3-cyanobenzaldehyde (1.31 grams, 10 mmoles), add TFA (0.25 milliliter) again.With gained solution heated overnight under refluxing.After concentrating, separate solid on strainer is used hexane wash, and drying obtains light yellow solid product 1 with quantitative yield. ¹H NMR (400MHz, DMSO-d ₆) δ 2.87 (m, 2H), 3.17 (m, 2H), 5.52 (s, 1H), 7.0-7.7 (the multiplet group, 8H), 10.65 (s, 1H); LC/MS; ES+274 (M+1), purity＞95%.

In three 15 milliliters of bottles that have a screw cap, add 1 (each 450 milligrams, each 1.7 mmole), add n-BuOH/H then ₂O (each 3m/3mL).To wherein adding NaN ₃(130 milligrams, 2.0 mmoles) add ZnBr then ₂(450 milligrams, 2 mmoles).With this suspension 130 ℃ of heated overnight.Adding H ₂Behind O and the hexane, separate solid on strainer, drying obtains white solid product 2 (totally 1.50 restraining 95%). ¹H NMR (400MHz, DMSO-d ₆) δ 0.83 (t, 1H, J=7.2Hz), 1.27 (m, 1H), 2.80 (m, 2H), 3.18 (m, 2H), 5.45 (s, 1H), 6.9-8.0 (the multiplet group, 8H), 10.60 (s, 1H); ES+317 (M+1), ES-315 (M-1), purity＞95%.

At ambient temperature, in 15 milliliters of bottles that have screw cap, add 2 (160 milligrams, 0.5 mmole), add DMF/DCM (2 milliliters/6 milliliters) then, 2,3 dichloro benzaldehyde (153 milligrams, 0.9 mmole) and AcOH (200 microlitre).In this solution, add NaBH (OAc) ₃(250 milligrams, 1.2 mmoles).With gained solution 40 ℃ of heated overnight.Pour solution into H ₂Among the O (20 milliliters), form solid, collect this solid, use hexane wash, drying, chromatogram purification (DCM: MeOH=95: obtain yellow solid product 3 (130 milligrams, 55%) 5). ¹H NMR (400MHz, CD ₃OD) δ 3.16 (m, 2H), 3.35 and 3.60 (two m, 2H), 4.33 (ABq, 2H, J=14.4Hz), 5.63 (s, 1H), 7.0-8.1 (the multiplet group, 11H); LC/MS ES+475 (M+1) ES-473 (M-1) purity＞95%.

Embodiment 4: depend on the bacterium of PPAT, a kind of antibiotic general target

The gene of PPAT is that coaD (perhaps kdtE) has obtained identification: referring to Geerlof etc., " from the purifying and the sign (Purification and characterization of Phosphopantetheine Adenylyltransferase from E.Coli) of colibacillary pantetheinphosphate adenylyl transferase " J.Biol.Chem., 1999,274 (38), the 27105-11 page or leaf, its full content is included this paper by reference in.Use

(the basic gopher of local sequence alignment (Basic Local Alignment Search Tool), can be online from Http:// www.ncbi.nkri.nih.gov/BLAST/Acquisition) in various bacteriums and Mammals, studied this gene order.The results are shown in the table 2.

Table 2: the conservative property of PPAT gene (coaD) in various bacterium kinds

PPAT is a high conservative in many bacterial pathogens according to observations.Therefore, PPAT is antibiotic general target.In addition, though there is PPAT in mammalian cell, the otherness of Mammals sequence is enough big, shows that the PPAT inhibitor that is disclosed has selectivity to bacterium PPAT.

