EP2240493A2 - Dérivés de tétrahydro-bêta-carboline antibiotiques - Google Patents

Dérivés de tétrahydro-bêta-carboline antibiotiques

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Publication number
EP2240493A2
EP2240493A2 EP08872407A EP08872407A EP2240493A2 EP 2240493 A2 EP2240493 A2 EP 2240493A2 EP 08872407 A EP08872407 A EP 08872407A EP 08872407 A EP08872407 A EP 08872407A EP 2240493 A2 EP2240493 A2 EP 2240493A2
Authority
EP
European Patent Office
Prior art keywords
alkyl
aryl
compound
independently
aralkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP08872407A
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German (de)
English (en)
Inventor
Roger Frechette
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biota Scientific Management Pty Ltd
Original Assignee
Biota Scientific Management Pty Ltd
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Filing date
Publication date
Application filed by Biota Scientific Management Pty Ltd filed Critical Biota Scientific Management Pty Ltd
Publication of EP2240493A2 publication Critical patent/EP2240493A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Definitions

  • the present invention relates to compositions which are PPAT inhibitors and methods and uses thereof.
  • antibiotics were developed that led to significant reductions in mortality.
  • widespread use has led to the rise of antibiotic resistant bacteria, e.g., methicillin resistant Staphyloccocus aureus (MRS A), vancomycin resistant enterococci (VRE), and penicillin-resistant Streptococcus pneumonias (PRSP).
  • MRS A methicillin resistant Staphyloccocus aureus
  • VRE vancomycin resistant enterococci
  • PRSP penicillin-resistant Streptococcus pneumonias
  • Some bacteria are resistant to a range of antibiotics, e.g., strains of Mycobacterium tuberculosis resist isoniazid, rifampin, ethambutol, streptomycin, ethionamide, kanamycin, and rifabutin.
  • global travel has spread relatively unknown bacteria from isolated areas to new populations.
  • Infectious bacteria employ the coenzyme A (CoA) biosynthesis pathway, and, particularly in the penultimate step of the pathway, depend on phosphopantetheine adenyl transferase (PPAT), which transfers an adenyl moiety from adenosine triphosphate (ATP) to 4'-phosphopanthetheine, forming dephospho-CoA (dPCoA).
  • PPAT phosphopantetheine adenyl transferase
  • ATP adenosine triphosphate
  • dPCoA dephospho-CoA
  • the present invention relates to certain bicyclic PPAT inhibitors.
  • the disclosed compounds have antibiotic activity against bacteria, including drug-resistant bacteria.
  • compounds that are PPAT inhibitors, methods of treatment with the disclosed PPAT inhibitors, and pharmaceutical compositions comprising the disclosed PPAT inhibitors are provided herein.
  • the invention provides a method of treating a subject for a bacterial infection, comprising administering to a subject in need of treatment for a bacterial infection an effective amount of a compound represented by structural Formula I:
  • the invention is useful for treating (therapeutically or prophylactically) bacterial infections, particularly infections caused by bacteria that depend on the CoA biosynthesis pathway, and more particularly, infections caused by bacteria that express the PPAT enzyme. Furthermore, it is useful against bacteria that have developed antibiotic resistance, especially multiple drug resistant strains, because it is believed to act through a different mechanism than existing, widely used antibiotics.
  • the invention is generally related to methods, compounds, and pharmaceutical compositions for treating and preventing bacterial infections.
  • the invention relates to tetrahydro- ⁇ -carboline derivatives that are PPAT inhibitors.
  • the compound is represented by structural Formula I:
  • J is -O-, -S-, or -NR2-, wherein R2 is -H or optionally substituted C1-C5 alkyl; or, J is -NR2'-, wherein R2' is optionally substituted aryl, aralkyl, heteroaryl, heteroaralkyl, C3-C7 cycloaliphatic, or C3-C7 cycloalkyl;
  • R3 is optionally substituted aryl, aralkyl, heteroaryl, heteroaralkyl, C3-C7 cycloaliphatic, or C3-C7 cycloalkyl;
  • L is -(CH 2 )-, -(CO)-, -(CS)-, -(SO)-, or -(SO 2 )-;
  • R4 is an aryl, biaryl, heteroaryl, biheteroaryl, heteroaryl-aryl, aryl-heteroaryl, aralkyl, heteroaralkyl, C1-C8 aliphatic, C3-C7 cycloalkyl, C5-C7 cycloaliphatic, or a 3-7 membered non-aromatic heterocyclic group; wherein R4 can be substituted with halogen, -(C0)0R a , -(C0)0(C0)R a , - (CS)OR a , -(SO)OR a , SO 3 R a , -OSO 3 R a , -P(OR a ) 2 , -(PO)(OR a ) 2 , -
  • R5 is -H, -(C0)0R a , -(C0)0(C0)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(0R a ) 2 , -(C0)NR b 2 , -NR c (C0)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; each R a and R c are, 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 nonaromatic heterocyclic group.
  • ring A in structural Formula I is an optionally substituted heteroaryl group, for example, an optionally substituted pyrazyl, furanyl, pyrrolyl, thienyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, or imidazolyl group.
