MXPA97003611A - Use of bis-arilfurans in the preparation of compositions for the inhibition of pneumonia porpneumocystis carinii, giardia lamblia ycryptosporidium par - Google Patents

Abstract

The present invention relates to methods of treating Pneumocystis carinii, Giardia lamblia and Cyrptosporidium paryum pneumonia in a subject in need of such treatment, the methods comprising administering to said subject a compound of Formula (I): wherein: R1 and R2 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, aryl, alkylaryl, aminoalkyl, aminoaryl, halogen, oxyalkyl, oxyaryl or oxyarylalkyl; R 3 and R 4 are each independently selected from the group consisting of H, alkyl of C 1 -C 6, oxyalkyl, alkylaryl, aryl, oxyaryl, aminoalkyl, aminoaryl or halogen, and X and Y are located in the para or meta positions and are selected from the group consisting of H, C 1 -C 6 alkyl, oxyalkyl, and wherein: each R5 is independently selected from the group consisting of H, C1-C6 alkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, cycloalkyl, aryl or alkylaryl or two groups R5 represent C 2 -C 10 alkyl, hydroxyalkyl or alkylene, and R 6 is H, hydroxy, C 1 -C 6 alkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylamino, alkylaminoalkyl, cycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aryl or alkylaryl, or a pharmaceutically acceptable salt thereof. The compounds are administered in an effective amount to treat the condition, the pi also includes novel compounds useful in the treatment of pneumonia caused by Pneumocystis carinii, as well as from Giardia lamblia and Cryptosporidium pary.

Description

USE OF BIS-ARI1 FURANS IN THE PREPARATION OF COMPOSITIONS FOR INHIBITION OF PNEUMONIA BY PNEUMOCYSTIS CARINII. GIARDIA LAMBLIA AND CRYPTOSPORIDIUM PARVUM The present invention was made with Government support under Grant Number U01-A1-3363 from the National Institutes of Health. The Government has certain rights over this invention.

RELATED APPLICATIONS This application is a continuation that is part of the Application d? Patent of E.U. . Series No. 08 / 238,766, filed on Hayo 6, 1994.

CRHPQ OF THE INVENTION The present invention relates to methods for combating Pneumocvstis c ri ii pneumonia with di-cationic compounds. Specifically, the present invention relates to methods for combating pneumonia by Pnßt-i-ior.vs is cari ni i with novel bis-aryl furans and bis-aryl furans useful therefor.

BACKGROUND OF THE INVENTION Pentamidine is useful for the treatment of Pneu occvst s c.ari pneumonia or by "POP". The importance of pentamidine has recently increased due to the marked increase in patients suffering from PCP. The increase in the population of affected patients is an unfortunate consequence of the growing presence of Acquired Immune Deficiency Syndrome ("AIDS"). It is now estimated that approximately 70 percent of AIDS patients get PCP. Due to the high incidence of PCP in patients with AIDS, pentamidine has found utility not only in the treatment of PCP, but also as prophylaxis, in the prevention or delay of initial access or recurrence of PCP, especially in patients with AIDS. Currently, pentamidine is most commonly administered as a therapeutic agent by intravenous infusion and as a prophylactic agent by aerosol dosage. However, an unfortunate side effect of pentamidine is its toxicity. Some fatalities have been attributed to severe hypotension, hypoglycemia, and cardiac arrhythmias in patients treated with pentamidine. Conversely, insufficient doses may result in the spread of the disease beyond the lung, an event of which it is associated with a poor prognosis. Currently, pentamidine is used in a limited way due to its cost and toxicity. The therapeutic monitoring of the drug is not used due to the cost and complexity of the testing techniques currently available, which require the extraction of plasma and analysis of high performance liquid chromatography. As a result, the toxicity of pentamidine is a major problem, which is leading the market towards the development of pentamidine substitutes able to avoid or minimize the undesirable side effects associated with the use of pentamidine. Accordingly, it is an object of the present invention to provide new methods of treating Pneumocvatis carinii pneumonia.

BRIEF DESCRIPTION OF THE INVENTION As a first aspect, the present invention provides a method of treating Pneumocvs is carinii pneumonia. The method includes the administration, to a subject requiring such treatment, of an effective amount to treat pneumonia due to Pneurnocvstis carinii. of a compound of formula (I): < D where: R-t. R-2 are each independently selected from the group consisting of H, C -Cß alkyl, aryl, alkylaryl, aminoalkyl, to inoaryl, halogen, oxyalkyl, oxyaryl or oxyarylalkyl; Ra and R * are each independently selected from the group consisting of H, C -C ?, alkyl, oxyalkyl, alkylaryl, aryl, oxyaryl, aminoalkyl, aminoaryl or halogen; and X and Y are located in the para or meta positions and are selected from the group consisting of H, C -C alquilo alkyl, oxyalkyl, and wherein: each Rs is independently selected from the group consisting of tf, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, cycloalkyl, aryl or alkylaryl or two R groups.

CS¡-C OA hydroxyalkyl or alkylene; and R "s is H, hydroxy, C ^ -C * alkyl, alkoxyalkyl, hydroxyalkyl, arninoalkyl, alkylamino, alkylalkalkyl, cycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aryl or alkylaryl. In another modality, two RS groups represent together wherein m is 1-3 and R7 is H or -CONHRaNR-3 »Ra.O, wherein Rβ is lower alkyl, and R-" and R or are each independently selected from the group consisting of H and lower alkyl , although these compounds are not currently preferred. As a second aspect, the present invention provides compounds useful for the treatment of Pneumocvstis carinii pneumonia. The compounds have the structural formula (I), described above. In particular, novel compounds useful for the treatment of Pneumocvstis carinii pneumonia include defined compounds wherein X and Y are located in the para position and are each and where: (a) Ra. is H, Ra is H or lower alkyl, R "is H, R * is H, Ra is H and RA is isoalkyl, such as isopropyl, isobutyl, isopentyl, and the like; (b) Ra. is H, Rs- is H, Ra is H, R * is H, Rs is H and R? is alkoxyalkyl Ca-Cß; (c) Rx is H, R2 is H or lower alkyl, R "is H, R * is H, R" is H and RA is hydroxyalkyl, such as hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl and hydroxyhexyl; (d) x ee H ,. R2 is H or lower alkyl, Ra is K, R is H, R »is H and R? it is propoxyethyl; (e) x is H, R2 is H or lower alkyl, R "is H, R * is H, Rs is H and R? it is proposed isopropyl; (f) Rx is H, R2 is H or lower alkyl, Ra is H, R * is H, Ra is H and R6 is aryl or alkylaryl; and (g) Rx ee H, Ra is H or lower alkyl, R3 is H, R? is H, Rs is H and R? it is alkylcycloalkyl; and pharmaceutically acceptable salts thereof. As a third aspect, the present invention provides a method of treating Giardia lamblia in a patient who requires said treatment. The method includes administering, to a patient in need of such treatment, a compound of formula III) above, in an amount effective to treat Giardia lamblia. Also disclosed are novel compounds useful for the treatment of Giardia lambi a. As a fourth aspect, the present invention provides a method for the treatment of CrVP Qsppritiiup. oarvurn in a patient who requires such treatment. The method includes administering to a patient in need of such treatment, a compound of formula (I) above, in an amount effective to treat Crvotosporidium narvurn. Also disclosed are novel compounds useful for the treatment of Crvotos DOri di urn oarvum. The foregoing and other objects and aspects of the present invention are explained in detail in the specification given below.

