TW418203B - Enantiomerically pure (-)-liarozole - Google Patents

Abstract

This invention relates to the novel enantiomerically pure laevorotatory isomer of liarozole of formula (I) and the pharmaceutically acceptable acid addition salt forms thereof. These compounds are particularly useful in treating disorders which are characterized by an increased proliferation and/or abnormal differentation of normal, preneoplastic or neoplastic epithelia cells. The compounds of formula (I) are particularly useful in the field of oncology. Also disclosed are compositions containing said novel compounds, methods of preparing said novel compounds as well as methods of using the mentioned compounds to treat the mentioned disorders.

Description

Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 418203 V. Description of the Invention (2) The subject matter of the present invention is para-isomeric pure L-isomer or (-)-isomer of Liarazole. This isomer will hereinafter be referred to as (-)-lehatin. Many organic compounds exist in optically active forms, meaning that they have the ability to rotate planes-planes of polarized light. When describing an optically active compound, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to its center of the palm. The prefix (+) and (-) or d and I are symbols used to indicate that the plane-polarized light is rotated by the compound, where (-) or 1 means the compound is left-handed, and where (+ ) Or d means that the compound is dextral. For a specific chemical structure, optically active isomers with opposite optical rotation signs are called para-isomers. The pair of palm isomers are the same, except that they are sharp images of each other. This 1: 1 complex of palmar isomers is called a racemic compound. Stereochemical purity is important in the medical field, as its individual paraisomers may have different potencies or may have different activities. Opposite isomers of a beneficial isomer may even be harmful, rather than just inert. Several examples of these differences are known in the art. As used herein, the " street palm isomerized stew w-word " means that the nuclear product contains at least 卯 wt% of one kind of palm isomers, and 10% or less of another kind of palm isomers体 物。 Structure. In the preferred embodiment, the term "paraisomeric isomerically pure quenching" means that the adduct contains at least 99% by weight of one street isomeric compound and 1% or less of another pair. Palm isomers. It should be noted that the optical rotation of chemical substances depends on experimental parameters. The values shown in the experimental section below are specific optical rotations, and the experimental conditions, such as temperature, plane used鸰 Aurora's wavelength, solvent and sample size of this paper are applicable to S country standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page) Installation-Line A7 B7 3 20 3 Five 'invention description (3) ........... / pack ... (Please read the notes on the back before filling this page) Expressed in a way. When, for example, an acid addition basket is formed, its precession can change (it can even change the sign!). When referring to the l-isomer of riarazole or (-)-riarazole , The optical rotation symbol 'in this form is the one that is desired under the specific experimental conditions shown below. It should also be noted that when a chemical reaction is not involved When it stands at the center of the hip, the absolute order of the center is still the same, but the optical rotation of the compound due to the chemical reaction may be different or even have the opposite sign. Therefore, to avoid confusion The intermediate with the same absolute hip-center position as the opposite palm isomer of the desired final product will be named after the prefix (A) before the reference number. The Central Consumers Bureau of the Ministry of Online Economics, Consumer Cooperative Cooperative System, as described above Its pharmaceutically acceptable acid addition moose is meant to include a therapeutically active, non-toxic acid addition basket that can be formed by a compound of formula (I >. The latter can be suitably treated by using dang acid Thus, the acids are, for example, inorganic acids, such as osmium A acid, such as osmic acid, osmium bromide, and the like; sulfuric acid; nitric acid; phosphoric acid, and the like; or organic acids, such as acetic acid, propionic acid, and acid. Acetic acid, 2-acrylic acid, 2-oxopropionic acid, oxalic acid, malonic acid, succinic acid, (Z) -2-butenedioic acid, (E) -2-butenedioic acid, 2 -Hydroxysuccinic acid, 2,3-dihydroxysuccinic acid, 2-hydroxy-1,2,3-propane Chinoic acid, f-alkanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexaneaminosulfonic acid, 2-hydroxybenzoic acid, 4-peptidyl-2- leptylbenzoic acid It is similar to acids. Conversely, this form can be converted into its free form using a test treatment. The word addition also includes the hydrate and solvent addition forms that can be formed by compounds of formula (I). This form Examples are, for example, hydrates, alcoholates, etc. This paper size applies the Chinese Standard (CNS) A4 specification (210 X 297 mm) V. Description of the invention (4 A7 B7 The preferred pharmaceutically acceptable acid is elk acid And (E) -2-butenedioic acid. The structure containing riarazole, a method for its preparation, has been widely described in EP-0,371,559 and EP-0,260,744. Para-isomerically pure (-)-rialazole is prepared by reacting the dimeric isomerically pure intermediate diamine of formula (A)-(II) with formic acid or a functional derivative thereof.

