MXPA98002840A - Fluorous derivatives from adamant - Google Patents

Abstract

The present invention relates to fluoro-substituted adamantane derivatives of formula (I), and to pharmaceutically acceptable salts thereof, wherein R 1, R 2, R 3 and R 4 are as defined in the specification. The invention also relates to methods for treating neurological disorders, such as memory loss and Parkinson's disease, and bacterial and viral infections, by administering a therapeutically effective amount of a compound of formula I. The invention relates to a method of increasing the metabolic stability of a pharmaceutical compound containing adamantane by incorporating a fluoro substituent in at least one bridgehead of the adamantyl group of said adamanta containing pharmaceutical compound

Description

FLUOROUS-DERIVED DERIVATIVES OF ADAMANTANE BACKGROUND OF THE INVENTION The present invention relates to fluorosubstituted adamantane derivatives that are more metabolically stable than the corresponding adamantane derivatives that are not fluorosulfated. According to the present invention, to increase the metabolic stability of a pharmaceutical compound including an adamantane moiety, a fluorosubstituted adamantane moiety can be introduced into the pharmaceutically active compound in place of the non-fluorinated adamantane moiety. The fluoro-substituted adamantane derivatives of the present invention can also be used as pharmaceuticals for the treatment or prevention of memory loss or for the treatment of Parkinson's disease or viral infections. The addition of an adamantane moiety to the chemical structure of a pharmaceutical compound is a recognized method of increasing the absorption of the compound in the central nervous system of a patient [J. Pharmaceutical Sciences, 83, 481 (1994)]. Since this property may be beneficial for pharmaceutical compounds targeting the central nervous system, efforts have been made to modify existing drugs to include the adamantane functionality [Biochem. Pharmacol. 41 (4), R5-R8, (1991)]. Several pharmaceutical compounds containing adamantane have been developed, including the following: amantadine hydrochloride (antiviral agent, treatment of Parkinson's disease), tro antadine (antiviral agent), amantol (antifungal agent, antibacterial agent), adatanserin (anxiolytic agent), rimantadine (antiviral agent), memantine (agent to stimulate memory), somantadine (antiviral agent) and adapalene (agent against acne). The adamantane moiety is lipophilic, which facilitates the distribution in the tissues of a drug containing the rest, but the lipophilic nature of the adamantane group can also facilitate the metabolic degradation of the adamantane group by oxidation. In accordance with the present invention, it has been found that by fluorinating one or more of the bridge heads carbons of the adamantane group, the metabolic stability of the adamantane group is increased without affecting the lipophilic nature of the group.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to compounds of formula and pharmaceutically acceptable salts thereof, wherein: R1 is -NC (0) R5, -C (0) NR5, - (CR5R6) nNR5R6 or - (CR5R6) nC02R5, wherein n is a varying integer from 0 to 4, each of R2, R3 and R4 are independently selected from the group consisting of H, fluoro, C?-C4 alkyl and hydroxy, with the proviso that at least one of R "% R'3 and R4 is fluoro and each of R5 and R6 are independently H or C? -C alkyl, with the proviso that: (1) when R1 is -C02H, then R2 is fluoro and R3 and R4 are not H Y (2) when R1 is -NH2, then R2 is fluoro and R3 is not H. Specific embodiments of the compounds of formula I include those in which R1 is -C02H or -NH2. Other specific embodiments of the compounds of formula I include those in which each of R R3 and R4 are fluoro. Other specific embodiments include the following compounds: methyl 3-fluoro-5-hydroxydamantane-1-carboxylate, 3,5-difluoroadamantan-1-ylamine, 3,5-difluoro-7-hydroxy-amino-mantane-1-methyl carboxylate, , 5, 7-trifluoroadamantane-1-carboxylic acid and 3, 5, 7-trifluoroadamantan-1-ylamine, and the pharmaceutically acceptable salts of the aforementioned compounds.

