AU3012699A - Substituted aromatic compounds for treatment of antibiotic resistant infections - Google Patents
Substituted aromatic compounds for treatment of antibiotic resistant infections Download PDFInfo
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- AU3012699A AU3012699A AU30126/99A AU3012699A AU3012699A AU 3012699 A AU3012699 A AU 3012699A AU 30126/99 A AU30126/99 A AU 30126/99A AU 3012699 A AU3012699 A AU 3012699A AU 3012699 A AU3012699 A AU 3012699A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
- C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
- C07C215/30—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings containing hydroxy groups and carbon atoms of six-membered aromatic rings bound to the same carbon atom of the carbon skeleton
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4458—Non condensed piperidines, e.g. piperocaine only substituted in position 2, e.g. methylphenidate
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- 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
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- 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
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- 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
- A61P31/10—Antimycotics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
- C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
- C07C2603/24—Anthracenes; Hydrogenated anthracenes
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
- C07C2603/26—Phenanthrenes; Hydrogenated phenanthrenes
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Hydrogenated Pyridines (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
WO 99/48461 PCT/US99/06494 Title: Substituted Aromatic Compounds for Treatment of Antibiotic Resistant Infections Field of the Invention: This invention relates to the treatment of antibiotic resistant infections, including particularly infections caused by bacteria, mycobacteria, fungi and yeasts. A preferred group of compositions of the invention contain as active agents compounds containing aryl ring systems, in cluding phenyl, naphthyl and anthracene ring systems, sub stituted by a carbon bound to an oxygen which is also bound to a nitrogen through a saturated carbon or carbon chain which may be substituted with halo, hydroxy, alkoxy, amino or alkylamino are disclosed, In preferred embodiments, the aryl ring system is further substituted by at least two halo substituents or halo-substituted substituents. Background of the Invention: The benefit from use of antibiotics as a means of treating infections has been increasingly compromised by the development of resistant strains of microorganisms. Most of the new drugs are derivatives of older compounds. It is necessary to develop new agents that will respond to the current needs for medicinals that will effectively control pathogenic microbial populations that are resistant to antibiotics. Halofantrine is a known antimalarial having a phenan threne ring system substituted by a carbon bound to an oxygen which is also bound to a nitrogen through a saturated
CH
2
-CH
2 chain to tertiary nitrogen having two butyl sub stituents. The phenanthrene ring system is further substi tuted with 2 chlorines and one trifluoromethyl. Summary of the Invention: This invention relates to compounds of the general formula: WO 99/48461 PCTIUS99/06494 2 A
R
3 (a)
R
4 (a)
R
2 (a) 5 R, wherein A is a aromatic hydrocarbon ring system and R is a 0 carbon bound directly to an oxygen and is also bound to a nitrogen through a saturated carbon and wherein at least one of R2, R3 and R 4 is an electron-rich substituent. The active agents are useful for treating patients suffering from infections including gram positive organisms, 5 such as streptococcus, staphylococcus, anthracis, gram negative bacteria such as neisseria species, yeasts and mycobacterium. These compounds are effective against strains which have shown resistance to other antimicrobial agents. 0 Detailed Description of the invention: This invention relates to compounds that have use in treating several infectious diseases which are now resistant to treatment to conventionally used antibiotics. Some of the compounds described herein have had previously been 5 suggested for use in treating malaria. Some of the com pounds are newly discovered. Most of the compounds are lipophilic. The lipid solubility of these compounds should permit the drugs to enter into cells, including cells of the central nervous system. Many of the compounds could be also 0 be absorbed from the intestinal tract when given orally. They may be administered as cyclodextrin inclusion complexes to increase bioavailability. They may also be administered transdermally. Using patches for transdermal administration makes it possible to more easily control dosage. 5 The active agents for use in accord with the teachings of this disclosure are of the general formula: WO 99/48461 PCT/US99/06494 3 A
R
3 (a) R 4 (a)
R
