MXPA00004400A - H3 receptor ligands of the phenyl-alkyl-imidazoles type - Google Patents

Abstract

Disclosed are novel phenyl-alkyl-imidazoles of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein A and R, are as defined in the specification. Also disclosed are methods of treating allergy, inflammation, hypotension, glaucoma, sleeping disorders, states of hyper and hypo motility of the gastrointestinal tract, hypo and hyperactivity of the central nervous system, Alzheimer's, schizophrenia, obesity and migraines, comprising administering an effective amount of a compound of formula (I) (or a salt or solvate thereof) to a patient in need of such treatment. Also disclosed are methods for treatment of upper airway allergic responses comprising administering a compound, or salt or solvate thereof, of formula (I) in combination or admixture with a histamine H1 receptor antagonist.

Description

LIGANDS OF THE H3 RECEPTOR OF THE TYPE PHENYL-ALQU1L-IMIDAZOLES FIELD OF THE INVENTION The present invention relates to novel phenyl-alkyl imidazoles which have valuable pharmacological properties, especially in CNS activities and activity against inflammatory diseases. The compounds of this invention are antagonists of the H3 receptor.

BACKGROUND OF THE INVENTION European patent application No. 0 420 396 A2 (Smith Kline and French Laboratories Limited) and Howson et al., Bioorg. And Med. Chem. Latters, Vol 2 No. 1 (1992), pages 77-78 describes the midazole derivatives having an amidine group as H3 agonists. Van der Groot et al (Eur. J. Med. Chem. (1992) Vol. 27, pages 511-517) describe histamine isothiourea analogs as potent agonists or antagonists of the histamine H3 receptor, and these analogues of Histamine isothiourea overlap in part with those of the two references cited above. Clapham et al ["Ability of Histamine H3 receptor Antagonists to improve Cognition and to increase Acetylcholine relase in vivo in the Rat", British Assn. For Psychopharmacol. (Abstr. Book), A17] describes the ability of histamine H3 receptor antagonists to improve the knowledge and increase the release of acetylcholine in vivo in rats. Clapham et al ["Ability of the selective Histamine H3 Antagonist Thioperamide Receptor to improve Short-term Memory and Reversal Learning in the Rat", Brit. J. Pharm. Suppl. 1993, 110, Abstract 65P] presents results that show that thioperamide can improve short-term memory and learning in rats and involve the inclusion of H3 receptors in the modulation of cognitive function. Yokoyama et al ["Effect of thioperamide, a histamine H3 receptor antagonist, on electrically induced convulsions in mice", Eur. J. Pharmacol., Vol 234 (1993), pages 129-122] report how thioperamide decreased the duration of each seizure phase and raised the electroconvulsive threshold, and continues to suggest that these and other findings support the hypothesis that the central histaminergic system is involved in the inhibition of stroke. International Patent Publication No. WO 9301812-A1 (SmithKine Beecham PLC) describes the use of S- [3- (4 (5) -imidazole) propyl] isothourea as a histamine H3 antagonist, especially to treat cognitive disorders, for example, Alzheimer's disease and age-related memory impairments. Schliker et al, ["Novel histamine H3 receptor antagonist: affinities in an H3 receptor binding essay and potencies in two functional H3 receptor models"] describes an amount of imidazolylalkyl compounds where the imidazolylalkyl group is linked to the guanidine group, an ester group or an amide group (including thioamide and urea), and compares them with thioperamide. Leurs et al ["The histamine H3-receptor: A target for developing new drugs", Progr. Drug. Res (1992) vol 39, pages 127-165] and Lipp et al ["Pharmacochemistry of H3-receptors" in The Histamine Receptor, eds.: Schwartz and Haas, Wiley-Liss, New York (1992), pages 57-72 ] review a variety of synthetic H3 receptor antagonists, and Lipp et al (ibid.) have defined the structural requirements needed for an H3 receptor antagonist. WO 95/14007 claims the H3 receptor antagonists of the formula: where A is selected from -O-CO-NR1, -O-CO-, -NR1-CO-NR1, -NR1-CO-, -NR1-, -O-, -CO-NR1-, -CO-O- , and -C (: NR1) -NR1-. the R1 groups which may be the same or different when there are two or three of these groups in the molecule of the formula I, are selected from hydrogen, and lower alkyl, aryl, cycloalkyl, heterocyclic alkyl groups and heterocyclyl-alkyl and groups of the formula - (CH2) and G, where G is selected from CO2R3, COR3, CONR3R4, or R3, SR3, NR3R4, heterooryl and phenyl, which phenyl is optionally substituted by halogen, lower alkoxy or minor polyhaloalkyl, and y is an integer between 1 and 3; R 2 is selected from hydrogen and halogen atoms, and alkyl, alkenyl, alkynyl and trifluoromethyl groups, and groups of formula OR 3, SR 3 and R j 3"and D R 4 are independently selected from hydrogen, minor alkyl groups and cycloalkyl groups, or R 3 and R4 together with the intervening nitrogen atom can form a saturated ring containing between 4 and 6 carbon atoms which can be substituted with one or two lower alkyl groups; with the proviso that, when y is 1 and G is OR3, SR3 or NR3R4, then neither R3 nor R4 is hydrogen; the group - (CH2) n-A-R1 is in the 3 or 4 position, and the group R2 is in any free position; M is an integer between 1 and 3; and Yn is 0 or an integer between 1 and 3; Or its pharmaceutically acceptable acid addition salt; Or its pharmaceutically acceptable salt with a base when G is CO2H; including its tautomeric form. The compounds are useful for treating various disorders, in particular those caused by allergy-induced responses. The US application series Nr.08 / 689951 filed on August 16, 1996 and the US application serial No. 08/909319 filed on August 14, 1997 (equivalent to Argentine patent application No. P97 01 03693) describes compositions for the treatment of the symptoms of allergic rhinitis using a combination of at least one histamine Hi receptor antagonist and at least one histamine H3 receptor antagonist. In view of the technical interest in the compounds that affect the H3 receptors, the new compounds that have antagonistic activity on the H3 receptors would be a welcome contribution to the technique. This invention provides just this contribution by providing the new compounds having the H3 antagonist activity.

