MXPA99008997A - Benzocycloheptathiophene compounds - Google Patents

Abstract

Disclosed are N-substituted hydroxyalkyl or carboxyalkyloxyalkyl analogs of 9- and/or 10-oxo-4Hbenzo[4,5]cyclohepta[1,2-b]thiophene compounds, or 9-OH and/or 10-OH-substituted analogs thereof, which possess antihistaminic and antiasthmatic properties with reduced sedative side effects. The optically active isomers and the pharmaceutically acceptable salts thereof are also described. The compounds were also found to prevent smooth muscle hyperreactivity.

Description

, BENZOCICLOHEPTATIOFENO COMPOUNDS TECHNICAL FIELD This invention relates to novel chemical entities as shown below with methods of treating disease states modulated by allergic, inflammatory or cholinergic activities in a mammal, using novel chemical entities. The compounds of the invention include the chemical entities of the following formula: where -AB- is a portion having the formula -CO-CH2- (a) -CH2-CO- (b) -CH2-CH2- (c) -CHOH-CH2- (d) -CHOH-CHOH- (e ) -CH2-CHOH- (f) REF .: 31372 or -CO-CO- (g) and wherein R is a hydroxyalkyl or a portion of a carboxyalkyloxyalkyl, and the pharmaceutically acceptable salts thereof, and the optically active isomers of the racemic compounds. The compounds of this invention have pharmacological properties that convert such useful compounds in the prevention and treatment of allergies, inflammations, various types of ocular diseases and different types of smooth muscle hyperreactivity (such as bronchial and uterine hyperresponsiveness, including hyperreactivity induced by drugs). More particularly, this invention relates to novel chemical entities and methods of treating allergic conditions (such as, for example, allergic rhinitis), pulmonary conditions (such as, for example, asthma, bronchitis, cough and bronchial hyperresponsiveness), skin conditions (such as, for example, urticaria, psoriasis and atopic dermatitis), gastrointestinal disorders (such as hypersecretory syndromes, including Zollinger-Ellison syndrome, gastric irritation and enteritis) and other inflammatory conditions and / or allergic conditions (such as, for example, ocular conjunctivitis and ocular keratitis), while avoiding side effects (such as sedation, cardiac arrhythmias and eye irritation), using novel chemical entities. This invention also relates to compositions, which contain at least one such novel chemical amount and the combination of the compounds herein with various other chemical entities.

BACKGROUND OF THE INVENTION This invention relates specifically to anti-inflammatory and antiallergic compounds, which have therapeutic and antiallergic use that have therapeutic use in various diseases, most importantly for patients suffering from diseases of hyperreactive airways and / or obstructive airways. , including asthma and bronchitis or for skin ailments and allergies, including urticaria, atopic dermatitis, allergic rhinitis and retinopathy or other diseases of the small vessels associated with diabetes mellitus or eye diseases, including conjunctivitis and keratitis .

The compounds of the present demonstrate chemical similarities with cetotifen (Zaditen®) and were not previously known to applicants. Collateral sedative effects have severely limited the therapeutic activity of cetotifen and such side effects can be reduced or eliminated using the compounds of the present invention. The pharmacology, toxicology, metabolism and clinical experience with cetotifen have been summarized by Sorkin et al. (Focus on Ketotifen, Ed. E. M. Sorkin, In Drugs, Sept. 1990. Vol. 40, No. 3, pp. 412-448).

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to certain novel chemical entities as described below, to methods of using such chemical entities for therapeutic purposes and to compositions comprising one or more inert pharmaceutically acceptable carriers and as an active ingredient. a therapeutically effective amount of at least one compound, the pharmaceutically acceptable acid addition salts thereof and the stereochemically isomeric forms thereof, having the formula: where R is a member selected from the group consisting of C2_6 hydroxyalkyl or carboxy-alkylaryl of C? -6-alkyl C? -6 and -AB- is a portion having the formula -CO-CH2- (a) -CH2-CO- (b) -CH2-CH2- (c) -CHOH-CH2- (d) -CHOH- CHOH- (e) -CH2-CHOH- (f) or -co-co- (q) The compounds of the present invention have been synthesized and studied pharmacologically. Significant pharmacological differences were found between the compounds of the present invention and cetotifen in this way, cetotifen. it has deep sedative side effects, whereas it has now been found that the compounds of the present have a reduced or absent sedative activity. It has also been established that the novel compounds have antihistaminergic and anti-inflammatory properties. It is important that novel compounds have potent pulmonary anti-inflammatory effects and that they potentially inhibit bronchial smooth muscle hyperreactivity. Since the inflammation of the pulmonary airways and the bronchial smooth muscle hyperreactivity are the contrasts of asthma, it was concluded that the novel compounds - besides being potent antihistamines - will have clinical utility for the treatment of asthma and brori-quitis, without the concomitant sedative side effects.

DETAILED DESCRIPTION BIOLOGICAL STUDIES OF THE COMPOUNDS OF THE PRESENT INVENTION As discussed above, it is now shown that the compounds of the present invention have beneficial pharmacological effects, useful in the treatment of various conditions, such as asthma, allergies and eye diseases. The new discoveries are described in the following biological studies. 1. Binding of histaminergic receptors The affinities of the test compounds for Hi receptors of histamine were evaluated using the [3H] pyrilamine binding assay, modified after Chan et al. Heterogeneity of Hi-Receptors of Histamine. J. Neurochem. 1979, 32: 1653-1663. Briefly, bovine cerebellum membranes were incubated with [3H] pyrilamine and the test compound at increasing concentrations. The specific binding of the radioactive ligand to the receptor was defined as the difference between the total binding and the non-specific binding, determined in the presence of an excess of unlabeled ligand. The IC 50 values (concentration required to inhibit 50% of the specific inhibition of [3 H] pyrilamine) were determined by means of a non-linear regression analysis of competitive curves.