  • Suitable optional substituents for substitutable ring atoms in Ring A are provided herein below in the section describing substituents for aryl and heteroaryl groups. More preferably, Ring A is optionally, independently, substituted at any substitutable ring atom with Rl.
  • Each Rl are, independently, halogen, -CN, -NO 2 , -CF 3 , -OCF 3 , -OR d , - (C0)R d , -(C0)0R d , -0(C0)R d , -(C0)0(C0)R d , -(CS)OR d , -(SO)OR d , -SO 3 R d , - C0NR e 2 , -0(C0)NR e 2 , -NR f (C0)NR e 2 , -NR f (C0)0R 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.
  • s is from 0 to 5
  • each R d and R f are, independently, -H, aryl, aralkyl, C1-C5 alkyl, or C1-C5 haloalkyl
  • each R c are, independently, -H, aryl, aralkyl, or C1-C5 alkyl
  • NR e 2 is a nonaromatic heterocyclic group, for example, piperidinyl, morpholinyl, and the like.
  • Rl is halogen, -CN, -NO 2 , -CF 3 , -OCF 3 , - OR d , -(C0)R d , -(C0)0R d , -0(C0)R d , -CONR e 2 , -0(C0)NR e 2 , -NR f (C0)0R d , - NR f C0R 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. Even more preferably, Rl is -H, -OH, -F, -CH 3 , -CF 3 , -OCH 3 or -OCF 3 . Most preferably, Rl is -H.
  • R3 in structural Formula I is an optionally substituted phenyl, pyridyl, benzo[l,3]dioxolyl, 2,3-dihydro-benzo[l,4]dioxinyl, pyrimidyl, pyrazyl, furanyl, pyrrolyl, thienyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, naphthyl, quinolinyl, biphenyl, benzopyrimidyl, benzopyrazyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzoisooxazolyl, benzothiazolyl, benzoisothiazolyl, or benzimidazolyl group. Suitable optional substituents for the group represented by R3 are provided herein below.
  • R3 in structural Formula I is represented by one of structural formulas R3-i to R3-v:
  • Y is -N-, -CH-, or -CRIl-;
  • Z is -NR Z -, -S-, or -O-, wherein R z is -H or C1-C3 alkyl, more preferably -H or methyl, or most preferably -H; the variable w is 0, 1, 2, or 3;
  • each RIl are, independently, halogen, -CN, -NO 2 , -CF 3 , -OCF 3 , -OR 1 , -(CO)R 1 , -(CO)OR 1 , -0(CO)R 1 , -(CO)O(CO)R 1 , -(CS)OR 1 , - (SO)OR 1 , -SO 3 R 1 , -C0NR m 2 , -0(C0)NR m 2 , -NR n (CO)NR m 2 , -NR 11 CCO)
  • each R 1 and R n are, independently, -H, aryl, or aralkyl, C1-C5 alkyl, or C1-C5 haloalkyl
  • each R m is independently -H, aryl, aralkyl, or C1-C5 alkyl, or NR m 2 is a nonaromatic heterocyclic group.
  • R3 in structural Formula I is represented by one of structural formulas R3-i' to R3-v':
  • R3-i' to R3-v' w is O, 1, 2, or 3, and each RIl is independently -OH, -NO 2 , -F, -Cl, -Br, C1-C4 alkyl, C1-C4 alkoxy, -CF 3 , Or -OCF 3 .
  • RIl is represented by one of structural formulas Rll-i to Rll-xxiii:
  • R3 is represented by one of structural formulas R3 a to R3 r :
  • R3 is represented by structural formula R3 e , or R3 is perfluorinated phenyl or tretrazole.
  • R4 in structural Formula I is optionally further substituted as described below in the section describing suitable substituents for aryl, heteroaryl, aliphatic, and cycloalkyl groups. More preferably, R4 is a substituted phenyl, pyridyl, pyrimidyl, pyrazyl, naphthyl, biphenyl, phenyl-pyridyl, quinolinyl, benzopyrimidyl, benzopyrazyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, or a C2-C8 alkenyl group. More preferably, R4 is represented by one of structural formulas R4-i to R4- vii:
  • each m is independently 0, 1, 2, or 3, and X is -N-, -CH-, or -CRlO-; 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 C1-C6 aliphatic; each RlO is independently halogen, -CN, -NO 2 , - CF 3 , -OCF 3 , -OR 1 , -(CO)R 1 , -(CO)OR 1 , -0(CO)R 1 , -(CO)O(CO)R 1 , -(CS)R 1 , -(SO)OR 1 , -SO 3 R 1 , -C0NR J 2, -0(C0
  • R4 is represented by one of 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;
  • each RlO is independently -OH, -NO 2 , -F, -Cl, -Br, C1-C4 alkyl, C1-C4 alkoxy, -CF 3 , or - OCF 3 .
  • R4 is aryl (e.g. phenyl) which is substituted by one of structural formulas R10-i to R10-xix:
  • R4 is represented by one of structural formulas R4 a to
  • R4 is represented by structural formula R4 a or R4 , or R4 is phenyl substituted with tetrazole.
