JP2011518108A - Antibacterial tetrahydro-β-carboline derivative - Google Patents

Abstract

Disclosed are compounds of formula (I), pharmaceutical compositions comprising compounds of formula (I) and methods of treating bacterial infections.
The disclosed compounds are inhibitors of PPAT (phosphopantetheine adenyl transferase) and treatment of diseases caused by bacteria, in particular bacteria dependent on PPAT, such as E. coli, Helicobacter pylori, Staphylococcus aureus, etc. And is useful for prevention.
[Selection figure] None

Description

  The present invention relates to compositions that are PPAT inhibitors and methods and uses thereof.

BACKGROUND OF THE INVENTION In the last century, antibiotics have been developed that lead to a significant reduction in death. Unfortunately, widespread use is due to antibiotic-resistant bacteria such as methicillin-resistant Staphyloccocus aureus (MRS A), vancomycin-resistant enterococci (VRE) and penicillin-resistant Streptococcus pneumonias (PRSP) Leading to the occurrence of
Some bacteria are resistant to various antibiotics, for example, strains of Mycobacterium tuberculosis are resistant to isoniazid, rifamupine, ethambutol, streptomycin, etionamide, kanamycin and rifabutin. In addition to resistance, global travel is spreading relatively unknown bacteria from remote areas to new populations. In addition, there is a bacterial threat as a biological weapon. These bacteria cannot be easily treated with existing antibiotics.

  Infectious bacteria use the coenzyme A (CoA) synthesis pathway, particularly in the penultimate step of the pathway, transferring the adenyl moiety from adenosine triphosphate (ATP) to 4'-phosphopantethein, Relies on phosphopantetheine adenyl transferase (PPAT) to form CoA (dPCoA). Although PPAT is present in mammalian cells, bacterial and mammalian PPAT enzymes differ substantially in primary sequence (approximately 18% identity) and physical properties. Thus, PPAT presents a desirable and selective target for new antibiotics.

Recent efforts have led to the identification of compounds that inhibit E. coli PPAT (Leslie et al., “Antibacterial Anthranilates with a Novel Mode of Action”; Zhao et al., “Inhibitors of Phosphopantetheine Adenylyltransferase”; Presented at Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), San Diego, CA, 2002).
However, these compounds are not suitable for pharmaceutical development. In addition, in some cases, the structure was a peptide, while in other cases, representative compounds showed poor activity against purified PPAT.

  Therefore, there is a need for new antibiotics that target PPAT, thereby treating bacterial infections that depend on PPAT.

SUMMARY OF THE INVENTION The present invention relates to certain bicyclic PPAT inhibitors. The disclosed compounds have antibiotic activity against bacteria, including drug resistant bacteria. Accordingly, provided herein are compounds that are PPAT inhibitors, methods of treatment using the disclosed PPAT inhibitors, and pharmaceutical compositions comprising the disclosed PPAT inhibitors.

で表される化合物、またはその医薬的に許容される塩、溶媒和物、水和物、エナンチオマー、立体異性体、回転異性体、互変異性体、ジアステレオマーもしくはラセミ体の有効量を、細菌感染症の治療が必要な対象に投与することを含む、対象の細菌感染症を治療する方法を提供する。 In one aspect, the present invention provides a structural formula I:

Or an effective amount of a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, rotamer, tautomer, diastereomer or racemate thereof, Provided is a method of treating a bacterial infection in a subject comprising administering to the subject in need of treatment of the bacterial infection.

The present invention treats (either therapeutically or prophylactically) bacterial infections, in particular infections caused by bacteria that depend on the CoA biosynthetic pathway, in particular infections caused by bacteria expressing the PPAT enzyme. Useful for.
Furthermore, the present invention is useful against bacteria producing antibiotic resistance, particularly multi-drug resistant strains, because it is believed to act by a different mechanism of action from existing and widely used antibiotics.

Detailed Description of the Invention The present invention relates generally to methods, compounds and pharmaceutical compositions for treating and preventing bacterial infections. In particular, the present invention relates to tetrahydro-β-carboline derivatives that are PPAT inhibitors.

［式中、
環Aは、置換可能な環原子において任意に置換されていてもよい、アリールまたはヘテロアリール基であり；
Jは、-O-、-S-または-NR2-（ここで、R2は-Hまたは任意に置換されていてもよいC1-C5アルキルである）であるか；または
Jは、-NR2'-（ここで、R2'は任意に置換されていてもよい、アリール、アラルキル、ヘテロアリール、へテロアラルキル、C3-C7脂環式基またはC3-C7シクロアルキルである）であり；
R3は、任意に置換されていてもよい、アリール、アラルキル、ヘテロアリール、へテロアラルキル、C3-C7脂環式基またはC3-C7シクロアルキルであり；
Lは、-(CH₂)-、-(CO)-、-(CS)-、-(SO)-または-(SO₂)-であり； In a preferred embodiment, the compounds of the invention have the structural formula I:

[Where:
Ring A is an aryl or heteroaryl group, optionally substituted at substitutable ring atoms;
J is -O-, -S- or -NR2-, wherein R2 is -H or optionally substituted C1-C5 alkyl; or
J is -NR2'- (wherein R2 'is an optionally substituted aryl, aralkyl, heteroaryl, heteroaralkyl, C3-C7 alicyclic group or C3-C7 cycloalkyl) Is;
R3 is an optionally substituted aryl, aralkyl, heteroaryl, heteroaralkyl, C3-C7 alicyclic group or C3-C7 cycloalkyl;
L is — (CH ₂ ) —, — (CO) —, — (CS) —, — (SO) — or — (SO ₂ ) —;

R4 is aryl, biaryl, heteroaryl, biheteroaryl, heteroaryl-aryl, aryl-heteroaryl, aralkyl, heteroaralkyl, C1-C8 aliphatic group, C3-C7 cycloalkyl, C5-C7 alicyclic group or A 3-7 membered non-aromatic heterocyclic group;
Here, R4 is halogen,-(CO) OR ^a ,-(CO) O (CO) R ^a ,-(CS) OR ^a ,-(SO) OR ^a , SO ₃ R ^a , -OSO ₃ R ^a , -P (OR ^a ) ₂ ,-(PO) (OR ^a ) ₂ , -O (PO) (OR ^a ) ₂ , -B (OR ^a ) ₂ ,-(CO) NR ^b ₂ , -NR ^c ( Optionally substituted with CO) R ^a , —SO ₂ NR ^b ₂ or —NR ^c SO ₂ R ^a ;

R5 is -H,-(CO) OR ^a ,-(CO) O (CO) R ^a ,-(CS) OR ^a ,-(SO) OR ^a , SO ₃ R ^a , -OSO ₃ R ^a ,- P (OR ^a ) ₂ ,-(PO) (OR ^a ) ₂ , -O (PO) (OR ^a ) ₂ , -B (OR ^a ) ₂ ,-(CO) NR ^b ₂ , -NR ^c (CO) R ^a , —SO ₂ NR ^b ₂ or —NR ^c SO ₂ R ^a ;
R6 is -H, -OH, halogen, or optionally substituted C1-C3 alkyl or alkoxy;
R ^a and R ^c are each independently —H, C1-C5 alkyl, aryl or aralkyl;
Each R ^b is independently —H, C1-C5 alkyl, aryl or aralkyl, or NR ^b ₂ is a non-aromatic heterocyclic group]
Or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, rotamer, tautomer, diastereomer or racemate thereof.

  In one embodiment, ring A of structural formula I is an optionally substituted heteroaryl group, such as an optionally substituted pyrazyl, furanyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl. Or an imidazolyl group.

Suitable optional substituents on the substitutable ring atoms of ring A are given in the sections describing substituents on aryl and heteroaryl groups herein below. More preferably, ring A is independently optionally substituted with R 1 at a substitutable ring atom.
R1 is independently _{halogen, -CN, -NO 2, -CF 3} , -OCF 3, -OR d, - (CO) R d, - (CO) OR d, -O (CO) R d, -(CO) O (CO) R ^d ,-(CS) OR ^d ,-(SO) OR ^d , -SO ₃ R ^d , -CONR ^e ₂ , -O (CO) NR ^e ₂ , -NR ^f (CO ) NR ^e ₂ , -NR ^f (CO) OR ^d , -NR ^f COR ^d ,-(SO ₂ ) NR ^e ₂ , -NR ^f SO ₂ R ^d ,-(CH ₂ ) _s NR ^d ₂ , or optionally Optionally substituted aryl, aralkyl or C1-C5 alkyl.