BRIEF DESCRIPTION OF THE INVENTION It has now been discovered that members of a narrow group of compounds that are within the scope of WO 95/14007 but not specifically described therein are particularly active and show valuable pharmacological properties. The compounds are those that have the general formula or its pharmaceutically acceptable acid salt or its solvate (or its tautomer), wherein: A is -CH 2 -NH-CO-NH-; -CH2-O-CO-NH- or -CH2CH2-CO-NH- (CH2) m-; M is 0.1 or 2; R is the group Where at least two of R1, R2, R3 and R4 are hydrogen and the other two are independently selected from H, halogen (e.g., Br, I, F, or Cl), CH3, CF3, OCH3, OCF3 or CN; and With the proviso that when A is -CH2-O-CO-NH- and R1, R3 and R4 are all hydrogen, then R2 can not be Cl. Another feature of the invention are the pharmaceutical compositions containing as active ingredient a a compound of the formula I defined above (or a salt, or a solvate or tautomer) together with a pharmaceutical carrier or excipient. Other features of the invention are methods for treating allergy (eg, asthma), inflammation, cardiovascular diseases, hypotension, increased infra-ocular pressure (such as glaucoma) - for example, a method for lowering intraocular pressure, sleep, (for example, hypersomnia, drowsiness, narcolepsy, inability to sleep such as insomnia), gastrointestinal tract diseases, hyper-or hypo-mobility states and acid secretion of the gastrointestinal tract, central nervous system disorders, hiccups and hyperactivity of the central nervous system (e.g., agitation and depression) and other CNS disorders, (e.g., Alzheimer's disease, schizophrenia, obesity, and migraine) which comprises administering an effective amount of a compound of formula I (or a salt , solvate or its tautomer) to a patient who needs this treatment. Another feature of this invention is a method for treating inflammation, which comprises administering to a patient suffering an inflammation an effective amount of a compound of the formula I (or its salt, solvate or tautomer) to a patient in need of this treatment. Another feature of this invention is a method for treating allergy, which comprises administering to a patient suffering from allergy an effective amount of a compound of formula I (or its salt, solvate or tautomer) to a patient in need of this treatment. Another feature of this invention is a method for treating diseases of the gastrointestinal tract, which comprises administering to a patient suffering from a gastrointestinal tract disease an effective amount of a compound of the formula I (or its salt, solvate or tautomer) to a patient who needs this treatment. Another feature of the invention is a method for treating disorders of the central nervous system, which comprises administering to a patient suffering from disorders of the central nervous system an effective amount of a compound of the formula I (or its salt, solvate or tautomer) to a patient who needs this treatment. The invention also includes the aspect of using the compounds of the formula I in combination with an antagonist of the histamine Hi receptor for the treatment of airway responses (eg, upper airways) induced by allergies.