  • R8 is -NR y 2 , -OH, C1-C5 alkoxy, or C1-C5 alkanoyloxy, wherein each R y is independently -H or C1-C3 alkyl. Even more preferably, R8 is - OH or C1-C4 alkoxy, or still more preferably, -OH, -OCH 3 , or -OCH 2 CH 3 . Most preferably, R8 is OCH 3 or -OCH 2 CH 3 .
  • R5 is:
  • R 5 is -H or -CO 2 H.
  • R8 is -OH, OCH 3 or- OCH 2 CH 3 .
  • R3 is represented by one of structural formulas R3-i to R3-v or R4 is represented by one of structural formulas 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 still another embodiment, in structural Formula I, R3 is represented by one of structural formulas R3-i' to R3-v' or R4 is represented by one of structural formulas 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'.
  • R3 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 .
  • 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 .
  • 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 .
  • 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 .
  • ring A is a phenyl moiety; J is N(H); R3 is phenyl optionally substituted one or more times with halogen or tetrazole; L is (CO) or (CH 2 ); R4 is phenyl optionally independently substituted one or more times with halogen, CO 2 H, or tetrazole; and R5 is H.
  • the compound of formula I is of the formula 5:
  • R 3 is a diazole, dioxolane, dioxane or benzene ring and R' and R" are each independently a hydrogen, halogen, carboxylic acid, alkyl, heterocycle, nitrile or hydroxyamide.
  • the compound of formula I is of the formula 6:
  • the compound is of formula I, wherein ring A is an aryl moiety; J is N(H); R3 is aryl optionally substituted one or more times with halogen or a heteroaryl; L is (CO) or (CH 2 ); R4 is phenyl optionally independently substituted one or more times with halogen, CO 2 H, or a heteroaryl; R5 is H, alkyl, alkoxyl, CO 2 H or C0 2 alkyl; and R6 is H, alkyl or alkoxyl.
  • the compound is of formula I, wherein ring A is a phenyl moiety; J is N(H); R3 is phenyl optionally substituted one or more times with halogen or tetrazole; L is (CO) or (CH 2 ); R4 is phenyl optionally independently substituted one or more times with halogen, CO 2 H, or a heteroaryl; R5 is H or CO 2 H; and R6 is H.
  • the compound is of formula I, wherein ring A is a phenyl moiety; J is N(H); R3 is phenyl optionally substituted with tetrazole; L is CH 2 ; and R4 is phenyl optionally independently substituted one or more times with halogen.
  • the compound, the compound of the method, and the compound of the pharmaceutical composition are each represented by the individual compounds provided in Table 1 :
  • the compounds of Table 1 can be used to treat a bacterial infection in a subject in need thereof.
  • compounds 4, 13, 22, 32, 49, 67, 71 and 72 can be used to treat a bacterial infection in a subject in need thereof.
  • a "subject” includes mammals, e.g., humans, companion animals (e.g., dogs, cats, birds, aquarium fish, reptiles, and the like), farm animals (e.g., cows, sheep, pigs, horses, fowl, farm-raised fish and the like) and laboratory animals (e.g., rats, mice, guinea pigs, birds, aquarium fish, reptiles, and the like).
  • the subject is a warm-blooded animal. More preferably, the subject is a mammal. Most preferably, the subject is human.
  • a subject in need of treatment has a bacterial infection (or has been exposed to an infectious environment where bacteria are present, e.g., in a hospital) the symptoms of which may be alleviated by administering an effective amount of the disclosed bicyclic derivatives.
  • a subject in need of treatment can have an infection for which the disclosed bicyclic derivatives can be administered as a treatment.
  • a subject in need of treatment can have an open wound or burn injury, or can have a compromised immune system, for which the disclosed PPAT inhibitors can be administered as a prophylactic.
  • a subject can be treated therapeutically or prophylactically. More preferably, a subject is treated therapeutically.
  • the subject is treated for a bacterial infection caused by a bacteria of a genus selected from Allochromatium, Acinetobacter, Bacillus, Campylobacter, Chlamydia, Chlamydophila, Clostridium, Citrobacter, Escherichia, Enterobacter, Enterococcus, Francisella, Haemophilus, Helicobacter, Klebsiella, Listeria,
  • a bacteria of a genus selected from Allochromatium, Acinetobacter, Bacillus, Campylobacter, Chlamydia, Chlamydophila, Clostridium, Citrobacter, Escherichia, Enterobacter, Enterococcus, Francisella, Haemophilus, Helicobacter, Klebsiella, Listeria,
  • Moraxella Mycobacterium, Neisseria, Proteus, Pseudomonas, Salmonella, erratia, Shigella, Stenotrophomonas, Staphylococcus, Streptococcus, Synechococcus, Vibrio, and Yersina.
