N,N'-SUBSTITUTED IMIDOCARBONIMIDIC DIAMIDES DERIVED FROM HYDROXYLAMINES

Abstract: There are provided compounds of formula (1) wherein R<1> is a substituted or unsubstituted divalent aliphatic group of 1 to 16 carbon atoms; wherein the substituents are mono or poly and are selected from the group consisting of lower alkyl, aryl and aralkyl, R<3> is selected from the group consisting of same group of values as R<5>, R<5> is selected from the group consisting of substituted and unsubstituted alkyl of 1-10 carbon atoms, aryl, cycloalkyl and heterocycloalkyl of 3-8 carbon atoms, wherein the substituents are mono or poly and are selected from the group consisting of lower alkyl, cycloalkyl of 3-8 carbon atoms, lower alkenyl, lower alkynyl, nitro, lower alkoxy, lower alkoxycarbonyl, phenyl lower alkyl, phenyl, mono and polyhalophenyl, phenoxy, mono and polyhalophenoxy, R<6> and R<7> may be the same or different and are hydrogen, alkanoyl or alkoxyalkanoyl, R<7> may also have the same value as R<5>, Y is oxygen or sulfur, m is 0 or 1, q is 0 or 1, wherein the prefix alk designates moieties which are straight chain or branched chain, and the term lower designates 1-6 carbon atoms and the unmodified term alk signifies 1-24 carbon atoms, the respective tautomers thereof, the parmaceutically acceptable salts and addition salts thereof and the hydrates of said salts and addition salts. There are further provided methods of protecting subjects liable thereto from infections caused by an organism of the group Plasmodium sp., Mycobacterium sp. and Pneumocystis carinii by administering to a subject liable to such infection, a prophylactically effective amount of a compound of the foregoing formula. These compounds will also reduce the level of infection where said subjects have already been infected.

Description: N.N'-Substituted Imidocarbonimidic Diamides derived from Hvdroxylamines. * BACKGROUND OF THE INVENTION 1. Field of the Invention This invention relates to N,N'-substituted asymmetrical imidodicarbonimi 5 diamides derived from hydroxylamines and their derivatives and to processes making them. 2. Discussion of the prior art. The related triazine derivatives (Onori, E. and Majori, G. Recent acquisiti 10 on chemotherapy and chemoprophylaxis of malaria. Ann 1 st Super Sani 255: 659-74) (1989) are poorly absorbed and have been shown to be l effective in eliciting cures when administered orally, as compared to injection, malaria-infected aotus monkeys. The related triazine derivatives, must administered by injection to observe activity comparable to or exceeding ot 15 known antimalarial drugs. (Knight, D.J. and Peters, W. The antimalarial acti of N-benzyloxy dihydrotriazines. I. Ann. Tropical Med. Parasitol. 74:393- (1980). The antimalarial activity of N-benzyl- oxydihydrotriazines. IV. Ann. Tr Med. Parasitol. 76:9-14. Knight, D.J. and Williamson, P. (1982), U.S. 4,232,022, U.S. PaT.4, 179,562). Additionally such triazines have been repor 20 as poorly tolerated when given by the oral route (Knight, D.J. and Williamson (1982) supra). SUMMARY OF THE INVENTION There are provided novel, pharmaceutically active compounds of the for 25 H N 3 < - I \ R β N 2 = C C = N 4 R 7 30 R 6 -Y q -R 1 -O-N • H I N 6 H m la / R 3 and all of its tautomers such as, for example: R β N 3 R 7 \ I \ I HN 2 C CN 4 H I i R δ -Y q -R 1 -O-N 1 H N 5 lb / R 3 N 3 R 7 / \ / R β N 2 = C CN 4 H R 5 -Y q -R 1 -O-N 1 H N 5 H r lc / R 3 R β N 3 \ / \ HN 2 C C = N 4 R 7 R^Y q -R^O-N^ N 5 H m Id / R 3 R β N 3 R 7 \ / \ / HN 2 HC CN 4 H I I R'-Y q -R'-O-N 1 N 6 H m le / R 3 all being subsumed under the general designation of formula I. Any one of the formulae used herein shall be considered as the equivalent of and subsume t others. In Formula I : R 1 is a substituted or unsubstituted divalent aliphatic group of 1 to 16 carbo atoms; wherein the substituents are mono or poly and are selected from th group consisting of lower alkyl, aryl and aralkyl, R 3 is selected from the group consisting of same group of values as R 5 , and ma also form, with the nitrogen to which it is attached a saturated heterocycle of 4- carbon atoms, R δ is selected from the group consisting of substituted and unsubstituted alk of 1-10 carbon atoms, cycloalkyl, heterocycioalkyl of 3-8 carbon atoms, mon and polycarbocycloaryl of 4-7 atoms per ring, wherein the substituents are mono or poly and are selected from the gro consisting of lower alkyl, halo lower alkyl, cycloalkyl of 3 - 8 carbon atoms, low alkenyl, lower alkynyl, nitro, lower alkoxy, lower alkoxycarbonyl, phen loweralkyl, phenyl, mono and polyhalophenyl, phenoxy, mono a polyhalophenoxy, and halo provided however, that such substitution is in a mo and polycarbocycloaryl of 4-7 atoms per ring, R β and R 7 may be the same or different when R β is hydrogen, alkanoyl alkoxyalkanoyl and may also form, with the nitrogen to which they are attache a saturated heterocycle of 4-8 carbon atoms, R 7 may also be selected from the group consisting of same group of values as Y is oxygen or sulfur, m is 0 or 1 , q is 0 or 1 , provided that unless otherwise stated the prefix alk designat moieties which are straight chain or branched chain, and the term lo designates 1-6 carbon atoms and the unmodified term alk signifies 1-24 carb atoms, the pharmaceutically acceptable salts and addition salts thereof and t hydrates of said salts and addition salts, and the mono and diacyl derivati thereof. It is believed the chemical formulas and names used herein correctly a accurately reflect the underlying chemical compounds. However, the nature a value of the present invention does not depend upon the theoretical correctn of these formulas, in whole or in part. Thus, it is understood that the formula used herein, as well as the chemical names attributed to the correspondingl indicated compounds, are not intended to limit and do not limit the invention i any way, including restricting it to any specific tautomeric form or to any specifi optical or geometric isomer. Compounds within the scope of the present invention have antimicrobial an antiparasitic activity of various kinds, including antimalarial activity and provid a novel pharmacological activity since unlike previously reported triazin derivatives the parent compound and its derivatives described herein are high bioavailable by virtue of their ability to be readily absorbed when taken orally. There is disclosed a method for