JPH09508915A - Enantiomerically pure (-)-liarosol - Google Patents

Abstract

(57) Summary The present invention relates to novel enantiomerically pure levorotatory isomers of Liarozole of formula (I) and pharmaceutically acceptable acid addition salts thereof. These compounds are particularly useful in treating diseases characterized by increased proliferation and / or abnormal differentiation of normal, preneoplastic or neoplastic epithelial cells. The compounds of formula (I) are particularly useful in the field of oncology. Also disclosed are compositions containing the novel compounds, methods of making the novel compounds, and methods of using the compounds described above to treat the diseases described above.

Description

Detailed Description of the Invention                Enantiomerically pure (−)-liarozole   The present invention provides for increased proliferation and / or abnormalities of normal, preneoplastic or neoplastic epithelial cells. Novel Mirror Image of Formula (I) Useful in the Treatment of Diseases Characterized by Differentiation Relates to a physically pure compound. These compounds have particular potential in the field of oncology. It is for. Compositions containing the novel compounds as well as the above for the treatment of the abovementioned diseases Also disclosed are methods of using the above compounds. Levorotatory compounds of formula (I) treat epithelial diseases It is useful for the manufacture of chemicals. Furthermore, the present invention provides the production of this novel compound. A method is also provided.   The novel compounds according to the invention are levorotatory isomers of the compound lialozole. And their pharmaceutically acceptable acid addition salts.   Liarozole is a racemic mixture, i.e. a mixture of its optical isomers, And specifically listed as compound 28 in EP-0,371,559. The feature Patent application describes the use of compounds similar to Liarozole in the treatment of epithelial diseases . EP-0,260,744 is a remedy for suppressing or reducing androgen production. It describes the use of compounds similar to allozoles. EP-0,371,559 and EP-0,260,744 is a compound similar to Liarozole with stereochemically isomeric forms. However, no example of the enantiomerically pure form of Liarozole is shown. Not.   Chemically, Liarozole is (±) -5- [3-chlorophenyl] -1H-Imidazo Ol-1-ylmethyl] -1H-Benzimidazole, and in formula (I) Is represented by As you can see from the chemical structure, Liarozole is a stereogel. Have a stereogenic center (indicated by an asterisk in formula (I) ).   The subject of the present invention is the enantiomerically pure levorotatory isomer of Liarozole, namely ( -)-Isomer. The isomer is hereinafter referred to as (−)-liarozole.   Many organic compounds exist in optically active forms, that is, they are of plane-polarized light. Has the ability to rotate a surface. In describing an optically active compound, one of the molecules Or the prefix D and to indicate the absolute configuration around the chiral center And L or R and S are used. Shows sign of rotation of plane polarized light by compound The prefixes (+) and (-) or d and 1 are used for where (-) or 1 Means that the compound is levorotatory and (+) or d is the compound is dextrorotatory. Means that. For certain chemical structures, optical activity with the opposite sign of optical rotation is The sex isomer is called the enantiomer. The enantiomers are such that they are mirror images of one another. Other than that, they are the same. A 1: 1 mixture of such enantiomers is referred to as a racemic mixture. Called.   Each enantiomer may have different potency or different activity As such, stereochemical purity is important in the pharmaceutical field. Mirror image of favorable isomer Isomers may be more harmful than simply inactive ones. Such differences Some examples of are known in the art.   The term "enantiomerically pure" means here that the product is at least 90% by weight. % One enantiomer and up to 10% by weight of another enantiomer Is meant to contain. In the most preferred embodiment, "enantiomerically pure" The term means that the composition is at least 99% by weight of one enantiomer and not more than 1% of other It is meant to contain the enantiomers of.   It should be noted that the rotation of a chemical depends on the experimental parameters. Less than The value shown in the experimental part of is the optical rotation and is eg the temperature, the plane used. Experimental conditions such as the wavelength of polarization, solvent and sample concentration are specified in a general manner. Have been. Optical rotation may change, for example, when acid addition salts are formed (which is Even the sign may change! ). Levorotatory isomers of Liarozole, i.e. (-)- When referring to Liarozole, the sign of the optical rotation of the base form is shown below. Under the experimental conditions of.   