DESCRIPTION OF THE INVENTION The compounds of the invention are basic and form pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for this salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other well-known mineral and carboxylic acids for those skilled in the art. The salts were prepared by contacting a free base form with a sufficient amount of desired acid to produce a salt in the conventional manner. The free base forms can be regenerated by treating the salt with a suitable diluted aqueous base solution such as for example, dilute aqueous sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from the corresponding salt forms in certain physical properties, such as, for example, solubility in polar solvents, weight, salts otherwise equivalent to their corresponding free base forms for the purpose of the invention. The compounds of formula I can exist in unsolvated forms as well as solvates including the hydrated form, for example, hemihydrate. In general, solvated forms with pharmaceutically acceptable solvents such as, for example, water ethanol and the like, are equivalent to unsolvated forms for the purpose of the invention. It is known that numerous chemical substances have histamine Hi receptor antagonist activity. Many useful compounds can be classified as ethanolamines, ethylenediamines, alkylamines, phenothiazines or piperidines. Representative Hi receptor antagonists include without limitation: astemizole, azathidine, azelastine, acrivastine, brompheniramine, cetiricin, chlorpheniramine, clemastine, cyclin, carebastine, cyproheptadine, carbinoxamine, descarboethoxy-thiatadine (also known as SCH-34117), diphenhydramine, doxylamine , dimetindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, quetotifen, loratadine, levocarbastine, mequitazine mizolastine, mianserin, noberastine, medicine, norastemizole, picumast, pyrilamine, promethazine, tergenadine, tripelenamine, temelastine, trimeprazine and triprolidine. Other compounds can be rapidly evaluated for activity at the Hi receptors by known methods, including specific blocking of the contractile response to histamine of the isolated guinea pig ileum. See, for example, WO 98/06394 published on February 19, 1998 (equivalent to Argentine patent application No. P 97 01 03693). For example, the H3 antagonists of this invention can be combined with a Hi antagonist selected from astemizole, azatadine, azelastine, brompheniramine, cetirizine, chlorpheniramine, clornastine, carebastine, descarboethoxyloratadine (also known as SCH-34117), diphenhydramine, doxylamine, ebastine, fexofenadine. , loratadine, levocabastine, mizolastine, norastemizole, or terfenadine. In addition, for example, the H3 antagonists of this invention can be combined with a Hi antagonist selected from azatadine, brompheniramine, cetirizine, chlorpheniramine, carebastine, descarboethoxyloratadine (also known as SCH-34117), diphenhydramine, ebastine, fexofenadine, loratadine or norastemizole. Representative combinations include: the H3 antagonists of this invention with loratadine, the H3 antagonists of this invention, descarboethoxyloratadine, the H3 antagonists of this invention with fexofenadine, and the H3 antagonists of that invention with cetirizine. Preferably, compound 8 is used in the methods of this invention. Those trained in the art will recognize that the term "upper airway" refers to the upper respiratory system, for example, the nose, throat and associated structures. This invention includes compounds wherein at least two of R1, R2, R3 and R4 are hydrogen and the other two are independently selected from H, F, Cl, CH3 > CF3, OCH3, OCF3 or CN. This invention further includes compounds wherein at least two of R1, R2, R3 and R4 are hydrogen and two of the others are Cl. This invention further includes compounds wherein at least two of R1, R2, R3 and R4 are hydrogen and the other two are Cl, and A is-CH2-NH-CO-NH-. Representative compounds of the invention include: Preferably, the compound is compound 8 (see example 3 below).

Processes for preparing the compounds The compounds of the formula I can be prepared by means of a process in which the left part of the molecule is represented by It binds to a compound to provide the remainder of the molecule, including the R group. Those skilled in the art will appreciate that Pg represents a suitable protecting group (e.g., trityl, abbreviated as "Te"). The following are examples for the processes for the preparation of these compounds.

Process 1 For the preparation of a compound of the formula I where A is -CH2-O-CO-NH-, the reaction of a hydroxy compound with a socianato: The hydroxy compound can be prepared by means of the reaction of a compound of the formula 28 (where Y and CHO). with a hydride reducing agent such as, for example, DiBALH, lithium aluminum hydride, sodium borohydride or the like.

Process 2 For the preparation of a compound of the formula I wherein A is -CH 2 -NH-CO-NH-, the reaction of an amino compound with a socianate: The amino compound can be prepared for example, by means of the reduction of a compound of the formula wherein Y is CN with a hydride reducing agent such as, for example, lithium aluminum hydride, or by means of catalytic hydrogenation, for example, Raney nickel or palladium on carbon.