The gene coaD of PPAT ruptures from various bacteriums by the allelotrope exchange and obtains; Referring to, above-mentioned Geerlof etc. for example, and Freiberg etc., 2001, " identification (Identification of novel essential Escherichia coli genes conserved among pathogenic bacteria) of the basic bacillus coli gene of conservative novelty in the pathogenic agent fungi " J Mol Microbiol Biotechnol 2001,3, the 483-9 pages or leaves, its full content is included this paper by reference in.Intestinal bacteria (Escherichia coli), Bacillus subtilus (Bacillus subtilis), streptococcus aureus (Staphylococcus aureus) and the survival condition of streptococcus pneumoniae (Streptococcus pneumoniae) in complicated growth medium have been studied.The bacterium of modifying can not survive under the situation of no coaD gene, and this shows that PPAT is that bacteria live is necessary, is potential microbiotic target therefore.

Another experiment can be tested the existence situation of intestinal bacteria in the medium that contains external source dephosphorylation CoA and/or CoA.Mammals comprises that people's cell can be by the pantothenic acid (vitamins B of catching from environment ₅) preparation CoA.Therefore, in people's object, people's cell/tissue can provide CoA to the bacterium that can not synthesize CoA.The intestinal bacteria of modifying can not survive in the medium that contains external source dephosphorylation CoA and/or CoA and illustrate that more PPAT is the antibacterium target.

The kinetic test that embodiment 5:PPAT suppresses

Determine under the different compound concentrations in 0.003～200 mcg/ml scope the compound that discloses to the IC of PPAT ₅₀(50% inhibition concentration) value.Use different testing method, IC ₅₀The compound of value＞200 has measurable IC50.These suppress to test can use with the similar method of above-mentioned filler test to carry out in 96 hole test panels.In the cumulative volume of 100 microlitres, reaction buffer should contain 20mM Hepes (pH 7.5), 100mM NaCl, 1mM MgCl ₂, 0.5mM DTT, 0.006%Brij 35,10% glycerol, 25 μ M PPT, 0.5mM ATP, 0.2 unit Pyrophosphate phosphohydrolase, 200ng PPAT.This reaction was carried out 2 minutes, used 150 milliliters of Victoria Green WPBs (Malachite Green) reagent to stop then.In colour developing back 10 minutes, measure absorbancy in 650 nanometers.Use XLfit (the ID business strategy company in Massachusetts, United States Cambridge city (Business Solutions Inc., Cambridge, MA)), according to four parametric technique fitting data, determine IC thus ₅₀IC ₅₀Value is obtained by the curve of the compound concentration of inhibitory enzyme reaction 50%.

In order to carry out IC ₅₀Test, need the PPAT of purifying.Intestinal bacteria PPAT gene clone (in the Nowe benefactor department of Wisconsin, USA Madison (Novagen, Inc., Madison, WT)), and is expressed in e. coli bl21 (DE3) cell to the pET28a expression vector.Chromatogram purification is manipulated the Q-agarose, and gel-filtration and MonoQ chromatogram are as mentioned below.The detailed description of this method sees above in the document of Geerlof etc.

Each cell precipitation thing is suspended in (50mM KH in the lysis buffer of 4 times of volumes ₂PO ₄PH 8.0,100mM NaCl, 2mM EGTA and 10% glycerol).Cell breaks for 4 times by microfluid (Microfiuidics) cytoclasis instrument, and cell lysate should be 3, centrifugal 20 minutes of 000g.Then, supernatant liquid is applied to through (10mM Tris-HCl pH 8.0,0.1mMEGTA, 1mM PMSF, 100mM NaCl, 10% glycerol, 0.1%p-mercaptoethanol and 0.02%Brij35) in the Q agarose column of pre-equilibration.Be used in NaCl gradient (0.1～1M) the wash-out PPAT in the level pad.Main peak partly merges and concentrates, and is applied to then (10mM Tris-HCl pH 7.5,150mM NaCl, 0.1mM EGTA, 0.1mM PMSF, 10% glycerol, 0.1% beta-mercaptoethanol and 0.02%Brij 35) in the Sephacryl S200HR post.With identical buffer reagent wash-out PPAT.Merge the main peak part, be loaded into through (10mM Tris-HCl, pH 7.0,0.1mM EGTA, 0.1mM PMSF, 10% glycerol, 0.1% beta-mercaptoethanol and 0.02%Brij 35) on the MonoQ post of pre-equilibration.Should use the NaCl gradient elution PPAT from 100mM to 1000mM.The peak part merges, and dialysis in store buffer liquid (0.1mMEGTA, 50% glycerol, 0.02%Brij 35 for 10mM MOPS pH7.0,150mM NaCl) is then-20 ℃ of storages.The data presentation of these experiments of The compounds of this invention is in table 3.