When a chemical reaction does not include a stereocenter, the absolute configuration of the stereocenter remains the same However, the optical rotations of the compounds resulting from the chemical reaction have different or opposite signs. It should also be noted that you may have Therefore, to avoid confusion , Having the absolute configuration of the same stereocenter as the desired enantiomer of the final product Interstitial spaces are displayed with a prefix (A) before the reference number.   The pharmaceutically acceptable acid addition salts mentioned above are capable of forming compounds of formula (I). It is meant to comprise a therapeutically active non-toxic acid addition salt form. The latter is convenient Includes a basic form of an inorganic acid such as a hydrohalic acid such as hydrochloric acid or hydrobromic acid; Sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids such as acetic acid, propanoic acid, hydroxy vinegar Acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, ethanenic acid, propane Nitric acid, butanic acid, (Z) -2-butenic acid, (E) -2-butenedioic acid, 2-hydro Xibutanedioic acid, 2,3-dihydroxybutanedioic acid, 2-hydroxy-1,2,3-propanetri Carboxylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4- Methylbenzenesulfonic acid, cyclohexanesulfamic acid, 2-hydroxyammonium With a suitable acid such as benzoic acid, 4-amino-2-hydroxybenzoic acid and similar acids. It is obtained by processing. Conversely, treatment of the salt form with an alkali will give the free base. It can also be converted into a shape. The term addition salt is capable of forming a compound of formula (I) It also comprises hydrates and solvent addition forms. Examples of such forms are eg hydrates, aldols For example, collate.   Suitable pharmaceutically acceptable acids are hydrochloric acid and (E) -2-butenedioic acid.   A general method for producing a structure containing liarosol is EP-0,371,559 and EP. -0,260,744.   Enantiomerically pure (-)-liarosole is an enantiomerically pure compound of formula (A)-(II). Manufactured by reacting a trendy intermediate diamine with formic acid or its functional derivatives Wear.   The functional derivatives of formic acid include halides, anhydrides, amides and ortho and imine. It is meant to comprise esters which also include the noester form. Methanimidamide Alternatively, an acid addition salt thereof can be used as a cyclizing agent.   General reaction conditions, processing steps and other conditions for carrying out the above and below reactions. And general isolation techniques are described in the prior art. More special requirements are required In some cases they are mentioned below.   The enantiomerically pure intermediate diamine of formula (A)-(II) is an intermediate of formula (A)-(III) It can be prepared by reducing the body with a standard nitro-amine reduction reaction.   The desired enantiomer of formula (A)-(II) uses an enantiomerically pure chiral acid. It can be prepared by fractional crystallization of a racemic mixture of the intermediate of formula (III). Up A suitable chiral acid for the above-mentioned fractional crystallization is 7,7-dimethyl-2-oxobicyclo [2. 2.1] Heptane-1-methanesulfonic acid (ie 10-camphorsulfonic acid) You.   Suitable solvents for carrying out the fractional crystallization are water; ketones such as 2-propano. 2-butanone; alcohols such as methanol, ethanol, 2-propanone It is Knoll. Mixtures of ketones and water are very suitable for the above fractional crystallization. Good Suitably a mixture of 2-propanone and water is used. Water / 2-propanone capacity The ratio can be varied from 1/10 to 1/2. The preferred range of the ratio is 1/5 to 1 / It is 3.   Fractional crystallization is suitably carried out below room temperature, preferably below 5 ° C. .   Subsequent reaction steps can be performed without appreciable racemization It was also found.   