  • the subject is treated for a bacterial infection from Allochromatium vinosum, Acinetobacter baumanii, Bacillus anthracis, Campylobacter jejuni, Chlamydia trachomatis, Chlamydia pneumoniae, Clostridium spp., Citrobacter spp., Escherichia coli, Enterobacter spp., Enterococcusfaecalis., Enterococcus faecium, Francis ella tularensis, Haemophilus influenzas, Helicobacterpylori, Klebsiella spp., Listeria moiwcytogenes, Moraxella catarrhalis, Mycobacterium tuberculosis, Neisseria meningitidis, Neisseria gonorrhoeae, Proteus mirabilis, Proteus vulgaris, Pseudomonas aeruginosa, Salmonella spp., Ser
  • a PPAT protein is a phosphopantetheine adenytransferase enzyme, i.e., systematic name ATP:pantetheine- 4'-phosphate adenylyltransferase, IUBMB systematic classification EC 2.7.7.3, (see International Union of Biochemistry and Molecular Biology, www.chem.qmul.ac.uk/iubmb/).
  • a subject is also concurrently treated for a fungal infection, for example, a fungal infection caused by a pathogenic dermatophyte, e.g., a species of the genera Trichophyton, Tinea, Microspormn, Epidermophyton and the like; or a pathogenic filamentous fungus, e.g., a species of genera such as Aspergillus, Histoplasma, Cryptococcus, Microspormn, and the like; or a pathogenic non- filamentous fungus, e.g., a yeast, for example, a species of the genera Candida,
  • a pathogenic dermatophyte e.g., a species of the genera Trichophyton, Tinea, Microspormn, Epidermophyton and the like
  • a pathogenic filamentous fungus e.g., a species of genera such as Aspergillus, Histoplasma, Cryptococcus, Microspormn, and the like
  • the subject is concurrently treated for a fungal infection resulting from a species of the genera Aspergillus or Trichophyton.
  • Trichophyton include, for example, T. mentagrophytes, T. rubrum, T. schoenleinii, T. tonsurans, T. verrucosum, and T. violaceum.
  • Species of Aspergillus include, for example, A. fumigatus, A.flavus, A. niger, A. amstelodami, A. candidus, A. carneus, A.
  • the subject is concurrently treated therapeutically for a fungal infection caused by a species of the genus Aspergillus selected from A. fumigatus, A. flavits, A. niger, A. canstelodami, A. candidus, A. carneus, A. nidulans, A oryzae, A. restrictus, A. sydowi, A. terreus, A. ustus, A.
  • the subject is concurrently treated therapeutically for a fungal infection caused by Aspergillus fumigatus or A spergillus niger, and most preferably, Aspergillus fumigatus.
  • an "effective amount" of a compound of the disclosed invention is the quantity that, when administered to a subject in need of treatment, improves the prognosis of the subject, e.g., delays the onset of and/or reduces the severity of one or more of the subject's symptoms associated with a bacterial infection.
  • the amount of the disclosed compound to be administered to a subject will depend on the particular disease, the mode of administration, co-administered compounds, if any, and the characteristics of the subject, such as general health, other diseases, age, sex, genotype, body weight and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors.
  • Effective amounts of the disclosed compounds typically range between about 0.01 mg/kg per day and about 100 mg/kg per day, and preferably between 0.1 mg/kg per day and about 10 mg/kg/day.
  • Techniques for administration of the disclosed compounds of the invention can be found in Remington: the Science and Practice of Pharmacy, 19' edition, Mack Publishing Co., Easton, PA (1995), the entire teachings of which are incorporated herein by reference.
  • a "pharmaceutically acceptable salt” of the disclosed compound is a product of the disclosed compound that contains an ionic bond, and is typically produced by reacting the disclosed compound with either an acid or a base, suitable for administering to a subject.
  • 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.
  • a suitable organic or inorganic acid such as hydrogen chloride, hydrogen bromide, acetic acid, perchloric acid and the like.
  • Compounds with a quaternary ammonium group also contain a counteranion such as chloride, bromide, iodide, acetate, perchlorate and the like.
  • Other examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g.
  • Salts of compounds containing a carboxylic acid or other acidic functional groups can be prepared by reacting with a suitable base.
  • Such a pharmaceutically acceptable salt may be made with a base which affords a pharmaceutically acceptable cation, which includes alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum salts and ammonium salts, as well as salts made from physiologically acceptable organic bases such as 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, dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine, collidine, quinine, quinoline, and basic amino acid such as lysine and arginine.
  • Certain compounds and their salts may also exist in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures thereof.
  • a "pharmaceutical composition” is a formulation containing the disclosed compounds in a form suitable for administration to a subject.
  • the pharmaceutical composition can be in bulk or in unit dosage form.
  • the unit dosage form can be in any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler, or a vial.
  • the quantity of active ingredient (i.e., a formulation of the disclosed compound or salts thereof) in a unit dose of composition is an effective amount and may be varied according to the particular treatment involved. It is appreciated that it may be necessary to make routine variations to the dosage depending on the age and condition of the patient.
  • the dosage will also depend on the route of administration. A variety of routes are contemplated, including topical, oral, pulmonary, rectal, vaginal, parenternal, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal and intranasal.
  • the compounds described herein, and the pharmaceutically acceptable salts thereof, can be used in pharmaceutical preparations 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 will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein. Techniques for formulation and administration of the disclosed compounds of the Invention can be found in Remington: the Science and Practice of Pharmacy, above.
