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N-Alkylamino Derivates of Aromatic, Tricyclic Compounds in the Treatment of Drug-Resistant Protozoal Infections

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N-Alkylamino Derivates of Aromatic, Tricyclic Compounds in the Treatment of Drug-Resistant Protozoal Infections Europaisches Patentamt 0 338 532 European Patent Office Qv Publication number: A2 Office europeen des brevets EUROPEAN PATENT APPLICATION 31/54 © Application number: 89107027.8 © mt.ci.4.A61K 31/38 , A61K @ Date of filing: 19.04.89 © Priority: 20.04.88 US 183858 © Applicant: MERRELL DOW 12.09.88 US 243524 PHARMACEUTICALS INC. 2110 East Galbraith Road @. Date of publication of application: Cincinnati Ohio 45215-6300(US) 25.10.89 Bulletin 89/43 © Inventor: Bitonti, Alan J. © Designated Contracting States: 7854 Carraway Court AT BE CH DE ES FR GB GR IT LI LU NL SE Maineville Ohio 45039(US) Inventor: McCann, Peter P. 3782 Cooper Road Cincinnati Ohio 45241 (US) Inventor: Sjoerdsma, Albert 5475 Waring Drive Cincinnati Ohio 45243(US) © Representative: Vossius & Partner Siebertstrasse 4 P.O. Box 86 07 67 D-8000 Munchen 86(DE) © N-alkylamino derivates of aromatic, tricyclic compounds in the treatment of drug-resistant protozoal infections. © Drug-resistant protozoal infection, particularly, drug-resistant malarial infection in humans, can be effectively treated with standard antiprotozoal agents if administered in conjunction with a tricyclic N-aminoalkyi iminodiben- zyl, dibenzylcycloheptane and cycloheptene, phenothiazine, dibenzoxazepine, dibenzoxepine, or thioxanthene derivative. CM < CM CO in oo CO CO LU Xerox Copy Centre EP 0 338 532 A2 N-ALKYLAMINO DERIVATIVES OF AROMATIC, TRICYCLIC COMPOUNDS IN THE TREATMENT OF DRUG- RESISTANT PROTOZOAL INFECTIONS This invention relates to the use of certain N-(aminoalkyl) derivatives of iminodibenzyl, dibenzyl- cycioheptane and cycloheptene, phenothiazine, dibenzoxazepine, dibenzoxepine, and thioxanthene in the treatment of drug-resistant malaria and in the treatment of other drug-resistant protozoal infections. Maiaria 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. Maiaria is a disease of warm blooded animals caused by infection with a parasite of the genus 10 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 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. 75 Red blood cells are at first altered and later destroyed by the infection. Drug therapy utilizing quinine, chloroquine, amodiaquine, primaquine, and other agents has been the mainstay of therapy against malaria. 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 20 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 imipramine and amitryptyline suppress P. falciparum growth, possibly by 25 virtue of the ability of these agents to interfere with riboflavin metabolism. While scientifically interesting, the practical use of imipramine and amitryptyline in the treatment of malaria would seem unlikely because of the lethal concentrations required to produce the anti-malarial effect in humans. While not practically useful in the treatment of non drug-resistant maiaria, applicants have now discovered that these and other such tricyclic antidepressant and antipsychotic compounds, when admininstered in subtoxic doses in conjunction 30 with standard antimalarial agents, are highly effective in treating drug-resistant malarial and other drug- resistant protozoal infections and are useful in the prophylaxis of drug-resistant malarial and other protozoal infections. Applicants have found that certain N-(aminoalkyl) derivatives of iminodibenzyl, dibenzylcycloheptane and cycloheptene, phenothiazine, dibenzoxazepine, dibenzoxepine, and thioxanthene derivatives of formula I 35 40 (i: 45 wherein Z is a divalent thio, 1 ,2-ethanediyl, 1,2-ethenediyl, or methyleneoxy radical; Y is a divalent radical of one of the formulae: 50 . EP 0 338 532 A2 Rl Ri / CH2 A — N —A— N^ CH \ I! \ R2 R2 c N / \ 10 Ri / N \ c R2 C 32 75 / \ / \ A is a alkylene group of from 1 to 4 carbon atoms; Ri and R2 are each, independently, a hydrogen or an alkyl group of from 1 to 4 carbon atoms or 20 Ri and R2 taken together with the nitrogen atom to which they are attached can form a N-piperazino- optionally substituted with a methyl, ethyl, or 