ES2369976T3 - OPTICALLY ACTIVE ISOMERS OF CETOTIPHEN AND PHARMACEUTICALLY ACCEPTABLE METABOLITES OF THE SAME. - Google Patents

Abstract

The S-isomer of a compound of structure (1) ** Formula ** or pharmaceutically acceptable salts or solvates thereof.

Description

Optically active isomers of ketotifen and pharmaceutically acceptable metabolites thereof

Technical field

The present invention relates to a compound and compositions for the treatment of diseases

5 inflammatory and allergic. More particularly, the present invention relates to methods for treating lung diseases (such as asthma, bronchitis) and skin disorders (such as urticaria and atopic dermatitis) and gastrointestinal disorders (such as gastric irritation and enteritis), while sedative and cardiovascular side effects that are commonly associated with antihistamine are avoided. In another embodiment, the present invention relates to a compound and compositions particularly useful for the treatment of

10 eye diseases such as conjunctivitis and keratitis.

Background of the invention

The present invention specifically relates to anti-inflammatory and antiallergic compounds that have therapeutic use in various diseases and, more importantly, for patients suffering from lung diseases including asthma and bronchitis, dermal diseases that include urticaria and atopic dermatitis and

15 gastrointestinal disorders that include gastric irritation and enteritis.

The compounds described in the present invention are ketotifen (4- (1-methyl-4-piperidilin) -4Hbenzo (4,5) cyclohepta- (1,2-b) thiophene-10-one) metabolites. Due to the serious sedative side effects that are related to ketotifen, that compound has limited therapeutic utility.

Ketotifen is metabolized in the body by several routes:

The metabolite norcetotifen (also called nor-ketotifen) is formed by demethylation of ketotifen:

The metabolites 10-hydroxy-ketotifen and 10-hydroxy-norcetotifen are formed by reduction of ketotifen and norcetotifen molecules, respectively.

10-HYDROXY-KETOTIPHENE 10-HYDROXY-NORCHETHYPHENE

Other ketotifen metabolites are also formed in the body after administration of cetotifen. Therefore, the ketotifen molecule can undergo N-glucuronidation and become the N-oxide ketotifen. The hydroxylated isomers can be further metabolized into 10-hydroxy-glucuronidates. Other metabolites can also be formed and the metabolic pathways are different in various species and can also be different between infants and adults.

The inventors are aware of unpublished pharmacological studies of racemates or isomers of norcetotifen, 10-hydroxy-ketotifen or 10-hydroxy-norcetotifen. The pharmacological properties of the isomers of ketotifen have been described by Polivka et al .: 4H-benzo (4,5) cyclohepta (1,2-b) thiophenes and 9,10-dihydro derivatives-sulfonium analogues of pizotifen and ketotifen; chirality of ketotifen; synthesis of the 2-bromo derivative of ketotifen. Collect Czech Chem. Commun. 1989, 54, 2443-2469.

The inventors are aware of the international patent publication WO98 43640 A (BRIDGE PHARMA INC.) Which discloses N-substituted hydroxyalkyl or carboxyalkyloxyalkyl analogs of 9-and / or 10-oxo4Hbenzo [4,5] cyclohepta [1,2- b] thiophene, or analogs substituted in 9-OH and / or 10-OH thereof, which possess antihistamine and anti-asthmatic properties with reduced sedative side effects. The optically active isomers and pharmaceutically acceptable salts thereof are also described. It was also found that the compounds prevented hyperreactivity of smooth muscle.

Summary of the Invention

Essential and optional features of the present invention are explained in the attached main and subordinate claims, respectively. Now the isomers of ketotifen have been synthesized and studied pharmacologically in vitro and in vivo. Various ketotifen metabolites have also been synthesized and pharmacologically studied. It has been found that the antihistamine effects of racemic norcetotifen are qualitatively similar to the antihistamine effects of racemic ketotifen. Therefore, both ketotifen and nor-ketotifen are histamine H-1 antagonists with varying degrees of histamine H-2 antagonism. However, surprisingly and, more importantly, a significant qualitative difference was found between racemic ketotifen and nor-ketotifen S-isomer (hereinafter referred to as "the compound of the invention"). The compound of the invention does not have the serious sedative and dose-limiting activity of ketotifen. It has now been established that racemic norcetotifen and particularly its isomer have potent anti-inflammatory and antihistamine properties with little or no sedative side effects. It was also found that while both isomers of ketotifen had approximately the same antihistamine activity, it was found that almost all sedative side effects resided in R (+) - ketotifen. It was also found that the metabolites 10-hydroxy-norcetotifen and 10-hydroxy-ketotifen and the isomers of both compounds also inhibited inflammation and blocked the histamine H-1 receptors, while producing significantly less sedation than ketotifen.