Table 3: the IC of the PPAT inhibitor of general formula I ₅₀Data

Embodiment 6: the PPAT inhibitor that measurement is disclosed is to the anti-microbial activity of drug-resistant bacteria

Estimate effectiveness, antimicrobial spectrum, target-specific and serum response by measuring MIC (minimum inhibitory concentration).This is to one group of pathogenetic bacteria, in continuous 2 times of diluents of compound, suppresses the minimum concentration of growth fully, and unit is a mcg/ml.The bacterial strain that constitutes this bacterium group obtains from American Type Culture Collection (ATCC, Manassas, Virginia), perhaps through genetically engineered to express the PPAT of various levels.The ATCC bacterial strain comprises following: intestinal bacteria (ATCC 35218), streptococcus aureus (ATCC 700699) and faecium (ATCC 700221).Other bacterial strain comprises streptococcus aureus RN4220, intestinal bacteria WO-0159, intestinal bacteria WO-0153 and Bacillus subtilus BD170, and endogenous PPAT breaks, at inducible promoter (P _{At interval}(P _Space)) regulation and control replenish down PPAT.

Substantially carry out the MIC test described in recommending according to NCCLS, its full content is included this paper (national clinical experiment center for standard (National Center for Clinical Laboratory Standards) by reference in, 1997, (to the method (Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria the Grow Aerobically) of the antimicrobial sensitivity tests of dilution of aerobic growth bacterium), the 4th edition; Standard through approval, NCCLS file M7-A4.NCCLS, Wayne PA.), but has a following difference: exist or do not exist the tryptic soy broth (Tryptic Soy broth) of serum and Miller-Xin Dun Er Shi agar meat soup (Mueller Hinton broth) all to be used as growth medium.The concentration range of test is 200-0.39mcg/ml.Make the concentration of 50 times of required ultimate densities by 2 times of serial dilutions in 96 hole microtiter plates, the transferase 12 microlitre is in test panel then.Cell is grown in suitable medium, is diluted to final 0.001 OD ₆₀₀, then 98 microlitres are inoculated in the test panel.Final volume in each test hole is 100 microlitres.37 ℃ be incubated overnight after, test panel is carried out reading.Determine MIC by causing growth-inhibiting to surpass 80% minimum concentration.

Government supports

The present invention finishes under the government of NIH (National Institutes ofHealth) supports.Government has certain right to the present invention.

Claims (25)

1. compound in structural formula I:

And the pharmacy acceptable salt of this compound, solvate, hydrate, enantiomer, steric isomer, rotational isomer, tautomer, diastereomer or racemic modification;

In the formula:

Ring A is aryl or heteroaryl, and it is chosen wantonly at any commutable annular atoms place and is substituted;

J is-O-,-S-or-NR2-, wherein R2 is-H or the optional C1-C5 alkyl that replaces;

Perhaps, J is-NR2 '-, wherein R2 ' is optional aryl, aralkyl, heteroaryl, heteroaralkyl, C3-C7 alicyclic group or the C3-C7 cycloalkyl that replaces;

R3 is optional aryl, aralkyl, heteroaryl, heteroaralkyl, C3-C7 alicyclic group or the C3-C7 cycloalkyl that replaces;

L is-(CH ₂)-,-(CO)-,-(CS)-,-(SO)-or-(SO ₂)-;

