HK1027961B - Benzocycloheptathiophene compounds - Google Patents

Description

Benzocycloheptathiophene compounds

Technical Field

The present invention relates to novel compounds as shown in the following figures, and methods of using these novel compounds to treat disease states mediated by allergic response, inflammation, or cholinergic activity in a mammal.

The compounds of the present invention include compounds represented by the following formula:wherein-A-B-is a moiety having the formula: -CO-CH₂- (a)-CH₂-CO- (b)-CH₂-CH₂- (c)-CHOH-CH₂- (d)-CHOH-CHOH- (e)-CH₂-CHOH- (f) -CO-CO- (g) R represents hydroxyalkyl or carboxyalkoxyalkyl, as well as their pharmaceutically acceptable salts and optically active isomers of their racemic compounds.

The compounds of the present invention have pharmacological activities for preventing and treating allergy, inflammation, various eye diseases, and various types of smooth muscle hyperactivity such as bronchial and uterine hyperactivity including hyperactivity caused by drug induction.

More particularly, the present invention relates to novel compounds and methods of using them to treat allergic diseases (e.g., allergic rhinitis), pulmonary diseases (e.g., asthma, bronchitis, cough, and bronchial hyperreactivity), dermatological diseases (e.g., urticaria, psoriasis, and atopic dermatitis), gastrointestinal diseases (e.g., hypersecretion syndrome including Zollinger-Ellison syndrome, gastric irritation, and enteritis), and other inflammatory and/or allergic diseases (e.g., ocular conjunctivitis and keratitis) while avoiding side effects (e.g., sedation, arrhythmia, and ocular irritation).

The invention also relates to compositions containing at least one of the novel compounds described above and to combinations of the compounds of the invention with various other compounds.

Background

The invention relates in particular to anti-inflammatory and antiallergic compounds having a therapeutic effect on a number of diseases, in particular hyperreactive and/or obstructive airways diseases, including asthma, bronchitis, skin diseases and allergic diseases, including urticaria, atopic dermatitis, allergic rhinitis and retinopathy, and microangiopathies associated with diabetes or including conjunctivitis and retinopathyEye diseases such as keratitis.Thiepdone

The compounds of the present invention and thalidomide (zaditen)^) Similar in chemical structure and not previously known to the applicant. The therapeutic efficacy of thalidomide is severely limited by its sedative side effects, which can be alleviated or even eliminated by the use of the compounds of the present invention.

Sorkin et al have summarized the content of pharmacological, toxicological, pharmacokinetic and clinical studies of thalidone (Studies of thalidone. Ed. E.M. Sorkin. in drugs. Sept.1990.Vol.40, No.3. pp.412-448).

Summary of The Invention

The present invention relates to certain novel compounds represented by the general formula; methods of their use in the treatment of disease; compositions comprising one or more pharmaceutically acceptable inert carriers and at least one therapeutically effective amount of the novel compounds as active ingredient; pharmaceutically acceptable acid addition salts of the novel compounds and stereochemically isomeric forms of the novel compounds. The structural formula of the novel compound is as follows:wherein R is selected from one of the following groups: hydroxy-C_2-6Alkyl or carboxy-C_1-6alkoxy-C_1-6Alkyl and-A-B-represents a group of formula-CO-CH₂- (a)-CH₂-CO- (b)-CH₂-CH₂- (c)-CHOH-CH₂- (d)-CHOH-CHOH- (e)-CH₂-CHOH- (f) or-CO-CO- (g)

The compounds of the present invention have been artificially synthesized and subjected to pharmacological studies. The compounds of the present invention are pharmacologically significantly different from thioperazone. Whereas bupropion has strong sedative side effects, the compounds of the present invention have been found to have only reduced or even no sedative activity. It has been determined that the novel compounds possess anti-histamine and anti-inflammatory properties. Most importantly, the novel compound has strong anti-lung inflammation effect and can effectively inhibit the hyperfunction of bronchial smooth muscle.

Since asthma is characterized by airway inflammation and bronchial smooth muscle hyperresponsiveness, it is certain that the novel compounds are effective antihistamines and can be clinically used for treating asthma and bronchitis without sedative side effects.

Detailed Description

Biological study of the Compounds of the invention

As mentioned above, the compounds of the present invention have been shown to have advantageous pharmacological effects and to be useful in the treatment of a number of diseases, such as asthma, allergy and ocular disorders. The following biological studies detail these new findings:

1. binding to histamine receptors

With modified Chang et al (Histamine H)₁Heterogeneity of receptors, journal of neurochemistry, 1979, 32: 1653 and 1663)³H]Evaluation of test Compounds on Histamine H by Piperamine binding assay₁The affinity of the receptor. Briefly, the method comprises taking the mucosa of the cerebellum of a bovine³H]Pyrilamine and test compounds at increasing concentrations were incubated. In the case of excess unlabeled ligand, specific binding of the radioactive ligand to the receptor is defined as the difference between total binding and non-specific binding. IC (integrated circuit)₅₀Value (inhibition [ [ alpha ] ]³H]The concentration required for 50% specific binding of pyrilamine) was determined by non-linear regression analysis of the competition curve.