Detailed description

Chemical synthesis of ketotifen, norcetotifen, 10-hydroxy-ketotifen and 10-hydroxy-norcetotifen, stereochemically isomeric forms and diastereomers thereof.

Ketotifen and racemic norcetotifen are prepared by the procedures described in Waldvogel et al. (Helv. Chim. Acta 59, 866-877, 1976), which is incorporated herein by reference. R - (+) - ketotifen and S - (-) - ketotifen are prepared by fractional crystallization of racemic ketotifen salts with () -O, O'-di (p-toluyl) -R-tartaric acid (+) - O, O'-di (p-toluyl) -S-tartaric, respectively, as described by Polivka et al. (Collect. Czech. Chem. Commun. 54, 2443-2469, 1989), which is incorporated herein by reference.

The preferred process for the preparation of the optically active isomers of norcetotifen, 10-hydroxycytotifen and 10-hydroxy-norcetotifen is from the individual R and S enantiomers of ketotifen. A new procedure for the synthesis of norcetotifen is claimed that avoids the energetic conditions of Waldvogel et al., 1976, which would produce the racemization of the product. Other procedures include stereoselective synthesis using chiral templates, resolution of corresponding racemates using conventional means such as fractional crystallization of diastereomeric salts with chiral acids and chromatography using chiral supports.

The 10-hydroxy derivatives are prepared by catalytic reduction of the corresponding ketotifen enantiomers by the procedures described by Waldvogel et al., 1976. It should be noted that the 10-hydroxy-ketotiphenes possess an additional chiral center and that the diastereomers of the corresponding R and S enantiomers of the ketotifenos. These can be separated by conventional crystallization or chromatographic procedures due to differences in solubilities and chromatographic mobilities of the diastereomeric isomers. Alternatively, the reduction of the R and S enantiomers of the ketotifenos with chiral reducing agents can be employed to prepare exclusively (or to greatly enrich mixtures in) the desired diastereomeric product.

Designation of absolute configurations

The enantiomers of ketotifen and norcetotifen do not have asymmetric carbon atoms as is typical of optical isomers. Rather, enantiomers result from molecular asymmetry due to the prevented interconversion of the seven-member ring. The (+) - ketotifen is designated R and has the configuration observed in the X-ray crystal structure of (-) - O, O'-di (p-toluyl) -R-tartrate of (+) - ketivifene by Polivka and col., 1989. (-) Ketotifen has the designation S.

An additional chiral center is present in the 10-hydroxy-ketotifen derivatives - carbon atom 10 and both R and S configurations exist as defined in standard stereochemistry rules. In the designation of the diastereomers resulting from the reduction of the ketotifen enantiomers, the first letter R or S refers to the configuration of the seven-member ring and the second letter R or S to the configuration of the carbon atom 10.

Synthesis of (R) and (S) -norcetotifen and smokers of (R) and (S) -norcetotifen (these syntheses are summarized in the scheme.)

(R) -4- (1- (2,2,2-Trichloroethoxycarbonyl) -4-piperidyliden) -9,10-dihydro-4H-benzo- (4,5) -cyclohepta (1,2-b) thiophene- 10-one: Anhydrous sodium carbonate (95.0 mg, 898 µmoles), (+) - (R) -cetotifen (278 mg, 898 µmoles) and benzyltriethylammonium chloride (BTEAC) (205 mg, 898 µmoles) were combined in a dry flask and placed under high vacuum for two days. Then freshly distilled dichloromethane (2 ml) was added to the mixture under N2 at room temperature with stirring, followed by the addition of 2,2,2-trichloroethyl chloroformate (556 µL, 4.04 mmol). The biphasic reaction mixture was refluxed for one hour and, after cooling to room temperature, was quenched by the addition of saturated aqueous sodium carbonate (7 ml). The resulting mixture was diluted with dichloromethane (50 ml) and the organic phase was separated, dried over sodium sulfate, filtered, evaporated and chromatographed (SiO2, ethyl acetate-petroleum ether 20: 1 to 10: 1 ). Fractions corresponding to the trichlorethyl carbamate intermediate were pooled, evaporated and placed under high vacuum giving 279 mg, 66% of the title compound: 1 H NMR (400 MHz, CDCl 3) δ 7.58 (s, 1 H), 7.37-7.30 (m, 1H), 7.23-7.19 (m, 2H), 7.18-7.11 (m, 1H), 7.03-7.00 (m, 1H ), 4.88-4.69 (m, 2H), 4.20 (d, 1H, J = 13.0 Hz), 4.03-3.84 (m, 2H), 3.78 (d, 1H, J = 13.0 Hz), 3.35-3.09 (m, 2H), 2.75-2.64 (m, 1H), 2.62-2.57 (M, 1H), 2 , 50-2.39 (m, 2H).