R4 is aryl, dibenzyl, heteroaryl, connection heteroaryl, heteroaryl-aryl, aryl-heteroaryl, aralkyl, heteroaralkyl, C1-C8 aliphatic group, C3-C7 cycloalkyl, C5-C7 alicyclic group or 3-7 unit non-aromatic heterocycle;

Wherein R4 can by halogen ,-(CO) OR ^aThe O of ,-(CO) (CO) R ^aThe OR of ,-(CS) ^aThe OR of ,-(SO) ^a, SO ₃R ^a,-OSO ₃R ^a,-P (OR ^a) ₂(the OR of ,-(PO) ^a) ₂,-O (PO) (OR ^a) ₂,-B (OR ^a) ₂The NR of ,-(CO) ^b ₂,-NR ^c(CO) R ^a,-SO ₂NR ^b ₂Or-NR ^cSO ₂R ^aReplace;

R5 is-H ,-(CO) OR ^aThe O of ,-(CO) (CO) R ^aThe OR of ,-(CS) ^aThe OR of ,-(SO) ^a, SO ₃R ^a,-OSO ₃R ^a,-P (OR ^a) ₂(the OR of ,-(PO) ^a) ₂,-O (PO) (OR ^a) ₂,-B (OR ^a) ₂The NR of ,-(CO) ^b ₂,-NR ^c(CO) R ^a,-SO ₂NR ^b ₂Or-NR ^cSO ₂R ^a

R6 is-H ,-OH, halogen or optional C1-C3 alkyl or the alkoxyl group that replaces;

R ^aAnd R ^cIndependently be separately-H, C1-C5 alkyl, aryl or aralkyl;

R ^bIndependently be separately-H, C1-C5 alkyl, aryl or aralkyl, perhaps NR ^b ₂It is non-aromatic heterocycle.

2. compound as claimed in claim 1 is characterized in that, ring A chooses wantonly at any commutable annular atoms place and replaced by R1, wherein R1 independently be separately halogen ,-CN ,-NO ₂,-OR ^dThe R of ,-(CO) ^dThe OR of ,-(CO) ^d,-O (CO) R ^dThe O of ,-(CO) (CO) R ^dThe OR of ,-(CS) ^dThe OR of ,-(SO) ^d,-SO ₃R ^d,-CONR ^e ₂,-O (CO) NR ^e ₂,-NR ^f(CO) NR ^e ₂,-NR ^f(CO) OR ^d,-NR ^fCOR ^d,-(SO ₂) NR ^e ₂,-NR ^fSO ₂R ^d,-(CH ₂) _sNR ^d ₂Or optional aryl, aralkyl or the C1-C5 alkyl that replaces;

Wherein:

R ^dAnd R ^fIndependently be separately-H, aryl, aralkyl, C1-C5 alkyl or C1-C5 haloalkyl;

R ^eIndependently be separately-H, aryl, aralkyl or C1-C5 alkyl, perhaps NR ^e ₂Be non-aromatic heterocycle, s is 0-5.

3. compound as claimed in claim 2 is characterized in that, ring A is optional phenyl, pyrazolyl, furyl, pyrryl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or the imidazolyl that replaces.

4. compound as claimed in claim 1, it is characterized in that, R3 is optional phenyl, pyridyl, the benzo [1 that replaces, 3] dioxa cyclopentenyl, 2,3-dihydro-benzo [1,4] dioxin base, pyrimidyl, pyrazolyl, furyl, pyrryl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, naphthyl, quinolyl, xenyl, benzo pyrimidyl, benzopyrazoles base, benzofuryl, indyl, benzothienyl, benzoxazolyl, benzoisoxazole base, benzothiazolyl, benzisothiazole base or benzimidazolyl-.

5. compound as claimed in claim 1, it is characterized in that R4 is phenyl, pyridyl, pyrimidyl, pyrazolyl, naphthyl, xenyl, phenyl-pyridyl, bipyridyl, quinolyl, benzo pyrimidyl, benzopyrazoles base, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl or the C2-C8 thiazolinyl that replaces.