2 (a) R, 0 wherein A is an aromatic ring system and R is bound directly to an oxygen and is also bound to a nitrogen through a saturated carbon. Ri is of the structure CHOZX wherein Z may be hydrogen, a second bond to the oxygen, or may be carbox 5 yl, ether or ester moiety wherein the ether or ester moiety may be alkyl of 1-8 carbons, phenyl, phenylalkyl, wherein the alkyl moiety consists of 1-4 carbons and wherein any said alkyl or phenyl group may, additionally, be substituted with hydroxy, alkyl of 1-2 carbons, alkenyl of 2-3 carbons, 0 halo, amino, or alkyl amino group, X is (CH 2 ) tN((CH2)n(CH 3 ))m wherein , is 1-3, n is <6, m is 1 or 2 with the proviso that when m is 2, at least one n is <3, or X may be (CH2)oJ where in 0 is 0-4 and J is a saturated nitrogen-containing ring system with up to 10 carbon atoms in the ring system and 5 may have up to 4 bridge carbons, wherein any saturated ring system may be substituted with alkyl, alkenyl, halo, alkoxy or haloalkyl moieties of 1-5 carbons or with phenyl, phe noxy, phenylalkyl, phenylalkoxy, carboxy or carbonyl groups, wherein the carboxy or carbonyl groups, including keto or ) ester moieties with alkyl groups of 1-4 carbons, alkenyl groups of 2-5 carbons or phenylalkyl wherein the alkyl is of 1-3 carbons or phenylalkoxy wherein the alkyl is of 1-3 carbons. Regarding substituents of R 2 (a), R 3 (a) and R 4 (a), a may be 0-4 with the proviso that at least one a is not 0. 5 R 2 , R 3 and R 4 may be alkyl (including cycloalkyl), a satu rated, nitrogen-containing ring of 4-10 atoms, alkoxy, aryl, aryloxy, aryloxyalkyl, amino, amino-alkyl, alkyl-aminoalkyl, WO 99/48461 PCT/US99/06494 4 arylamino, alkenyl, arylalkenyl, arylalkylaminoalkyl, carboxyalkyl, hydroxy, halo, alkenyl, alkenyloxy, haloalkyl (including perhaloalkyl), wherein any alkyl has 1-8 carbons, alkenyl has 2-8 carbons, wherein halo is chloro, fluoro or 5 bromo and aryl is a ring system of 1-3 rings with the provi sion that at least one of R 2 , R 3 and R 4 is an electron-rich substituent. Z and X may be linked to form a heterocylic ring system. Furthermore, any alkyl or aryl at R 2 , R 3 and R 4 may be further substituted with aryl of 1-2 rings, halo, 0 (including multiple halo substitutions) alkyl, haloalkyl or alkoxy. Preferred halo substituents are chloro or bromo and a preferred haloalkyl is trifluoromethyl. Compounds wherein X is (CH 2 )oJ and o is 2-4 are novel. Particularly useful compounds are those of Formulas I, 5 II, III and IV. F2 R3 R4 R7 R5 Formula I 0 0~Rg R, R10 In compounds of Formula I, any of R 2 8 may be substituents designated under R 2 ' R 3 and R4 in the general formula above, with the proviso that at least one of R 28 is an electron 5 rich substituent and any one of R 1 , R 9 or R1 is a substituent as defined as R in the general formula. Preferred compounds are those having at least two halos groups on the compound, with chloro or trifluoromethyl being particularly preferred groups. O
R
4 R 5
R
3 R6 Formula II R2 R7 5 R, R8 WO 99/48461 PCT/US99/06494 5 In compounds of Formula II, any of R 2 , may be substituents identified as R 2 , R 3 or R4 in the general formula with the proviso that at least one substituents is an electron-rich moiety and R is as designated for R, (CHOZX) for the general 5 formula above. Many of the preferred compounds have at least two halo or halo-substituted substituents. R4
R
3 P 5 0 Formula III R, 5 wherein Ri is defined as in the general formula and R2-6 is defined in the same manner as R 2 , R 3 and R4 in the general formula. May of the preferred compounds have least two halo or halo-substituted substituents. A particularly valuable compound of Formula II is of 0 the formula: C1 C1
OCH
3 OH-CHN Compounds of Formulas I, II and III can be made using ) the following methods: WO 99/48461 PCT/US99/06494 6 3.5 -Bis(Arv/l)phenvItoIuene 0 CH3 AC 1 .) Ac2O / H 2
SO
4 0 2.) HCLO 4 CIO, Ar 0 Ar
CH
3
NO
2 I KOt-Bu Sn/HC C 3 c Ar 2 Ar Ae CH NH2NO 2 NaNO,/ HBF, OH,
CH
3 Ar Ar NaBH N2Ar Ar Ar X Where X is mono- or di- halo, alkoxy, or halogen substituted alkyl. Otherwise X ishydrogen.
WO 99/48461 PCTIUS99/06494 7 Preparing starting materials: 0 0 11/ \ --OHO 11I x /CHO +OH 3 C \ Y /N Y- - -C-H=CH C \ 1OH 3 MgI
OH
3
CHOCH
3
OH
3 0 - I II - Ph 3
P=CHOCH
3 -I X CH- C HC Y X /CH-CIHC-- Y
-H
2 0
OH
3 x Y A general method for production: 0 0 Li CKCNH +CHOH 2
CHCH
2 Li CH-,C-NF\ + nBu ArCH., NBS/0-C1 4 ArOH 2 B (Ph),P 0 B ® 1.)KOtBu AC=H 2rArOH 2 P(Ph) 3 Br 2.)HCHO AOOH mn-Cl.Ph-&OOH in CHC1 3 ArCHOHCH 2
NR
2
R
2 NH /rH H WO 99/48461 PCT/US99/06494 8 $ide Chain Introductions ArCH 3 NB/C, ArCH 2 Br AgO b ArCHO ......-...-.-.-........-.- ..-------------------------------- ... CQ, 8H 3 Pb(OAOy, ArCH, ~ ArC OOH -- ArC H 2 OH AI-CHO (2) /Pyr/N 2 (1) ---------------------------------------------------
I------------
(1) BH, 1)+Li(CH2)rCN
AFCHOH(CH
2 ),CN - ArCHOH(CH 2 ),CHNH, n=1,2 0OLi0 (1) + Ii BH, rH 3 CHC ,H (1) + LiCH 2 C-NR --- ~ArCHOHCH 2 CNHRACHCHHNH 0 0H ()+ BrZnCH 2 CNR4 2 Ar-CHOHCH 2 C NH 2 -- ArCHOHCHCH 2
NHR
2 ------ ---- ------- ---- --------------------------------------------------------- (2) + 2-Br-Pyridine/BuLi 0 ______ O N -OHCI ArCI!O N N H (2) EtOH/HG 0 Caen 0 ArC-O~tArCCH 2 CO.Et 30cp H00 (2) Ar-i C 2 N, II ArC-CH 2
N
2 - 0 ArC-CH 2 Bi
BH
3 0 ArCHOHCH 2
NR
2 AnC-CH 2
NR
2 ArCHOHCH2NR 2 y 2 H ArC-CH 2 WO 99/48461 PCT/US99/06494 9 -(2-PIPERIDYL)-4, 5-DICHLORO-9ANTHRACENEMETHANoL (WR 218394) 0 0 0 ~1. Zn, NHOH 0 0 0 - 2. HCl Cl 0 Cl C 2 (37%) C HO
CH
3 OCH CI, 2 -Pyrid v11ithjumn AiCI,, CHCGI0 2 1I c I 3 (42%) H HO CH N CH0 010 0
H
2 , PtO, 0 0 0 EtOH C CI C I Ci 4 (39-54%) 5 (10%) WO 99/48461 PCTUS99/06494 10 Compounds of the general formula wherein A is a phenan threne ring are known. Compounds of the following formula: 5
R
2 (a) Formula IV
R
3 (a) 0a R1 wherein R is a carbon bound directly to an oxygen and is also bound to a nitrogen through a saturated carbon and is 5 of the structure CHOZX wherein Z may be hydrogen, a second bond to the oxygen, or may be carboxyl, ether or ester moiety wherein the ether or ester moiety may be alkyl of 1-8 carbons, phenyl, phenylalkyl, wherein the alkyl moiety consists of 1-4 carbons and wherein any said alkyl or phenyl 0 group may, additionally, be substituted with hydroxy, alkyl of 1-2 carbons, alkenyl of 2-3 carbons, halo, amino, or alkyl amino group, X is (CH29tN((CH2),(CH3))m wherein , is 1-3, n is <6, m is 1 or 2 with the proviso that when m is 2, at least one n is <3, or X may be (CH 2 )oJ as defined in the 5 general formula, wherein R 2 and R3 are as defined in the general formula and a is 0 to 3, with the proviso that for at least one of R 2 or R3 a is 1 - 3. Preferred halo substit uents are chloro or bromo and preferred haloalkyl is tri fluoromethyl. A particularly useful member of this group of 0 compounds is desbutylhalofantrin, a compound of the formula: 5 WO 99/48461 PCT/US99/06494 11 which has now been found to be superior to halofantrine for treatment of malaria. (See U.S. Patent 5,711,966, which is incorporated herein by reference in its entirety.) The phenanthrenes may be made by several methods, in 5 cluding the following scheme:
CH
2 C02H CHO NO AC 0 FC CF3 KN KCO3 ' C=C 10 CF 3
CF
3 H CO2H 2 F 15 F 3 Raney Nickel F 3 C , CF 3 15 c'- >-_ I~ =1_Q H COH 2 H CO2HNH 20 F 3 C CF 3 a) C 5 H 11 0N0/HCl CO 2 H C C b) NaH 2
PO
2 /CuSO F 3 C N H | CO 2H 2 2 CF 3 01 25
CO
2 N 2-BrPyr N BuLi
F
3 C C F 3 C
CF
3
CF
3 3 0 OH C N
H
2 /Pt H N ____ ___ ____ ___H-HCl
F
3 MeOH/HC F3I 35 CF 3
CF
3 WO 99/48461 PCTIUS99/06494 12 The phenanthrene compounds may also be prepared using the phenanthroic acid chlorides. Example 1: To a solution of 2g of 10-(w-bromoacetyl)-2,7 5 dichlorophenanthrene in 25 ml of THF is added 2.9 g. of di n-heptylamine in 5 ml of THF at ambient temperature. After one hour, the THF is evaporated, the residue triturated with pentane, and filtered. The pentane residue is dissolved in EtOH/THF and reacted with 0.42 g of NaBH 4 for 1.5 hours. The 0 resulting reaction mixture is concentrated, the diluted with
H
2 H, extracted with Et 2 O, and acidified with gaseous HCl to yield the dichlorophenanthraceneaminoalcohol HCl salt. Several active agents of the invention were tested for activity against several infectious organisms. Some of the 5 methods used in testing are described below. Media: The strains were streaked on blood agar plates (trypti case soy broth containing 5% sheep cells). A single colony was isolated and grown in Mueller-Hinton Broth (MHB) as 0 recommended by the national Committee for Clinical Laborato ry Standards for rapidly growing bacteria. Candida species and related yeasts were isolated in a similar manner on brain-heart infusion agar (BHI). Susceptibility tests: 5 The antibiotic susceptibility profile of each strain was determined using standard microtiter dilution plates obtained from the Clinical Microbiology Laboratory at Ohio State University Hospitals. The Inocula were prepared by suspending a 4 hour log phase growth in MHB visually equal 0 in turbidity of an 0.5 McFarland standard. Inocula were further diluted and added to microdilution trays to achieve a final density of approximately 1 x 105 CFU/ml. The trays were incubated for 16 to 20 hours at 35"C. The highest dilution at which wells remained clear was considered to be 5 the minimum inhibitory concentration (MIC). The MIC and minimum bacterial concentration (MBC) of the strains to the active agents were determined by two-fold WO 99/48461 PCT/US99/06494 13 dilutions in Mueller-Hinton broth. Susceptibility tests for ATCC-obtained microorganisms and clinical isolates of gram positive bacteria including methicillin-susceptible and resistant staphylococci, streptococci, pneumococci and gram 5 negative bacteria, including Enterobacteriaceae, Pseudomo nas, Hemophilus and Neisseria, were performed in microtiter plates as described above. Compounds of the invention were dissolved in 1 ml of methanol and stored in aliquots at -70*C. They were diluted 0 in Mueller-Hinton broth for final screening. Compositions were tested in 0.1 ml volumes by serial dilution in micro titer plates against Staphylococcus aureus methicillin sensitive ATCC 29213 and the methicillin-resistant wild type T67738, as described above. The T67738 was resistant to 5 most antimicrobial drugs, including ciprofloxacin. The most active compounds were studied further by time and dose-related killing curve analysis using large inocula (1 X 10 7 CFU/ml). The dosage and method of administration will depend on 0 the location of the infection, the condition of the patient and the availability of professional supervision. Methods of administration include parenteral, oral, buccal, nasal or endotracheal routes. The active agents may be administered as sprays. For nasal administration, the active agent may 5 be delivered as a powder that is snorted. Inclusion com plexes such as cyclodextrin inclusion complexes would be particularly useful for buccal administration of these active agents. The compounds of the invention may also be admin 0 istered topically by any means, including by rectal route. Suppositories, solutions for use as retention enemas, and creams or jellies are appropriate carriers for use in rectal administration. The agents may be administered directly to infected tissue. For example, in case of open wounds, the 5 active agents may be administered in the form of sprays or ointments. Compounds of the invention may be applied to the skin WO 99/48461 PCT/US99/06494 14 or mucosa, including the vaginal mucosa, using creams, jellies, suppositories, or solutions. The active agents of the invention may be delivered directly to the epithelial tissue topically. For example, during surgery compositions 5 containing the active agents of the invention to the applied directly to target tissues and prosthetic devices. The compositions could be given by aerosol into the trachea or administered in mist along with other agents into the respi ratory tract. 