(R) -4- (4-Piperidiliden) -9,10-dihydro-4H-benzo- (4,5) -cyclohepta (1,2-b) thiophene-10-one ((R) -norcetotifen): added cadmium powder (178 mg, 1.59 mmol) and a 10% pair of cadmium / lead (356 mg, 3.174 mmol) to a rapidly stirred mixture of trichlorethyl carbamate (279 mg, 592 µmoles) in THF (5 , 5 ml) and aqueous ammonium acetate (1 M, 3.0 ml) under nitrogen. After 2 hours, the mixture was filtered through Celite and washed with abundant dichloromethane and water. The filtrate was basified with saturated aqueous sodium carbonate and the organic phase was separated, dried over sodium sulfate, filtered and evaporated to give the crude (R) -norcetotifen (157 mg, 90%). 1H NMR (400 MHz, CDCl3) δ 7.54 (d, 1H, J = 5.2 Hz), 7.34-7.29 (m, 1H), 7.23-7.13 (m, 3H) , 7.02 (d, 1H, J = 5.2 Hz), 4.20 (d, 1H, J = 13.6 Hz), 3.76 (m, 1H, J = 13.6 Hz), 3 , 21-3.14 (m, 1H), 3.13-3.05 (m, 1H), 2.86-2.76 (m, 1H), 2.75-2.58 (m, 3H) , 2.47-2.39 (m, 2H). The enantiomeric purity was measured by analytical chiral HPLC (Merck Chiradex 5 µm, mobile phase 95: 5 at pH 4.0, sodium phosphate-acetonitrile, flow rate 1 ml / min, chart rate 0.3 cm / min, 254 nm): Rt 13.0 min, 95% ee.

(

fumaric

(R) -norcetotifen fumarate: The crude (R) -norcetotifen (157 mg, 533 µmoles) was taken up in dichloromethane (1 mL) and added to a solution of fumaric acid (61.8 mg, 533 µmoles) in ethanol (2 ml). After evaporation of 50% of the solvent, the (R) -norcetotifen fumarate crystals were collected and washed with ethanol to give 117

5 mg of product, 57%, after drying under high vacuum: 1H NMR (DMSO-d6) δ 7.99 (m, 1H), 7.40-7.31 (m, 1H), 7.307.11 (m , 4H), 6.43 (s, 2H) 4.35 (d, 1H, J = 13.2 Hz), 3.65 (d, 1H, J = 13.2 Hz), 3.25-3, 08 (m, 2H), 2.99-2.89 (m, 1H), 2.83-2.74 (m, 1H), 2.70-2.54 (m, 2H), 2.50- 2.40 (m, 1H), 2.38-2.28 (m, 1H). The enantiomeric purity was measured by analytical chiral HPLC (Merck Chiradex 5 µm, mobile phase 95: 5 at pH 4.0, sodium phosphate-acetonitrile, flow rate 1 ml / min, chart rate 0.3 cm / min, 254 nm): Rt 13.0 min, 95% ee.

10 (S) -4- (1- (2,2,2-Trichloroethoxycarbonyl) -4-piperidiliden) -9,10-dihydro-4H-benzo- (4,5) -cyclohepta (1,2-b) thiophene -10-one: Following the procedure explained briefly above for the (R) -enantiomer gave the (S) -enantiomer in similar yields: 1H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.37 -7.30 (m, 1H), 7.23-7.19 (m, 2H), 7.18-7.11 (m, 1H), 7.03-7.00 (m, 1H), 4 , 88-4.69 (m, 2H), 4.20 (d, 1H, J = 13.0 Hz), 4.03-3.84 (m, 2H), 3.78 (d, 1H, J = 13.0 Hz), 3.35-3.09 (m, 2H), 2.75-2.64 (m, 1H), 2.62-2.57 (M, 1H), 2.50- 2.39 (m, 2 H).

15 (S) -4- (4-Piperidiliden) -9,10-dihydro-4H-benzo- (4,5) -cyclohepta (1,2-b) thiophene-10-one; Following the procedure explained briefly above to obtain the (R) -enantiomer gave the (S) -enantiomer in similar yields: 1H NMR (400 MHz, CDCl3) δ 7.54 (d, 1H, J = 5.2 Hz), 7.34-7.29 (m, 1H), 7.23-7.13 (m, 3H), 7.02 (d, 1H, J = 5.2 Hz), 4.20 (d, 1H, J = 13.6 Hz), 3.76 (m, 1H, J = 13.6 Hz), 3.21-3.14 (m, 1H), 3.13-3.05 (m, 1H), 2.86-2.76 (m, 1H), 2.75-2.58 (m, 3H), 2.47-2.39 (m, 2H). The enantiomeric purity was measured by analytical chiral HPLC (Merck Chiradex 5 µm, mobile phase 95: 5 at pH 4.0, sodium phosphate-acetonitrile, flow rate 1 ml / min, chart rate 0.3 cm / min, 254 nm): Rt 7.5 min, 95% ee.

