Claims
- 1. A method of reversing drug-resistance in a patient having a drug-resistant malarial infection which comprises administering to the patient a drug-resistance reversing amount of a compound of the formula ##STR3## wherein R.sub.1 is a C.sub.1 -C.sub.3 alkylene,
- n, p and q are each independently 0, 1 or 2,
- Y and X are each independently lower alkyl, lower alkoxy, hydroxy, CF.sub.3, halogeno or when p or q are 2 and each of the Y or each of the X groups are on adjacent aryl carbon atoms, both of the X or both of the Y groups can be taken together to form a methylene dioxy moiety,
- R.sub.2 and R.sub.3 are each independently hydrogen or lower alkyl, R.sub.4 is an oxy or thio,
- or an acid addition salt thereof.
- 2. A method of claim 1 wherein R.sub.2 is methyl and R.sub.3 is hydrogen.
- 3. A method of claim 1 wherein R.sub.2 and R.sub.3 are each methyl.
- 4. A method of claim 1 wherein R.sub.1 is --CH.sub.2 -- or --CH.sub.2 CH.sub.2 --.
- 5. A method of claim 1 wherein n is 1.
- 6. A method of claim 1 wherein p is O.
- 7. A method of claim 1 wherein Y is chloro and p is 1.
- 8. A method of claim 1 wherein X is CF.sub.3 and q is 1.
- 9. A method of claim 1 wherein X is methoxy and q is 1.
- 10. A method of claim 1 wherein q is O.
- 11. A method of claim 1 wherein X is chloro and q is 1.
- 12. A method of claim 1 wherein R.sub.4 is oxy.
- 13. A method of claim 1 wherein the drug-resistant malarial infection is a chloroquine-resistant material infection.
CROSS-REFERENCE TO RELATED APPLICATION
This is a continuation of application Ser. No. 07/278,689 filed Dec. 1, 1988, now abandoned.
This invention relates to the use of certain phenoxy and phenylthio, amino substituted benzocycloalkane derivatives in the treatment and prevention of drug-resistant malaria and in the treatment and prevention of other drug-resistant protozoal infections.
Malaria remains a significant health threat to humans despite massive international attempts to eradicate the disease. Over 200 million people are said to have malaria and over one million deaths per year are associated with malaria in Africa alone. In many of the endemic areas, local supply of food is quite limited, a problem which is greatly aggravated by the presence of protozoal infections in cattle and other farm animals.
Malaria is a disease of warm blooded animals caused by infection with a parasite of the genus Plasmodium. Four species, P. vivax, P. falciparum, P. malariae, and P. ovale, are known to infect humans. The parasite is transmitted to humans by the bite of Anopheles mosquitoes. Subsequent to humans by the bite of Anopheles mosquitoes. Subsequent to mosquito bite, the parasite rapidly invades the blood cells of the victim and after a incubation period, generally lasting about 10 to 14 days, symptoms, consisting of chills, fever, headache, muscle pains, spenomegaly, and anemia, appear. This incubation period may be prolonged for many weeks and onset can be quite insidious. Red blood cells are at first altered and later destroyed by the infection. After an acute episode, the victim may be reinfected by the parasite which persists in the liver.
Drug therapy utilizing quinine, chloroquine, amodiaquine, primaquine, and other agents has been the mainstay of therapy against malaria and diseases caused by infection by other protozoa such as various species of Leishmaniasis and Trypanosomiasis. However, drug-resistant strains of protozoa have developed and in some cases strains are resistant to many or all of the current therapeutic agents. In particular, P. falciparum malaria is quite prone to exhibit single and even multiple drug-resistance. While new agents are continually developed and introduced, resistance to such new agents also quickly develops. For example mefloquine-resistant malaria was reported even before mefloquine licensure was completed. There is, thus, an urgent need for antimalarial and antiprotozoal agents which can be used in the treatment of drug-resistant malaria and other protozoal diseases.
Recently it was reported that the antidepressant compounds imipramine and amitryptyline suppress P. falciparum growth by virtue of the ability of these agents to interfere with riboflavin metabolism. While scientifically interesting, the practical use of imipramine and amitryptyline and other antidepressant compounds in the treatment of malaria would seem unlikely because of the lethal doses required to produce the anti-malarial effect in humans. Applicants have now discovered that certain antidepressant phenoxy and phenylthio, amino substituted benzocycloalkane derivatives, when administered in subtoxic doses in conjunction with standard antimalarial agents, are highly effective in treating and preventing drug-resistant malarial and other drug-resistant protozoal infections.
Applicants have found that certain phenoxy and phenylthio, amino substituted benzocycloalkane derivatives of formula 1 ##STR1## wherein R.sub.1 is a C.sub.1 -C.sub.3 alkylene,
US Referenced Citations (1)
| Number |
Name |
Date |
Kind |
|
4177292 |
Nedelec et al. |
Dec 1979 |
|
Non-Patent Literature Citations (5)
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Continuations (1)
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Number |
Date |
Country |
| Parent |
278689 |
Dec 1988 |
|
Patent Grant
5134168