Process 3 For the preparation of a compound of the formula I wherein A is -CH 2 CH 2 -CO-NH- (CH 2) m-. the reaction of an ester with a dialkylaluminoamine, preferably one of the formula Me2-AINH- (CH2) m-R (wherein R6 is a lower alkyl group, eg, methyl or ethyl).

Preparation of starting materials and intermediates The starting materials for processes 1, 2 and 3 can be prepared by means of the methods explained above, where: Y represents a group convertible to -CH2CH2-CO-OR6, -CH2NH2, or -CH2OH. In a first step, compound 28 is prepared: M is MgX (X = Br or I), Y is CN or CH (OR2), TCDI is thiocarbonyldiimidazole, and AIBN is azoisobutylnitrile.

For process 1, and preferably -CH2OH. In an initial step an aldehyde is formed: where R7 is a lower alkyl group, for example, methyl or ethyl. The aldehyde 36 is then converted to a starting compound for process 1 as described above. For process 2, Y is preferably -CH2.NH2 which is obtained by means of the reduction of compound 28 where Y = CN, for example, compound 28B.

For compounds where Y is -CH2CH2CO2R6, the starting material is acetal which can be converted in the corresponding manner to the aldehyde. The aldehyde is then reacted with the midazole organometallic reagent and the resulting reduced alcohol. The unsaturated compound is then reduced to -CH2CH2-CO2R6.

The resulting ester is then used as a starting compound for process 3. Those skilled in the art will appreciate that compound 37 can be prepared by treating 41 With a phosphorus ylide such as, for example, the one generated from (EtO) 2POCH2C? 2R6 / NaN (SiMe3) 2. The last step is merely the deprotection of any of the protective groups. This can be achieved by various methods known in the art. The protective group is preferably that which can be removed by means of hydrolysis or hydrogenolysis; it can, for example, be a trifyl group (C6H5) 3C_. Which is preferably removed by means of hydrolysis in an aqueous organic solvent. The hydrolysis can, for example, be carried out by means of a mineral acid in an organic solvent miscible with aqueous water, such as, for example, minor alkanol, especially methanol or ethanol. Other protecting groups can be used (and their removal method) include t-Bu-OCO [often abbreviated as t-BOC] (which can be removed with acid, or with hydrazine, ammonia and minor alkanol, for example, methanol or ethanol ), and groups (2-trialkyl minor silyl) -ethoxymethyl, especially Me3Si (CH2) 2? CH2- [often abbreviated as SEM] (which can be removed with an acid or fluorine ion). The compounds useful in this invention are exemplified by means of the following examples, which should not be considered as limiting the scope of the description.

EXAMPLE 1 Step 1 A solution of alcohol 41 (0.3 gm, 0.7 mmoleses) and isocyanate (0.16 gm, 0.84 mmoleses) in dry THF (10 ml) was stirred under a nitrogen atmosphere at 22 ° C for 2 hours. The reaction was concentrated under reduced pressure, diluted with methylene chloride (50 ml) and washed with brine. The organic layer was separated, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a flash column (1: 1 hexane: ethyl acetate) to give product 42 as a white solid (0.4 gm, 92%).

Step 2 Compound 42 (0.4 gm, 0.65 mmoles) in 3N HCl in methanol (40 ml) was heated to 60 ° C under a nitrogen atmosphere for 2 hours. The reaction was cooled to 22 ° C and concentrated under reduced pressure. The residue was dissolved in methanol (30 ml), neutralized with concentrated ammonium hydroxide, and reconcentrated. The residue was purified on a flash column (10% methanol saturated with ammonia in methylene chloride) to give the product. This material was treated with 3N HCl (20 ml) to form the HCl 13a salt which gave a powder as a white powder after concentration under reduced pressure (0.22 gm, 84%). Mass spectrum: (FAB) 376 (M + H).

EXAMPLE 2 Step 1 A solution of amine 43 (0.32 gm, 0.75 mmoles) in dry THF (4 ml) was added dropwise to a solution of the socianate (0.14 gm, 0.94 mmoleses) in THF (3 ml) under a nitrogen atmosphere at 22 ° C. Additional THF (3 ml) was used to rinse the vial and syringe. After 2 hours, the TCL (5% methanol saturated with ammonia in methylene chloride) indicated the complete consumption of the amine. The reaction was concentrated under reduced pressure and purified on a column by flash evaporation (120 gm of silica gel, 2.5% methanol saturated with ammonia in methylene chloride) to give a white foam (0.22 gm). The mixed fractions were repurified using the same conditions to give the additional product (0.14 gm, total yield = 82%); Mass spectrum (FAB) = 583 (M +1).