IC50 (M) CETOTIFEN. 8.15 x 10-9 NORCETOTIFEN 4.36 x 10-8 10-OH-NORCETOTIFEN 1.13 x 10-7 IC50 (M) EXAMPLE 2, where n = 2 5.85 x 10-9 EXAMPLE 5, where n = 2 6.95 x 10-8 TRIPROLIDINE HCl 1.41 x 10-8 (reference compound) 2. Binding to muscarinic receptors The affinities of the test compounds for the My muscarinic receptors were evaluated using the [3 H] pirincepin binding assay, modified after Luthin et al. Binding of [3H] pirincepin and [3H] QNB to muscarinic cholinergic receptors of the brain. Molec. Pharmac, 1984, 26: 164-169. Briefly, the experiments were carried out on the bovine striatal membranes expressing the My muscarinic receptors. After incubation with the test article and the appropriate radioligand and washing, the bound radioactivity was determined with a flashing counter in the liquid state, using a commercial flash cocktail. The binding of the specific radioligand to each receptor was defined as the difference between the total binding and the non-specific binding determined in the presence of an excess of the unlabeled ligand. The IC 50 values (concentrations required to inhibit 50% of the specific binding) were determined by means of a non-linear regression analysis of the competitive curves.

IC50 (M) CETOTIFEN 7.11 x 10-8 NORCETOTIFEN. 2.62 x 10-7 EXAMPLE 2, where n = 2 2.35 x 10-7 EXAMPLE 5, where n = 2 8.80 x 10.7 ATROPIN Sulfate 5.74 x 10-10 (reference compound) 3. Studies on sedative effects. The physostigmine-induced lethality test in these tests is a modification of the sedation test technique reported by COLLIER et al, in Br. J. Pharmac, 1968, 32: 295-310. Briefly, physostigmine (1.9 mg / kg s.c.) produces a 100% lethality when given to mice grouped with 10 animals in a plastic cage (approximately 11x26x13 cm). Mice given an antihistamine sedative before physostigmine are protected and survive. In the present study, the test compounds were administered orally 60 minutes before physostigmine. The number of survivors was counted 30 minutes after the administration of physostigmine. The doses in the tests in the CNS were half the molecular weights of the test compounds, expressed in mg / kg of body weight.

Oral treatment (mg / kg) Survivors Cetotifen (107) 9/10 Nor-ketotifen (83) 3/10 EXAMPLE 2, where n = 2 (94) 3/10 EXAMPLE 5, where n = 2 (108) 0/10 Vehicle 0/10 Astemizole (115) 1/10 Non-sedating antihistamine reference compound 4. Anti-inflammatory effects (inhibition of bronchial eosinophil accumulation) The inhibition of eosinophil accumulation in the lung was determined in guinea pigs (400 to 600 grams) after intraperitoneal injection of 0 μg of PAF (platelet aggregation factor) in 0.25% of bovine serum albumin in saline. Twenty-four hours later the animals were sacrificed with barbiturate. The trachea was exposed and cannulated. Aliquots of 6 x 10 ml of modified, buffered Tyrode solution (composition: aHC03 11 9, NaCl 136.9, KCl 2.7, Na2HP04 0.4, glucose 5.6, EDTA 19.8, gelatin 0.1% w / v, BSA 0.5% by weight / volume, pH 7.4) were introduced successively and aspirated by gentle compression of the lungs. The recovery of the total fluid normally exceeded 80%. The cell suspensions were concentrated by low speed centrifugation and the resulting cell pellet was resuspended in 1 ml of Tyrode solution. The total cell counts were made by diluting lOμl of cell suspension in 90μl of Turk's fluid. The differential cell counts were made from smears fixed in methanol (100%) and stained in Leishman's stain. A total of at least 500 cells were counted per smear at a 1000-fold amplification, to differentiate cell types. The drugs were administered for 7 days as a sustained subcutaneous infusion from an implanted Alza minipump, so that exposure to PAF occurred only after a five-day pretreatment period with the test compounds.

. Studies on gastric effects. The effects of the compounds of the invention on isolated bradykinin-induced contractions of guinea pig ileus were studied. The tissue was pretreated with various concentrations of the test compounds before the contractile response to bradykinin (in the absence or presence of 1 μM atropine). The effects of the compounds on gastric ulcerations were studied in the rat. The ulcerations were produced by the subcutaneous injection of 30 mg / kg indomethacin. The study groups received the test compounds 100 μg / 100 g body weight, p.o. 30 minutes before and 5 hours after the administration of indomethacin. The reduction of the ulcerated area was measured (mm).

CHEMICAL SYNTHESIS OF NOVEDOUS COMPOUNDS, EXAMPLES The synthesis of cetotifen, norOetotifen and (RS) -10-OH-quetotifen has been described by Waldvogel et al. (Helv Chem Acta, 1976, 59: 866-877), the subject matters of which are incorporated herein by reference. The novel compounds of the present invention are of the general formula, shown in Table I, below. The starting compounds for these syntheses were obtained as described in Waldvogel et al .: Compound (1) 4- (4-piperidylidene) -9,10-dihydro-4H-benzo [4,5] cyclohepta [1,2-b] thiophen-9-one. Compound (2) 4- (4-piperidylidene) -9,10-dihydro-4 _? -benzo [4,5] cyclohepta [1,2-b] thiophen-10-one. Compound (3) 4- (4-piperidylidene) -9,10-dihydro-4i? -benzo [4,5] cyclohepta [1,2-b] thiophene.