0 The compositions of the invention may also be used prophylactically to protect from infection by pathogenic organisms. Dosage forms containing about 25 to 1000 mg for admin istration by mouth are suggested for use in adults. Howev 5 er, because the condition and size of the patient and the infectring organisms may differ greatly, eventual dosage requirements must be adjusted by the physician. Hence, dosage suggestions are provided to give general guidance to those of skill in the art. In accord with the purposes of 0 providing such guidance, the following data is provided. The information provided is useful The concentration required to provide benefit was studied in culture and provides guidance for effective concentration in the blood of the infected animal. The 5 results of these studies may be seen in Tables I and II WO 99/4846 1 PCT/US99/06494 15 0 -H ci C) LO CN > 0. H 0) -4-) (14 4 4-4 .H ~ ~ xci1) U) I I Cj -- 0HQ~ a)) a)II 00 4 0 H1 H H 04) .04 0 I I I (3)~ 1 - 104-) () c1) H (mm Cd c ( 4 1 CdH 01co H X ,4j = ~LO4-) H rlU co ) U co ) 110)ed 1 r-i 0 If Cdi 0 ifO 0 10 0 LO H- H- (N (N WO 99/48461 PCTIUS99/06494 16 H co OD HH 4-3 0 m' 0 M N H ( Cd 0 U > -4 00 -p ) H H HL) 44 0 >1 -- Q4 gH0 ~4-) 4 0 na 0 0 0 ~ C 4 1'4 P4 1 4-) 0p r- u 1%fI 0d z 0' 040 U: z z a) 0 -4 0z rH -H X*H H 04 ~ 4 4 -4 * I II IIa) ) ) a) 04 O U) -H o NNN 04 04 P4 4 0- 04 04 04 04 ( >d Cd Cd I I O 0(N ((N N 4 )I I H Io Cd 44 N N N H cj H C~j c'j r'i SH H H Cd 11 U) U) C (4-4 P4 Z Z N4 P44 N N N~ LO 0 LO C H H (N WO 99/48461 PCTIUS99/06494 17 -) 0 4-) 10; 00 1 0 1) CP0 1 1 N CO( 1 U) A H H H' H H N' H0 0H' U) ) -H - 4 M (1)) 44 Cd~ UU H H H H H (N H HHH N 14 4 -H~~- H a) H H C ~~ 4-) 04 C) C ) CO C ) C) ro C) )4 to rr , N > ~ ~ H4 H4 4 4 H4 H 4 4 0 'C H ( id H HH r - M - 0 0*: '4 NO CO _ O H H H NN WO 99/48461 PCT/US99/06494 18 Example 2: Capsules of a formulation of active agent designated #184366 for oral administration are prepared by containing 250 mg. of the active agent, 100 mg. starch, and 5 mg. 5 magnesium stearate. The capsules are administered daily or twice a day to achieve a daily dosage of 500 mg. per day. Example 3: A preparation for application to the skin or mucosa may be prepared in the following manner: 0 Ingredient %w/w Compound #185308 15.0% glyceryl monostearate 3.0% Petrolatum 83.5% Example 4: 5 A formulation for administration as a retention enema may be formulated in the following manner: Ingredient w/w % Compound #218394 15% Propylene glycol 85% 0 When the active agent is administered to the mucosa of the oral cavity, it may be administered as a buccal tablet or spray for use in the oral-pharyngeal cavity and the nasal cavities. 5 Example 5: To 15 ml of phosphate buffered saline is added 3 mg of compound #185308. The composition is placed in a bottle having a stopper with a smooth glass rod extending into the solution. The composition is applied to boils using the 0 smooth glass rod as an applicator. The composition may also WO 99/48461 PCTIUS99/06494 19 be administered as a spray from a bottle with an atomizer. Example 6: To a 4 X 4 inch bandage having a smooth surface on one side there is applied to the smooth surface .02 ml of the 5 solution prepared as a 2 AM solution of active agent desig nated # 183308 in PBS. The prepared bandage is then en closed in a foil covering which is made air-tight. For application, the bandage is unwrapped and is applied smooth side down on the wound. 0 Example 7: A composition is prepared for use on the skin or mucosa in the following manner: Ingredient %w/w Agent designated #201683 0.5% 5 propylene glycol 13.0% Phosphate buffered saline 86.5% When the active agent is administered to the mucosa of the oral cavity, it may be administered as a buccal tablet or spray for use in the oral-pharyngeal cavity and the nasal 0 cavities.
WO 99/48461 PCT/US99/06494 20 Example 8: A composition prepared as a gel for application to the skin: Ingredient %w/w 5 active agent #1843660 0.5% propylene glycol 10.0% Polyethylene glycol 89.5% Example 9: A composition prepared for administration as a supposi 0 tory: Ingredient (%w/w) Active agent #185308 0.5 mg glyceryl monosterate 1.0 Gm hydrogenated coconut oil 1.0 Gm 5 glyceryl monopalmitate 1.0 Gm Example 10: A composition for intravenous administration is pre pared comprising: 184366 300 mg. 0 10% glucose in 1/2 normal saline to 300 ml. Regarding the compounds of Formula IV (Phenanthrenes), the following examples are provided: Example 11: 5 Capsules of a formulation of active agent designated #1 for oral administration are prepared by containing 250 mg. of the active agent, 100 mg. starch, and 5 mg. magnesium stearate. The capsules are administered daily or twice a WO 99/48461 PCT/US99/06494 21 day to achieve a daily dosage of 500 mg. per day. Example 12: A preparation for application to the skin or mucosa may be prepared in the following manner: 5 Ingredient %w/w Compound #3 15.0% glyceryl monostearate 3.0% Petrolatum 83.5% Example 13: 0 A formulation for administration as a retention enema may be formulated in the following manner: Ingredient w/w % Compound #10 15% Propylene glycol 85% 5 When the active agent is administered to the mucosa of the oral cavity, it may be administered as a buccal tablet or spray for use in the oral-pharyngeal cavity and the nasal cavities. D Example 14: To 15 ml of phosphate buffered saline is added 3 mg of compound #11. The composition is placed in a bottle having a stopper with a smooth glass rod extending into the solu tion. The composition is applied to boils using the smooth glass rod as an applicator. The composition may also be administered as a spray from a bottle with an atomizer. Example 15: To a 4 X 4 inch bandage having a smooth surface on one WO 99/48461 PCT/US99/06494 22 side there is applied to the smooth surface .02 ml of the solution prepared as a 2 AM solution of active agent desig nated # 4 in PBS. The prepared bandage is then enclosed in a foil covering which is made air-tight. For application, 5 the bandage is unwrapped and is applied smooth side down on the wound. Example 16: A composition is prepared for use on the skin or mucosa in the following manner: 0 Ingredient %w/w Agent designated #9 0.5% propylene glycol 13.0% Phosphate buffered saline 86.5% When the active agent is administered to the mucosa of 5 the oral cavity, it may be administered as a buccal tablet or spray for use in the oral-pharyngeal cavity and the nasal cavities.