Step 2 In a similar manner to that described for example 1, step 2, compound 44 of step 1, (0.3 gm, 0.52 mmoleses) was converted to product 5A (0.052 gm, 27%): Mass spectrum (Cl) = 216 (7%), 188 (35%), 171 (87%), 154 (100).

EXAMPLE 3 Step 1 To a Parr 1 L flask containing 5.2 g of Raney nickel (washed with ethanol (4 x 10 ml) was added 400 ml of saturated NH3 methanol and 9.8 g of the hydroxy nitrile compound (22.2 mmoleses), and the mixture was mixed with water. hydrogenated at 45 psi H2 for 8 hours.The reaction mixture was filtered and concentrated.The product was purified by flash column (silica gel) eluting with 20: 1: 0.1 and 10: 1: 0.1 CH2Cl2-MeOH -NH3 aqueous to give 7.65 g of the desired product 46 (17.2 moles, 77% yield) 1 H-NMR (CD3OD) 7.2-7.5 (20 H, m), 6.84 (1 H, s), 5.78 (1 H, s) and 3.82 (2H, s).

Step 2 To a solution of compound 46 (7.65 g, 17.2 mmol) dissolved in THF (700 ml) was added a solution of 3,5-dichlorophenyl-isocyanate (3.27 g, 17.4 mmol) dissolved in THF (50 ml). The reaction mixture was allowed to stir overnight and concentrated to give a clean crude product 47 as a white foam. The crude product was used in the next step without further purification. 1 H-NMR (CD3OD and D6-DMSO) 7.2-7.5 (22H, m), 7.08 (1 H, s) 6.84 (1 H, s), 5.77 (1 H, s), 4.43 (2H, s).

Step 3 To a solution of the crude compound 47 (-17.2 mmoleses) and Nal (21.5 g, 144 mmol) in CH2Cl2 (200 ml) and acetone (200 ml) were added 12.6 ml of dimethylsilane dichlor (103 mmoles). After stirring at room temperature for 30 min, the reaction mixture was added to CH2Cl2 (500 ml) and washed with 10% sodium thiosulfate (500 ml, 4 x 250 ml), and HO (250 ml) and brine (250 ml), dried with MgSO2 and concentrated. The product was purified by flash chromatography (silica gel) eluting with 50: 1 and 20: 1 CH2Cl2-MeOH to give 9.10 g of the desired product 48 as a white solid (14.7 mmoleses, 86% yield for Two steps). 1 H-NMR (CDC) 8.71 (1 H, s), 7.44 (1 H, s), 7.1-7.4 (H, m), 6.88 (1 H, s), 6.71 (1 H, s), 5.99 1 H , d, J = 5.8 Hz), 4.15 (2H, d, J = 5.8 Hz), 3.80 (2H, s).

Step 4 The trifly group was removed and converted to its HCl salt by standard procedures. The HCl salt was crystallized from EtOH-7erc-butyl methyl ether to give the desired product 8A of white crystals (mp 182.5-184 ° C). HRMS (FAB, M + H +): m / e calculated for [C18H17Cl2N4O] +: 375.0779, found 375.0787. 1 H-NMR (CD 3 OD) 8.88 (1 H, s), 7.50 (2 H, d, J = 1.8 Hz), 7.40 (2 H, d, J = 8.1 Hz), 7.37 (1 H, s), 7.32 (2 H, d , J = 8.1 Hz), 7.05 (1 H, t, J = 1.8 Hz), 4.44 (2 H, s), 4.15 (2 H, s).

EXAMPLE 4 Step 1 A solution of 1 M sodium bis (trimethylsilyl) amide in THF (100 ml 110 mmol) cooled to 0 ° C was treated with triethylphosphonoacetate (23.5 ml, 118 mmol). After 20 minutes, the reaction mixture was warmed to room temperature, and terephthalaldehyde mono- (diethyl acetal) (19.3 ml, 97.0 mmoleses) dissolved in THF (250 ml) was added over 25 minutes. The reaction mixture was stirred at 35 ° C for 3.5 h and concentrated. The residue was suspended in EtOAc (250 ml), washed with H 2 O (100 ml) and brine (100 ml), dried with MgSO 4 and concentrated to give 27 g of the crude intermediate. The crude intermediate (27 g) was dissolved in acetone (350 ml) and H 2 O (4.5 ml), treated with Amberlyst-15 resin (3.1 g) for 2.5 hours, filtered and concentrated to give the aldehyde intermediate.