Compound (4) 4- (4-piperidylidene) -9,10-dihydro-4'-benzo [4, 5] cyclohepta [1,2- b] thiophen-9,10-dione. where R is a member selected from the group consisting of hydroxy-C2_e alkyl or C6_6-carboxy-alkyloxy-C6_6alkyl, and --A-B- is a portion having the formula (a) .Hr -CC- (b): H -CH2 (c) -CHOH-CH2 (d) -CHOH-CHOH- (e) H2-CHOH- (f) : o- (g) Table 1. Novel compounds of the present invention Example 1 The Compound of Table 1, where R is - (CH2) nOH and where -A-B- has the formula -CO-CH2-, and where n = 2, was prepared by treating the starting Compound (1) with a 2-haloethanol, such as 2-bromoethanol or 2-chloroethanol, in the presence of a basic catalyst such as potassium carbonate in such a solvent such as N, N-dimethyl formamide (DMF) with stirring, with or without heating to cause the reaction. After removal of the solvent by evaporation, the residue was mixed with water and extracted with an organic solvent such as chloroform, methylene chloride or ethyl acetate. After removal of the organic solvent by evaporation, the product can be purified by crystallization of a solvent such as methanol or ethanol. Similar compounds, where n = 3-6, can be prepared by the same method but with the use of? -halo alcohols, X- (CH2) 3_6-OH, where X is chlorine or bromine. The products can be converted to the hydrochloride salts by dissolving in a solvent mixture such as chloroform / diethyl ether and adding a solution of hydrogen chloride in dioxane. The evaporation of the solvents gives the product as the hydrochloride.

Example 2 The Compound of Table 1, where R is - (CH2) nOH and where --A-B- has the formula -CH2-CO-, and where n = 2, was prepared by the reaction of one gram of the Compound (2) with a 2-chloroethanol (3 equivalents) potassium carbonate (3 equivalents) and potassium iodide (0.4 equivalents) in 10 ml of dimethylformamide. After stirring for four days at room temperature, the solvent was evaporated in vacuo, the residue was dissolved in chloroform (50 ml), and the solution was washed with water and dried with magnesium sulfate. The solvent was removed and the crude product was purified by chromatography on silica gel with 5% methanol in chloroform as eluent. The product was dissolved in chloroform / diethyl ether, and a solution of hydrogen chloride in dioxane was added. The solvents were evaporated in vacuo leaving Example 2 (n = 2) as the hydrochloride. Yield: 0.87 grams. The NMR of the proton was consistent with the proposed structure.

Example 3 The Compound of Table 1, where R is - (CH2) nOH and where - -B- has the formula -CH2-CH2-, and where n = 2, was prepared by treating the starting Compound (3) with a 2-haloethanol, such as 2-bromoethanol or 2-chloroethanol, in the presence of a basic catalyst such as potassium carbonate in a solvent such as N, N-di-ethylformamide (DMF) with stirring, with or without heating to cause the reaction. After removal of the solvent by evaporation, the residue was mixed with water and extracted with an organic solvent such as chloroform, methylene chloride or ethyl acetate. After removal of the organic solvent by evaporation, the product can be purified by crystallization of a solvent such as methanol or ethanol. Similar compounds, where n = 3-6, can be prepared by the same method but with? -halo alcohols. X- (CH2) 3_6-OH, where X is chloro or bromo. The products can be converted to the hydrochloride salts by dissolving in a mixture of solvents such as chloroform / diethyl ether and adding a solution of hydrogen chloride in dioxane. The evaporation of the solvents gives the product as the hydrochloride.

Example 4 The Compound of Table 1, where R is - (CH2) n-0-CH2-COOH and where - -B- has the formula -CO-CH2-, and where n = 2, was prepared from the Compound of Table 1, where R is - (CH2) nOH and where --A-B- has the formula -CO-CH2-, and where n = 2, by treatment with a haloacetic acid. X-CH2COOH where X = chlorine or bromine, in the presence of a basic catalyst such as potassium carbonate in a solvent such as DMF with stirring, with or without heating to cause the reaction. After removal of the solvent by evaporation, the residue was mixed with water, the solution was neutralized to pH 5-6, and the aqueous solution was extracted with an organic solvent such as chloroform, methylene chloride or ethyl acetate. After removal of the organic solvent by evaporation, the product can be purified by crystallization of a solvent such as methanol or ethanol. Similar compounds, where n = 3-6, can be prepared by the same method from the compounds of Table 1, where R is - (CH 2) n -O-CH 2 -COOH and where -A-B- has the formula -, and where n = 3-6. Alternatively, the compounds of Table 1, where R is - (CH2) n-H2-COOH and where --A-B- has the formula -CO-CH2-, and where n = 2-6, can be synthesized according to the general method described under "Example 5" below.

Example 5. The compound of Table 1, where R is - (CH 2) n -O-CH 2 -COOH and where - -B- has the formula and where n = 2, was prepared in two steps. In the first step, 1.9 grams of Compound (2) were treated with (2-chloroethoxy) acetonitrile (2 equivalents) and potassium carbonate (2.4 equivalents) in 10 ml of dimethylformamide. After stirring for four days at room temperature, the solvent was evaporated in vacuo and 10 ml of water was added to the residue. The resulting suspension was extracted with 3 x 10 ml portions of chloroform, and the combined extracts were evaporated and the crude product was purified by chromatography on silica gel with 2% methanol and chloroform as eluent. The intermediate, N- [(2-cyanoethoxy) ethyl] ñor cetotifen (0.75 grams) was heated in concentrated hydrochloric acid for 12 hours. The solvent was evaporated in vacuo, and the residue. The rose was dissolved in methanol, treated twice with activated charcoal, filtered, and the solvent evaporated in vacuo to give the hydrochloride of Example 5 (n = 2) as a pink foam. Yield: 0.71 grams. The NMR of the proton was consistent with the proposed structure.