  • the disclosed compounds or salts thereof can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, pills, powders, syrups, solutions, suspensions and the like.
  • the tablets, pills, capsules, and the like contain from about 1 to about 99 weight percent of the active ingredient and a binder such as gum tragacanth, acacias, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch or alginic acid; a lubricant such as magnesium stearate; and/or a sweetening agent such as sucrose, lactose or saccharin.
  • a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
  • 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 dye and a flavoring such as cherry or orange flavor, and the like.
  • aqueous or organic media for parental administration of the disclosed compounds, or salts, solvates, or hydrates thereof, can be combined with sterile aqueous or organic media to form injectable solutions or suspensions.
  • solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically- acceptable salts of the compounds.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the compounds may also be formulated as a depot preparation.
  • suitable formulations of this type include biocompatible and biodegradable polymeric hydrogel formulations using crosslinked or water insoluble polysaccharide formulations, polymerizable polyethylene oxide formulations, impregnated membranes, and the like.
  • Such long acting formulations may be administered by implantation or transcutaneous delivery (for example subcutaneously or intramuscularly), intramuscular injection or a transdermal patch.
  • they are implanted in, or applied to, the microenvironment of an affected organ or tissue, for example, a membrane impregnated with the disclosed compound can be applied to an open wound or burn injury.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials, for example, as an emulsion in acceptable oil, or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • suitable formulations may include biocompatible oil, wax, gel, powder, polymer, or other liquid or solid carriers.
  • Such formulations may be administered by applying directly to affected tissues, for example, a liquid formulation to treat infection of conjunctival tissue can be administered dropwise to the subject's eye, a cream formulation can be administer to a wound site, or a bandage may be impregnated with a formulation, and the like.
  • suitable pharmaceutical compositions are, for example, topical preparations, suppositories or enemas.
  • suitable pharmaceutical compositions are, for example, topical preparations, pessaries, tampons, creams, gels, pastes, foams or sprays.
  • the compounds may also be formulated to deliver the active agent by pulmonary administration, e.g., administration of an aerosol formulation containing the active agent from, for example, a manual pump spray, nebulizer or pressurized metered-dose inhaler.
  • pulmonary administration e.g., administration of an aerosol formulation containing the active agent from, for example, a manual pump spray, nebulizer or pressurized metered-dose inhaler.
  • Suitable formulations of this type can also include other agents, such as antistatic agents, to maintain the disclosed compounds as effective aerosols.
  • pulmonary refers to any part, tissue or organ whose primary function is gas exchange with the external environment, i.e., O 2 /CO 2 exchange, within a patient. "Pulmonary” typically refers to the tissues of the respiratory tract.
  • pulmonary administration refers to administering the formulations described herein to any part, tissue or organ whose primary function is gas exchange with the external environment (e.g., mouth, nose, pharynx, oropharynx, laryngopharynx, larynx, trachea, carina, bronchi, bronchioles, alveoli).
  • pulmonary is also meant to include a tissue or cavity that is contingent to the respiratory tract, in particular, the sinuses.
  • a drug delivery device for delivering aerosols comprises a suitable aerosol canister with a metering valve containing a pharmaceutical aerosol formulation as described and an actuator housing adapted to hold the canister and allow for drug delivery.
  • the canister in the drug delivery device has a head space representing greater than about 15% of the total volume of the canister.
  • the polymer intended for pulmonary administration is dissolved, suspended or emulsified in a mixture of a solvent, surfactant and propellant. The mixture is maintained under pressure in a canister that has been sealed with a metering valve.
  • a solid or a liquid carrier can be used for nasal administration.
  • the solid carrier includes a coarse powder having particle size in the range of, for example, from about 20 to about 500 microns and such formulation is administered by rapid inhalation through the nasal passages.
  • the formulation may be administered as a nasal spray or drops and may include oil or aqueous solutions of the active ingredients.
  • a formulation can optionally include, or be co-administered with one or more additional drugs, e.g., other antibiotics, antiinflammatories, antirungals, antivirals, immunomodulators, antiprotozoals, steroids, decongestants, bronchodialators, and the like.
  • additional drugs e.g., other antibiotics, antiinflammatories, antirungals, antivirals, immunomodulators, antiprotozoals, steroids, decongestants, bronchodialators, and the like.
  • the disclosed compound can be co-administered with drugs such as such as ibuprofen, prednisone (corticosteroid) pentoxifylline, Amphotericin B, Fluconazole, Ketoconazol, Itraconazol, penicillin, ampicillin, amoxicillin, and the like.
  • the formulation may also contain preserving agents, solubilizing agents, chemical buffers, surfactants, emulsifiers, colorants, odorants and sweeteners.
  • derivative e.g., in the term “bicyclic derivatives,” refers to compounds that have a common core structure, and are substituted with various groups as described herein.
  • all of the compounds represented by structural Formula I are tetrahydro- ⁇ -carboline derivatives, and have structural Formula I as a common core.
  • a dashed line indicates a bond by which the depicted or moiety or group is connected to the remainder of the molecule.
  • the dashed line in R4-i indicates the bond that connects the depicted group to another structural formula.