WO 99/48461 PCTIUS99/06494 23 Example 17: A composition prepared as a gel for application to the skin: Ingredient %w/w active agent designated #3 0.5% propylene glycol 10.0% Polyethylene glycol 89.5% Example 18: A composition prepared for administration as a supposi tory: Ingredient (%w/w) Active agent #8 0.5 mg glyceryl monosterate 1.0 Gm hydrogenated coconut oil 1.0 Gm glyceryl monopalmitate 1.0 Gm Example 19: A composition for intravenous administration is pre pared comprising: Desbutylhalofantrine: 300 mg. 10% glucose in 1/2 normal saline to 300 ml. The compositions for intravenous administration are particularly valuable for administration intravenously during heart surgery and to patients suffering from endocar ditis.
Claims (24)
1. A method of treating or preventing infection caused by bacteria, mycobacterium or fungi by administration of a 5 composition containing as an active agent a bacteria, mycobacterium or yeast growth-inhibiting effective amount of a compound of the formula: A 0 R 3 (a) R 4 (a) R 2 (a) 5 R, wherein A is a hydrocarbon aromatic ring system, R is bound directly to an oxygen and is also bound to a nitrogen through a saturated carbon or carbon chain, with R being of the structure CHOZX wherein Z may be 0 hydrogen, a second bond to the oxygen, or may be car boxyl, ether or ester moiety wherein the ether or ester moiety may be alkyl of 1-8 carbons, phenyl, phenyl alkyl, wherein the alkyl moiety consists of 1-4 carbons and wherein any said alkyl or phenyl group may, addi 5 tionally, be substituted with hydroxy, alkyl of 1-2 carbons, alkenyl of 2-3 carbons, halo, amino, or alkyl amino group and X is (CH 2 )t N((CH2)n(CH 3 ) )m wherein L is 1 to 3, n is <6, m is 1 or 2 with the proviso that when m is 2, at least one of n is <3, or X may be (CH2)oJ 0 wherein o is 0-4 and J is a saturated nitrogen-contain ing ring system with up to 10 carbon atoms in the ring system and may have up to 4 bridge carbons, and where in any saturated ring system may be substituted with alkyl, alkenyl, halo, alkoxy or haloalkyl moieties of 5 1-5 carbons or with phenyl, phenoxy, phenylalkyl, phenylalkoxy, carboxy or carbonyl groups, wherein the carboxy or carbonyl groups, including keto or ester WO 99/48461 PCT/US99/06494 25 moieties, with alkyl groups having 1-4 carbons, alkenyl groups of 2-5 carbons or phenylalkyl wherein the alkyl is of 1-3 carbons or phenylalkoxy wherein the alkyl is of 1-3 carbons and, further, wherein X and Z may be 5 linked to form a heterocyclic ring system and (a) is 0 4 with the proviso that at least one of (a) is not 1, R 2 , R 3 and R 4 may be alkyl (including cycloalkyl), a saturated, nitrogen-containing ring of 4-10 atoms, al koxy, aryl, aryloxy, aryloxyalkyl, amino, amino-alkyl, D alkyl-aminoalkyl, arylamino, alkenyl, arylalkenyl, arylalkylaminoalkyl, carboxyalkyl, hydroxy, halo, al kenyl, or alkenyloxy, halo-substituted alkyl, wherein any alkyl has 1-8 carbons, alkenyl has 2-8 carbons, wherein halo is chloro, fluoro or bromo and aryl is a ring system of 1-3 rings and wherein any alkyl or aryl at R 2 , R 3 and R 4 may be further substituted with halo (including multiple halo subtitutions), aryl of 1-2 rings, alkyl, haloalkyl or alkoxy, with the proviso that at least one of R 2 , R 3 and R4 is an electron-rich substituent.
2. A method of claim 1 of treating or preventing infection caused by bacteria, mycobacterium or fungi by adminis tration of a composition containing as an active agent a bacteria, mycobacterium or yeast growth-inhibiting effective amount of a compound of the formula: R2 R3 R4 R7 R5 Formula I R8 R6 R9 R, R10 wherein any of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R. may be H, alkyl (including cycloalkyl), a saturated, nitrogen containing ring of 4-10 atoms, alkoxy, aryl, aryloxy, aryloxyalkyl, amino, amino-alkyl, alkyl-aminoalkyl, arylamino, alkenyl, arylalkenyl, arylalkylaminoalkyl, WO 99/48461 PCT/US99/06494 26 carboxyalkyl, hydroxy, halo, alkenyl, or alkenyloxy, halo-substituted alkyl, wherein any alkyl has 1-8 car bons, alkenyl has 2-8 carbons, wherein halo is chloro, fluoro or bromo and aryl is a ring system of 1-3 rings 5 and wherein any alkyl or aryl may be further substi tuted with halo (including multiple halo subtitutions), aryl of 1-2 rings, alkyl, haloalkyl or alkoxy, with the proviso that at least one of R 2 1 R 3 1 R 4 , R 5 , R 6 , R 7 and R. is an electron-rich substituent and one of R 1 , R 9 or R 10 0 is bound directly to an oxygen and is also bound to a nitrogen through a saturated carbon or carbon chain, being of the structure CHOZX wherein Z may be hydrogen, a second bond to the oxygen, or may be carboxyl, ether or ester moiety wherein the ether or ester moiety may 5 be alkyl of 1-8 carbons, phenyl, phenylalkyl, wherein the alkyl moiety consists of 1-4 carbons and wherein any said alkyl or phenyl group may, additionally, be substituted with hydroxy, alkyl of 1-2 carbons, alkenyl of 2-3 carbons, halo, amino, or alkyl amino group and X 0 is (CH 2 )(N((CH2)n(CH 3 ))m wherein , is 1-3, n is <6, m is 1 or 2 with the proviso that when m is 2, at least one n is <3, or X may be (CH 2 )oJ wherein o is 0-4 and J is a saturated nitrogen-containing ring system with up to 10 carbon atoms in the ring system and may have up to 4 5 bridge carbons, and wherein any saturated ring system may be substituted with alkyl, alkenyl, halo, alkoxy or haloalkyl moieties of 1-5 carbons or with phenyl, phe noxy, phenylalkyl, phenylalkoxy, carboxy or carbonyl groups, wherein the carboxy or carbonyl groups, includ 0 ing keto or ester moieties, with alkyl groups having 1 4 carbons, alkenyl groups of 2-5 carbons or phenylalkyl wherein the alkyl is of 1-3 carbons or phenylalkoxy wherein the alkyl is of 1-3 carbons and, furthermore, X and Z may be linked to form a heterocyclic ring system. 5
3. A method of claim 2 wherein at least two of R 2 , R3, R4, WO 99/48461 PCT/US99/06494 27 R 5 , R 6 , R 7 and R. are Cl or F3C.