In the above, s is 0 to 5, R ^d and R ^f are each independently -H, aryl, aralkyl, C1-C5 alkyl or C1-C5 haloalkyl, and R ^c is independently- H, aryl, aralkyl or C1-C5 alkyl, NR ^e ₂ is a non-aromatic heterocyclic group such as piperidinyl, morpholinyl and the like.
More preferably, R1 is _{halogen, -CN, -NO 2, -CF 3} , -OCF 3, -OR d, - (CO) R d, - (CO) OR d, -O (CO) R d, - CONR ^e ₂ , -O (CO) NR ^e ₂ , -NR ^f (CO) OR ^d , -NR ^f COR ^d ,-(SO ₂ ) NR ^e ₂ , -NR ^f SO ₂ R ^d ,-(CH ₂ ) _s NR ^d ₂ , or optionally substituted aryl, aralkyl or C1-C5 alkyl. More preferably, R1 is —H, —OH, —F, —CH ₃ , —CF ₃ , —OCH ₃ or —OCF ₃ . Most preferably, R1 is -H.

  In one embodiment, R3 in Structural Formula I is optionally substituted, phenyl, pyridyl, benzo [l, 3] dioxolyl, 2,3-dihydro-benzo [l, 4] dioxinyl, pyrimidyl, pyrazyl, Furanyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, naphthyl, quinolinyl, biphenyl, benzopyrimidyl, benzopyrazyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl Or a benzimidazolyl group. Suitable optional substituents in the group represented by R3 are given herein below.

の一つで表される。 More preferably, R3 in Structural Formula I is represented by Structural Formulas R3-i to R3-v:

It is represented by one of

In Structural Formulas R3-i to R3-v, Y is —N—, —CH—, or —CR11—; Z is —NR ^z —, —S—, or —O— (where R ^z is —H Or C1-C3 alkyl, more preferably —H or methyl, most preferably —H; the variable w is 0, 1, 2 or 3; and each R11 is independently halogen, —CN, -NO ₂ , -CF ₃ , -OCF ₃ , -OR ¹ ,-(CO) R ¹ ,-(CO) OR ¹ , -O (CO) R ¹ ,-(CO) O (CO) R ¹ ,- (CS) OR ¹ ,-(SO) OR ¹ , -SO ₃ R ¹ , -CONR ^m ₂ , -O (CO) NR ^m ₂ , -NR ⁿ (CO) NR ^m ₂ , -NR ⁿ (CO) OR ¹ , -NR ⁿ COR ¹ ,-(SO ₂ ) NR ^m ₂ , -NR ⁿ SO ₂ R ¹ ,-(CH ₂ ) _u NR ¹ ₂ , or optionally substituted aryl, aralkyl or C1- C5 alkyl.
In the above, u is 0 to 5, R ¹ and R ⁿ are each independently -H, aryl, aralkyl, C1-C5 alkyl or C1-C5 haloalkyl, and R ^m is independently- H, aryl, aralkyl or C1-C5 alkyl or NR ^m _2, is a non-aromatic heterocyclic group.

の一つで表される。 More preferably, R3 in Structural Formula I is represented by Structural Formulas R3-i ′ to R3-v ′:

It is represented by one of

In structural formulas R3-i ′ to R3-v ′, w is 0, 1, 2 or 3, and R11 is independently —OH, —NO ₂ , —F, —Cl, —Br, C 1 — C4 alkyl, C1-C4 alkoxy, —CF ₃ or —OCF ₃ .

（式中、Rは独立して、-H、アリールもしくはアラルキル、C1-C5アルキルもしくはC1-C5ハロアルキルである）
の一つで表される。 More preferably, R11 is represented by structural formulas R11-i to R11-xxiii:

Wherein R is independently -H, aryl or aralkyl, C1-C5 alkyl or C1-C5 haloalkyl.
It is represented by one of

の一つで表される。 Even more preferably, R3 is structural formulas R3 ^a to R3 ^r:

It is represented by one of

Most preferably, R3 is either represented by structural formula R3 ^e, or R3 is a perfluorinated phenyl or tetrazole.
R4 in Structural Formula I may be optionally further substituted with substituents described in the following sections describing suitable substituents on aryl, heteroaryl, aliphatic groups and cycloalkyl groups.
More preferably, R4 is substituted, phenyl, pyridyl, pyrimidyl, pyrazyl, naphthyl, biphenyl, phenyl-pyridyl, quinolinyl, benzopyrimidyl, benzopyrazyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl or C2-C8 An alkenyl group.

の一つで表される。 More preferably, R4 is represented by structural formulas R4-i to R4-vii:

It is represented by one of

In structural formulas R4-i to R4-vii, m is each independently 0, 1, 2 or 3, X is —N—, —CH— or —CR10—; ring B is C3-C6 Cycloalkyl or C3-C6 cycloalkenyl; Rings C and D are each independently aryl or heteroaryl; R8 is —OR ^q or —NR ^r ₂ ; R9 is —H, aryl, aralkyl or A C1-C6 aliphatic group; each R10 is independently halogen, —CN, —NO ₂ , —CF ₃ , —OCF ₃ , —OR ⁱ , — (CO) R ⁱ , — (CO) OR ^i; , -O (CO) R ⁱ ,-(CO) O (CO) R ⁱ ,-(CS) R ⁱ ,-(SO) OR ⁱ , -SO ₃ R ⁱ , -CONR ^j ₂ , -O (CO) NR ^j ₂ , -NR ^k (CO) NR ^j ₂ , -NR ^k (CO) OR ⁱ , -NR ^k COR ⁱ ,-(SO ₂ ) NR ^j ₂ , -NR ^k SO ₂ R ⁱ ,-(CH ₂ ) _t NR ^j ₂ , or optionally substituted, aryl, aralkyl or C1-C5 alkyl; variable t is 0-5, R ⁱ and R ^k are each independently -H, Aryl, aralkyl, C1-C5 It is alkyl or C1-C5 haloalkyl; R ^j and R ^r are each independently -H, aryl, or aralkyl or C1-C5 alkyl, or NR ^j ₂ and NR ^r ₂ is independently non An aromatic heterocyclic group; R ^q is —H or an optionally substituted aryl, aroyl, aralkyl, aralkanoyl, C1-C5 alkyl or C1-C5 alkanoyl;

の一つで表される。 More preferably, R4 is represented by structural formulas R4-i ′ to R4-vii ′:

It is represented by one of

In structural formulas R4-i ′ to R4-vii ′, each m is independently 0, 1, 2 or 3; R8 is —OH, C1-C5 alkoxy or C1-C5 alkanoyloxy; R9 is -H or C1-C6 aliphatic group; R10 are each _{independently, -OH, -NO 2, -F,} -Cl, -Br, C1-C4 alkyl, C1-C4 alkoxy, -CF ₃ or - OCF ₃ .

の一つで置換されたアリール(例えば、フェニル)である。 More preferably, R4 has the structural formula R10-i to R10-xix:

Aryl substituted with one of (eg phenyl).

の一つで表される。 More preferably, R4 is formula R4 ^a to R4 ^q:

It is represented by one of

Most preferably, R4 is either represented by structural formula R4 ^a, or R4 ^b, or R4 is phenyl substituted with tetrazole.
In R4 ^a to R4 ^q, R8 is -NR ^y _2, -OH, C1-C5 alkoxy or C1-C5 alkanoyloxy (where, R ^y is independently -H or C1-C3 alkyl) with is there. More preferably, R8 is —OH or C1-C4 alkoxy, more preferably —OH, —OCH ₃ or —OCH ₂ CH ₃ . Most preferably, R8 is OCH ₃ or -OCH ₂ CH _3.

である。
最も好ましい態様において、R⁵は-Hまたは-CO₂Hである。
構造式Iの好ましい態様において、R8は-OH、OCH₃または-OCH₂CH₃である。 In a preferred embodiment, R5 is

It is.
In the most preferred embodiment, R ⁵ is —H or —CO ₂ H.
In preferred embodiments of Structural Formula I, R8 is —OH, OCH ₃ or —OCH ₂ CH ₃ .

In Structural Formula I, R3 is represented by one of Structural Formulas R3-i to R3-v, or R4 is represented by one of R4-i to R4-vii. More preferably, R3 is represented by one of structural formulas R3-i to R3-v, and R4 is represented by one of structural formulas R4-i to R4-vii.
In yet another embodiment of structural formula I, R3 is represented by one of structural formulas R3-i ′ to R3-v ′, or R4 is one of structural formulas R4-i ′ to R4-vii ′. It is represented by More preferably, R3 is represented by one of structural formulas R3-i ′ to R3-v ′, and R4 is represented by one of structural formulas R4-i ′ to R4-vii ′.

In another preferred embodiment, R3 of structural formula I, or is represented by one of structural formulas R3 ^a to R3 ^r, or R4 is represented by one of structural formulas R4 ^a to R4 ^q. Preferably, R3 is represented by one of structural formulas R3 ^a ~R3 ^r, R4 is represented by one of structural formulas R4 ^a to R4 ^q. More preferably, R3 is either represented by structural formula R3 ^d, R3 ^e, or R3 ^f, or R4 is represented by structural formula R4 ^a, R4 ^c, or R4 ^e. More preferably, R3 is represented by structural formula R3 ^d, R3 ^e, or R3 ^f, R4 is represented by structural formula R4 ^a, R4 ^c, or R4 ^e.