6. compound as claimed in claim 5 is characterized in that, R4 is with a kind of expression the among the formula R 4-i to R4-vii:

Wherein:

M independently is 0,1,2 or 3 separately;

X is-N-,-CH-or-CR10-;

Ring B is C3-C6 cycloalkyl or C3-C6 cycloalkenyl group;

Ring C and D independently are aryl or heteroaryl separately;

R8 is-OR ^qOr-NR ^r ₂

R9 is-H, aryl, aralkyl or C1-C6 aliphatic group;

R10 independently be separately halogen ,-CN ,-NO ₂,-CF ₃,-OCF ₃,-OR ⁱThe R of ,-(CO) ⁱThe OR of ,-(CO) ⁱ,-O (CO) R ⁱThe O of ,-(CO) (CO) R ⁱThe OR of ,-(CS) ⁱThe OR of ,-(SO) ⁱ,-SO ₃R ⁱ,-CONR ^j ₂,-O (CO) NR ^j ₂,-NR ^k(CO) NR ^j ₂,-NR ^k(CO) OR ⁱ,-NR ^kCOR ⁱ,-(SO ₂) NR ^j ₂,-NR ^kSO ₂R ⁱ,-(CH ₂) _tNR ^j ₂Or optional aryl, aralkyl or the C1-C5 alkyl that replaces;

R ^jAnd R ^kIndependently be separately-H, aryl, aralkyl, C1-C5 alkyl or C1-C5 haloalkyl;

R ^jAnd R ^rIndependently be separately-H, aryl, aralkyl or C1-C5 alkyl, perhaps NR ^j ₂And NR ^r ₂Independently be non-aromatic heterocycle separately;

R ^qBe-H or optional aryl, aroyl, aralkyl, aralkanoyl, C1-C5 alkyl or the C1-C5 alkyloyl that replaces;

T is 0-5.

7. compound as claimed in claim 6 is characterized in that, R4 is with a kind of represent of formula R 4-i ' to the R4-vii ':

Wherein:

M independently is 0,1,2 or 3 separately;

R8 is-OH, C1-C5 alkoxyl group or C1-C5 alkanoyloxy;

R9 is-H or C1-C6 aliphatic group;

R10 independently is separately-OH ,-NO ₂,-F ,-Cl ,-Br, C1-C4 alkyl, C1-C4 alkoxyl group ,-CF ₃Or-OCF ₃

8. compound as claimed in claim 4 is characterized in that, R3 is with a kind of expression the among the formula R 3-i to R3-v:

Wherein:

Y is-N-,-CH-or-CR11-;

Z is-NR ^z-,-S-or-O-, wherein R ^zBe-H or C1-C3 alkyl;

Variable w is 0,1,2 or 3;

R11 independently be separately halogen ,-CN ,-NO ₂,-CF ₃,-OCF ₃,-OR ¹The R of ,-(CO) ¹The OR of ,-(CO) ¹,-O (CO) R ¹The O of ,-(CO) (CO) R ¹The OR of ,-(CS) ¹The OR of ,-(SO) ¹,-SO ₃R ¹,-CONR ^m ₂,-O (CO) NR ^m ₂,-NR ⁿ(CO) NR ^m ₂,-NR ⁿ(CO) OR ¹,-NR ⁿCOR ¹,-(SO ₂) NR ^m ₂) ,-NR ⁿSO ₂R ¹,-(CH ₂) _uNR ¹ ₂, or optional aryl, aralkyl or the C1-C5 alkyl that replaces;

U is 0-5, R ¹And R ⁿIndependently be separately-H, aryl or aralkyl, C1-C5 alkyl or C1-C5 haloalkyl;

R ^mIndependently be separately-H, aryl, aralkyl or C1-C5 alkyl, perhaps NR ^m ₂It is non-aromatic heterocycle.