synthesizing the novel compounds of t present invention by reacting an appropriately substituted hydroxylamin thioamine or isosteric amine with a substituted dicyanodiamide in the presen of an acid catalyst to form a disubstituted imidodicarbonimidic diamide with N a N' substituents. These products may then be further salified or further reacted produce additional substituents in the biguanide. The aforesaid substituted hydroxylamines may be synthesized follows: R 5 -Y q -H (II) + NaOH — > R 6 -Y q -Na (Ha) + H 2 O R B -Y q -Na + BrR 1 Br (III) > R 6 -Y q -R 1 Br (IV) + NaBr + H 2 O NaOH/EtOH + HO.NH.Ac — > Na.O.NH.Ac (V) + H 2 O R 6 -Y q -R 1 Br (IV) + Na.O.NH.Ac — > R B -Y q -R 1 .O.NH.Ac (VI) + NaBr R 5 -Y q -R\O.NH.Ac (VI) + HCI + H 2 O > R δ -Y q -R 1 .O.NH 2 .HCI (VII) + HAc R 5 -Y q -R 1 .O.NH 2 .HCI (VII) + N 3 R 7 N 3 R 7 / \ / / \ / N 2 =.C CN H > HN 2 = C C-N 4 H N 5 IH (Villa) I I R 5 -Y q -R 1 -O-N 1 H N δ H m . H R 3 / R 3 The foregoing route is valid where Y q is O or S and R 7 is hydrogen, alkano or alkoxyalkanoyl. However where R 7 is selected from the R 6 group a differe route is desirable to compound (VII) and then to (I). R 3 -N = C = S (XXXI) + NaHNC_≡_N > N 3 N 3 / \ / \ N 2 .≡.C CSNa + CH 3 I N 2 ≡ C CSCH 3 + R 7 NH 2 I I N 5 H (XXIII) N 5 H (XXXIII) / / R 3 N 3 R 7 / \ / N 2 = C C-N H + R 6 -Y q -R 1 .O.NH 2 .HCI (VII) --- N 6 H (I) (XXXIV) Thus there are also provided methods of protecting subjects liable theret from infections caused by an organism selected from the group consisting Plasmodium sp., Mycobacterium sp and Pneumocystis carinii which compris administering to a subject liable to infection by exposure to such organisms, prophylactically effective amount of a compound of the above formula I. Simila there are provided methods of reducing the level of infection in subjects sufferi from infections caused by an organism selected from the foregoing group whi comprise administering to such subjects an effective amount of a compound formula I. Prophylactic and treatment compositions for the foregoing purposes are al provided which comprise a prophylactically or infection reductively effect amount of a compound of formula I and a pharmaceutically acceptable carrier. Such compositions may be formulated for oral administration by which rout these compounds and compositions are well absorbed, especially as tablets o capsules. DESCRIPTION OF THE PREFERRED EMBODIMENTS There are provided pharmaceutically active compounds of the formula H N 3 / \ R Θ N 2 = C C = N 4 R 7 I I R 5 -Y q -R 1 -O-N 1 H N B H m la / R 3 wherein: R 1 is substituted or unsubstituted divalent aliphatic group of 1 to 16 carbo atoms, suitably lower alkyl such as methyl, ethyl, n-propyl, iso-propyl, isobutyl n-pentyl, n-decyl, or cycloalkyl such as cyclopentyl, cyclohexyl, cycloheptyl. The substituents are mono or poly and are selected from the group consisting o lower alkyl such as methyl, ethyl, n-propyl, iso-propyl, isobutyl, n-pentyl, n-decy or cycloalkyl such as cyclopentyl, cyclohexyl, cycloheptyl, aryl, suitably pheny napthyl, tetrahydronapthyl, indanyl, indenyl, benzofuranyl, benzopyranyl, an aralkyl such as benzyl and phenethyl, R 3 is selected from the group consisting of same group of values as R δ , if desire it may also form , with the nitrogen to which it is are attached, a saturat heterocycle of 4-8 carbon atoms such as pyrrolidyl, piperidinyl or pyrrolidinyl, R δ is selected from the group consisting of substituted and unsubstituted alk of 1 -10 carbon atoms such as methyl, ethyl, n-propyl, iso-propyl, isobutyl, pentyl, n-decyl, or cycloalkyl such as cyclopentyl, cyclohexyl, cycloheptyl, ar suitably phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, benzofuran benzopyranyl, biphenylyl, heterocycloalkyi such as tetrahydrofuranyl, pyrrolidin piperidyl and morpholinyl, wherein the substituents are mono or poly and a selected from the group consisting of lower alkyl, such as methyl, ethyl, n-prop iso-propyl, isobutyl, n-pentyl, halo lower alkyl such as trifluoromethyl or cycloalk such as cyclopentyl, cyclohexyl, or cycloheptyl, lower alkenyl, such as etheny n-propenyl, iso-propenyi, isobutenyl, n-pentenyl, lower alkynyl, such as ethyny n-propynyl, iso-propynyl, isobutynyl, n-pentynyl, nitro, lower alkoxy, such a methoxy, ethoxy, n-propoxy, iso-propoxy, isobutoxy, n-pentoxy, low alkoxycarbonyl, such as formyloxy, acetoxy, propionyloxy, and butyryloxy, phen loweralkyl, such as benzyl, phenyl, phenoxy, mono and polyhalophenyl, mono an polyhalophenoxy, wherein the halo group is fluoro, chloro or bromo, which ma also serve as mono and poly substituents for the above named aryl moieties. R β and R 7 may be the same or different and are hydrogen or alkanoyl, suitabl formyl, acetyl, propionyl, and butyryl. If desired they may also form , with t nitrogen to which they are attached a saturated heterocycle of 4-8 carbon ato such as pyrrolidyl, piperidinyl or pyrrolidinyl. Y is oxygen or sulfur. m is 0 or 1. q is 0 or 1 , the pharmaceutically acceptable salts and addition salts thereof and the hydrat of said salts and addition salts. Also included are the mono and diacyl derivatives thereof, suitably alkano or aralkanoyl derivatives such as acetyl and benzyl derivatives. The compounds of formula I of the present invention may be synthesized a number of routes of which the following is of most general applicability and preferred. In this multi-step process, some of the intermediates may commercially available, however for the sake of completeness, the followi process description commences with readily commercially obtainable starti materials. Where it is intended to form a compound wherein Y is oxygen or sulfur a q is 1 , the starting material is an alkanol, a phenol or a mercaptan (II). Where starting material is an alkanol, there is utilized an excess of the alkanol and th desired quantity to be reacted is treated with one equivalent of alkali met sodium to form the alkali metal salt in alkanolic solution. In the case of mercaptans or phenols there is utilized an excess of aqueou alkali, suitably sodium hydroxide, which forms the appropriate sodium salt ambient temperatures in a few minutes. There is then added an excess, suitabl a 2-fold excess of a dihaloalkane over the calculated amount of alkali metal sal the position of the halo groups determining the length of the R 1 moiety. T mixture is heated under reflux for from about 1 to about 4 