MXPA01009094A - Imidazole compounds substituted with a six or seven membered heterocyclic ring containing two nitrogen atoms - Google Patents

Abstract

This invention discloses novel imidazoles substituted with a six or seven membered heterocyclic ring which contains two nitrogen atoms as part of the heterocyclic ring structure. These compounds have excellent histamine-H3 receptor antagonist activity. Also disclosed are methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising such imidazoles as well as methods of using them to treat allergy (for example asthma), inflammation, hypertension, raised intraocular pressure (such as glaucoma) - i.e., a method of lowering intraocular pressure, sleeping disorders, states of hyper and hypomotility and acidic secretion of the gastrointestinal tract, hypo and hyperactivity of the central nervous system (for example, agitation and depression) and other CNS disorders (such as Alzheimer's Disease, schizophrenia, and migraine).

Description

COMPOSITES OF IMIDAZOL REPLACED WITH A HETEROCICLIC RING OF SIX OR SEVEN MEMBERS THAT CONTAINS TWO ATOMS OF NITROGEN FIELD OF THE INVENTION The present invention relates to cyclic amine compounds C- or N- (imidazolylalkyl) substituted with valuable pharmacological properties, especially activities in the central nervous system ("CNS") and activity against inflammatory diseases and allergic disorders. The compounds of the present invention are agonists or antagonists of the histamine H3 receptor.

BACKGROUND OF THE INVENTION The H3 receptor sites are known and currently attract interest among those skilled in the art as a therapeutic target. U.S. Patent No. 4,767,778 (Arrang et al.) Discloses certain imidazoles that behave as agonists of the H3 receptors in the brain of the rat. European Patent Application No. 0 420 396 A2 (Smith Kline &French Laboratories Limited) and Howson et al., (Bioorg. & Med. Chem. Letters, (1992), Vol. 2, No. 1, p. 77-78) describe imidazole derivatives having an amidine group as H3 agonists. Van der Groot et al (Eur. J.

Med. Chem. (1992) Vol. 27, p. 511-517) describe isothiourea analogs of histamine as potent histamine H3 receptor agonists or antagonists, and these histamine isothiourea analogues partially overlap those of the histamine analogues. two references cited above. Clapham et al., ["Ability of Histamine-H3 Antagonist Receptor to Improve Cognition and to Increase Acetylcholine Relay in vivo in the Rat", British Assn. for Psychopharmacology, July 25-28 (1993), unveiled in J. Psychopharmacol. (Abstr. Book), A17] describe the ability of histamine H3 receptor antagonists to improve cognition and increase the in vivo release of acetylcholine in the rat. Clapham et al., ["Ability of the selective Histamine-H3 Antagonist Receptor Thioperamide to Improve Short-term Memory and Reversal Learning in the Rat", Brit. J. Pharm. Suppl. 1993, 110, Abstract 65P] present results that demonstrate that thioperamide can improve short-term memory and retro-learning in the rat and suggest that H3 receptors are involved in the modulation of cognitive function. Yokoyama et al., ["Effect of Thioperamide, a Histamine-H3 Antagonist Receptor, on Electrically Induced Convulsions in Mice", Eur. J. Pharmacol., (1993), Vol. 234, p. 129-133] report how thioperamide reduced the duration of each seizure phase and raised the electroconvulsive threshold and further suggest that these and other findings support the hypothesis that the central histaminergic system is involved in the inhibition of seizure events. International patent publication No. WO 9301812-A1 (SmithKIinne Beecham PLC) describes the use of S- [3- (4 (5) -imidazolyl) propyl] isothourea as a histamine H3 antagonist, especially for treating cognitive disorders , for example, Alzheimer's disease and the deterioration of age-related memory. Schlicker et al., ["Novel Histamine-H3 Receptor Antagonists: Affinities in an H3 Receptor Binding Assay and Potencies in Two Functional H3 Receptor Models", British J. Pharmacol., (1994), Vol. 112, 1043-1048] describe a number of imidazolylalkyl compounds in which the imidazolylalkyl group is linked to a guanidine group, an ester group, an amide group, a thioamide group and a urea group, and compared these compounds with thioperamide. Leurs et al., ["The Histamine-H3-receptor: A Target for Developing New Drugs". Progr. Drug Res. (1992), Vol. 39, p. 127-165] and Lipp et al., ["Pharmacochemistry of H3-receptors" in The Histamine Receptor, editors: Schwartz and Haas, Wiley-Liss, New York (1992), p. 57-72] report a variety of synthetic H3 receptor antagonists and Lipp et al., (Ibid.) Have proposed the necessary structural requirements for an H3 receptor antagonist.

WO 95/14007 claims antagonists of the H3 receptors of the formula wherein A, m, n, R1 and R2 are defined therein. The compounds are described as being useful for treating various disorders, especially that caused by allergy-induced responses. WO 93/12093 discloses imidazolylmethylpiperazines and diazepines as H3 antagonists. U.S. Patent Application Serial No. 08 / 965,754, filed on November 7, 1997 discloses heterocyclic ring compounds substituted with midazolylalkyl as H3 receptor antagonists. U.S. Patent Application Serial No. 08 / 966,344, filed on November 7, 1997, discloses phenylalkylimidazoles as antagonists of the H3 receptors. Reference is also made to the US application, serial number 08 / 689,951, filed August 16, 1996, which claims the combined use of a histamine Hi receptor antagonist and a histamine H3 receptor antagonist for the treatment of airway responses of allergic origin. Reference is also made to JR Bagley et al. "Journal of Medicinal Chemistry, (1991), Vol. 34, 827-841, which describes, among others, cyclic amine compounds substituted with N- (imidazolylalkyl) which serve as analgesics, as the amine compound that has the formula: H U.S. pending patent application Serial No. 09 / 173,642, filed October 16, 1998 (R. Wolin et al.), Discloses N- (imidazolylalkyl) substituted cyclic amine compounds with H3 antagonist activity. In view of the prevailing interest in the art for compounds that affect the H3 receptor, it would be a welcome contribution to the technique that of novel compounds with agonist or antagonist activity on the H3 receptors. This invention offers just that contribution by presenting novel compounds with agonist or antagonist activity on H3.