  • a dashed or solid line across a bond in a ring indicates that the represented bond can be connected to any substitutable atom in the ring.
  • a zig-zag line indicates either cis or trans arrangement of the respective substituents with respect to the bond represented by the dashed line.
  • aryl group refers to carbocyclic aromatic groups such as phenyl, naphthyl, and anthracyl.
  • heteroaryl refers to hetero aromatic groups such as imidazolyl, isoimidazolyl, thienyl, furanyl, pyridyl, pyrimidyl, pyranyl, pyrazolyl, pyrrolyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl, 1,2,3- triazolyl, 1,2,4-triazolyl, and tetrazolyl.
  • a "heteroaryl” group is a 5 membered carbocyclic ring containing at least one N, S, or O atom and two double bonds, or a 6 membered carbocyclic ring containing at least one N, S, or O atom and three double bonds.
  • nonaromatic heterocyclic refers to non-aromatic ring systems typically having four to eight members, preferably five to six, in which one or more ring carbons, preferably one to four, are each replaced by a heteroatom such as N, O, or S.
  • non-aromatic heterocyclic rings examples include 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-raorpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl, A- thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrorolidinyl, 1-piperazinyl, 2- piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl, 5-diazolonyl, N-substituted
  • the disclosed compounds can contain one or more chiral centers.
  • the presence of chiral centers in a molecule gives rise to stereoisomers.
  • a pair of optical isomers referred to as "enantiomers”
  • enantiomers exist for every chiral center in a molecule.
  • a pair of diastereomers exists for every chiral center in a compound having two or more chiral centers.
  • alkyl used alone or as part of a larger moiety ⁇ e.g., aralkyl, alkoxy, alkylamino, alkylaminocarbonyl, haloalkyl), is a straight or branched non-aromatic hydrocarbon which is completely saturated. Typically, a straight or branched alkyl group has from 1 to about 10 carbon atoms, preferably from 1 to about 5 if not otherwise specified.
  • 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 Cl-ClO straight or branched alkyl group or a C3-C8 cyclic alkyl group can also be referred to as a "lower alkyl" group.
  • alkoxy group refers to an alkyl group that is connected through an intervening oxygen atom, e.g., methoxy, ethoxy, 2- propyloxy, tert-butoxy, 2-butyloxy, 3-pentyloxy, and the like.
  • optionally halogenated alkyl and “optionally halogenated alkoxy”, as used herein, includes the respective group substituted with one or more of -F, -Cl, -Br, or-I.
  • alkanoyl indicates the respective group connected through an intervening carbonyl, for example, -
  • alkanoyloxy indicates the respective group connected through an intervening carboxylate, for example, -0(CO)CH 2 CH 3 , -0(CO)C 6 H 5 , and the like.
  • cycloalkyl group is a cyclic alkyl group has from 3 to about 10 carbon atoms, preferably from 3 to about 7.
  • suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • a "cycloalkoxy” group refers to a cycloalkyl group that is connected through an intervening oxygen atom, e.g., cyclopentyloxy, cyclohexyloxy, and the like.
  • aliphatic includes branched and linear alkyl groups that contain one or more units of carbon-carbon unsaturation, i.e., carbon-carbon double or triple bonds.
  • a cycloaliphatic group is a cyclic aliphatic group, for example, cyclohexenyl or cyclopentenyl.
  • aralkyl refers to aryl, heteroaryl, cycloalkyl, cycloaliphatic, and nonaromatic heterocyclic groups, respectively, that are connected through an alkyl chain, e.g., benzyl, -CH 2 -CH 2 - pyridine, (3-cyclohexyl)propyl, and the like.
  • biaryl, biheteroaryl, aryl-heteroaryl and heteroaryl-aryl indicate two aryl groups connected by a single covalent bond, two heteroaryl groups connected by a single covalent bond, an aryl and heteroaryl group connected by single covalent bond, and a heteroaryl and aryl group connected by a single covalent bond, respectively.
  • Examples of biaryl, biheteroaryl, heteroaryl-aryl and aryl-heteroaryl groups include biphenyl, bipyridyl, pyrimidyl-phenyl, and phenyl- pyridyl, respectively.
  • a biaryl, biheteroaryl, heteroaryl-aryl or aryl-heteroaryl group is a substituent, as in the definition of R4 for structural Formula I, the first recited group is bonded to the remainder of the molecule, i.e., "L" in structural Formula I.
  • R4 in structural Formula I is a phenyl-pyridyl group
  • the phenyl of the phenyl-pyridyl group is bonded to L.
  • An "acyclic" group is a substituent that does not contain a ring.
  • “monocyclic” group contains only a single ring, for example, a phenyl ring that is not fused to another ring.
  • a “polycyclic” group is a group that contains multiple fused rings, for example, naphthyl.
  • a “substitutable atom” is any atom such as nitrogen or carbon that is bonded through a single covalent bond to a hydrogen atom, wherein the hydrogen atom can be replaced with another group.
  • a “substitutable ring atom” in an aromatic ring is any ring atom, e.g., a carbon or nitrogen, which is bonded by a single covalent bond to a hydrogen atom, wherein the hydrogen atom can be replaced with another group.