IC₅₀(M)

Thiepdone 8.15×10^-9

Demethylthiopiperazone 4.36X 10^-8

10-OH-demethyl-thiopenone 1.13X 10^-7

Example 2 where n is 25.85 × 10^-9

Example 5 where n is 26.95 × 10^-8

Phenylpropidin hydrochloride (control Compound) 1.41X 10^-8

2. Binding to muscarinic receptors

Adopts the improved Luthin and the like ([ 2 ]³H]Pyramine and [ alpha ], [ beta ], [ alpha ]³H]QNB binding to muscarinic cholinergic receptors in the brain, molec. pharmac.1984.26: 164 phase 169)³H]Piperamine binding assay for detecting test compounds and muscarinic M₁-affinity of the receptor. Briefly, muscarinic M is taken from the striatal membranes of cattle₁The receptor is tested and after incubation with the test substance and the radioactive ligand and washing, the bound radioactivity is determined on a liquid scintillation counter using a commercially available liquid scintillation cocktail. In the case of an excess of unlabeled ligand, the specific binding of the radioactive ligand to each receptor is defined as the difference between total binding and non-specific binding. IC (integrated circuit)₅₀The value (the concentration required to inhibit 50% of specific binding) was determined by non-linear regression analysis of the competition curve.

IC₅₀(M)

Thiepdone 7.1L 10^-8

Demethylthiopiperazone 2.61X 10^-7

Example 2 where n is 22.35 × 10^-7

Example 5, where n-28.80 × 10^-7

Atropine sulfate (control compound) 5.74X 10^-10

3. Investigation of sedative Effect

The physostigmine-induced lethality test used in these experiments was performed in accordance with the sedation assay reported by modified COLLIER et al (Br. J. Pharmac., 1968, 32: 295- & 310). Briefly, 10 mice per plastic cage (approximately 11X 26X 13cm in size) injected subcutaneously with physostigmine at 1.9mg/kg per mouse yielded 100% mortality. Mice were protected from survival by the administration of sedating antihistamines prior to physostigmine administration. In this study, the test compounds were administered orally to mice 60 minutes before physostigmine administration. The number of surviving mice was counted 30 minutes after physostigmine administration. The dose size used in the CNS assay was half the molecular weight of the test compound expressed in mg/kg body weight.

Survival number of oral treatment (mg/kg)

Thiepdone (107) 9/10

Demethylthiopiperazone (83) 3/10

Example 2, where n-2 (94) 3/10

Example 5, where n-2 (108) 0/10

Vehicle 0/10

Astemizole 1/10

(antihistaminic control Compound without sedative Effect)

4. Anti-inflammatory action (inhibition of bronchial eosinophil aggregation)

Experiment for inhibiting eosinophil aggregation in lung A guinea pig (400-600 g) was used, and 10. mu.g of PAF (platelet aggregation factor) dissolved in physiological saline containing 0.25% bovine serum albumin was intraperitoneally injected. After 24 hours, the guinea pigs were killed with barbiturate, the trachea exposed, a cannula inserted, and the Taiwanese solution (composition: NaHCO) introduced continuously through the cannula₃ 11.9，NaCl 136.9，KCl 2.7，Na₂HPO₄0.4, glucose 5.6, EDTA 19.8, gelatin 0.1% w/v, serum albumin (BSA) 0.5% w/v; pH7.4), the lung is slightly pressed to suck and suck the liquid in the cannula. The overall liquid recovery is typically over 80%. The cell suspension obtained was concentrated by low speed centrifuge, the cell pellet obtained by centrifugation was again suspended in 1ml of Taiwan's solution, and 10. mu.l of the cell suspension was again diluted with 90. mu.l of Turk's solution to count the cells and make cell smear, fixed in formic acid (100%), and stained in Leishman stain. The cells were then counted under a 1000-fold magnification microscope with at least 500 cells per smear to distinguish between different cell types. The administration was performed subcutaneously from an implanted Alza micropump for 7 days and the experiment was performed with PAF 5 days after prior treatment with the test compound.

5. Study of the action on the stomach

Experimental studies of the effect of the compounds of the invention on the stomach were performed on isolated guinea pig ileum contracted with bradykinin induction. The ileum was previously treated with various concentrations of test compounds (with or without 1 μ M atropine in solution) before inducing contractile responses in the ileum with bradykinin.

Studies to test the effect of compounds on gastric ulcers were performed in rats. An animal model of gastric ulcer was caused by subcutaneous injection of 30mg/kg of anti-inflammatory disease. Test compounds were orally administered at a dose of 100. mu.g/100 g body weight in the experimental group 30 minutes before and 5 hours after the administration of indomethacin, respectively. Finally, the area of ulcer (mm) is measured³) The degree of reduction of (a).

Examples of chemical Synthesis of novel Compounds

Waldvogel et al have reported methods for the synthesis of thalidone, desmethylthalidone, and (RS) -10-OH-thalidone (Helv Chem Acta, 1976, 59: 866-877), the contents of which are incorporated herein by reference.

The novel compounds of the present invention have the general formula shown in table 1 below.

The novel compounds of the present invention can be used to obtain starting materials for synthesis according to the method reported by Woldvogel et al. The compound (1) 4- (4-piperidylidene) -9, 10-dihydro-4H-benzo [4, 5 ]]Cyclohepta [1, 2-b ]]Thiophene-9-one Compound (2) 4- (4-piperidylidene) -9, 10-dihydro-4H-benzo [4, 5 ]]Cyclohepta [1, 2-b ]]Thiophene-10-one Compound (3) 4- (4-piperidylidene) -9, 10-dihydro-4H-benzo [4, 5 ]]Cyclohepta [1, 2-b ]]Thiophene Compound (4) 4- (4-Piperidinylidene) -9, 10-dihydro-4H-benzo [4, 5]Cyclohepta [1, 2-b ]]Thiophene-9, 10-dionesWherein R is selected from hydroxy-C_2-6Alkyl or carboxy-C_1-6alkoxy-C_1-6An alkyl group. -A-B-is a group of formula-CO-CH₂- (a)-CH₂-CO- (b)-CH₂-CH₂- (c)-CHOH-CH₂- (d)-CHOH-CHOH- (e)-CH₂-CHOH- (f) or-CO-CO- (g)

TABLE 1 novel Compounds of the invention

Example 1.