BRIEF DESCRIPTION OF THE INVENTION This invention presents novel compounds with agonist or antagonist activity on the H3 receptor, compounds having the general formula illustrated in formula I, including the enantiomers, stereoisomers and tautomers thereof, as well as the pharmaceutically acceptable salts or solvates of said compounds: Formula I wherein G is a spacer portion selected from the group consisting of C-C7 alkyl, C2-C alkenyl, C2-C alkynyl, C-? -C7 alkyl-NHCO- and -S02-, wherein said alkyl, alkenyl or alkynyl is optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, alkylaryl, -O-alkyl and -CO2-substituted or unsubstituted alkyl and wherein said substituents are selected from the group consisting of alkyl, aryl, aralkyl and halogen and T is a six-membered ring or a seven-membered ring containing two ring nitrogens and pertaining to formula a below, ring T which is connected to said portion G at a ring carbon atom of the ring. T ring or a ring N ring nitrogen atom. where n is 1 or 2 and R2, R3, R4, R5, Re, and R7 can be the same or different, with the proviso that no pair of said R3, R4, R5 and Re can be attached to the same carbon atom of the ring T except when at least one of said R3, R > Re and Re is H, wherein said R2 and R are independently selected from the group consisting of H, substituted or unsubstituted CrC6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, aryl, aralkyl , alkylaryl, -C (= O) R8 > -CO2R8, -SO2R8, S (O) R8, -C (O) NR8R9 and -C (= NR8) NR8R9 and said R3, R4, R5 and R6 may be identical or different and are independently selected from the group consisting of in H, substituted or unsubstituted C6-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, aryl, aralkyl, alkylaryl, -C (= O) R8, -CO2R8, -SO2R8 , S (O) R8 >; -C (O) NR8R9, -C (= NR8) NR8R9, -CO-Rβ, -OC (O) R8, -N (R8) 2, -NR8R9, -SR8, -OH, -OR8, -CH2OR8, - CH2N (R8) 2, CH2SR8, -NR8 (CO) NR8R9, -CX (R8) 2, -CX2R8, -CX3, -OCX3, -N (R8) -S (O) R9, -N (R8) -SO2R9 , (= O), (= N-OR8), -NR8-SO2-NR8R9, -SO3H and -PO3H2) where R8 and R9 are independently H or substituted or unsubstituted C-? -C6 alkyl, substituted or unsubstituted aryl , substituted or unsubstituted aralkyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted alkenylaryl, substituted or unsubstituted alkenyl, heteroaryl and X is halogen, and where further, when there is a spacer portion G linked to a ring nitrogen atom of the ring T, then one of said R2 or R7 is absent in the ring nitrogen atom bound to the portion G and the other of said R2 or R7 is present in the ring nitrogen atom that is not bound to the portion G, and where, in addition, when G is C7 alkyl and is linked to a ring nitrogen of the ring T, then said R2 or R of the other T ring ring trogen is not hydrogen, substituted or unsubstituted C 6 alkyl or unsubstituted or substituted C 2 -C 6 alkenyl or aryl. The term "substituted" in the phrase "substituted or unsubstituted" refers to an appropriate substitution with suitable portions such as, for example, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, aralkyl, alkylaryl, cycloalkyl, heterocyclic or halogen. This invention also presents methods for preparing compounds of formula 1. This invention features pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I. This invention furthermore presents a method for the treatment of allergy ( for example, asthma), inflammation, hypertension, elevated intraocular pressure (such as glaucoma) - that is, a method to reduce intraocular pressure, sleep disturbances (eg, hypersomnia, drowsiness, narcolepsy, and lack of sleep, such as insomnia) ), hyper and hypomotility states and acid secretion of the gastrointestinal tract, hypo and hyperactivity of the central nervous system (for example, agitation and depression) and other CNS disorders (such as Alzheimer's disease, schizophrenia and migraine) consisting of administering a effective amount of a composition comprising a compound of formula I a a patient who needs such treatment.

The invention also relates to the aspect of the use of a compound of the formula I for the treatment of disorders of the upper respiratory tract. The invention further covers the aspect of using a compound of formula I in combination or in admixture with an H-i receptor antagonist for the treatment of upper respiratory disorders.

DETAILED DESCRIPTION OF THE INVENTION In the context of the present, the following terms have the following meanings, unless otherwise indicated: alkyl - represents a straight or branched saturated hydrocarbon chain with 1 to 6 carbon atoms; cycloalkyl - represents a carbocyclic ring saturated with 3 to 6 carbon atoms; halogen - (halo) represents fluorine, chlorine, bromine or iodine; aryl - represents a carbocyclic group with 6 to 14 carbon atoms and having at least one benzenoid ring, where all the free aromatic carbon atoms of the carbocyclic group to be substituted must be possible binding sites, a carbocyclic group which is optionally substituted with 1 to 3 R9 groups, each of which is independently selected from halo, alkyl, hydroxy, lower alkoxy, phenoxy, amino, lower alkylamino, lower dialkylamino, polyhalo lower alkyl and polyhaloalkoxy lower. Preferred aryl groups include substituted phenyl and phenyl, 1-naphthyl, 2-naphthyl and indanyl; heterocyclic - represents, in addition to the heteroaryl groups defined below, saturated or unsaturated cyclic organic groups having at least one O, S and / or N atom that interrupts a carbocyclic ring structure consisting of a ring or two rings fused, where each ring is 5, 6 or 7 members and may or may not have double bonds lacking delocalized pi electrons, ring structure having 2 to 8, preferably 3 to 6 carbon atoms, for example 2- or 3-piperidinyl, 2- or 3-piperazinyl, 2- or 3-morpholinyl or 2- or 3-thiomorpholinyl; heteroaryl - represents a cyclic organic group having at least one O, S and / or N atom that interrupts a carbocyclic ring structure having a sufficient number of delocalized p-electrons to confer the aromatic character, where the aromatic heterocyclic group has 2 to 14, preferably 4 or 5 carbon atoms, for example 2-, 3-or 4-pyridyl, 2- or 3-furyl, 2- or 3-thienyl, 2-, 4- or 5-thiazolyl, 2- or 4-imidazolyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl or 3- or 4-pyridazinyl, etc. Preferred heteroaryl groups are 2-, 3- and 4-pyridyl; DMF - N, N-dimethylformamide SEM-2- (trimethylsilyl) ethoxymethyl THF - tetrahydrofuran DBU = 1,8-diazabicyclo [5.4.0] undec-7-ene DBN = 1,5-diazabicyclo [4.3.0] non-5 -ene EDCI = 1- (3-d.methylaminopropyl) -3-ethylcarbodiimide HOBT = 1 -hydroxybenzotriazole DCC = dicyclohexylcarbodiimide Dibal-H = diisobutylaluminum hydride LAH = lithium aluminum hydride NaBH (OAc) 3 = sodium triacetoxyborohydride LDA = lithium diisopropylamide p-TsOH = p-toluenesulfonic acid TMAD = N, N, N ', N'-tetramethylazodicarboxamide CSA = camphorsulfonic acid NMM = N-methylmorpholine DCE = dichloroethane A preferred group of compounds of the formula I has the formula II .

Formula II wherein the symbols are as defined for formula I. Within this group, compounds of formula II in which n is 1 are of particular interest. The preferred meaning of R2 is Y- (CH2) P-R6 where Y is a bond or -CO or -SO2-, p is 0 or 1 and Rβ is mono- or disubstituted or unsubstituted phenyl. When there is a group R7 present, each R7 independently represents hydrogen, benzyl or a group according to that defined above for R2, where R2 and R7 may be the same or different. Preferably, the group R that is not bonded to nitrogen is hydrogen. The substituents on the phenyl ring are preferably chlorine. A second preferred group of compounds within formula I has the formula HA: Formula HA in which symbols are as defined for formula I. Within this group, compounds of the formula HA in which n is 1 and G is C, -C7 alkyl are of particular interest. Certain compounds of the present invention can exist in different isomeric forms (e.g., enantiomers or diastereomers). The invention contemplates all said isomers, both in pure form and in mixtures, including in racemic mixtures. The enol forms are also included. The compounds of the formula I can exist in unsolvated as well as solvated forms, including hydrated forms, for example hemihydrate. In general, solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and so forth are equivalent to unsolvated forms for the purposes of the present invention. Certain basic compounds of the present invention can also form pharmaceutically acceptable salts, for example, acid addition salts. For example, nitrogen atoms can form salts with acids. Examples of acids suitable for the formation of salts are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic, and other mineral and carboxylic acids. known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms can be regenerated by treating the salt with a suitable dilute aqueous basic solution such as sodium hydroxide, potassium carbonate, ammonia and dilute aqueous sodium bicarbonate. The free base forms differ to some extent from their respective salt forms in certain physical properties, such as solubility in polar solvents, although otherwise, the acid and base salts are equivalent to their respective free base forms for the purposes of the present invention. All such acid and base salts should be pharmaceutically acceptable salts within the scope of the present invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for the purposes of the present invention.

