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WO1991006299A1 - Procede de traitement d'une infection opportuniste - Google Patents

Procede de traitement d'une infection opportuniste Download PDF

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Publication number
WO1991006299A1
WO1991006299A1 PCT/US1990/006202 US9006202W WO9106299A1 WO 1991006299 A1 WO1991006299 A1 WO 1991006299A1 US 9006202 W US9006202 W US 9006202W WO 9106299 A1 WO9106299 A1 WO 9106299A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
mammal
dhfr
compound
carbon atoms
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.)
Ceased
Application number
PCT/US1990/006202
Other languages
English (en)
Inventor
James R. Piper
John A. Montgomery
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.)
Southern Research Institute
Original Assignee
Southern Research Institute
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 Southern Research Institute filed Critical Southern Research Institute
Publication of WO1991006299A1 publication Critical patent/WO1991006299A1/fr
Anticipated expiration legal-status Critical
Ceased 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim

Definitions

  • This invention relates to a method for the treatment of an opportunistic infection in a mammalian host while minimizing the effect of the treatment on the host.
  • folic acid In order for an infectious organism to multiply in a host mammal such as man, folic acid must be reduced to tetrahydrofolic acid by the enzyme dihydrofolate reductase (DHFR) in the process of DNA synthesis and cellular replication. Any compound which will completely inhibit DHFR from the infectious organism will be fatal to the organism. However, most compounds which inhibit DHFR from an infectious organism also inhibit DHFR in the host mammal, thus leading to toxicity problems.
  • DHFR dihydrofolate reductase
  • X is CH_ , 0, S, or NH
  • Ar is a lipophilic aromatic group
  • this invention provides a method for the treatment of a mammal, such as man, afflicted with an opportunistic infection which comprises administering to said mammal a therapeutically effective amount of the compound of Formula I, wherein X and Ar are as previously defined, in a pharmaceutically acceptable carrier, said amount being sufficient to substantially inhibit DHFR from the infectious organisms, but being insufficient to substantially inhibit mammalian DHFR.
  • aromatic lipophilic groups i.e., substituent Ar in Formula I
  • substituent Ar include phenyl and naphthyl groups which may be unsubstituted or substituted with groups or combinations of groups such as alkyl containing from one to about eight carbon atoms, alkyloxy containing from one to about eight carbon atoms, aryl, aryloxy, alk lthio containing from one to about eight carbon atoms, arylthio, halogen, or pseudohalogen.
  • Two particularly preferred compounds are those compounds of Formula I wherein the group XAr is
  • the compounds of this invention form pharmaceutically acceptable salts with both organic and inorganic acids.
  • suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicyclic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic, and the like.
  • the salts are prepared by contacting the free base form with an equivalent amount of the desired acid in the conventional manner.
  • the free base forms may be regenerated by treating the salt form with a base.
  • dilute aqueous base solutions may be utilized.
  • Dilute aqueous sodium hydroxide, potassium carbonate, ammonia, and sodium bicarbonate solutions are suitable for this purpose.
  • the free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base forms for purposes of the invention.
  • the active compounds of this invention may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard or soft shell gelatin capsules, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet.
  • the active compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers and the like.
  • Such compositions and preparations should contain at least 0.1% of active compound.
  • the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 and about 60% of the weight of the unit.
  • compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains between about 5 and about 200 milligrams of active compound.
  • the tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of wintergreen or cherry flavoring.
  • a binder such as gum tragacanth, acacia, corn starch or gelatin
  • excipients such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid and the like
  • a lubricant such as magnesium stea
  • the dosage unit form When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills or capsules may be coated with shellac, sugar or both.
  • a syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor.
  • any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
  • the active compounds may be incorporated into sustained-release preparations and formulations.
  • the active compounds may also be administered parenterally or intraperitoneally.
  • Solutions of the active compound as a free base or pharmaceutically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that easy syringability exists.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like) , suitable mixtures thereof and vegetable oils.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and the freeze-drying technique which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • Dosage unit form refers to physically discrete units suitable as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the novel dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active material for the treatment of disease in living subjects having a diseased condition in which bodily health is impaired as herein disclosed in detail.
  • the principal active ingredient is compounded for convenient and effective administration in effective amounts with a suitable pharmaceutically-acceptable carrier in dosage unit form as hereinbefore disclosed.
  • a unit dosage form can, for example, contain the principal active compound in amounts ranging from about 0.1 to about 400 mg, with from about one to about 30 mg being preferred. Expressed in proportions, the active compound is generally present in from about 0.1 to about 400 mg/ l of carrier.
  • the dosages are determined by reference to the usual dose and manner of administration of the said ingredients. The following example illustrates the invention.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (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)

Abstract

Procédé de traitement d'un mammifère souffrant d'une infection opportuniste, ce procédé consistant à administrer au mammifère une quantité thérapeutiquement efficace d'un composé ayant la formule (I) dans laquelle X représente CH2, O, S, ou NR (R représente H ou alkyle), et Ar est un groupe aromatique lipophile, dans un excipient pharmaceutiquement acceptable, la quantité étant suffisante pour inhiber sensiblement DHFR des organismes infectieux provquant l'infection opportuniste, mais étant insuffisante pour inhiber sensiblement DHFR mammifère.
PCT/US1990/006202 1989-10-24 1990-10-24 Procede de traitement d'une infection opportuniste Ceased WO1991006299A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US42601589A 1989-10-24 1989-10-24
US426,015 1989-10-24

Publications (1)

Publication Number Publication Date
WO1991006299A1 true WO1991006299A1 (fr) 1991-05-16

Family

ID=23688938

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1990/006202 Ceased WO1991006299A1 (fr) 1989-10-24 1990-10-24 Procede de traitement d'une infection opportuniste

Country Status (2)

Country Link
AU (1) AU6720190A (fr)
WO (1) WO1991006299A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0453556A4 (en) * 1989-11-15 1993-02-03 The Regents Of The University Of California Pneumocystis carinii dihydrofolate reductase gene and methods for its use

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4694007A (en) * 1986-05-20 1987-09-15 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Use of trimetrexate as antiparasitic agent

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4694007A (en) * 1986-05-20 1987-09-15 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Use of trimetrexate as antiparasitic agent

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF HETEROCYCLIC CHEMISTRY, Vol. 16, April 1979, MONTGOMERY, pages 537-539. *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0453556A4 (en) * 1989-11-15 1993-02-03 The Regents Of The University Of California Pneumocystis carinii dihydrofolate reductase gene and methods for its use

Also Published As

Publication number Publication date
AU6720190A (en) 1991-05-31

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