(S) -norcetotifen fumarate: Following the procedure explained briefly above to obtain the (R) enantiomer gave the (S) -enantiomer in similar yields: 1H NMR (400 MHz, DMSO-d6) δ 7.99 (m, 1H ), 7,407.31 (m, 1H), 7.30-7.11 (m, 4H), 6.43 (s, 2H) 4. 35 (d, 1H, J = 13.2 Hz), 3, 65 (d, 1H, J = 13.2 Hz), 3.25-3.08 (m, 2H), 2.99-2.89 (m, 1H), 2.83-2.74 (m, 1H), 2.70-2.54 (m, 2H), 2.50-2.40 (m, 1H), 2.38-2.28 (m, 1H). The enantiomeric purity was measured by analytical chiral HPLC (Merck Chiradex 5 µm, mobile phase 95: 5 at pH 4.0, sodium acetonitrile phosphate, flow rate 1 ml / min, chart rate 0.3 cm / min, 254 nm ): Rt 7.5 min, 95% ee.

Pharmacological studies of ketotifen, norcetotifen, 10-OH-ketotifen, 10-OH-nor-ketotifen and the optically active isomers thereof.

As discussed above, it has now been shown that the S-isomer of ketotifen, and the racemates and isomeric forms of norcetotifen, 10-OH-ketotifen and 10-OH-nor-ketotifen, have beneficial pharmacological effects useful in the treatment of diseases such as, for example, allergic disorders, lung disorders, skin disorders and gastrointestinal disorders, while not causing the serious sedative side effects of ketotifen. The surprising findings are described in the following examples.

TEST PROCEDURE 1: Binding to histamine receptors

The affinities of racemic and isomeric test compounds for the histamine H1 receptor are evaluated using the 3H-pyrilamine binding assay as described by Dini et al. (Agents and Actions, 1991, 33: 181-184). Briefly, guinea pig cerebellum membranes are incubated with 3H-pyrilamine and varying concentrations of the test compound (s). The specific binding of the radioactive ligand to the receptor is defined as the difference between total binding and non-specific binding, determined in the presence of an excess of unlabeled ligand. The results are expressed as percentage of specific binding in the presence of compounds. The IC50 values (concentration required to inhibit 50% of the specific binding) and the Hill coefficients (nH) are determined by non-linear regression analysis of the competition curves. These parameters are obtained by adjusting curves to the Hill equation using Sigmaplot ™ software.

TEST PROCEDURE 2: In vitro antihistamine effects

Strips of bronchial tissues or other smooth muscle are extracted from the body of male guinea pigs weighing 400-600 g. The tissues are suspended in an oxygenated buffer of the composition (mM): NaCl, 133; KCI, 4.7; CaCl2, 2.5; MgSO4, 0.6; NaH2PO4, 1.3; NaHCO3, 16.3; and glucose, 7.7, or in a solution of similar composition. The solution is maintained at 37.5 ° C. Contractions are recorded with isometric transducers (model FT-10) on a Grass polygraph.

In order to assess the viability of each tissue and to serve as a frame of reference, the contractions of each strip of tissue are initially recorded in response to exposure to an oxygenated buffer in which NaCl has been replaced with KCI giving a concentration of 137.7 mM KCl. This is followed by the return to the standard oxygenated buffer, and then by exposures to progressively increasing concentrations of histamine, with separate exposures at each concentration only until the peak response has been recorded. Then, leaving a strip of tissue untreated, the remaining strips are each exposed for a predetermined time interval at a concentration of an antagonist. Finally, responses to increasing concentrations of histamine are recorded a second time followed by exposure to 137.7 mM KCI.

TEST PROCEDURE 3: Binding to muscarinic receptors

The experiments are carried out on membranes prepared from SF9 cells infected with baculovirus to express subtypes of human recombinant muscarinic receptors. After incubation with the test object and the appropriate radioligand and washing, the bound radioactivity is determined with a liquid scintillation counter using a commercial scintillation mixture. Specific radioligand binding to each receptor is defined as the difference between total binding and non-specific binding determined in the presence of an unlabeled excess ligand. The IC50 values (concentrations required to inhibit 50% of the specific binding) are determined by non-linear regression analysis of the competition curves.