General Preparation Schemes: The compounds of the present invention can be prepared according to suitable processes known in the art to prepare similar compounds, for example the processes described in the literature cited above. Unless otherwise specified, the reactions are carried out at an appropriate temperature which allows the reaction to proceed at a reasonable speed until its completion. The basic principle for producing the compounds of the present invention comprises first preparing a compound of the formula III: Formula or a compound of formula IV: Formula IV in which PG is a protective group. As can be seen, the compounds of formulas III and IV differ as to whether G is connected to an annular carbon (formula III) or an annular nitrogen (formula IV) of the T ring. compounds of the formula III and of the formula IV with a compound introducing the desired R2 group (and, if appropriate or convenient, a R7 group) after which removal of the protective group is carried out using suitable methods. The compounds of formulas III and IV may be known or standard processes well known in the art, or they may be prepared according to what is described below. The selection of the starting compounds for the preparation of the compounds of the formulas III and IV generally depends on the meaning of G. The following schemes illustrate the preparation of the compounds of the formula III: PREPARATION OF COMPOUNDS OF FORMULA III (REACTION SCHEME 1) Step 2 SCHEME 1 In the formulas set forth, G2 is a group G with a less carbon atom and Pg is a suitable protecting group such as, for example, triphenylmethyl ("trityl") or 2- (trimethylsilyl) ethoxymethyl. In scheme 1, in step 1, compound 1 is diluted in an organic solvent such as, for example, tetrahydrofuran, and treated with a base such as, n-butyllithium. Next, an aldehyde 2 is added and compound 3 is obtained. In step 2, compound 3 is dissolved in a suitable alcohol such as, for example, ethanol and hydrogenated at a pressure of (16-60 psi) in the presence of a suitable catalyst such as, for example, platinum oxide to produce compound 4. In step 3, compound 4 is suitably reacted with R2L (where L is a leaving group such as Cl, Br, I, OH or activated versions of OH such as OSO2CF3 generated independently or in situ) to place R2 in the indicated nitrogen to produce compounds 5 and 6. The ratios of 5 and 6 can be modified by the amount of R2L used. The reactions can be carried out in the appropriate solvents, including, for example, ether, tetrahydrofuran, dioxane, dimethisulfoxide, dimethylformamide, water, methylene chloride, toluene, with or without the presence of a suitable base such as, for example, triethylamine or diisopropylamide of lithium or sodium hydride, at temperatures on the scale of -78 ° to 200 ° C. In addition, compound 4 can be treated, for example with trimethylaluminum in solvents such as toluene or tetrahydrofuran, before the addition of R2L where R2L is RCO2R "and R" is a lower alkyl such as ethyl to produce compounds 5 and 6 in which R2 is -CO- (CH2) pR6. In step 4, compound 5 is reacted with R2L to place R7 at the indicated nitrogen in order to produce compound 7. L is a leaving group as defined above and the reactions can be carried out under the conditions described. The deprotection of compounds 5, 6 and 7 can be carried out using standard procedures well known in the art. For example, if P is trityl, treatment with a dilute aqueous acid such as, for example, HCl or HBr at temperatures of about 25 ° to 100 ° C gives rise to the final compounds. On the other hand, the compounds of the formula III in which G is CH2CH2- can be obtained by reaction scheme 2: SCHEME 2 In Scheme 2, step 1, compound 8 is dissolved in a suitable solvent such as, for example, diisopropylamine. Trimethylsilylacetylene, dichlorobis / (triphenylphosphine) palladium chloride and copper iodide are added and allowed to react at temperatures between 25 ° and 60 ° C to provide the compound of formula 9. In step 2, compound 9 is dissolved and compound 10 in a suitable organic solvent such as, for example, dimethylformamide and treated with a base such as potassium acetate and a catalyst such as tetrakis- (triphenylphosphine) palladium at temperatures between 25 and 200 ° C to produce the compound 11. In step 3, compound 11 is dissolved in a suitable organic solvent such as ethanol and hydrogenated at a pressure of (16-60 psi) in the presence of a suitable catalyst such as, for example, platinum oxide to produce compound 12. Compounds of formula IV in which G is linked to a nitrogen atom of the T ring can be prepared according to that described in scheme 3: SCHEME 3 In scheme 3, in step 1, compound 13 is reacted with an aldehyde of structure 2, in which Pg represents a protective group such as triphenylmethyl, 2- (trimethylsilyl) ethoxymethyl and the like, under standard conditions of amination Reductive such as, for example, treatment with sodium triacetoxyborohydride in acid to give compound 14. In step 2, compound 14 is reacted with R2L in order to place R2 at the indicated nitrogen to produce compound 15. L is an outgoing group such as Cl, Br, I, OH or activated versions of hydroxyl such as, for example, OSO2CF3 generated independently or in situ. The reaction can be carried out in a suitable solvent or solvents including, for example, ether, tetrahydrofuran, dioxane, dimethisulfoxide, dimethylformamide, water, methyl chloride, toluene with or without the presence of a suitable base such as triethylamine or lithium diisopropylamide. or sodium hydride at temperatures on the scale of -78 ° C to 200 ° C. The compound 15 can then be deprotected according to the standard procedures described above. On the other hand, it is possible to proceed as follows: In step 3, compound 13 is reacted with R2L to place R2 in the indicated nitrogens to produce compounds 16 and 17. The ratio between compounds 16 and 17 is can be modified according to the amount of R2L used. L is as defined above. The aforementioned reaction conditions can be applied. In step 4, compound 16 is reacted with an aldehyde of structure 2, under standard reductive amination conditions, such as, for example, treatment with sodium triacetoxyborohydride in acid to give compound 15. The deprotection of produces a compound of the present invention. The compounds of the formula III can also be synthesized by the methods illustrated in scheme 4: SCHEME 4 In scheme 4, step 1, compound 18 is condensed, in which R is hydrogen, alkyl or aryl and n = 1-10, Z represents a protective group such as triphenylmethyl, 2- (trimethylsilyl) ethoxymethyl or the like, with acid pyrazinecarboxylic acid under standard amidation conditions such as 1-3 (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, hydroxybenzotriazole and N-methylmorpholine in organic solvents such as dimethylformamide and methylene chloride to produce compound 19. In compound 2, it is dissolved compound 19 in an organic solvent such as methylene chloride and diluted with an alcohol such as methanol. Hydrogenation of 19 at pressures in the range of 16 to 60 psi in the presence of a suitable catalyst such as platinum oxide gives compound 20. In step 3, compound 20 is reacted with YL to place Y in the nitrogen indicated to produce compounds 21 and 22. The ratios of 21 and 22 can be modified according to the amount of YL used. And it can be VXRi, where V can be chosen from CO, CO2, CH2, SO2 > X can be (CH2) o-? O and Ri can be chosen from the group consisting of hydrogen, alkyl, cycloalkyl, benzyl, substituted benzyl, allyl, aryl, substituted aryl, heteroaryl or propargyl. L is a leaving group such as Cl, Br, I, OH and activated versions of OH such as OSO2CF3 generated independently or in situ. The reactions can be carried out in suitable solvents including ether, tetrahydrofuran, dioxane, dimethyl sulfoxide, dimethylformamide, water, methylene chloride, toluene with or without the presence of a suitable base such as triethylamine or lithium diisopropylamide or sodium hydride at temperatures on the scale from -78 ° C to 200 ° C. In addition, compound 20 can be treated with trimethylaluminum in solvents such as toluene or tetrahydrofuran before addition of Y-L where Y-L is RCO2R "and R" is lower alkyl such as ethyl to give compounds 21 and 22 and is COR. The compound 20 can also be reacted with aldehydes of the R-iCHO structure under standard reductive amination conditions such as treatment with sodium triacetoxyborohydride in acetic acid to give compounds 21 and 22, in which Y is CH2R- ?. The ratio of 21 and 22 can be modified by means of the amount of R-iCHO used. In step 4, compound 21 is reacted with Y1-L to place Y1 on the indicated nitrogens to produce compound 23. Y1 can be VXR ^ where V can be chosen from CO, CO2, CH2, SO2, X can be chosen from (CH2) 0-? or CO, CO2, SO2, SO, O, N, NR, and R1 may be selected from the group consisting of hydrogen, alkyl, cycloalkyl, benzyl, substituted benzyl, allyl, aryl, aryl substituted, heteroaryl or propargyl. L is a leaving group such as Cl, Br, I, OH and activated versions of OH such as OSO2CF3 generated independently or in situ. The reactions can be carried out in suitable solvents including ether, tetrahydrofuran, dioxane, dimethyl sulfoxide, dimethylformamide, water, methylene chloride, toluene with or without the presence of a suitable base such as triethylamine or lithium diisopropylamide or sodium hydride at temperatures on the scale of - 78 ° C to 200 ° C. In addition, compound 23 can be treated with trimethylaluminum in solvents such as toluene or tetrahydrofuran before the addition of Y 1 -L where Y 1 -L is RCO 2 R "and R" is lower alkyl such as ethyl to give compound 23 wherein Y is COR. Compound 21 can also be reacted with aldehydes of the R.CHO structure under standard reductive amination conditions such as treatment with sodium triacetoxyborohydride in acetic acid to give compound 23, where Y1 is CH2R, in step 5, when Z is triphenylmethyl, compound 23 is deprotected by treatment with a dilute aqueous acid such as HCl or HBr at a temperature of about 25 ° to 100 ° C to produce compound 24. Similarly, compounds 19, 20, 21 and 22 can be deprotected. Other protecting groups are removed by methods well known in the art. The compounds thus prepared can be analyzed for their composition and purity, as well as characterized by standard analytical techniques, such as elemental analysis, NMR, mass spectroscopy and IR spectra. The compounds of the invention can be easily evaluated for their activity at the level of the H3 receptors by known methods, including, for example, the guinea pig brain membrane test and the ileo-neuronal contraction test in guinea pigs, both described in U.S. Patent No. 5,352,707. Another useful assay utilizes rat brain membranes and has been described by West et al., ("Identification of two H3-Histamine Receptor Subtypes", Molecular Pharmacology (1990), vol 33, 640-613. present compounds have H3 antagonist activity.