Example 6. The compound of Table 1, where R is - (CH2) n-0-CH2-COOH and where -AB- has the formula -CH2-CH2-, and where n = 2, was prepared from the compound of Table 1, where R is - (CH2) nOH and where -AB- has the formula -CH2-CH2-, and where n = 2, by treatment with a haloacetic acid, X-CH2COOH, where X = chlorine or bromine , in the presence of a basic catalyst such as potassium carbonate in a solvent such as DMF with stirring, with or without heating to cause the reaction. After removal of the solvent by evaporation, the residue was mixed with water, the solution was neutralized to pH 5-6, and the aqueous solution was extracted with an organic solvent such as chloroform, methylene chloride or ethyl acetate. After removal of the organic solvent by evaporation, the product can be purified by crystallization of a solvent such as methanol or ethanol. Similar compounds, where n = 3-6, can be prepared by the same method from the compounds of Table 1, where R is - (CH2) n-0H and where -AB- has the formula -CH2-CH2 -, and where n = 3-6. Alternatively, the compounds of Table 1, where R is - (CH 2) n-0-CH 2 -COOH and where -AB- has the formula -CH 2 -CH 2 -, and where n = 2-6, can be synthesized according to the general method described under "Example 5".

Example 7. The compound of Table 1, where R is - (CH2) n-OH and where -AB- has the formula -CHOH-CH2-, and where n = 2, was prepared from the compound of Table 1 , where R is - (CH2) nOH and where -AB- has the formula -CO-CH2-, and where n = 2, by treatment with sodium borohydride in a solvent such as ethanol at room temperature. After the decomposition of the excess reagent with acetone, the solvents were removed by evaporation and the residue was recrystallized from a solvent such as methanol or ethanol, with or without diethyl ether. Similar compounds, where n = 3-6, can be prepared by the same method from the compounds of Table 1, where R is - (CH2) nOH and where -AB- has the formula -CO-CH2-, and where n = 3-6. The products can be converted to the hydrochloride salts by dissolving in a mixture of solvents such as chloroform / diethyl ether and adding a solution of hydrogen chloride in dioxane. The evaporation of the solvent gives the product as the hydrochloride.

Example 8. The compound of Table 1, where R is - (CH2) n-0-CH2-COOH and where -AB- has the formula -CHOH-CH2-, and where n = 2, was prepared from the compound of Table 1, where R is - (CH2) nOH and where -AB- has the formula -CO-CH2-, and where n = 2, by treatment with sodium borohydride in a solvent such as ethanol at room temperature. After the decomposition of the excess reagent with acetone, the solvents were removed by evaporation, and the residue was mixed with water, the solution was neutralized with an acid such as dilute hydrochloric acid, and extracted with a solvent such as ethyl acetate. After removal of the organic solvent by evaporation, the residue was crystallized from a solvent such as methanol or ethanol, with or without diethyl ether. Similar compounds, where n = 3-6, can be prepared by the same method from the compounds of Table 1, where R is - (CH2) nOH and where -AB- has the formula -CO-CH2-, and where n = 3-6. Alternatively, the compounds of Table 1, where R is - (CH 2) n-0-CH 2 -COOH and where -AB- has the formula -CHOH-CH 2 -, and where n = 2-6, can be synthesized according to the general method described under "Example 5".

Example 9. The compound of Table 1, where R is - (CH2) nOH and where -AB- has the formula -CH2-CHOH-, and where n = 2, was prepared from the compound of Table 1, where R is ~ (CH2) nOH and where -AB- has the formula -CH2-CO-, and where n- '2, by treatment with sodium borohydride in a solvent such as ethanol at room temperature. After the decomposition of the excess reagent with acetone, the solvents were removed by evaporation and the residue was crystallized from a solvent such as methanol or ethanol, with or without diethyl ether. Similar compounds, where n = 3-6, can be prepared by the same method from the compounds of Table 1, where R is - (CH2) nOH and where -AB- has the formula -CH2-CO-, and where n = 3-6. The products can be converted to the hydrochloride salts by dissolving in a mixture of solvents such as chloroform / diethyl ether and adding a solution of hydrogen chloride in dioxane. The evaporation of the solvents gives the product as the hydrochloride.

Example 10. The compound of Table 1, where R is - (CH2) n-0-CH2-COOH and where -AB- has the formula -CH2-CHOH-, and where n = 2, was prepared from the compound of Table 1, where R is - (CH2) n-0-CH2-COOH and where -AB- has the formula -CH2-C0-, and where n = 2, by treatment with sodium borohydride in a solvent such as the ethanol at room temperature. After the decomposition of the excess reagent with acetone, the solvents were removed by evaporation, and the residue was mixed with water, the solution was neutralized with an acid such as dilute hydrochloric acid, and extracted with a solvent such as acetate. of ethyl. After removal of the organic solvent by evaporation, the residue was crystallized from a solvent such as methanol or ethanol, with or without diethyl ether. Similar compounds, where n = 3-6, can be prepared by the same method from the compounds of Table 1, where R is - (CH 2) n -CH 2 -COOH and where -AB- has the formula -CH 2 -CO-, and where n = 3-6. Alternatively, the compounds of Table 1, where R is - (CH 2) n-0-CH 2 -COOH and where -AB- has the formula -CH 2 -CHOH-, and where n = 2-6, can be synthesized according to the general method described under "Example 5".