The invention also relates to a pharmaceutical composition for treating or preventing a neurological disorder, such as memory loss or Parkinson's disease, or a bacterial or viral infection in a mammal, in particular in a human being, comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The invention also relates to a method of treating or preventing a neurological disorder, such as memory loss or Parkinson's disease, or a bacterial or viral infection in a mammal, in particular in a human being, which comprises administering to said mammal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt of the same. The present invention also relates to a method of increasing the metabolic stability of a pharmaceutically active compound of adamantane, which comprises including a fluoro substituent on at least one bridgehead of the adamantyl group of said adamantane compound. In the aforementioned process, the bridge heads are carbons 1, 3, 5 and 7 of the adamantyl group. As used herein, the term "pharmaceutically active compound of adamantane" includes, unless otherwise indicated, any pharmaceutically active compound having an adamantane moiety as part of its structure and pharmaceutically acceptable salts thereof. The term "pharmaceutically active compound of adamantane" also includes pharmaceutically active compounds that form a salt with an adamantane derivative, such as the amantadine salt of N-acetyl-DL-phenylalanine. Examples of pharmaceutically active compounds of adamantane include the following: amantadine, adatanserin, tromantadine, amantaninium bromide, rimantadine, memantine, somantadine, adapalene, N-1-adamanty1-N'-cyclohexyl-4-morpholinocarboxamidine, dopamantine, adaprolol maleate, (-) -N- [2- (8-methyl-1,4-benzodioxan-2-ylmethyl-amino) ethyl] adamantane-1-carboxamide, N- (1-adamantyl) -N ', N'-. { 1, 5- [3- (4 (5) -lH-imidazolylpentanediyl)]} idina form, adamantoyl-Lys-Pro-Tyr-Ile-Leu, 1- (2-pyridyl) -4- [l-methyl-2- (1-adamantylamino-) ethyl] piperazine, adafenoxate, (IR, 3S) - 3- (1-adamantyl) -1-aminomethyl-3, 4-dihydro-5,6-dihydroxy-1H-2-benzopyran, adamantylamide L-Ala-L-isoGlu, 2-adamantylaminobenzoic acid, N (a) - (1-adamantanesulfonyl) -N- (4-carboxybenzoyl) -L-lysylalanyl-L-valine, 4-acylamino-l-azaadamantane, L-leucyl-D-methionylglucyl-N- (2-adamantyl) -L-phenylalanylamide, Tyr- (D) -Met-Gly-Phe-adamantane, 1-N- (p-bromobenzoyl) methylanedylamine, 4-butyl-l, 2-dihydro-5- [(1-adamantanecarbonyl) oxy] -1, 2- diphenyl-3H-pyrazol-3-one, N (a) - (1-adamantanesulfonyl) -N (e) -succinyl-L-lysyl-L-propyl-L-valine and the amantadine salt of N-acetyl-DL -phenylalanine.

The aforementioned pharmaceutically active compounds of adamantane find utility as antifungal agents, antiviral and antibacterial agents, membrane permeability stimulants, anxiolytic agents, antidepressants, memory stimulators, anti-acne agents, anti-inflammatory agents, analgesics, antihistamines, antihypertensives. , agents against glaucoma and antiarrhythmic agents. The aforementioned adamantane compounds can also find utility in the treatment of Parkinson's disease, psoriasis and emphysema. As used herein, the term "alkyl" includes, unless otherwise indicated, monovalent saturated hydrocarbon radicals having straight, cyclic or branched moieties, or combinations thereof. It is understood that, in said alkyl group, at least three carbon atoms are required for the cyclic moieties. As used herein, the phrase "pharmaceutically acceptable salt (s)" includes, unless otherwise indicated, salts of acidic or basic groups which may be present in the compounds of formula I. The compounds of formula I which are basic in nature can form a wide variety of salts with various inorganic and organic acids. Acids which can be used to prepare pharmaceutically acceptable salts, by the addition of acids, of such basic compounds of formula I are those which form non-toxic salts by addition of acids, that is, salts containing pharmacologically acceptable anions, such as hydrochloride salts , hydrobromide, hydroiodide, nitrate, sulfate, 1-bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate , formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [ie, 1,1 t-methylene-bis (2-hydroxy-3-naphthoate)]. The compounds of formula I which include an amino moiety can form pharmaceutically acceptable salts with various amino acids, in addition to the salts with aforementioned acids. The compounds of formula I which are acidic in nature can form salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline earth metal salts and, particularly, the calcium, magnesium, sodium and potassium salts of the compounds of formula I. Certain compounds of formula I may have asymmetric centers and, therefore, they can exist in different enantiomeric and diastereomeric forms. This invention relates to the use of all isomers and stereoisomers of the compounds of formula I and to mixtures thereof and to all pharmaceutical compositions, methods of treatment and methods of increasing the metabolic stability of the pharmaceutical compounds containing adamantane, defined above, who can use them or contain them. The present invention includes the compounds of formula I and pharmaceutically acceptable salts thereof, wherein one or more hydrogens, carbons or other atoms are replaced by isotopes thereof. Such compounds may be useful as research and diagnostic tools in pharmacokinetic studies of metabolism and in binding assays.

DETAILED DESCRIPTION OF THE INVENTION The preparation of the compounds of the present invention is illustrated in the following scheme. Unless otherwise indicated, in the reaction scheme and in the discussion that follows, R1, R2, R3 and R4 are as defined above.