In another embodiment of formula I, ring A is a phenyl moiety; J is N (H); R3 is phenyl optionally substituted with one or more halogens or tetrazole; L is (CO) or (CH ₂ ); R 4 is phenyl optionally substituted independently with one or more halogen, CO ₂ H or tetrazole; R 5 is H.

（式中、JおよびR₃は前で定義されたものと同じであり、Aはジアゾール、ジオキソラン、ジオキサンまたはベンゼン環であり、R'およびR''はそれぞれ独立して、水素、ハロゲン、カルボン酸、アルキル、複素環、ニトリルまたはヒドロキシアミドである）。 In another embodiment, the compound of formula I is a compound of formula 5:

Wherein J and R ₃ are the same as previously defined, A is a diazole, dioxolane, dioxane or benzene ring, and R ′ and R ″ are each independently hydrogen, halogen, carboxylic Acid, alkyl, heterocycle, nitrile or hydroxyamide).

（式中、J、R₃およびR₅は、前記で定義されたものと同じであり、YはC=OまたはCH₂であり、Aはジアゾール、ジオキソラン、ジオキサンまたはベンゼン環であり、R'およびR''はそれぞれ独立して、水素、ハロゲン、カルボン酸、アルキル、複素環、ニトリルまたはヒドロキシアミドである）。 In yet another embodiment, the compound of formula I is a compound of formula 6:

Wherein J, R ₃ and R ₅ are the same as defined above, Y is C═O or CH ₂ , A is a diazole, dioxolane, dioxane or benzene ring, R ′ And R ″ are each independently hydrogen, halogen, carboxylic acid, alkyl, heterocycle, nitrile or hydroxyamide).

In another embodiment, the compounds of the invention are those wherein Ring A is an aryl moiety; J is N (H); and R3 is aryl optionally substituted with one or more halogen or heteroaryl. Yes; L is (CO) or (CH ₂ ); R4 is phenyl optionally independently substituted with one or more halogen, CO ₂ H or heteroaryl; R5 is H, alkyl , alkoxy, CO ₂ H or CO ₂ alkyl; R6 is H, alkyl or alkoxy, the compounds of formula I.

In yet another embodiment, the compounds of the present invention are those wherein Ring A is a phenyl moiety; J is N (H); and R3 is phenyl optionally substituted with one or more halogen or tetrazole. Yes; L is (CO) or (CH ₂ ); R4 is phenyl optionally substituted independently with one or more halogen, CO ₂ H or heteroaryl; R5 is H or CO ₂ H; a compound of formula I, wherein R 6 is H.

In another embodiment, the compounds of the invention are wherein ring A is a phenyl moiety; J is N (H); R3 is phenyl optionally substituted with tetrazole; and L is CH ₂ Yes; a compound of Formula I, wherein R4 is phenyl optionally independently substituted with one or more halogens.

  In other embodiments, the compounds of the present invention, the compounds in the methods, and the compounds in the pharmaceutical compositions are represented by individual compounds given in Table 1, respectively.

In certain embodiments, the compounds of Table 1 can be used to treat bacterial infections in subjects in need thereof.
In another embodiment, compounds 4, 13, 22, 32, 49, 67, 71 and 72 can be used to treat bacterial infections in subjects in need thereof.

  As used herein, a “subject” is a mammal, such as a human, a companion animal (eg, a dog, a cat, a bird, an ornamental fish, a reptile, etc.), a livestock (eg, a cow, sheep, pig, horse, chicken, aquaculture). Fish) and laboratory animals (eg, rats, mice, guinea pigs, birds, ornamental fish, reptiles, etc.). Alternatively, the subject is a warm-blooded animal. More preferably, the subject is a mammal. Most preferably the subject is a human.

The subject in need of treatment has a bacterial infection (or is exposed to an infectious environment where bacteria are present (eg, in a hospital)). The symptoms can then be alleviated by administering an effective amount of the disclosed bicyclic derivative. For example, a subject in need of treatment has an infection for which a bicyclic derivative disclosed as a therapeutic agent can be administered.
In another example, the subject in need of treatment has an open wound or burn for the disclosed PPAT inhibitor to be administered as a prophylactic, or has an immunodeficiency. Thus, the subject can be treated therapeutically or prophylactically. More preferably, the subject is treated therapeutically.

  In general, subjects include Allochromatium, Acinetobacter, Bacillus, Campylobacter, Chlamydia, Chlamydophila, Clostridium, Citrobacter, Citrobacter, Escherichia), Enterobacter, Enterococcus, Francisella, Haemophilus, Helicobacter, Klebsiella, Listeria, Moraxella, Mycobacterium (Mycobacterium) , Neisseria, Proteus, Pseudomonas, Salmonella, erratia, Shigella, Stenotrophomonas, Staphylococcus, Streptococcus (Streptococcus) , Kitten Kkasu (Synechococcus), are treated for Vibrio (Vibrio) and Erushina bacterial infection caused by bacteria of the genus selected from (Yersina).

  More preferably, the subject is an Allochromatium vinosum, Acinetobacter baumanii, Bacillus anthracis, Campylobacter jejuni, Chlamydia, Chlamydia tram (Clostridium) spp., Citrobacter spp., Escherichia coli, Enterobacter spp., Enterococcus faecalis, Enterococcus faecium, Francisella tularenular (Francisella tularenular) Haemophilus influenzas, Helicobacter pylori, Klebsiella spp., Listeria moiwcytogenes, Moraxe Catalaris (Moraxella catarrhalis), Mycobacterium tuberculosis, Neisseria meningitides, Neisseria gonorrhoeae, Proteus mirabilisul, Proteus mirabilisul aeruginosa), Salmonella spp., Serratia spp., Shigella spp., Stenotrophomonas maltophilia, Staphyloccocus aureus, Staphylococcus taureus epidermidis), Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Elsinapeste It is treated for scan (Yersinapestis) and Erushina Entekorichika (Yersina enterocolitica) bacterial infection caused by such.

  Preferably, the subject is treated for a bacterial infection caused by bacteria expressing the PPAT protein. As used herein, PPAT protein is a phosphopantetheine adenyl transferase enzyme, i.e. strain ATP: pantethein-4'-phosphate adenyl transferase, IUBMB systematic classification EC 2.7.7.3 (International Union of Biochemistry and Molecular Biology, see www.chem.qmul.ac.uk/iubmb/).

  In one embodiment, the subject has a fungal infection, such as a genus such as a pathogenic dermatophyte, such as Trichophyton, Tinea, Microspormn, Epidermophyton, etc. Species; or species of a genus such as pathogenic filamentous fungi, such as Aspergillus, Histoplasma, Cryptococcus, Microspormn; or non-filamentous fungi, such as yeast Caused by Candida, Malassezia, Trichosporon, Rhodotorula, Torulopsis, Blastomyces, Paracoccidioides, Coccidioides, etc. The same fungus infection is also treated.

  Preferably, the subject is also treated for fungal infections caused by species of the genus Aspergillus or Trichophyton. Trichophyton species include, for example, Trichophyton metagluphytes (T. mentagrophytes), Trichophyton rubrum (T. rubrum), Trichophyton schoenleinii (T. schoenleinii), Trichophyton tonslance (T. tonsurans), Trichophyton bellcolum (T. verrucosum) and trichophyton T. violaceum.

  Aspergillus species include, for example, Aspergillus fumigatus (A. fumigatus), Aspergillus flavus (A. flavus), Aspergillus niger (A. niger), Aspergillus amsterodami (A. candulus) A. carneus), Aspergillus nidulans (A. nidulans), Aspergillus oryzae (A. restrictus), Aspergillus Sidwi (A. sydowi), Aspergillus terreus (A. terreus), Aspergillus A. ustus), Aspergillus bergicolor (A. versicolor), Aspergillus caesiellus (A. caesiellus), Aspergillus clavatus, A. avenaceus (A. avenaceus) and Aspergillus deflectus (A. deflectus).

  More preferably, the subject is Aspergillus fumigatus, Aspergillus flavitos (A. flavits), Aspergillus niger, Aspergillus canstellodami (A. canstelodami), Aspergillus candidus, Aspergillus carneus, Aspergillus nidulans , Aspergillus ustus, aspergillus bergicolol, aspergillus caesieras, aspergillus clavatas, aspergillus abenaceus and aspergillus deflectus, which are treated therapeutically at the same time. The subject is more preferably simultaneously treated therapeutically against a fungal infection caused by Aspergillus fumigatus or Aspergillus niger, most preferably Aspergillus fumigatus.

  An “effective amount” of a disclosed compound of the invention improves the prognosis of a subject when administered to a subject in need of treatment, for example, delays the onset of one or more symptoms in a subject associated with a bacterial infection, And / or an amount that reduces the severity. The amount of a disclosed compound administered to a subject depends on the particular disease, the mode of administration, the compound being administered at the same time, the overall health of the subject, other diseases, age, sex, genotype Will depend on the characteristics of the subject, such as body weight and resistance to drugs.