In another embodiment, this invention features pharmaceutical compositions comprising imidazolylalkyl compounds as an active ingredient. The pharmaceutical compositions generally comprise, in addition to a pharmaceutically acceptable diluent, carrier, excipient or carrier (hereinafter collectively referred to as carrier materials). Because of its H3 antagonist activity, such pharmaceutical compositions are useful in the treatment of allergy, inflammation, nasal congestion, hypertension, glaucoma, sleep disorders, hyper and hypomotility states of the gastrointestinal tract, hypo - and hyperactivity of the central nervous system, Alzheimer's disease, schizophrenia, migraines and similar diseases. In another of its embodiments, the present invention describes methods for preparing pharmaceutical compositions comprising the imidazolylalkyl compounds of the present invention as an active ingredient. In the pharmaceutical compositions and methods of the present invention, the active ingredients are typically administered mixed with suitable carrier materials correctly selected with respect to the intended administration form, for example, oral tablets, capsules (either solid, semi-solid filled) or liquid), powders for constitution, oral gels, elixirs, dispersible granules, syrups, suspensions and others, and in accordance with conventional pharmaceutical practices. For example, for oral administration in the form of tablets or capsules, the active drug component can be combined with any inert oral non-toxic pharmaceutically acceptable carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, sodium sulfate, calcium, talc, mannitol, ethyl alcohol (liquid forms) and others. Moreover, when necessary or convenient, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. The powders and tablets may be composed of about 5 to about 95 percent of the inventive composition. Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethyl cellulose, polyethylene glycol and waxes. Among the lubricants that may be mentioned for use in these dosage forms are boric acid, sodium benzoate, sodium acetate, sodium chloride and the like. The disintegrants include starch, methylcellulose, guar gum and so on. Sweetening and flavoring agents as well as preservatives may also be included, if appropriate. Some of the aforementioned terms, that is disintegrants, diluents, lubricants, binders and so on, are described below in more detail. In addition, the compositions of the present invention can be formulated in sustained release form to produce the controlled rate release of one or more of the active ingredients or components, for the purpose of optimizing the therapeutic effects, ie, antihistaminic activity and the rest. Suitable dosage forms for sustained release include stratified tablets containing layers with varying disintegration rates or controlled release polymer matrices impregnated with active components and molded into a tablet or capsule containing said impregnated or encapsulated porous polymer matrices. Liquid form preparations include solutions, suspensions and emulsions. As an example there may be mentioned water or water-propylene glycol solutions for parenteral injections or the addition of sweeteners and opacifiers for solutions, suspensions and oral emulsions. Solutions for intranasal administration may also be included among the liquid form preparations. Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier such as an inert compressed gas, for example nitrogen. For the preparation of suppositories, a wax with a low melting point, such as a mixture of fatty acid glycerides such as cocoa butter, is first melted and then the active ingredient is dispersed homogeneously therein by agitation or technique. of similar mixing. The molten homogeneous mixture is then poured into molds of suitable size, allowed to cool and thus solidify. Also included are solid form preparations intended to be converted, shortly before use, into liquid form preparations for oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions. The compounds of the present invention can also be administered transdermally. The transdermal compositions may take the form of creams, lotions, aerosols and / or emulsions and may be included in a transdermal patch of the matrix or reservoir type, both conventional in the art for this purpose. Preferably, the compound is administered orally. Preferably, the pharmaceutical preparation is presented in unit dosage form. In that form, the preparation is subdivided into appropriately sized unit doses containing appropriate amounts of the active components, for example an effective amount to obtain the proposed fine. The amount of active composition of the invention in a unit dose of the preparation can be varied or adjusted in general between about 0.01 milligrams and about 1000 milligrams, preferably from about 0.01 to about 950 milligrams, more preferably about 0.01 and about 500 milligrams and typically from about 1 to about 250 milligrams, according to the specific application. The actual dose used can be varied depending on the age, sex, weight of the patient, as well as the severity of the condition being treated. Such techniques are well known to those skilled in the art. Generally, the oral dosage form for humans containing the active ingredients can be administered 1 or 2 times per day. The amount and frequency of administration is regulated according to the criteria of the attending physician. A generally recommended daily oral dosage regimen may vary between about 0.04 milligrams and about 4,000 milligrams daily, in single or divided doses. Capsule - refers to a special package or wrap made of methylcellulose, polyvinyl alcohols or denatured gelatins or starch to hold or contain compositions comprising the active ingredients. Hard shell capsules are typically made from mixtures of bone gelatins and pig skin with relatively high gelification. The capsule itself may contain small amounts of dyes, opacifying agents, plasticizers and preservatives. Tablet (tablet) - refers to a molded or compressed solid dosage form containing the active ingredients with suitable diluents. The tablet can be prepared by compressing mixtures or granulations obtained by wet granulation, dry granulation or by compaction. Oral gels - refers to the active ingredients dispersed or solubilized in a hydrophilic semisolid matrix. Powders for reconstitution - refers to powder substances that contain the appropriate active ingredients and diluents that can be suspended in water or juices.