TEST PROCEDURE 4: Inhibition of bronchial eosinophil accumulation

The inhibition of eosinophil accumulation in the lung is determined in sensitized guinea pigs (400 to 600 grams) after intraperitoneal injection of an allergen such as, for example, PAF (platelet aggregation factor) or bovine serum albumin. At a predetermined moment after this, the animals are sacrificed with a barbiturate. The trachea is exposed and cannulated. Subsequently, 6 x 10 ml aliquots of buffered modified Tyrode solution (composition: NaHCO3 11.9, NaCl 136.9, KCI 2.7, Na2HPO4 0.4, glucose 5.6, EDTA 19.8, gelatin 0 are introduced) , 1% by weight / volume; pH 7.4) and aspirated by careful compression of the lungs. Total fluid recovery typically exceeds 80%. The cell suspensions are concentrated by low speed centrifugation (200 g for 10 min) and the resulting cell pellet is resuspended in 1 ml of modified Tyrode solution. Total cell numbers are prepared by diluting 10 µl of cell suspension in 90 µl of Turk fluid. Differential cell numbers are prepared from smears fixed in methanol (100%) and stained in Leishman stain. A total of at least 500 cells are counted per smear at 1000 magnifications in order to differentiate cell types. The drugs are administered as sustained subcutaneous infusions from an implanted Alza minipump (Alzet 2001 or similar) or by repeated oral or repeated parenteral injections.

TEST PROCEDURE 5: Dermal anti-inflammatory effects

The dermal anti-inflammatory effects are tested using the croton oil inflammation procedure of the mouse ear. This test procedure is based on Tarrida, J. et al., Meth. Find. Exp. Clin. Pharmacol (1996) 18 (4): 233-234 and Blazzo et al., Prostaglandins (1995) 50: 161-168. Briefly, male mice (25-30 g) are treated with 5 ml / kg of a 2 mg / ml solution of each test compound in physiological saline by intraperitoneal injection. Thirty minutes after the injection, croton oil (0.20 µl of 1.0% croton oil in acetone) or acetone (control) is administered topically to both ears of each mouse. Animals are retained during application of croton oil or acetone and then left in a cage. Before and at predetermined time intervals after application of the croton oil or acetone, the groups of animals are anesthetized with halothane and euthanized by cervical dislocation. The ears are removed and weighed. The average weight of the ears is represented as a function of time. A total of 4 animals are tested per moment of time for each compound and vehicle control.

TEST PROCEDURE 6: Studies on sedative side effects

The physostigmine-induced lethality test is being used in the present studies. This test is a modification of the sedation test technique reported by VILLANI et al. in US Pat.

4,659,716. In short, physostigmine (1.9 mg / kg s.c.) produces 90-100% lethality when administered to mice grouped with 10 animals in each plastic cage (11 cm x 26 cm x 13 cm). Mice given a sedative agent such as, for example, an antihistamine sedative before physostigmine are protected and survive. In the present study, test compounds are administered orally 60 minutes before physostigmine. Survivor numbers are counted 30 minutes after administration of physostigmine.

Pharmaceutical compositions

The terms "pharmaceutically acceptable salts" or "a pharmaceutically acceptable salt thereof" refer to salts or solvates prepared from pharmaceutically acceptable non-toxic acids. Pharmaceutically acceptable acid addition salts suitable for the compound of the present invention include acetic, benzenesulfonic (besylate), benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic , methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic and the like. Particularly preferred is hydrogen fumarate.

The present invention provides pharmaceutical compositions comprising the compound of the invention formulated together with one or more pharmaceutically acceptable carriers. The pharmaceutical compositions may be specially formulated for oral administration, conjunctival instillation, sublingual administration, parenteral administration, transdermal administration, rectal administration, oral administration or for topical administration, or for administration by inhalation or insufflation of powder or aerosol.

The pharmaceutical compositions of the present invention can be administered to humans and other mammals orally, sublingually, parenterally, cutaneously, transdermally, rectally, orally, topically, by conjunctival instillation or as an oral or nasal spray or aerosol. 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.) that can facilitate or modify the transport or absorption of the drug through the skin. The term "topical" refers to the administration of a composition containing a drug on the skin or on the mucous membranes.

Forms of oral administration

The pharmaceutical compositions of the present invention for oral administration of solid pharmaceutical forms include capsules, granules, pills, powders and tablets. In such solid pharmaceutical forms, the active compound may be mixed with one or more pharmaceutically acceptable excipients or carriers (e.g., sodium citrate, dicalcium phosphate), fillers or fillers (e.g., starch, lactose, sucrose, glucose, mannitol, silicic acid), binders (for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, gum arabic), humectants (e.g. glycerol), dissolution retarding agents (e.g. paraffin), disintegrating agents (for for example, agar-agar, calcium carbonate, starch, alginic acid, silicates, sodium carbonate), absorption accelerators (for example, quaternary ammonium compounds), wetting agents (for example, cetyl alcohol, glycerol monostearate), absorbents ( for example, kaolin, clay bentonite), lubricating agents (for example, talc, calcium stearate, magnesium stearate, polyethylene glycols, sodium lauryl sulfate o) and / or buffering agents.

Solid forms of capsules, sugar-coated tablets, granules, pills and tablets may have coatings and / or pods (eg enteric coatings) known in the art. The compositions can also be designed to release the active ingredient (s) in a certain part of the gastrointestinal tract or in a controlled release, slow release or delayed release mode.