To a cooled (0 ° C) solution of 4-iodo-1-trityl imidazole (41.3 g, 96.9 mmol) in CH2Cl2 (500 mL) was added 3M EtMgBr in ether (35 mL, 105 mmol) for 15 minutes. After 30 minutes at 0 ° C the reaction mixture was warmed to room temperature, and a solution of the aldehyde intermediate in CH 2 Cl 2 (50 ml) was added. After 2 hours, the reaction mixture was added to 1 l of saturated NH CI. The organic layer was partitioned and the aqueous layer was washed with brine (250 ml), dried with MgSO 4 and concentrated. The product was purified by silica gel chromatography eluting with 1: 1 CH2Cl2-EtOAc to give 30.2 g of the product 50 (59 mmol, 61% of total product); 1 H NMR (CDCl 3) d 1.34 (t, J = 7.1 Hz, 3 H), 4.26 (q, J = 7.1 Hz, 2 H), 5.79 (s, 1 H), 6.40 (d, J = 16.0 Hz, 1 H) , 6.59 (s, 1 H), 7.1-7.5 (m, 20H), 7.65 (d, J = 16.0 Hz, 1 H).

Step 2 To a compound solution 50 (102 g, 19.9 mmol), CH 2 Cl 2 (115 mL), acetone (115 mL) and Nal (11.9 g 79.3 mmol) was added dichlorodimethylsilane (19.4 mL, 159 mmol). After 15 minutes, the reaction mixture was added to CH2Cl2 (600 ml) and washed with 10% aqueous sodium thiosulfate (5 x 400 ml), H2O (2 x 400 ml) and brine (400 ml), dried over MgSO4 and concentrated. The product was purified by silica gel chromatography eluting with 2: 1 followed by 1: 1 CH2Cl2-EtOAc to give 7.2 g of product 51 (14 mmol, 72% yield). 1 H NMR (CDCl 3) d 1.33 (t, J = 7.0 Hz, 3 H), 3.90 (s, 2 H), 4.26 (q, J = 7.0, 2 H), 6.39 (d, J = 16.0 Hz, 1 H), 6.58 (s, 1 H), 7.1-7.5 (m, 20H), 7.65 (d, J = 16.0 Hz, 1 H).

Step 3 To a suspension of compound 51 (6.2 g, 12 mmol) in MeOH (65 ml) was added magnesium (0.65 g, 27 mmol), stirred at room temperature for 2 hours. More magnesium (0.71 g, 29 mmol) was added and the reaction mixture was stirred for an additional 1.5 hours. The reaction mixture was added 3M HCl (80 ml) and extracted with CH2Cl2 (3 x 50 ml). The combined organic layers were washed with brine (60 ml), dried with MgSO 4, concentrated and purified by silica gel chromatography eluting with 30: 1 and 10: 1 CH 2 Cl 2 -MeOH to give 5.0 g of methyl intermediate 52 saturated ester (10 mmoleses, 86% yield). 1 H NMR (CDCl 3) d 2.60 (t, J = 7.4 Hz, 2 H), 2.91 (t, J = 7.4 Hz, 2 H), 3.67 (s, 3 H), 3.87 (s, 2 H), 6.56 (2, 2 H) , 7.1-7.4 (m, 20H).

Step 4 To a cooled (0 ° C) solution of 2- (4-chlorophenyl) ethylamine (76 μL, 0.57 mmol) in toluene (10 mL) was added 2M trimethyl aluminum in toluene (0.55 mL, 1.1 mmol) and stirred at room temperature, for 45 min. A solution of compound 52 (0.28 g) was added to the reaction mixture., 0.54 mmoles) in toluene (5.0 ml). After heating at 65 ° C for 3.5 hours, the reaction mixture was cooled, warmed carefully with saturated NaSO 4 (aqueous), concentrated and purified by silica gel chromatography eluting with 5% saturated NH 3 MeOH in CH 2 Cl 2 give 0.16 g of the amide intermediate (0.26 mmol, 48% yield). A solution of the amide intermediate (0.16 g, 0.26 mmol) in EtOH (5.0 mL) was treated with 3M HCl (5.0 mL) at 65 ° C for 2 hours and concentrated. Purification by chromatrog raphy by silica gel eluting with 5% sat. NH3. MeOH in CH2Cl2 followed by acidification with 3M HCl and concentration gave 35 mg of the title product 24a (0.095 mmol, 37% yield). HRMS (M + H +): m / e calculated [C2? H23N3Ocl] +: 368.1533, found 368.1530. Following the previous examples using the starting compounds and suitable reaction conditions for the compounds used. The compounds 1-4, 6, 7, 9, 12 and 14-23 described above were prepared as their HCl salt. The results of the mass spectrometry with the HCl salts are given in the following table.