DESCRIPTION DETAILED PE Lfl INVENTION The term "lower alkyl", as used herein, refers to linear or branched Cx-C * alkyl, such as methyl, ethyl, propyl, butyl, isopropyl, sec-butyl, tert-butyl, pentyl, isopentyl and hexyl. Isoalkyl groups such as isopropyl, isobutyl, isopentyl, and the like are currently preferred. The term "lower alkoxy"? "oxyalkyl", as used herein, refers to CX-C alkoxy? linear or branched, such as methoxy, ethoxy, propyloxy, butyloxy, isopropyloxy and t-butyloxy. Methoxy is currently preferred. As indicated above, the methods of the present invention are useful for the treatment of pneumonia due to neurosis VStis? Arinii, Giardia lamblia and CrvDtosDoridium oarvurn. The methods of the present invention are useful for the treatment of these conditions in that they inhibit the onset, development or propagation of the condition, cause regression of the condition, cure the condition or, otherwise, improve the general well-being of the subject affected by the condition. the condition or that is at risk of contracting it. The subjects to be treated by the methods of the present invention are typically human subjects, although the methods of the present invention may be useful with any appropriate subject known to those skilled in the art. As indicated above, the present invention provides pharmaceutical formulations comprising the above-mentioned compounds of formula (I), or pharmaceutically acceptable salts thereof, in pharmaceutically acceptable carriers for oral, parenteral and aerosol administration, as discussed in more detail below. Also, the present invention provides said compounds or salts thereof, which have been lyophilized and which can be reconstituted to form pharmaceutically acceptable formulations for administration, as well as by intravenous or intramuscular injection. Obviously, the therapeutically effective dose of any specific compound, whose use is within the scope of the present invention, will vary somewhat from one compound to another, from one patient to another, and will depend on the condition of the patient and the route of administration. As a general proposal, a dose of almost 0.1 to almost 50 mg / kg will have therapeutic efficacy, potentially using even higher doses for oral and / or aerosol administration. Problems of toxicity at the higher level can restrict intravenous doses to a lower level such as up to almost 10 mg / kg, all weights being calculated based on the weight of the active base, including cases where a salt is used. Typically a dose of almost 0.5 mg / kg to almost 5 mg / kg will be used for intravenous or intramuscular administration. A dose of almost 10 mg / kg to almost 50 mg / kg can be used for oral administration. The duration of treatment is usually once per day for a period of two to three weeks or until the condition is essentially controlled. Lower doses given less frequently may be used to prevent or reduce the incidence or reciviva of the infection. According to the present method, a compound of formula (I), or a pharmaceutically acceptable salt thereof, can be administered orally or by inhalation as a solid, or it can be administered intramuscularly or intravenously as a solution, suspension or emulsion. Alternatively, the compound or salt can also be administered by inhalation, intravenously or intranuscularly as a liposomal suspension. When administered by inhalation, the compound or salt should be in the form of a plurality of solid particles or droplets having a particle size of from about 0.5 to about 5 microns, preferably from almost 1 to almost 2 microns. In addition to providing a method for the treatment of Pneumocvstis carinii pneumonia. The compounds of formula (I) also provide a method for the prophylaxis against Pneumocvstis carinii pneumonia in an immunocompromised patient, such as one suffering from AIDS, who has had at least one episode of Pneurnocvs is carinii pneumonia. but who at the time of treatment is not exhibiting signs of pneumonia. In view of the fact that Pneumocvst s carinii pneumonia is an especially and potentially devastating disease for immunocompromised patients, it is preferable to avoid the onset of Pneumocvstis carinii pneumonia. when compared to the treatment of the disease after it has become symptomatic. Accordingly, the present invention provides a method for the prophylaxis against Pneumocvstis? Arinii pneumonia which comprises administering, to a patient, a prophylactically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The forms for the administration of the compound or of the salt, according to this method, can be identical to those used for the purpose of the actual treatment of a patient suffering from Pneumocvstis ca ini.i pneumonia. Another useful aspect of the present invention is a method for the prophylaxis against an initial episode of Pneumocvstis carinii pneumonia in an immunocompromised patient who has never experienced an episode of Pneurnocvstis carinii pneumonia. In this regard, in a patient who has been diagnosed is immunocompromised, such as someone suffering from AIDS or ARC (complex related to AIDS), even before the start of an initial episode of Pneurnocvstis carinii pneumonia. it can be avoided or postponed suffering from infection by administering a prophylactically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The compound or salt can be administered in the same way as in the treatment of patients suffering from pneumonia due to Pneu.np? Vs? - carinii The present invention also provides novel pharmaceutical compositions suitable for intravenous or intramuscular injection. The pharmaceutical compositions comprise a compound of formula (I), or a pharmaceutically acceptable salt thereof, in any pharmaceutically acceptable carrier. If a solution is desired, water is the vehicle of choice with respect to water-soluble compounds or salts. With respect to compounds or salts insoluble in water, an organic carrier, such as glycerol, propylene glycol, polyethylene glycol ,. or mixtures thereof, may be appropriate. In the latter case, the organic vehicle may contain a substantial amount of water. The solution in any case can then be sterilized in any convenient manner, preferably by filtration through a 0.22 micron filter. After sterilization, the solution can be poured into appropriate receptacles, such as depyrogenated glass jars. In fact, the spill must be done by aseptic method. Sterile caps can then be placed on the bottles and, if desired, the contents of the bottles can be lyophilized. In addition to the compounds of formula (I) or their salts, the pharmaceutical compositions may contain other additives, such as pH adjusting additives. In particular, useful pH adjusting agents include acids, such as hydrochloric acid, bases or pH regulators, such as sodium lactate, sodium acetate, sodium phosphate, sodium citrate, sodium borate or sodium gluconate. In addition, the compositions may contain microbial preservatives. Useful microbial condoms include ethyl para, propyl paraben and benzyl alcohol. The microbial condom is typically used when the formulation is placed in a vial intended for use by ultidosis. Indeed, as indicated, the pharmaceutical compositions of the present invention can be lyophilized using techniques well known in the art. In still another aspect of the present invention, a stable and sterile injectable composition comprising a compound of formula (I), or a salt thereof, in a unit dose form in a sealed container is provided. The compound or salt is provided in the form of a lyophilizate which is capable of being reconstituted with a suitable pharmaceutically acceptable vehicle to form a liquid composition suitable for injection thereof into man. The unit dosage form typically comprises from about 10 mg to about 10 grams of the compound or salt. When the compound or salt is substantially insoluble in water, a sufficient amount of agent and ulsifier, which is physiologically acceptable, can be used in amounts sufficient to emulsify the compound or salt in an aqueous vehicle. Said useful emulsifying agent is phosphatidyl choline. Other pharmaceutical compositions can be prepared from the water-insoluble compounds of the formula (I), or salts thereof, such as or aqueous-based emulsions. In such a case, the composition will contain a sufficient amount of the pharmaceutically acceptable emulsifying agent to emulsify the desired amount of the compound of formula (I) or salt thereof. Particularly useful emulsifying agents include the phosphatidyl cholines and the lecithin. In addition, the present invention provides liposomal formulations of the compounds of formula (I) and salts thereof. The technology for the formation of liposomal suspensions is well known in the art. When the compound of formula (I) or the salt thereof is an aqueous soluble salt, using the conventional technique on liposomes, they can be incorporated into lipid vesicles. In such a case, due to the water solubility of the compound or salt, the compound or salt will be substantially entrained within the hydrophilic core or nucleus of the liposomes. The lipid layer employed may be of any conventional composition and may contain cholesterol or may be free of cholesterol. When the compound or salt of interest is insoluble in water, again using conventional liposome formation technology, the salt can be entrained substantially within the hydrophobic lipid bilayer, which forms the structure of the liposome. In any case, the lipoeomas that are produced can be of reduced size, as through the use of normal sonication and homogenization techniques. In fact, liposomal formulations containing the compounds of formula (I) or salts thereof, can be lyophilized to produce a lyophilizate which can be reconstituted with a pharmaceutically acceptable carrier, such as water, to regenerate a hygroscopic suspension. . Pharmaceutical formulations are also provided which are suitable for administration as an aerosol, by inhalation. These formulations comprise a solution or suspension of the desired compound of formula (I) or a salt thereof, or a plurality of solid particles of the compound or salt. The desired formulation can be placed in a small chamber and be nebulized. The nebulization can be carried out by compressed air or by ultrasonic energy to form a plurality of liquid droplets or solid particles comprising the compounds or salts. Liquid droplets or solid particles should have a particle size on the scale of almost 0.5 to almost 5 microns. The solid particles can be obtained by processing the solid compound of formula (I) or a salt thereof, in any suitable procedure known in the art, such as by nicronization. Preferably, the size of the solid particles or droplets will be from almost 1 to almost 2 microns. In this regard, commercial nebulizers are available to achieve this purpose. Preferably, when the pharmaceutical formulation suitable for administration as an aerosol is in the form of a liquid, the formulation will comprise a water-soluble compound of formula (I) or a salt of the same, in a carrier which comprises water. A surfactant may be present, which lowers the surface tension of the formulation sufficiently to result in the formation of droplets within the scale of desired size when subjected to nebulization. As indicated, the present invention provides water-insoluble and water-soluble compounds and salts. As used in the present specification, the term "water-soluble" is intended to define any composition that is soluble in water in an amount of almost 50 mg / ml, or greater. Asymisne, as used in the present specification, the term "water-insoluble" is intended to define any composition having a solubility in water of less than about 20 mg / ml. For certain applications, water-soluble compounds or salts may be convenient, while, in the same way, for other applications, compounds or water-insoluble salts may be convenient. The compounds of formula (I) above, which are particularly preferred for the methods of treating pneumonia by Pn? Ujnocys is fiflrinü. Giardi to lamb f a and CrvptosDoridiurn oarvurn. they include a variety of compounds. For example, particularly preferred compounds are defined by formula (I), wherein X and Y are each and (a): Rx is H, Ra is H, Ra is H, R * is H, Rs is H and? is H, alkyl, hydroxyalkyl, aminoalkyl, alkylamino or alkylaminoalkyl; (b): R is H or lower alkyl, Ra is lower alkyl, Ra is H, R * is H, Rs is H and R * is H or lower alkyl; (c); R is H, or oxyalkyl. R »is H, oxyalkyl? oxyarylalkyl, Ra is H ,. * is H, two groups Rs represent alkyl C ", and R *. is H, lower alkyl or hydroxyalkyl; (d): R is H, R2 is H or oxyarylalkyl, Ra is H, R? is H, two R "groups together represent alkyl Ca and R? it's H; (f): R? is H, Ra is H, Ra is H, R * is H, two groups R »represent together wherein m is 1, and R7 is H or wherein Rβ is lower alkyl, and R9 and 0 are each H, and? it's H; and (e): Rx is H, 2 is H, Ra is H, R * is H, two groups Rs represent alkyl *, and Rβ is H. Examples of exemplary compounds of formula Cl) above include, but are not limited to: 2, 5-bis (4-g? Anil phenyl) furan, 2,5-bis (4-guanylphenyl) -3,4-dimethyl furan, 2,5-di-pC2 (3,4,5,6-tetrahydro? Irimidyl) ) phenyl] furan, 2,5-bisC4- (2-imidazolinyl-phenyl) furan, 2 ^ 5- [bis. {4- (2-tetrahydropyrimidinyl).}. phenyl] 3-p (tolyloxy) furan 2,5-Cbis. { 4- (2-imidazolinyl)} phenyl] 3-p (tolyloxy) furan, 2,5-bis. { 4- [5- (N-2-aminoethylamido) benzyl idazol-2-i 1] f eni 1.}. furan, 2,5 ~ Bisí- (3a, 4,5,6,7,7a-hexahydro-lH-benzimidazol- -il) phenyl] urano, 2,5-bis- (4,5, .6,7- tetrahydro-lH-l, 3-diazepin-2-yl) enyl] urane, 2,5-bis (-N, N-dimet i Icarbox hydrazide phenyl) furan, 2,5-bis. { 4C2- (N-2-hydroxyethyl) imidazole inyl] -phenyl} furan, 2,5-bisC - (N-ieopropylamidino) enyl Jf? rano, 2, 5-bis. { 4-C 3- (dimethylamineopropylamine] phenyl} furan, 2,5-bis-. {4-tN- (3-aminopropyl) amidino] phenyl}. Furan, 2,5-bisC2- ( imidazolinyl) phenyl] -3, -bis (ethoxymethyl) urane, 2,5-bisC4-N- (3-dimethylaminoethyl) guanyl] phenyl furan, 2,5-bis ~. {4 - [(N-2-hydroxyethyl) ) guanyl] phenyl} furan, 2,5-bis-C4-N- (cyclopropylguanyl) phen.yl] furan, 2,5-bis-C4- (N, N-diethylaminopropyl) guanyl] phenyl f? embedded image Rare, 2,5-bis-C4-C2- (N ~ (3-ethynylnidazolinyl)].}. phenyl furan, 2,5-bis-. {4-CN- (3-pentylguanyl).} phenyl furan, 2,5-bis-C "4- (2-imidazolinyl) phenyl 3-3-methoxy furan, 2,5-bis [4- (N-isopropylamidino) phenyl3-3-methyl furan, and the pharmaceutically acceptable salts The compounds used to practice the present invention can be prepared according to techniques known to those skilled in the art (see, for example, BP Das, et al., Syntheeis and antiprotozoal activity of 2,5-Bis). (4-g? Anylphenil) furans, J. Med. Chem. 20: 531 (1977), whose description ion is incorporated herein by reference in its entirety), particularly in light of the description and the examples given below. As indicated, the compounds used in the present invention may be present as pharmaceutically acceptable salts. Said salts include the salts of gluconate, lactate, acetate, tartrate, citrate, phosphate, borate, nitrate, sulfate and hydrochloride. The salts of the present invention can be prepared, in general, by reacting two equivalents of the pyrimidine base compound with the desired acid, in solution. After the reaction has ended, the salts are crystallized from the solution by the addition of an appropriate amount of solvent in which the salt is insoluble. The methods for combating Siartia lamfrl-ia with the compounds of formula (I) are carried out in essentially the same manner as above. and the pharmaceutical formulations of the compounds of formula (I) to combat Giardia lamblia are prepared in essentially the same manner as given above. The methods for combating Crvptqsporidiim parvum with the compounds of formula (I) are carried out in essentially the same manner as given above, and the pharmaceutical formulations of the compounds of formula (I) for combating Crvptosporidium parvum. they are prepared essentially in the same way as given above. The compounds of the present invention are useful not only in methods for the treatment of pneumonia by Pneup.ocvs is carinii, Siartia lamblia and crvptosporidium parvum. but also in inhibition methods of enzymes such as topoisomerase. The compounds of formula (I) are particularly useful for the inhibition of topoisomerase II. See, S. Doucc-Racy et al., Proc, Nati, Acad. Sci. USA 83: 7152 (1986). As indicated above, compounds useful in the methods of the present invention can be prepared according to techniques known in the art. According to one method, the compounds of formula (I) can be prepared by: (a) cyclodehydrating furanization of 1,4-diketones according to the procedure taught by R.E. Lutz et al., 3. Am. Chem, Soc. 56: 2698 (1934) to form 2.5-bis- (4-brornophenyl) furan; (b) nitrilization of 2,5-bis (4- omo phenyl)? rano using copper (I) cyanide to produce the corresponding bis-nitrile 2, 5-bis- (-cyanophenyl) furan; and (c) conversion of the bis-nitrile to the desired bis-dicationic aryl furan of formula (I). This method is illustrated below in scheme 1.

SCHEME I According to a second method, compounds of formula (I) can be prepared by (a) conversion of the appropriate broaceacetophenone to the ethyl ophenyloxopropionate bro, using sodium hydride and diethyl carbonate in tetrahydrofuran, (b) bromophenyl conversion ethyl-o-xopropionate to ethyl bis-bromobenzoylpropionate using bromo-enacyl bromide, (c) conversion of bis-bro-obenzoylpropionate to bis-bro of ethyl ethylphenol using ethanol and hydrochloric acid, (d) hydrolysis of ethyl bis-bromophenyl-furan to the bis-bro or enyl furan carboxylic acid using potassium hydroxide followed by hydrochloric acid, (e) conversion of the carboxylic acid to the corresponding bis-nitrile with copper (I) cyanide and heat, and conversion of the bis-nitrile to the aryl furan bis-dicationic appropriate. This method is illustrated below in scheme 2 SCHEME 2 (dL The conversion of bis-nitrile to the bis-dicationic aryl furan of formula (I) can be carried out according to various methods known to those skilled in the art. According to a commonly preferred method, the conversion of bis-nitrile to bis-dicationic aryl urane is carried out by converting intermediate intermediates to steree using the classical Pinner methodology, followed by the reaction of this compound and intermediates with ammonia. with the appropriate diamine, for example ethylenediamine, 3-propanediamine, etc., as exemplified in the examples set forth below. According to a second commonly preferred method, the bis-nitrile is converted to the bis-dicationic aryl furan by the fusion of the bis-nitryl directly with the hydrochloride salt of the appropriate diamine by thermolysis. This technique is particularly useful for the preparation of compounds in which two Ra groups together form a cyclic alkyl. The present invention is explained in greater detail in the following examples. As used herein, "pf" means melting point, "NMR" means nuclear magnetic resonance, "MHz" means egahertz, "BAR" means fast atomic bombardment, "IE" means electronic ionization, "IR" means spectra. infrared, "EMH means spectroscopy of aeae," Hz "means hertz," g "means grams," rml "means milliliters," L "means liters," hr "means hours, < < ° Q »means degrees Celsius," SODM "means dimethyl sulfoxide ,. "DMF" means di ethylphoramide and, rm / c "means mass divided by charge These examples are illustrative and are not to be construed as limiting the invention.These melting points are recorded using a Thomas Hoover melting point capillary apparatus. Uni-Melt) and are not corrected, the H NMR and aC NMR spectra are recorded using a Varian GX400 spectrometer and the chemical changes (6) are in ppm with respect to TMS unless otherwise indicated. mass spectra on a VG Instruments 70-SE spectrometer The IR spectra are recorded using a Michelson 100 instrument.