The compound of Table 1, wherein R is- (CH)₂)_nOH and wherein-A-B-has the formula-CO-CH₂And wherein N ═ 2 can be prepared by treating starting compound (1) with a 2-haloethanol such as 2-bromoethanol or 2-chloroethanol (with or without stirring to cause reaction) in the presence of a basic catalyst such as potassium carbonate in a solvent such as N, N-dimethylformamide. After removal of the solvent by evaporation, the residue is mixed with water and extracted with an organic solvent such as chloroform, dichloromethane or ethyl acetate. After removal of the organic solvent by evaporation, the product is purified by crystallization using a solvent such as methanol or ethanol. Analogous compounds, where n ═ 3-6, can be prepared by the same method, but using ω -haloethanol, X- (CH)₂)_3-6-OH, wherein X is chloro or bromo.

The product can be converted to the hydrochloride salt by dissolving it in a solvent mixture such as chloroform/diethyl ether and adding a solution of hydrogen chloride in dioxane. Evaporation of the solvent gave the product as the hydrochloride salt.

Example 2.

The compound of Table 1, wherein R is- (CH)₂)_nOH and wherein-A-B-has the formula-CH₂-CO-, and wherein n ═ 2, was prepared from 1 gram of compound (2) reacted with 2-chloroethanol (3 eq), potassium carbonate (3 eq), and potassium iodide (0.4 eq) in 10ml of dimethylformamide. After stirring at room temperature for 4 days, the solvent was evaporated in vacuo and the residue was dissolved in chloroform (50ml), the solution was washed with water and dried over magnesium sulfate. After removal of the solvent, the crude product was purified by chromatography on silica gel using chloroform containing 5% methanol as eluent. This product was dissolved in chloroform/diethyl ether, a dioxane solution of hydrogen chloride was added, and the solvent was evaporated in vacuo to leave the hydrochloride salt of example 2 (n-2). Yield: 0.87 g. Proton nmr spectroscopy is consistent with the proposed structure.

Example 3.

The compound of Table 1, wherein R is- (CH)₂)_nOH and wherein-A-B-has the formula-CH₂-CH₂And wherein N ═ 2 can be prepared by treating starting compound (3) with a 2-haloethanol such as 2-bromoethanol or 2-chloroethanol (with or without stirring to cause reaction) in the presence of a basic catalyst such as potassium carbonate in a solvent such as N, N-dimethylformamide. After removal of the solvent by evaporation, the residue is mixed with water and extracted with an organic solvent such as chloroform, dichloromethane or ethyl acetate. After removal of the organic solvent by evaporation, the product is purified by crystallization using a solvent such as methanol or ethanol. Analogous compounds, where n ═ 3-6, can be prepared by the same method, but using ω -haloethanol, X- (CH)₂)_3-6-OH, wherein X is chloro or bromo.

The product can be converted to the hydrochloride salt by dissolving it in a solvent mixture such as chloroform/diethyl ether and adding a solution of hydrogen chloride in dioxane. Evaporation of the solvent gave the product as the hydrochloride salt.

Example 4.

The compound of Table 1, wherein R is- (CH)₂)_n-O-CH₂-COOH and-A-B-have the formula-CO-CH₂-, and wherein N ═ 2, can be prepared by reaction with a haloacetic acid (X-CH) in the presence of a basic catalyst such as potassium carbonate in a solvent such as N, N-dimethylformamide₂COOH, wherein X is chloro or bromo, to the compound of Table 1 (wherein R is- (CH)₂)_nOH and wherein-A-B-has the formula-CO-CH₂-, wherein n ═ 2) (with or without heating under stirring to cause a reaction). After removal of the solvent by evaporation, the residue is mixed with water, the solution is neutralized to pH5-6, and the aqueous solution is extracted with an organic solvent such as chloroform, dichloromethane or ethyl acetate. After evaporation of the organic solvent, the product is purified by crystallization using a solvent such as methanol or ethanol. Analogous 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-CH₂-COOH, wherein-A-B-has the formula-CO-CH₂-, where n is 3-6. In addition, the watch1 wherein R is- (CH)₂)_n-O-CH₂-COOH, wherein-A-B-has the formula-CO-CH₂Wherein n is 2 to 6, can also be synthesized as described in example 5 below.

Example 5.

The compound of Table 1, wherein R is- (CH)₂)_n-O-CH₂-COOH and wherein-A-B-has the formula-CH₂-CO-, wherein n is 2, in a two-step synthesis. In a first step, 1.9 g of compound (2) are treated with (2-chloroethoxy) acetonitrile (2 eq), potassium carbonate (2.4 eq) in 10ml of dimethylformamide, after stirring for 4 days at room temperature, the solvent is evaporated in vacuo, 10ml of water are added to the residue, the resulting suspension is extracted with 3 × 10ml of chloroform, after evaporation of the combined extracts, the crude extract is purified by chromatography on silica gel, using 2% methanol in chloroform as eluent. Intermediate N- [ (2-cyanomethoxy) ethyl]Demethyl-thiotifen (0.75 g) was heated in concentrated hydrochloric acid for 12 hours, the solvent evaporated in vacuo and the resulting pink residue dissolved in methanol, treated twice with charcoal, filtered and the solvent evaporated in vacuo to give the pink foam-like hydrochloride of example 5 (n-2). Yield: 0.71 g. Proton nmr spectroscopy is consistent with the proposed structure.