Diluent - refers to substances that usually make up the bulk of the composition or dosage form. Suitable diluents include sugars such as lactose, sucrose, mannitol and sorbitol; starches derived from wheat, corn, rice and potato and cellulose such as microcrystalline cellulose. The amount of diluent in the composition may range from about 10 to about 90% by weight of the total composition, preferably from about 25 to about 75%, more preferably from about 30 to about 60% by weight, even more preferably from about 12. to approximately 60%. Disintegrants - refers to materials added to the composition to contribute to their separation (disintegration) and release of the drugs. Suitable disintegrants include starches, modified "cold water soluble" starches such as sodium carboxymethyl starch; natural and synthetic gums such as those of locust bean, karaya, guar tragacanth and agar; cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose; microcrystalline celluloses and cross-linked microcrystalline celluloses such as croscarmellose sodium; alliginators such as alginic acid and sodium alginate; clays such as bentonites and effervescent mixtures. The amount of disintegrant included in the composition can range from about 2 to about 15% by weight of the composition, more preferably from about 4 to about 10% by weight.

Binders - refers to substances that agglutinate or "stick" the powders together and make them cohesive forming granules, thus acting as the "adhesive" of the formulation. The binders add to the existing cohesive force in the diluent or reinforcing agent. Suitable binders include sugars such as sucrose, starches derived from wheat, corn, rice and potatoes; natural gums such as acacia, gelatin and tragacanth; marine algae derivatives such as alginic acid, sodium alginate and calcium and ammonium alginate; cellulosic materials such as methylcellulose and sodium carboxymethylcellulose, as well as hydroxypropylmethylcellulose, polyvinylpyrrolidone and inorganic materials such as magnesium aluminum silicate. The amount of binder included in the composition can range from about 2 to about 20% by weight of the composition, more preferably from about 3 to about 10% by weight, even more preferably from about 3 to about 6% by weight. Lubricant - designates a substance added to the dosage form to allow the tablet, granules, etc., to be released from the mold or matrix, once compressed, reducing friction or wear. Suitable lubricants include metal stearates such as magnesium stearate, calcium stearate or potassium stearate, stearic acid, waxes with high melting point and water-soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium, sodium oleate, polyethylene glycols and dl-leucine. The lubricants are usually added in the last step before compression, since they must be present on the surface of the granules and between these and the parts of the tablet press. The amount of lubricants included in the composition can range from about 0.2 to about 5% by weight of the composition, preferably from about 0.5 to about 2%, more preferably from about 0.3 to about 1.5% by weight. Slides - materials that prevent agglomeration and improve the flow characteristics of the granulations, so that the flow is smooth and uniform. Suitable glidants include silicon dioxide and talc. The amount of glidants included in the composition can range from about 0.1% to about 5% by weight of the total composition, preferably between about 0.5 and about 2%, by weight. Coloring agents - excipients that impart coloration to the composition or dosage form. Such excipients may include food grade dyes and food grade dyes adsorbed on a suitable adsorbent such as clay or aluminum oxide. The amount of coloring agent can vary between about 0.1 and about 5% by weight of the composition, preferably between about 0.1 and about 1%. Bioavailability - refers to the rate and extent to which the active pharmacological ingredient or therapeutic portion is absorbed into the systemic circulation from a dosage form administered as compared to a standard or control. Conventional methods of tablet preparation are known. Such methods include dry methods such as direct compression and compression of granulation produced by compaction, or wet methods or other special procedures. Conventional methods for preparing other administration forms such as, for example, capsules, suppositories and the like are also known. Another embodiment of the present invention describes the use of the pharmaceutical compositions described above for the treatment of diseases such as, for example, allergy, inflammation, nasal congestion, hypertension, glaucoma, sleep disorders, hyper- and hypomotility states of the gastrointestinal tract. , hyperactivity and hyperactivity of the central nervous system, Alzheimer's disease, schizophrenia, migraine and others. The method consists in administering a therapeutically effective amount of the pharmaceutical composition of the invention to a patient having said disease or diseases and in need of such treatment. In another of its embodiments, the present invention describes pharmaceutical compositions comprising the imidazolylalkyl compounds of the invention in combination with one or more histamine H3 receptor antagonists. Optionally, there may be a pharmaceutically acceptable carrier present. It is known that numerous chemical substances have Histamine H3 receptor antagonist activity. Many of these compounds can be broadly classified as ethanolamines, ethylenediamines, alkylamines, phenothiazines, piperidines and others. Illustrative receptor antagonists Hi in the practice of the present invention include, but are not limited to, astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine (also known as desloratadine or "DCL"), doxylamine, dimetindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, meclizine, mizolastine, mequitazine, mianserin, noberastine, norastemizole, picumast, pyrilamine, promethazine, terfenadine, tripelenamine, temelastina, trimeprazina and tripolidina. Other compounds can be readily evaluated for activity at the level of H-i receptors by known methods, including for example the specific blockade of the contractile response to guinea pig isolated guinea histamine. All said H-i receptor antagonists are suitable for preparing the pharmaceutical compositions. Another embodiment of the present invention describes methods for preparing pharmaceutical compositions comprising the imidazolyalkyl compounds of the invention and one or more histamine receptor antagonists. And another of its modalities describes the use aspect of such compositions for the treatment of allergic responses of the airways (ie, of the upper airways). Those skilled in the art will appreciate that the term "upper airway" means the upper respiratory tract - that is, the nose, throat and associated structures. It is obvious to those skilled in the art that numerous modifications can be made, variations and alterations to the present description, both with respect to materials and methods. Said modifications, variations and alterations should be considered included in the spirit and scope of the present invention. The following examples are presented for the purpose of illustrating the present invention. They are for illustrative purposes only; the scope of the present invention should not be considered limited in any way by said examples. It is assumed that modifications and reasonable alterations are within the spirit and scope of the invention.