hours. A furth excess of alkali is added and the reaction mixture held at between 50 and 70° for about 1/2 hour. The mixture is cooled, the lower organic layer separate washed, and distilled under reduced pressure to give water, unreact dihaloalkane and the desired R 5 oxy or thioalkyl halide (IV). Acetohydroxamic acid is converted into the corresponding alkali met hydroxamate (V) by addition of alkanoic, suitably an ethanolic solution of alk metal hydroxide such as sodium or potassium hydroxide. The oxy or thioal halide (IV) produced as above, is then added and the mixture heated under reflu suitably from about 4 to about 8 hours and cooled. Precipitated alkali me halide salt is removed by filtration, the solvents removed under reduced pressu and the residue dissolved in a polar, water miscible, organic solvent, suita acetone solution, again filtered and concentrated under reduced pressure to yi the corresponding oxy or thioalkyl acetohydroxamate (VI). Where q is 0, for example where R e -R 1 is benzyl, the corresponding R δ -R 1 h compound (IV) such as benzyl bromide, may be commercially obtained and t is then reacted directly with the alkali metal acetohydroxamate as descri above. The acetohydroxamate (VI) is taken up in an alkanol, to which is added a excess of dilute mineral acid, suitably hydrochloric acid, the mixture heated und reflux for about 2 to about 6, suitably from 4 hours, the solvents removed und pressure and the residue extracted with dry diethyl ether. The solvent is the removed under reduced pressure and the residue recrystallized from an alkano suitably ethanol or isopropanol, to give the desired alkyloxyamine hydrochlorid (VII). The alkyloxyamine hydrochloride (VII) is taken up in an alkanol and treate with concentrated aqueous hydrochloric acid until the solution is clearly acidi The appropriate omega-substituted dicyandiamide, for example, a lower alk dicyan-diamide (VIII), is added in excess. The mixture heated under reflux f about 2 to about 6 hours, the solvents removed by evaporation under reduc pressure to yield the desired alkoxy omega-substituted iminodicarbonimid diamide hydrochloride (I). This oil, upon treatment and trituration with anhydro ether, gives a solid precipitate which may be recrystallized, suitably from eth acetate, as the hydrate. Where reagent (VIII) is a mono omega-substituted dicyandiamide carrying substitution on the remaining imino nitrogen, then R 7 in compound (VIII) hydrogen and the thus obtained product of formula I will carry no substituents the N 2 and N 4 nitrogens, that is to say, R β and R 7 will be hydrogen. Where bo nitrogens of the imino groups are substituted, then R 7 will be other th hydrogen. Where it is desired either to place the same substituent on both the N 2 a N 4 nitrogens or, where R 7 is other than hydrogen, to place a different substitue on the N 2 nitrogen, the hydrochloride hydrate (I) is suspended in a suitable wa immiscible reaction inert organic solvent, suitably ethyl acetate, shaken with excess of aqueous alkali, suitably aqueous sodium hydroxide, the organic la separated, dried, and heated under reflux for from about 1 to about 4 hours w an excess of a suitable acylating agent, for example acetyl chloride. After completion of the reaction, the volatile components are removed under reduced pressure to yield the desired N 2 acylated compound. As illustrated above, where R 7 has a value selected from the R 5 group a different synthetic route is desirable. The methodology is that of Curd, F.H.S, et al J. Chem Soc. 1630-45 (1948) and Davidson, J.S., Chemistry and Industry. 1977-8 (1965). The R 3 isothiocyanate (XXXI) is added to a suspension of sodium cyanamide in alkanol, such as ethanol, which precipitates the sodium salt of N-cyano-N'-R 3 thiourea (XXXII) which is filtered off, washed with alkanol. Methyl iodide is added with rapid stirring at ambient temperature. The product separates. The suspension is cooled in an ice bath, the solids filtered off and washed with water and dried to give N-cyano-N'-R 3 -S-methylisothiourea (XXXIII). The isothiourea (XXXIII) is added to an alkanoiic solution of R 7 amine and th mixture heated for 4 hours in a pressure bottle at about 50°C. The resulting clea solution is gradually diluted with water (75 cc) and product crystallizes out to giv the dicyano R 3 ,R 7 diamide (XXXIV). This can then be reacted with th hydroxylamine hydrochloride salt (VIII) as described previously to obtain th desired compound (I). The compounds of the present invention may be made in the form of th monohydrohalic acid addition salts and/or the soivated compound, for exampl the hydrochloride hydrate or the hydrobromide. Other salts may be mad however by simple reaction of a base with acid and may be desirable in order t modify the properties of the product such as its toxicity, taste, physical form o rate of release into the body. For example the compounds may be made in th form of the picrate, saccharinate, acetate, acid maleate, acid phthalate, succinat phosphate, nitro-benzoate, stearate, mandelate, N-acetyl-glycinate, pamoate sulfonate, di-sulfonate, cyclohexyl sulphamate, citrate, tartrate, or gluconate. Stable salts are normally formed with a ratio of one molecule of N, N ' pol substituted imidodicarbonimidic diamides to 1 or 2 molecules of monobasic aci (or more than one molecule of compound 1 in the case of polybasic acids) but th possibility of having basic groups as substituents in R 5 for example means tha further quantities of acid may be combined with the disubstitute imidodicarbonimidic diamide in some cases. In addition the above molecules ma contain various hydrated forms with molecules of water or other solvent include in the molecular formula of the stable entity. The presence of the imino biguanide nitrogens on the molecule create th possibility of forming acyl derivatives by reaction with appropriate substrates. There is disclosed an improved mode of prophylaxis and treatment infections by one or more of Plasmodia; mycobacteria; toxoplasmosis a pneumocystis organisms; and agents causing nocardia infections. The N,N substituted asymmetrical biguanides of Formula I of the present invention and/ salts and/or derivatives have antimalarial and antibacterial activity as well effectiveness against some fungi, protozoans, parasites and viruses. Additionall the N" and N'" substituted derivatives of formula I exhibit like