SCHEME The compounds of the present invention are prepared easily. In the scheme indicated above, the starting compound of formula II can be prepared according to procedures known to those skilled in the art. Such procedures are found in several patents published or granted, including U.S. Patents 2,937,211 (issued May 17, 1960) and 3,352,912 (issued November 14, 1967) and United Kingdom Patent 1,069,563 (published May 17, 1967). ). The alcohol of formula II can be converted to the corresponding fluorosubstituted compound of formula III by first treating the compound of formula II with diethylaminosulfur trifluoride (DAST) in a solvent such as dichloromethane, at a temperature ranging from room temperature (20-25 ° C). C) to reflux, to provide the corresponding fluorosubstituted ester. The fluorosubstituted ester can be converted to the acid of formula III by hydrolyzing the ester according to procedures known to those skilled in the art, such as by base catalyzed hydrolysis. The acid of formula III can be converted to the corresponding amine of formula IV by first treating the acid of formula III with triethylamine, diphenylphosphoryl azide and benzyl alcohol and refluxing the reaction mixture, to provide the corresponding intermediate benzyl carbamate which can be converted into the amine of formula IV catalytically hydrogenating the intermediate benzyl carbamate. The amine of formula IV includes a single fluoro group on a bridgehead carbon of the adamantane group. To add a second fluoro group to another bridgehead carbon of the adamantane group, the acid of formula III (wherein R ° is H) can be converted to the compound of formula V. In step 3 of the scheme, the acid of Formula III can be hydroxylated by treating the compound of formula III with potassium hydroxide and potassium permanganate. The resulting compound can then be treated with an aqueous solution containing tetrabutylammonium hydrogensulfate and sodium bicarbonate to provide the salt of the acid moiety, followed by treatment with methyl iodide to provide the ester of formula V. The ester of formula V can be converted in the acid of formula VI according to the procedure described above for step 1 of the scheme. The acid of formula VI can be converted to the amine of formula VII according to the procedure described above for step 2 of the scheme. To add a third fluoro group to a bridgehead carbon of the adamantane moiety, the acid of formula VI (wherein R 4 is H) can be hydroxylated and esterified as described above for step 3 of the scheme. Then, the ester of formula VIII can be converted to the corresponding fluorosubstituted acid of formula IX as described above for step 1 of the scheme. The acid of formula IX can be converted into the corresponding amine of formula X as described above for step 2 of the scheme.

The compounds cited as examples in the above scheme can be converted to other compounds of formula I or they can be introduced into a pharmaceutical compound containing adamantane to replace a non-fluorinated adamantane group, according to various methods known to those skilled in the art. In particular, the acid moiety of the acids of formulas III, VI and IX can be esterified according to procedures known to those skilled in the art. The amino moiety of the amines of formulas IV, VII and X can be acylated or alkylated to provide secondary and tertiary amines and amides. Methods of modifying the compounds of formula I and the compounds specifically set forth in the above scheme are found in several patents granted, including U.S. Patents 2,937,211 and 3,352,912 and U.S. Patent 1,069,563, all of which referenced above, as well as the following United States patents: 3,391,142 (granted July 2, 1968), 3,152,180 (granted October 6, 1964), 3,705,194 (granted December 5, 1972). ), 4,288,609 (granted on September 8, 1981), 4,476,319 (granted on October 9, 1984), 4,514,332 (granted on April 30, 1985), 4,578,382 (granted on March 25) of 1986), 4,623,639 (granted on November 18, 1986), 4,661,512 (granted on April 28, 1987), 4,717,720 (granted on January 5, 1988), 4,829,086 (granted on 9 May 1989), 5,098,895 (granted on March 24, 1992), 5,212,303 (granted May 18, 1993), 5,480,905 on January 2, 1996), 5,482,940 (granted on January 9, 1996) and 5,599,998 (granted on February 4, 1997). The compounds of the present invention can have asymmetric carbon atoms and, therefore, can exist in different enantiomeric and diastereomeric forms. The diastereomeric mixtures can be separated into their individual diastereomers based on differences in their physical properties by methods known to those skilled in the art, for example, by chromatography or fractional crystallization. The enantiomers can be separated by converting the enantiomer mixtures into a diastereomeric mixture by reaction with an appropriate optically active compound (eg, an alcohol), separating the diastereomers and converting (for example, hydrolyzing) the individual diastereomers in the corresponding pure enantiomers. All these isomers, including mixtures of diastereomers and pure enantiomers, are considered part of the present invention. The compounds of formula I which are basic in nature can form a wide variety of different salts with various inorganic and organic acids, including amino acids. Although such salts must be pharmaceutically acceptable for administration to mammals, in practice it is sometimes desirable to initially isolate the compound of formula I in the form of a pharmaceutically acceptable salt from the reaction mixture, then simply convert the latter into the compound in free base form by treatment with an alkaline reagent and subsequently converting the latter free base into a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of the invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid, in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. By careful evaporation of the solvent, the desired solid salt is easily obtained. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding an appropriate mineral or organic acid to the solution. The compounds of formula I which are acidic in nature can form salts by addition of bases with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline earth metal salts and particularly the sodium and potassium salts. All these salts are prepared by conventional techniques. The chemical bases which are used as reactants for preparing the pharmaceutically acceptable salts by addition of bases of this invention are those which form non-toxic salts by addition of bases with the acidic compounds of formula I.