Persons of ordinary skill in the art will be able to determine appropriate dosages according to these and other factors. In general, an effective amount of a disclosed compound ranges from about 0.01 mg / kg to about 100 mg / kg per day, preferably from 0.1 mg / kg to about 10 mg / kg per day.
Methods for administration of the disclosed compounds of the present invention can be found in Remington: the Science and Practice of Pharmacy, 19th edition, Mack Publishing Co., Easton, PA (1995), the entire teachings of which Are incorporated herein by reference.

  A “pharmaceutically acceptable salt” of a disclosed compound is the product of the disclosed compound containing ionic bonds, which generally converts the disclosed compound to an acid or base suitable for administration to a subject. It is manufactured by making it react with either.

  For example, an acid salt of a compound containing an amine or other basic group can be obtained by reacting the compound with a suitable organic or inorganic acid such as hydrogen chloride, hydrogen bromide, acetic acid, perchloric acid, and the like. it can. Compounds having a quaternary ammonium group also contain counter ions such as chloride, bromide, iodide, acetate, perchlorate and the like. Other examples of such salts are hydrochloride, hydrobromide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate (e.g. ( +)-Tartrate, (-)-tartrate or mixtures thereof including racemic mixtures), salts with amino acids such as succinate, benzoate and glutamic acid.

  Salts of compounds containing carboxylic acids or other acidic functional groups can be prepared by reaction with a suitable base. Such pharmaceutically acceptable salts provide pharmaceutically acceptable cations including alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum salts and ammonium salts. Bases can be made and similarly salts can be trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, N, N'-dibenzylethylenediamine, 2-hydroxyethylamine, bis- (2-hydroxyethyl) Amine, tri- (2-hydroxyethyl) amine, procaine, dibenzylpiperidine, N-benzyl-3-phenethylamine, dehydroabiethylamine, N, N'-bisdehydroabiethylamine, glucamine, N-methylglucamine, collidine, Physiology like quinine and quinoline It may be made from acceptable organic bases, and lysine and basic amino acids such as arginine.

  Certain compounds and their salts may exist in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures thereof.

As used herein, a “pharmaceutical composition” is a formulation comprising a disclosed compound in a form suitable for administration to a subject. The pharmaceutical composition may be present in bulk or unit dosage form.
Unit dosage forms can exist in any of a variety of forms, for example, capsules, IV bags, tablets, single pumps with aerosol nebulizers, or vials. The amount of active ingredient in a unit dosage composition (ie, the formulation of the disclosed compound or salt thereof) is an effective amount and may vary depending on the particular treatment involved. It will be appreciated that it is necessary to make periodic variations in dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. Various routes are contemplated, including topical, oral, pulmonary, rectal, vaginal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal and intranasal.

The compounds described herein and their pharmaceutically acceptable salts can be used in pharmaceutical formulations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions.
The compounds of the invention will be present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the ranges described herein. Methods for formulating and administering the disclosed compounds of the present invention can be found in Remington: the Science and Practice of Pharmacy, supra.

  For oral administration, the disclosed compounds or their salts are suitable solid or liquid carriers or diluents to form capsules, tablets, pills, powders, syrups, solutions, suspensions, etc. Can be combined.

  Tablets, pills, capsules and the like contain from about 1 to about 99% by weight of the active ingredient and a binder such as gum tragagant, gum acacia, corn starch or gelatin; excipients such as dicalcium phosphate; corn starch, Disintegrants such as potato starch or alginic acid; lubricants such as magnesium stearate; and / or sweeteners such as sucrose, lactose or saccharin. When the unit dosage form is a capsule, it can contain, in addition to a substance of the above type, a liquid carrier such as a fatty oil.

  Various other materials may be present as coating agents or to change the physical form of the unit dosage. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a coloring agent and flavoring such as cherry or orange odor.

  For parenteral administration, the disclosed compounds or their salts, solvates or hydrates can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. For example, solutions of sesame or peanut oil, aqueous polyethylene glycol, and the like, as well as aqueous solutions of water-soluble pharmaceutically acceptable salts of the compounds can be used. Dispersions can also be produced in glycerol, liquid polyethylene glycols and mixtures thereof in oil. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

  In addition to the formulations described above, the compounds of the present invention can also be formulated as a depot preparation. Suitable formulations of this type include polymeric hydrogel formulations that use biocompatible and biodegradable crosslinks or water-insoluble polysaccharide formulations, polymerizable polyethylene oxide formulations, impregnated membranes, and the like. Such long acting formulations may be administered by implantation or transdermal delivery (eg subcutaneously or intramuscularly), intramuscular injection or a transdermal patch. Preferably, they are embedded or painted in the microenvironment of the organ or tissue to be acted on, for example membranes impregnated with the disclosed compounds can be applied to wounds or burns with open wounds. Thus, for example, the compounds of the present invention may be formulated with suitable polymeric or hydrophobic substances, such as acceptable emulsions in oil or ion exchange resins, or as slightly soluble derivatives, for example, as slightly soluble salts. It can be formulated.

  For topical administration, suitable formulations may include biocompatible oils, waxes, gels, powders, polymers or other liquid or solid carriers. Such formulations are administered by direct application to the tissue to be worked on. For example, a liquid formulation for treating conjunctival tissue infection can be administered dropwise to the subject's eye, a cream formulation can be administered to the wound site, or a bandage can be impregnated with the formulation, etc. .

Formulations suitable for rectal application are, for example, topical preparations, suppositories or enemas.
Suitable formulations for vaginal administration are, for example, topical formulations, vaginal suppositories, tampons, creams, gels, pastes, foams or sprays.

  In addition, the compounds of the present invention may be formulated to deliver active agents by pulmonary administration, such as administration of aerosol formulations containing the active agent from, for example, manual pump sprays, nebulizers or pressurized metered dose inhalers. Suitable formulations of this type may also contain other agents such as antistatic agents to maintain the disclosed compounds as effective aerosols.

As used herein, the term “lung” means any part, tissue or organ whose primary function is gas exchange in the external environment inside the patient, ie O ₂ / CO ₂ exchange. To do. In general, “lung” means respiratory tissue. Thus, the phrase “pulmonary administration” refers to any part, tissue or organ whose main function is gas exchange in the external environment (eg mouth, nose, pharynx, oropharynx, pharynx, larynx, trachea, Means administration to the trachea keel, bronchus, bronchiole, alveoli) of the formulation described herein. For the purposes of the present invention, “lung” is also meant to include tissues or cavities associated with the respiratory tract, in particular the sinus.

  A pharmaceutical delivery device for aerosol delivery includes a suitable aerosol canister with a metering valve comprising the pharmaceutical aerosol formulation described herein and an actuator adapted to hold the canister and deliver the pharmaceutical Including chambers. The canister in the drug delivery device has a head space that is greater than about 15% of the total volume of the canister. Often, a polymer suitable for pulmonary administration is dissolved, suspended or emulsified in a mixture of solvent, surfactant and propellant. The mixture is stored under pressure in a canister sealed with a metering valve.

  For nasal administration, either a solid or liquid carrier can be used. Solid carriers include, for example, crude powder having a particle size in the range of about 20 to about 500 microns, and such formulations are administered by rapid inhalation through the nasal cavity. When a liquid carrier is used, the preparation can be administered as a nasal spray or nasal spray, and it can contain an oil or aqueous solution of the active ingredient.

In addition to the above formulation, the formulation may optionally include one or more additional drugs, such as other antibiotics, anti-inflammatory agents, antifungal agents, antiviral agents, immunomodulators, antiprotozoal agents, steroid agents, decongestants Agents, bronchodilators, etc. can be included or administered simultaneously.
For example, the disclosed compounds can be administered concurrently with a medicament such as ibuprofen, prednisone (corticosteroid) pentoxifylline, amphotericin B, fluconazole, ketoconazole, itraconazole, penicillin, ampicillin, amoxicillin and the like. The formulations may also contain preservatives, solubilizers, chemical buffers, surfactants, emulsifiers, coloring agents, flavoring agents and sweetening agents.

  For example, the term “derivative” in the term “bicyclic derivative” means a compound having a common core structure and substituted with various groups described herein. For example, all compounds represented by Structural Formula I are tetrahydro-β-carboline derivatives and have Structural Formula I as a common nucleus.

  In the structural formulas depicted herein, the dashed lines indicate bonds where the depicted or portion or group is attached to the rest of the molecule. For example, a broken line in R4-i indicates a bond in which the drawn group is bonded to another structural formula. A dashed or solid line across a bond in the ring, for example, a solid line from R11 of R4-i indicates that the bond shown can be attached to any substitutable atom in the ring. The zigzag line indicates either the cis or trans configuration of the respective substituent for the bond represented by the dashed line.