activities. particular, these N,N' - substituted asymmetrical biguanides and salts, as well their N" and N' π substituted derivatives exhibit antiparasitic activity includi activity against the Plasmodia of malaria, P. falciparum exhibit antimicrob activity against mycobacteria including but not limited to M. avium intercellula M. avium complex, M. tuberculosis, M. leprae and Toxoplasma gondii a Pneumocystis organisms such as P. carinii associated with but not limited immunocompromised patients. In addition, these compounds have activ against nocardia infections. These compounds can also be potentiated combination with sulfonamides or sulfones to improve the biological spectrum an potency of these compounds of Formula I. Our use data have been confirmed by additional extensive animal studie supported by the U. S. Department of the Army. It is our finding that the novel compounds of the present invention show hig levels of effectiveness when given orally, as compared to the related triazin derivatives which are known to be poorly absorbed. Unlike the related triazin derivatives, this novel series of compounds need not be administered by injectio to observe activity comparable to or exceeding other known antimalarial drugs EXAMPLES OF BIOLOGICAL ACTIVITY OF THE INVENTION BIOLOGICAL ACTIVITY AGAINST PLASMODIUM FALCIPARUM The method of testing for activity against human malaria parasites i described in detail by L.H. Schmidt, Am. J. Troo. Med. & Hvαiene. 1978 27:718-737. The detailed methods include all aspects of animal treatmen infection and evaluation of drug efficacy. The testing is carried out by in vivo screening in a system accepted as th standard for identifying effective antimalarial compounds in humans. The te system utilizes night monkeys (Aotus, Trivergatus) native to Colombia. Th monkeys are infected with various selected strains of malaria by means of a intravenous inoculation of 5 x 10 β trophozoites. These trophozoites are obtain directly from P. falciparum infections isolated from humans and the infectio organisms are well characterized with respect to their response to medicatio The Aotus system is unique in that it makes possible the evaluation of hum falciparum malaria. The drugs are administered to the monkeys via stomach tub and the usual schedule of testing involves daily dosing of the test animals f seven days. Activity is determined by the clearance or the eradication of t malarial infection. In Table 1. provided, the activity of title compound JPC777 N-[3-(2,4,5-trichloro- phenoxy)propoxy]-N'-(1-methylethyl)imidodicarbonimi diamide, is compared to two known antimalarial drugs and is tested comparativ in the highly drug resistant Vietnam Smith strain of Plasmodia falciparu JPC7776 elicited a clearcut dose response with 8/8 animals treated with mg/kg daily for three days showing clearance of parasites (100% respons Three of eight subjects were cured (37.5%). Higher doses produced higher c rates of 75% and 100% at doses of 30.0 and 150.0 mg/kg. Comparison w proguanil or cycloguanil up to 150 mg/kg for three days showed no activity ( response). TABLE 1. ACTIVITY OF JPC7776 AGAINST PLASMODIUM FALCIPARUM INFECTIONS MALARIA DOSE mg/kg PRIMARY TREATMENTS STRAIN TOTAL DAILY CLEARED CURED MALARIA DOSE mg/kg PRIMARY TREATMENTS STRAIN TOTAL DAILY CLEARED CURED MALARIA DOSE mg/kg PRIMARY TREATMENTS STRAIN TOTAL DAILY CLEARED CURED Comparative tests in vivo in mice against Plasmodium have been carried ou Confirming tests conducted under the auspices of the U. S. Department of th Army demonstrate favorable oral activity. Results demonstrate the superi bioavailability and effectiveness of JPC7776 via the oral route as compared to i corresponding triazine WR99210 and the antimalarial proguanil. These data i Table 2 show the number of cures and the effective dose curing 50% of infecte animals (ED-50) when drugs were administered in peanut oil via the subcutaneou route (SQ) or when administered as a single oral dose (PO). Premature deaths o animals (earlier than five days post infection) are considered as indications o toxicity. Table 2 summarizes the reduced toxicity of JPC7776 in this screenin test and the superior oral efficacy. A second widely recognized standard test is also presented in Table demonstrating a direct comparison of subcutaneous (SQ) versus oral (PO) dosag of P. Berghei in mice. These tests systems are described in detail in publication by L. Rane and D.S. Rane, 9th Int. Conor. Troo. Med. Malaria. (1973) 1: 28 (#406) and (2) T.S. Osdedne, P.B. Russell and L. Rane, J. Med. Chem. 196 10:431. In this methodology, groups of 5 or 10 mice are infected with a standar inoculum of a blood-induced P. berghei infection and are treated with a sing subcutaneous dose (9 ng/kg) of test drug suspended in peanut oil or a single or dose of test drug suspended in hexamethyl cellulose and Tween. The animals a then observed for a maximum of thirty days. Control animals normally li between 6 and 7 days. For a drug to be considered effective, test animals mu survive at least twice as long as untreated infected control animals. Anima surviving for thirty days are considered cured. TABLE 2 ACTIVITY OF JPC7776, TRIAZINE WR99210 AND PROGUANIL AGAINST P BERGHEI INFECTIONS. COMPARISON OF INJECTED VS. ORAL DOSES TEST DRUG 50% CURE; INJECTED 50% CURES; ORAL SQ ED-50; MG/KG PO ED-50; MG/KG JPC7776 498 567 (7/10 Cures 640) Not Toxic TRIAZINE WR99210 245 No Cures @ 640 PROGUANIL NO CURES No Cures oxic @>160 TABLE 3 COMPARATIVE ORAL AND SUBCUTANEOUS EFFICACY OF JPC7776 GIVEN T MICE INFECTED WITH P. BERGHEI: ENHANCED SURVIVAL AND CURES SC Dose; SC Dose; PO Dose; PO Dose; *denotes active with survival greater than 2x controls or cures based on 3 day animal survival. Table 4 below provides comparative data for the efficacy of JPC7776 again various strains of malaria as tested in vitro with and without a sulfonamide t determine the benefits, if any, of such coadministration with the compound which are the subject of this invention. The results shown below, measured a the in vitro dose to inhibit 50% growth (ID-50) of the malarial parasites grow in standard culture, (C.S. Genther and C.C. Smith, J. Med. Chem. 1977. 