Such non-toxic salts by addition of bases include those derived from pharmacologically acceptable cations, such as sodium, potassium, calcium, magnesium, various amine cations, etc. These salts can be easily prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they can also be prepared by mixing solutions in lower alkanols of the acidic compounds and the desired alkali metal alkoxide and then evaporating the resulting solution to dryness in the same manner as above. In all cases, stoichiometric amounts are preferably employed to ensure that the reaction is complete and that maximum yields of the desired final product are obtained. Like pharmaceutical compounds containing non-fluorinated adamantane, structurally related to the compounds of formula I, the compounds of formula I and the pharmaceutically acceptable salts thereof can be used to treat or prevent neurological disorders, such as memory and disease loss. of Parkinson's, as well as bacterial and viral infections in a mammal, in particular, in a human being. It is well known that pharmaceutical compounds containing non-fluorinated adamantane, related to the compounds of formula I, include amantadine (1-aminoadamantane), somantadine [1- (2-amino-2-methyl) propyladamantane] and rimantadine [1-amino] - (1-adamantane) ethane], each of which is useful as an antiviral agent, as well as memantine (3, 5-dimethyl-l-adamantanoamine), which is also useful for the treatment of memory loss and disease of Parkinson. The activity of the compounds of formula I and the pharmaceutically acceptable salts thereof in the treatment or prevention of a neurological disorder, such as memory loss or Parkinson's disease, can be evaluated according to one or more of the indicated tests. in U.S. Patent 4,476,319 referenced above. The activity of the compounds of formula I and the pharmaceutically acceptable salts thereof in the treatment of bacterial or viral infections can be evaluated according to one or more of the tests indicated in the aforementioned US Pat. No. 3,705,194. . The compounds of formula I and the pharmaceutically acceptable salts thereof (hereinafter "the active compounds") can be administered orally, parenterally, topically or rectally. In general, these compounds are most desirably administered in doses ranging from about 1 to about 300 mg per day, in a single dose or in divided doses (ie, from 1 to 4 doses per day), although there may be necessary variations depending on the species, weight and condition of the patient to be treated and the particular route of administration chosen. However, a dose level that is in the range of about 0.1 mg to about 30 mg per kg of body weight and per day is most desirably employed. However, there may be variations depending on the species of animal to be treated and its individual response to said medication, as well as the type of pharmaceutical formulation chosen and the period of time and interval in which said administration is performed. In some cases, dose levels below the lower limit of the aforementioned range may be more than adequate, while in other cases even higher doses may be employed without causing harmful side effects, provided that said higher doses are divided into several small doses for administration throughout the day. The active compounds can be administered alone or in combination with pharmaceutically acceptable carriers or diluents, by the routes indicated above, and said administration can be carried out in a single dose or in divided doses. More particularly, the active compounds can be administered in a wide variety of different dosage forms, that is, they can be combined with various inert, pharmaceutically acceptable carriers, in the form of tablets, capsules, lozenges, tablets, hard candies, powders, sprays, creams , ointments, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups and similar compositions. Such vehicles include solid diluents or fillers, sterile aqueous media, various non-toxic organic solvents, etc. In addition, oral pharmaceutical compositions can be sweetened and / or flavored appropriately. In general, the active compounds are present in said dosage forms at concentration levels ranging from about 5.0% to about 70% by weight. For oral administration, tablets containing various excipients may be used, such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine, together with various disintegrants, such as starch (and preferably corn starch, potato or tapioca), alginic acid and certain complex silicates, together with granulation binders, such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, for the formation of the tablets, lubricating agents, such as magnesium stearate, sodium lauryl sulfate and talcum are sometimes very useful. Solid compositions of a similar type can also be employed as fillers in gelatin capsules; Preferred materials in this regard also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the active compound can be combined with various sweetening or flavoring agents, coloring matter or dyes and, if desired, also with emulsifying and / or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerol and various similar combinations thereof. For parenteral administration, solutions of an active compound in sesame or peanut oil or in aqueous propylene glycol can be employed. The aqueous solutions must be suitably buffered (preferably at a pH above 8) and first, if necessary, the liquid diluent should be made isotonic. These aqueous solutions are suitable for intravenous injections. Oily solutions are suitable for intra-articular, intramuscular and subcutaneous injections. The preparation of all these solutions under sterile conditions is easily accomplished by standard pharmaceutical techniques well known to those skilled in the art. Additionally, it is also possible to administer topically the active compounds of the present invention and this can be done by means of creams, jellies, gels, pastes, patches, ointments and similar compositions, in accordance with standard pharmaceutical practice. The metabolic stability of the active compounds can be evaluated according to the following procedure. A standard microsomal incubation is prepared to evaluate the rate of metabolism of the active compound in liver microsomes. The microsomal incubation condition comprises buffer of 100 mM potassium phosphate (pH 7.4), 10 mM MgCl2, 0.5 mM NADP + (nicotinamide adenine dinucleotide phosphate), 4 mM glucose-6-phosphate, glucose-e-phosphate dehydrogenase 10 units / ml, 0.2 μM microsomal cytochrome P450 and 10 μM active compound. The incubation is started by adding substrate to the reaction mixture that has been preincubated for about 3 minutes at 37 ° C. An aliquot is removed at 0, 1, 2, 5, 10 and 20 minutes and added to an equal volume of methanol to cut off the reaction. The precipitate is separated from the samples by centrifugation and the supernatants are stored at -20 ° C. Samples are analyzed by standard LC / MS to determine the amount of active compound that has been metabolically degraded.

