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WO1991005771A1 - Promedicaments d'acylpyrazinamide lipophiles - Google Patents

Promedicaments d'acylpyrazinamide lipophiles Download PDF

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Publication number
WO1991005771A1
WO1991005771A1 PCT/US1990/005855 US9005855W WO9105771A1 WO 1991005771 A1 WO1991005771 A1 WO 1991005771A1 US 9005855 W US9005855 W US 9005855W WO 9105771 A1 WO9105771 A1 WO 9105771A1
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WO
WIPO (PCT)
Prior art keywords
composition
liposome
compound
targeted
group
Prior art date
Application number
PCT/US1990/005855
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English (en)
Inventor
Hans Schreier
Ricardo J. Gonzalez-Rothi
Original Assignee
Hans Schreier
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 Hans Schreier filed Critical Hans Schreier
Publication of WO1991005771A1 publication Critical patent/WO1991005771A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant

Definitions

  • She present invention relates to pharmaceutical compounds and, more particularly, to lipophllio pyrazinamide prodrugs, which possess antimicrobial activity as well as compositions containing these prodrugs and methods of use.
  • Microorganisms have adopted a wide variety of strategies which enable them to colonise a host. Among those organisms which are pathogenic those which are capable of causing or residing in the intracellular milieu are among those which are most difficult to treat. Such organisms are of a wide variety and include bacteria, protosoa, fungi, and viruses.
  • a typical representative of this group is Mycobacterium avium-intracellulare complex (MAIC).
  • MAIC Mycobacterium avium-intracellulare complex
  • lipophilic drugs should be more likely to be absorbed into the intracellular domain of the host cell, their lipophilic nature tends to make them insoluble such that they cannot be utilized intravenously and, as a consequence, must typically be administered in oral dosage form.
  • oral delivery of drugs is the least efficient with respect to the amount of drug reaching the target site ("bioavailability") which may be due to poor absorption through the gut, high metabolism (inactivation) in the liver, high systemic distribution into all body tissues, or a combination of some or all of the above.
  • bioavailability the amount of drug reaching the target site
  • Pyrazinamide is a drug of moderate efficacy when administered to patients suffering from pulmonary infections. However, because it is quite toxic, pyrazinamide therapy should only be utilized if other therapy fails. In the case of pulmonary M. avium-intracellulare infections, the organisms reside in pulmonary alveolar macrophages such that the organism is protected from the drug which, in turn, allows the macrophages to act as a reservoir for chronic infection. Pyrazinamide is potentially more efficacious and less toxic when given in encapsulated form, for example, in a liposoae, either directly to the lung via inhalation or systemically via intravenous injection.
  • the present invention relates to novel lipophilic prodrugs of pyrazinamide which are useful in the treatment of diseases caused by intracellular pathogens. Because of their lipophilic nature, these prodrugs are particularly amenable to incorporation in a targeted drug delivery system, such as a liposome.
  • the prodrugs comprise a core comprising pyrazinamide which is materially modified to have from about 13 to about 17 carbon atoms.
  • Prodrugs consist of a parent drug and a second chemical moiety covalently linked to the parent drug which provides certain desired modifications of the physicochemical properties of the parent drug. Prodrugs can also be designed to protect drugs from rapid degradation, to direct drugs to specific areas in the body, or to make drugs more hydrophilic.
  • a prodrug can be active in itself, or be inactive and become active following chemical or enzymatic cleavage and release of the original drug.
  • the term "effective amount” denotes both microbicidal (killing) or mlcrobistatic (inhibiting) activity of a compound or composition of the invention.
  • the prodrugs of the invention are effective en intracellular pathogens such as bacteria, viruses, fungi, and protozoans. These prodrugs are especially effective against bacteria of the genus Mycobacterium.
  • the lipophilic prodrugs of the invention have the formula
  • R 1 is selected from saturated or unsaturated straight or branched chain alkyl moieties having from about 13 to about 17 carbon atoms. Preferred compounds wherein R 1 is lauroyl, syristoyl, palaitoyl, and stearoyl.
  • the lipophilic prodrugs of the invention can be preferably synthesized by the reaction of pyrazinamide with an acid chloride in the presence of chloroform. Preferred are acid chlorides of the formula
  • R 2 is from about 12 to about 16 carbon atoms.
  • R 1 and R 2 are selected from saturated or unsaturated, straight or branch chain alkyl moieties.
  • Other R 1 and R 2 groups that function aquivalently to yield a lipophilic acylpyrazinamide are known to those of skill in the art and are within the scope of the invention.
  • the prodrugs of the invention are especially suited for use in targetable drug delivery systems such as synthetic or natural polymers in the form of macromolecular complexes, nanocapsules, microspheres, or beads, and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, liposomes, and resealed erythrocytes.
  • targetable drug delivery systems such as synthetic or natural polymers in the form of macromolecular complexes, nanocapsules, microspheres, or beads, and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, liposomes, and resealed erythrocytes.
  • colloidal drug delivery systems are known collectively as colloidal drug delivery systems.
  • colloidal particles containing the dispersed drugs are about 50 nm - 2 ⁇ m in diameter. The size of the colloidal particles allows them to be administered intravenously such as by injection, or as an aerosol.
  • colloidal systems are typically sterilizable via filter sterilization, nontoxic, and biodegradable, for example albumin, ethylcellulose, casein, gelatin, lecithin, phospholipids, and soybean oil.
  • Polymeric colloidal systems are prepared by a process similar to the coacervation of microencapsulation.
  • Most preferred as a targeted delivery system for the prodrugs of the invention are liposomes.
  • phospholipids When phospholipids are gently dispersed in aqueous media, they swell, hydrate, and spontaneously form multilamellar concentric bilayer vesicles with layers of aqueous media separating the lipid bilayer.
  • Such systems are usually referred to as multilamellar liposomes or multilamellar vesicles (MLVs) and have diameters ranging from about 100nm to about 4um.