Example 6.

The compound of Table 1, wherein R is- (CH)₂)_n-O-CH₂-COOH and wherein-A-B-has the formula-CH₂-CH₂-, and wherein N ═ 2, can be prepared by reaction with a haloacetic acid (X-CH) in the presence of a basic catalyst such as potassium carbonate in a solvent such as N, N-dimethylformamide₂COOH, wherein X is chloro or bromo, to the compound of Table 1 (wherein R is- (CH)₂)_nOH and wherein-A-B-has the formula-CH₂-CH₂-, wherein n ═ 2) (with or without heating under stirring to cause a reaction). After removal of the solvent by evaporation, the residue is mixed with water, the solution is neutralized to pH5-6, and the aqueous solution is extracted with an organic solvent such as chloroform, dichloromethane or ethyl acetate. After evaporation of the organic solvent, use is made of a solvent such as methanol orThe product was purified by crystallization from ethanol. Analogous compounds, where n ═ 3-6, can be prepared by the same method from the compounds of table 1, where R is — (CH)₂)_nOH, wherein-A-B-has the formula-CH₂-CH₂-, where n is 3-6. In addition, the compound of Table 1, wherein R is- (CH)₂)_n-O-CH₂-COOH, wherein-A-B-has the formula-CH₂-CH₂Wherein n is 2 to 6, can also be synthesized according to the method described in example 5.

Example 7.

By treating the compounds of Table 1 (wherein R is- (CH) with sodium borohydride in a solvent such as ethanol at room temperature₂)_nOH, wherein-A-B-has the formula-CO-CH₂-, where n ═ 2, the compounds of table 1 (where R is- (CH) can be prepared₂)_nOH, wherein-A-B-has the formula-CHOH-CH₂-, where n ═ 2). After the excess reagent has been decomposed with acetone, the solvent is evaporated off and the residue is crystallized from a solvent such as methanol or ethanol (with or without diethyl ether). Similar compounds, wherein n ═ 3-6, can be prepared by the same method from the compounds of table 1 (wherein R is — (CH)₂)_nOH, wherein-A-B-has the formula-CO-CH₂-, and wherein n ═ 3-6). The product can be converted to the hydrochloride salt by dissolving it in a solvent mixture such as chloroform/diethyl ether and adding a solution of hydrogen chloride in dioxane. Evaporation of the solvent gave the product as the hydrochloride salt.

Example 8.

By treating the compound of Table 1 (wherein R is- (CH) with sodium borohydride in a solvent such as ethanol at room temperature₂)_nOH and wherein-A-B-has the formula-CO-CH₂-, where n ═ 2, the compounds of table 1 (where R is- (CH) can be prepared₂)_n-O-CH₂-COOH and wherein-A-B-has the formula-CHOH-CH₂And wherein n ═ 2) after decomposing excess reagent with acetone, the solvent is evaporated off, the residue is mixed with water, the solution is neutralized with an acid such as dilute hydrochloric acid, and extracted with a solvent such as ethyl acetate. After evaporation of the organic solvent, the residue is removed from the solvent, e.g. methanol or ethanol (with or without)No ether). Similar compounds, wherein n ═ 3-6, can be prepared by the same method from the compounds of table 1 (wherein R is — (CH)₂)_nOH, wherein-A-B-has the formula-CO-CH₂-, and wherein n ═ 3-6).

In addition, the compound of Table 1, wherein R is- (CH)₂)_n-O-CH₂-COOH, and wherein-a, B-has the formula-CHOH-CH₂The compound (n) is 2 to 6, and can be synthesized by the method described in example 5.

Example 9.

By treating the compounds of Table 1 (wherein R is- (CH) with sodium borohydride in a solvent such as ethanol at room temperature₂)_nOH, wherein-A-B-has the formula-CH₂-CO-, wherein n ═ 2, can be used to prepare the compounds of table 1 (wherein R is- (CH)₂)_nOH, wherein-A-B-has the formula-CH₂-CHOH-, wherein n ═ 2). After the excess reagent has been decomposed with acetone, the solvent is evaporated off and the residue is crystallized from a solvent such as methanol or ethanol (with or without diethyl ether). Similar compounds, wherein n ═ 3-6, can be prepared by the same method from the compounds of table 1 (wherein R is — (CH)₂)_nOH, wherein-A-B-has the formula-CH₂-CO-, and wherein n-3-6). The product can be converted to the hydrochloride salt by dissolving it in a solvent mixture such as chloroform/diethyl ether and adding a solution of hydrogen chloride in dioxane. Evaporation of the solvent gave the product as the hydrochloride salt.

Example 10.