PREPARATION OF PRECURSOR COMPOUNDS 2 - . 2 -5-Bis (D-bromo phenyl) furan. A procedure according to the literature was used as is known in the art for the preparation of trans-di-p-bromobenzoylethylene from bromobenzene and fumaryl chloride. 3.B. Conant and R.E. Lutz, 3. Arn. Chern. Soc. 47.881 (19251. The ethylene compound was reduced with Zn-HOAc to prepare 1,4-di-p-bromo-phenyl-1,4-butanedione E. Campaigne and UO Foye, J. Org. Chem. 17.1405 (1952) The 1,4-diketone (7.9 g, 0.02 mmol) saturated in 80 nmol of AC20 was suspended and the mixture was heated to reflux, the concentrated HaSO * (4-5 dots) was added and the reflux continued for 5 hours. minutes The solution was poured into the granita (1 liter), stirred well and filtered: crude product 7, g (93%). Recrystallization from acetic acid gave 5.6 g (75X) .pdf 198-1990C (lit. RE Lutz and UM Eisner, J.A. Chem. Soc. 56, 2698 (1934)) pf. 200-201 ° C). A mixture of 2? 5-Bis (p-cinophenyl) furan 7.2 g (0.02 mol) of 2.5.bis- (4-bromophenyl) furan and 4 g (0.045 mol) of Cu (CN) in 45 ml was refluxed. of quinoline for 2 hours. The mixture was poured into 300 μl of a diluted HCl solution (caution, HCN is released) and filtered. The solid was washed with HaO, dilute NaOH, dilute HCl and again with H20. The solid bis-nitrile was dissolved in acetone, filtered to remove the inorganic residue and passed through a short column of alumina to remove the traces of copper salts. The copper salts must be separated since they are transferred to the bis-amidines from which it is difficult to purify. A convenient method to detect the presence of copper salts is a flame test. Evaporation of the eluent from the alumina column and recrystallization of the ethanol gave 3.5 g (65%), mp 294-295 ° C.

EXAMPLE 2 Preparation < tei dihitiroclpruro of 2.5-Bis (4-amid nofenil? furan) 2,5-Bis (4-cyanophenyl) furan (3 g, 0.011 mol) (prepared as described in Example 1) was saturated in a mixture of 100 ml of dioxane and 25 ml of absolute ethanol with dry HCl gas at 5 ° C. ° C. The solution was placed in a pressure bottle and stirred for 3 days (at room temperature). An intermediate product, an i-idate ester hydrochloride, was precipitated, precipitated as a yellow solid, and dried under vacuum at room temperature overnight. The IR spectra of imidate ester hydrochloride were free of adsorption to the nitrile and used directly without further characterization. A suspension of imidate ester hydrochloride (3.5 g) was saturated in 100 ml of absolute ethanol at 5 ° C with anhydrous ammonia. The suspension was stirred (in a pressure bottle) for 3 days at room temperature. The reaction mixture was filtered and dried and the solid dissolved in hot absolute ethanol (ca. 1.5 L). The solution was acidified with anhydrous HCl at 5 ° C, concentrated in vacuo at room temperature and 2.5 g (60%) of yellow crystals were obtained. Recrystallization from absolute ethanol gave mp. 400-401 ° C dec.

EXAMPLE 3 Preparation of 2,5-Bis-, 5-dihydro-IH-imidag-2-yl? phenyl Jfurano A solution of an intermediate of imidate ester hydrochloride, synthesized as described in Example 2, 2.1 g (0.005 mol), and 0.6 g (0.01 mmol) of ethylenediamine and 50 ml of absolute ethanol was refluxed during the night. The solid that formed was filtered and recrystallized from absolute ethanol saturated with anhydrous HCl to give 2,5-Bist4- (2-imidazolinyl) phenyl] furan, 1.9 g (90%), mp 409-410 ° C dec.

EXAMPLE Preparation of the dihydrate dihydrochloride of 2.5-Bis-4-f4.6-dihydro-lH-imidazol-2-yl? enilJfurano Bis-nitrile (0.5 g, 1.9 mmol), ethylenediamine dihydrochloride (4.9 g, 37 mmol), ethylendiarnine (2.5 ml, 37 rnols) were mixed. The mixture is heated at 300-310 ° C for 10 minutes in a sand bath. After cooling, the mixture is dissolved in hot water. The yellow crystals separate on cooling. The compound of the boiling water is recrystallized to give 208 rng (24%). and then dried under vacuum at 80 ° C for 12 hours. CCD (CHCl3: CHa0H: 25% NH 0H = 11: 4: 1, one dot), mp; 360 ° C. The calculated analysis for CaaHaaN ^ .O-HCl-2HaO: C: 56.78, H.-5.60, N: 12.04, - found C: 56.69, H: 5.63, N: 12.07. XH-NMR (SODM-d *, TMS), d 4.01 (s, 8H), 7.45 (s, 2H), 8.08 (d, 4H, 3 = 8.3 Hz), 8.15 (d, 4H, ZJ = 8.3 Hz) , 8.15 (d, 4H, J = 8.3 Hz), 10.50 (brs, 4H). 3 C-NMR (SODM-d *, TMS), 6 45.5, 113.2, 121.6, 125.3 ,. 130.1, 135.8, 141.3, 153.4, 165.8. IR (KBr): 3412, 3123, 2971, 1608, 1580, 1491, 1367, 1287, 1033, 850, 745, 673 c "3. MS m / c 356 (free base).

EXAMPLE 5 Preparation of 2.5-Bis-_4-i 1.4.5.6-i-etrahydroDirip-idin-2- iDfeni 11 furan In a manner similar to that set forth in Example 3, imidate ester hydrochloride synthesized as described above in Example 2 was reacted with 1,3-propanediamine to give (90%) of the 2,5-BisC4- ( 1,4,5,6-tetrahydropyrimidin-2-yl) phenyl] -furan, mp 430-431 ° C dec.

EXAMPLE 6 Preparation of 2.5-BisC4- (.5.6.7-tetrahydro-lH-1,3-diazepin-2-yl) phenyl-1-furan dihydrochloride The imidate ester of bis-ethoxyethanol (1, g, 0.002 mmol), 1,4-diaminofuran (0.5 g) in 10 ml of l-2-dimethoxyethane are subjected to reflux for 2 days. The solvent is removed under vacuum and water is added. The precipitate is filtered, washed with water and dried in a vacuum oven (mp> 300 ° C). The filtrate is neutralized using 2M sodium hydroxide and another free base portion is obtained. The crude free base is converted to hydrochloride (mp> 300 ° C) by hydrogen chloride in methanol. The total product of the free base is 51%. The analysis calculated for Ca * HaßN 0-HCl -3.5Ha0 (548.50): c: 56.93, H: 6.80, n: 10.22; found C: 56.99, H: 6.80, N: 10.26. ^ -H-NMR (SODM-d?) D 2.02 (s, 8H), 3.71 (s, 8H), 7.38 Cs, 2H), 7.86 (d, 4H, 3 = 8.3 Hz.), 8.04 (d, 4H , 3 = 8.3 Hz), 9.77 (s, 4H). aC-NMR (DaO (CHa) s SyCHaCHaNa), 5 28.0, 47.0, 113.9, 126.5, 129.7 ,. 131.2, 137.0, 154.5, 167.1. IR (KBr) ,. 687, 747, 814, 930, 1131, 1364, 1459, 1597, 3008, 3164 cm "3- EM (IE) m / e 412 (free base).

EXAMPLE 7 Preparation of dihydrochloride of, 5-BisC4-t 3a. .5.6.7.7a-hexahydro-lH- & engimidazoi-2-il? fenillfuran 1, 2-Diaminocyclohexane (9 ml) is treated with ethanolic HC. The solution is evaporated to dryness and the new portion of amine (9 ml) and 2,5-bis (4-cyanophenyl) urane (2 g) are added. The mixture is maintained at 300-310 ° C in a sand bath for approximately 10 minutes. The progress of the reaction is monitored by CCD (CHCla: CHa0H: NH * OH = 44: 8: 1, vjvjv). After cooling, the water residue is recrystallized to give analytically pure yellow crystals CaoHaaN * 0-2HCl-0.25HaO: C: 66.48, H: 6.42, N: 10.34; found: C: 66.47 ,. H: 6.40, N: 10.30. XH-NMR (S0DM-d., TMS) d 1.30-2.00 (rn, 16H), 4.36 (s, 4H), 7.46 (s, 2H), 8.18 (m, 8H), 10.87 (s, 4H). * -3C-NMR (SODM-d *, D20) & 18.9, 25.8, 57.0, 112.7, 122.3, 125.0, 130. 0, 135.5, 153.4. 164.9, IR (KBr), 3413, 2991, 1597, 1501, 1354, 1293, 1016, 930, 853, 796, 747, 676 cm-1. MS m / c 464 (free base).

EXAMPLE 8 Preparation of dihydrate dihydrochloride of 2,5-BisC4- (.5-dihydride) -l- (hydroxy-1H-lH-imidaZOl - ^ - in furan) A mixture of N- (2-hydroxyethyl) ethylene, diamine (09.64 g, 0.006 mol) in 15 ml absolute ethanol and the imidate ester (0.87 mol, 0.002 mol) is heated during reflux for 12 hours. The solvent is distilled off and the resulting residue is triturated with ice water, the pH is adjusted to 10 with 2M NaOH and the precipitated solid is filtered, washed with water, dried and recrystallized from ethanol-ether to give a light yellow crystalline solid of 0.72 g (81%) which has a mp of 119-120 ° C. IR (KBr) 3390, 3290, 3132, 2864, 1615, 1595, 1421, 1276, 1059, 849 cm "3- * H-NMR (S0DM-d ?.) d 7.87 (d, 4H, 3 = 8.3), 7.64 (d, 4H, 3 = 8.3), 7.16 (s, 2H), 3.75 Ct, 4H, 3 = 9.8), 3.53 (t, 4H, 3 = 9.8) .3.53 ít, 4H, 3 = 5.8) 3.47 ( t, 4H, 3 = 9.8), 3.1 (t, 4H, 3 = 5.8). * -aC ~ NMR (S0DM-dA, d 165.8, 152.4, 130.8, 128.7, 123.1, 109.2, 59.3, 52.6, 51.4. 51.1 MS m / c 444. The free base is suspended 0.45 g (0.001 mol) in 10 milliliters of ethanolic HCl and heated under reflux for 30 minutes, concentrated in vacuo and triturated with dry ether to give a yellow crystalline substance. The solid is filtered, washed with ether and dried in vacuo to give 0.45 g (89%) having an mp of 178-179 ° C. IR (KBr) 3407, 3089, 2919, 1615, 1569, 1370, 1288, 1067, 853, 669 cm "3- ^ H-NMR (SODM-d * / 50 ° C) d 10.8 (brs, 2H), 8.9 (d, 4H, 3 = 8.6), 7.87 (d, 4H, 3 = 8.6), 7.4 (s, 2H), 5.45 (vbr, 2H), 4.18-4.10 (m, 4H), 3.99-3.92 (m, 4H), 3.66-3.5 (m, 4H), 3.48- 3.42 (ni, 4H). ^ C-NMR (DMSO-d ^ / dO ^ C) &165.9, 152.3, 133.4, 129.8, 123.7, 121.5, 111.2, 56.6, 49.4, 49.2, 42.5. Analysis calculated for: Ca? H2? N 0a.2HCl-Ha0: 0: 61.80, H: 6.38, N: 11.09; found: C: 61.62, H: 6.51. N: 10.89.