9. compound as claimed in claim 8 is characterized in that, R3 is with a kind of represent of formula R 3-i ' to the R3-v ':

Wherein:

W is 0,1,2 or 3;

R11 independently is separately-OH ,-NO ₂,-F ,-Cl ,-Br, C1-C4 alkyl, C1-C4 alkoxyl group ,-CF ₃Or-OCF ₃

10. compound as claimed in claim 5 is characterized in that, R4 is by the phenyl of a kind of replacement among the formula R 10i to R10xix:

11. compound as claimed in claim 8 is characterized in that, R11 is with a kind of expression the among the formula R 11-i to R11-xxiii:

Wherein, R independently is-H, aryl or aralkyl, C1-C5 alkyl or C1-C5 haloalkyl.

12. compound as claimed in claim 1 is characterized in that, R3 formula R 3 ^aTo R3 ^rIn a kind of expression:

13. compound as claimed in claim 1 is characterized in that, R4 formula R 4 ^aTo R4 ^qIn a kind of expression:

Wherein, at R4 ^aTo R4 ^qIn, R8 is-NR ^y ₂,-OH, C1-C5 alkoxyl group or C1-C5 alkanoyloxy, wherein R ^yIndependently be separately-H or C1-C3 alkyl.

14. compound as claimed in claim 1 is characterized in that:

R3 formula R 3 ^aTo R3 ^rIn a kind of expression; With

R4 formula R 4 ^aTo R4 ^qIn a kind of expression.

15. compound as claimed in claim 1 is characterized in that R5 is

16. compound as claimed in claim 1 is characterized in that, ring A is an aryl moiety; J is N (H); R3 is optional by the aryl of halogen or heteroaryl replacement one or many; L is (CO) or (CH ₂); R4 be randomly, independently by halogen, CO ₂H or heteroaryl replace the phenyl of one or many; R5 is H, alkyl, alkoxyl group, CO ₂H or CO ₂Alkyl; R6 is H, alkyl or alkoxyl group.

17. compound as claimed in claim 1 is characterized in that, ring A is a phenyl moiety; J is N (H); R3 is optional by the phenyl of halogen or tetrazolium replacement one or many; L is (CO) or (CH ₂); R4 be randomly, independently by halogen, CO ₂H or heteroaryl replace the phenyl of one or many; R5 is H or CO ₂H or CO ₂Alkyl; R6 is H.

18. compound as claimed in claim 1 is characterized in that, ring A is a phenyl moiety; J is N (H); R3 is the optional phenyl that is replaced by tetrazolium; L is CH ₂R4 is the phenyl that is replaced one or many randomly, independently by halogen.

19. compound as claimed in claim 1 is characterized in that, the compound of general formula I is selected from each compound that provides in the table 1.

20. the method for a treatment target infectation of bacteria, this method comprise that the object to needs treatment infectation of bacteria gives the compound as claimed in claim 1 of significant quantity.

21. method as claimed in claim 20 is characterized in that, compound as claimed in claim 1 is selected from each compound that table 1 provides.

22. method as claimed in claim 20 is characterized in that, and is described to liking the people.

23. method as claimed in claim 20 is characterized in that, described infection is by expressing the bacterial of pantetheinphosphate adenylyl transferase.

24. method as claimed in claim 20, it is characterized in that described infection is caused by the bacterium that is selected from following bacterium genus: acinetobacter, Bacillaceae, campylobacter, chlamydozoan, criticize Chlamydobacteria, fusobacterium, Citrobacter, escherichia, intestinal bacteria belongs to, enterococcus spp, the Frances Bordetella, hemophilus, Helicobacter, klebsiella, listeria, Moraxella, Mycobacterium, eisseria, proteus, Rhodopseudomonas, salmonella, Serratia, Shigella, the oligotrophy zygosaccharomyces, Staphylococcus, strep belongs to and yersinia's genus.

25. pharmaceutical composition that comprises compound as claimed in claim 1.