By treating the compound of Table 1 (wherein R is- (CH) with sodium borohydride in a solvent such as ethanol at room temperature₂)_n-O-CH₂-CHOH and wherein-A-B-has the formula-CH₂-CO-, wherein n ═ 2, can be used to prepare the compounds of table 1 (wherein R is- (CH)₂)_n-O-CH₂-COOH and wherein-A-B-has the formula-CH₂-CHOH-, and wherein n ═ 2) after cleavage of excess reagents with acetone, the solvent is evaporated off, the residue is mixed with water, the solution is neutralized with an acid, such as dilute hydrochloric acid, and extracted with a solvent, such as ethyl acetate. After evaporation of the organic solvent, the residue is removedThe residue is crystallized from a solvent such as methanol or ethanol (with or without diethyl ether). Similar compounds, wherein n ═ 3-6, can be prepared by the same method from the compounds of table 1 (wherein R is — (CH)₂)_n-CH₂-COOH, wherein-A-B-has the formula-CH₂-CO-, and wherein n-3-6).

In addition, the compound of Table 1, wherein R is- (CH)₂)_n-O-CH₂-COOH and wherein-A-B-has the formula-CH₂-CHOH-, n-2-6, also synthesized as described in example 5.

Example 11.

The compound of Table 1, wherein R is- (CH)₂)_nOH and wherein-a-B-has the formula-CO-, and wherein N ═ 2, can be prepared by treating starting compound (4) with a 2-haloethanol such as 2-bromoethanol or 2-chloroethanol (with or without stirring to cause reaction) in the presence of a basic catalyst such as potassium carbonate in a solvent such as N, N-dimethylformamide. After removal of the solvent by evaporation, the residue is mixed with water and extracted with an organic solvent such as chloroform, dichloromethane or ethyl acetate. After removal of the organic solvent by evaporation, the product is purified by crystallization using a solvent such as methanol or ethanol. Analogous compounds, where n ═ 3-6, can be prepared by the same method, but using ω -haloethanol, X- (CH)₂)_3-6-OH, wherein X is chloro or bromo.

The product can be converted to the hydrochloride salt by dissolving it in a solvent mixture such as chloroform/diethyl ether and adding a solution of hydrogen chloride in dioxane. Evaporation of the solvent gave the product as the hydrochloride salt.

Example 12.

The compound of Table 1, wherein R is- (CH)₂)_n-O-CH₂-COOH and-a-B-have the formula-CO-, and wherein N ═ 2, can be prepared in the presence of a basic catalyst such as potassium carbonate in a solvent such as N, N-dimethylformamide by reaction with a haloacetic acid (X-CH)₂COOH, wherein X is chloro or bromo, to the compound of Table 1 (wherein R is- (CH)₂)_nOH and wherein-a-B-has the formula-CO-, wherein n ═ 2) (with or without stirring to cause reaction). After removal of the solvent by evaporation, the residue was mixed with water and the solution was neutralized to pH 5-6. The aqueous solution is extracted with an organic solvent such as chloroform, dichloromethane or ethyl acetate. After evaporation of the organic solvent, the product is purified by crystallization using a solvent such as methanol or ethanol. Analogous compounds, where n ═ 3-6, can be prepared by the same method from the compounds of table 1, where R is — (CH)₂)_nOH, wherein-a-B-has the formula-CO-, wherein n ═ 3-6.

In addition, the compound of Table 1, wherein R is- (CH)₂)_n-O-CH₂-COOH, wherein-a-B-has the formula-CO-, wherein n is 2-6, can also be synthesized as described in example 5 below.

Example 13.

By treating the compounds of Table 1 (wherein R is- (CH) with sodium borohydride in a solvent such as ethanol at room temperature₂)_nOH, where-a-B-has the formula-CO-, where n ═ 2, can make the compounds of table 1 (where R is- (CH)₂)_nOH, wherein-a-B-has the formula-CHOH-, wherein n ═ 2). After the excess reagent has been decomposed with acetone, the solvent is evaporated off and the residue is crystallized from a solvent such as methanol or ethanol (with or without diethyl ether). Similar compounds, wherein n ═ 3-6, can be prepared by the same method from the compounds of table 1 (wherein R is — (CH)₂)_nOH, wherein-a-B-has the formula-CO-, and wherein n-3-6).

The product can be converted to the hydrochloride salt by dissolving it in a solvent mixture such as chloroform/diethyl ether and adding a solution of hydrogen chloride in dioxane. Evaporation of the solvent gave the product as the hydrochloride salt.

Example 14.

By treating the compound of Table 1 (wherein R is- (CH) with sodium borohydride in a solvent such as ethanol at room temperature₂)_n-O-CH₂-COOH and wherein-a-B-has the formula-CO-, wherein n ═ 2) can prepare the compounds of table 1 (wherein R is-(CH₂)_n-O-CH₂-COOH and wherein-a-B-has the formula-CHOH-, and wherein n ═ 2), after cleavage of excess reagent with acetone, the solvent is evaporated off, the residue is mixed with water, the solution is 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 is crystallized from a solvent such as methanol or ethanol (with or without diethyl ether). Similar compounds, wherein n ═ 3-6, can be prepared by the same method from the compounds of table 1 (wherein R is — (CH)₂)_n-O-CH₂-COOH, wherein-a-B-has the formula-CO-, and wherein n-3-6).

In addition, the compound of Table 1, wherein R is- (CH)₂)_n-O-CH₂-COOH, and wherein-a-B-has the formula-CHOH-, n-2-6, can also be synthesized as described in example 5.

The present invention provides the above-mentioned compounds, isomers of racemic compounds including novel compounds, and pharmaceutically acceptable acid addition salts and solvates of the novel compounds.