EXAMPLE 9 Preparation of the dihydrate dihi rochloride of 2.5-Bisr4- (4,5-dihydro-l- (ethyl? -lH-imidazol-2-yl? Phenyl3furan) To a suspension of imidate ester (0.65 g, 0.0015 mol) in 10 ml of absolute ethanol is added N-ethylethylen diamine (0.4 g, 0.0045 mol), and the mixture is heated under reflux under nitrogen for 12-14 hours . The solvent was removed by distillation under vacuum, the remaining oil was diluted with ice water and basified with 1 M NaOH to pH 10. A gummy solid was separated from the aqueous phase. The solid is washed with water, dried in vacuo and recrystallized from ethanol: CHCl to give a yellow hygroscopic solid, 0.45 g (73%) MS m / e 412. The free base is dissolved (0.41 g, 0.001 mole) in 10 ml of ethanolic HCl and stirred at 35-40 ° C for 1 hour. The excess solvent is distilled under vacuum and the resulting semi-solid was triturated with dry ether. The ether was removed under vacuum and dried in resulting solid under vacuum to give a very hygroscopic yellow crystalline solid mp 163-4 ° C. H NMR (D.O / SODMd *) d8.08 (d, 4H, 3 = 8.3) ,. 7.76 (d, 4H, .3 = 8.3), 7.26 (s, 2H), 4.24-4.06 (ffi, 8H), 3.6-3.55 (, 4H), 1.34 (brt, 6H). "H NMR (DaO / SODMd?) 6 165.0, 154.2, .1.33.5, 129.3, 123.9, 121.3, 111.3, 48.9, 42.5, 41.7, 12.4.Analysis calculated by CaßHaßN 0.2HCl-H20: C: 61.17, H -.6.32, N: 10.97, found: C: 60.93, H: 6.44, N: 10.85.

EXAMPLE 10 PREPARATION OF 2.5-BTS C4- (N-ISOPROPILi-AMINDIN? 3FENIL> FURflNO Isopropyl i to dry (0.47 g, 0.008 mol) was added to a suspension of an imidate ester as described in Example 2 C1.3 g, 0.003 mol) in 45 rnl of absolute ethanol. Within 0.5 hr, the imidate ester was dissolved and the mixture of imidate ether and isopropylamine was colored. After approximately 3 hours a white solid precipitated; the slurry was stirred overnight at room temperature. The solvent was removed under reduced pressure, diluted with water, filtered and washed with water. After the solid was dried, it was recrystallized from a mixture of ethanol and ether to give a white solid 0.9 g (78%): mp 233-4 ° C. XH NMR (SODM-d *) / 60 ° C) 7.79 (brs, 8H), 7.11 (s, 2H), 6.25 (br, 4H, 3.81 (br, 2H), 1.14 (d, 6H, 3 = 5.9) .? C NMR (SODM-d <60 ° C) 125.4, 142.0, 136.6, 130.4, 126.8, 122.8, 108.7, 43.5, 22.8.

EXAMPLE 11 PREPARATION OF DIHYDROCHLORIDE OF 2. 5-BISC4- (N-ISOPR PTI - AMINDINO) FENIL3FURANO The free base (0.78 g, 0.002 mole) prepared as described in Example 10 was dissolved in 10 ml of absolute ethanol and treated with 10 ml of ethanol saturated with hydrogen chloride and heated for 2 hours. The mixture was reduced in volume to 5 ml. Addition of 20 rnl of dry ether produced a bright yellow precipitate which was filtered, washed with 3x5 rnl of dry ether and dried under vacuum at 65 ° C for 2 hours to give 0.8 g (87%) Pf 27d-7 ° C (dec). IR (KBr). ^ -H NMR (DODM-d) 9.72 (s, ÍH) 9.69 (s, ÍH), 9.57 (s, 2H), 9.24 (s, 2H), 8.06 (d, 4H, 3 = 8.1), 7.86 (d , 4H, 3 = 8.1), 7.42 (s, 2H), 4.14 (s, 2H, 3 = 6.6), 1.29 (d, 12H), 3 = 6.6). 3C NMR (S0DM-dβ) 161.1, 152.3, 133.6, 129.2, 127.7, 123.5, 111.3 ,. 45.1, 21.1. Analysis calculated for: Ca- * HasN ^ .0.2HCl.l .25 Ha0: C, 59.57 ,; H, 6.79: N, 11.57. Found: C, 60.00; H, 6.80; N, 11.52.

EXAMPLE 12 PREPARATION OF 2.5-BIS-- -.4.5-PIHIPRQ-1H-IMIDAZQL-2- IL? FENIL? 3-3-.4-TQLILQXI? FURANQ l- (4-tolyloxy) -l, 2-bis (4-bron.obenzoyl) ethylene-, To a solution of l-2-dibromo-l, 2-di (4-bromobenzoyl) ethane (11.1 g, 0.02 mol ) in 35 ml of THF was added a suspension of sodium-4-methyl peroxide [prepared from 0.92 g (0.04 mol) Na and 4.32 g (0.04 mol) 4-methyl phenol in 30 ml of THF by refluxing for 4-5 hours]. The yellow mixture was refluxed for 2-3 hours (TLC continued) after which the THF was removed under reduced pressure. The residue was treated with water and the solid filtered, washed with water, dried (NaaSO-J, and dissolved in chloroform.) The chloroform solution was passed through a silica column (elution with 2 ~ 5). % ether in hexane) The result was a whitish crystalline solid, 4.95 g (50%), mp 137-8 ° C. IR (KBr) 3087, 3035, 2868, 1687, 1646, 1587, 1572, 1557, 1502, 1399, 1364, 1194, 1068, 1009, 971, 876, 815, 772, 526. H NMR (CDCla / 35 ° C) 7.92 (d, 2H, 3 = 8.8), 7.65 (d, 2H, 3 = 8.8), 7.55 (d, 2H, 3 = 8.8), 7.48 (d, 2H, 3 = 8.8), 7.27id, 2H, 3 = 8.3), 7.11 (d, 2H, 3 = ( .3), 6.32 (s, ÍH), 2.4 (s, 3H), 3C NMR (CDCla / 35 ° C) 189.4, 187.6, 168.4, 150.9, 136.6, 136.0, 133.4, 132.3, 131.8, 130.9, 130.3, 129.6 , 129.2, 128.2, 120.6, 101.8, 20.95, MS m / C 500 (M *). 2,5-bis (4-bromophenyl) -3- (p-tolyloxy) urane. A solution of 5.0 g (0.01 mmol) of l- (4-tolyloxy) -1,2-bis- (4-bromobenzoyl) ethylene in 10 ml of phosphorus trichloride was heated under reflux for 3-4 hours (TLC continued ). Distillation was carried out by excess PCla and the residue was filtered with ice water (exothermic reaction). The solution was extracted with dichloromethane (75 rnl) and the dichloromethane layer was washed with saturated sodium bicarbonate solution, water and dry (NaaSOa). . The solvent was removed under reduced pressure. The residual solid was chromatographed on silica gel using ether: hexane (2: 8 to 1: 1) as eluent. Obtain a whitish crystalline solid, 2.78 g (56%), mp 92-3 ° C. IR (KBr) 2923, 2851, 1560, 1506, 1467, 1390, 1209, .1.072, 1066, 945, 825, 707, 486. H NMR (CDCla / 35 ° C) 7.69 (dA 2H), 3 = 8.8) , 7.46-7.43 (m, 6H) "7.12 (d, 2H), 3 = 8.3), 7.0 (d, 2H, 3 = 8.3), 6.47 (s, ÍH), 2.31 (s, 3H). * -3 CRMN (CDC13 / 135 ° C) 150.8, 150.1 ,. 142.8, 139.3, 133.0, 131.9, 131.7, 130.3,129.1, 128.6, 125.1, 125.0, 121.8, 120.5, 117.1, 102.7, 20.6. MS m / e 484 (M *). 2, 5-bis (4-cyanophenyl) -3- (4-tolyloxy) furan. A mixture of the above-prepared dibromo compound (2.5 g, 0.0051 mole) and copious cyanide (1.81 g, 0.02 mole) in 8 rnl dry N-rnetyl-2-? I-rolidone at about 200 ° C was heated. under a nitrogen atmosphere for 2.5 hours (TLC continued), cooled and poured into 200 ml of water. The precipitated solid was filtered, resuspended in 100 mL of water and 100 mL of 10% NaCN was added and the mixture was stirred for 3-4 hours. The solid was filtered, washed with water and placed in a Soxhlet device using acetone for about 24 hours. The acetone extract was reduced in volume and passed through a short column of neutral aluminum, the eluate was evaporated and the resulting solid was recrystallized from CHCla: ether (2: 8) to give a yellow crystalline solid 1.2 g. (62%). mp 198-9 ° C. IR (KBr) 3067, 2223, 1618, 1303, 1505, 1402, 1220, 1169, 1008, 926, 840, 820, 668, 546 cpr. H NMR (CDCla / 35 ° C) 7.98 (d, 2H, 3 = 8.8) ,. 7.75 (d, 2H, 8.3), 7.68 (d, 2H, 3 = 8.8), 7.65 (d, 2H, 3 = 8.8), 7.19 (d, 2H, 3 = 8.3), 7.05 (d, 2N, 3 = 8.3), 6.66 (s, ÍH), 2.36 (s, 3H). 3C NMR (CDCla / 35 ° C) 15436? 15036, 14538, 139.1, 134.0, 133.6, 133.3, 132.7, 132.6, 130.5, 124.2, 123.8, 119.0, 118.6, 117.8, 111.5, 110.0, 104.5, 20.7. Analysis calculated for: CaaHa «iN Oa: C, 79.76; H, 4.28; N, 7.44; Found: C, 79.68 H, 4.31; N, 7.39. E m / c 376 (M *). 2, 5-bisC C - (, 5-dihydro-lH-ylidazol-2-yl) enyl) 3-3-C-tolyloxy) furan. The previously prepared bisnitrile Cl g (0.0026 mol)] was placed in 20 ml of absolute ethanol and 50 rnl of absolute dioxane which was saturated with dry HCl gas at 0 ° C.

The mixture was allowed to stir at room temperature for 4 days.

A thick yellow precipitate was formed, 100 ml of dry ether was added and the solid filtered, washed with 100 ml of dry ether and dried in vacuo at 25 ° C for 5 hours to give 0.78 g (66%). of imidate ether hydrochloride. The imidate ester was resuspended in 25 ml of dry ethanol and heated to gentle reflux with 0.31 g (0.0053 mole) of ethylenediamine for 12 hours. The excess ethanol was distilled off and the residue was treated with water, basified with 1 M NaOH (stirring and cooling). The yellow precipitate was filtered, washed with water, dried and recrietalized from boiling ethanol to give 0.6 g (74%), pp 156-7 ° C. IR (KBr) 3218, 2927, 2862, 1609, 1506, 1398, 1218, 1105, 987, 848, 669 cpr. XH NMR (SODM-d-6/50 ° C) 7.947.B4 (m, 8H), 7.21 / d, 2H, 3 = 8.3), 7.12 (e, ÍH), 7.08 (d, 2H, 3 = 8.79) , 3.63 (s, 4H), 3.62IS, 4H), 2.28 (s, 3H). aC NMR (SODM-d./50 ° C) 163.0, 162.9, 154.3, 150.4, 142.8, 139.0, 132.4, 130.8, 130.4, 130.1, 129.7, 128.5, 127.5, 127.4, 123.2, 122.6, 116.5, 104.0, 49.3, 49.2, 19.9. MS m / c 462 (M-). The free base C0.5 g (0.0001 mol)] was heated in 10 mL of ethanolic HCl under reflux for 3 hours and added to 50 mL of dilute dry ether. The resulting yellow precipitate was filtered, washed with dry ether and dried in vacuo at 80 ° C for 24 hours, 0.48 g (90%), mp; 300 ° C. Analysis calculated for: Ca9H ~ 26N 0a-2 HCl: C, 64.04; H, 5.27; N, 10.46. Found: C, 64.83; H, 4.99; N. 10.22. IR (KBr) 3422, 3235, 2964, 2775, 1609, 1506, 1370, 1289, 1206, 848, 667 cm-3. H NMR (SODM-dA / DaO / TSP / 60 ° C) 7.98-7.86 (m, 8H), 7.19 (d, 2H, 3 = 8.79), 7.09 (s, ÍH,), 7.03 (d, 2H, 3 = 8.3), 3.88 (s, 4H), 3.76 (s, 4H), 2.24 (s, 3H). aC NMR (SODM-d * / DaO / TSP / 60βC) 165.3, 165.3, 154.7, 151.2, 145.7, 139.5, 134.3, 134.2, 135.1, 131.2, 129.6, 129.5, 124.8, 124.1, 123.3, 121.6, 117.7, 106.0, 45.8, 45.6, 20.7.