2-hydroxyethyl group, N-piperidino-, N-morpholino-, or N- pyrrolidino radical; R and r' are each, independently, a hydrogen, hydroxy, bromo, chloro, iodo, or trifluoromethyl group or an alkyl or alkoxy of from 1 to 4 carbon atoms; 25 group or a pharmaceutically acceptable salt thereof when administered conjunctively with an antiprotozoal agent are useful in the treatment of individuals suffering from and prevention of drug-resistant malaria and other drug-resistant protozoal infections. As used herein the term "alkyl group of from 1 to 4 carbon atoms" encompasses the straight, branched, and cyclic alkyl groups such as methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, 30 tert-butyl, sec-butyl, cyclopropylmethyl, cyclobutyl, n-pentyl, isopentyl, sec-pentyl, cyclopentyl, cyclobutyl- methyl, cyclopropylethyl, and methylcyclopropylmethyl. The term "alkoxy group of from 1 to 4 carbon atoms" means those alkoxy groups wherein the alkyl portion is an alkyl group of 1 to 4 carbon atoms as defined. As used herein, the term "alkylene group of from 1 to 4 carbon atoms" means those saturated straight 35 and branched divalent hydrocarbon groups wherein the open valancies are on other than adjacent carbon atoms. Examples of such alkylene groups are 1,2-ethanediyl, 1,3-propanediyl, 1-methyl-1,2-ethanediyl, 1,4- butanediyl, and 2-methyl-1,3-propanediyl. The iminodibenzyl, dibenzylcycloheptane and cycloheptene, phenothiazine, dibenzoxazepine, dibenzox- epine, and thioxanthene derivatives of this invention are well known compounds, and are members of the 40 class of antidepressant compounds referred to as the tricyclic antidepressant compounds. These com- pounds are widely available or can be readily prepared by those of ordinary skill in the art of preparing benzocyclic compounds. Examples of tricyclic antidepressant and antipsycotic compounds encompassed within the method of this invention are: 45 Chlorpromazine hydrochloride; Promazine hydrochloride; Triflupromazine hydrochloride; Fluphenazine hydrochloride; Perphenazine; 50 Prochlorperazine maleate; Trifluoperazine hydrochloride; Chlorprothixine; Cidoxepin hydrochloride; Clomacran phosphate; 55 Clopenthixol; Dimeprozan; Doxepin hydrochloride; EP 0 338 532 A2 Trimerprazine; Imipramine; Desipramine; Amitriptyline; 5 Trimipramine; Nortriptyline; 2-Hydroxyimipramine; 2-Hydroxydesipramine; and Protriptyline. 10 The preferred compounds of formula 1 to be used in the method of this invention are those compounds wherein at least one of Ri and Ffe are an alkyl group of from 1 to 5 carbon atoms, as well as those compounds of formula 1 wherein R and R are each, independently, a hydrogen. More preferred are those compounds wherein one of Ri and R2 are a methyl group and the other os a hydrogen or a methyl group as well as those compounds having from one to three carbon atoms between the tricyclic ring and the 75 nitrogen atom to which the Ri and R2 groups are attached. Even more preferred are those iminodibenzyl, dibenzocycloheptane, and dibenzocycloheptene compounds of formula 1 wherein there are at least two, and preferably three, carbon atoms between the tricyclic ring and the nitrogen atom to which the Ri and R2 groups are attached as well as those compounds wherein at least one of Ri and R2 is a methyl group and the other is a hydrogen or a methyl group. Most preferred are those iminodibenzyl, dibenzylcycloheptane, 20 and dibenzylcycloheptene compounds wherein there are three carbon atoms between the tricyclic ring and the nitrogen atom to which the Ri and R2 groups are attached, wherein R and r' are each a hydrogen, and wherein one of Ri and R2 is a methyl group and the other is a hydrogen or wherein both of Ri and R2 are methyl groups. The compounds imipramine, desipramine, amitriptyline, and protriptyline are examples of the most preferred compounds with desipramine being preferred above all other compounds for use in the 25 methods of this invention. Prophylactic therapy of protozoal infections such as malarial infections is normally accomplished by administration of the antiprotozoal agent in a once or twice a week dosage form. When the compounds of formula 1 are administered in conjunction with an antiprotozoal agent for protozoal infection prophylaxis,
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