PICTURE The compounds illustrated in the chemical formula provided by the above table were prepared as described in PCT patent application WO 95/29909, published on November 9, 1995, entitled "New cyclic and acyclic amides as stimulants of neurotransmitter release. " The compounds illustrated above are pharmaceutically active compounds that stimulate the release of neurotransmitters such as acetylcholine, dopamine and serotonin and, therefore, are useful for treating Alzheimer's disease, memory impairment associated with age, Parkinson's disease. and other disorders of the central nervous system in mammals, in particular in humans. The metabolic stability of the above compounds was evaluated according to the procedure described above. The above table provides the metabolic stability of the above compounds in the column labeled "% loss", which indicates the amount of compound that was metabolically degraded after 10 minutes in a standard microsomal incubation condition prepared as described above. As the table illustrates, the compounds in which the adamantane moiety is fluorinated, in particular the trifluorinated species, are more metabolically stable than the corresponding compound in which the adamantans moiety is not fluorinated. The examples given below illustrate specific embodiments of the invention. It should be understood that the invention is not limited to the specific details of these examples.

EXAMPLE 1 Fluoroacyanatan-1-carboxylic acid Under a nitrogen atmosphere, 26.17 ml (0.20 moles) of diethylaminosulfur trifluoride (DAST) were added to 24 ml of dry dichloromethane which had been cooled to -78 ° C. To this solution was added dropwise a solution in dichloromethane (10 ml) of methyl 3-hydroxydamantane-l-carboxylate (42.0 g, 0.20 mol). The solution was warmed to room temperature and stirred for 1 hour. To the resulting solution was added water (500 ml). The organic layer was separated, washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give 41.6 g (98%) of crude product, m.p. < 34 ° C, which crystallized slowly. NMR ^ H (CDC13): 1.70-1.80 (6H, m), 2.20-2.35 (3H,), 2.50-2.60 (6H,), 7.00-7, 70 (5H, m). 13 C-NMR (CDC13): 30.84 (10.11), 34.79 (0.91), 37.56, 41.81 (17.73), 43.70 (20.15), 44.86 (10.16), 51.86, 92.13 (184.14). Under a nitrogen atmosphere, 100 ml of methanol, 75 ml of tetrahydrofuran (THF) and 50 ml of water were added to the crude ester (41.6 g, 0.196 mol), followed by 16.0 g (0.40 mol) of water. NaOH in lentils. The solution was stirred overnight. The organic layer was separated under reduced pressure, water (200 ml) was added and the solution was acidified to a pH of 1.0 with 6? HCl. The resulting solids were filtered, washed with water and dried to give 37.0 g (95%) of 3-fluoroadamantane-1-carboxylic acid (mp 154-156 ° C). An analytical sample of the title compound was obtained after recrystallization from EtOAc / hexane. The crystals from the recrystallization were suitable for X-ray analysis. Analysis calculated for C 11 H 15 O 2 F: C 66.65; H 7.63; F 9.58. Found: C 66.44; H 7.72; F 9.22.

EXAMPLE 2 3-Fluoroadamantan-l-ilamine Under a nitrogen atmosphere 7.65 g (38.6 millimoles) of 3-fluoroadamantane-1-carboxylic acid were added to 150 ml of dry benzene. To this solution were added 5.37 ml (38.8 millimoles) of triethylamine (TEA), followed by 8.31 ml (38.8 millimoles) of diphenylphosphorylazide. The reaction mixture was heated to reflux for 45 minutes and then cooled to room temperature, at which point 5.37 ml (38.8 mmol) of benzyl alcohol was added. The mixture resulting from the reaction was refluxed for 72 hours. The crude reaction mixture was cooled, concentrated in vacuo and chromatographed on silica gel using hexane: EtOAc 4: 1., giving 9.3 g (79%) of benzylcarbamate of 3-fluoroadamantan-1-ylamine. NMR- ^? (CDCl 3): 1.53 (2H, m), 1.75-1.95 (8H, m), 2.10 (2H, m), 2.33 (2H, broad s), 4.76 (1H). , s wide), 5.03 (2H, broad s), 7.33 (5H, m). 13 C-NMR (CDC13): 30.80 (10.19), 34.52 (1.81), 40.25, 41.48 (17.74), 46.57 (18.79), 53.80 (12.23), 66.07, 92.30 (184.30), 127.99, 128.43, 136.47, 154.14. The benzyl carbamate was dissolved in 100 ml of HOAc, combined with 2 g of 10% Pd / C and hydrogenated (345 kPa) over a period of 5 hours. The crude mixture of the reaction was filtered, the catalyst was washed with HOAc and the filtrate was concentrated in vacuo, giving 7.4 g (>100%) of the crude title compound in the form of its acetate salt.