EXAMPLE 13 PREPARATION OF .S-BISC4 (2-TETRAHYDRO-PYRIMIDINYL 1FENIL1-3- f - A stirred mixture of imidate ester (1.08 g, 0.002 mol) and 1,3-diaminopropane (0.43 g, 0.006 mol) in 30 ml absolute ethanol under reflux (protected from moisture) for 12 hours was heated moderately. The excess ethanol was removed under reduced pressure and the residue was filtered with 50 ml of distilled water. The mixture was basified with 1 M NaOHlpH 10) while cooling and stirring; the precipitated free base was filtered, washed with water, the dried was recrystallized from the hot ethanol to give 0.80 g (81.6%); Pr 190-191 ° C, UR (KBr): 3267, 2931, 2858, 1609, 1505, 1369, 1216, 846, 666 atr. H NMR (SODM-f «/ 50 ° C) 7.88-7.78 (m, 8H), 7.2 (d, 2H, 3 = 8.8), 7.12 (s, ÍH), 7.07 (d, 2H, 3 = 8.8), 3.38 (t, 8H, 3 = 5.1), 2.28 (s, 3H), 1.75 (tt, 4H, 3 = 5.1): C NMR (SODM-d * / 50 ° C) 154.4, 153.8, 153.4, 150.5, 142.8 , 139.0, 134.5, .132.9 ,. 132.4, 130.6, 130.3, 130.6, 126.8, 126.7, 123.1, 122.5, 116.6, 104.1, 41.0, 40.8, 20.0, 19.8; MS m / c 490 (M *). A suspension of 0.5 g (0.001 rnolee) of free base in 5 ml of absolute ethanol was treated with 10 ml of ethanolic HCl and heated under gentle reflux for 2 hours. 50 ml of dry ether were added and the yellow precipitate thus obtained was filtered and washed with dry ether and dried under vacuum at 60 ° C for 12 hours. The product of the yellow solid 0.46 g (82%). Pf > 320 ° C. IR (KBr): 3432, 3117 ,. 3002, 1638, 1609, 1507, 1507, 1375, 1315, 1202, 846, 669 crn "3-. H NMR (SOD -dA / D-20 / TSP / 65 ° C) 8.12 (d, 2H, 3 = 7.8 ), 8.08 (d, 2H, 3 = 7.3), 7.88 (d, 4H, 3 = 8.3), 7.32 (d, 2H, 3 = 8.3), 7.22 (s, ÍH), 7.16 (d, 2H, 3 = 8.3), 3.6 íbr m, 8H), 2.37 (s, 3H), 2.1 íbr, 4n), 3C NMR (SODM-d * / DaO / TSP / 65 ° C): 159.5, 154.8, 151.1, 145.1, 140.9, 139.6, 134.1, 133.9, 133.5, 133.2, 128.7, 128.5, 127.2, 124.8, 117.6, 105.9, 41.5, 41.4, 20.6-n 18.2 Analysis calculated for: Ca3.HaoN Oa-2HCl, C 66.06; H, 5.36; N 9.94 Found: C, 65.91; H, 5.21; N, 9.88.

EXAMPLE 14 PEL PREPARATION 2.5-BISE4- (2-IMIPAZQLINIL? FENIL3-3-METQXI FURANQ 1, 2-bis (4-bromobenzoyl) -l-netoxyethane. To a solution of 1, 2-dibromo-1,2-di (4-bromobenzoyl) ethane (11.lg, 0.02 mol) in 150 ml of dry methanol was added a solution of sodium methoxide in methanol (0.92 g of sodium in 50 mL of methanol). The yellowish brown mixture was refluxed for 1-1.5 hours. The solvent was distilled off, the residue was suspended in water and the mixture was extracted with 100 ml of chloroform. The chloroform extract was washed with water, dried (NaaSC) and concentrated. The residue obtained was filtered with dry methanol-ether (3: 1) to give a whitish crystalline solid. 6.6 g (78%) ,. mp 153-154 ° C. IR (KBr): 3106, 3062, 2932, 1689, 1649, 1583, 1556, 1403, 1223, 1202, 1182, 1086, 1010, 1000, 857, 814, 738, 618, 472 cm ~. XH (SODM-d «s, / 40 ° C); 7.95 (D, 2H, 3 = 7.8), 7.77 (4H, 3 = 8.8), 7.72 (d, 2H, 3 = 7.8), 6.89 (e, ÍH), 4.03 (s, 3H). xaC (SODM-dβ / 40 ° C): 189.9, 187.2, 168.8, 139.9, 135.9, 133.1, 132.2, 131.8, 130.3, 128.1, 127.4, 98.6, 58.5. MS m / c 424 (M *). 2,5-bis --- 4-bro »ofenyl-l-3-methoxyfuran. The methoxyethane prepared above was dissolved in 5 ml of PCla and heated to reflux for 3 hours. The excess PCla was distilled off. When treated with ice and water, the residue formed a gummy mass. The mixture was extracted with chloroform and the organic layer was washed with water, dried (NaaSO) and purified by column chromatography on silica gel using hexane: ether (4: 1 to 2: 1). A whitish solid was obtained in 62% product; mp 112-113 ° C [lit. mp 113 ° C; RE. Lutz, 3.Am. Chem. Soc. 51.3008 (1929)]. IR (KBr) 3062, 2908, 2877, 1617 ,. 490, 1391, 1211, 1160, 1099, 1073, 1034, 1006, 925, 827, 787. H NMR (CDC-13) 7.69 (d, 2H, 3 = 8.8), 7.67.5 (m, 4H). 7.47 (d, 2H, 3 = 8.8), 6.64 (s, ÍH), 3.9 (s, 3H). aC NMR (CDClA 149.7, 147.5, 135.5, 131.9, 131.5, 129.4, 129.3, 125.0, 124.5, 121.5, 119.3, 98.6, 5B.6 MS m / c 408 (M +). 2,5-bis (4-cyanophenyl) -3-methoxyfuran. A mixture of 2.5-bis (bromophenyl) -3-rnetoxifuran (4.08 g, 0.01 mole) and cuprous cyanide (3.09 g, 0.035 mole) in 10 ml of dry N-rnetyl-2-pyrrolidone was heated at about 200 ° C under nitrogen during 2.5 hours. The mixture was cooled and poured into 200 ml of water and the precipitated yellowish-brown solid was filtered and washed well with water. The solid was resuspended in water (50 ml) and 100 ml of 10% NaCN and stirred for 2 hours. The slurry was filtered, washed with water, dried and suspended in 250 ml of acetone and passed through a column of neutral alumina. After eluting with acetone, a yellow solid resulted. After recrystallization of CHCla: ether (1: 1) gave (1.8 g, 60%) mp 257-258 ° C. IR (KBr) 3128 ,. 1599, 1501, 1409, 1174, 1163, 1027, 924, 836, 815, 651, 537 cm ~. H NMR (DMSO / 45 ° C) 8.03 Cd, 2H, 3 = 8.3), 7.95 (d, 2H, 3 = 8.79), 7.91 (d, 2H, 3 = 8.3), 7.85 (d, 2H, 3 = 8.79 ), 7.62 (s, ÍH), 4.0 (s, 3H). aC NMR (SODM / 45 ° C) 150.0, 149.8, 134.6, 133.4, 133.2, 132.7, 132.5, 124.0, 122.7, 118.9, 118.5, 110.0, 107.6, 102.4, 59.0. MS m / c 300 (M +). Analysis calculated for: C ^ Hxa aOOOO.Sl): C, 75.98; H, 4.03; N, 9.33; Found: C, 76.02; H ,. 4.04; N, 9.36. 2,5-bisC4- (2-ip? Idazolinyl) phenyl-J-3-methoxyfuran. The bis-nitrile prepared above (0.9 g, 0.003 mol) in 70 ml of dry ethanol was suspended, saturated with dry HCl gas at 0-5 ° C and stirred under dry conditions for 3-4 days. The mixture was diluted with 200 ml of dry ether and the yellow imidate ester was filtered and washed with dry ether and the solid was dried -in vacuo for 5-6 hours to give 1.2 g (86%). The solid was reslurried in 30 rnl of dry ethanol and gently refluxed with 0.46 g (0.008 mol) of dry ethylenediamine for 12 hours. It is sep > the solvent was distilled. The residue was suspended with 50 ml of cold water and made basic with 1M NaOH. The yellow precipitate was presipitated, washed with water and dried. Recrystallization from the ethanol-ether mixture gave 0.74 g (75%) m.p. 186-187 ° (dec). IR (KBr) 3444, 3245, 2931, 2857, 1601 ,. 1512, 1397 ,. 1366, 1277, 1162, 1104, 1031, 926, 842, 743, 670 cm *. H (DMS0-d «» / 60oC) 7.93-7.86 (m, 8H), 7.32 (s, ÍH), 3.98 (s, 3H), 3.69 is, 4H), 3.67 (s, 4H), xaC NMR (DMSO -d? / 60 ° C: 163.3, 163.1, 150.0, 148.6, 138.3, 134.7, 131.9, 131.3, 128.9, 127.6, 126.1, 123.0, 121.9, 100.6, 58.7, 49.0, 48.5, MS m / e 386 (M + J The free base 0.58 g (0.0015 mol) was dissolved in 10 ml of hot ethanol and treated with 10 ml of saturated ethanolic HCl The mixture was heated to reflux for 30 minutes. 5-6 ml The resulting mixture was diluted to 60 rnl of dry ether The yellow crystalline solid obtained was filtered, washed with dry ether and dried under vacuum at 60 ° C for 12 hours to give 0.62 g (83%) , mp 189-190 ° C (dec.). IR (KBr): 3422, 3128, 2975., 1599, 1510, 1405, 1363, 1285, 1207, 1028, 845, 666 cm *. H (DaO / TSP / 50 ° C) 7.52-7.43 (, 8H), 6.87 (s, ÍH), 3.92 (s, 3H), 3.86 (s, 8H), aC (D-2O / TSP / 50 ° C) 167.2, 153.1, 152.4 , 137.6, 137.2, 130.9, 130.7, 126.5, 125.4, 122.1, 119.8, 104.2, 61.5, 47.0, 46.9. lculated for Ca3HaaN - ». Oa-0.5 Ha0-2HC1: C, 58.97: H, 5.38; N, 11.96. Found C, 59.16; H, 5.35; N, 11.80.

EXAMPLE 15 PREPARATION OF 2 5-BIS-T4 (N-CICLOPOPILGUANIL) FENIL FURflNO A mixture of the imidate ester (1.3 g, 0.003 mole), cyclopropylole (0.43 g, 0.0075 mole) in 35 ml of dry ethanol was stirred overnight. The solvent was removed in vacuo and water was added to make a solution to spike. The solution was made basic with 1 M NaOH while cooling and stirring. The solid that formed was filtered, washed with water and dried. The solid was dissolved in chloroform, dried over zS0A and the solvent was removed. The residue was recrystallized from ether: CHCl3 (5: 1) to give a pale yellow solid 0.8 g / 709%) mp 185-186 ° C (dec.). IR (KBr): 3464, 3320, 3080, 1610, 1510, 1364, 1022, 848, 791 cpr. H NMR (CDC a): 7.71 (br s, 8 H), 6.78 (s, 2 H), 5.3 (v br, 4 H), 2.6 (br, 2 H), 0.87-0.81 (, 4 H), 0.367 + 0.62 (m , 4H). aC NMR (CDC a-DMSO-d *): 159.6, 152.2, 134.8, 130.7, 126.4, 122.6, 107.7, 25.7, 6.04 MS m / e 388 (M +). The free base (0.6 g, 0.0015 mol) was suspended in 3 ml of dry ethanol and treated with 6 ml of ethanol HCl and heated gently at 35 ° C for 1 hour. The yellow solution was diluted with 50 ml of dried ether and filtered, washed with dry ether and dried under vacuum at 75 ° C for 12 hours. The yield of the yellow solid was 0.55 g (80%), mp; 310 ° C (des.). IR (KBr): 3369, 3181, 3037, 1665, 1607, 1502, 1032, 782, 674 crn. "XH NMR (DMSO-d *.): 10.24 (s, 2H), 9.86 (s, 2H), 9 , 27 (s, 2H), 8.06 (d, 4H, 3 = 7.94), 7.95 (d, 4H, 3 = 8.54), 7.42 (s, 2H), 2.87 (br m, 2H), 1.09-0.85 (m, 8H) X3C NMR (DMSO-d *): 163.9, 152.3, 133.7, 129.1, 126.6, 123.5, 111.3, 24.7, 6.5 Anal.Calcd for Ca ^ Ha * N- * 0-2HCl: Cal. C, 63.02, H. 5.73: N, 12.25, Found: C, 62.89; H, 5.95; N, 12.00.