The composition can also be designed for lymphatic absorption of the active substance (s).

The active compound (s) may also be microencapsulated (s) with one or more of the aforementioned excipients.

Liquid pharmaceutical forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. The liquid pharmaceutical form may also contain 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, dimethylformamide, oils, oleic acid, glycerol, polyethylene glycols, sorbitan fatty esters and mixtures thereof.

In addition to inert diluents, 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 art of the pharmaceutical formulation.

Forms of topical administration

Compositions for topical administration of the compound of the present invention include solutions, suspensions, droplets, sprays, ointments, creams and powders. Compositions intended for dermal applications may contain penetration promoting agents and others as those skilled in the art know. Patches, bandages, etc., may also be used for dermal drug application purposes.

In addition to the therapeutically active principles, the composition of the present invention for topical administration, which includes various formulations intended for topical ophthalmic administration, may additionally comprise various formulation components such as antimicrobial preservatives and tonicity agents. Examples of suitable antimicrobial preservatives include: benzalkonium chloride, thimerosal, chlorobutanol, methylparaben, propylparaben, phenylethyl alcohol, disodium edetate, sorbic acid, ONAMER M and other agents known to those skilled in the art. Such preservatives, if used, will normally be used in an amount of 0.001% to 1.0% 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 used 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.

As those skilled in the art understand, the compositions can be formulated in various pharmaceutical forms suitable for topical ophthalmic administration including solutions, suspensions, emulsions, gels and erodable solid eye inserts.

Forms of parenteral administration

Pharmaceutical compositions for parenteral injections include sterile pharmaceutically acceptable aqueous or non-aqueous solutions, dispersions, suspensions, emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions before use. Various excipients, diluents, solvents and aqueous and non-aqueous vehicles (for example, water, ethanol, glycerol, glycol) may be used, in addition to vegetable oils (for example, olive oil) and organic esters (for example, ethyl oleate) , or mixtures thereof. Fluidity can be maintained using coating material such as lecithin, restricting particle size and using surfactants.

The compositions may also contain adjuvants such as preservatives, humectants, emulsifiers, dispersants, antibacterial agents, antifungal agents, isotonic agents and / or absorption retarding agents. Effects that prolong absorption or slow absorption can be achieved by injecting a crystalline or amorphous suspension with low water solubility. Delayed absorption can also be obtained by dissolving or suspending the drug in an oil vehicle or using injectable prolonged release forms (e.g., microencapsulated matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, polyorthoesters, polyanhydrides) or using various types of liposomes or microemulsions

to contain the drug. Formulations for injection can be sterilized by various procedures.

Administration by inhalation

The compound of the invention can be administered by inhalation, which may be a preferred route of administration in certain patients such as, for example, patients suffering from asthma. Various inhalation devices may be used such as, for example, metered dose inhalers, dry powder inhalers and nebulizers, as is known to those skilled in the art.

Forms of rectal administration

Compositions for rectal administration are preferably suppositories.

Forms of oral administration

Compositions for oral administration are preferably toothpastes, mouthwashes, sublingual preparations, chewing gum, etc.

Forms of sublingual administration

Various galenic formulations can be used: concentrated solutions or suspensions of the drug can be applied sublingually by various drip devices; various aerosol devices can be used to spray the drug on the membranes of the oral mucosa; tablets, capsules or quick dissolution powders specifically designed for rapid administration of the full dose may also be used.

Forms of transdermal administration

Compositions for transdermal administration of the compounds of the present invention include various known patches, bandages, etc..

Administration of oral (buccal) or nasal sprays or droplets

Compositions for oral or nasal sprays or droplets may be in the form of solutions, suspensions or dry powders and may be designed for nasal, oral, bronchial / pulmonary and / or gastric absorption of the drug.

Therapeutic dose levels

Since the compound of the invention does not express the serious sedative and dose-limiting side effects of ketotifen, the compound of the invention can be administered in doses greater than those currently used for ketotifen.

The actual dosage levels of active ingredients in the pharmaceutical compositions of the present invention can be varied so that the desired therapeutic effect is obtained. Therefore, the amount of drug used varies and may depend on factors such as the form of administration, the severity of the disease, the dosage frequency, etc. For use as a medication for patients suffering from benign respiratory or bronchial disorders (such as asthma, bronchitis, etc.), oral doses of the compound of the invention are used at dose levels of 0.5 mg to about 200 mg, preferably 1 mg to 20 mg, once to four times a day to a patient weighing 60 kg. The daily dose can be increased or decreased depending on various factors, for example, the patient's weight and disease status.