  The term “aryl” group means carbocyclic aromatic groups such as phenyl, naphthyl and anthracyl. The term `` heteroaryl '' group is imidazolyl, isoimidazolyl, thienyl, furanyl, pyridyl, pyrimidyl, pyranyl, pyrazolyl, pyrrolyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, 1,2,3-triazolyl, 1,2,3 Heteroaromatic groups such as 4-triazolyl and tetrazolyl are meant. As used herein, a “heteroaryl” group is a carbocyclic 5-membered ring containing at least one N, S, or O atom and two double bonds, or at least one N, S, or O atom. And a carbocyclic six-membered ring containing three double bonds.

The term “non-aromatic heterocyclic” generally refers to 4 to 4 wherein one or more ring carbons, preferably 1 to 4 ring carbons, are each replaced by a heteroatom such as N, O or S. By non-aromatic ring system having 8 members, preferably 5-6 members.
Examples of non-aromatic heterocycles are 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, [l, 3] -dioxalanyl, [1,3] -dithiolanyl, [l , 3] -dioxanyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl, 4-thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, Including 3-pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl, 5-diazolonyl, N-substituted diazolonyl and 1-phthalimidinyl.

The disclosed compounds can contain one or more chiral centers. The presence of chiral centers in the molecule results in stereoisomers. For example, a pair of optical isomers called “enantiomers” exist for any chiral center in the molecule. A pair of diastereomers exists for every chiral center in a compound having two or more chiral centers.
For example, when the structural formula does not specify stereochemistry, as in Structural Formula I, these formulas may represent enantiomers without the corresponding optical isomer, racemic mixtures, one enantiomer for that corresponding optical isomer. Rich mixture, diastereomers that do not contain other diastereomers, a pair of diastereomers that do not contain other diastereomeric pairs, a mixture of diastereomers, a mixture of diastereomeric pairs, one diastereomer Is a mixture of diastereomers that is abundant with respect to the other diastereomer (s), and a mixture of diastereomeric pairs with one diastereomer pair being abundant with respect to the other diastereomer pair (s) It should be understood to encompass

  The term “alkyl” used alone or as part of a larger moiety (eg, aralkyl, alkoxy, alkylamino, alkylaminocarbonyl, haloalkyl) is a fully saturated, linear or branched non-aromatic It is a hydrocarbon. Generally, a straight chain or branched alkyl group has 1 to about 10 carbon atoms, preferably 1 to about 5 carbon atoms, unless otherwise specified. Examples of suitable straight or branched alkyl groups include methyl, ethyl, n-propyl, 2-propyl, w-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl or octyl. A C1-C10 linear or branched alkyl group or a C3-C8 cyclic alkyl group may also be meant as a “lower alkyl” group. An “alkoxy” group refers to an alkyl group attached through an intervening oxygen atom, for example, methoxy, ethoxy, 2-propyloxy, tert-butoxy, 2-butyloxy, 3-pentyloxy, and the like.

  As used herein, the terms “optionally halogenated alkyl” and “optionally halogenated alkoxy” are substituted with one or more —F, —Cl, —Br or —I. Each group is included.

As used herein, terms such as “alkanoyl”, “aroyl” and the like indicate each group attached through an intervening carbonyl, such as — (CO) CH ₂ CH ₃ , benzoyl, and the like. As used herein, terms such as “alkanoyloxy”, “aroyloxy” and the like refer to the respective groups attached through an intervening carboxylate, such as —O (CO) CH ₂ CH ₃ , —O (CO) C. ₆ H ₅ etc. are shown.

  The term “cycloalkyl group” is a cyclic alkyl group having from 3 to about 10 carbon atoms, preferably from 3 to about 7 carbon atoms. Examples of suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. A “cycloalkoxy” group refers to a cycloalkyl group attached through an intervening oxygen atom, such as cyclopentyloxy, cyclohexyloxy, and the like.

  The term “aliphatic group” includes branched and straight chain alkyl groups containing one or more carbon-carbon unsaturated units, ie, carbon-carbon double or triple bonds. An alicyclic group is a cyclic aliphatic group such as cyclohexenyl or cyclopentenyl.

“Aralkyl”, “heteroaralkyl”, “cycloalkylalkyl”, “alicyclic alkyl” and “non-aromatic heterocyclic alkyl” are aryl, heteroaryl, cycloalkyl, alicyclic, respectively, attached through an alkyl chain. And a non-aromatic heterocyclic group such as benzyl, —CH ₂ —CH ₂ -pyridine, (3-cyclohexyl) propyl and the like.

As used herein, biaryl, biheteroaryl, aryl-heteroaryl and heteroaryl-aryl are two aryl groups joined by one covalent bond, two heteroaryl groups joined by one covalent bond, An aryl and heteroaryl group bonded by one covalent bond and a heteroaryl and aryl group bonded by one covalent bond are shown.
Biaryl, biheteroaryl, heteroaryl-aryl and aryl-heteroaryl groups include biphenyl, bipyridyl, pyrimidyl-phenyl, and phenyl-pyridyl, respectively. When a biaryl, biheteroaryl, heteroaryl-aryl or aryl-heteroaryl group is a substituent as defined for R4 in structural formula I, the first listed group is the rest of the molecule, i.e. in structural formula I. To "L". For example, when R4 in Structural Formula I is a phenyl-pyridyl group, phenyl in the phenyl-pyridyl group is bonded to L.

An “acyclic” group is a substituent that does not contain a ring. A “monocyclic” group includes only one ring, eg, a phenyl ring that is not fused to another ring. A “polycyclic” group is a group containing multiple fused rings, such as naphthyl.
A “substitutable atom” is any atom such as nitrogen or carbon that is bonded to a hydrogen atom by only one covalent bond, in which case the hydrogen atom can be replaced by another group. A “substitutable ring atom” in an aromatic ring is any atom that is bonded to a hydrogen atom by only one covalent bond, such as carbon or nitrogen, in which case the hydrogen atom is replaced by another group. obtain.

Suitable substituents are those that do not substantially interfere with the pharmaceutical activity of the disclosed compound. A compound or group may have one or more substituents that may be the same or different. Examples of suitable substituents for substitutable carbon atoms in alkyl, aliphatic groups, cycloalkyl, alicyclic groups, non-aromatic heterocyclic groups, aryl or heteroaryl groups are -OH, halogen (-Br , -Cl, -I and -F), -R, -OR, -CH ₂ R, -CH ₂ CH ₂ R, -OCH ₂ R, -CH ₂ OR, -CH ₂ CH ₂ OR, -CH ₂ OC (O) R, -O-COR, -COR, -SR, -SCH ₂ R, -CH ₂ SR, -SOR, -SO ₂ R, -CN, -NO ₂ , -COOH, -SO ₃ H,- _{NH 2, -NHR, -N (R} ) 2, -COOR, -CH 2 COOR, -CH 2 CH 2 COOR, -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 ₂ NH ₂ , -SO ₂ NHR , -SO ₂ NR ₂ , -SH, -SO _k R (k is 0, 1 or 2) and -NH-C (= NH) -NH ₂ .

Each R is independently an optionally substituted alkyl, cycloalkyl, benzyl, aromatic, heteroaromatic or N-anilinyl group. Preferably R is unsubstituted. In addition, —N (R) ₂ can be taken together to form a substituted or unsubstituted heterocyclic group such as pyrrolidinyl, piperidinyl, morpholinyl and thiomorpholinyl. Examples of substituents in the group represented by R are amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl , Hydroxy, haloalkoxy or haloalkyl.

Suitable substituents on the nitrogen of a heterocyclic group or heteroaromatic group, -R ', - N (R ') 2, -C (O) R ', - CO 2 R, -C (O) C (O) R ', - C (O) CH 2 C (O) R', - SO 2 R ', - SO 2 N (R') 2, -C (= S) N (R ') 2, - C (= NH) -N (R ') ₂ and -NR'SO ₂ R' (where R 'is hydrogen, optionally substituted, alkyl, alkoxy, cycloalkyl, cycloalkoxy, phenyl , Phenoxy, benzyl, benzyloxy, heteroaromatic or heterocyclic groups).
Examples of the substituent in the group represented by R ′ are amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkyl Including carbonyl, hydroxy, haloalkoxy or haloalkyl. Preferably R ′ is not substituted.

  Advantageously, the present invention also provides kits for use by consumers to treat diseases. The kit describes a) a pharmaceutical composition comprising an antibiotic and a pharmaceutically acceptable carrier, vehicle or diluent, and optionally b) a method of using the pharmaceutical composition to treat a particular disease. Includes instructions for use. The instructions for use may also indicate that the kit is intended to treat the disease while substantially reducing the attendant impairment of side effects associated with antibiotic administration.

