WO1991006299A1

WO1991006299A1 - Method for the treatment of an opportunistic infection

Info

Publication number: WO1991006299A1
Application number: PCT/US1990/006202
Authority: WO
Inventors: James R. Piper; John A. Montgomery
Original assignee: Southern Research Institute
Current assignee: Southern Research Institute
Priority date: 1989-10-24
Filing date: 1990-10-24
Publication date: 1991-05-16
Anticipated expiration: 1992-04-24
Also published as: AU6720190A

Abstract

There is disclosed a method for the treatment of a mammal afflicted with an opportunistic infection, which comprises administering to said mammal a therapeutically effective amount of a compound having formula (I) wherein X is CH2, O, S, or NR (R is H or alkyl), and Ar is a lipophilic aromatic group, in a pharmaceutically acceptable carrier, the amount being sufficient to substantially inhibit DHFR from the infectious organisms causing the opportunistic infection, but being insufficient to substantially inhibit mammalian DHFR.

Description

METHOD FOR THE TREATMENT OF AN OPPORTUNISTIC INFECTION

Background of the Invention

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. 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.

Both Pneumocystis carinii and Toxoplasma gondii have been established to be causes of fatality in man if not successfully treated. Both infections occur in patients who are afflicted with immune system deficiencies. Such infections are referred to as opportunistic infections and are particularly likely to develop in AIDS patients.

Summary of the Invention It has now been discovered that compounds having the formula

wherein X is CH_ , 0, S, or NH, and Ar is a lipophilic aromatic group, are potent inhibitors of DHFR from the two infections organisms, Pneumocystis carinii and Toxoplasma gondii, but are remarkably less inhibitory toward DHFR from a mammalian source. Thus, 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.

Detailed Description of the Invention

Examples of aromatic lipophilic groups, i.e., substituent Ar in Formula I, 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

(Compound A) and

(Compound B) Both of these compounds are reported by Montgomery et al in J. Heterocycl. Che . , 16, 537-539 (1979) , and one, Compound A, is included in U.S. Patent Nos. 4,077,957 and 4,079,056. The Montgomery et al article states that agents described therein that are capable of inhibiting dihydrofolic reductase might be useful for the treatment of tumors.

The compounds of this invention form pharmaceutically acceptable salts with both organic and inorganic acids. Examples of 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. For example, 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. For oral therapeutic administration, 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. The amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained. Preferred 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. 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. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, 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. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. 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. In many cases, it will be preferable to include 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. Generally, 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. In the case of sterile powders for the preparation of sterile injectable solutions, 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.

As used herein, "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.

It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein 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. In the case of compositions containing supplementary active ingredients, the dosages are determined by reference to the usual dose and manner of administration of the said ingredients. The following example illustrates the invention.

Example 1

The activities of Compound A, Compound B and 3 clinical agents (trimethoprim, pyrimethamine, and trimetrexate) in a dihydrofolate reductase screen were determined. The results are set forth in Table 1. In this table, "Pc" means

Pneumocystis carinii, RL means rat liver, and "Toxo" means Toxoplasma gondii. ICo_cru_ι Values

Toxo DHFR Ratio

0.77 319

0.076 16.6

These test results on Compound A and Compound B show high favorable ratios when the IC,.- values (the concentrations of the agents required to reduce the enzyme activity of DHFR by 50%) of these compounds against typical mammalian DHFR (from rat liver) are compared with those against DHFR from the infectious organisms. The value of the ratios reflect the selectivity of the agents. Compare the ratios for the first three compounds listed in Table 1. It is obvious that Compound A is by far the most selective agent listed. The clinical agent pyrimethamine shows no selectivity, and trimetrexate shows the reverse of the desired effect exerting greater potency against mammalian DHFR than against Pneumocystis carinii DHFR. Compound B, a more potent inhibitor than Compound A, is less selective than Compound A, but its greater potency along with its still considerable selectivity makes it valuable in the practice of this invention.

Claims

WHAT IS CLAIMED IS:

1. A method for the treatment of a mammal afflicted with an opportunistic infection which comprises administering to said mammal a therapeutically effective amount of a compound having the formula

wherein X is CH„, 0, S, or NR (R is H or alkyl) , and Ar is a lipophilic aromatic group, in a pharmaceutically acceptable carrier, said amount being sufficient to substantially inhibit DHFR from the infectious organisms causing the opportunistic infection, but being insufficient to substantially inhibit mammalian DHFR.

2. A method as defined in claim 1 wherein said mammal is a human.

3. A method as defined in claim 2 wherein the group Ar is a phenyl or naphthyl group unsubstituted or substituted with groups or combinations of groups such as alkyl containing from one to about eight carbon atoms, alkoxy containing from one to about eight carbon atoms, aryl, aryloxy, alkylthio containing from one to about eight carbon atoms, arylthio, halogen, or pseudohalogen.

4. A method as defined in claim 2 wherein the group XAr is

5. A method as defined in claim 2 wherein the group

6. The use of a compound having the formula

wherein X is CH,,, 0, S, or NR (R is H or alkyl) , and Ar is a lipophilic group for the manufacture of a medicament for use in the treatment of a mammal afflicted with an opportunistic infection by administering to said mammal a therapeutically effective amount of said compound in a pharmaceutically acceptable carrier, said amount being sufficient to substantially inhibit DHFR from the infectious organisms causing the opportunistic infection, but being insufficient to substantially inhibit mammalian DHFR.

7. The use as defined in claim 6, wherein said mammal is a human.

8. The use as defined in claim 6, wherein the group Ar is a phenyl or naphthyl group unsubstituted or substituted with groups or combinations of groups such as alkyl containing from one to about eight carbon atoms, alkoxy containing from one to about eight carbon atoms, aryl, aryloxy, alkylthio containing from one to about eight carbon atoms, arylthio, halogen, or pseudohalogen.

9. The use as defined in claim 6, wherein the group XAr is

10. The use as defined in claim 6, wherein the group XAr is