EXAMPLE 16 In Examples 16-19, the results are presented for a series of compounds. In all the following designations of compounds are used. Compound Name 1 2, 5-bis (-fuanyl phenyl) furan 2 2,5-bisC4- (2-imidazolinyl) phenyl] furan 3 2,5-di-p [2 (3,4,5,6-tetrahydropyrimidyl) phenol] furan 4 2,5-bisC4,5,6,7-tetrahydro-lH-l, 3-diazepin-2-yl) phenyl] furany 5 2,5-bieC4- (3a, 4,5,6 , 7a-hexahydro-lH-benzyl idazol-2-yl) phenyl] furan 6 2,5-bis. { 4C2- (N-2-hydroxyethyl) i idazolinyl] enyl} f? rano 7 2, 5-bis-. { Bis-. { 4-E2- (N-ethylimidazolinyl)] phenyl} f? rano 8 2,5-bis (4-guanilfenil) -3,4-dimethyl f? rano 9 2,5- [bis. { 4- (2-imidazolinyl)} fer.il] 3-p-tolyloxy f? rano .10 2.5-Cbis. { 4-í2-tetrahydropyrin idinyl)} phenyl] 3] p] tolixi furan 11 2,5-bie. { 4-E5- (N-2-aminoethylarnido) benzinidazol-2-yl] phenyl} f? rano 122.5-bis (4-N, N-dimethylcarboxhi razidef nil) furan 13 2,5-bisC4- (N-isorpo? iammidino) phenyl] fr? an? 14 2,5-bis. { 4-C3- (dimethylaminopropyl) amidino] phenyl} f, 15, 2,5-bis-C4-N- (cyclopropylguanyl) phenyl] furan, 16, 2,5-bis-. { 4 - [(N-2-hydroxyethyl) guanyl] phenyl} f? rano 17 2, 5-bisl-4-N- (imethylaminoethyl) guanyl] phenyl furan 18 2,5-bis [2- (imidzaolinyl) phenyl] -3,4-bis (ethoxyrnethyl) f? rano 19 2, 5- Bis. { 4 ~ l-N- (3-aminorpopil) amidino] phenyl} furan 20 2,5-bisC 4 - (N-isopropylamidino) phenyl] -3-methyl furan, FUSION END DNA The thermal fusion curves for DNA and its complexes with compounds of examples 4, 6 and 7-9 are determined as previously described in FA Tanious, et al., 3. Biomol, Sructure a Dynamics 11: 1063 (1994) and UD Uilson et al., Biochemistry 32: 4098 (1993), following the absorption change at 260 nn as a function of temperature. The values of T were determined from the graphs of first derivative. Compounds are compared by the increment in T (Tm = Tm of cornpex - Tm of free nucleic acid) produced in MES pH regulator (0.01M 2- (N-morpholino) ethylene-nesonic acid, EDTA at 0.001 M, 0.1 M NaCl adjusted to pH 6.0) in compound saturation amounts (0.3 mole ratio of nucleic acid-based compound) unless otherwise indicated.

CUAPRQ 1 NUCLEIC ACID LINK FITS FOR DIARILFURANS DICATIONTCOS Increase in thermal fusion of polyA-poliT. See, U.D. Uilson et al., Biochemistry 32: 4098 (1993). ^ Increase in thermal fusion of oligomer d (6C6CAATTGCGC) a- See, F.A. Tanious, and others, 3. Biornol. Structure a Dynamics 11: 4063 (1994).

EXAMPLE 17 TNHTBTCTON OF TOPOISOMERASE II AND INHIBITION OF GIARDIA LAFIBLIA BY DTARTt FURANO DICATIONICOS CUAPRQ 2 TNHTBTCTON OF TOPOISOMERASA II AND ANTI-GIARDIA LAMBLIA 50% inhibition of Giardia lamblia topoieomeraea II aielada. See, C.A. Bell, and others, Antimicrob. Agents and Chernother. 37: 2668 (1993). 250% inhibition of topoisomerase II isolated from PrpsQphila rnelanpqaf? Er- 350% inhibition of topoieomerase I isolated from Pnewnocvs is carinii, * 50% inhibition of Giardia lamblia growth in in vitro culture. See, C.A.

EXAMPLE 18 ACTIVITY AGAINST NEUNONIA BY PNEUMQCYSTIS CARINII TABLE 3 ACTIVITY IN VIVO OF DIARIL DICATIONICOS AGAINST PNEUMOXYSITIS QBRMS1 Intravenous dose except as indicated. 2 A detailed explanation of the toxicity scale is described in R.R. Tidwell, and other Anti icrob. Agents and Chernother. 37: 1713 (1993). Generally, the larger the value the more severe the toxicity will be. The values higher than 2 indicate deaths of some animals. 3 Quiet counted in a blind protocol in lung tissue reported as a percentage of controls treated with saline. See, R.R. Tidwell, and others, supra. * Oral dose for forced feeding.

EXAMPLE 19 Activity Against Crvptosporidium parvup- CUAPRQ Activity of Diaril urans Dicathion against Crvotosporidium parvum 1. Swiss mice fed with Suckling ICR seeBlahb? Rn and other Antimicrobial Agnets and Chemotherapy 35: 1520 (1991). 2. Average count of Occidentales. 3. Standard error of the average. 4. Score of Mannhitney Z.

. Probability.

PRFAPARACTON DF 2.5-BIS - 4- (N-2-METOXYETHYLGUANIL) PHENYL3FURAN To a stirred suspension of 0.87 g (0.002 mole) of the furan hydrochloride α-idaethoester in 15 ml of ethanol is added 0.45 g (0.006 mole) of 2-methox et et al. to freshly distilled. The mixture is stirred for 2 hours, the solvent is distilled under vacuum, ice water is poured off and the solvent is flashed with 1 M NaOH at pHlO. An oily paste is separated from water, washed with water, dissolved in CHCla and dried over anhydrous sodium sulfate. The solvent is removed under vacuum, and the solid obtained is recrystallized from ether: chloroform (8: 1) to give a single 0.58 g (69%) having a mp of 11B-120 ° C. IR (KBr): 3430.3370.2887, 1647, 1603, 1547, 1367, 1192, 1110, 1021, 847, 787, 681 Cm ~. H NMR (CDCl) 7.75 (d, 4H, 3 = 8.5), 7.63 (d, 4H, 3 = 8.5), 6.8 (s, 2H), 3.68-3.61 (m, mH), 3.60-3.75 (n, 4H ), 3.41 (s, 3H). 3 C NMR (CDCl 3) d 136.2, 153.0, 136.5, 131.9, 126.6, 123.8, 100.5, 71.4, 58.8, 58.7. MS: m / e 420? M +). The free base (0.42 g, 0.001 mole) is dissolved in 4 ml of ethanolic HCl and stirred at 40-45 ° C for 2 hours, the solvent is removed under vacuum and the solid obtained is triturated with dry ether. The solid was filtered, washed with ether and dried under vacuum at 60 ° C for 12 hours. The yield is 0.44 g (89%) of yellow solid which has a mp of 208-210 ° C dec. IR (KBr): 3410, 3320, 3095, 1674, 1615, 1503, 1291, 1197, 1112, 788 cm- ?. XH NMR (S0DM-d *) 6 10.0 (brs, 2H), 9.65 (brs, 2H), 9.24 (brs, 2H), 8.09 (d, 4H, 3 = 8.3), 7.91 (d, 4H, 3 = 8.7 ), 7.42 (s.2H), 3.7-3.62 (m, 8H), 3.33 (s, 6H). S3C NMR (SODM-d?), D 162.4, 152.4, 133.8, 129.1, 127.3, 123.6, 111.4, 69.0, 58.2, 42.6. Analysis calculated for 2HC1 1.5HS0; theory C: 55.38, H: 6.39, N: 10.76 found C: 55.23, H: 6.41, N: 10.61.

EXAMPLE 21 PREPARATION OF 7 .5-BIS [4fN- (3-PENTILGUANIL) > ] FURANO Freshly distilled 3-arnomethane (0.34 g, 0.004 mole) is added to a stirred suspension of the furan bis-irnidatoester (0.65 g, 0.0015 rnoles) in 10 nr of absolute ethanol, after 5 minutes the reaction becomes clear. This mixture is stirred for 12 hours, and the solvent is removed under vacuum, the residue is treated with 10 ml of ice cold water, and it is poured into pHIO with 1M NaOH. The whitish presipitate is filtered, washed with water, dried and recrystallized from CHCla: ether (1: 3) to give 0.51 g (76%) of pale solid which +? Ene? N pf of 55-156 ° C. IR (KBr): 3245, 3120, 2962, 1593, 1544, 1380, 1194, 848, 784 cr-r. XH NMR (SODM ~ d?) Or 157.3, 152.5, 136.7, 130.5, 127.0, 122.8, 108.8, 55.0, 27.3, 10.5. MS: m / e 444 μM +). The free base (0.35 g, 0.00078 moles) is dissolved in rnl of warm dry ethanol. Ethanolic HCl (5 ml) is added and the solution is allowed to stir at room temperature for 4 hours. The solvent is removed under vacuum and the oil obtained is triturated with dry ether. A yellow solid is collected by filtration, washed with ether and dried at 75 ° C for 12 hours under vacuum. The yield is 0.36 g (90%) of product that has a pf > 360 °. IR (KBr): 3410, 3235, 3105, 1668, 1613, 1500, 1459, 1368, 1126, 1025 cm-. H NMR (DssOO / DMSO-d6 / 45 ° C) 6 7.93 (d, 4H, 3 = 8.5), 7.76 (d, 4H, 3 = 8.5), 7.13 (s.2H), 3.88-3.65 (rn, 2H ), 1.9-1.8 (fll, 4H), 1.78-1.66 (m, 4H), 1.05 (t, 6H, 3 = 7.3). 3C NMR (Da0 / S0DM ~ d645 ° C) 6 165.1, 154.1, 136.2, 130.0, 129.0, 125.8, 112.9, 59.1, 27.8, 11.5. Analysis calculated for 2HC1 1.5H20; theory: 0: 58.32, H: 7.16, N: 9.7.l; found C: 58.26, H: 7.31, N: 9.63.