Alternatively, the (−)-isomer of the compound of formula (I) relates to the cyclization of the intermediate of formula (A)-(II) Cyclize the intermediate of formula (A)-(IV) according to the procedure described above and It can also be produced by desulfurizing the thus obtained intermediate of formula (A)-(V). Wear. In formulas (A)-(IV) and (A)-(V), R is C_1-6Represents alkyl, here At C_1-6Alkyl is a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, For example, it means methyl, ethyl, propyl, butyl, pentyl, hexyl. Good Suitably R is methyl. The intermediate of formula (A)-(IV) is obtained by reacting the intermediate of formula (A)-(VI) with the reagent of formula (VII), Alkylating the thiourea derivative of formula (A)-(VIII) thus prepared, Thereafter, the intermediate of formula (A)-(IX) is cyclized and the nitro group of intermediate (A)-(X) is It can be produced by reduction. Formulas (VII), (A)-(VIII), (A)-(IX) and ( In A)-(X), R is C as defined above._1-6Represents alkyl.   Enantiomerically pure intermediates of formulas (A)-(VI) may be prepared by separation techniques known in the art. , For example by chromatography using a chiral stationary phase or Due to the formation of the rheomer compound, for example an enantiomerically pure chiral acid, for example α -By formation of an amide with hydroxybenzeneacetic acid (mandelic acid), or To generate diastereomeric salt forms using enantiomerically pure chiral acids Can be manufactured more.   Liarozole has a retinoid-mimicking effect in vivo and in vitro You. This is because this compound seems to suppress retinoic acid (RA) metabolism. Increased retinoic acid (RA) levels also have a pronounced RA effect at the tissue or cell level It means to take it down. Liarozole is an effective inhibitor of androgen biosynthesis It is also shown. Preclinical and clinical research in the fields of oncology and dermatology The utility of Liarozole in   Unexpectedly, (−)-liarosol was either (+)-liarosole or racemic rear. It showed higher activity in some tumor models than Rosol. Enantiomerically pure ( -)-The field of oncology by administration of Lialozole Showed that more "targeted" treatment would be possible. In particular( -)-Lialozole can be used to treat prostate cancer.   (−)-Lialozole and its pharmaceutically acceptable acid addition in the method of the present invention The use of salting may be performed with retinoids such as all-trans-retinoic acid, 13-cis- Due to their useful properties to delay the metabolism of retinoic acid and their derivatives Based on. The latter was slower / higher than retinoids as well as various tissue concentrations. Results in improved differentiation regulation of cell types and growth. (-)-Lialozole This (-)-realosomes gave the same effect as when the retinoid was administered. The action of ole is also referred to as retinoin mimetic activity. Therefore, (-)-Lialozole is a normal, preneoplastic and neoplastic epithelial cell growth and differentiation rate It can be used to adjust the degree.   (−)-Lialozole and its pharmaceutically acceptable acid addition salts are therefore For the treatment of diseases characterized by increased proliferation and / or abnormal differentiation And is useful. (−)-Lialozole is an androgen or an Substantially unmediated by or insensitive to the action of strogen Cells, especially growth and differentiation, are sensitive to the action of retinoids. Shows activity against cells. (−)-Lialozole is a tumor of head and neck, tumor of lung , Breast, cervical, gastrointestinal, skin, bladder and prostate tumors It is particularly useful in treating such tumors. (−)-Lialozole and its pharmacy Tolerable acid addition salts are useful for the manufacture of a medicament for treating epithelial tumors .   Generally characterized by excessive proliferation and / or abnormal differentiation of tissues An effective amount for treating the associated disease is 0.001 mg / kg to 20 mg / k g body weight and more preferably 0.01 mg / kg to 10 mg / kg body weight it is conceivable that.   The compound of formula (I) used in the method of the present invention is most preferably in the form of a suitable composition. Applied to Suitable compositions include those commonly used for systemically or locally administered drugs. And all the compositions used in. Producing the pharmaceutical composition of the present invention For this purpose, it may be in an effective amount as the active ingredient, optionally in the acid-addition salt form. The particular compound is intimately mixed with a pharmaceutically acceptable carrier and the carrier is Various forms can be taken depending on the form of preparation desired for administration. These drugs The composition is particularly suitable for oral, rectal, subcutaneous or parenteral injection A unit dosage form is desirable. For example, to prepare a composition in oral dosage form, one Common pharmaceutical vehicles such as suspensions, syrups, elixirs and solutions Water, glycols, oils, alcohols, etc. in the case of oral liquid preparations; In the case of solutions, pills, capsules and tablets, solid