  • Suitable substituents are those that do not substantially interfere with the pharmaceutical activity of the disclosed compound.
  • a compound or group can have one or more substituents, which can be identical or different.
  • substituents for a substitutable carbon atom in an alkyl, aliphatic, cycloalkyl, cycloaliphatic, non-aromatic heterocyclic, aryl, or heteroaryl group include -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, -0-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, -
  • Each R is independently an alkyl, cycloalkyl, benzyl, aromatic, heteroaromatic, or iV-anilinyl group that is optionally substituted.
  • R is unsubstituted.
  • -N(R) 2 taken together, can also form a substituted or unsubstituted heterocyclic group, such as pyrrolidinyl, piperidinyl, morpholinyl and thiomorpholinyl.
  • substituents on group represented by R include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl.
  • substituents on the groups represented by R' include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl.
  • R' is unsubstituted.
  • kits for use by a consumer for treating disease comprise a) a pharmaceutical composition comprising an antibiotic and a pharmaceutically acceptable carrier, vehicle or diluent; and, optionally, b) instructions describing a method of using the pharmaceutical composition for treating the specific disease.
  • the instructions may also indicate that the kit is for treating disease while substantially reducing the concomitant liability of adverse effects associated with antibiotic administration.
  • a “kit” as used in the instant application includes a container for containing the separate unit dosage forms such as a divided bottle or a divided foil packet.
  • the container can be in any conventional shape or form as known in the art which is made of a pharmaceutically acceptable material, for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag (for example, to hold a "refill” of tablets for placement into a different container), or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule.
  • the container employed can depend on the exact dosage form involved, for example a conventional cardboard box would not generally be used to hold a liquid suspension. It is feasible that more than one container can be used together in a single package to market a single dosage form. For example, tablets may be contained in a bottle which is in turn contained within a box.
  • Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process, recesses are formed in the plastic foil. The recesses have the size and shape of individual tablets or capsules to be packed or may have the size and shape to accommodate multiple tablets and/or capsules to be packed. Next, the tablets or capsules are placed in the recesses accordingly and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed.
  • the tablets or capsules are individually sealed or collectively sealed, as desired, in the recesses between the plastic foil and the sheet.
  • the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
  • a written memory aid where the written memory aid is of the type containing information and/or instructions for the physician, pharmacist or subject, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested or a card which contains the same type of information.
  • a calendar printed on the card e.g., as follows "First Week, Monday, Tuesday," . . . etc. . . "Second Week, Monday, Tuesday, . . . " etc.
  • a "daily dose” can be a single tablet or capsule or several tablets or capsules to be taken on a given day.
  • kits are a dispenser designed to dispense the daily doses one at a time.
  • the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen.
  • a memory- aid is a mechanical counter, which indicates the number of daily doses that, has been dispensed.
  • a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.
  • R' and R" are, e.g. each indepently a hydrogen, carboxylic acid, halogen, alkyl, heterocycle, nitrile or hydroxyamide; R 3 is, e.g. an optionally substituted aryl.
  • Example 4 Bacteria are dependent on PPAT, a general target for antibiotics
  • the gene for PPAT has been identified: see Geerlof, et al, "Purification and characterization of Phosphopantetheine Adenylyltransferase from E. CoIi" J. Biol. Chem., 1999, 274(38), pp. 27105-11, the entire teachings of which are incorporated herein by reference.
  • the gene sequence has been searched in a range of bacteria and in mammals using BLAST® (Basic Local Alignment Search Tool, available online at http://www.ncbi.nkri.nih.gov/BLAST/). The results are provided in Table 2.
  • PPAT is seen to be highly conserved across a range of bacterial pathogens. Thus, PPAT is a general target for antibiotics. Furthermore, although PPAT is present in mammalian cells, the mammalian sequence is sufficiently different to indicate that the disclosed PPAT inhibitors can be selective for bacterial PPAT.
  • the gene for PPAT, coaD is disrupted from a range of bacteria by allelic exchange; see, for example, Geerlof, et al, above, and Freiberg, et al. 2001. "Identification of novel essential Escherichia coli genes conserved among pathogenic bacteria" J MoI Microbiol Biotechnol 2001, 3, pp 483-9, the entire teachings of which are incorporated herein by reference. The survival of Escherichia coli, Bacillus subtilis, Staphylococcus aureus, and Streptococcus pneumoniae in complex growth media is studied. The inability of the modified bacteria to survive without the coaD gene indicates that PPAT is necessary for bacterial survival and is thus a potential antibiotic target.
  • IC 50 Inhibition Concentration at 50 percent
  • concentrations of the compounds in a range of 0.003 ⁇ 200 ⁇ g/ml can be determined with various concentrations of the compounds in a range of 0.003 ⁇ 200 ⁇ g/ml.
  • Compounds with IC 50 values >200 can have a measurable IC50 using a different assay method.
  • These inhibition assays can be performed in 96-well assay plates, using a similar method to the screening assay above.