20:23 w243) are presented in nanograms per milliliter (ng/ml). These data show th the intrinsic activity of JPC7776 is potentiated from 4 to 19 fold (see ID-5 values) by sulfonamides in the presence of certain drug resistent parasites. TABLE 4 POTENTIATION OF JPC7776 BY SULFONAMIDES IN MALARIAL PARASITE INHIBITED IN VITRO. POTENTIATION FACTOR* *Potentiation factor is the ratio of 50% inhibition value (ID-50) of test dr without sulfonamide divided by the ID-50 against the same parasite using equivalent standard value of sulfonamide. BIOLOGICAL ACTIVITY AGAINST PNEUMOCYSTIS CARINII Evaluation of drugs for activity against Pneumocystis carinii is carried out in t widely recognized and well defined testing system developed and published by Walter T. Hughes. It is widely referred to and is a generally accepted meth clearly defined in the literature as to animal maintenance, infection, treatm protocol and evaluation by autopsy and survival of efficacy. A description of methodology described by W. Hughes et al. is found in Antimicrob. Aαe Chemother. 1988, 32:623-625. In this method rats are immunosuppressed with high doses of glucocorticosteroids while being protected from bacterial infection by concurrent administration of the antibiotic tetracycline. In a standard evaluation animals are immunosuppressed with steroids and various doses of test compounds are administered for six weeks during which time unprotected animals will develop pneumocystis pneumonitis. The percentage of animals free of the disease represents the effectiveness of a selected dose of test drug. When the animals are immunosuppressed and treated according to the accepted methodology it is normal to observe 75% or more of the test subjects spontaneously developing pneumocystis. A customary method to produce pneumocystis in the animals is to administer 2 mg of dexamethasone and 50 mg tetracycline hydro-chloride per liter of drinking water. The test compounds are integrated in the food. For the positive treatment control compound sulf amethoxazole-trimethoprim (SMX/TMP) is fully effective to protect the animals from pneumocystis when given at a dosage of 250 mg/kg SMX in combination with 50 mg/kg of TMP. Another widely used fully effective compound is Dapsone at a dosage of 125 mg/kg. Table 5 demonstrates the effectiveness of JPC7776 as compared to these known active treatments which are used in treating and preventing pneumocystis infections in humans. JPC 7776 is 100% effective and is effective as Dapsone which is a recommended antipneumocystis drug in humans. TABLE 5. PREVENTION OF PNEUMOCYSTIS CARINII (PCP) INFECTION TREATMENT DAILY DOSE # TREATED # INFECTED EFFICACY JPC7776 25 mg/kg 10/10 0/10 100% Dapsone 125 mg/kg 10/10 0/10 100% SMX/TMP 250/50 mg/kg 10/10 0/10 100% none 10/10 10/10 0% SUBSTITUTE SHEET ACTIVITY AGAINST MYCOBACTERIAL INFECTIONS Testing of new drugs for activity against Mycobacterial infections is carried o in vitro and in vivo in well defined laboratory procedures which have been widel published. The method used to test for biological activity against growin Mycobacterium avium complex (MAC), Mycobacterium tuberculosis (MTB) an Mycobacterium kanasii (MK) are described by A. H. Gonzalez et al. in __ Antimicrob. Chemother. 1989, 24:19-22; S. Majumder and M. H. Cynamo Amer. Soc. for Microbiology Mtgs. U-4, May 1992, abstract. Activity in vitro was determined against clinical isolates of MAC, MTB and M using a broth dilution method. Mycobacteria were grown for several days in 7H1 broth, ph 6.6, with 10% OADC enrichment and 0.05% Tween 80. Seri two-fold dilutions of antimicrobial drugs were prepared in 7H10 broth at 1 //g/ml and less. Cultures containing a final concentration of approximately 2.5 10 4 to 6.3 x 10 6 CFU/ml were incubated on a rotary shaker at 37° C for 7 da and read where the minimum inhibitory concentration was defined as the MIC the lowest concentration without visual turbidity. JPC7766 in these studies w compared to known active antimicrobial drugs Proguanil (PG), Cycloguanil (C Sulfamethazine (SM) and/or Dapsone (DDS). The results are considered favora at concentrations below 64 μg/ml and are shown in Table 6. JPC7776 tests superior to the other drugs. TABLE 6. ACTIVITY OF JPC7776 AND OTHER DRUGS AGAINST MYCOBACTERI ISOLATES M. avium (MAC) , M. tuberculosis (MTB) and M. kanasii (MK) . [Concentrations (MIC) , μg/ml , to inhibit growth in vitro] • ISOLATE ID JPC7766 DDS PG CG SM μg/ml μg/ml μg/ml μg/ml μg/ml MAC 101 16 16 >128 - >128 >128 32 16 64 64 64 64 64 64 PHARMACEUTICAL COMPOSITIONS: The present invention also provides pharmaceutical compositions comprising as active ingredient a compound according to the present invention together with a pharmaceutically acceptable carrier. The water solubility of the hydrochloride of the parent compound and most other salts are not very great, so when solutions are required it may often b necessary to add solubilizing agents to the water, choose non-aqueous solvents, or find a more soluble salt or prepare very dilute solutions. Oral formulations are preferred and this invention has the advantage ove related products of being readily absorbed by mammals in sufficient levels t make the compounds of the present invention orally active as therapeutic agents Formulations for oral or injected use are based on sufficient solubility as to allo the therapeutic agent to enter solution in the stomach or in an injectable medium The drug formulations will include tablets, pills, capsules, sachets, granules powders, chewing gums, suspensions, emulsions and solutions: particularl preferred for oral use are tablets and capsules of all varieties and microbe-fre solutions for injection or infusion. Where appropriate and necessary th formulations may include diluents, binding agents, dispersing agent surface-active agents, lubricating agents, coating materials, flavoring agent coloring agents, controlled release formulations, sweeteners or any oth pharmaceutically acceptable additives, for example, gelatin, sodium starc giycoiate, lactose, starch, talc, magnesium stearate, microcrystaliine cellulos Povidone, hydrogenated or unsaturated oils, polyglycols, syrups or other aqueo solutions. Where the formulations are tablets or capsules and the like th formulations may be presented as premeasured unit doses or in multidos containers from which the appropriate unit dose may be withdrawn. The injectable form may be an aqueous or nonaqueous solution, suspension o emulsion in a pharmaceutically acceptable liquid, e.g. sterile pyrogen-free wate or parenterally acceptable oils or mixture of liquids which may contai bacteriostatic agents, antioxidants or other preservatives and