  • MLV' s are sonicated, small unilamellar vesicles (SOVs) with diameters in the range of from about 20 to about 50 nm are formed, which contain an aqueous solution in the core of the SUV.
  • SOVs small unilamellar vesicles
  • composition of the liposome is usually a combination of phospholipids, particularly high-phase-traneition- temperature phospholipids, usually in combination with steroids, especially cholesterol.
  • phospholipids particularly high-phase-traneition- temperature phospholipids
  • steroids especially cholesterol.
  • Other phospholipids or other lipids may also be used.
  • lipids useful in liposome production include phosphatidyl compounds, such as phosphatidylglycerol. phosphatidylcholine, phosphatidylserine, phosphatidyle- thanolaaine, sphingolipids, cerebrosides, and gangliosides. Particularly useful are diaoylphosphatidylglycerols, where the lipid moiety contains from 14-18 carbon atoms, particularly from 16-18 carbon atoms, and are saturated.
  • Illustrative phospholipids include egg phosphatidylcholine, dipalnitoylphosphatidyloholine, and distearoylphosphatidylcholine.
  • Anatomical classification is based on the level of selectivity, for example, organ-specific, cell-specific, and organellespecific. Mechanistic targeting can be further distinguished based upon whether it is passive or active. Passive targeting utilizes the natural tendency of liposomes to distribute to cells of the retioulo-endo- thelial system (RES) in organs which contain sinusoidal capillaries. Active targeting, on the other hand, involves the alteration of the liposome by coupling the liposome to a specific ligand such as a monoclonal antibody, sugar, glycolipid, or protein, or by changing the composition or size of the liposomes themselves in order to achieve targeting to organs and cell types other than the naturally occurring sites of localisation. Alternatively, liposomes may physically localize in capillary beds such as the lung or may be given by site-specific injection.
  • a specific ligand such as a monoclonal antibody, sugar, glycolipid, or protein
  • Another targeted delivery system which can be used with the prodrugs of the invention is resealed erythrocytes.
  • erythrocytes When erythrocytes are suspended in a hypotonic medium, swelling occurs and the cell membrane ruptures. As a consequence, pores are formed with diameters of approximately 200-500 A which allow equilibration of the intracellular and extracellular environment. If the ionic strengths of this surrounding media is then adjusted to isotonic conditions and the cells incubated at 37oC, the pores will close such that the erythrocyte reseals.
  • This technique can be utilized with the prodrugs of the invention to entrap the prodrug inside the resealed erythrocyte.
  • the resealed erythrocyte containing the prodrug can then be used for targeted delivery.
  • Non-lipid material nay be conjugated via a linking group to one or more hydrophobic groups, for example, alkyl chains from about 12- 20 carbon atoms.
  • lipid groups can be incorporated in to the lipid bylayer of the liposome in order to maintain the compound in stabile association with the liposomal bilayer.
  • Various linking groups can then be used for joining the lipid chains to the compound.
  • the number of molecules bound to a liposome will vary with the size of a liposome, as well as the size of the molecule, the binding of affinity the molecule to the target cell receptor or ligand, as the case may be, and the like. In most instances, the bound molecules will be present on the liposome in from about 0.05 to about 2 mol%, preferably from about 0.1 to about 1 mol%, based on the percent of bound molecules to the total number of molecules in the outer membrane bilayer of the liposome.
  • the compounds to be bound to the surface of the targeted delivery system will be ligand ⁇ and receptors which will allow the targeted delivery system to actively "home in” on the desired tissue
  • a ligand may be any compound of interest which will specifically bind to another compound, referred to as a receptor, such that the ligand and receptor form and a homologous pair.
  • the compounds bound to the service of the targeted delivery system may vary from small haptens of from about 125-200 molecular weight to much larger antigens with molecular weights of at least about 6000, but generally of less than 1 million molecular weight.
  • Proteinaceous ligand ⁇ and receptors are of particular interest.
  • receptors In general, the surface membrane proteins which bind to specific effector molecules are referred to as receptors. As presently used, however, most receptors will be antibodies. These antibodies may be monoclonal or polyclonal and may be fragments thereof such as Fab, and F(ab') 2 , which are capable of binding to an epitopic determinant.
  • the targeted delivery system containing the prodrug of the invention may be administered in a variety of ways to a host, particularly a mammalian host, such as intravenously, intramuscularly, subcutaneously, intraperitoneally, intravascularly, topically, intra ⁇ avity, transdermally, intranasally, and by inhalation.
  • concentration of the prodrug will vary upon the particular application, the nature of the disease, the frequency of administration, or the like.
  • the targeted delivery system-encapsulated prodrug may be provided in a formulation comprising other drugs as appropriate and an aqueous physiologically acceptable medium, for example, saline, phosphate buffered saline, or the like.
  • N-Acylpyrazinamides (lll)-(V) where prepared ae noted in Scheme 2.
  • a mixture of 200 ml chloroform and a few drops (approximately 0.25 ml) of aoetylchloride were refluxed for about 30 minutes in a 250 ml three-necked round-bottom flask in order to remove moisture from the chloroform and glass surfaces.
  • 4.3 g (0.035 mol) of (I) and amounts of either caproyl chloride, capryl chloride and palmitoyl chloride corresponding to 0.03 mol each were added and the mixture refluxed for 24 hours.
  • the HPLC set-up consisted of a Rabbit-HP pump (Rainin) equipped with a M190 injector, a Waters model 440 absor-nadoe detector, set to 254 nm, and a Fisher Recordall series 5000 recorder. Phosphate buffer (pH 3.4)/- acetonitril 95:5 (v/v) was used as mobile phase. An ODS (Zorbax CDS) column (4.6mmx 15cm) was employed. The flowrate was set to 1.m./min. Nicotinamide served as internal standard.
  • Rf-values resulting from thin layer chromatography are shown in Table 3. Thin layer chromatography was performed on silica gel plates with fluorescent indicator (Eastman Kodak, Rochester, N.Y.) in chloroform (containing 1.1% ethanol) as mobile phase, and UV detection at 254 nm.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Dispersion Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