A “kit” used for immediate application includes a container for containing a unit dosage form such as a divided bottle or a divided foil pocket. The container can be any conventional form or form known in the art made from pharmaceutically acceptable materials, such as paper or cardboard boxes, glass or plastic bottles or jars, resealable bags (e.g., different It can be a “refill” of tablets for placement in a container), or a blister pack with individual doses to be pushed out of the pack according to a treatment schedule.
The container used may depend on the exact dosage form involved. For example, in general, a conventional cardboard box will not be used to contain a liquid suspension. One or more containers may be used together in a single package for selling a single dosage form. For example, a tablet can be placed in a bottle that can then be placed in a box.

  An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). In general, a blister pack consists of a sheet of relatively rigid material, preferably covered with a foil of a transparent plastic material. A storage part is formed in the plastic foil during the packaging process. The receptacle may have the size and shape of the individual tablets or capsules to be packed, or it may have the size and shape to accommodate a large number of tablets and / or capsules to be packed. The tablets or capsules are then placed in the storage accordingly and the sheet of relatively stiff material is sealed against the plastic foil at the surface of the foil opposite the direction in which the storage was formed. . As a result, the tablets or capsules are individually sealed or collectively sealed as desired in the storage between the plastic foil and the sheet. Preferably, the strength of the sheet is such that the tablet or capsule can be taken out of the blister pack by manually applying pressure to the storage portion to form an opening at the location of the storage portion. The tablet or capsule can then be removed from the opening.

  It may be desirable to provide a memory aid document, wherein the memory aid document is of the type that includes information and instructions for a doctor, pharmacist or subject, eg, adjacent to a tablet or capsule In the form of a number, whereby the number corresponds to the number of days of the regimen in which to take the tablet or capsule so identified, or to a card containing the same type of information. Another example of such a memory aid is, for example, “first week, Monday, Tuesday”, etc., etc., “second week, Monday, Tuesday, ...”, etc. Is the calendar printed on the card. Other variations of memory assistance will be readily apparent. A “daily dose” can be a single tablet or capsule or several tablets or capsules taken that day.

  Another specific embodiment of the kit is a dispenser designed to dispense daily doses one by one. Preferably, the dispenser includes a memory aid to further facilitate compliance of the regimen. An example of such a memory aid is a mechanical counter that indicates the number of daily doses dispensed. Another example of such a memory aid is, for example, a liquid crystal display or audio that outputs the day when the last daily dose was taken and / or reminds the day when the next dose should be taken A battery-powered microchip memory combined with a caution signal.

Illustrative Example 1: Synthesis of PPAT inhibitors of structural formula I:

To a stirred solution of amine 1 in CH ₂ Cl ₂ is added aldehyde 2 followed by TFA. The resulting solution is heated at reflux overnight. After concentration, the solid formed is filtered, washed with hexane and dried to give 3. 3 is stirred in a vial with DMF, benzaldehyde 4 at room temperature and AcOH is added followed by NaBH (OAc) ₃ . The resulting solution is heated at 50 ° C. overnight. Excess benzaldehyde may be added to complete the reaction. The reaction mixture is taken up in EtOAc, washed with saturated NaHCO ₃ , brine and dried (Na ₂ SO ₄ ) to give 5 which is further purified by flash chromatography.

Example 2: PPAT inhibitor 2- (4- (2H-tetrazol-5-yl) benzyl) -1- (2,3-dichlorophenyl) -2,3,4,9-tetrahydro-1H-pyrido [3, Synthesis of 4-b] indole:

  To a stirred solution of tryptamine (3.2 g, 20 mmol) in dichloroethane (100 mL) was added 2,3-dichlorobenzaldehyde (3.5 g, 20 mmol) followed by TFA (0.5 mL). The resulting solution was heated at reflux overnight. After concentration, the solid formed was filtered, washed with hexane and dried to give 1 as a pale yellow solid in quantitative yield.

To a 15 mL vial with a screw cap, 1 (316 mg, 1.0 mmol), DMF (5 mL), 4-cyanobenzaldehyde (300 mg, 2.3 mmol) and AcOH (200 μL) were added at room temperature. To this solution was added NaBH (OAc) ₃ (640 mg, 3 mmol). The resulting solution was heated at 50 ° C. overnight. Additional 4-cyanobenzaldehyde (200 mg, 1.5 mmol) and NaBH (OAc) ₃ (210 mg, 1 mmol) were added to the solution. After heating at 50 ° C. overnight, the solution was taken up in EtOAc (50 mL). The organic solution was washed with saturated NaHCO ₃ (25 mL), brine (10 mL), dried (Na ₂ SO ₄ ) and purified by flash chromatography (acetone: hexane = 20: 80) as a white solid 3 (260 mg, 60%) was obtained.

¹ H NMR (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 (1 set of m, 11H); LC / MS ES- 430 (M-1);> 95% purity

A 15 mL vial with a screw cap was charged with 2 (140 mg, 0.32 mmol) followed by MeOH (5 mL). To this was added NaN ₃ (150 mg, 2.5 mmol) followed by ZnBr ₂ (225 mg, 1 mmol). The suspension was heated at 100 ° C. overnight. Additional NaN ₃ (150 mg, 2.5 mmol) was added followed by heating at 100 ° C. overnight. After concentration, the residue was triturated with 1N HCl followed by CHCl ₃ and dried to give a solid that was purified by flash chromatography (EtOAc) to give 3 (100 mg, 70%) as a pale yellow solid. It was.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.61 and 2.85 (2 m, 2H + 2H), 3.64 and 3.80 (2 d, 2H J = 13.6 Hz), 5.31 (s, 1H), 6.9-8.0 (1 set of m, 11H): LC / MS ES- 473 (M-1), ES + 475 (M + 1),> 95% purity

Example 3: PPAT inhibitor 1- (3- (1H-tetrazol-5-yl) phenyl) -2- (2,3-dichlorobenzyl) -2,3,4,9-tetrahydro-1H-pyrido [3 , 4-b] indole synthesis:

To a stirred solution of tryptamine (1.60 g, 10 mmol) in dichloroethane (50 mL) was added 3-cyanobenzaldehyde (1.31 g, 10 mmol) followed by TFA (0.25 mL). The resulting solution was heated at reflux overnight. After concentration, the solid was isolated on a filter, washed with hexane and dried to give 1 as a pale yellow solid in quantitative yield.
¹ H NMR (400MHz, DMSO-d ₆ ) δ 2.87 (m, 2H), 3.17 (m, 2H), 5.52 (s, 1H), 7.0-7.7 (one set of m, 8H), 10.65 (s, 1H LC / MS; ES + 274 (M + 1),> 95% purity.

Three 15 mL vials with screw caps were charged with 1 (450 mg / respectively, 1.7 mmol / respectively) followed by n-BuOH / H ₂ O (3 m / 3 mL each). To this was added NaN ₃ (130 mg, 2.0 mmol) followed by ZnBr ₂ (450 mg, 2 mmol). The suspension was heated at 130 ° C. overnight. After addition of H ₂ O and hexane, the solid was isolated on a filter and dried to give 2 (1.50 g total, 95%) as a white solid.
¹ H 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 (1 set of m, 8H), 10. 60 (s, 1H); ES + 317 (M + 1), ES- 315 (M-1),> 95% purity.

In a 15 mL vial with a screw cap, add 2 (160 mg, 0.5 mmol) followed by DMF / DCM (2 mL / 6 mL), 2,3-dichlorobenzaldehyde (153 mg, 0.9 mmol) and AcOH (200 μL) At room temperature. To this solution was added NaBH (OAc) ₃ (250 mg, 1.2 mmol). The resulting solution was heated at 40 ° C. overnight. The solution is poured into H ₂ O (20 mL) to form a solid that is collected, washed with hexane, dried, purified by chromatography (DCM: MeOH = 95: 5) and then as a yellow solid. (130 mg, 55%) was obtained.
¹ H NMR (400MHz, CD ₃ OD) δ 3.16 (m, 2H), 3.35 and 3.60 (2 m, 2H), 4.33 (ABq, 2H, J = 14.4Hz), 5.63 (s, 1H), 7.0- 8.1 (1 set of m, 11H); LC / MS ES + 475 (M + 1) ES- 473 (M-1)> 95% purity

Example 4: Bacteria rely on PPAT, a common target for antibiotics
A gene for PPAT called coaD (or kdtE) has been identified: Geerlof et al., “Purification and characterization of Phosphopantetheine Adenylyltransferase from E. Coli” J. Biol., the entire teachings of which are incorporated herein by reference. See Chem., 1999, 274 (38), pp. 27105-11. The gene sequence is searched in various bacteria and mammals using the BLAST® (Basic Local Alignment Search Tool, available online at http://www.ncbi.nkri.nih.gov/BLAST/) It was done. The results are shown in Table 2.

  It can be seen that PPAT is highly conserved through various bacterial pathogens. Therefore, PPAT is a common target for antibiotics. Furthermore, although PPAT is present in mammalian cells, the mammalian sequences are sufficiently different, indicating that the disclosed PPAT inhibitors can be selective for bacterial PPAT.