EXAMPLE 22 PREPARATION PE 2, 5-BIS -CIANQFENTILJFURANQ To a suspension of NaH (2.5 g, 0.11 mol) in 50 mL of dry THF under nitrogen, a solution of diethyl carbonate (11.8 g, 0.1 rnoles) in 20 mL of dry THF is added. After stirring for 5 minutes, 4'-bromoacetophenone (19/9 g, 0.1 rnoles) is added dropwise in 50-60 rnl of dry THF durin 3-4 hours. The yellow reaction mixture is stirred overnight, the solvent is removed under vacuum and the remaining oil is diluted with water. The mixture is then extracted with 2x100 ml portions of ether. The ether is dried over anhydrous sodium sulfate and stirred to give a pale oil. The oil is purified by column chromatography on silica gel (elution: hexane-5: hexane: ether) or distilled under high vacuum (pressure 0.01 nm) to give a yellow oil 18.8 g (70%). The product is stored at Q ° C and used immediately. 3-C4-Brornofenill-3-oxopropionate ethyl (13.5 g, 0.05 rnolee) previously obtained, in 20 ml of dry EtOH is added to a solution of sodium ethoxide (1.15 g Na. I .05 rnoles in 30 ml of ethanol) under nitrogen. The solution is stirred for 30 minutes, cooled and 4-bromophenacyl bromide (13.85 g, 0.05 mole) in 75 ml of dry EtOH is added slowly over a period of 30-40 minutes. The mixture is allowed to stir at room temperature for 3 days. The solvent is removed under vacuum, the oil is diluted with water, extracted with ether, washed with water and dried over magnesium sulfate. The solution is filtered and the solvent is removed to give a crude oil, 16.0 g (68%). Any remaining solvent is removed by placing it under vacuum for 2 hours at room temperature. The crude oil (0.034 moles), ethyl 2,3-bisC4-brrnobenzoyl] propionate is dissolved in 75-80 rnl EtOH, saturated with dry HCl at 0 ° C, and allowed to stir at room temperature for 24 hours. The resulting solid is filtered, washed with ethanol, cooled and then suspended in water and extracted with CH2Cla. The organic layer is dried over magnesium sulfate and the solvent is removed to give 7.4 g (48%) of the furan ester as a white crystalline solid having a mp of 125-127 ° C. XH NMR (CDCL3) d 7.97 (d, 2H, 3 = 8.8), 7.58 Cd, 2H, 3 = 8.8), 7.56-7.52 (m, 4H), 7.07 (s, ÍH), 4.3 (q, 2H , 3 = 8.8), 1.38 (t, 3H, 3 = 8.8). X3C NMR (CDC13) d 163.2, 155.5, 151.5, 132., 1131.5, 139.8, 128.5, 128.4, 125.5, 123.9, 122.2, 116.4, 108.7, 60.9, 14.3. The ester (7.0 g, 0.015 mol) is suspended in 75 ml of 20% KOH and 10 ml of EtOH, and heated and refluxed 4-5 hours. After cooling and acidification with concentrated HCl, the solid precipitate is filtered, washed with water, dried in air and under vacuum to give 5.4 g (82%) of the acid which has a mp of 252 ~ 254 ° C. H NMR (CDC13) d 8.03 (d, 2H, 3 = 8.8), 7.77 (d, 2H, 3-8.4), 7.67 (d, 2H, 3 = 8.8), 7.62 (d, 2H, 3-8.4 ), 7.37 (s, ÍH), 3.4 (br, ÍH). srC NMR (CDCla d 153.8, 153.9, 150.8, 131.7, 131.1, 129.6, 128.2, 128.1, 125.7, 122.7, 121.2, 117.2, 109.6) A mixture of carboxylic acid of 2,5-bis (4-brornophenyl) -3- furan, 0.85 g (0.002 mole), CuCN 0.45 g (0.005 mole) in 10 ml of distilled quinoline is heated under reflux for 3 hours.The mixture is cooled and 100 l of dilute aqueous HCl are added and the mixture is stirred for 30 minutes. The solid is washed with water and then with hexane, the yellow solid resulting in acetone and passed through a column of alumina (neutral) to give a yellow crystalline solid, 0.37 g (68%). , which has a mp of 293-295 ° C. The product is identical to the one described in example i.

EXAMPLE 23 PREPARATION OF 2.5-BIS- (N-ISOPROPILGUANIL) PHENYL-13-METHYLPHURAN To a suspension of imidatoester dihydrochloride (0.45 g, 0.001 rnolee) in 10 in. Of dry ethanol is added distilled ispropylamine (0.187 g, 0.003 mole) and the mixture is stirred for 12 hours. The solvent is removed under vacuum and the residue is stirred with 10 ml of ice / water, basified with 1 M NaOH and the pH adjusted to 10. The solid obtained is filtered, dried and crystallized from ether: CHCl3 (3: 1) to give 0.31 g (77%) of yellow bromous solid. MS: m / e 402 (M *) The free base (0.20 g, 0.0005 mole) is dissolved in 5 ml of ethanol and stirred with 5 ml of ethanolic HCl for 2 hours. The ethanol is distilled under vacuum and the residue is triturated with dry ether to give 0.29 g of yellow solid (73%) having a mp of 260-262 ° C. IR (KBr): 3377, 3210, 3050, 1668, 1611, 1508, 1391, 1128, 932, 842 Cflr. H NMR (D ^ O / ÜMSOd *) d 9.65 (br, 2H), 9.55 (br, 2H), 9.7 (br-, 2H), 8.0 (d, 2h, 3 = 8.8), 7.94 (d, 2H) , 3 = 8.79), 7.91 (d, 2H, 3 = 8.3), 7.84 (d, 2H, 3 = 8.3), 7.29 (s, 1H), 4.10 (brm, 2H,) 2.38 (s, 3H), 1.27 (bd, 12H), aC NMR (Ds, OSODMd * / 65ßC) d 163.1, 163.0, 151.6, 148.2, 136.6, 135.5, 129.3, 129.1, 127.7, 126.9, 125.9, 125.1, 124.3, 115.9, 47.1, 21.9, 13.2 . Analysis calculated for CzsHaoN 0-.2HC1.HaO: theory: C: 60.S4, H: 6.94, N: 11.35, find C; 60.79, H: 7.04, N: 11.27. The foregoing is illustrative of the present invention and should not be considered as limiting thereof. The invention is defined by the following claims, including equivalents of the claims therein.

Claims (2)