νη2 νη2

The functional derivatives of formic acid are meant to include its derivatives, anhydrides, amidines, and '', including its original '' and subpancreatine forms. It is also possible to use pinaneimine or amine or its acid addition Λ as a cyclizing agent. The general reaction conditions, processing procedures and valuable separation techniques used to perform the upper and lower reaction are described in the previous art. When more special conditions are needed, they are pointed out below. The p-isomerically pure intermediate diamine of the formula (A) · (II) can be prepared by reducing the standard nitro-amine to the amine by making the intermediates of the formula (A)-(ΙΠ) of hydrazone. Please read the item A on the back first | Binding Page Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs NI ^ Ν〇2

N \ .— j * * \ / CI (Α)-(ΙΠ) C, (A)-(II) The desired isomers of the intermediates (A)-(m), can be borrowed by (in ) -6 * The size of the paper is suitable for Chinese painting a standard (CNS) A4 (210 X 297 mm) A 7 B7 V. Description of the invention (5) Intermediate} Xiao Xuan washing compound and a pair of palms It is made by the fractional crystallization of isomerically pure palmitic acid. The preferred palmitic acid for the above-mentioned fractional crystallization is 7,7-dimethyl-2-oxobicyclofluorene [2.2.1] heptan-1-methanesulfonic acid (meaning 10-camphoric acid) . The solvent used to carry out the fractional crystallization is water; brights such as 2-acetone and 2-butanone; fluorenes such as formamidine, ethanol and 2-propanol. The complex of ketones and water is extremely immersed in the above-mentioned fractional crystals. It is preferred to use 2_acetone and water. The hip area ratio of water / 2-acetone can be changed from ι / 10 to 1/2. The preferred range of this ratio is 1/5 to 1/3. This dehydration crystallization is carried out at a temperature below room temperature, preferably below. It has also been found that subsequent reaction steps can be performed without any slight racemization. Alternatively, the (_) _ isomer of the compound of formula (I>) can be prepared in the following manner, and the formula (a) _ (IV) in W is cyclized, and the intermediates of formula (A)-(v) thus obtained are broken. In formula U)-([V), (A)-(V), R represents Cj-e alkyl. Where (; Bu 6 is a straight or split chain saturated hydrocarbon group having 1 to 6 broken atoms, such as methyl, ethyl, propyl, butyl, fluorenyl, hexyl. Preferably R is methyl . The consumer cooperation of the Central Government Bureau of the Ministry of Economic Affairs of the People's Republic of China Du printed a suitable piece of paper, a piece of paper, and a piece of paper *) Public 97 4 ιϋ 20 3 A7 B7 V. Description of the invention (6

Cl

i) y ~ sK ch- ^ JLnh2

(A)-(V) (A)-(IV)

Cl

(-)-(i) The intermediate of formula (A)-(IV) can be prepared in the following manner. The intermediate of formula (A)-(VI) is reacted with the reagent of formula (VI〇), and thus formed formula (A )-(VIII) Sulfurization of the overlying derivative, followed by cyclization of the intermediate of formula (A)-(IX) and reduction of the nitro group of intermediate U)-(X). In formulae (VII), (A)-(VIII), (A)-(IX), and (A)-(χ), r represents a Cl-6 alkyl group as defined above.

OR Please read the notes of the memorandum first.

S-R

NH-C-NH-CH2-CH alone 'OR (VE〇

Cl s

N〇2 line

Printed by OR Consumer Cooperatives, Central Bureau of Standards, Ministry of Economic Affairs

(AHVIII)