EXAMPLES EXAMPLE 1 () A mixture of 2-chloropyrazine (7.1 ml, 80 mmol), trimethylsilylacetylene (17.0 ml, 120 mmol), dichlorobistriphenylphosphine palladium chloride (5.62 g, 8 mmol) and copper iodide (01.52 g, 8 mmol) was heated at 40 ° C. ) in diisopropylamine 8200 ml). The reaction darkens and becomes very thick. Thin layer chromatography ("TLC") (20% ethyl acetate / hexanes) after 3 hours indicated that some of the initial material still remained. The mixture was heated to 50 ° C. After 2 more hours, the TLC indicated that the reaction had not been completed. More trimethylsilylacetylene (5.7 ml, 40 mmol) was added and the mixture was allowed to stir at 50 ° C overnight. The mixture was cooled to room temperature and filtered with celite. The filter cake was washed thoroughly with ethyl acetate until the TLC of the filtrate indicated that all of the desired product had eluted. The filtrate was concentrated with sufficient silica gel in such a manner that a slippery powder was obtained. The powder was loaded onto a chromatography column previously packed with 5% ethyl acetate / haxanes. Elution with 5% ethyl acetate / hexanes followed by 10% ethyl acetate / hexanes gave 13.4 g (95%) of 26 as a dark oil. (I) A mixture of 26 (3.68 g, 21 mmol), 4-iodo-1-triphenylmethylimidazole (10.1 g, 23 mmol), potassium acetate (3.1 g, 31.5 mmol) and tetrakistriphenylphosphine palladium (1.99 g, 2.1 mmoles). TLC (20% ethyl acetate / hexanes) indicated the consumption of the starting material. The mixture was cooled to room temperature and filtered with celite. The filter cake was washed thoroughly with ethyl acetate. The filtrate was concentrated with sufficient silica gel so that a sliding powder was obtained. The powder was loaded on a chromatography column previously packed with 20% ethyl acetate / hexanes. Elution with the same solvent gave 3.7 g (93%) of 27 as an oil. 27 (7.2 g, 17.4 mmol) was dissolved in ethanol (500 ml) and purged with nitrogen. Platinum oxide (0.71 g, 3.1 mmol) was added and the resulting mixture was hydrogenated on a Parr apparatus at 30 psi (209 kPa). TLC (20% methanol / methylene chloride) indicated that, although the material had been consumed from the start, multiple products were observed. Additional platinum oxide (1 g, 4.4 mmol) was added and the mixture was hydrogenated in a Parr apparatus at 30 psi overnight. The mixture was filtered with celite and the filter cake washed thoroughly with ethanol. The filtrate was concentrated on silica gel in such a way that a sliding powder was obtained. The powder was loaded onto a chromatography column on silica gel pre-packaged with 10% methanol / methylene chloride. Elution with 10% methanol / methylene chloride followed by 5% ammonium hydroxide (conc.) / 10% methanol / methylene chloride yielded 5.1 grams (69%) of 28 as an amber and impure oil 29. The compound 29 chromatographed again with 100% ethyl acetate followed by 5% tiethylamine / ethyl acetate to give 0.56 g (8%) of pure 29 as a clear oil. (iv) 29 (0.51 g, 1.22 mmol) was dissolved in HCl (30 mL, 4M, in dioxane) and heated at 60 ° C overnight. A precipitate formed. The mixture was cooled to room temperature and the precipitate was collected by vacuum filtration, washed with ethyl acetate and dried to give 0.233 g (67%) of 30 as an amber solid.

EXAMPLE 2 4-Chlorobenzenesulfonyl chloride (0.24 g, 1.1 mmol) was added to a solution at room temperature of 28 (0.54 g, 1.3 mmol) and triethylamine (0.27 mL, 1.9 mmol) in methylene chloride (5 mL). The resulting mixture was stirred overnight. TLC (5% methanol / ethyl acetate) indicated that the starting material had been consumed. The reaction mixture was concentrated on sufficient silica gel, whereby a sliding powder was obtained. The powder was loaded onto a chromatography column on silica gel pre-packaged with 5% methanol / ethyl acetate. Elution with 5% methanol / ethyl acetate followed by 10% methanol / methylene chloride gave 0.63 g (93%) of pure 31 as a white foam. Deprotection according to the above-described process yielded the desired compound.

EXAMPLE 3 1-3- (Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.94 g, 3.2 mmol) was added to a room temperature solution of 28 (1.0 g, 2.4 mmol), 4-chlorobenzoic acid (0.38 g, 2.4 mmol), N-methylmorpholine (0.8 ml, 7.3 mmol) and hydroxybenzotriazole (0.4 g, 2.9 mmol) in dimethylformamide (6 ml) and methylene chloride (3 ml). The resulting mixture was stirred overnight. TLC (10% methanol / methylene chloride) indicated the consumption of the starting material. The mixture was transferred to a separatory funnel, diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated on sufficient silica gel to obtain a sliding powder. The resulting powder was loaded onto a chromatography column previously packed with silica and with 10% methanol / methylene chloride. Elution with 10% methanol / methylene chloride followed by 5% ammonium hydroxide (conc.) / 10% methanol / 85% methylene chloride gave 0.89 g (65%) of 32 and 0.25 g (15%) of 33. Deprotection produced the corresponding deprotected compound.

EXAMPLE 4 Triacetoxyborohydride (0.72 g, 3.4 mmol) was added to a solution at room temperature of 28 (1.0 g, 2.4 mmol) and 4-chlorobenzaldehyde (0.34 g, 2.4 mmol) in dichloroethane (6 mL). The resulting mixture was stirred overnight. The mixture was quenched with saturated sodium bicarbonate and stirred rapidly for 2 hours. The mixture was transferred to a separatory funnel, diluted with methylene chloride, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated on sufficient silica gel to obtain a sliding powder. The resulting powder was loaded onto a chromatography column previously packed with silica and with 10% methanol / methylene chloride. Elution with 10% methanol / methylene chloride followed by 5% ammonium hydroxide (conc.) / 10% methanol / 85% methylene chloride gave 0.22 g (14%) of 34 and 0.82 g (62%) of 35. Deprotection provides the corresponding deprotected compounds.

EXAMPLE 5 36 (4.71 g, 9.7 mmol) was dissolved in methylene chloride (50 ml) diluted with methanol (100 ml) and purged with nitrogen. Platinum oxide (0.47 g) was added and the mixture was hydrogenated overnight in a Parr apparatus at 60 psi. TLC (10% methanol / methylene chloride) indicated the consumption of the starting material. The mixture was filtered with celite and the filter cake washed thoroughly with methanol. The filtrate was concentrated with sufficient silica gel so that a sliding powder was obtained. The resulting powder was loaded onto a chromatography column previously packed with silica and 10% methanol / methylene chloride. Elution with 10% methanol / methylene chloride followed by 5% ammonium hydroxide (conc.) / 10% methanol / methylene chloride gave 4.24 g (89%) of 37 as an oil. Deprotection the corresponding deprotected compounds.