The optical isomers of the compounds of the present invention can also be prepared by resolution of the racemates thereof by conventional methods, such as fractional crystallization of diastereomeric salts with chiral acids. Other standard resolution methods known in the art including, but not limited to, crystallization on chiral substances and chromatography may also be used. Optical isomers of the compounds of the present invention may also be prepared by stereoselective synthetic methods.

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

The invention also provides pharmaceutical compositions comprising one or more compounds of the invention formulated together with one or more pharmaceutically acceptable carriers. Such pharmaceutical compositions may be particularly formulated for oral, conjunctival instillation, sublingual, parenteral, transdermal, rectal, buccal or topical administration, or administration by inhalation or insufflation of powders or aerosols.

The pharmaceutical composition of the invention can be administered or administrated to a human or other mammal by oral administration, sublingual administration, parenteral administration, cutaneous administration, transdermal administration, rectal administration, buccal administration, topical administration, conjunctival instillation, or by way of an oral or nasal aerosol. The term "parenteral" administration includes intravenous, intraarterial, intramuscular, intraperitoneal, intradermal, subcutaneous or intraarticular injection, and infusion. The term "transdermal" administration includes the use of any number of designs (e.g., "patches" and the like) that promote or improve the transdermal delivery or absorption of a drug.

Oral administration form

Oral solid dosage forms of the pharmaceutical composition of the present invention include capsules, granules, pills, powders and tablets. In such solid dosage forms, the active compound may be combined with one or more pharmaceutically acceptable substances including excipients or carriers such as sodium citrate, dicalcium phosphate, fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, silicic acid, binders (carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, acacia), humectants such as glycerol, fluid blockers such as paraffin, disintegrating agents such as agar-agar, calcium carbonate, starch, alginic acid, silicates, sodium carbonate, absorption enhancers such as quaternary ammonium compounds, wetting agents such as cetyl alcohol, glycerol monostearate, absorbents such as kaolin, bentonite, lubricants such as talc, calcium stearate, magnesium stearate, polyethylene glycol, sodium lauryl sulfate, and/or buffering agents.

Solid dosage forms such as capsules, dragees, granules, pills and tablets may have coatings or coatings (e.g., enteric coatings) known in the pharmaceutical formulation art. The composition may also be designed to release its active ingredient only at a site in the gastrointestinal tract, or in a controlled, sustained or delayed release form.

The composition may also be designed to take up its active ingredient in the lymphatic vessels.

The active compounds may also be formulated as microencapsulated formulations prepared from one or more of the excipients mentioned above.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Liquid dosage forms also contain diluents (e.g., water, other solvents, solubilizing agents), emulsifiers (e.g., ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, butylene glycol, dimethylformamide, oils, oleic acid, glycerol, polyethylene glycol, sorbitan fatty esters), and mixtures thereof.

Besides inert diluents, the oral compositions can also contain adjuvants such as wetting agents, emulsifying agents, suspending agents, sweetening agents, or flavoring agents.

The suspension may comprise one or more suspensions known in the art of pharmaceutical formulation.

Topical administration forms

(including conjunctival instillation forms)

Compositions for topical administration of the compounds of the present invention include solutions, suspensions, microdroplets, aerosols, ointments and powders.

In addition to therapeutically active ingredients, the compositions of the present invention for topical ocular or conjunctival administration may also contain a variety of formulation ingredients, such as antimicrobial preservatives and tonicity adjusting agents. Examples of suitable antimicrobial preservatives include benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben (methyl paraben), propyl paraben, phenylethyl alcohol, disodium edetate, sorbic acid, ONAMER M, and other commonly used materials. These preservatives, used in amounts of 0.001% to 1.0% by weight, examples of suitable substances which can be used to adjust the tonicity or osmolality of the formulation include sodium chloride, potassium chloride, mannitol, dextro-glycerol and propylene glycol. These materials are used in amounts of 0.1 to 10.0% by weight. The composition preferably contains a suitable amount of water, and preferably has a pH in the range of 3.5 to 8.0 and an osmolality in the range of 280 to 320 mmol/L.

The compositions may also be formulated in a number of formulations suitable for topical ophthalmic administration, including solutions, suspensions, emulsions, gels, and erodible (erodible) intraocular solid inserts, as known to those skilled in the art.

Parenteral administration form

Pharmaceutical compositions for parenteral injection include pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions, emulsions, and sterile injectable powders for reconstitution into sterile injectable solutions or dispersions for constitution with a sterile injectable solution or dispersion before use. Many aqueous or non-aqueous vehicles, diluent solvents and vehicles (e.g., water, ethanol, glycerol, ethylene glycol), vegetable oils (e.g., olive oil) and organic esters (e.g., ethyl oleate), or mixtures thereof, may be used. Fluidity can be maintained by the use of a coating material, such as lecithin, by the limitation of the particle size and by the use of surfactants.

The compositions may also contain adjuvants, such as preserving, wetting, emulsifying, dispersing, antibacterial, antifungal, isotonic and/or absorption delaying agents. Prolonged or slow absorption can be obtained by injection of a crystalline or amorphous suspension of low water solubility. Delayed absorption can be achieved by dissolving or suspending the drug in an oily vehicle or using injectable inclusion forms (e.g., microencapsulating the drug with biodegradable polymers in the body, e.g., using polylactides, polyglycolides, polyorthoesters, polyanhydrides) or using liposome or microemulsion forms. Injections can be sterilized in many ways.

Rectal administration form

Compositions for rectal administration are preferably suppositories.

Oral administration form

The composition for oral administration is preferably formulated into toothpaste, collutory, sublingual preparation, chewing gum, etc.