The PPAT gene, coaD, is split from various bacteria by allelic exchange: eg, Freiberg, described above by Geerlof et al., And all their teachings, incorporated herein by reference. Et al., 2001. "Identification of novel essential Escherichia coli genes conserved among pathogenic bacteria" J Mol Microbiol Biotechnol 2001, 3, pp 483-9.
The survival of E. coli, Bacillus subtilis, Staphylococcus aureus and Staphylococcus pneumoniae in complex growth media is studied. The inability of bacteria modified without the coaD gene indicates that PPAT is required for bacterial survival and is therefore a potential target for antibiotics.

Further experiments on the survival of E. coli in media containing exogenous dephospho-CoA and / or CoA can be tested. Mammals, including human cells, can make CoA from pantothenate (vitamin B ₅ ) captured from the environment. Thus, in human subjects, human cells / tissues can supply CoA to bacteria that cannot synthesize CoA. The inability of E. coli modified in media containing exogenous dephospho-CoA and / or CoA further indicates that PPAT can be an antibacterial target.

Example 5: Kinetic assay for PPAT inhibition
IC ₅₀ (inhibitory concentration at 50%) values of the disclosed compounds against PPAT can be measured at various concentrations ranging from 0.003 to 200 μg / ml of compound. A compound with an IC ₅₀ value> 200 may have an IC ₅₀ that can be measured using different assays. These inhibition assays can be performed in 96-well assay plates using methods similar to the screening assays described above.
Reaction buffer in a total volume of 100μl, 20mM Hepes (pH 7.5) , l00mM NaCl, 1mM MgCl 2, 0.5mM DTT, 0.006% Brij 35,10% glycerol, 25 [mu] M PPT, 0.5 mM ATP, 0.2 units pyro Should contain phosphatase, 200ng PPAT. The reaction is carried out for 2 minutes and then stopped with 150 ml malachite green reagent. After 10 minutes of color development, the absorption is measured at 650 nm. IC ₅₀ is determined by fitting the data to a four parameter method using XLfit (ID Business Solutions Inc., Cambridge, MA). IC ₅₀ values are derived from the curve as the concentration of compound that gives 50% inhibition of the enzymatic reaction.

Purified PPAT is required to perform the IC ₅₀ assay. The E. coli PPAT gene is cloned into the pET28a expression vector (Novagen, Inc., Madison, WT) and expressed in E. coli BL21 (DE3) cells. The chromatographic purification method uses Q-Sepharose, gel filtration and MonoQ chromatography as follows. The method is described in detail in the aforementioned Geerlof et al.

Each cell pellet is suspended in 4 volumes of cell lysis buffer (50 mM KH ₂ PO ₄ pH 8.0, 100 mM NaCl, 2 mM EGTA, and 10% glycerol). Cells should be ground by passing 4 times through a Microfluidics cell grinder and the cell lysate should be centrifuged at 3,000 g for 20 minutes. The supernatant was then added to a pre-equilibrated Q-sepharose column (10 mM Tris-HCl pH 8.0, 0.1 mM EGTA, 1 mM PMSF, 100 mM NaCl, 10% glycerol, 0.1% p-mercaptoethanol, and 0.02% Brij 35 ). PPAT is eluted with a NaCl gradient (0.1-1 M) in equilibration buffer. Large peak fractions were pooled and concentrated, followed by Sephacryl S200 HR column (10 mM Tris-HCl pH 7.5, 150 mM NaCl, 0.lmM EGTA, 0.lmM PMSF, 10% glycerol, 0.1% β-mercaptoethanol, and 0.02% Call Brij 35). Elute PPAT with the same buffer. Accumulate large peak fractions onto a pre-equilibrated MonoQ column (10 mM Tris-HCl, pH 7.0, 0.lmM EGTA, 0.lmM PMSF, 10% glycerol, 0.1% β-mercaptoethanol, and 0.02% Brij 35) Fill. PPAT should be eluted with a gradient of NaCl from 100 mM to l000 mM. The peak fractions are pooled and dialyzed in storage buffer (10 mM MOPS pH 7.0, 150 mM NaCl, 0.1 mM EGTA, 50% glycerol, 0.02% Brij 35) and then stored at −20 ° C. Data from these experiments for the compounds of the invention are shown in Table 3.

Example 6: Measurement of antibiotic activity of disclosed PPAT inhibitors against drug-resistant bacteria The effect of potency, spectrum, target specificity and serum is assessed by measuring MIC (minimum inhibitory concentration). For a panel of pathogens, the lowest concentration is μg / mL in a series of 2-fold dilutions of compounds that completely inhibit growth. Strains containing a panel of bacteria are obtained from the American Type Culture Collection (ATCC, Manassas, VA) or are genetically modified to express different levels of PPAT. ATCC strains include the following: E. coli (ATCC 35218), Staphylococcus aureus (ATCC 700699) and Enterococcus faecium (ATCC 700221). Other strains include Staphylococcus aureus RN4220, E. coli WO-0159, E. coli WO-0153 and Bacillus subtilis BD170 in which endogenous PPAT is disrupted and complemented with PPAT under the control of an inducible promoter, P _space .

The MIC assay is basically incorporated herein by reference in its entirety, with the exception that both serum-containing and serum-free Tryptic Soy broth and Mueller Hinton broth are used as growth media. As described in the NCCLS Recommendation (National Center for Clinical Laboratory Standards, 1997, (Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria the Grow Aerobically), 4th edition; NCCLS document M7-A4. NCCLS, Wayne, PA.) Is done. The concentration range tested is 200-0.39 mcg / ml. The desired final concentration of 50-fold concentration is made by 2-fold serial dilution in a 96-well microtiter plate, after which 2 μL is transferred to the assay plate. Cells are grown in appropriate medium and diluted to a final OD ₆₀₀ of 0.001 before seeding 98 μL in assay plates. The final volume in each assay well is 100 μL. Read the assay plate after overnight incubation at 37 ° C. MIC is measured as the lowest concentration that produces> 80% growth inhibition.

Related Application Claim priority of US Provisional Application No. 60 / 991,520 at 006-1. The contents of all patents, patent applications and references cited throughout this specification are hereby incorporated by reference in their entirety.

Government support This invention was made with government support from the National Institutes of Health. The government has certain rights in the invention.

Claims (25)

Structural formula I:

[Where:
Ring A is an aryl or heteroaryl group, optionally substituted at substitutable ring atoms;
J is -O-, -S- or -NR2-, wherein R2 is -H or optionally substituted C1-C5 alkyl; or
J is -NR2'- (wherein R2 'is an optionally substituted aryl, aralkyl, heteroaryl, heteroaralkyl, C3-C7 alicyclic group or C3-C7 cycloalkyl) Is;
R3 is an optionally substituted aryl, aralkyl, heteroaryl, heteroaralkyl, C3-C7 alicyclic group or C3-C7 cycloalkyl;
L is — (CH ₂ ) —, — (CO) —, — (CS) —, — (SO) — or — (SO ₂ ) —;
R4 is aryl, biaryl, heteroaryl, biheteroaryl, heteroaryl-aryl, aryl-heteroaryl, aralkyl, heteroaralkyl, C1-C8 aliphatic group, C3-C7 cycloalkyl, C5-C7 alicyclic group or A 3-7 membered non-aromatic heterocyclic group;
Here, R4 is halogen,-(CO) OR ^a ,-(CO) O (CO) R ^a ,-(CS) OR ^a ,-(SO) OR ^a , SO ₃ R ^a , -OSO ₃ R ^a , -P (OR ^a ) ₂ ,-(PO) (OR ^a ) ₂ , -O (PO) (OR ^a ) ₂ , -B (OR ^a ) ₂ ,-(CO) NR ^b ₂ , -NR ^c ( Optionally substituted with CO) R ^a , —SO ₂ NR ^b ₂ or —NR ^c SO ₂ R ^a ;
R5 is -H,-(CO) OR ^a ,-(CO) O (CO) R ^a ,-(CS) OR ^a ,-(SO) OR ^a , SO ₃ R ^a , -OSO ₃ R ^a ,- P (OR ^a ) ₂ ,-(PO) (OR ^a ) ₂ , -O (PO) (OR ^a ) ₂ , -B (OR ^a ) ₂ ,-(CO) NR ^b ₂ , -NR ^c (CO) R ^a , —SO ₂ NR ^b ₂ or —NR ^c SO ₂ R ^a ;
R6 is -H, -OH, halogen, or optionally substituted C1-C3 alkyl or alkoxy;
R ^a and R ^c are each independently —H, C1-C5 alkyl, aryl or aralkyl;
Each R ^b is independently —H, C1-C5 alkyl, aryl or aralkyl, or NR ^b ₂ is a non-aromatic heterocyclic group]
Or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, rotamer, tautomer, diastereomer or racemate thereof. Ring A may be optionally substituted with R1 in the substitutable ring atoms, R1 is each independently ^{_{halogen, -CN, -NO 2, -OR d}} , - (CO) R d, - (CO ) OR ^d , -O (CO) R ^d ,-(CO) O (CO) R ^d ,-(CS) OR ^d ,-(SO) OR ^d , -SO ₃ R ^d , -CONR ^e ₂ , -O (CO) NR ^e ₂ , -NR ^f (CO) NR ^e ₂ , -NR ^f (CO) OR ^d , -NR ^f COR ^d ,-(SO ₂ ) NR ^e ₂ , -NR ^f SO ₂ R ^d ,- (CH ₂ ) _s NR ^d ₂ , or optionally substituted aryl, aralkyl or C1-C5 alkyl (wherein R ^d and R ^f are each independently —H, aryl, aralkyl, C1-C5 alkyl or C1-C5 haloalkyl, each R ^e is independently -H, aryl, aralkyl or C1-C5 alkyl, or NR ^e ₂ is a non-aromatic heterocyclic group , S is from 0 to 5). 3. A compound according to claim 2, wherein ring A is an optionally substituted phenyl, pyrazyl, furanyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or imidazolyl group. R3 is optionally substituted, phenyl, pyridyl, benzo [l, 3] dioxolyl, 2,3-dihydro-benzo [l, 4] dioxin, pyrimidyl, pyrazyl, furanyl, pyrrolyl, thienyl, oxazolyl, Isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, naphthyl, quinolinyl, biphenyl, benzopyrimidyl, benzopyrazyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl or benzimidazolyl group Item 1. The compound according to Item 1. R4 is substituted phenyl, pyridyl, pyrimidyl, pyrazyl, naphthyl, biphenyl, phenyl-pyridyl, bipyridyl, quinolinyl, benzopyrimidyl, benzopyrazyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, or C2-C8 2. The compound according to claim 1, which is an alkenyl group. R4 is represented by the structural formulas R4-i to R4-vii:

(Where
each m is independently 0, 1, 2 or 3;
X is -N-, -CH- or -CR10-;
Ring B is C3-C6 cycloalkyl or C3-C6 cycloalkenyl;
Rings C and D are each independently aryl or heteroaryl;
R8 is -OR ^q or -NR ^r ₂ ;
R9 is -H, aryl, aralkyl or a C1-C6 aliphatic group;
R10 is each independently _{halogen, -CN, -NO 2, -CF 3} , -OCF 3, -OR i, - (CO) R i, - (CO) OR i, -O (CO) R i, -(CO) O (CO) R ⁱ ,-(CS) R ⁱ ,-(SO) OR ⁱ , -SO ₃ R ⁱ , -CONR ^j ₂ , -O (CO) NR ^j ₂ , -NR ^k (CO ) NR ^j ₂ , -NR ^k (CO) OR ⁱ , -NR ^k COR ⁱ ,-(SO ₂ ) NR ^j ₂ , -NR ^k SO ₂ R ⁱ ,-(CH ₂ ) _t NR ^j ₂ , or optionally Optionally substituted, aryl, aralkyl or C1-C5 alkyl;
R ⁱ and R ^k are each independently —H, aryl, aralkyl, C1-C5 alkyl or C1-C5 haloalkyl;
R ^j and R ^r are each independently -H, aryl, aralkyl or C1-C5 alkyl, or NR ^j ₂ and NR ^r ₂ are each independently a non-aromatic heterocyclic group. Yes;
R ^q is —H, or optionally substituted, aryl, aroyl, aralkyl, aralkanoyl, C1-C5 alkyl or C1-C5 alkanoyl;
t is 0-5)
6. The compound of claim 5, which is represented by one of: R4 is represented by the structural formulas R4-i ′ to R4-vii ′:

(Where
each m is independently 0, 1, 2 or 3;
R8 is -OH, C1-C5 alkoxy or C1-C5 alkanoyloxy;
R9 is -H or C1-C6 aliphatic group;
Each R10 is independently —OH, —NO ₂ , —F, —Cl, —Br, C1-C4 alkyl, C1-C4 alkoxy, —CF ₃ or —OCF ₃ )
7. The compound of claim 6, which is represented by one of: R3 is represented by structural formulas R3-i to R3-v:

(Where
Y is -N-, -CH- or -CR11-;
Z is —NR ^z —, —S— or —O—, wherein R ^z is —H or C1-C3 alkyl;
The variable w is 0, 1, 2 or 3;
R11 is each independently _{halogen, -CN, -NO 2, -CF 3} , -OCF 3, -OR 1, - (CO) R 1, - (CO) OR 1, -O (CO) R 1, -(CO) O (CO) R ¹ ,-(CS) OR ¹ ,-(SO) OR ¹ , -SO ₃ R ¹ , -CONR ^m ₂ , -O (CO) NR ^m ₂ , -NR ⁿ (CO ) NR ^m ₂ , -NR ⁿ (CO) OR ¹ , -NR ⁿ COR ¹ ,-(SO ₂ ) NR ^m ₂ , -NR ⁿ SO ₂ R ¹ ,-(CH ₂ ) _u NR ¹ ₂ , or optionally Optionally substituted, aryl, aralkyl or C1-C5 alkyl;
u is 0-5,
R ¹ and R ⁿ are each independently —H, aryl, aralkyl, C1-C5 alkyl or C1-C5 haloalkyl;
R ^m are each independently, -H, aryl, or aralkyl or C1-C5 alkyl, or NR ^m ₂ is a nonaromatic heterocyclic group)
5. The compound of claim 4, which is represented by one of: R3 is represented by structural formulas R3-i ′ to R3-v ′:

(Where
w is 0, 1, 2 or 3;
Each R11 is independently —OH, —NO ₂ , —F, —Cl, —Br, C1-C4 alkyl, C1-C4 alkoxy, —CF ₃ or —OCF ₃ )
9. The compound of claim 8, which is represented by one of: R4 is structural formula R10-i to R10-xix:

6. A compound according to claim 5 which is phenyl substituted with one of R11 is represented by structural formulas R11-i to R11-xxiii:

Wherein R is independently -H, aryl, aralkyl, C1-C5 alkyl or C1-C5 haloalkyl.
9. The compound of claim 8, which is represented by one of: R3 is, structural formulas R3 ^a ~R3 ^r:

2. The compound of claim 1, which is represented by one of: R4 is, the structural formula R4 ^a ~R4 ^q:

Wherein R8 is —NR ^y ₂ , —OH, C1-C5 alkoxy or C1-C5 alkanoyloxy (wherein R ^y is independently —H or C1-C3 alkyl).
2. The compound of claim 1, which is represented by one of: R3 is represented by one of structural formulas R3 ^{a to} R3 ^r ,
R4 is represented by one of structural formulas R4 ^a to R4 ^q, A compound according to claim 1. R5 is

The compound of claim 1, wherein Ring A is an aryl moiety; J is N (H); R3 is aryl optionally substituted with one or more halogens or heteroaryl; L is (CO) or (CH ₂ ) R4 is phenyl optionally independently substituted with one or more halogen, CO ₂ H or heteroaryl; R5 is H, alkyl, alkoxy, CO ₂ H or CO ₂ alkyl 2. The compound of claim 1, wherein R6 is H, alkyl or alkoxy. Ring A is a phenyl moiety; J is N (H); R3 is phenyl optionally substituted with one or more halogens or tetrazole; L is (CO) or (CH ₂ ) Yes; R4 is phenyl optionally optionally substituted with one or more halogen, CO ₂ H or heteroaryl; R5 is H, CO ₂ H or CO ₂ alkyl; R6 is H The compound of claim 1, wherein Ring A is a phenyl moiety; J is N (H); R3 is phenyl optionally substituted with tetrazole; L is CH ₂ ; R4 is optionally one or more halogens 2. A compound according to claim 1 which is independently substituted phenyl. The compound of claim 1, wherein the compound of formula I is selected from the group consisting of the individual compounds shown in Table 1. 2. A method of treating a bacterial infection in a subject comprising administering an effective amount of the compound of claim 1 to a subject in need of treatment of the bacterial infection. 21. The method of claim 20, wherein the compound of claim 1 is selected from the group consisting of the individual compounds shown in Table 1. 21. The method of claim 20, wherein the subject is a human. 21. The method of claim 20, wherein the infection is caused by a bacterium that expresses phosphopantetheine adenyl transferase. Infectious diseases include Acinetobacter, Bacillus, Campylobacter, Chlamydia, Chlamydophila, Clostridium, Citrobacter, Escherichia, Enterobacter, Enterococcus, Francisella, Hemophilus, Helicobacter, Klebsiella, Listeria, Moraxella, Mycobacterium, Neisseria, Proteus, Pseudomonas 21. The method of claim 20, caused by a bacterium of a genus selected from Serratia, Shigella, Stenotrophomonas, Staphylococcus, Streptococcus and Elsina. A pharmaceutical composition comprising the compound of claim 1.