Promédicaments d'acylpyrazinamide lipophiles efficaces contre des germes pathogènes intracellulaires. Ces promédicaments sont particulièrement utiles contre des éléments du gène Mycobacterium, et peuvent être utilisés dans des systèmes d'administration ciblés, notamment des liposomes.
PCT/US1990/005855 1989-10-13 1990-10-11 Promedicaments d'acylpyrazinamide lipophiles WO1991005771A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US42151689A 1989-10-13 1989-10-13
US421,516 1989-10-13

Publications (1)

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WO1991005771A1 true WO1991005771A1 (fr) 1991-05-02

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993002709A1 (fr) * 1991-07-31 1993-02-18 Microcarb Inc. Conjugues comprenant un recepteur, destines a cibler des medicaments et autres agents
US5599535A (en) * 1995-06-07 1997-02-04 Regents Of The University Of California Methods for the cyto-protection of the trabecular meshwork
US5674888A (en) * 1995-06-07 1997-10-07 University Of California Method for the treatment of a trabecular meshwork whose cells are subject to inhibition of cell division
US6171788B1 (en) 1997-01-28 2001-01-09 The Regents Of The University Of California Methods for the diagnosis, prognosis and treatment of glaucoma and related disorders
US6475724B1 (en) 1997-01-28 2002-11-05 The Regents Of The University Of California Nucleic acids, kits, and methods for the diagnosis, prognosis and treatment of glaucoma and related disorders
US7138511B1 (en) 1997-01-28 2006-11-21 The Regents Of The University Of California Nucleic acids, kits and methods for the diagnosis, prognosis and treatment of glaucoma and related disorders

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2632009A (en) * 1952-01-18 1953-03-17 American Cyanamid Co N-acetylpyrazinecarboxamide and methods of preparing the same

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2632009A (en) * 1952-01-18 1953-03-17 American Cyanamid Co N-acetylpyrazinecarboxamide and methods of preparing the same

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
S. KUSHNER et al., J. AMER. CHEM. SOC. 74, 3617 (1952), See Experimental on page 3620. *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993002709A1 (fr) * 1991-07-31 1993-02-18 Microcarb Inc. Conjugues comprenant un recepteur, destines a cibler des medicaments et autres agents
US5599535A (en) * 1995-06-07 1997-02-04 Regents Of The University Of California Methods for the cyto-protection of the trabecular meshwork
US5674888A (en) * 1995-06-07 1997-10-07 University Of California Method for the treatment of a trabecular meshwork whose cells are subject to inhibition of cell division
US6171788B1 (en) 1997-01-28 2001-01-09 The Regents Of The University Of California Methods for the diagnosis, prognosis and treatment of glaucoma and related disorders
US6475724B1 (en) 1997-01-28 2002-11-05 The Regents Of The University Of California Nucleic acids, kits, and methods for the diagnosis, prognosis and treatment of glaucoma and related disorders
US7138511B1 (en) 1997-01-28 2006-11-21 The Regents Of The University Of California Nucleic acids, kits and methods for the diagnosis, prognosis and treatment of glaucoma and related disorders

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AU6521790A (en) 1991-05-16

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