Sublingual administration form

Many galenic (galenic) formulations can be used: concentrated solutions or suspensions of the drug can be applied sublingually by various drop devices; various aerosol devices can be used to spray the drug onto the oral mucosal surface; a specially designed fast dissolving tablet, capsule, or powder can also be used to rapidly deliver a full dose of drug.

Transdermal administration mode

The composition preparation for transdermal administration of the compound of the present invention includes various known patches, dressings (bandaging), and the like.

Oral nasal aerosol or microdroplet administration

The aerosol or droplet composition for oral or nasal administration may take the form of a solution, suspension or dry powder, and may be designed for nasal, buccal, bronchial/pulmonary and/or gastric absorption in a pharmaceutical form.

Therapeutic dosage

The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention will depend upon the desired therapeutic effect. Thus, the amount of drug employed may vary depending on factors such as the mode of administration, the severity of the condition, the number of administrations, and the like. For patients suffering from benign tracheal or bronchial diseases (e.g., asthma, bronchitis, etc.), the compounds of the present invention are administered orally in an amount ranging from 0.5mg to about 200mg, preferably in an amount of 0.5mg to 10mg (1-4 times a day) for a patient weighing 60 kg. The daily dosage can be increased or decreased depending on various factors such as body weight and severity of the disease.

For example, a dose of 0.1mg to about 100mg of a compound of the present invention is administered orally to a patient suffering from allergic conjunctivitis, and a dose of 0.2 to 10mg (1 to 4 times per day) is preferably administered to a patient weighing 60 kg. For patients with seasonal allergic conjunctivitis, the concentration of the solution of demethyl tiaperidone instilled into the conjunctival sac is from 0.01% to 2.0%, preferably from 0.02% to 1.0%. The frequency and dosage of the drug administered will be determined by a physician, in view of a number of clinical factors, such as body weight and the severity of the patient's condition. The usual application is to apply 1-2 drops (or a certain amount of solid or semi-solid preparation) to the affected eye 1-4 times a day.

Oral unit dose formulations

EXAMPLE 15 tablets

Each dosage of 10,000 pieces of the composition

Example 5 Compound 2mg 20g

Microcrystalline cellulose 30mg 300g

Lactose 70mg 700g

Calcium stearate 2mg 20g

FD&C Blue#1 Lake 0.03mg 300g

The active ingredient (in this example, the compound of example 5, where n ═ 2) was mixed with lactose and cellulose until a homogeneous mixture was formed. The lake is then added and further mixed and finally calcium stearate is added and the resulting mixture is compressed into tablets using a shallow concave punch tablet press of 9/32 inches (7 mm). Tablets of other dosages may be prepared by varying the ratio of the active ingredient to the excipients or to the total weight of the tablet.

The present invention provides methods for treating and/or preventing various forms of bronchial asthma, allergic bronchitis, multiple system allergic reactions, allergic rhinitis and allergic skin disorders in mammals such as humans, while avoiding the sedative side effects of thalidomide and other toxic reactions. These methods comprise administering to a mammal in need of such treatment and/or prevention an effective amount of at least one compound of the present invention or a pharmaceutically acceptable salt thereof.

The present invention also provides methods of using one or more compounds of the present invention in combination with an adrenergic beta-receptor agonist, including but not limited to salbutamol, terbutaline, fenoterol, formoterol or salmeterol, thereby eliminating or reducing the bronchial hyperresponsiveness that may be induced by the beta-receptor agonist treatment. The present invention also provides methods of using the compounds of the present invention in combination with other agents that cause bronchial hyperreactivity, including but not limited to adrenergic beta-receptor blockers or cyclooxygenase inhibitors, to eliminate or reduce the bronchial hyperreactivity induced by the agents during treatment.

The present invention provides methods for treating and/or preventing ocular disorders such as allergic conjunctivitis or allergic keratitis and inflammatory disorders such as blepharitis, conjunctivitis, episcleritis, scleritis, keratitis, anterior uveitis, posterior uveitis, endophthalmitis, optic neuritis, cranial arteritis, sympathetic ophthalmia, and the like in mammals such as humans while avoiding ocular irritation, sedation, and other toxic side effects of tiaperidone and steroids. These methods comprise administering to a mammal in need of such treatment and/or prevention an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

The present invention also provides methods of administering a compound of the invention in combination with at least one of the following classes of agents: ocular antihypertensives, adrenergic receptor agonists or antagonists, antibacterial agents, antiviral agents, steroids, cyclooxygenase inhibitors, leukotriene antagonists, lipoxygenase inhibitors, and other ocular disease treatment agents. In particular, the invention also provides methods of using the compounds of the invention in combination with ophthalmic decongestants such as phenyl efavirenz, naphazoline, tetrahydroxyoxazoline or with antibacterial agents such as bacitracin, neomycin, and polymyxin.

The present invention also provides methods of use for administering the compounds of the present invention to reduce inflammation and irritation during surgery and to promote healing after surgery.