Example 11. The compound of Table 1, where R is - (CH2) nOH and where -AB- has the formula -CO-CO-, and where n = 2, was prepared by treating the starting compound (4) with a 2-haloethanol, such as 2-bromoethanol or 2-chloroethanol, in the presence of a basic catalyst, such as potassium carbonate in a solvent such as N, N-dimethylformamide (DMF) with stirring, with or without heating to cause the reaction. After removal of the solvent by evaporation, the residue was mixed with water and extracted with an organic solvent such as chloroform, methylene chloride or ethyl acetate. After removal of the organic solvent by evaporation, the product can be purified by crystallization of a solvent such as methanol or ethanol. The compounds • similar, where n = 3-6, can be prepared by the same method, but with? -halo alcohols, X- (CH2) 3-6-OH, where X is chlorine or bromine.

The products can be converted to the hydrochloride salts by dissolving in a mixture of solvents such as chloroform / diethyl ether and adding a solution of hydrogen chloride in dioxane. The evaporation of the solvents gives the product as the hydrochloride.

Example 12. The compound of Table 1, where R is - (CH2) n_0-CH2-COOH and where -AB- has the formula -CO-CO-, and where n = 2, was prepared from the compound of the Table 1, where R is - (CH2) n-OH and where -AB- has the formula -CO-CO-, and where n = 2, by treatment with haloacetic acid, X-CH2COOH, where X = chlorine or bromine, in the presence of a basic catalyst such as potassium carbonate in a solvent such as DMF with stirring, with or without heating to cause the reaction. After . of solvent removal by evaporation, the residue was mixed with water, the solution was neutralized to pH 5-6, and the aqueous solution was extracted with an organic solvent such as chloroform, methylene chloride or ethyl acetate. After removal of the organic solvent by evaporation, the product can be purified by crystallization of a solvent such as methanol or ethanol. Similar compounds, where n = 3-6, can be prepared by the same method from the compounds of Table 1, where R is ~ (CH2) nOH and where -AB- has the formula -CO-CO-, and where n = 3-6. Alternatively, the compounds of Table 1, where R is - (CH 2) n-0-CH 2 -COOH and where -AB- has the formula -CO-CO-, and where n = 2-6, can be synthesized according to the general method described under "Example 5".

Example 13. The compound of Table 1, where R is - (CH2) nOH and where -AB- has the formula -CHOH-CHOH-, and where n = 2, was prepared from the compound of Table 1, where R is - (CH2) nOH and where -AB- has the formula -CO-CO-, and where n = 2, by treatment with sodium borohydride in a solvent such as ethanol at room temperature. After the decomposition of the excess reagent with acetone, the solvents were removed by evaporation and the residue was crystallized from a solvent such as methanol or ethanol, with or without diethyl ether. Similar compounds, where n = 3-6, can be prepared by the same method from the compounds of Table 1, where R is - (CH2) nOH and where -A-B- has the formula -CO-CO-. The products can be converted to the hydrochloride salts by dissolving in a mixture of solvents such as chloroform / diethyl ether and adding a solution of hydrogen chloride in dioxane. The evaporation of the solvents gives the product as the hydrochloride.

Example 14. The compound of Table 1, where R is - (CH2) n-0-CH2-COOH and where -AB- has the formula -CHOH-CHOH-, and where n = 2, was prepared from the compound of Table 1, where R is - (CH2) n-0-CH2-COOH and where -AB- has the formula -CO-CO-, and where n = 2, by treatment with sodium borohydride in a solvent such as the ethanol at room temperature. After the decomposition of the excess reagent with acetone, the solvents were removed by evaporation, and the residue was mixed with water, the solution was neutralized with an acid such as dilute hydrochloric acid, and extracted with a solvent such as acetate. of ethyl. After removal of the organic solvent by evaporation, the residue was crystallized from a solvent such as methanol or ethanol, with or without diethyl ether. Similar compounds, where n = 3-6, can be prepared by the same method from the compounds of Table 1, where R is - (CH 2) n-0-CH 2 -COOH and where -AB- has the formula -CO-CO-. Alternatively, the compounds of Table 1, where R is - (CH 2) n-0-CH 2 -COOH and where -AB- has the formula -CHOH-CHOH-, and where n = 2-6, can be synthesized according to the general method described under "Example 5". The present invention provides the compounds described above, including the isomers of the racemic compounds and the pharmaceutically acceptable acid addition salts and solvates of the novel compounds. The optically active isomers of the compounds of this invention can be prepared by resolution of the racemate using conventional means such as fractional crystallization of the diastereomeric salts with chiral acids. Other standard resolution methods, known to those skilled in the art, include but are not limited to, crystallization and chromatography on a chiral substrate and may also be used. . The optically active isomers of the present invention can also be prepared by stereoselective synthesis. The terms "pharmaceutically acceptable salts" or "pharmaceutically acceptable salts thereof" refer to salts prepared from pharmaceutically acceptable non-toxic acids. Suitable pharmaceutically acceptable acid addition salts for the compound of the present invention include the salts of acetic acid, benzenesulfonic (besylate), benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic. , maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, patothenic, phosphoric, p-toluenesulfonic, succinic, sulfuric, tartaric and the like. Hydrogen fumarate is particularly preferred. The present invention also provides pharmaceutical compositions, which comprise one or more compounds of the invention, formulated together with one or more pharmaceutically acceptable carriers. The pharmaceutical compositions can be formulated especially for oral administrationconjunctival instillation, sublingual administration, parenteral administration, transdermal administration, rectal administration, buccal administration or for topical administration, or for administration by inhalation, powder or aerosol insufflation. The pharmaceutical compositions of this invention can be administered to humans and other mammals orally, sublingually, parenterally, cutaneously, transdermally, rectally, buccally, topically by conjunctival instillation, or an oral or nasal spray or spray. The term "parenteral" administration includes intravenous, intraarterial, intramuscular, intraperitoneal, intracutaneous, subcutaneous or intraarticular injection and infusion. The term "transdermal" includes the use of various devices ("patches", etc.), which may facilitate or modify the transport or absorption of the drug through the skin.