  • the reaction buffer should contain 2OmM Hepes (pH 7.5), 10OmM NaCl, ImM MgCl 2 , 0.5mM DTT, 0.006% Brij 35, 10% Glycerol, 25 ⁇ M PPT, 0.5mM ATP, 0.2 Unit of pyrophosphatase, 200ng of PPAT in a total volume of lOO ⁇ l.
  • the reaction is performed for 2 minutes, and then stopped with 150ml Malachite Green reagent. Absorption at 650nm is measured after 10 minutes of color development.
  • the ICso's are determined with fitting data to the four-parameter method using XLfit (ID Business Solutions Inc., Cambridge, MA).
  • the IC 50 value is derived from the curve as the compound concentration that gives 50% inhibition of the enzymatic reaction. In order to perform the IC 50 assays, purified PPAT is needed.
  • PPAT gene is cloned into the pET28a expression vector (Novagen, Inc., Madison, WT) and expressed in E. coli BL21(DE3) cells.
  • a chromatographic purification procedure employs Q-sepharose, gel filtration, and MonoQ chromatography, as follows. The methods are described in detailed in Geerlof, et al, above. Each cell pellet is suspended in a 4 fold- volume of lysis buffer (5OmM
  • the major peak fractions are pooled and concentrated, then applied to a Sephacryl S200 HR column (1OmM Tris-HCl pH 7.5, 15OmM NaCl, O.lmM EGTA, O.lmM PMSF, 10% glycerol, 0.1% ⁇ -mercaptoethanol, and 0.02% Brij 35).
  • PPAT is eluted with the same buffer.
  • the major peak fractions are pooled and loaded on a pre-equilibrated MonoQ column (1OmM Tris-HCl, pH 7.0, O.lmM EGTA, O.lmM PMSF, 10% glycerol, 0.1% ⁇ -mercaptoethanol, and 0.02% Brij 35).
  • PPAT should be eluted with a gradient of NaCl from 10OmM up to 100OmM.
  • the peak fractions are pooled and dialyzed in the storing buffer (1OmM MOPS pH7.0,150mM NaCl, O.lmM EGTA, 50% glycerol, 0.02% Brij 35), then stored at -2O 0 C.
  • Table 3 IC 5 O data for PPat inhibitors of formula I
  • Example 6 Measuring disclosed PPAT inhibitors' antibiotic activity against drug-resistant bacteria
  • the strains comprising the bacterial panel are either obtained from American Type Culture Collection (ATCC, Manassas, VA), or genetically engineered to express varying levels of PPAT.
  • ATCC American Type Culture Collection
  • VA Manassas
  • the ATCC strains include the following: Escherichia coli (ATCC 35218),
  • Staphylococcus aureus (ATCC 700699), and Enterococcusfaeciim (ATCC 700221).
  • Other strains include Staphylococcus aureus RN4220, Escherichia coli WO-0159, Escherichia coli WO-0153, and Bacillus subtilis BD170 with endogenous PPAT disrupted and complemented with PPAT under the regulation of inducible promoter, "space,-
  • the MIC assays are performed essentially as described in the NCCLS recommendations, the entire teachings of which are incorporated herein by reference (National Center for Clinical Laboratory Standards, 1997, (Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria the Grow Aerobically), 4th ed.; approved standard. NCCLS document M7-A4. NCCLS, Wayne, PA.), with the following exceptions: both Tryptic Soy broth, and Mueller Hinton broth with and without the presence of serum are used as the growth medium. The concentration range tested is from 200 to 0.39 mcg/ml.
  • Concentrations of 50-fold the desired final concentration are made by 2-fold serial dilutions in 96-well microtiter plates, after which 2 ⁇ L are transferred to the assay plates. Cells are grown up in the appropriate culture media and diluted back to final OD 60O of 0.001, after which 98 ⁇ L is inoculated into the assay plates. The final volume in each assay well is 100 uL. After an overnight incubation at 37 0 C, the assay plates are read. The MIC is determined as the minimal concentration that results in >80% inhibition of growth.

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Abstract

La présente invention concerne des composés de Formule I, des compositions pharmaceutiques comprenant la Formule I et des procédés de traitement des infections bactériennes. Les composés décrits sont des inhibiteurs de la PPAT (phosphopantéthéine adényl transférase) et sont utiles dans le traitement et la prévention de maladies causées par des bactéries, en particulier des bactéries dépendant de la PPAT, par exemple, des espèces telles qu’Escherichia coli, Helicobacter pylori, Staphyloccocus aureus et analogue.
EP08872407A 2007-11-30 2008-11-26 Dérivés de tétrahydro-bêta-carboline antibiotiques Withdrawn EP2240493A2 (fr)

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WO2009073534A2 (fr) 2007-11-30 2009-06-11 Maxthera Inc. Inhibiteurs de ppat bicycliques utilisés en tant qu'agents antibactériens
EP2687531B1 (fr) 2011-03-18 2016-07-13 ONO Pharmaceutical Co., Ltd. Dérivé de tétrahydrocarboline
CN111012779A (zh) * 2011-10-25 2020-04-17 新疆华世丹药物研究有限责任公司 去氢骆驼蓬碱衍生物在制备抗菌药物中的应用
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