EXAMPLE 3 3-Fluoro-5-hydroxiadaman ano-l-carboxylate methyl To an aqueous solution (400 ml) containing potassium hydroxide (13.0 g, 0.20 mol) was added 34.76 g (0.22 mol) of potassium permanganate and the solution was heated in a steam bath (at approximately 50 ° C). To this solution, 39.8 g (0.20 mol) of 3-fluoroadamantane-1-carboxylic acid were added in one portion. After the addition was complete, the reaction mixture was heated to a gentle reflux and stirred until all the potassium permanganate was consumed (approximately 1.5 hours). Then the reaction mixture was cooled and acidified with 6N HCl. Sodium bisulfite was added to remove Mn02 and the white suspension was filtered and washed with water, giving recovered starting material (19.0 g). The aqueous filtrate was saturated with NaCl and extracted with EtOAc: MeOH 95: 5 (4x350 ml). The organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo, giving 18.3 g (43%; 81% based on 3-fluoroadamantane-1-carboxylic acid recovered) of 3-fluoro-5-hydroxiadamantane-1-carboxylic acid. To an aqueous solution (250 ml) containing tetrabutylammonium hydrogensulfate (42 g, 0.124 mol) was added potassium bicarbonate (41.0 g, 0.496 mol) in one portion. The solution was stirred for 20 minutes, at which time 26.5 g (0.124 mole) of 3-fluoro-5-hydroxiadamantane-1-carboxylic acid were added portionwise. The reaction mixture was stirred for 30 minutes, concentrated in vacuo to give a viscous oil which was dissolved in acetone (300 ml), mixed with methyl iodide (40 ml) and stirred for 48 hours. The crude mixture of the reaction was filtered, concentrated in vacuo and triturated with Et20 to remove tetrabutylammonium iodide and the crude filtrate was concentrated in vacuo to give 31 g of crude ester which was chromatographed on 800 g of silica gel using hexane: ethyl acetate 2: 1, giving 23.5 g (83%) of the title compound. P.f. 51.5-52, 6 ° C. RMN-1 !! (CDC13): 1.60-1.70 (4H, m), 1.75-1.82 (4H, m), 1.88-1.92 (3H, m), 1.94-1.98 (2H, m), 2.42-2.50 (HH, m), 3.67 (3H, s). 13 C-NMR (CDCl 3): 30.52 (10.33), 36.36, 40.35, 42.60 (20.38), 45.16, 45.42 (10.18), 49.44 ( 17.36), 51.94, 70.62, (12.53), 92.71 (186.33), 175.04. Analysis calculated for C? 2H? 703F: C 63.14; H 7.51; F 8.32. Found: C 63.25; H 7.38; F 8.52.

EXAMPLE 4 3,5-difluoroadamantane-1-carboxylic acid Under a nitrogen atmosphere 22.8 g (100 mil-imols) of methyl 3-fluoro-5-hydroxydamantane-1-carboxylate were added to 400 ml of dry chloroform and the resulting solution was cooled to -50 ° C. To this solution, 13.1 ml (100 millimoles) of DAST was added dropwise. The suspension was heated to room temperature and then heated to reflux for 1.5 hours. The resulting solution was cooled and treated with water (400 ml). The organic layer was separated and the aqueous layer was washed again with chloroform (50 ml). The organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give 23.2 g of crude product. Under a nitrogen atmosphere, 22.0 g (95.6 millimoles) of 3,5-difluoroadamantane-1-methyl carboxylate generated in this step were added to 75 ml of methanol, 50 ml of THF and 250 ml of water, followed by of 8.0 g (200 millimoles) of NaOH in lentils. The solution was stirred overnight. The aqueous solution was extracted with ethyl acetate. The aqueous layer was acidified with 1N HCl to a pH of 1.0 and the resulting solution was extracted with ethyl acetate (200 ml) and this organic extract was washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give 19.8 g (96%) of 3,5-difluoroadamantane-l-carboxylic acid. An analytical sample of this compound was obtained after recrystallization from EtOAc / hexane. P.f. 162-164 ° C. 13 C-NMR (DMSO) 30.16, 35.67, 39.55, 42.09, 44.92, 46.92, 93.29. The crystals of the recrystallization were suitable for X-ray analysis. Analysis calculated for CnH? 402F2: C 61.10; H 6.53; F 17.57. Found: C 61.00; H, 6.57; F 17.32.