Forms of Oral Administration The pharmaceutical compositions of this invention for the oral administration of solid dosage forms, include capsules, granules, pills, powders and tablets. In such solid dosage forms, the active compound can be mixed with one or more pharmaceutically acceptable excipients or carriers (eg, sodium citrate, dicalcium phosphate), fillers or extenders (eg, starch, lactose, sucrose, glucose, mannitol, acid). silicic), binders (e.g., carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, acacia), humectants (e.g., glycerol), solution retarding agents (e.g., paraffin), disintegrating agents (e.g. agar, calcium carbonate, starch, alginic acid, silicates, sodium carbonate), absorption insurers (for example, quaternary ammonium compounds), wetting agents (for example cetyl alcohol, glycerol monostearate), absorbents (for example kaolin, bentonite clay), lubricating agents (eg, talc, calcium stearate, magnesium stearate, polyethylene glycols, sodium lauryl sulfate) and / or damping agents. The solid forms of the capsules, dragees, granules, pills and tablets may have coatings and / or protections (for example enteric coatings) known in the pharmaceutical formulating art. The compositions may also be designed to release the active ingredients in a certain part of the gastrointestinal tract or in a controlled release, slow release or in a delayed release form. The composition can also be designed for lymphatic absorption of the active ingredients. The active compounds can also be microencapsulated with one or more of the aforementioned excipients. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. The liquid dosage forms may also contain the commonly known diluents (e.g. water, other solvents, solubilizing agents), emulsifiers (e.g. ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol , butylene glycol, dimethyl formamide, oleic oils, glycerol, polyethylene glycols, fatty esters of sorbitan and mixtures thereof). In addition to the inert diluents, the oral compositions may also include adjuvants such as humectants, emulsifiers, suspending agents, sweeteners or flavorings. The suspensions may contain one or more suspending agents known in the pharmaceutical formulating art.

Forms of topical administration (including forms for conjunctival instillation) Compositions for topical administration of the compounds of this invention include solutions, suspensions, drops, sprays, ointments and powders. In addition to therapeutically active ingredients, the composition of this invention for topical conjunctival or ocular administration may further comprise various formulation ingredients, such as antimicrobial preservatives and tonicity agents. Examples of suitable antimicrobial preservatives include: benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, ONAMER M and other agents, known to those skilled in the art. Such condoms, if used, will typically be employed in an amount from 0.001% to 1.0% by weight (% by weight). Examples of suitable agents that can be used to adjust the tonicity or osmolality of the formulations include sodium chloride, potassium chloride, mannitol, dextrose, glycerin and propylene glycol. Such agents, if used, will be employed in an amount of 0.1% to 10.0% by weight (% by weight). The compositions are preferably aqueous, and have a pH in the range of 3.5 to 8.0 and an osmolality in the range of 280 to 320 millimoles per liter. As understood by those skilled in the art, the compositions may be formulated in various dosage forms suitable for topical ophthalmic release, including solutions, suspensions, emulsions, gels and erodable solid eye inserts.

Forms for parenteral administration Pharmaceutical compositions for parenteral injections include sterile, pharmaceutically acceptable solutions, dispersions, suspensions, aqueous and non-aqueous emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions before use. Various carriers, diluents, solvents and vehicles, aqueous and non-aqueous (e.g., water, ethanol, glycerol, glycol), as well as vegetable oils (e.g. olive oil), and organic esters (e.g. ethyl oleate) can be used, or mixtures thereof. The fluidity can be maintained by the use of the coating material such as lecithin, by restricting the particle size or by the use of surfactants. The compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, antibacterial agents, antifungal agents, isotonic agents and / or absorption retarding agents. The effects of prolongation of absorption and deceleration of absorption can be achieved by injecting a crystalline or amorphous suspension with low solubility in water. The delayed absorption can also be obtained by dissolving or suspending the drug in an oily vehicle or by using injectable storage forms (for example microencapsulated matrices of the drug in biodegradable polymers, such as polylactide-polyglycolide, polyorthoesters, polyanhydrides) or by the use of Various types of liposomes or microemulsions to retain the drug Formulations for injection can be sterilized by several methods.

Form for rectal administration Compositions for rectal administration are preferably suppositories.

Forms for buccal administration The compositions for buccal administration are preferably toothpaste, mouthwashes, sublingual preparations, chewing gums, etc.

Forms for sublingual administration Several galenic formulations can be used: concentrated solutions or suspensions of the drug can be applied sublingually by various blocking devices; various aerosol devices can be used to spray the drug on the oral mucous membranes; Quickly designed tablets, capsules or powders designed specifically for the rapid release of a full dose can be used. 15 Forms for transdermal administration Compositions for the transdermal administration of the compounds of this invention include "* several known patches and bandages, etc. 20 Oral or nasal spray or drop administration Oral or nasal spray compositions or drops may be in the form of solutions, suspensions or dry powders, and may be designed for nasal absorption, buccal, bronchial / pulmonary and / or gastric drug.