carriers such as starch, sugar, kaori Agents, lubricants, binders, disintegrants and the like can be used. For ease of administration In addition, tablets and capsules are the most advantageous oral dosage unit forms, in which case Of course, solid pharmaceutical carriers are used. For parenteral compositions, the carrier will generally Typically comprises at least a majority of sterile water, but other It may contain components. For example, the carrier may be saline solution, glucose solution or food. Injectable solutions can be prepared that comprise a mixture of saline and glucose solution. Injection suspension It is also possible to produce a preparation, in which case an appropriate liquid carrier, suspending agent, etc. can be used. Wear. Of solid form, which will be prepared in liquid form just before use Dispensing is also included. In compositions suitable for subcutaneous administration, the carrier may optionally include a penetration enhancer. And / or a suitable wetting agent, optionally in small proportions of suitable additives of either nature. May be included in combination with the agent, this additive has significant adverse effects on the skin. It's not something that looks like it. Suitable compositions for topical application include topically administered drugs, eg For example, cream, jelly, bandage, shampoo, tincture, pasta, ointment, All commonly used for wax, powders, liquid or semi-liquid preparations etc. All compositions. Applications of the composition include, for example, nitrogen, carbon dioxide, phleio. Aerosol with a propellant such as Sprays, drops, lotions, or semi-solids, such as thick concentrates that can be applied by swabs The chemical composition is used. Certain compositions include, for example, wax, creams, and powders. Semi-solid compositions such as starches, jellies, ointments and the like will generally be used .   For ease of administration and uniformity of dosage, the pharmaceutical composition described above may be used in a dosage form. It is particularly advantageous to formulate in the form. Used in the description and claims Dosage unit form is calculated here so that each unit produces the desired therapeutic effect. Unit dose containing a predetermined amount of the active ingredient together with the required pharmaceutical carrier As a physically separate unit. Examples of such dosage unit forms are Tablets (including scored or coated tablets), capsules, pills, powder sachets , Wafer, injection solution or suspension, 1 teaspoon, 1 tablespoon, etc. To those separated minutes.   Other compositions are cosmetic type preparations, such as lotions, packs, lotions, and lotions. Milk or emulsion. In addition to the active ingredient, the preparation It contains the ingredients commonly used in such formulations. Examples of such ingredients are oils and fats ・ Wax, surface active agent, wetting agent, thickening agent, antioxidant, viscosity stabilizer, cleanser Examples include a topping agent, a buffer, an antiseptic, a fragrance, a dye, and a lower alkanol. Desired Other ingredients, such as anti-inflammatory agents, antibacterial agents, antifungal agents, fungicides, vitamins , Sunscreens, antibiotics, or other anti-acne agents may be included in the composition.   In another aspect of the invention, an inert carrier, an effective amount of (−)-liarozole or acid thereof. Addition salt forms and effective amounts of retinoic acid, its derivatives, or its stereochemical isomerism There is provided a pharmaceutical or cosmetic composition comprising a body shape.   Retinoic acid and its derivatives, especially retinol, and (−)-liarosol Can act in a synergistic way. In fact, a combination of two substances The combined effect is greater than the sum of their respective effects when administered separately. the above A composition containing retinoic acid for treating acne or for the effects of skin aging. To delay and improve the properties of the skin in general, and of human facial skin in particular Especially useful. Dermatologically retinoic acid or its derivatives as active ingredients Pharmaceutical or cosmetic compositions containing intimate admixture with an acceptable carrier are conventional admixtures. Japanese techniques, for example cyclodextrins or any thereof known in the art Topical application of retinoic acid and its derivatives, optionally mixed with these derivatives Known in the art. Suitable for topical application The composition comprises 0.001-0.5% (especially 0.01-0.1%) all-trans-retino. In acid, 13-cis-retinoic acid or its derivatives, especially retinol, and 0.1-5% of (-)-liarosol or Or its dermatologically acceptable acid addition salts as a semi-solid or liquid diluent. Or in the form of a cream, ointment or lotion contained in a carrier. .   