4. A method of claim 2 wherein Z=H, X=CH 2 -(2-piperidine) R2 and R4 are Cl. 5
5. A method of claim 2 wherein R, is CHOZX and Z=H, X=CH 2 N(C 4 H) (C 3 H 7 ) and R5 and R6 are Cl.
6. A method of claim 2 wherein R is CHOZX and Z=H, 0 X=(CH2 2 NH(C 3 H 7 ) and R3 is Cl.
7. A nethod of claim 2 wherein R is CHOZX and Z=H, X=(CH 2 ) 2 NH(C 3 H7), R 3 is Cl and R5 is CF 3 . 5
8. A method of of claim 1 of treating or preventing infec tion caused by bacteria, mycobacterium or fungi by administration of a composition containing as an active agent a bacteria, mycobacterium or yeast growth-inhib iting effective amount of a compound of the formula: 0 R 4 R 5 Formula II R3 R6 5 R2 **Ry R, R wherein any of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 may be H, alkyl (including cycloalkyl), a saturated, nitrogen o containing ring of 4-10 atoms, alkoxy, aryl, aryloxy, aryloxyalkyl, amino, amino-alkyl, alkyl-aminoalkyl, arylamino, alkenyl, arylalkenyl, arylalkylaminoalkyl, carboxyalkyl, hydroxy, halo, alkenyl, or alkenyloxy, halo-substituted alkyl, wherein any alkyl has 1-8 car 5 bons, alkenyl has 2-8 carbons, wherein halo is chloro, fluoro or bromo and aryl is a ring system of 1-3 rings and wherein any alkyl or aryl may be further substi- WO 99/48461 PCT/US99/06494 28 tuted with halo (including multiple halo subtitutions), aryl of 1-2 rings, alkyl, haloalkyl or alkoxy, with the proviso that at least one of R 2 , R 3 f R 4 1 R 5 , R 6 1 R7 and R. is an electron-rich substituent and one of R 1 , is bound 5 directly to an oxygen and is also bound to a nitrogen through a saturated carbon or carbon chain, being of the structure CHOZX wherein Z may be hydrogen, a second bond to the oxygen, or may be carboxyl, ether or ester moiety wherein the ether or ester moiety may be alkyl 0 of 1-8 carbons, phenyl, phenylalkyl, wherein the alkyl moiety consists of 1-4 carbons and wherein any said alkyl or phenyl group may, additionally, be substituted with hydroxy, alkyl of 1-2 carbons, alkenyl of 2-3 carbons, halo, amino, or alkyl amino group and X is 5 (CH 2 )tN((CH2)n(CH3))m wherein L is 1-3, n is <6, m is 1 or 2 with the proviso that when m is 2, at least one n is <3, or X may be (CH 2 )oJ wherein o is 0-4 and J is a saturated nitrogen-containing ring system with up to 10 carbon atoms in the ring system and may have up to 4 D bridge carbons, and wherein any saturated ring system may be substituted with alkyl, alkenyl, halo, alkoxy or haloalkyl moieties of 1-5 carbons or with phenyl, phe noxy, phenylalkyl, phenylalkoxy, carboxy or carbonyl groups, wherein the carboxy or carbonyl groups, includ 5 ing keto or ester moieties, with alkyl groups having 1 4 carbons, alkenyl groups of 2-5 carbons or phenylalkyl wherein the alkyl is of 1-3 carbons or phenylalkoxy wherein the alkyl is of 1-3 carbons and, furthermore, X and Z may be linked to form a heterocyclic ring system.
9. A method of claim 8 wherein Z=H, X=CH 2 -(2-piperidine) R6 = Cl, R 7 = OCH 3 , R 3 = 4-Cl-phenyl.
10. A method of claim 8 wherein Z=H, X=CH 2 -(2-piperidine) R 6 = Cl, R 7 = OCH 3 , R 3 = 3,4 dichloro-phenyl.
11. A method of claim 8 wherein Z=H, X=CH 2 -(2-piperidine) WO 99/48461 PCT/US99/06494 29 R 6 =Cl, R 7 =CF 3 , R 3 =4-Cl-phenyl.