Therapeutic dose levels The levels of the actual doses between the active ingredients in the pharmaceutical compositions of this invention can be varied to obtain the desired therapeutic effect. In this way, the amount of drug used varies and may depend on factors such as the form of administration, severity of the disease, frequency of dosing, etc. For use as a medicament for patients suffering from benign diseases of the airways or bronchial (such as asthma, bronchitis, etc.), oral doses of the compound of this invention are used at dose levels of 0.5 mg to about 200 mg, preferable way from 0.5 mg to 10 mg one to four times a day for patients weighing 60 kg. The daily dose may be increased or decreased depending on several factors, for example, the weight and state of the patient's disease. As an example to be used as a medicament for patients suffering from allergic conjunctivitis, the oral doses of the compound of this invention are used at dose levels of 0.1 mg to about 100 mg, preferably from 0.2 to 10 mg one to four times daily for a patient weighing 60 kg. For patients suffering from allergic conjunctivitis during certain season of the year, the concentration of solution of norcetotifen for instillation conjunctival sac fluctuates from 0.01% to 2.0%, preferably from 0.02% to 1.0%. The frequency and amount of the dose will be determined by the clinician on the basis of various clinical factors, such as for example the weight and severity of the patient's disease. The use will typically comprise the topical application of one to two drops (or an amount of a solid or semi-solid dosage form) to the affected eye one to four times per day.

Formulation of the oral unit dose EXAMPLE 15. Tablet Formulations Ingredients per tablet per batch of 10,000 tablets Compound of Example 5 2 mg 20 g Microcrystalline cellulose 30 mg 300 g Lactose 70 mg 700 g Calcium stearate 2 mg 20 g Blue # 1 Dye FD &C 0.03 mg 300 mg The active ingredient (in this example, the compound of Example 5, where n = 2) was mixed with the lactose and cellulose until a uniform mixture formed. The dye was added and mixed further. Finally, the calcium stearate was mixed and the resulting mixture compressed into tablets using a shallow 9/32 inch (7 mm) concave punch. Tablets of other strengths can be prepared by altering the ratio of the active ingredient to the excipients or the final weight of the tablet. This invention provides methods for the treatment and / or prophylaxis of all forms of bronchial asthma, allergic bronchitis, multiple system allergies, allergic rhinitis and allergic skin conditions in mammals, such as humans, while avoiding the effects Side sedatives and other toxic manifestations of cetotifen. Those methods comprise administering to the mammal in need of such treatment and / or prophylaxis, effective amounts of at least one compound of the invention or a pharmaceutically acceptable salt thereof. This invention also provides methods for the co-administration of one or more compounds of the invention with beta-receptor agonist agonists, including, but not limited to albuterol, terbutaline, fenoterol, formoterol or salmeterol, thereby eliminating or decreasing bronchial hyperreactivity. which can be induced by such beta agonist therapy.

The invention also provides methods for the co-administration of a compound of this invention with other agents or drugs that cause bronchial hyperreactivity, including, but not limited to, agents that block the beta adrenergic receptor or cyclooxygenase inhibitors, eliminating or decreasing at both the bronchial hyperreactivity that is induced by such therapy.

This invention provides methods for the treatment and / or prophylaxis of forms of eye diseases such as allergic conjunctivitis or allergic keratitis and inflammatory diseases such as blepharitis, conjunctivitis, episcleritis, scleritis, keratitis, anterior uveitis, posterior uveitis, endophthalmitis, neuritis. optics, cranial arteritis, sympathetic ophthalmia in mammals, such as humans, while avoiding ocular irritation, sedation and other toxic manifestations of cetotifen and steroids. Those methods comprise administering to the mammal in need of such treatment and / or prophylaxis, effective amounts of a compound of this invention, or pharmaceutically acceptable salts thereof. This invention also provides methods for the co-administration of a compound of this invention, with at least one drug of the following class: ocular antihypertensive agents, adrenergic agonists or antagonists, antibacterial agents, antiviral agents, steroids, cyclooxygenase inhibitors, antagonists of leukotriene, lipoxygenase inhibitors and other therapeutic ocular remidia. In particular, the present invention is provided for the co-administration of a compound of this invention with ophthalmic decongestants, such as for example phenylephedrine, naphazoline, tetrahydrozoline, or with antibacterial agents, such as bacitracin, neomycin or polymyxin. The invention also provides methods for administering a compound of this invention in conjunction with surgical procedures to minimize inflammation or irritation and improve the postsurgical healing process.

This invention provides methods for the treatment and / or prophylaxis of forms of gastroenterological diseases such as hypersecretory syndromes including Zollinger-Ellison syndrome, gastric irritation, enteritis, gastric or duodenal ulcers, acid ingestion, heartburn or undesirable acid secretion. gastric. Those methods comprise administering to the mammal in need of such treatment and / or prophylaxis effective amounts of a compound of this invention, or pharmaceutically acceptable salts thereof.

