EP1318806A1 - Inhibiteurs des syntases d'acides gras - Google Patents

Inhibiteurs des syntases d'acides gras

Info

Publication number
EP1318806A1
EP1318806A1 EP01971255A EP01971255A EP1318806A1 EP 1318806 A1 EP1318806 A1 EP 1318806A1 EP 01971255 A EP01971255 A EP 01971255A EP 01971255 A EP01971255 A EP 01971255A EP 1318806 A1 EP1318806 A1 EP 1318806A1
Authority
EP
European Patent Office
Prior art keywords
azetidin
oxo
compound
compounds
methyl
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Withdrawn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
EP01971255A
Other languages
German (de)
English (en)
Other versions
EP1318806A4 (fr
Inventor
Robert A. Daines
Israil Pendrak
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.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of EP1318806A1 publication Critical patent/EP1318806A1/fr
Publication of EP1318806A4 publication Critical patent/EP1318806A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • 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

Definitions

  • This invention relates to the use of N-acyl beta lactam compounds as inhibitors of the fatty acid synthase FabH.
  • the pathway for the biosynthesis of saturated fatty acids is very similar in prokaryotes and eukaryotes.
  • Vertebrates and yeasts possess type I fatty acid synthases (FASs) in which all of the enzymatic activities are encoded on one or two polypeptide chains, respectively.
  • FOSs type I fatty acid synthases
  • ACP acyl carrier protein
  • each of the reactions are catalyzed by distinct monofunctional enzymes and the ACP is a discrete protein.
  • Mycobacteria are unique in that they possess both type I and II FASs; the former is involved in basic fatty acid biosynthesis whereas the latter is involved in synthesis of complex cell envelope lipids such as mycolic acids. There therefore appears to be considerable potential for selective inhibition of the bacterial systems by broad-spectrum antibacterial agents (Jackowski, S. 1992. In Emerging Targets in Antibacterial and Antifungal Chemotherapy. Ed. J. Sutcliffe & N. Georgopapadakou. Chapman & Hall, New York; Jackowski, S. et al. (1989). J. Biol. Chem. 264, 7624-7629.)
  • the first step in the biosynthetic cycle is the condensation of malonyl-ACP with acetyl-CoA by FabH.
  • malonyl-ACP is condensed with the growing-chain acyl-ACP (FabB and FabF, synthases I and II respectively).
  • the second step in the elongation cycle is ketoester reduction by NADPH-dependent ⁇ - ketoacyl-ACP reductase (FabG).
  • Fab H is therefore a major biosynthetic enzyme, which is also a key regulatory point in the overall synthetic pathway (Heath, R.J. and Rock, CO. 1996. J.Biol.Chem. 271, 1833-1836; Heath, R.J. and Rock, CO. 1996. J.Biol.Chem. 271, 10996- 11000).
  • the antibiotic thiolactomycin has broad-spectrum antibacterial activity both in vivo and in vitro and has been shown to specifically inhibit all three condensing enzymes. It is non-toxic and does not inhibit mammalian FASs (Hayashi, T. et al.,1984. J. Antibiotics 37, 1456-1461; Miyakawa, S. et al., 1982. J. Antibiotics 35, 411-419; Nawata, Y et al., 1989. Acta Cryst. C45, 978-979; Noto, T. et al., 1982. J. Antibiotics 35, 401-410; Oishi, H. et al., 1982. J. Antibiotics 35, 391-396.
  • cerulenin is a potent inhibitor of FabB & F and is bactericidal but is toxic to eukaryotes because it competes for the fatty-acyl binding site common to both FAS types (DAgnolo, G. et al.,1973. Biochim. Biophys. Acta. 326, 155-166). Extensive work with these inhibitors has proved that these enzymes are essential for viability. Little work has been carried out in Gram-positive bacteria.
  • This invention involves N-acyl beta-lactam compounds and pharmaceutical compositions containing these compounds and their use as FabH inhibitors that are useful as antibiotics for the treatment of Gram positive and Gram negative bacterial infections.
  • This invention further constitutes a method for treatment of a Gram negative or Gram positive bacterial infection in an animal, including humans, which comprises administering to an animal in need thereof, an effective amount of a compound of this invention.
  • Rl is selected rom the group consisting of Me, CO2R4, COR4, CONR5R6,
  • R2 represents H, or Cl - C4 alkyl
  • R3 represents H, or Cl - C4 alkyl
  • R4 represents Cl - C4 alkyl
  • R5 and R6 are, independently, H, lower alkyl or together form a 5 or 6 membered heterocycle selected from the group consisting of piperidine, mo ⁇ holine, piperazine,
  • n is an integer from 1 to 12.
  • alkyl means both straight and branched chains of 1 to 6 carbon atoms, unless the chain length is otherwise limited, including, but not limited to, methyl, ethyl, -propyl, wo-propyl, n-butyl, sec-butyl, w ⁇ -butyl, tert-butyl, n- pentyl and the like.
  • the alkyl may cany substituents such as hydroxy, carboxy, alkoxy, and the like.
  • the compounds of this invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds and diastereomers are contemplated to be within the scope of the present invention.
  • solvates may be formed.
  • This invention includes within its scope stoichiometric solvates including hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation.
  • the antibiotic compounds of the invention are intended for use in pharmaceutical compositions it will readily be understood that they are each provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 95% pure, particularly at least 98% pure (% are on a weight for weight basis).
  • Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1%, more suitably at least 5% and preferably from 10 to 49% of a compound of the formula (I) or salt thereof.
  • Preferred compounds of the present invention include: l-(3-phenyl-propanoyl)-azetidin-2-one; 1 -hexanoyl-azetidin-2-one; l-(2-phenyl-ethanoyl)-azetidin-2-one;
  • the present invention provides compounds of formula (I).
  • Compounds of the formula I were prepared via the method outlined in Scheme 1.
  • Rl is phenyl
  • the base utilized in the above example is not limited to the use of BEMP on polystyrene or to the use of polymer bound reagents in general.
  • a variety of soluble bases may also be employed to obtain the desired results.
  • suitable bases include NaH, sodium bis(trimethylsilyl)amide, 2-tert-butylimino-2-diethylamino- l,3-dimethyl-perhydro-l,3,2-diazaphosphorine (BEMP) or n-butyl lithium.
  • Azetidinone 3 (Bioorg ⁇ nic and Medicinal Chemistry Letters, 1996, 6(8), 983-986) is treated with 2 equivalents of a strong base such lithium diisopropylamide (LDA), followed by the addition of 2 equivalents of methyl iodide (Scheme 2).
  • LDA lithium diisopropylamide
  • Scheme 2 The silyl protecting group is then removed under non-nucleophilic conditions using methanol and aqueous HC1. This method affords the dimethyl azetidinone 4.
  • Other alkylating agents can be used in place of methyl iodide to afford alternative dialkylated derivatives.
  • BEMP 2-tert-butylimino-2-diethylamino- 1 ,3-dimethyl-perhydro- 1 ,3,2- diazaphosphorine.
  • Example 4 The title compound was prepared according to the procedure described for Example 1 substituting phenylacetyl chloride for hydrocinnamoyl chloride. The product was obtained, following purification by HPLC, as a white solid. LC/MS (ES+) m/e 190.0 [M+HJ+. Example 4
  • the title compound was prepared according to the procedure for 6b, above, with the modification of substituting 7a in place of 6a.
  • FabH was assayed in a coupled format using his-tagged S.aureus FabD, and acyl carrier protein (ACP) purchased from Sigma. Lyophilized ACP was reduced using ⁇ -mercaptoethanol in phosphate buffer. Malonyl-CoA, and FabD were added to the reduced ACP, thus generating malonyl-ACP. After the FabD reaction reached equilibrium, [ ⁇ C] acetyl-CoA and inhibitors were added, and the reaction started by the addition of FabH. TCA precipitation and filtration was used to separate [ ⁇ C] acetyl-CoA substrate from [l ⁇ C] acetoacetyl-ACP product.
  • ACP acyl carrier protein
  • the present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition which comprises a compound of formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, and a pharmaceutically acceptable carrier.
  • the compositions of the invention include those in a form adapted for oral, topical or parenteral use and may be used for the treatment of bacterial infection in mammals including humans.
  • the antibiotic compounds according to the invention may be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other antibiotics.
  • compositions may be formulated for administration by any route, such as oral, topical or parenteral, especially oral.
  • the compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
  • the formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • suitable conventional carriers such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • Such carriers may be present as from about 1% up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.
  • Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or
  • Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.
  • fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing.
  • the solution preferably contains a buffer (such as phosphate) to keep the pH in the range of about 3.5 to 7.
  • DMSO or alcoholic solvents may also be present (at concentrations such as 0.01 to 10 mL/liter) to aid solubility and penetration of the compound of Formula (I)
  • agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration.
  • the compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • compositions may contain from 0.1% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will preferably contain from 50-500 mg of the active ingredient.
  • the dosage as employed for adult human treatment will preferably range from 1 to 140 mg/kg of body weight, depending on the route and frequency of administration.
  • Inhibitors of ⁇ -ketoacyl-ACP Synthase (FabH) can be administered by injection in solutions either intravenously, intramuscularly, intraperitoneally, or orally.
  • the solution preferably contains a buffer (such as phosphate) to keep the pH in the range of about 3.5 to 7.
  • DMSO or alcoholic solvents may also be present (at concentrations such as 0.01 to 10 mL/liter) to aid solubility and penetration of the ⁇ - ketoacyl-ACP Synthase (FabH) inhibitor.
  • FSH ⁇ - ketoacyl-ACP Synthase
  • the compound of formula (I) may be the sole therapeutic agent in the compositions of the invention or a combination with other antibiotics or compounds which enhance the antibacterial activity of a compound of formula (I)may be employed.
  • the antibiotic compounds of the present invention are active against a wide range of organisms including both Gram-negative organisms such as Escherichia coli and Klebsiella pneumoniae and Gram-positive organisms such as Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecalis and Enterococcus faecium, including isolates resistant to existing antibiotics.