12. A method of claim 8 wherein Z=H, X=CH 2 -(2-piperidine) R 6 =CF 3 , R 7 =OCH 3 , R 3 =3, 4-diclhoro-phenyl. 5
13. A method of claim 1 of treating or preventing infection caused by bacteria, mycobacterium or fungi by adminis tration of a composition containing as an active agent a bacteria, mycobacterium or yeast growth-inhibiting D effective amount of a compound of the formula: R 4 R 3 R5 Formula III R2*R6 R, wherein any of R 2 ' R 3 , R 4 , R 5 , and R 6 , may be H, alkyl (including cycloalkyl), a saturated, nitrogen-contain ing ring of 4-10 atoms, alkoxy, aryl, aryloxy, aryloxyalkyl, amino, amino-alkyl, alkyl-aminoalkyl, arylamino, alkenyl, arylalkenyl, arylalkylaminoalkyl, carboxyalkyl, hydroxy, halo, alkenyl, or alkenyloxy, halo-substituted alkyl, wherein any alkyl has 1-8 car bons, alkenyl has 2-8 carbons, wherein halo is chloro, fluoro or bromo and aryl is a ring system of 1-3 rings and wherein any alkyl or aryl may be further substi tuted with halo (including multiple halo subtitutions), aryl of 1-2 rings, alkyl, haloalkyl or alkoxy, with the proviso that at least one of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is an electron-rich substituent and one of R 1 , is bound directly to an oxygen and is also bound to a nitrogen through a saturated carbon or carbon chain, being of the structure CHOZX wherein Z may be hydrogen, a second bond to the oxygen, or may be carboxyl, ether or ester moiety wherein the ether or ester moiety may be alkyl of 1-8 carbons, phenyl, phenylalkyl, wherein the alkyl moiety consists of 1-4 carbons and wherein any said alkyl or phenyl group may, additionally, be substituted WO 99/48461 PCT/US99/06494 30 with hydroxy, alkyl of 1-2 carbons, alkenyl of 2-3 carbons, halo, amino, or alkyl amino group and X is (CH 2 )tN((CH2)n(CH 3 ))m wherein L is 1-3, n is <6, m is 1 or 2 with the proviso that when m is 2, at least one n is <3, or X may be (CH 2 )oJ wherein o is 0-4 and J is a saturated nitrogen-containing ring system with up to 10 carbon atoms in the ring system and may have up to 4 bridge carbons, and wherein any saturated ring system may be substituted with alkyl, alkenyl, halo, alkoxy or haloalkyl moieties of 1-5 carbons or with phenyl, phe noxy, phenylalkyl, phenylalkoxy, carboxy or carbonyl groups, wherein the carboxy or carbonyl groups, includ ing keto or ester moieties, with alkyl groups having 1 4 carbons, alkenyl groups of 2-5 carbons or phenylalkyl wherein the alkyl is of 1-3 carbons or phenylalkoxy wherein the alkyl is of 1-3 carbons, and, furthermore, X and Z may be linked to form a heterocyclic ring sys tem.
14. A method of claim 13 wherein Z=H, X=CH 2 -(2-piperidine) R3 and R 5 are 4-Cl-phenyl.
15. A method of claim 13 wherein Z=H, X=CH 2 -(2-piperidine) R 3 =Cl, R 5 =4-OCH 3 -phenyl.
16. A method of claim 13 wherein Z=H, X=CH 2 CH 2 (2-piperidine) R 3 =Cl, R 5 =4 -OCH 3 -phenyl
17. A method of of claim 1 of treating or preventing infec tion caused by bacteria, mycobacterium or fungi by administration of a composition containing as an active agent a bacteria, mycobacterium or yeast growth-inhib iting effective amount of a compound of the formula: WO 99/48461 PCTIUS99/06494 31 R2(a) 5 R 3 (a) Formula IV R, 0 wherein any (a) is 1-3 and R2, and R 3 , may be H, alkyl (including cycloalkyl), a saturated, nitrogen-contain ing ring of 4-10 atoms, alkoxy, aryl, aryloxy, aryloxy alkyl, amino, amino-alkyl, alkyl-aminoalkyl, arylamino, alkenyl, arylalkenyl, arylalkylaminoalkyl, carboxy 5 alkyl, hydroxy, halo, alkenyl, or alkenyloxy, halo substituted alkyl, wherein any alkyl has 1-8 carbons, alkenyl has 2-8 carbons, wherein halo is chloro, fluoro or bromo and aryl is a ring system of 1-3 rings and wherein any alkyl or aryl may be further substituted 0 with halo (including multiple halo subtitutions), aryl of 1-2 rings, alkyl, haloalkyl or alkoxy, with the proviso that at least one of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R. is an electron-rich substituent and one of R 1 , is bound directly to an oxygen and is also bound to a nitrogen 5 through a saturated carbon or carbon chain, being of the structure CHOZX wherein Z may be hydrogen, a second bond to the oxygen, or may be carboxyl, ether or ester moiety wherein the ether or ester moiety may be alkyl of 1-8 carbons, phenyl, phenylalkyl, wherein the alkyl 0 moiety consists of 1-4 carbons and wherein any said alkyl or phenyl group may, additionally, be substituted with hydroxy, alkyl of 1-2 carbons, alkenyl of 2-3 carbons, halo, amino, or alkyl amino group and X is (CH2) N((CH2),(CH3))m wherein L is 1-3, n is <6, m is 1 5 or 2 with the proviso that when m is 2, at least one n is <3, or X may be (CH 2 )oJ wherein o is 0-4 and J is a saturated nitrogen-containing ring system with up to 10 WO 99/48461 PCT/US99/06494 32 carbon atoms in the ring system and may have up to 4 bridge carbons, and wherein any saturated ring system may be substituted with alkyl, alkenyl, halo, alkoxy or haloalkyl moieties of 1-5 carbons or with phenyl, phe 5 noxy, phenylalkyl, phenylalkoxy, carboxy or carbonyl groups, wherein the carboxy or carbonyl groups, includ ing keto or ester moieties, with alkyl groups having 1 4 carbons, alkenyl groups of 2-5 carbons or phenylalkyl wherein the alkyl is of 1-3 carbons or phenylalkoxy 0 wherein the alkyl is of 1-3 carbons, and, furthermore, X and Z may be linked to form a heterocyclic ring sys tem.