As an example, for use as a medication for patients suffering from a seasonal allergic condition such as, for example, allergic rhinitis, the oral dose of a compound of the invention can be used at dose levels of 0.1 mg to about 100 mg, preferably from 1 mg to 20 mg, once to four times a day to a patient weighing 60 kg. For patients suffering from seasonal allergic conjunctivitis, the concentration of a solution containing a compound of the invention for instillation in the conjunctival sac may contain 0.01% to 4.0%, preferably 0.02% to 2.0%. of the active substance For patients suffering from asthma, a compound of the invention is used at an oral dose level of 2 to 100 mg, preferably 2 to 20 mg, once to four times a day to a patient weighing 60 kg. The frequency and amount of the dosage will be determined by the doctor based on various clinical factors such as, for example, the weight and severity of the patient's disease. The ocular use will normally comprise the topical administration of one to two drops (or an amount of a solid or semi-solid pharmaceutical form) to the affected eye one to four times a day. Dermal use will normally comprise dermal administration of an ointment containing from 0.1% to 10.0% of a compound of the invention.

Therapeutic indications

The compound of the invention can be used for various therapeutic indications that include those indications for which ketotifen may be useful. The compound of the invention has pharmacological effects that are similar to those of cetotifen, but the present compound does not have the serious sedative side effects that are dose limiting when the parent compound (cetotifen) is used for therapeutic purposes.

The compositions of the invention can be used for the treatment and / or prophylaxis of all forms of allergic disorders that include, but are not limited to, allergic rhinitis, multisystemic allergies, dermal and ocular allergies. These methods comprise administering to a mammal the compound of the invention in composition with a pharmaceutically acceptable salt or solvate thereof.

The compositions of the invention can be used for the treatment and / or prophylaxis of bronchial and pulmonary disorders that include, but are not limited to, asthma, bronchitis, bronchial hyperreactivity, cough and chronic obstructive pulmonary disease (COPD). These methods comprise administering to a mammal the compound of the invention with a pharmaceutically acceptable salt or solvate thereof.

The compositions of the invention can be used for the treatment and / or prophylaxis of dermal disorders that include, but are not limited to, atopic dermatitis, urticaria, other pruritic or inflammatory conditions and psoriasis. These methods comprise administering to a mammal the compound of the invention with a pharmaceutically acceptable salt or solvate thereof.

The compositions of the invention can be used for the treatment and / or prophylaxis of forms of eye diseases such as conjunctivitis, keratitis, blepharitis, episcleritis, scleritis, anterior uveitis, posterior uveitis, endophthalmitis, optic neuritis, cranial arteritis, sympathetic ophthalmia in mammals such as human beings, while avoiding eye irritation, sedation and other toxic manifestations of ketotifen and steroids. These methods comprise administering to a mammal the compound of the invention with a pharmaceutically acceptable salt or solvate thereof.

The compositions of the invention can be used for the treatment and / or prophylaxis of forms of gastroenterological diseases such as, for example, hyperactivity syndromes or hypersecretors that include Zollinger-Ellison syndrome, gastric irritation, enteritis, gastric or duodenal ulcers, hyperchlorhydria. , heartburn, motility disorders, gastric reflux or unwanted gastric acid secretion. This comprises administering to a mammal the compound of the invention with a pharmaceutically acceptable salt or solvate thereof.

Co-administration

It is possible to co-administer the compound of the invention optionally together with one or more of 10-hydroxycytotifen, 10-hydroxy-nor-ketotifen, or optically active isomers thereof, or optically active isomers of ketotifen with adrenergic agonists that include, but they are not limited to, albuterol, terbutaline, fenoterol, formoterol or salmeterol, thus eliminating or reducing the side effects that may be induced by such beta-agonist therapy.

Co-administration of the compound of the invention is also possible with agents or drugs that produce bronchial hyperreactivity that include, but are not limited to, beta-adrenergic receptor blocking agents or cyclooxygenase inhibitors, thereby eliminating or decreasing bronchial hyperreactivity. which is induced by such therapy. It is also possible to co-administer the compound of the present invention with at least one drug of the following classes: ocular antihypertensive agents, adrenergic antagonists, antibacterial agents, antiviral agents, steroids, cyclooxygenase inhibitors, leukotriene antagonists, inhibitors of lipoxygenase, local anesthetics and therapeutic eye remedies. It is also possible to co-administer the compound of the present invention with decongestants such as, for example, phenylephedrine, nafazoline, tetrahydrozoline or with antibacterial agents such as bacitracin, neomycin and polymyxin.

EQUIVALENTS

Those skilled in the art will recognize, or may determine, using nothing more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. The equivalents include numerous forms of pharmaceutically acceptable salts, for example, sulfate, hydrobromide, hydrochloride, dihydrochloride, methanesulfonate, fumarate, hydroxynaphthoate or, where appropriate, one or more of the hydrate forms thereof, see Merck Index 11th edition (1989 ) points 9089, 209, 3927, 4628, 8223, 5053, 5836, 8142, 2347, 7765, 1840, 9720, 7461, 1317, 4159 and 963 and the references cited therein and Am. Rev. Resp. Dis. 1988, 137: (4; 2/2) 32. The equivalents also include co-administration of the compound of the invention with any other drug that is used to combat diseases in mammals, mentioned herein. Those skilled in the art may also realize that higher or lower doses may be preferred to those indicated herein and that the doses may be administered more or less frequently than suggested herein.