-8 This paper size is in accordance with China National Standard (CNS) A4 specification (210X 297 mm) 418203 A7 B7 V. Description of the invention (7) A pair of palm isomerically pure intermediates of formula (A)-(VI) can be borrowed Technically known analytical techniques, such as by chromatography, using a palmar stationary phase, or by forming diastereomeric compounds, such as a palmar isomer, and a pure palmar is intended to form a pyramine, which P-palmitic acid such as β-hydroxyphenylacetic acid (phenylglycolic acid), or by using p-palmitomers on pure p-palmitic acid to form diastereomeric forms. Liaruo Jun has the effect of imitating the sight flag inside and outside of Live II. This means that salty iridium will inhibit the retinoic acid (RA) catabolism, so that the addition of retinoic acid (RA) content will lead to the RA effect in the degree of tissue or cell. Learosin has also been shown to be an effective inhibitor of androgen biosynthesis. The pre-syndrome and clinical research departments have further shown the utility of riarozole in oncology and dermatology. (·)-Riarozole has surprisingly been shown to have a higher activity than certain (+)-Riarozole or racemic Riazozole in certain pain-sparing modes. It has been shown that by administering para-isomerically pure (-)-riarazole, in the field of edema, more " target " treatment can be achieved. In particular, (-)-rialazole can be used to treat prostate cancer. (-)-Riarozole and its pharmaceutically acceptable acid addition basket, the use in the method of the present invention * is based on its useful properties of delaying retinoic acid catabolism, such as retinoic acid such as All-trans-retinoic acid, 13-cis-retinoic acid and derivatives thereof. The latter will result in a more delayed / higher tissue concentration of retinoids and improved control of the differentiation and growth of various cell types. This effect of (-)-rialazole is also called retinoic acid activity, because administration of (-)-rialazole will cause the same effect as retinoic acid. In accordance with this standard, the paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 4; 8 2 j 3 at V. Description of Invention (8), which can be used ( -)-Liarosone to control the rate of growth and differentiation of normal epithelial cells before tumorigenesis and neonatal neoplasm. (-)-Riarozole and its pharmaceutically acceptable acid addition hydrazone can therefore be used for the treatment of conditions in which epithelial cells have an increased proliferation effect and / or abnormal differentiation effect. (-)-Riarozole is shown to be active in cells in which growth differentiation is not substantially mediated or insensitive to the effects of androgenic or estrogen effects, especially growth and differentiation Retinoic acid with sensitive retinoic acid cells is active. Riarozole is particularly useful in the treatment of ridges, such as head and palate swelling, lung swelling, chest palate, uterine swollen palate, Swelling of gastric phosphine tract, pain of skin canal, cystitis and prostate swelling. (-)-Liarodine and its pharmaceutically acceptable acid addition salts can be used in the manufacture of drugs for the treatment of epithelial swelling. In general, what is intended to be covered is an effective amount for the treatment of conditions characterized by excessive tissue proliferation and / or abnormal differentiation, ranging from 0_001 mg / kg to 20 mg / kg «weight, and more preferably 0.01 mg / kg to 10 mg / kg tt. The compound of formula (I) used in the method of the present invention is preferably applied in the form of a suitable composition. All the compositions commonly used for systemic or local administration can be cited as the effective compositions. In order to prepare the pharmaceutical composition of the present invention, an effective amount of a specific compound as an active ingredient may be used in the form of an acid addition, and a pharmaceutically acceptable carrier is combined into a close compound. It can take a variety of forms, depending on the form of preparation to be administered. Such pharmaceutical compositions are generally expected to be in a single dosage form, particularly for oral, direct, percutaneous, or non-nitrile injection. For example, in the system of -10-this paper standard uses the standard of China (CNSJA4 specification (210X297 mm) ........ .Assembling ...... Ordering line (please read the precautions on the back to write this page) 、 Explanation of invention (9 A7 ΒΊ When the employees of the Central Bureau of Standards of the Ministry of Economic Affairs cooperate to print the composition in oral dosage form, any commonly used medical medium can be used, such as oral liquid hip preparations such as floats, syrups, tinctures and solutions In this case, use oaths such as water, glycols, oils, tinctures, etc .; or in the case of powders, pills, capsules, and tablets, use solid "planting agents, such as" powder, sugar, kaolin, tincture Lubricants, binders, disintegrating agents, etc. Because tablets and capsules are easy to administer, they represent the most advantageous oral dosage unit form. In this case, solid pharmacological agents are used. For non-phosphine-containing compositions In general, this plant usually includes sterile water, at least most of it, but can also include other ingredients, such as to help dissolve. For example, injectable solutions can be prepared, where the plant agent includes Fresh water solution, glucose solution or a mixture of common salt and grape rust solution. Injectable suspensions can also be prepared. In this case, tincture liquid "planting agent, suspension agent, etc." can also be used. Also includes solid Preparation of the form i, which is intended to be converted to a liquid hip preparation before use. In a compound for compound-grade skin administration, the agent may optionally include a penetration enhancer and / or a逋 When used as a wetting agent, a small amount of additives with any properties may be used when combined. This additive will not introduce significant harmful effects on the skin. It can attract all Λ compounds commonly used in topical administration as a topical administration.逋 When the composition, such as lotions, gels, dressings, shampoos, tinctures, tinctures, plasters, ointments, powders, liquid hip or semi-liquid hip formula, etc., the application of these Λ compounds can be borrowed Sols, such as propellants, such as argon, carbon dioxide, tritium, or non-vertebrates, such as pumped mists, drops, lotions, or semi-solid "I, such as thickened combinations Material, which can be coated with cotton swabs. For fixed meal composition • Semi-solid tt compositions, such as oil tinctures, emulsions, gels, plasters, etc. can be suitably used. -11-This paper size applies to the national standard (CNS) A4 specification (210 X 297 mm) read