18. A method of claim 17 wherein the active agent is desbutyl 5 halofantrine.
19. A method of claim 17 wherein the active agent is chosen from among compounds wherein 0 z x R 2 , n R3 n H piperidinyl (#1) CF 3 1 CF 3 1 H piperidinyl (#2) Cl 1 CF 3 1 H piperidinyl (#3) Cl 2 CF 3 1 H piperidinyl (#4) Br 1 Br 1 5 H piperidinyl (#5) Cl 1 Cl 1 H CH 2 -piperidinyl (#6) Cl 1 Cl 1 H piperidinyl (#7) CF 3 2 Cl 2 H piperidinyl (#8) CF 3 1 CF 3 1 H CH 2 -piperidinyl (#9) Cl 2 CF 3 1 0 ZX= - (#10) CF 3 1 CF 3 1 0 H CH 2 NHCH(CH 2 CH 3 ) 2 (#11) CF 3 1 CF 3 1 H (CH 2 )NH(CH 2 ) 3 CH 3 (#12) CF 3 1 Cl 2 5 WO 99/48461 PCT/US99/06494 33
20. A compound of the formula: A R 3 (a) R R 2 (a) R, 0 wherein A is a hydrocarbon aromatic ring system, R is bound directly to an oxygen and is also bound to a nitro gen through a saturated carbon or carbon chain, with R being of the structure CHOZX wherein Z may be hydrogen, a 5 second bond to the oxygen, or may be carboxyl, ether or ester moiety wherein the ether or ester moiety may be alkyl of 1-8 carbons, phenyl, phenylalkyl, wherein the alkyl moiety consists of 1-4 carbons and wherein any said alkyl or phenyl group may, additionally, be substituted with hydroxy, alkyl of 1-2 carbons, alkenyl of 2-3 car bons, halo, amino, or alkyl amino group and X (CH 2 )oJ wherein o is 2-4 and J is a saturated nitrogen-containing ring system with up to 10 carbon atoms in the ring system and may have up to 4 bridge carbons, and wherein any saturated ring system may be substituted with alkyl, alkenyl, halo, alkoxy or haloalkyl moieties of 1-5 carbons or with phenyl, phenoxy, phenylalkyl, phenylalkoxy, car boxy or carbonyl groups, wherein the carboxy or carbonyl groups, including keto or ester moieties, with alkyl groups having 1-4 carbons, alkenyl groups of 2-5 carbons or phenylalkyl wherein the alkyl is of 1-3 carbons or phenylalkoxy wherein the alkyl is of 1-3 carbons, and (a) is 0-4 with the proviso that at least one of (a) is not 1, R 2 , R 3 and R 4 may be alkyl (including cycloalkyl), a satu rated, nitrogen-containing ring of 4-10 atoms, alkoxy, WO 99/48461 PCT/US99/06494 34 aryl, aryloxy, aryloxyalkyl, amino, amino-alkyl, alkyl aminoalkyl, arylamino, alkenyl, arylalkenyl, arylalkyl aminoalkyl, carboxyalkyl, hydroxy, halo, alkenyl, or alkenyloxy, halo-substituted alkyl, wherein any alkyl has 1-8 carbons, alkenyl has 2-8 carbons, wherein halo is chloro, fluoro or bromo and aryl is a ring system of 1-3 rings and wherein any alkyl or aryl at R 2 , R 3 and R 4 may be further substituted with halo (including multiple halo subtitutions), aryl of 1-2 rings, alkyl, haloalkyl or alkoxy, with the proviso that at least one of R 2 . R 3 and R4 is an electron-rich substituent.
21. A compound of claim 20 wherein A is a benzene ring.
22. A compound of claim 20 wherein A is a phenanthrene ring.
23. A compound of claim 20 wherein A is naphthalene ring.
24. A compound of claim 20 wherein A is anthracene ring.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US7938398P | 1998-03-26 | 1998-03-26 | |
| US60079383 | 1998-03-26 | ||
| PCT/US1999/006494 WO1999048461A2 (en) | 1998-03-26 | 1999-03-25 | Substituted aromatic compounds for treatment of antibiotic resistant infections |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU3012699A true AU3012699A (en) | 1999-10-18 |
Family
ID=22150207
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU30126/99A Abandoned AU3012699A (en) | 1998-03-26 | 1999-03-25 | Substituted aromatic compounds for treatment of antibiotic resistant infections |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP1066035A4 (en) |
| JP (1) | JP2002507557A (en) |
| AU (1) | AU3012699A (en) |
| CA (1) | CA2325689A1 (en) |
| GB (1) | GB2333454B (en) |
| WO (1) | WO1999048461A2 (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2002254133B2 (en) | 2001-03-08 | 2006-12-21 | The University Of Pennsylvania | Facially amphiphilic polymers as anti-infective agents |
| EP2471525A3 (en) | 2003-03-17 | 2012-12-12 | The Trustees Of The University Of Pennsylvania | Facially amphiphllic polymers and oligomers and uses thereof |
| DE10316081A1 (en) * | 2003-04-08 | 2004-10-21 | Morphochem AG Aktiengesellschaft für kombinatorische Chemie | New compounds with antibacterial activity |
| DE102010055322A1 (en) * | 2010-12-21 | 2012-06-21 | Christian-Albrechts-Universität Zu Kiel | Antibacterial and antifungal substances |
| TW202244048A (en) | 2017-03-20 | 2022-11-16 | 美商佛瑪治療公司 | Pyrrolopyrrole compositions as pyruvate kinase (pkr) activators |
| EP3853206B1 (en) | 2018-09-19 | 2024-04-10 | Novo Nordisk Health Care AG | Treating sickle cell disease with a pyruvate kinase r activating compound |
| CN113226356A (en) | 2018-09-19 | 2021-08-06 | 福马治疗股份有限公司 | Activating pyruvate kinase R |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4327022A (en) * | 1973-08-16 | 1982-04-27 | Sterling Drug Inc. | Heterocyclic alkyl naphthols |
| IL60530A (en) * | 1979-08-16 | 1984-10-31 | American Cyanamid Co | Animal feed compositions useful as growth promotors and for reduction of fat in animals,comprising phenylethanolamine derivatives and certain such novel compounds |
| GB9107843D0 (en) * | 1991-04-12 | 1991-05-29 | Patterson Laurence H | Anti-cancer compounds |
| US5711966A (en) * | 1995-08-25 | 1998-01-27 | Woosley; Raymond | Method of treating malaria with desbutylhalofantrine |
-
1999
- 1999-03-25 GB GB9909183A patent/GB2333454B/en not_active Expired - Fee Related
- 1999-03-25 AU AU30126/99A patent/AU3012699A/en not_active Abandoned
- 1999-03-25 JP JP2000537515A patent/JP2002507557A/en not_active Withdrawn
- 1999-03-25 WO PCT/US1999/006494 patent/WO1999048461A2/en not_active Application Discontinuation
- 1999-03-25 EP EP99911497A patent/EP1066035A4/en not_active Withdrawn
- 1999-03-25 CA CA002325689A patent/CA2325689A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| WO1999048461A2 (en) | 1999-09-30 |
| GB9909183D0 (en) | 1999-06-16 |
| GB2333454A (en) | 1999-07-28 |
| WO1999048461A3 (en) | 1999-12-16 |
| JP2002507557A (en) | 2002-03-12 |
| EP1066035A2 (en) | 2001-01-10 |
| EP1066035A4 (en) | 2001-05-09 |
| GB2333454B (en) | 2000-08-09 |
| CA2325689A1 (en) | 1999-09-30 |
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