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne l'utilisation de composés comme inhibiteurs des syntases FabH d'acides gras.
EP01971255A 2000-09-22 2001-09-20 Inhibiteurs des syntases d'acides gras Withdrawn EP1318806A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US23460000P 2000-09-22 2000-09-22
US234600P 2000-09-22
PCT/US2001/029490 WO2002024197A1 (fr) 2000-09-22 2001-09-20 Inhibiteurs des syntases d'acides gras

Publications (2)

Publication Number Publication Date
EP1318806A1 true EP1318806A1 (fr) 2003-06-18
EP1318806A4 EP1318806A4 (fr) 2004-01-21

Family

ID=22882034

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01971255A Withdrawn EP1318806A4 (fr) 2000-09-22 2001-09-20 Inhibiteurs des syntases d'acides gras

Country Status (4)

Country Link
EP (1) EP1318806A4 (fr)
JP (1) JP2004513887A (fr)
AU (1) AU2001291160A1 (fr)
WO (1) WO2002024197A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HUE045701T2 (hu) 2013-03-13 2020-01-28 Forma Therapeutics Inc 2-Hidroxi-1-{4-[(4-fenilfenil)karbonil]piperazin-1-il}etán-1-on származékok és rokon vegyületek mint zsírsav szintáz (FASN) inhibitorok, rák kezelésére
TWI767148B (zh) 2018-10-10 2022-06-11 美商弗瑪治療公司 抑制脂肪酸合成酶(fasn)
CN113382633A (zh) 2018-10-29 2021-09-10 福马治疗股份有限公司 (4-(2-氟-4-(1-甲基-1H-苯并[d]咪唑-5-基)苯甲酰基)哌嗪-1-基)(1-羟基环丙基)甲酮的固体形式

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5175283A (en) * 1990-06-04 1992-12-29 Bristol-Myers Squibb Company Azetidin-2-one derivatives as serine protease inhibitors
US5594134A (en) * 1995-03-31 1997-01-14 Merck & Co., Inc. Process of synthesizing N-acyl auxiliaries

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BRICKNER, STEVEN J. ET AL: "N-Acyl 3-alkylidenyl- and 3-alkyl azetidin-2-ones: a new class of monocyclic.beta.-lactam antibacterial agents. 2. Synthesis and structure-activity relationships of heteroatom substituted 3-isopropylidene and 3-isopropyl analogs" BIOORGANIC & MEDICINAL CHEMISTRY LETTERS (1993), 3(11), 2241-6 , vol. 3, no. 11, 1993, pages 2241-2246, XP009021759 *
MAZAAHIR KIDWAI ET AL.: "Synthesis of new 4-thiazolidinones and 2-azitidiones with their in vitro biological activities" INDIAN JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 57, no. 6, 1995, pages 252-259, XP009021776 *
See also references of WO0224197A1 *

Also Published As

Publication number Publication date
AU2001291160A1 (en) 2002-04-02
JP2004513887A (ja) 2004-05-13
WO2002024197A1 (fr) 2002-03-28
EP1318806A4 (fr) 2004-01-21

Similar Documents

Publication Publication Date Title
US6469046B1 (en) Indole compounds useful for treating bacterial infections
US6608059B1 (en) Fatty acid synthase inhibitors
US6559179B1 (en) Fatty acid synthase inhibitors
US6723749B2 (en) Fatty acid synthase inhibitors
US6670388B1 (en) Fatty acid synthase inhibitors
US6486211B1 (en) Indole compounds
WO2002055661A2 (fr) Inhibiteurs de la synthase des acides gras
EP1318806A1 (fr) Inhibiteurs des syntases d'acides gras
US6486192B1 (en) Indole compounds useful for treating bacterial infections
US6498187B1 (en) Fatty acid synthase inhibitors
US20030220392A1 (en) Fatty acid synthase inhibitors
WO2002002119A1 (fr) Inhibiteurs de la synthase d'acides gras
EP1206463A1 (fr) Inhibiteurs de synthase d'acide gras
JPH01258667A (ja) 高脂血症治療用組成物
EP1322331A2 (fr) Inhibiteurs de synthase d'acide gras
JP2004137185A (ja) チオフェン骨格を有する抗菌剤
JP2000509726A (ja) 糖尿病処置用のオキシランカルボン酸
WO2001030752A2 (fr) Composes d'indole

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20030307

AK Designated contracting states

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

A4 Supplementary search report drawn up and despatched

Effective date: 20031204

RIC1 Information provided on ipc code assigned before grant

Ipc: 7A 61P 31/04 B

Ipc: 7A 61K 31/397 B

Ipc: 7A 61K 31/395 A

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20040327