EXAMPLE 6 Step 1 and 2 39 40 To a stirred solution of 4-carbonaldehyde 38 (13.3 g, 35 mmol) and tere-butyl 1-piperzinocarboxylate (6.5 g, 35 mmol) in 130 ml of 2,2,2-trifluoroethanol was added 13 g of molecular sieves. "3A" followed by the portionwise addition of sodium cyanoborohydride (2.2 g, 35 mmol). The mixture was stirred at room temperature for two days and then concentrated. The residue was taken up in ethyl acetate, washed consecutively with dilute sodium carbonate, brine and concentrate. The residue was chromatographed on SiO2 eluting with MeOH / CH2Cl2 (1: 9) to give 12.4 g (65%) of product 39 in the glass form. MS FAB m / z 551 (MH +).

A solution of 39 (3.7 g, 6.9 mmol) in 20 ml of methanol and 20 ml of a 8.7% anhydrous hydrochloric acid / ether solution was stirred at room temperature for 18 hours and concentrated. The residue was basified with dilute sodium hydroxide and extracted with ethyl acetate. The concentration of the ethyl acetate solution resulted in 2.8 g of a viscous residue which was purified by flash chromatography on SiO2 eluting with CH2Cl2 / MeOH-28% NH4OH (90: 8: 1) to give 0.9 g of 40 in dry form. of syrup. MS FAB m / z 451 (MH +). Steps 3 and 4: To a stirred solution of 40 (0.6 g, 1.33 mmol) in 20 mL of THF-ether (1: 2) was added 4-trifluoromethylphenyl isocyanate (0.33 g, 1.75 mmol). The mixture was stirred at room temperature for 2 hours and concentrated. The residue was chromatographed on SiO2 eluting with % MeOH in CH 2 Cl 2 to yield 0.6 g of gummy product 41.

MS FAB m / z 638 (MH +). A solution of 41 (0.55 g, 0.86 mmol) and maleic acid (0.22 g, 1.89 mmol) in 20 ml of 90% MeOH was maintained at reflux for 1 hour. The mixture was concentrated and the solid residue was triturated with ethyl acetate and filtered to give 0.47 g (mp 175-180 ° C) of dimaleate 42. MS FAB m / z 396 (MH +). Anal (C19H24F3N5O »2C4H4O4) C, H, N.

EXAMPLE 7 Steps 1 and 2 Four. Five To a stirred suspension of 60% sodium hydride in oil dispersion (0.18 g, 4.4 mmol) in 20 ml of anhydrous DMF at 0 ° C was added 0.6 g (1 mmol) of trichlorhydrate 40, followed by a solution of 43 g. (0.29 g, 1.1 mmol) in 10 ml of DMF. The mixture was heated at 50 ° C for 18 hours and poured into ice water (30 ml). Extraction with methylene chloride and the subsequent concentration gave a viscous residue which was chromatographed on SiO 2 eluting with 8% MeOH in CH 2 Cl 2 to yield 0.33 g of gummy product 44. MS FAB m / z 632 (MH +). A solution of 44 (0.32 g, 0.5 mmol) and maleic acid (0.2 g, 1. 7 mmoles) in 25 ml of 90% MeOH was kept under reflux for 1 hour, diluted with ethyl acetate and cooled in an ice water bath. The pure crystalline product was precipitated in the form of the trimaleate salt and filtered (0.22 g, mp 151-152 ° C). MS Cl m / z 390 (MH +). Anal. (C20H28CIN5O.3C4H4O4) C, H, N.

EXAMPLE 8 46 47 To a stirred suspension of 1.04 g (3.27 mmol) of the trichlorohydrate salt of 46 in 40 ml of anhydrous DMF was added in portions 0.4 g (9.6 mmol) of 60% NaH in dispersion in oil, followed by 1 ml of triethylamine, 0.44 g, (3.27 mmoles) of HOBt, 0.48 g (3.27 mmoles) of trans-cinnamic acid 47 and 0.63 g (3.27 mmoles) of DEC. The reaction mixture was stirred at room temperature for 2 days, diluted with water and extracted with CH 2 Cl 2. The organic solution was concentrated and the residue was chromatographed on SiO2 eluting with 28% CH2Cl2-MeOH in NH4OH (90: 9: 0.5) to yield 0.32 g (mp 143-145 ° C) of product 48. MS Cl m / z 339 (MH +).

EXAMPLE 9 Step 1: 49 50 51 A mixture of trans-3- (3-pyridyl) -acrylic acid 49 (4.01 g, 26.88 mmol), 1-hydroxybenzotriazole (HOBt, 3.63 g, 26.88 mmol), 1- (3-dimethylaminopropyl) hydrochloride 3-ethylcarbodiimide (DEC 5.15 g, 26.88 mmol), tere-butyl 1-piperazinecarboxylate 50 (5.0 g, 26.88 mmol) and triethylamine (3.7 ml, 26.88 mmol) in 200 ml of anhydrous DMF was stirred at room temperature for 24 h, diluted with water and extracted with CH2Cl2. The organic solution was washed with Na 2 HCO 3, brine and concentrated. The residue was triturated with hexane and filtered to obtain 7.77 g of product 51 (mp 174-176 ° C). MS FAB m / z 318 (MH +).

Step 2: 51 51 A solution of 51 (1.15 g, 3.6 mmol) in 20 ml of CH 2 Cl 2 and 3 ml of trifluoroacetic acid was stirred over a period of 18 h, basified with 15% NaOH and extracted thoroughly with CH 2 Cl 2. The organic solution was dried with anhydrous MgSO 4 and concentrated. Trituration with ether-hexane (1: 2) and filtration of the residue gave 0.34 g (mp 98-100 ° C) of the product 52. MS CI m / z 218 (MH +).