stabilizers, buffer (preferably but not limited to a physiological pH range of 6.5 - 7.7, solutes t render the solution isotonic with the blood, thickening agents, suspending agent or other pharmaceutically acceptable additives. Such forms will be presented i unit dose form such as ampules or disposable injection devices or in multi-dos forms such as a bottle from which the appropriate dose may be withdrawn, or a a solid form or concentrate which can be used to quickly prepare an injectabl formulation. All formulations for injection are preferable as sterile and pyroge free. Suppositories containing the compound will also contain suitable carrier e.g. cocoa butter, polyglycols or other state-of-the-art carriers. In addition to standard pharmaceutical additives there may be included withi formulations of the compound other therapeutic agents, particularly includi other antimalarials and antiinfectives. The preferred dosage range is between 0.5 and 10 mg/kg/day. The range quite large because the physician must use his judgement on whether the dosa is prophylactic and if given to an infected subject, on what the level of infecti is. When given as tablets the tablets may contain 25 - 250 mg of active materi EXAMPLE 1 N-f3-(2.4.5-trichlorophenoxy)propoxy1-N'-(1-methylethyl)imidodicarbonimidicdi mide hydrochloride. (XV) A mixture of 39.5 grams (0.20 mol) of 2,4,5-trichlorophenol and 33 mL o 25% aqueous sodium hydroxide were combined and stirred at ambien temperature for 15 minutes at which time 80 grams (40.7 mL, 0.4 mol) 1 , dibromopropane were added. The reaction mixture was refluxed for 2 hours a which time an additional 51 mL 14 percent aqueous sodium hydroxide was adde and the reaction mixture held at 50-70°C for 30 minutes. Upon cooling the lowe layer was separated and washed five times with water. The residual organic laye was distilled at 1 mm given several fractions and gave on distillation water an dibromopropane at 30-40°C, and the product which distilled between 120-157°C Fifty grams of a colorless oil was collected which solidified on standing to yiel 79% of 3-(2,4,5-trichlorophenoxy) propyl bromide (XII). Acetohydroxamic acid (8.5 grams, 0.13 mol) was added to 110 mL of a ethanolic solution of sodium hydroxide (4.0 grams, 0.1 mol). Th 3-(2,4,5-trichlorophenoxy) propyl bromide (XII) (31.8 grams, 0.1 mol) was adde and the mixture refluxed for 6 hours and cooled to room temperature. Th solution was filtered and evaporated, the residue dissolved in 100 mL acetone an the solution filtered and concentrated to yield 16.0 grams (51 %) 3-(2,4,5-trichlorophenoxy) propyl acetohydroxamate (XIII), melting poi 102-104°C. The acetohydroxamate (XIII) (31.3 grams, 0.1 mol) was dissolved in 120 of methanol. Hydrochloric acid (30 mL of a 12% solution) was added and t mixture refluxed for 4 hours. The residue was evaporated to dryness und vacuum, washed with dry diethyl ether and recrystallized from isopropyl alco (90 mL) giving 15.5 grams (58.7%) 3-(2,4,5-trichlorophenoxy) propyloxy ami hydrochloride (XIV) , melting point 158-168°C. The hydroxylamine hydrochloride (XIV) (10 grams, 0.0267 mol) in 160 m ethanol was treated with 6N aqueous HCI until the solution was acidic. Isopropy dicyano-diamide (4.4 grams, 0.0347 mol) was added and the mixture heated a reflux for 4 hours at which time the solvent was evaporated off. The resultin solid material was soluble in water and ethyl acetate and the resulting oil wa treated with anhydrous ether to give a solid precipitate that was filtered, washe with ether and dried. The resulting white solid, recrystallized from ethyl acetat after charcoaling yielded 2.0 grams of the titled compound (XV) as a monohydrat with a melting point of 100°C; In accordance with the above procedure but where, in place of 1 ,3-dibromo propane there is utilized methylene dibromide, 1 ,2-dibromoethane, 1 ,4 dibromobutane or 1 ,5-dibromopentane there is obtained the correspondin methoxy, ethoxy, butoxy or pentoxy analogue respectively. In accordance with the above procedure but where, in place of 1 ,3-dibrom propane there is utilized 1 ,2-dibromopropane, 1 ,3-dibromo-2-methoxypropan 1 ,4-dibromo-2-ethoxybutane or 1 ,5-dibromo-3-ethoxypentane there is obtaine the corresponding 2-methylethyl, 2-methoxypropoxy, 2-ethoxybutoxy or ethoxy pentoxy analogue respectively. EXAMPLE 2 N-r3- ( 2.5-dichlorothio p henoxy )p ropoxyT-N , -(1 -methylethyl)imidodicarbonimid diamide hydrochloride. (XVII) In similar fashion to the synthesis of (XV) 2,5-dichlorothiophenol (35.8 gram 0.2 mol) was treated with sodium hydroxide (40 mL of 20% aqueous solutio and then combined with 1 ,3-dibromopropane (160 grams, 0.8 mol) and reflux for 4 hours. The mixture was cooled, the aqueous layer separated and neutraliz with 20% sodium hydroxide solution, and the lower layer washed five times wi water and distilled at 1 mm Hg. The main fraction was collected between 1 - 145°C as a colorless oil (50 grams, 84%) of 2,5-dichiorothiophenoxy prop 24 bromide (XVI) is further reacted with acetohydroxamic acid as describe p re v i o u s l y i n Ex a m p l e 1 a n d h yd ro lyze d t o g i v e t h 3-(2,5-dichlorothiophenoxy)propyioxamine hydrochloride (XVII) which is the reacted with isopropyl dicyanodiamide as described previously in Example 1 t give the title compound (XVIII). In accordance with the above procedure but where, in place of 2,5-dichiorothio phenol, there is utilized n-propyl mercaptan, cyclohexyl mercaptan, and 3 tetrahydro-pyranol there is obtained the corresponding N-3-(1 -propylthio- cyclohexylthio-, and N-3-tetrahydropyranyloxy)propyloxy-N'-(1 -methylethy imidodicarbonimidic diamide hydrochloride. EXAMPLE 3 N-3-(4-chlorothiophenoxy)propyloxy-N , -(1 -methylethyl)imidodicarbonimid diamide hydrochloride (XXI) In similar fashion to the synthesis of (XV), 4-chlorothiophenol (28.9 grams, 0. mol) was treated with sodium hydroxide (40 mL of 20% aqueous solution) an then combined with 1 ,3-dibromopropane (160 grams, 0.8 mol) and refluxed f 4 hours. The mixture was cooled, the aqueous layer separated and neutralize with 20% sodium hydroxide solution, and the lower layer washed five times wit water and distilled at 1 mm Hg. The main fraction was collected between 12 - 130°C as a colorless oil (47.5 grams, 90%) which crystallized on standing give 4-chloro-thiophenoxy propyl bromide (XIX) is then further reacted wi acetohydroxamic acid as described previously in Example 1 