1. NOVELTY OF THE INVENTION REIVINPICACIQNES The use of a compound of formula (I): wherein: R and Rz are each independently selected from the group consisting of H, Cx-C * alkyl, aryl, alkylaryl, aminoalkyl, aminoaryl, halogen, oxyalkyl, oxyaryl or oxyarylalkyl; R3 and R are each independently selected from the group consisting of H, C -C? Alkyl, oxyalkyl, alkylaryl, aryl, oxyaryl, aminoalkyl, aminoaryl or halogen; and X and Y are located in the pair or meta positions and are selected from the group consisting of H, oxyalkyl alkyl, and wherein: each Ra is independently selected from the group consisting of H, C 1 -C 4 alkyl, alkoxyalkyl, hydroxyalkyl, to inoalkyl, alkylaminoalkyl, cycloalkyl, aryl or alkylaryl or two Rs groups together represent alkyl Ca-C or hydroxyalkyl or alkylene; Y ? is H, hydroxy, Cx-3 alkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylamino, alkylaminoalkyl, cycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aryl or alkylaryl; or a pharmaceutically acceptable salt thereof, in the preparation of compositions for treating pneumonia caused by Pneurnocvstis carinii in a subject that needs such treatment.
2. 2. The use according to claim 1, further characterized in that said subject suffers from pneumonia caused by Pneufflocys is carinii- 3. The use according to claim 1, further characterized in that said subject is at risk of developing pneumonia caused by Fneuroocvstis C? ri ii and the composition obtained is administered in a prophylactically effective amount 4. The use according to claim 1, further characterized in that in the compound used X and Y are in para position. The use according to claim 1, further characterized in that in the compound used X and Y are each And why said used compound of formula (I) is selected from the group consisting of compounds wherein (a) each Rx is H, Ra is H, Ra is H, A is H, Ra is H and R? it's H; (b) R is H, R2 is H, Ra is H, R is H, two groups R »together represent alkyl of Ca, and R? it's H; (c) x is H, a is H, Ra is H, RA is H, two groups R »together represent alkyl of Ca, and? it's H; (d) R is Cx-O * alkyl, Ra is C? -CA alkyl, Ra is H, R * is H, Rs is H and R "& it's H; (e) Rx is oxyalkyl, Ra is oxyalkyl, Ra is H, R ^. is H, two Rs groups together represent C2 alkyl, and A is H; (f) R is H, Ra is oxyalkyl, Ra is H, RA is H, two groups Rs together represent alkyl of C2, and R * is H; (g) R is H, Ra is oxyarylalkyl, Ra is H, is H, two groups Ra together represent alkyl of C2, and * is H; (h) R is H, Ra is H, Ra is H, R * is H, two groups R "together represent Cz alkyl, and A is hydroxyalkyl; (i) R is H, R2 is oxyarylalkyl, Ra is H, R * is H, two Rs groups together represent alkyl of Ca, and R. * is H; (j) Rx is H, R2 is H, R3 is H, R is H, Rs is H and Rβ is aminoalkyl; (k) Rx is H, Ra is H, Ra is H, is H, two groups R »together represent CA alkyl, and RA is H; (1) R is H, Ra is H, Ra is H, RA is H, two groups R »together represent alkyl of C, and R? it's H; () Rx is H, Ra is H, Ra is H, RA is H, R »is H and R * is alkylamino; (n) Rx is H, Ra is H, Ra is H, A is H, R "is H and R * is hydroxyalkyl; (o) R is H, Ra is H, Ra is H, RA is H, R is H and RA is alkylaminoalkyl; (p) R is H, z is C -C alkyl, Ra is H, RA is H, R ee H and RA is C -C alkyl; (q) Rx is H, Ra is H, Ra is H, RA is H, two groups Ra together represent alkyl of Ca, and R? it is C-Cß alkyl. 6. The use according to claim 1, further characterized in that said used compound of Formula (I) is selected from the group consisting of: 2,5-bis (4-guanylphenyl) furan, 2,5-bis (4) -guanylphenyl) -3, 4-dimet.il furan, 2,5-di-pC2 (3,4,5,6-tetrahydropyridyl) phenyl 3-furan, 2,5-bisC4- (2-imidazolinyl) phenylfurane, 2,5-Cbis. { 4- (2-tetrahydropyrrnidinyl)} phenyl3-p (tolyloxy) furan, 2,5-Cbis. { 4- (2 ~ irnidazolinyl)} phenyl] -p (tolyloxy) furan,. 2,5-Cbist4-C2- (N-2-hydroxyethyl) imidazole nor 11-phenyl} Furan, 2,5-bisC4- (2- (N-isopro-pillamidino) phenyl-furan, 2,5-bis. {4-C2- (3- (dimethylaminopropyl) -amidionol phenyl}. furan, 2.5 -bis-C4- [2- (N-3-aminopropyl) amidino-3-phenyl} -furan, 2,5-bisC-2-imi-azole) phenyl-3,4-bis (methoxy-methyl) furan, 2, 5-bis [4-N- (dimethylaminoethyl) guanyl-3-phenyl-furan, 2,5-bis-C4-C (N-2-hydroxyethyl) guanyl-3-phenyl}. Furan, 2,5-bisC4-N- (cyclopropylguanil) phenyl furan, 2, .5-bisC4- (N, N-diethyl-aminopropy-D-guani-13-phenyl-furan, 2,5-bis-C4-C2- (N-ethylimidazole-n-phenyl) -furan, 2,5-bis { 4 ~ [.N- (3-pentylguanyl) amidino} phenyl-furan, 2,5-bieC4- (2-irnidazolinyl) phenyl3-3-methoxyfuran, 2,5-bisC4- (N-isopropylamine) ) phenyl 3 -3-methyl furan, and the pharmaceutically acceptable salts thereof 7.- The use of a compound of formula (I): (D wherein: R and R2 are each independently selected from the group consisting of H, Cx-C * alkyl, aryl, alkylaryl, aminoalkyl, aminoaryl, halogen, oxyalkyl, oxyaryl, oxyarylalkyl, Ra and RA are selected each independently of the group consisting of H, C -C * alkyl, oxyalkyl, alkylaryl, aryl, oxyaryl, aminoalkyl, aminoaryl or halogen, and X and Y are located in the para or meta positions and are selected from the group consisting of of H, C? -C alkyl, oxyalkyl, and wherein: each Ra is independently selected from the group consisting of H, C? -C alkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, cycloalkyl, aryl or alkylaryl or two Ra groups together represent alkyl Ca-C 0, hydroxyalkyl or alkylene; and R * is H, hydroxy, C? -C alkyl, alkoxyalkyl, hydroxyalkyl ,. aminoalkyl, alkylamino, alkylaminoalkyl, cycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aryl or alkylaryl; or a pharmaceutically acceptable salt thereof, in the preparation of compositions for treating Giardia lamblia in a subject in need of such treatment. 8. The use according to claim 7, further characterized in that said subject suffers from Giardia lamblia. 9. The use according to claim 7, further characterized in that said subject is at risk of developing lamblia filaria and the composition obtained is administered er. A prophylactically effective amount. 10. The use according to claim 7, further characterized in that in the used compound X and Y are in the para position. 11. The use according to claim 7, further characterized in that in the compound used X and Y are each and in that said used compound of formula (I) is selected from the group consisting of compounds wherein (a) each Rx is H, R2 is H, Ra is H, RA is H, Rs is H and Re is H; (b) Rx is H, Ra is H, Ra is H, RA is H, two groups Ra together represent alkyl of Ca, and Re. is H; (c) Rx is H, Ra is H, Ra is H, A is H, two groups Ra together represent alkyl of Ca, and R? it's H; (d) R is C? -Ce alkyl, Ra is C? -CA alkyl, Ra is H, RA is H, Ra is H and Re is H; (e) Rx is oxyalkyl, a is oxyalkyl, Ra is H, RA is H, two Ra groups together represent C2 alkyl, and R? it's H; Cf) R is H, R2 is oxyalkyl, Ra is H, RA is H, two groups Ra together represent alkyl of C2, and Re is H; (g) R is H, Ra is oxyarylalkyl, Ra is H, RA is H, two Ra groups together represent alkyl of Ca, and R-s. it's H; (h) Rx is H, Ra is H, Ra © s H, RA is H, two groups Ra together represent alkyl of Ca, and Re is hydroxyalkyl; (i) Rx is H, Rβ is oxyarylalkyl, Ra is H, RA is H, two groups Ra together represent alkyl of Ca, and e is H; (j) R is H, Ra is H, Ra is H, RA is H, Ra is H and Re is aminoalkyl; ik) Rx is H, Ra is H, Ra is H, is H, two groups Ra together represent alkyl of CA, and * is H; (1) is H, a is H, Ra is H, RA is H, two groups Ra together represent alkyl of CA, and Re is H; () R is H, Ra is H, Ra is H, R is H, Ra is H and Re is alkylamino; (n) Rx is H, R is H, R3 is H, RA is H, Rs is H and R? it is hydroxyalkyl; (o) R is H, R2 is H, Ra is H, RA is H, Ra is H and e is alkylaminoalkyl; Íp) R is H, Ra is Cx-Ce alkyl, Ra is H, RA is H, Ra is H and Re is C? -Ce alkyl; (q) Rx is H, a is H, Ra is H, R is H, two groups Ra together represent alkyl of Ca, and R? is C -Ce alkyl. 12. The use according to claim 7, further characterized in that said used compound of Formula (I) is selected from the group consisting of: 2,5-bis (4-guanyl phenyl) furan, 2,5-bis ( 4-guanylphenyl) -3,4-dimethyl furan, 2,5-di-pC2 (3,4,5,6-tetrahydropyrimidyl) enyl-furan, 2,5-bieC4- (2-imidazolinyl) phenyl 3 furan, 2 , 5-Cbis. { 4- (2-tetrahydropyrin idinyl)} phenyl-polythyloxy) furan, 2,5-Cbis. { 4- (2-irnidazolinyl)} phenyl 3-p (tolyloxy) f? rano, 2,5-Cbis. { 4-C2- (N-2-hydroxyethyl-J-imidazolinyl-3-phenyl) -furan, 2,5-bis [.4- (2- (N-isopro-pilamidino) phenyl-3-furan), 2,5-bis. { 4-C2- (3- (dimethylaminopropyl) -amidiono3 phenyl} furan, 2,5-bis. {4-C2- (N-3-amino? Ropil) amidino-3-phenyl} furan, 2.5 -bisC2 ~ i idazolinyl) phenyl 3-3.4-bie (methoxy-ethyl) furan, 2,5-bis-4-N- (dimethylaminoethyl) guanyl-3-phenyl-furan, 2,5-bis. { 4-C (N-2-hydroxyethyl) guanyl-3-phenyl} furan, 2,5-bisl [4-N- (cyclopropylguanyl) phenyl 3-furan, 2,5-bisC4- (N, N-diethyl-aminopropy-D-guani-13-phenyl-furan, 2,5-bis-C4-t2- (N- ethylimidazoli-nil) phenyl.} furan, 2,5-bist-4-CN- (3-pentylguanyl) amidino.) phenyl-frannin, 2,5-bieC4- (2-imidazolinyl) phenyl-3-methoxy furan, 2,5-bisC4- (N-isopropylamine) phenyl3-3-methylfuran, and pharmaceutically acceptable salts thereof 13.- The use of a compound of formula (I): wherein: R and Ra are each independently selected from the group consisting of H, C? -C? alkyl, aryl, alkylaryl, aminoalkyl, aminoaryl, halogen, oxyalkyl, oxyaryl or oxyarylalkyl; R3 and A are each independently selected from the group consisting of H, C -Ce alkyl, oxyalkyl, alkylaryl, aryl, oxyaryl, aminoalkyl, arninoaryl or halogen; and X and Y are located in the oara or meta positions and are selected from the group consisting of H, C -Ce alkyl, oxyalkyl, and wherein: each Ra is independently selected from the group consisting of H, Cx-Ce alkyl, alkoxyalkyl, hydroxyalkyl, arninoalkyl, alkylaminoalkyl, cycloalkyl, aryl or alkylaryl or two Ra groups together represent Ca-C ?alkyl, hydroxyalkyl or alkylene; and R is H, hydroxy, C? -Ce alkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylamino, alkylaminoalkyl, cycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aryl or alkarylaryl; or a pharmaceutically acceptable salt thereof, in the preparation of compositions for treating CrvptosDori iurn parvum in a subject in need of such treatment. 14. The use according to claim 13, further characterized in that said subject suffers from CrvotosDoridium narvum. 15. The procedure according to claim 13, further characterized in that said subject is at risk of developing Crvotosporidium oarvurn and the composition obtained is administered in a prophylactically effective amount. 16. The use according to claim 13, further characterized in that in the used compound X and Y are in the para position. 17. The use according to claim 13, further characterized in that in the compound used X and Y are each NR- -cf XNR-R. and in that said used compound of formula (I) is selected from the group consisting of compounds wherein (a) each R is H, Rs is H, Ra is H, RA is H, Ra is H and e is H; (b) R is H, Ra is H, Ra is H, A is H, two groups Ra together represent alkyl of Ca, and * is H; (c) is H, Ra is H, Ra is H, RA is H, two groups Rs together represent alkyl of Ca, and Re is H; (d) R is C ^ -d alkyl. , R is C -Ce alkyl, a is H, R is H, Ra is H and Re is H; (e) x is oxyalkyl, Ra is oxyalkyl, Ra is H, RA is H, two groups Ra together represent alkyl of Ca, and R is H; (f) R is H, Ra is oxyalkyl, Ra is H, RA is H, two groups Ra together represent alkyl of C2, and Re is H; (g) R is H, Ra is oxyarylalkyl, Ra is H, RA is H, two groups Ra together represent alkyl of Ca, and R * is H; (h) Rx is H, Rβ is H, Ra is H, RA is H, two groups Ra together represent alkyl of Ca, and Re is hydroxyalkyl; (i ") R is H, R2 is oxyarylalkyl, Ra is H, RA is H, two groups Ra together represent alkyl of Ca, and A is H; (j) R is H, Ra is H, Ra is H, RA is H, Ra is H, and? is aminoalkyl, (k) Rx is H, Ra is H, Ra is H, A is H, two groups Ra together represent alkyl of CA, and Re is H; (1) RX is H , Ra is H, Ra is H, A is H, two groups Ra together represent alkyl of CA, and R is H; () R is H, R2 is H, R3 is H, A is H, Rs is H and Rβ is alkylenine, (n) Rx is H, Ra is H, Ra is H, RA is H, Ra is H and R is hydroxyalkyl, (o) Rx is H, Ra is H, R3 is H, A is H, Ra is H and Re is alkylaminoalkyl, (p) R is H, Ra is C-Ce alkyl, Ra is H, RA is H, Ra is H and Re is Cx-Ce alkyl, "(q) Rx is H , a is H, Ra is H, RA is H, two groups Ra together represent alkyl of Ca, and * is alkyl of C? -Ce- 18. Use according to claim 13, further characterized in that said compound used of Formula (I) is selected from the group consisting of: 2,5-bis (4-guanyl phenyl) furan, 2,5-bis (4-gu anilphenyl) -3,4-dimethylfuran, 2,5-di-pC2 (3,4,5,6-tetrahydropyrimidyl) phenyl3-furan, 2,5-bieC4- (2-imidazolinyl) phenyl3furan, 2,5- [bis] . { 4- (2-tetrahydropyrimidinyl)} phenyl 3-p (tolyloxy) furan, 2,5-Cbis. { 4 ~ (2-imidazolinyl)} phenyl3-p (tolyloxy) furan, 2,5- [bis. { 4- [2- (N-2-hydroxyethyl) imidazole inyl-phenyl} furan, 2,5-bisC4- (2- (N-isopro-pilami ino) phenyl 3 furan, 2, 5-bis. { 4-C 2- (3- (dimet i laminopropy lo) -amidiono phenyl} furan, 2,5-bis. {4-C- (N-3-aminopropyl) amidino-3-phenyl} furan, 2 , 5-xylene-2-imidazolinyl) phenyl-3-3,4-bis (methoxy-rnethyl) -franne, 2,5-biet-4-N- (dimethylaminoethyl) guanyl-3-phenyl-2-yl, 2,5-bie. { 4-C (N-2-hydroxyethyl) guani 13 phenyl} furan, 2,5-bisC-N- (cyclo? ropilguanyl) phenyl 3 furan, 2,5-bisC 4- (N, N-diethylaminopropyl) g? anil 3 phenyl furan, 2,5-bis. { 4-C2- (N-ethylimidazoli-nyl) phenyl} Furan, 2,5-bie. { 4-CN- (3-pentylguanyl) amidino} phenyl-furan, 2,5-bieC4- (2-imidazolinyl) phenyl3-3-methoxyfuran, 2,5-bisC4- (N-isopropylamine) phenyl3-3-β-ethylfuran, and the pharmaceutically acceptable salts thereof. 19. A compound of formula (I): where: X and Y are located in the position for and each one is and in that said compounds of formula (I) are selected from the group consisting of compounds wherein (a) R is H, Ra is H or alkyl of C? _e, s is H, RA is H, Ra is H and R is isoalkyl; (b) R is H, R2 is H, Ra is H, RA is H, Ra is H and Re is C3_a alkoxyalkyl; (c) R is H, R2 is H or C ?e alkyl, Ra is H, A is H, Ra is H and Re is hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl or hydroxyhexyl; (d) Rx is H, a is H or C alquiloe alkyl, R a is H, RA is H, R a is H and R is propoxyethyl; (f) Rx is H, R2 is H or C alquiloe alkyl, Ra is H, RA is H, Ra is H and RA is propoxyisopropyl; (g) Rx is H, Ra is H or C?-e alkyl, a is H, A is H, Ra is H and Re is aryl or alkylaryl; and () Rx is H, R2 is H or alkyl of C_e, Ra is H, RA is H, Ra is H and Re is alkylcycloalkyl; and the pharmaceutically acceptable salts thereof. SUMMARY OF THE INVENTION The present invention provides methods of treating pneumonia by Pneufl-occvstis carinii. Giardia lamhl-A and CrvptosDoridiurn parvurn in a subject in need of such treatment; the methods comprise administering to said subject a compound of Formula (I): wherein: R and Ra are each independently selected from the group consisting of H, C -Ce alkyl, aryl, alkylaryl, aminoalkyl, aminoaryl, halogen, oxyalkyl, oxyaryl or oxyarylalkyl; Ra and R are each independently selected from the group consisting of H, Cx-Ce alkyl, oxyalkyl, alkylaryl, aryl, oxyaryl, aminoalkyl, aminoaryl or halogen; and X and Y are located in the p or meta positions and are selected from the group consisting of H, C? -Ce alkyl, oxyalkyl, and wherein: each Rs is independently selected from the group consisting of H, C? -Calkyl, alkoxyalkyl, hydroxyalkyl, arninoalkyl, alkylaminoalkyl, cycloalkyl, aryl or alkylaryl or two Ra groups together represent alkyl Ca-C? o, hydroxyalkyl or alkylene; and Re is H, hydroxy, C? -Ce alkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylamino, alkylaminoalkyl, cycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aryl or alkarylaryl; or a pharmaceutically acceptable salt thereof; The drugs are administered in an effective amount to treat the condition; pi also includes novel compounds useful in the treatment of pneumonia caused by Pneumocvstis carinii. as well as lambí a fíiardia and CrVP-QSP? rÍ < -Iímmt. parvmn. MG / 33 / lss * lmd * apm P97 / 479F