These suitable compositions should preferably be non-irritating and, if possible, They should be colorless and non-toxic. Composition for ease of application to the skin In general, some organic emollients, compositions other than water or organic solvents Emulsifiers, humectants, preservatives and skin active agents for the aqueous and / or non-aqueous phases of Contains agents that facilitate the penetration and retention ofExperimental part A.Production of intermediates Example 1 a) (4-amino-3-nitrophenyl) (3-chlorophenyl) methanone (50 g ), Formamide (375 ml) and formic acid (63 ml) over 17 hours. Stirred and refluxed. After cooling, the mixture was poured on ice. The precipitate is filtered off And dried, 55 g (99.4%) of (±)-N-[(4-amino-3-nit Rophenyl) (3-chlorophenyl) methyl] formamide (Intermediate 1) was produced. . b) Intermediate (1) (50.7 g), 6N hydrochloric acid (350 ml) and 2-propano The mixture of tools (70 ml) was stirred and refluxed for 17 hours. occured The precipitate was filtered off and dried in vacuo to give 51 g (97.8%) of (±) -4-amido. No-α- (3-chlorophenyl) -3-nitrobenzenemethanamine monohydrochloride; A point of 263 ° C. (Intermediate 2) was produced. c)N,N-Diethylethanamine (13.8 g) was used as intermediate (2) (43 g) was added to a solution of tetrahydrofuran (400 ml) and stirred at room temperature. (R)-(−)-α-hydroxy-benzeneacetic acid (20.8 g) was added. 1-Hide Roxybenzotriazole (22.2g) in tetrahydrofuran (200ml) Add the medium solution, thenN,N′ -Methanetetrayl-biscyclohexaneami Solution of benzene (33.9 g) in dichloromethane (300 ml) was added. Reaction mixture Was stirred at room temperature for 2 hours. Dichloromethane (400 ml) was added andN,N′ -Dicyclohexylurea was filtered off. Wash the filtrate with 10% aqueous potassium carbonate And dry the organic layer (MgSO 4_Four), Filter and evaporate the solvent to give 6 0 g of (I) (mixture of diastereomers) was produced. Intermediate (2) (16 The same experiment starting from g) gives a 26 g yield of (II) (mixture of diastereomers) ) Has occurred. Fractions (I) and (II) are combined and combined with a high performance liquid chromatograph. Fee (eluent: CH₂Cl₂/ Ethyl acetate 90/10). two Fraction groups were collected. 27 g of the solvent of the fraction group with a relatively high Rf value was evaporated. (-)-(R, A)-N-[(4-amino-3-nitrophenyl) (3-chlorophenyl L) Methyl] -α-hydroxybenzeneacetamide (Intermediate 3) was produced. d) Intermediate (3) (27 g) in 12N hydrochloric acid (300 ml) and 1-propanol The mixture in toluene (100 ml) was stirred and refluxed for 18 hours. Cool down The reaction mixture was poured onto ice. This mixture was made alkaline with ammonium hydroxide. And extracted with dichloromethane. The separated organic layer was dried (MgSO 4_Four), Filtered and the solvent was evaporated. The residue (19 g) was subjected to column chromatography. On silica gel (eluent: CH₂Cl₂/ CH_ThreeOH 98/2) purified. Pure Collect the trendy fractions And the solvent was evaporated to give 6 g (33%) of (−)-(A) -4-amino-α. = -27.00 (c = 1% in methanol) (Intermediate 4) was produced. e) Intermediate (4) (11.6 g) and 1,1-dimethoxy-2-isothiocyanana A mixture of To-ethane (7.3g) in methanol (120ml) was added over 2 hours. Stir and reflux. The solvent was evaporated to give 17.8 g of theoretical (-)-(A) −N-[(4-amino-3-nitrophenyl) (3-chlorophenyl) methyl] -N ' -(2,2-Dimethoxyethyl) thiourea (Intermediate 5) was produced. f) Potassium carbonate (6.95 g) as intermediate (5) (17.8 g) in 2-propanone (200 ml) in solution. Add iodomethane (3.1 ml) and react The mixture was stirred at room temperature for 48 hours. The solvent is evaporated and the residue is dichloromethane With stirring. The organic layer was separated, washed with water, dried (MgSO4)._Four), Filtered shiso Then the solvent was evaporated and 17 g (92%) of (-)-S-methyl (A)-N− [(4- Amino-3-nitrophenyl) (3-chlorophenyl) methyl] -N '-(2,2-di Methoxyethyl) carbamimidothioate (Intermediate 6) was produced. g) intermediate (6) (16 g) was cooled to 0 ° C. and sulfuric acid (cooled to 5 ° C.) added. The mixture was stirred at 5 ° C. to complete dissolution. Warm the solution to room temperature, then 2 Stirred for hours. The solution was poured on ice and made alkaline with ammonium hydroxide . The aqueous solution was extracted with ethyl acetate. The separated organic layer was dried (MgSO 4_Four),filtration And the solvent was evaporated. The residue (16g) was subjected to column chromatography On silica gel (eluent: CH₂Cl₂/ CH_ThreeOH98 / 2) purified. Pure Collect and melt the fractions The medium was evaporated and 10 g (74%) of (-)-(A) -4-[(3-chlorophenyl) [ 2- (methylthio) -1H-Imidazol-1-yl] methyl] -2-nitrobenze Amine (intermediate 7) was produced. h) A mixture of intermediate (7) (10 g) in methanol (200 ml) was stirred at room temperature (2- Raney nickel (10 g) as a catalyst for 2 hours at a bar pressure of Pal device) Hydrogenated over. After uptake of hydrogen (3 equivalents), the catalyst is filtered off and the filtrate is evaporated. The theoretical 9.3 g of (−)-(A) -4-[(3-chlorophenyl) [2- (meth Tiltio) -1H-Imidazol-1-yl] methyl] -1,2-benzenediamine (Intermediate 8) was produced. i) a mixture of intermediate (8) (9.3 g) and methanimidamide acetate (8.4 g). The mixture in tanol (200 ml) was stirred and refluxed for 3 hours. Dissolution The medium was evaporated and the residue was dissolved in dichloromethane. 10% N organic solution aHCO_ThreeWash with solution, dry (MgSO 4_Four), Filtered and evaporated solvent . The oily residue (10 g) was purified by column chromatography on silica gel (elution) Agent: CH₂Cl₂/ CH_ThreeOH95 / 5) purified. Collect pure fractions and solvent Was evaporated to give 6.2 g (65%) of (−)-(A) -5-[(3-chlorophenyl) [ 2- (methylthio) -1H-Imidazol-1-yl] methyl] -1H-Benzimi Dazole (Intermediate 9) was produced.Example 2 A) (±) -4-[(3-chlorophenyl) -1H-Imidazol-1-ylmethyl] 2-Nitrobenzenamine (500 g) and (+)-(1S) -7,7-dimethyl Le-2-oxo-bicyclo [2.2.1] heptane-1-methanesulfonic acid (353 0.3 g) of 2-propanone (2000 ml) The medium mixture was stirred at 20 ° C. until it became homogeneous. Crystallization occurs rapidly Was. Water (100 ml) was added and the mixture warmed to 38 ° C. The mixture is homogeneous And then inoculated with crystals. Stir for 20 hours at 20 ° C and 2 at 0 ° C The compound crystallized spontaneously during stirring for a period of time. The precipitate is filtered off, 2-propanone / water Wash with 95/5 (250 ml), then dry (50 ° C), 288.90 g ( 33.86%; 67.7% with respect to enantiomers) (-)-(A) -4-[(3-chloro) Phenyl) -1H-Midazol-1-ylmethyl] -2-nitrobenzenamine ( 1S) -7,7-Dimethyl-2-oxobicyclo [2.2.1] heptane-1-meta % In methanol) (Intermediate 10). b) Intermediate (10) (167.7 g) in methanol (615 ml) and methano Solution in ammonia / ammonia (30.7 ml) on activated carbon at 20-25 ° C. In the presence of thiophene (0.5g) using platinum (5%) (12.3g) as a catalyst Hydrogenated at. After uptake of hydrogen (3 equivalents), the catalyst was filtered off and the 2-propanol It was washed with a filter (30 ml). Hydrochloric acid in 2-propanol (487 ml) was added to the filtrate. Added at <30 ° C. The mixture is stirred at 20 ° C. for 18 hours and then at 0 ° C. Stir for 3 hours. The precipitate formed was filtered off, washed with methanol (100 ml) and rinsed. And dried (50 ° C.) to give 180.40 g of product (86.7%). Mother liquor The layers were evaporated to yield 25.12 g (12.1%) product. Total yield is 2 05.52 g (98.8%) of (-)-(A) -4-[(3-chlorophenyl) -1H− Imidazol-1-ylmethyl] -1,2-benzenediamine trihydrochloride (Intermediate 1 It was 1). B.Production of final compounds Example 3   Using a mixture of intermediate (9) (6.2 g) in ethanol (100 ml) as a catalyst Raney nickel (6 g) was stirred and refluxed for 24 hours. The mixture is stirred and refluxed for 5 days and additional Raney nickel ( 6 g / addition) was added daily. Then the catalyst is filtered off and the filter residue is diluted with dichloromethane. Rinse with methane. The filtrate was evaporated. Column chromatography of the residue (4g) On silica gel (eluent: CH₂Cl₂/ CH_ThreeOH 95/5 and C H₂Cl₂/ CH_ThreeOH / NH_FourOH 80/20/3) purified. Collection of pure fractions And the solvent was evaporated. The residue (2.58 g of free base) was treated with 2-propanol. And converted to the hydrochloride salt (1: 1) using HCl / ethanol. Was. Crystallization was induced by the addition of methyl ethyl ketone. The precipitate is filtered off and After drying, 2.3 g (38%) of (-)-(A) -5-[(3-chlorophenyl) -1.H -Imidazol-1-ylmethyl] -1H− (C = 1% in methanol) (Compound 1) was produced.Example 4   Intermediate (11) (177.35 g) in water (491 ml), hydrochloric acid (277 ml) And the mixture in formic acid (70.6 ml) was heated to 50-55 ° C. The reaction mixture The mixture was stirred at 55 ° C for 3 hours. The mixture was cooled to 20 ° C. Dichloromethane (117 3 ml) was added. Ammonium hydroxide (700 ml) was added with cooling ( pH> 9). The mixture was stirred at 20 ° C. for 30 minutes. Separate the organic layer and wash with water (500 ml), dried and filtered. And solvent evaporated at 45-50 ° C to give 