and hydrolyzed to gi the 3-(4-chlorothio-phenoxy)ρropyloxamine hydrochloride (XX). This in turn reacted with isopropyl dicyanodiamide as described previously in Example 1 give the title compound (XXI). In accordance with the above procedure but where, in place of isopro dicyanodiamide, there is utilized N"-phenyl-N-isopropyl dicyanodiamide or oth N"-substituent such as methyl, ethyl or phenylmethyl, there is obtained t corresponding N-3-(4-chlorothiophenoxy) propoxy N"'-phenyl or methyl, ethyl phenylethyl, N'-(1-methylethyl)imidodicarbonimic diamide hydrochloride. Where it is desired to form the N",N"'-dialkanoyl or respective monoalkano derivatives of the foregoing unsubstituted derivatives in Figure 1 , the latter a treated in the manner set forth in Example 4 below, such that an appropriate 1 molar ratio or an acid chloride or anhydride for mono-substituted or 2:1 mol ratio for the disubstituted derivatives allows the product to be obtained. EXAMPLE 4 N"-acetoxy-N-3-(2.4.5-trichlorothiophenoxy)propoxy1-N'-(1 -methyleth imidodicarbonimidic diamide hydrochloride (XXII). N-[2-(2,4,5-trichlorophenoxy) propoxy]-N'-(1 -methylethyl)imidodicarbonimi diamide hydrochloride hydrate (XV) (1.0 gram, 0.002 mol) was suspended in et acetate (20 mL) and shaken with 0.1 mL of 25% aqueous sodium hydroxi solution. The organic layer was separated and dried (magnesium sulfate), 0.1 of acetyl chloride added and the mixture refluxed for 2 hours. The subsequ mixture was concentrated to give 0.5 grams (47%) of the title compound (X as white crystals, melting point 160 -170°C. EXAMPLE 5 N-r3-(2.4.5-trichlorophenoxy) ethoxyl-N'-d-methylethvDimidodicarbonimi diamide hydrochloride (XXVI) A mixture of 39.5 grams (0.20 mol) of 2,4,5-trichiorophenol was dissolve 40 mL of 20% aqueous sodium hydroxide and added dropwise to reflux dibromoethane (85.8 mL, 1 mol) over 1 hour. The mixture was refluxed fo hours and allowed to cool to room temperature. Upon cooling the lower la was separated and washed four times with water. The residual organic layer distilled at 1 mm to give the main fraction between 145-155°C as colorless (51.4 grams, 85%) which was 2-{2,4,5-trichiorophenoxy) ethyl bromide (XX The trichlorophenoxy ethyl bromide (XXIII) (30,4 g, 0.1 mol) was added to aceto-hydroxamic acid (8.5 grams, 0.13 mol) in 1 10 mL of ethanolic sodium hydroxide (4.0 grams, 0.1 mol) as described previously in Example 1 and the mixture refluxed for 6 hours, cooled to room temperature, filtered, the ethanol evaporated and the residue dissolved in acetone ( 100 mL) the solution filtered and concentrated to yield 19.2 grams (68%) of 2-(2,4,5-trichlorophenoxy) ethyl acetohydroxamate (XXIV), melting point 160-162°C. The acetohydroxamate (XXIV) was hydrolyzed to the 2-(2,4, 5-trichlorophenoxy ethoxy amine hydrochloride (XXV) as described for the corresponding propy aceto-hydroxamate (XIII). The ethoxyamine hydrochloride was reacted wit isopropyl dicyanodiamide as previously described in Example 1 to give th N-[2-(2,4,5-trichloro-phenoxy) ethoxy]-N'-(1-methylethyl)imidodicarbonimidi diamide hydrochloride (XXVI). EXAMPLE 6 N-(2.4,5-trichlorobenzoxy)-N / -(1 -methylethyl)imidodicarbonimidic diamid hydrochloride (XXX) 2,4,5-Trichlorobenzyl bromide (XXVII) (16.1 g, 0.1 mol) is added to aceto hydroxamic acid (8.5 grams, 0.13 mol) in 110 mL of ethanolic sodium hydroxid (4.0 grams, 0.1 mol) as described previously in Example 1 and the mixtur refluxed for 6 hours, cooled to room temperature and filtered. The ethan evaporated and the residue dissolved in acetone (100 mL) the solution filtered an concentrated to yield 2-(2,4,5-trichlorobenzyl)acetohydroxamate (XXVIII). The acetohydroxamate (XXVIII) is hydrolyzed to the 2,4,5-trichlorobenzox amine hydrochloride (XXIX) as described for the corresponding prop acetohydroxamate (XIII). The benzoxyamine hydrochloride (XXIX) was reacte with isopropyl dicyano-diamide as previously described in Example 1 to give th N-(2,4,5-trichlorobenzoxy)- N'-(1 -methylethyl)imidodicarbonimidic diamid hydrochloride (XXX). Example 7 N-3-(2.4.5-trichlorophenoxy)propoxy-N , -(p-chlorophenyl)-N"-methyl-imidodicarbo imidic diamide (XXVa) . p-Chiorophenyl isothiocyanate (XXXIa)(50.7 grams) is added to a suspensio of sodium cyanamide (19.2 g) in ethanol (30 mL) with stirring which slowl dissolves and precipitates the sodium salt of N-cyano-N'-p-chlorophenylthioure (XXXIIa) which is filtered off, washed with ethanol and dried to yield 36.2 gram which are suspended in 200 mL of ethanol and combined with 37.6 grams o methyl iodide with rapid stirring at ambient room temperature. The produ separates as heat is evolved. The suspension is cooled in an ice bath, the solid filtered, washed with water and dried to give N-cyano-N'-p-chlorophenyl- methylisothiourea (XXXIIIa). In accordance with the above procedure but where in place of p-chiorophen isothiocyanate there is utilized the corresponding methyl, ethyl, iso-propyl, prop and benzyl derivative, there is obtained the corresponding N-cyano-N'-meth ethyl, iso-propyl, propyl and benzyl-S-methylisothiourea. The S-methylisothiourea (XXXIIIa) prepared as above is added to an ethanol solution of methylamine (79.4 mL containing 4.2 g methylamine) and the mixtu heated for 4 hours in a pressure bottle at 50°C. The resulting clear solution w gradually diluted with water (75 cc) and product crystallizes out, is filtered off give the desired dicyanodiamide (XXXIVa). In accordance with the above procedure but where in place of methylami there is utilized the corresponding phenyl, ethyl, iso-propyl, propyl and ben amine, there is obtained the corresponding dicyan-N'-phenyl, ethyl, iso-prop propyl and benzyl diamide. 28 The dicyanodiamide (XXXIVa) is then reacted with N-3-(2,4,5-trichloroρhenoxy propoxyamine hydrochloride (XIV) as described previously in Example I to yiel the title compound. EXAMPLE 8 Pharmaceutical Composition Ta le s — p — N-f3-(1 .4,5-trichlorophenoxv)propoxv1-N'-(1 .3-methylethyl imi o ipgr pn imidic digmide hydro-chloride hydrate, One tablet contains 25 mg-500 mg of active ingredient depending upon th specific organism being treated, due to differential sensitivity of the infectiou microbe. The formulation is for production of 100,000 tablets (15.8-94.8 kg). T tablets will be coated with hydroxypropyl methylcellulose, color, titanium dioxid polyethylene glycol 6000 and Carnuba Wax to approximate weight 2-5% of t tablet weight.