Step 3: 52 53 A solution of 38 (0.6 g, 1.58 mmol) in 10 ml of 6 M hydrochloric acid and 20 ml of MeOH was stirred at room temperature for 20 h and concentrated to a viscous residue, mixed with 52 (0.31 g, 1.43 mmoles), 3 g of molecular sieves "3A" in 20 ml of 2,2,2-trifluoroethanol and 0.077 g (1.24 mmoles) of sodium cyanoborohydride (NaCNBH3). The mixture was stirred for 20 h at room temperature, filtered and concentrated. The residue was basified with 5% cold NaOH and extracted with CH2Cl2. The organic solution was concentrated and the residue chromatographed on SiO2 eluting with CH2Cl2-MEOH-NH4OH 28% (90: 10: 1) to yield 0.062 g (mp 130-133 ° C) of product 53. MS Cl m / z 340 (MH +). Following the processes described and exemplified above, the compounds listed in Table 1 were prepared: TABLE 1 Table 2 contains a list of other prepared compounds corresponding to formula 1. TABLE 2 Procedure for the assay of binding to the H3 receptor The source of H3 receptors for this experiment was the brain of guinea pig. The animals used weighed 400 - 600 g. The tissue was homogenized using a Polytron in a 50 mM Tris solution, pH 7.5. The final tissue concentration in the homogenization buffer was 10% w / v. The homogenates were centrifuged at 100 x g for 10 min to eliminate the clumps of tissue and waste. The resulting supernatants were then centrifuged at 50,000 x g for 20 min. to sediment the membranes, which were then washed 3 times in homogenization buffer (50,000 x g for 20 min each). The membranes were frozen and stored at -70 ° C until needed. All the compounds to be analyzed were dissolved in DMSO and then diluted in the binding buffer (50 mM Tris, pH 8.5) in such a way that the final concentration was 2 μg / ml with 0.1% DMSO. Then the membranes (400 μg of protein) were introduced into the reaction tubes. The reaction was started by the addition of 3 nM of [3 H] -Ra-methylhistamine (8.8 Ci / mmoles) or [3 H] -N-methylhistamine (80 Ci / mmoles) and incubated at 30 ° C for 30 minutes. min. The bound ligand was separated from the loose by filtration and the amount of radioactive ligand bound to the membranes was quantified by liquid scintillation spectrometry. All incubations were performed in duplicate and the standard error was less than 10% in all cases. Compounds that inhibited more than 70% of the specific binding of the radioactive ligand to the receptor were serially diluted to determine a Ki (nM) or% inhibition for H3. The results are recorded in table 1.

Claims (15)

NOVELTY OF THE INVENTION CLAIMS

1. A compound having the general formula illustrated in formula I, including the enantiomers, stereoisomers and tautomers thereof, as well as the pharmaceutically acceptable salts or solvates of said compounds:

H Formula I wherein G is a spacer portion selected from the group consisting of C-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C7-alkyl-NHCO- and -SO2-, wherein said alkyl, alkenyl or alkynyl is optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, alkylaryl, -O-alkyl and -CO2-substituted or unsubstituted alkyl and wherein said substituents are selected from the group consisting of alkyl, aryl, aralkyl and halogen and T is a six-membered ring or a seven-membered ring containing two ring nitrogens and belonging to the formula a below, ring T which is connected to said portion G at a ring carbon atom of the ring T or a ring nitrogen nitrogen atom: where n is 1 or 2 and R2, R3, R4, R5 and R7 can be the same or different, except that no pair of said R3, R4, R5 and R6 can be attached to the same carbon atom of the T ring except when at least one of said R3, R4, R5 and RT is H, wherein said R2 and R7 are independently selected from the group consisting of H, substituted or unsubstituted C6-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl; substituted, substituted or unsubstituted C2-C6 alkynyl, aryl, aralkyl, alkylated, -C (= O) R8, -CO2R8, -SO2R8, S (O) R8, -C (O) NR8R9, -C (= NR8) NR8R9 and said R3, R4, R5 and Re may be the same or different and are independently selected from the group consisting of H, substituted or unsubstituted C6? -C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, C2- alkynyl C6 substituted or unsubstituted, aryl, aralkyl, alkylaryl, -C (= O) R8, -CO2R8 > -SO2R8, S (O) R8, -C (O) NR8R9, -C (= NR8) NR8R9 -CO-R8, -OC (O) R8, -NR8R9, -SR8, -OH, -OR8, -CH2OR8, -CH2N (R8) 2, CH2SR8, -NR8 (CO) NR8R9, -CX (R8) 2, -CX2R8, -CX3, -OCX3, -N (R8) -S (O) R9, -N (R8) - SO2R9, (= O), (= N-OR8), NR8-SO2-NR8R9, -SO3H and -PO3H2, where R8 and R9 are independently H or substituted or unsubstituted C -C3 alkyl, substituted or unsubstituted aryl, substituted aralkyl or unsubstituted, substituted or unsubstituted alkylaryl, substituted or unsubstituted alkenylaryl, substituted or unsubstituted alkenylheteroaryl, and X is a halogen, and where further, when the spacer portion G is linked to a ring nitrogen atom of the T ring, then one of said R2 and R7 is absent in the ring nitrogen atom to the portion G and the other of said R2 and R7 is present in the nitrogen atom of the ring that is not bound to the portion G, and where, in addition , when G is C -? - C7 alkyl and is linked to a ring nitrogen of the T ring, then said R2 or R7 of the other n T ring ring itrogen is not hydrogen, substituted or unsubstituted C- | C6 alkyl, C2.C6 alkenyl or substituted or unsubstituted aryl. 2. The compound according to claim 1 having the formula: wherein the symbols are as defined in claim 1.

3. The compound according to claim 1 having the formula: wherein the symbols are as defined in claim 1.

4. The compound according to claim 2, wherein G is C.sub.6-alkyl or C.sub..C.sub.7 -NHCO alkyl and R.sub.2 is H.

5. The compound according to claim 3, wherein R2-C (= O) R8, -CO2R8, or -C (O) NR8R9.

6. The compound according to claim 2, wherein R2 is selected from the group consisting of H, substituted or unsubstituted C6, C6 alkyl, substituted or unsubstituted C2.C6 alkenyl, substituted C2.C6 alkynyl. or unsubstituted, aryl, aralkyl, alkylaryl, -C (= O) R8, -CO2R8, -SO2R8, S (O) R8, -C (O) NR8R9, -C (= NR8) NR8R9.

7. A compound selected from the group consisting of the molecules represented by the following chemical structures: 15 20

8. - A pharmaceutical composition comprising a compound according to claim 1 as an active ingredient.

9. A pharmaceutical composition, for use in the treatment of allergy, inflammation, hypertension, glaucoma, sleep disorders, hyper- and hypomotility states of the gastrointestinal tract, hypo- and hyperactivity of the central nervous system, Alzheimer's disease, schizophrenia and migraines comprising a pharmaceutically acceptable carrier and an effective amount of a compound according to claim 1.

10. The use of a compound as claimed in claim 1 for the manufacture of a medicament for treating allergy. , inflammation, hypertension, glaucoma, sleep disorders, hyper- and hypomotility states of the gastrointestinal tract, hypo- and hyperactivity of the central nervous system, Alzheimer's disease, schizophrenia and migraines.

11. The use of a compound as claimed in claim 1, in combination with a histamine H-i receptor antagonist for the manufacture of a medicament for treating allergic responses of the upper airways.

12. - A pharmaceutical composition comprising, as an active ingredient, a compound according to claim 7. 13.- A pharmaceutical composition for use in the treatment of allergy, inflammation, hypertension, glaucoma, sleep disorders, hyper-e states. hypomotility of the gastrointestinal tract, hypo- and hyperactivity of the central nervous system, Alzheimer's disease, schizophrenia and migraines, comprising a pharmaceutically acceptable carrier and an effective amount of a compound according to claim 7. 14.- The use of a compound as claimed in claim 7, for the manufacture of a medicament for treating allergy, inflammation, hypertension, glaucoma, sleep disorders, hyper- and hypomotility states of the gastrointestinal tract, hypo- and hyperactivity of the central nervous system, disease of Alzheimer's, schizophrenia and migraines. 15. The use of a compound as claimed in claim 7, in combination with a histamine H-i receptor antagonist for the manufacture of a medicament for treating allergic responses of the upper airways.