Those skilled in the field of pharmacology realize that bronchial hyperreactivity is commonly observed in patients suffering from various lung conditions such as, for example, asthma. In addition, those skilled in the art also realize that bronchial hyperreactivity can be induced by drugs such as, for example, beta-adrenergic receptor agonists.

The compound of the invention, which has certain pharmacological properties (such as inhibitory activity on various types of histamine receptors, PAF antagonist activity, effects on nitric oxide synthase, mast cell stabilizing activity, etc.), is useful for other indications other than the one listed here. Such indications are equivalent to the specific embodiments of the invention described herein.

Using the individual isomer of a compound of the invention it is possible to avoid side effects residing in

5 the corresponding dimer. Such side effects may include, for example, cardiovascular side effects such as, for example, heart depression and cardiac arrhythmias, gastrointestinal side effects such as, for example, irritation, or CNS side effects such as, for example, sedation or drowsiness. All equivalents are intended to be included in this present invention.

Claims (11)

1. The S-isomer of a compound of the structure (1) or pharmaceutically acceptable salts or solvates thereof. 2. A pharmaceutical composition comprising the S-isomer of claim 1, and pharmaceutically acceptable salts and solvates thereof, together with a pharmaceutically acceptable carrier, said composition being free of sedative side effects. 3. A process for the synthesis of the S-isomer of claim 1 comprising the conversion of the isomer corresponding stereochemical of ketotifen in a nor-intermediate of 1- (2,2,2-trichloroethoxycarbonyl), followed by cleavage catalyzed by Cd / Pb.

Four.

The composition according to claim 2 for use in the prevention or treatment of a disease selected from the group consisting of respiratory disorders, allergic disorders, dermal disorders, gastrointestinal disorders and eye disorders.

5.

The composition of claim 4, wherein

15 (i) said respiratory disorder is selected from the group consisting of chronic obstructive pulmonary disease (COPD), asthma, cough, bronchitis and bronchial hyperreactivity; or (ii) said allergic disorder is selected from the group consisting of allergic rhinitis, hives, allergic conjunctivitis and allergic keratitis; or (iii) said dermal disorder is selected from the group consisting of atopic dermatitis, urticaria, other pruritic or inflammatory conditions and psoriasis; or (iv) said gastrointestinal disorder is selected from the group consisting of hypersecretory syndromes that include Zollinger-Ellison syndrome, gastric irritation, enteritis, gastric and duodenal ulcers, gastric reflux, hyperchlorhydria, motility disorders and heartburn; or (v) said ocular disorder is selected from the group consisting of conjunctivitis, keratitis, blepharitis, episcleritis, scleritis, uveitis, neuritis and arteritis. 6. The composition of claim 4, wherein the therapeutically active compound or a pharmaceutically acceptable salt or solvate thereof is administered by nasal inhalation or insufflation or by parenteral, topical, dermal, transdermal, rectal, sublingual, conjunctival or orally. 7. The composition according to claim 4, wherein the therapeutically active compound or a pharmaceutically acceptable salt or solvate thereof is administered orally.

8.

The composition according to claim 4, wherein the therapeutically active compound or a pharmaceutically acceptable salt or solvate thereof is administered orally in a sustained release formulation.

9.

The composition according to claim 4, wherein the therapeutically active compound or a pharmaceutically acceptable salt or solvate thereof is administered topically.

The composition according to claim 4, wherein the therapeutically active compound or a pharmaceutically acceptable salt or solvate thereof is administered transdermally.

eleven.

The composition of claim 4, wherein the amount of the therapeutically active compound is administered from about 0.5 mg to about 200 mg, one to four times a day.

12.

The composition of claim 4, wherein a solid, semi-solid, liquid pharmaceutical composition, in

suspension, aerosol or topical or transdermal comprising a therapeutically effective amount of the therapeutically active compound, or a pharmaceutically acceptable salt or solvate thereof, is administered in combination with a pharmaceutically acceptable vehicle or vehicle system.

13.

A composition for use in therapy, said composition comprising a therapeutically amount

5 of the S-isomer of claim 1, or a pharmaceutically acceptable salt or solvate thereof, together with one or more drugs of the class consisting of adrenergic antagonists, analgesics, antihypertensive agents, calcium antagonists, antihistamines, anticholinergic agents , antibacterial agents, antiviral agents, anti-inflammatory agents, bronchodilators, decongestants, steroids, leukotriene antagonists, lipoxygenase inhibitors, local anesthetics, vasoconstrictors, vasodilators, suppressants 10 cough and expectorants.