The invention also provides methods of treating and/or preventing gastrointestinal disorders, such as hypersecretion syndrome including Zollinger-Ellison syndrome, gastric irritation, inflammatory bowel disease, gastric or duodenal ulcers, hyperacidity dyspepsia, heartburn, or unwanted hypersecretion of gastric acid. These methods comprise administering to a mammal in need of such treatment and/or prevention an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

Equivalents of the formula

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents include the single isomer or compositions containing the isomer for therapeutic use, but avoid the side effects of the corresponding isomer. These equivalents also include many pharmaceutically acceptable salt forms such as sulfate, hydrobromide, hydrochloride, dihydrochloride, fumarate, formate, hydroxynaphthoate, or one or other hydrate forms thereof, see merck index 11 th edition (1989) items 9089, 209, 3927, 4628, 8223, 5053, 5836, 8142, 2347, 7765, 1840, 9720, 7461, 1317, 4159, and 963, and references cited therein and am.rev.resp.dis.1988, 137: (4; 2/2)32. these equivalents also include methods of administering at least one compound of the invention in combination with any other agent that treats the diseases mentioned herein. Those skilled in the medical arts will also appreciate that it may be more advantageous to administer a slightly higher or lower dose of a compound of the invention than described herein as the case may be and that the drug may be administered slightly more or less frequently than is set forth herein. Pharmacologists know that certain pharmacological effects of the compounds of the invention (e.g., antihistamine activity, PAF-antagonistic activity, mast cell stabilizing activity, etc. at various receptor types) may also find use in other contexts not mentioned herein.

It will be appreciated by those skilled in the art that the use of a single isomer (eutomer) of any of the racemic compounds of the present invention, desmethylhexythinone, 10-OH-desmethylhexythinone, makes it possible to avoid the side effects of the other isomers. These side effects may include cardiovascular side effects, such as cardiac arrest, or central nervous system side effects, such as sedation. All equivalent compounds are included in the present invention.

Claims (20)

1. A compound having the formula:including stereochemically isomeric forms thereof and pharmaceutically acceptable salts thereof, wherein: r is selected from hydroxy-C_2-6Alkyl or carboxy-C_1-6alkoxy-C_1-6An alkyl group, a carboxyl group,

-A-B-is a group of formula

-CO-CH₂- (a)

-CH₂-CO- (b)

-CH₂-CH₂- (c)

-CHOH-CH₂- (d)

-CHOH-CHOH- (e)

-CH₂-CHOH- (f)

Or

-CO-CO- (g)。

2. The compound of claim 1, wherein-a-B-has the formula-CH₂-CO, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, wherein R is- (CH)₂)_nOH, and wherein-A-B-has the formula-CH₂-CO-, wherein n-2-6, or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1, wherein R is- (CH)₂)_n-O-(CH₂)_n-COOH, wherein-A-B-has the formula-CH₂-CO-, wherein n-1-6, or a pharmaceutically acceptable salt thereof.

5. Use of a compound according to claim 1 for the manufacture of a medicament for the treatment of allergic diseases.

6. The use of claim 5, wherein the allergic disease comprises allergic rhinitis, bronchitis, urticaria, atopic dermatitis, and enteritis.

7. The use of a compound according to claim 1 for the preparation of a medicament for the treatment of an ocular disorder.

8. The use of claim 7, wherein the ocular disease comprises anterior uveitis, blepharitis, conjunctivitis, cranial arteritis, endophthalmitis, episcleritis, keratitis, keratoconjunctivitis, optic neuritis, posterior uveitis, retinopathy, and scleritis.

9. Use of a compound according to claim 1 for the manufacture of a medicament for the treatment of a respiratory disorder.

10. The use of claim 9, wherein the respiratory disease comprises Chronic Obstructive Pulmonary Disease (COPD), asthma, cough, and bronchitis.

11. Use of a compound according to claim 1 for the preparation of a medicament for the treatment of smooth muscle hyperreactivity.

12. The use of a compound according to claim 1 for the manufacture of a medicament for the treatment of gastrointestinal disorders.

13. The use of claim 12, wherein the gastrointestinal disease comprises hypersecretion syndrome, Zollinger-Ellison syndrome, gastric irritation, enteritis, gastric ulcer, hyperacidity dyspepsia, heartburn.

14. The use according to claims 5, 7, 9, 11 and 12, wherein the medicament is prepared for administration in a form selected from the group consisting of inhalation, conjunctival instillation, nasal inhalation, parenteral, transdermal, buccal, rectal, sublingual, nasal, topical and oral.

15. The use of claim 14, wherein the pharmaceutical is in the form of a delayed release, sustained release or other controlled release agent.

16. The use according to claim 14, wherein the dose is from about 0.2mg to about 200mg, preferably from 0.5mg to 20mg, 1-4 times daily for a patient weighing 60 kg.

17. Use according to claim 7, wherein the compound as defined in claim 1 is administered by 1-4 conjunctival instillations of a solution having a concentration of 0.01% to 2.0% per day.

18. A pharmaceutical composition in the form of a solid, semi-solid, liquid, suspension, aerosol, or transdermal formulation comprising a therapeutically effective amount of a compound as defined in claim 1 in association with a pharmaceutically acceptable carrier or carrier system.

19. Use of a composition comprising a therapeutically effective amount of a compound as defined in claim 1 and one or more agents such as analgesics, antibacterials, anti-inflammatories, vasoconstrictors, vasodilators, cough suppressors and expectorants in the manufacture of a medicament for the treatment of a mammal.

20. Use of a composition comprising a therapeutically effective amount of a compound as defined in claim 1 in combination with one or more drugs such as cholinergic agents, antimuscarinic agents, cholinesterase inhibitors, adrenergic beta-receptor blockers, antibacterials, sympathomimetic agents, carbonic anhydrase inhibitors, anti-inflammatory agents, decongestants, astringent bases, expectorants and local anesthetics for the manufacture of a medicament for topical treatment of the eye of a mammal.