Claims: We Claim: 1. A compound of the formula H N 3 / \ R β N 2 = C C = N 4 R 7 R^Y-.-R'-O-N'H N 6 H m / R 3 wherein: R 1 is substituted or unsubstituted divalent aliphatic group of 1 to 16 carbo atoms; wherein the substituents are mono or poly and are selected from th group consisting of lower alkyl, aryl and aralkyl, R 3 is selected from the group consisting of same group of values as R 6 , and whe further bonded to the nitrogen to which it is attached, a saturated heterocycl of 4-8 carbon atoms, R e is selected from the group consisting of substituted and unsubstituted alk of 1-10 carbon atoms, cycloalkyl, heterocycloalkyl of 3-8 carbon atoms, mon and poly- carbocycloaryl of 4-7 atoms per ring, wherein the substituents are mon or poly and are selected from the group consisting of lower alkyl, halo lower alky cycloalkyl of 3 - 8 carbon atoms, lower aikenyl, lower alkynyi, nitro, lower alkox lower alkoxy-carbonyl, phenyl ioweralkyl, phenyl, mono and polyhaiopheny phenoxy, mono and polyhalophenoxy and halo provided however, that suc substitution is in a mono and polycarbocycloaryl of 4-7 atoms per ring, R β and R 7 are the same or different when R β is hydrogen, alkanoyl or alkox alkanoyl, and when further bonded to the nitrogen to which either is attache a saturated heterocycle of 4-8 carbon atoms, when R 7 is other than R β its value is selected from the group consisting of sa group of values as R 5 , and when further bonded to the nitrogen to which it attached, a saturated or unsaturated heterocycle of 4-8 carbon atoms, Y is oxygen or sulfur, q is 0 or 1 , 30 provided that unless otherwise stated the prefix alk designates moieties whic are straight chain or branched chain, and the term lower designates 1-6 carbo atoms and the unmodified term alk signifies 1-24 carbon atoms, the respective tautomers thereof, the pharmaceutically acceptable salts and addition salts thereof and the hydrate of said salts and addition salts and mono and diacyl derivatives thereof. 2. The compound of claim 1 wherein: R 5 is selected from the group consisting of substituted and unsubstituted methy ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl and n-decy phenyl, benzyl, phenethyl, phenylpropyl, cyclopentyl, cyclohexyl, cycloheptyl a methyl-cyclohexyl, wherein the substituents are mono or poly and are select from the group consisting methyl, ethyl, cyclohexyl, cyclopentyl and cyclohept di- and tri halophenyl, di- and tri halophenoxy, and halo provided however, th such substitution is in an aryl moiety. 3. The compound of claim 1 wherein R 3 is substituted a unsubstituted straight or branched chain alkyl of 1 to 16 carbon atoms. 4. The compound of claim 1 wherein R 3 is joined to form, with the a heterocycle of 1 to 16 carbon atoms. 5. The compound of claim 1 wherein the R 6 moiety is unsubstitut and is selected from the group consisting of methyl, ethyl, n-propyl, iso-prop isobutyl, n-pentyl, n-decyl, cyclopentyl, cyclohexyl, cycloheptyl and phenyl. 6. The compound of claim 1 wherein the substituents on the R 5 moi may be mono or poly substituents and are selected from the group consisting methyl, ethyl, cyclopentyl, cyclohexyl, cycloheptyl, nitro, methoxy, ethoxy, propoxy, benzyl, phenethyl, biphenylenyl chloro, bromo and fluoro, provided however said halo substitutions occurs onl on an aryl moiety. 7. The compound of claim 1 wherein R 3 moiety is substituted and sai substituents are mono or poly substituents and are selected from the grou consisting of: methyl, ethyl, cyclopentyl, cyclohexyl, cycloheptyl, methoxy, ethoxy, propoxy, benzyl, phenethyl, biphenylenyl. 8. The compound of claim 3 wherein R 3 is selected from the gro consisting of methyl, ethyl and iso-propyl. 9. The compound of claim 3 wherein R 3 , is substituted and t substituents selected from the group consisting of alkoxy of 1-6 carbon atom 10. The compound of Claim 1 of the formula N 3 R 7 / \ / R β N 2 = C CNH | | (CI) n -ø-Y e| -R , -0-N 1 H N 5 H / R 3 wherein: ø is a substituted phenyl, n is an integer of 1-4, Y is O, R 1 is (CH 2 ) r where z is integer of 1-4 and R 3 is isopropyl, its tautomers, a non-toxic acid addition salt, a mono or diacetyl derivative thereof. 1 1. The compound of claim 1 which is N-[3-(2,4,5-trichlorophenoxy) propoxy]-N'-(1-methylethyl)imidodicarbonimidic diamide, its tautomers, a non- toxic acid addition salt, or a mono or diacetyl derivative thereof. 12. The compound of claim 1 which is N-[3-(2,5-dichlorothiophenoxy) propoxy]-N'-(1-methylethyl)imidodicarbonimidic diamide, its tautomers, a non- toxic acid addition salt, or a mono or diacetyl derivative thereof. 13. The compound of claim 1 which is N-3-(4-chlorothiophenoxy) propoxy-N'-(1-methylethyl)imidodicarbonimidicdiamide, its tautomers, a non-toxic acid addition salt, or a mono or diacetyl derivative thereof. 14. The compound of claim 1 which is N'-acetoxy-N-[3-(2,4,5-tri chlorothiophenoxy) propoxyj-N'-(1-methylethyl)imidodicarbonimidic diamide, it tautomers, a non-toxic acid addition salt, or a mono or diacetyl derivative thereof. 15. The compound of claim 1 which is N-[3-(2,4,5-trichlorothiophenoxy ethoxy]-N'-(1-methylethyl)imidodicarbonimidicdiamide, its tautomers, a non-toxi acid addition salt, or a mono or diacetyl derivative thereof. 16. The compound of claim 1 which is N-3,4-dichlorobenzoxy -N' (1-methylethyDimidodicarbonimidic diamide, its tautomers, or a non-toxic aci addition salt or a mono or diacetyl derivative thereof. 17. A method of protecting subjects liable thereto from infection caused by an organism selected from the group consisting of Plasmodium sp Myco-bacterium sp and Pneumocystis carinii which comprises administering to subject liable to infection by exposure to such organisms, a prophylacticall effective amount of a compound of Claim 1. 18. A method of Claim 17 wherein the organisms are selected from th group consisting of P. falciparum, M. avium complex, M. tuberculosis and M Kanasii. X 19. A method of reducing the level of infection in subjects sufferin therefrom caused by an organism selected from the group consisting Plasmodium sp., Mycobacterium sp and Pneumocystis carinii which comprise administering to an infected subject an infection reductively effective amount a compound of Claim 1. 10 20. A method of Claim 19 wherein the organisms are selected from th group consisting of P. falciparum, M. avium complex, M. tuberculosis and Kanasii. 15 21. A prophylactic composition for protecting subjects liable there from infections caused by an organism selected from the group consisting Plasmodium sp., Mycobacterium sp and Pneumocystis carinii which comprises prophylactically effective amount of a compound of Claim 1 and pharmaceutically acceptable carrier. 20 22. A composition of Claim 21 wherein the organisms are selected fro the group consisting of P. falciparum, M. avium complex, M. tuberculosis and Kanasii. 25 23. A composition for reducing the level of infection in subje suffering from infections caused by an organism selected from the gro consisting of Plasmodium sp., Mycobacterium sp. and Pneumocystis carinii whi comprises an infection reductively effective amount of a compound of Claim and a pharmaceutically acceptable carrier. 30 24. A composition of Claim 23 wherein the organisms are selected from the group consisting of P. falciparum, M. avium complex, M. tuberculosis and M. Kanasii. 25. A composition of claim 21 formulated for oral administration. 26. A composition of claim 23 formulated for oral administration. 27. A composition of claim 25 formulated for administration as tablets or capsules. 28. A composition of claim 26 formulated for administration as tablets or capsules. 29. A method of potentiating the method of claim 17 which comprises the coadministration with sulfonamides or sulfones. 30. A method of potentiating the method of claim 19 which comprise the coadministration with sulfonamides or sulfones.

Inventors: CANFIELD CRAIG, JACOBUS DAVID, LEWIS NEIL, CANFIELD, CRAIG, JACOBUS, DAVID, LEWIS, NEIL
Applicants: JACOBUS PHARMA CO INC, JACOBUS PHARMACEUTICAL CO., INC.
Application year: 1993
Main classification: C07C321
IPC codes: A61K31, A61P31, A61P33, C07C279, C07C321, C07C323