Physical data Surprisingly, it has been found that these selection compounds are in general substantially more active than the preferred compounds of WO 95/14007. However, their most substantial advantage is that they provide higher blood levels of the compound and are believed to be more bioavailable and more easily absorbed orally. This makes them particularly useful as medicines.

Hg receptor binding assay The source of the H3 receptor is this experiment was guinea pig brain. The animals weighed 400-600 g. The brain tissue was homogenized using Polytron in a solution of 50 mM tris, pH 7.5. The final tissue concentration in the homogenization regulator was 10% w / vol. The homogenates were centrifuged at 1,000 x g for 10 min. to remove the groups of tissue and debris. The resulting supernatant was then centrifuged at 50,000 x g for 20 min to pellet the membranes, which were then washed three times in a homogenization regulator (50,000 x g for 20 minutes each). The membranes were frozen and stored at -70 ° C until needed. All the compounds to be tested were dissolved in DMSO and then diluted in the binding buffer (50 mM tris, pH 7.5) such that the final concentration was 2 μg / ml with 0.1% DMSO: The membranes were then they added (400 μg of protein) to the reaction tubes. The reaction was started with the addition of 3 nM [3H] R-α-methylhistamine (8.8 Ci / mmoles) or 3 nM 3H] Na-methylhistamine (80 Ci / mmoles) and incubation was continued at 30 ° C for 30 minutes. The bound ligand was separated from the unbound linkage by means of filtration, and the amount of the radioactive ligand bound by means of filtration, and the amount of the radioactive ligand bound to the membranes was quantified by liquid scintillation spectrometry. All incubations were done in duplicate and the standard error was always less than 10%. 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). The results are given in the following table for the HCl salt of the indicated compound. Compounds 1-24 had a Ki within a range between 1-32 nM. Compound 8 had Ki values of 4 and 12 nM. Of these test results and general knowledge about the compounds described in the references in the "background of the invention" section, it is expected that the compounds of the invention are useful for treating inflammation, allergy, gastrointestinal tract diseases, cardiovascular diseases, or disorders of the central nervous system. The inert pharmaceutically acceptable carriers used to prepare the pharmaceutical compositions of the compounds of the formula I and their salts may be solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may comprise between about 5 to about 70 percent of the active ingredient. Suitable solid carriers are known in the art, for example, magnesium carbonate, magnesium stearate, talc, sugar, lactose. Tablets, powders cachets and capsules can be used as solid dosage forms suitable for oral administration. The preparation in liquid form includes solutions, suspensions and emulsions, for example, water or water-propylene glycol solutions for parenteral injection. Preparations in liquid form also include solutions for intranasal administration. Also included are solid form preparations that are ready for conversion, shortly before use, into liquid form preparations for oral or parenteral administration. These liquid forms include solutions, suspensions and emulsions. Aerosol preparations suitable for inhalation may include solutions and solids in powders, which may be in combination with a pharmaceutically acceptable carrier such as, for example, an inert compressed gas. To prepare suppositories, a low melting wax such as, for example, a mixture of fatty acid glycerides or cocoa butter is first fused, and the active ingredient is dispersed homogeneously by means of stirring. The molten homogeneous mixture is then conveniently poured into molds as a measure, and allowed to cool and thus solidify. Preferably, the compound is administered orally. Preferably, the pharmaceutical preparation has the form of a unit dose. In this form, the preparation is subdivided into unit doses containing suitable amounts of the active component, for example, an effective amount to achieve the desired purpose. The amount of the active compound in a unit dose can be varied or adjusted between about 0.1 mg and 1,000 mg, more preferably between about 1 mg and 500 mg, according to the particular application. The actual dose used may vary depending on the requirements of the patient and the severity of the condition to be treated. The determination of the appropriate dose for a particular condition is within the capacity of the technician. Generally, treatment starts with lower doses that are less than the optimum dose of the compound. Then, the dose is increased in small quantities until the optimum effect is achieved for those circumstances. For reasons of convenience, the total daily dose may be divided and administered in portions during the day, if desired. The amount and frequency of administration of the compounds of the invention and their pharmaceutically acceptable salts will be regulated according to the judgment of the physician considering factors such as, for example, the age, condition, and weight of the patient as well as the severity of the symptoms to be treated. A recommended dosage regimen is oral administration of between 1 mg and 2,000 mg / day, preferably between 10 and 1,000 mg / day, from one to four divided doses to achieve relief of symptoms. The compounds are non-toxic when administered in therapeutic doses. The following are examples of pharmaceutical dosage forms containing a compound of the invention. As used herein, the term "active compound" is used to designate one of the compounds of formula I or its salt.