134.16 g (100%) of (- )-(A) -5-[(3-chlorophenyl) -1H-Imidazol-1-ylmethyl] -1H-Benzimidazole; melting point 132.7 ° C; did.Example 5   A mixture of compound (2) (2.66 g) in ethanol (28.5 ml) was brought to 20 ° C. Stir until it is homogenous. Add (E) -2-butenedioic acid (2 g) The mixture became homogeneous after 10 minutes. The product is natural over a 20 hour period Crystallized. The precipitate was filtered off, washed with ethanol (5 ml) and dried, 1.72 g (41.4%) of (-)-(A) -5-[(3-chlorophenyl) -1H-B Midazol-1-ylmethyl] -1H-Benzimidazole (E) -2-butenedi Oate (2: 3): (Compound 3) was produced.Example 6   Compound (2) (114.5 g) was dissolved in 2-butanone (1854 ml). Was. 2-propanol hydrochloric acid (68.5 ml) and 2-butanone (556 ml) ) Was added at 20 ° C. over a period of 2 hours. Reaction mixture at 20 ° C It was stirred for 16 hours. The precipitate was filtered off, washed with 2-butanone (185 ml) and rinsed. And dried (vacuum; 80 ° C.), 122.6 g (99.5%) of (−)-(A) -5-[( 3-chlorophenyl) -1H-Imidazol-1-ylmethyl] -1H-Benzi Midazole monosalt (In compound) (compound 1). C.Composition examples   The following formulations are systemic or local to animal and human subjects according to the invention. 6 illustrates a typical pharmaceutical composition suitable for administration.   The "active ingredient" (AI) used throughout these examples is a compound of formula (I) Or a pharmaceutically acceptable acid addition salt thereof.Example 7: Oral drops   500 g of AI is added to 0.5 liter of 2-hydroxypropanoic acid and 1.5 Dissolve in polyethylene glycol in a bottle at 60-80 ° C. 30 After cooling to ~ 40 ° C, add 35 liters of polyethylene glycol and The mixture was well stirred. Then 1750 g of sodium saccharin 2.5 liters Solution of purified cocoa and 2.5 L of cocoa flavor and Add enough polyethylene glycol to bring the volume to 50 liters and add 10 m An oral drop solution comprising g / ml AI was given. Store the resulting solution in a suitable container Filled.Example 8: Oral liquid preparation   9 g of methyl 4-hydroxybenzoate and 1 g of 4-hydroxybenzoate Ropil was dissolved in 4 liters of boiling purified water. In 3 liters of this solution First 10 g of 2,3-dihydroxybutanedioic acid and then 20 g of A. I. was dissolved. Combine the latter solution with the rest of the former solution and Liter of 1,2,3-propanetriol and 3 liter of sorbitol 70 % Solution was added to it. 40 g sodium saccharin in 0.5 liter water Dissolve in 2 ml of gooseberry essence was added. Combine the latter solution with the former, 2 Add enough water to bring the volume to 0 liters, per teaspoon (5 ml) An oral solution comprising 5 mg AI was given. Fill the appropriate liquid with the resulting liquid did.Example 9: Capsules   20 g AI, 6 g sodium lauryl sulphate, 56 g starch, 56 g la Glucose, 0.8 g of colloidal silica dioxide, and 1.2 g of stearic acid The gnesium was vigorously stirred together. The resulting mixture is subsequently treated with 20 mg of each Fill into 1000 suitable hard gelatin capsules to contain AI did.Example 10: Film-coated tablets Tablet core manufacturing   A mixture of 100 g AI, 570 g lactose and 200 g starch was fine. Mix thoroughly and then add 5 g of sodium dodecyl sulfate and 10 g of polyvinyl chloride. Lupillidone (Kollidon-K90^RMoistened with about 200 ml of a solution of a) in water. Moist The powder mixture was screened, dried and screened again. Then 100 g Microcrystalline cellulose (Avicel^R) And 15 g of hydrogenated vegetable oil (Sterotex^R ) Was added. The whole was mixed well and compressed into tablets, each with 10 mg of activity 10,000 tablets comprising the ingredients were given.Coating   10 g of methyl cellulose (Methocel 60 HG^R) 75 ml of denatured ethanol 5 g of ethyl cellulose (Ethocel 22 cps^R) 150 ml dichloro A solution in methane was added. Then 75 ml of dichlorometa And 2.5 ml of 1,2,3-propanetriol were added. 10g of poli The ethylene glycol was melted and dissolved in 75 ml of dichloromethane . The latter solution was added to the former and then 2.5 g of magnesium octadecanoate, 5 g polyvinylpyrrolidone and 30 ml concentrated colorant suspension (Opaspray K-1 -2109^R) Was added and the whole was homogenized. Place the tablet core in this coating machine. The mixture thus obtained was coated.Example 11: Injection solution   1.8 g methyl 4-hydroxybenzoate and 0.2 g 4-hydroxybenzoate Propyl perfume was dissolved in about 0.5 liter of boiling water for injection. To about 50 ℃ After cooling, while stirring, 4 g of lactic acid, 0.05 g of propylene glycol and And 4 g of AI was added. It was sufficient to cool the solution to room temperature and bring it to 1 liter. Mineral water for injection was supplemented to give a solution of 4 mg / ml AI. This solution Sterilized by filtration (U.S.P. XVII p.811) and filled into a sterilization container.Example 12: Suppository   3 g of AI was added to 3 g of 2,3-dihydroxy-butanedioic acid in 25 ml of poly (ethylene glycol). Dissolved in solution in Tylene glycol 400. 