EXAMPLE 5 3,5-Difluoroadamantan-l-ilamine The procedure of Example 2 was used for the conversion of 3-fluoroadamantane-1-carboxylic acid to 3-fluoroadamantan-1-ylamine. 4.32 g (20 millimoles) of 3,5-difluoroadamantane-1-carboxylic acid gave, after 96 hours, a crude product which was chromatographed on silica gel using hexane: EtOAc 4: 1, giving 4.7 g ( 73%) of benzyl carbamate. P.f. 71.9-72.9 ° C. RMN-1 !! (CDC13) 1.80-1.90 (7H, m), 2.02-2.25 (6H, m), 2.40-2.50 (IN, m), 4.84 (1H, broad s) ), 5.04 (2H, broad s), 7.30-7.40 (5H, m). 13 C-NMR (CDCl 3) 29.07, 38.98, 40.15, 45.54, 47.16, 54.25, 66.37, 92.24 (188.67), 128.09, 128.17 , 128.52, 128.56, 136.26, 154.18.

Analysis calculated for C? 8H2? N02F2: C 67.27; H 6.59; N 4.36; F 11.82.

Found: C 66.96; H 6.54; N 4.33; F 11.71. Hydrogenation (HOAc / Pd / C / 345 kPa) of 7.84 g (24.4 mmol) of this intermediate over a period of 5 hours gave 7.8 g (> 100%) of 3,5-difluoroadamantan-1- ilamine in the form of its acetate salt.

EXAMPLE 6 3,5-Difluoro-7-hydroxydamantane-1-methyl carboxylate The procedure used for the conversion of 3-fluoroadamantane-1-carboxylic acid to methyl 3-fluoro-5-hydroxydamantane-1-carboxylate, described above, was modified. The treatment of 3,5-difluoroadamantane-1-carboxylic acid (19.8 g, 91.6 millimoles) with 17.37 (110 millimoles) of potassium permanganate and 5.95 g of potassium hydroxide in 200 ml of water was given, after 18 hours of reflux and normal work-up (extraction with ethyl acetate), 18.9 g of white solids containing 3, 5-difluoro-7-hydroxydiamantane-1-carboxylic acid and starting acid. Esterification of this mixture using tetrabutylammonium hydrogensulfate (30.51 g, 0.090 mole), sodium bicarbonate (30.24 g, 0.36 mole) and methyl iodide (30 ml), as described above, gave 9, 7 g of 3,5-difluoroadamantane-l-carboxylic acid in the form of its methyl ester and 9.22 g of 3,5-difluoro-7-hydroxydamantane-1-methyl carboxylate (title compound).

P.f. 99.5-101 ° C. 13 C-NMR (CDC13) 41.97, 43.92, 44.58, 46.46, 48.65, 52.69, 70.86, 92.28 (192.37). Analysis calculated for C? 2H? 603F2: C 58.53; H 6.55; F 15.43. Found: C 58.51; H 6.51; F 15.17.

EXAMPLE 7 3, 5, 7-trifluoroadamantane-1-carboxylic acid The procedure for the conversion of methyl 3-fluoro-5-hydroxydamantane-1-carboxylate into 3,5-difluoroadamantane-1-carboxylic acid was modified. The treatment of methyl 3,5-difluoro-7-hydroxydamantane-1-carboxylate (8.5 g, 34.5 mmol) with DAST (4.5 ml, 34.5 mmol) gave, after 8 hours of reflux and a standard processing, a crude product which was purified on silica gel (hexane: EtOAc 2: 1) to give 5.02 g of 3,5,7-trifluoro-adamantane-1-methyl carboxylate. P.f. 108.5-110 ° C. RMN-1 !! (CDC13) 1.95-2.22 (12H, m), 3.72, (3H, s). 13 C-NMR (CDCl 3) 41.80, 43.06, 46.23, 52.44, 81.57 (191.16), 173.20. Analysis calculated for Ci2H? 502F3: C, 58.06; H 6.09; F 22.96. Found: C 58.37; H 6.13; F 22.89. The product was saponified giving, after normal processing, 4.43 g (55%) of 3,5,7-trifluoroadamantane-1-carboxylic acid as a white solid. P.f. 198-199 ° C. NMR-XH (CDC13) 1.90-2.25. 13 C-NMR (CDC13) 41.54, 43.03, 46.21, 91.49 (191.61), 179.35. An analytical sample of this compound was obtained after recrystallization from EtOAc / hexane. By slow evaporation in EtOAc / hexane, crystals suitable for X-ray analysis were obtained. Analysis calculated for C 11 H 13 O 2 F 3: C 56.41; H, 5.59; F 24.33. Found: C 56.23, H 5.42; F 24.10.