EXAMPLES OF THE PHARMACEUTICAL DOSAGE FORM EXAMPLE A Tablets Manufacturing method Mix the items Nr 1 and 2 in a suitable mixture for 10 to 15 minutes. Granulate the mixture with item Nr 3. Grind the wet granules through a coarse screen (eg, 4, 0.63 cm) if necessary. Dry the wet granules. Sieve the wet granules if necessary and mix with the item Nr 4 and mix for 10-15 minutes. Add item No. 5 and mix for 1 to 3 minutes. Compress the mixture to a suitable size and weigh on a machine to form tablets.

EXAMPLE B Capsules Manufacturing method Mix items 1, 2 and 3 in a suitable mixer during to 15 minutes. Add item No. 4 and mix for 1 to 3 minutes. Place the mixture in two-piece hard gelatin capsules in a suitable encapsulating machine. While we have described a number of embodiments of this invention, it is obvious that the embodiments may be altered to provide other embodiments utilizing the compositions and processes of this invention. Therefore, it will be appreciated that the scope of this invention includes alternative embodiments and variations that are defined in the above specification and in the appended claims; and the invention should not be limited to the specific embodiments that have been presented here by way of example.

Claims (17)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of the formula or its pharmaceutically acceptable acid addition salt or tautomer thereof; where A is -CH 2 -NH-CO-NH-; -CH 2 -O-CO-NH-o-CH 2 CH 2 -CO-NH- (CH 2) m-; M is 0, 1 or 2; R is the group where at least two of R1, R2, R3 and R4 are hydrogen and the other two are independently selected from H, halogen (e.g., Br, I, F, or Cl), CH3, CF3, OCH3, OCF3 or CN; and with the proviso that when A is -CH2-O-CO-NH + - and R1, R3 and R4 are all hydrogen, then R2 can not be Cl; and with the proviso that the compound is not

2. - The compound of claim 1 wherein said halogen is

F or CI. 3. The compound of claim 1 wherein A is -CH2-NH-CO-NH-. 4. The compound of claim 1 wherein two of R1 to R4 are

Cl.

5. The compound of claim 4 wherein A is -CH 2 -NH-CO-NH-.

6. The compound of claim 3 selected from:

7. - The compound of claim 1 wherein A is -CH 2 -O-CO-NH-.

8. The compound of claim 7 selected from:

9. - The compound of claim 1 wherein A is -CH2CH2-CO-NH-.

10. The compound of claim 9 selected from:

11. - A compound of the formula:

12. A pharmaceutical composition comprising an effective amount of a compound, its salt or solvate, of any of claims 1-11, in combination with a pharmaceutically acceptable carrier or excipient.

13. The use of a compound, its salt or solvate, of any of claims 1-11 for the manufacture of a medicament for the treatment of allergy, inflammation, cardiovascular diseases, hypotension, glaucoma, sleep disorders, diseases of the gastrointestinal tract, states of hyper and hypo-mobility of the gastrointestinal tract, diseases of the central nervous system, hypo and hyperactivity of the central nervous system, Alzheimer's disease, schizophrenia, obesity and migraines.

14. The use of a compound, or its salt or solvate, of any of claims 1-11, for the manufacture of a medicament for use in combination with a medicament manufactured to be used as an antagonist of the Hi receptor, for the treatment of the allergic responses of the upper airways.

15. The use of claim 14 wherein said Hi antagonist is selected from: loratadine, descarboethoxyloratadine, fexofenadine, cetirizine.

16. The use of claim 14 wherein said Hi antagonist is loratadine.

17. The use of claim 14 wherein said Hi antagonist is descarboethoxyloratadine.