EQUIVALENTS Those skilled in the art will recognize, or be able to determine, using, no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents include the therapeutic use of a single isomer and a composition containing the same while avoiding side effects residing in the corresponding isomers. Such equivalents also include numerous forms of pharmaceutically acceptable salts, for example, sulfate, bromohydrate, hydrochloride, dihydrochloride, fumarate, methanesulfonate, hydroxynaphthoate or where one or other of the hydrate formulas thereof are appropriate, see the second edition of the Merck Index (cf. 1989) items 9089, 209, 3927, 4628, 8223, 5053, 5386, 8142, 2347 ^ '7765, 1840, 8720, 7461, 1317, 4159, and 963 and the references cited there and Am. Rev. Resp. Dis. 1988, 137: (4; 2/2) 32. Such equivalents also include the co-administration of at least one compound of the present invention with any other drug that is used to combat diseases in mammals, mentioned herein. Those skilled in the art of medicine can also understand that higher or lower doses than those indicated herein may be preferred and that doses may occur more or less frequently than suggested herein. Those skilled in the art of pharmacology can understand that the compounds of the invention, which have certain pharmacological properties (such as antihistaminic activity on various types of receptors, PAF antagonist activity, mast cell stabilizing activity, etc.) can be useful for other indications than those listed here. Such indications are equivalent for the specific embodiments of the invention described herein. Those skilled in the art will understand that by using a single isomer (eutomer) of any of the racemic compounds of the invention or of norcetotifen or 10-OH-norcetotifen, it is possible to avoid side effects residing in the other isomer. Such side effects may include for example side cardiovascular effects, such as for example cardiodepression, or side effects on the central nervous system, such as for example sedation. It is intended that all equivalents be included in this present invention. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (20)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: A compound that has the formula including the stereochemically isomeric forms thereof and the pharmaceutically acceptable salts thereof, characterized in that; R is a member selected from the group consisting of C2-6 hydroxyalkyl and C6-6-C6-alkylcarboxyalkyloxy. and - -B- is a portion having the formula -CO-CH; (a) _H2-CC (b) -CH2-CH2 (c) -CHOH-CH2 _d) -CHOH-CHOH- (e1 -CH? -CHOH- (f) -CO-CO- (g)
2. 2. The compound according to claim 1, characterized in that -A-B- has the formula -CH2-CO- or a pharmaceutically acceptable salt thereof.
3. 3. The compound according to claim 1, characterized in that R is - (CH2) nOH, and where -A-B- has the formula -CH2-CO-, and where n is 2 to 6, or a pharmaceutically acceptable salt of the same.
4. 4. The compound according to claim 1, characterized in that R is - (CH2) n-0- (CH2) n -COOH and where -A-B- has the formula -CH2-CO-, and where n is from 1 to 6, or a pharmaceutically acceptable salt thereof.
5. A method for preventing or treating allergic conditions, characterized in that it comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to claim 1.
6. 6. The method according to claim 5, characterized in that the allergic condition is selected from the group consisting of allergic rhinitis, bronchitis, urticaria, atopic dermatitis and enteritis.
7. A method for preventing or treating ocular conditions, characterized in that it comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to claim 1.
8. 8. The method according to claim 7, characterized in that The ocular condition is selected from the group consisting of anterior uveitis, blepharitis, conjunctivitis, cranial arteritis, endophthalmitis, episcleritis, keratitis, keratoconjunctivitis, optic neuritis, posterior uveitis, retinopathy and scleritis.
9. 9. A method for preventing or treating respiratory ailments, characterized in that it comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to claim 1.
10. The method according to claim 9, characterized in that The respiratory condition is selected from the group consisting of chronic obstructive pulmonary disease (COPD), asthma, toxicities and bronchitis.
11. 11. A method for preventing or treating smooth muscle hyperreactivity, characterized in that it comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to claim 1.
12. 12. A method for preventing or treating gastrointestinal disorders, characterized because it comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to claim 1.
13. 13. The method according to claim 12, characterized in that the gastrointestinal condition is selected from the group consisting of hypersecretory syndrome. , Zollinger-Ellison syndrome, gastric irritation, enteritis, gastric ulcer, ingestion of acid and heartburn.
14. A method, characterized in that a compound according to claim 1 is administered to a mammal by inhalation, or by conjunctival instillation, or by nasal insufflation or by parenteral, transdermal, buccal, rectal, sublingual, nasal, topical or oral administration .
15. The method according to claim 14, characterized in that a compound according to claim 1 is administered to a mammal in a sustained, prolonged, or controlled release formulation.
16. 16. A method, characterized in that a compound according to claim 1 is administered to a mammal of about 0.2 mg to about 200 mg, preferably 0.5 mg to 20 mg, one to four times a day to a patient weighing 60 kg. .
17. 17. The method according to claim 7, characterized in that a compound according to claim 1 is administered by conjunctival instillation of a solution containing approximately 0.01% to 2.0%, one to four times a day.
18. 18. A solid, semi-solid, liquid, suspension, aerosol or transdermal pharmaceutical composition, characterized in that it comprises a therapeutically effective amount of a compound according to claim 1, in. combination with a pharmaceutically acceptable carrier or carrier system.
19. 19. A method, characterized in that it comprises administering to a mammal in need thereof a composition, the composition comprises a therapeutically effective amount of a compound according to claim 1, together with one or more drugs of the class consisting of analgesics, antibacterial agents, anti-inflammatory agents, decongestants, vasoconstrictors, vasodilators, suppressors of toxicities and expectorants.
20. 20. A method, characterized in that it comprises administering topically to a mammalian eye in need of the same composition, the composition comprises a therapeutically active amount of a compound according to claim 1, together with one or more drugs of the class consisting of of cholinergic agents, antimuscarinic agents, choline estease inhibitors, beta adrenergic receptor blocking agents, antibacterial agents, sympathomimetics, carbonic anhydrase inhibitors, decongestant antiinflammatory agents, astringents, substances for adjusting viscosity and topical anesthetics.