EXAMPLE 8 3,5,7-Trifluoroadamantan-1-ylamine The procedure used for the conversion of 3-fluoroadamantane-1-carboxylic acid into 3-fluoroadamantan-1-ylamine, described above in Example 2, was used. 4.00 g (17.1 mmol) of acid 3, 5, 7-trifluoroadamantane-1-carboxylic acid gave, after 18 hours, a crude product which was chromatographed on silica gel using hexane: EtOAc 4: 1, giving 4.12 g (71%) of benzylcarbamate. P.f. 91.5-92.0 ° C. MN ^ H (CDC13) d * 2.02-2.23 (2H, m), 2.33 (2H, broad s), 4.76 (1H, broad s), 5.03 (2H, * s width), 7.33 (5H, m). 13 C-NMR (CDC13) 44.68, 46.29, 52.09, 90.69 (189.96). Analysis calculated for Ci8H2oN02F3: C 63.71; H 5.94; N, 4.13; F 16.79. Found: C 63.80; H, 5.88; N, 4.15; F 16,68. The hydrogenation (HOAc / Pd / C / 345 kPa) of 3.8 g (11.2 mmol) of this intermediate over a period of 5 hours gave 4.5 g (> 100%) of 3.5.7- trifluoroadamantan-1-ylamine in the form of its acetate salt.

Claims (10)

NOVELTY OF THE INVENTION CLAIMS

1. A compound of formula or a pharmaceutically acceptable salt thereof, wherein: R1 is -NC (0) R5, -C (0) NR5, - (CR5R6) "NR5R6 or - (CR5R6) nC02R5, wherein n is an integer which ranges from 0 to 4, each of R2, R3 and R4 are independently selected from the group consisting of H, fluoro, C?-C4 alkyl and hydroxy, with the proviso that at least one of R2, R3 and R4 is fluoro , and each of R5 and R6 are independently H or C? -C alkyl; with the proviso that: (1) when R1 is -C02H, then R2 is fluoro and R3 and R4 are not H, and (2) when R1 is -NH2, then R2 is fluoro and R3 is not H.

2. The compound according to claim 1, wherein R1 is -C02H or -NH2

3. The compound according to claim 1, wherein each of R2, R3 and R4 are fluoro.

4. The compound according to claim 1, selected from the group consisting of: methyl 5-fluoro-5-hydroxiadamantane-l-carboxylate, 3,5-difluoroadamantan-1-ylamine, 3,5-difluoro-7- hydroxydamantane-1-methyl carboxylate, 3,5,7,7-trifluoroadamantane-1-carboxylic acid and 3, 5, 7-trifluoroadamantan-1-ylamine, and the pharmaceutically acceptable salts of the aforementioned compounds. *

5. A pharmaceutical composition for treating or preventing a neurological disorder or a bacterial or viral infection in a mammal, comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.

6. The pharmaceutical composition according to claim 5, wherein said neurological disorder is memory loss or Parkinson's disease. The use of the compound of claim 1 or a pharmaceutically acceptable salt thereof for preparing a composition for treating or preventing a neurological disorder or a bacterial or viral infection in a mammal, comprising administering to said mammal. 8. The use according to claim 7, wherein said neurological disorder is memory loss or Parkinson's disease. 9. A method of increasing the metabolic stability of a pharmaceutically active compound of adamantane, which comprises including a fluoro substituent in at least one bridgehead of the admantyl group of said adamantane compound. The method according to claim 9, wherein said pharmaceutically active compound of adamantane is selected from the group consisting of amantadine, adatanserin, tromantadine, amantannium bromide, rimantadine, memantine, somantadine, adapalene, Nl-adamantyl-N '-cyclohexyl-4-morpholinocarboxamidine, dopamantine, adaprolol maleate, (-) - N- [2- (8-methyl-1, 4-benzodioxan-2-ylmethylamino) ethyl] adamantane-1-carboxy ida, N- ( 1-adamantyl) -Nf, N'-. { 1, 5- [3- (4 (5) -1H-imidazolylpentanediyl)]} formamidine, adamantoyl-Lys-Pro-Tyr-Ile-Leu, 1- (2-pyridyl) -4- [l-methyl-2- (1-adamantylamino) ethyl] piperazine, adafenoxate, (IR, 3S) -3- (1 '-adminyl) -l-aminomethyl-3, 4-dihydro-5,6-dihydroxy-lH-2-benzopyran, adamantylamide L-Ala-L-isoGlu, 2-adamantylaminobenzoic acid, N (a) ~ (1 -adamantanesulfonyl) -N- (4-carboxybenzoyl) -L-lysylalanyl-L-valine, 4-acyl-l-azaadamantane, L-leucyl-D-methionylglucyl-N- (2-adamantyl) -L-phenylalanylamide, Tyr- (D) -Met-Gly-Phe-adamantane, 1-N- (p-bromobenzoyl) methylanedylamine, 4-butyl-l, 2-dihydro-5- [(1-adamantanecarbonyl) oxy] -1,2-diphenyl-3H-pyrazol-3-one, N (a) - (1-adamantanesulfonyl) -N (e) -succinyl-L-lysyl-L-prolyl-L-valine and the amantadine salt of N-acetyl-DL-phenylalanine.