12G surfactant (SPAN^R ) And enough triglycerides to reach 300 g (Witepsol555^R) Together Thawed. The latter mixture was mixed well with the former solution. Obtained in this way The resulting mixture was poured into a mold at a temperature of 37-38 ° C, each containing 300 mg of active ingredient. 100 suppositories containing were produced.Example 13: 2% topical gel   2 mg in a solution of 200 mg hydroxypropyl β-cyclodextrin in purified water Add 0 mg AI with stirring. Add hydrochloric acid until completely dissolved and then Add sodium hydroxide to pH 6.0. 10 mg of this solution Add Genan PJ to 50 mg dispersion in propylene glycol with mixing. With slow mixing, heat the mixture to 50 ° C and allow it to cool to about 35 ° C. , Where 50 mg of 95% (vol / vol) ethyl alcohol is added. 1g Sufficient purified water balance is added and the mixture is mixed to homogeneity.Example 15: Aerosol a) of 0.1 g of hydroxypropyl β-cyclodextrin (MS = 0.43) 730 .mu.g of 0.1N hydrochloric acid solution and 2.5 mg of A. in 0.7 ml of distilled water. I. was added. After stirring for 10 minutes at room temperature, the p of the solution thus obtained is The H was adjusted to pH 5.5 by adding 0.1N sodium hydroxide solution. Next To this were continuously added 4 mg of sodium chloride and 0.15 mg of phenylmercuric acetate. Then, the whole was stirred to dissolve completely. Distilled water is then added to a volume of 1.0 ml And quantity. With a mechanical pump that dispenses 0.1 ml per puff during administration Fill into a closed glass bottle. b) 6 g of a solution of 0.1 g of dimethyl β-cyclodextrin in 0.7 ml of distilled water. 00 μg of 0.1N hydrochloric acid solution and 2 mg of AI were added. Stir at room temperature for 10 minutes After stirring, 10 mg of polyvinyl alcohol was dissolved in the mixture and this The pH of the solution thus obtained is adjusted by adding 0.1N sodium hydroxide solution. The pH was adjusted to 5.5 with and. Then 4 mg of sodium chloride and 2 mg of chloride Phenylethyl alcohol The addition was continued and the whole was stirred to complete the dissolution. 1.0m including distilled water A mechanical pump with a volume of 1 and dispensing 0.1 ml per puff during administration. It was filled in a glass bottle which was closed with a stopper.

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Claims (1)

[Claims] 1. Formula (I) A levorotatory compound or a pharmaceutically acceptable acid addition salt thereof. 2. Compound (-) - 5- [3-chlorophenyl] -1 H - imidazol-1-ylmethyl] -1 H - benzimidazole hydrochloride (1: 1) compound ranging first claim of claim is. 3. Compound (-) - 5- [3-chlorophenyl] -1 H - imidazol-1-ylmethyl] -1 H - benzimidazole (E)-2-butenedioate (3: 2) first the claims is The compound according to the item. 4. A composition for treating epithelial tumors comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to any of claims 1-3. 5. A composition according to claim 4 in which said composition is in a form suitable for systemic administration. 6. The composition of claim 5 wherein said composition also comprises an effective amount of retinoic acid, its derivatives or stereochemically isomeric forms thereof. 7. Use of the compound according to any one of claims 1 to 3 as a drug. 8. Use of a compound for the manufacture of a medicament for treating epithelial tumors. 9. Use of a compound for the manufacture of a medicament for treating prostate tumor. 10. Formula (A)-(II) An enantiomerically pure intermediate or an acid addition salt thereof. 11. a) an intermediate of formula (III) in a suitable solvent in an enantiomerically pure chiral acid such as 7,7-dimethyl-2-oxobicyclo [2.2.1] heptane-1-methanesulfonic acid. B) reducing the thus obtained enantiomerically pure intermediate of formula (A)-(III), c) Cyclization of the enantiomerically pure intermediates of formula (A)-(II) with methanimidamide, formic acid; functional derivatives thereof to give enantiomerically pure compounds of formula (I) Form a compound, And, if desired, the compound of formula (I) is converted to its pharmaceutically acceptable acid addition salt form by treatment with a suitable acid, or conversely, the acid-addition salt is free base with an alkali. The method for producing the compound according to claim 1, wherein the compound is converted into