I order A7 B7 418 20 3 V. Description of the invention (10) It is particularly advantageous to formulate the aforementioned pharmaceutical composition into a dosage unit form that is easy to administer and dose uniformity. The dosage unit form used in this patent specification and the patent application here refers to a physically discontinuous unit that cooperates as a single dose, and each unit contains a predetermined amount calculated to produce the desired therapeutic effect The active ingredient is accompanied by the required medicinal vehicle. Examples of such dosage unit forms are tablets (including scored or coated tablets>, capsules, pills, powder packs, tablets, injectable solutions or suspensions, teaspoons, large spoons Etc. and its multiple drug penalties. Other grades are cosmetic preparations, such as lotions, loaves, lotions, skin lotions or lotions. In addition to the active ingredients, the preparation contains commonly used ingredients. Ingredients in such preparations. Examples of such ingredients are oils, hemp fats, waxes, surfactants, emollients, tincture enhancers, anti-aliasing agents, viscosity stabilizers, chelating agents, retarders Agents, preservatives, fragrances, dyes, low-breaking enzymes, etc. If necessary, other ingredients can be incorporated into these compositions, such as anti-inflammatory tincture, fungicides, anti-bactericides, disinfectants, androgens, Sunscreen, antibiotics or other anti-acne agents. In another aspect of the present invention, a special medicinal or cosmetic composition is provided, which includes an inert vehicle, an effective amount of (-)-rialazole or its acid. Addition of retinoic acid and an effective amount of a retinoic acid Biology or its hip isochemically isomeric forms. This retinoic acid and its derivatives, especially retinoids, and (-)-riarazole are acting in a synergistic manner. In fact The combined effect of the two substances is greater than the combined effect of the individual effects when administered separately. The above-mentioned retinoic acid-containing composition is particularly useful for treating acne or blocking the skin-12-This paper is suitable for the standard ® 0 home standard (CNS > A4 specification (210 X 297 mm) A7 B7 I ο 2 J 3 V. Description of the invention (11) The effect of skin aging, and generally improve the quality of skin, especially human facial skin A pharmaceutical or cosmetic composition containing retinoic acid or a derivative thereof as an active ingredient and a dermatologically acceptable vehicle in a close admixture, which can be prepared by blending techniques, such as Regarding retinoic acid and its derivatives, it is optionally performed in a manner known for the topical application of a cyclodextrin or its derivative known in the art to form a compound. A preferred composition for topical application, Is in the form of an emulsion, plaster or lotion, which contains 0.001 to 0. 5% (especially 0.01 to 0.1%) all-trans-retinoic acid, 13-cis-retinoic acid or derivatives thereof, especially retinase, and 0.1 to 5% (-)-riarazole or Its dermatologically acceptable acid addition is used in semi-solid or liquid hip diluents or implants. These preferred compositions should be relatively non-irritating, and their values may be odorless and non-toxic In order to facilitate the application to the skin, this compound usually contains some specific organic lubricants in addition to water or organic solvents, and is an emulsifier for the aqueous and / or non-aqueous phase of the nuclear composition. Moisturizing agents, preservatives, and agents that help the active agent penetrate and retain in the skin. Pipeline component A. Carrier f. Example 1 a) Put (4-amino-3-nitrophenyl) (3-Gaphenylphenylhydrazone (50 charge), a mixture of formamidine (375 ml) and formic acid (63 ml), stir and reflux for 17 hours. After cooling, the mud was placed on ice. The sediment was dried and dried to produce 55 g (99.4%) (±) -N-[(4-fluorenyl-3-nitrophenyl) (3- -13-This paper size applies to Chinese national standards ( CNS) A4 specification (2WX297 public love) B7 V. Description of the invention (12) Gas phenyl printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs f-methyl] methane (intermediate 1). b) The intermediate (1) (50.7 g), 6N (350 ml) and 2-propane (70 ml) were mixed and refluxed for 17 hours. The formed precipitate was filtered and dried in the air, yielding 51 g (97.8%) of (earth) -4-amino-β- (3-chlorophenyl) -3-nitrobenzoic acid Salt; melting point 2631 (Intermediate 2). c) Ν, Ν-diethylethylamine (13.8 g) was added to a solution of the intermediate (2) (43 g) and tetramethylfuran (400 ml), and stirred at room temperature. (Chlorophenylacetic acid (20.8 g) was added. A solution of 1-Chlorophenyltritene (22.2 g) and tetrahydrofuran (200 ml) was added, followed by N, N, -Pentane tetrakis-dicyclohexylamine (33.9 g). ) And diargon methane (300 ml). The reaction washes were stirred at room temperature for 2 hours. Digas methane (400 ml) was added, and N, N'-dicyclohexyl urea was filtered. The filtrate was filtered with It was washed with 10% potassium carbonate aqueous solution, and the organic layer was dried (MgS04), filtered and evaporated to leave 60 g (I) (a diastereomeric adduct). From the intermediate (2) (16 G), starting with the same experiment, resulting in a yield of (11) (a diastereomeric adduct) of 26 g. The (I) and (II) fractions were combined and purified by high performance liquid chromatography (Eluent: CHgClz / Acetylacetate 90/10). Collect two dissociative groups. Evaporate the solvent of the dissociative group with a higher Rf value to produce 27 g (-)-(R, A) -N- [(4-Amino-3-nitrophenyl) (3-Gaphenyl) methyl] -β-Epiphenylacetophenamine (Intermediate 3) 〇d) Will be M (3) (27 G) in hydrochloric acid 12N (300 ml) and 1- Hwang leaven composition (100 ml), the plant and mixed with stream 18 Jun hours. The cooled reaction mud was poured onto ice. This mud was turned to hydrogenation and extracted with dichloromethane. Separate the dried organic layer (MgS04), filter and evaporate 14-This paper size is applicable to China® House Standard (CNS) A4 specification (210X 297 mm) Please read the note first and write this page to bind A7 B7 4 18203 5. Description of the invention (13) Solvent. The residue (19 g) was purified by column chromatography on silica gel (eluent: CH2Cl2 / CH3OH 98/2). The pure fractions were collected and the solvent was evaporated, yielding 6 g (33%) of (-) _ (A) -4-amino-α- (3-aerophenyl) -3-nitrobenzylamine; U] ^^ 27.00e (c = 1% in methanol) (Intermediate 4). e > A mixture of the intermediate (4 > (11.6 g) and 1,1-dimethoxy-2-isofluorenylthio-ethane (7.3 g) in methyl form (120 ml), stir And reflux for 2 hours. The solvent was evaporated to yield theoretically 17.8 g of (-)-(A) -N-[(4-amino-3-nitrophenyl) (3-aminophenyl) methyl] -N ' -(2,2-Dimethylaminoethyl) thiourea (Medium product 5>. F) Carbonic acid (6.95 g) was added to the intermediate (5) (17.8 g) and 2-acetone (200 ml) The solution was added. Methyl iodide (3.1 ml) was added, and the reaction mixture was stirred at room temperature for 48 hours. The solvent was evaporated and the residue was stirred in methane. The organic layer was separated and washed with water. , Dried (MgS04), filtered and evaporated to produce 17 g (92%) (-)-S- (A) -N-[(4-amino-3-nitrophenyl) (3-chlorobenzene [Base group] -ίΓ- (2,2-Dimethylfluorenylhexyl) methyl urethoroate (intermediate 6) 〇 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (6) (16 g) Cool to 0 ×: and add sulfuric acid (cool to 5 ° C). Stir the mud mixture at 5X: until completely dissolved. Warm this solution to room temperature, then 攒2 hours. This solution was placed on ice and gunned with ammonium oxide. The aqueous solution was extracted with ethyl acetate. The organic layer separated from rhenium was dried (MgS04), dried and evaporated. The residue (16 G) Purified by column chromatography on silica gel (eluent: CH2Cl2 / CH30H98 / 2). The pure eluate was collected and the solvent was evaporated, yielding 10 g (74%) (-)-(A) -4-[(3 -Phenylphenyl group] [2_ (fthio) -1H-Weszol-1 · yl] f-jib 2-nitroaniline (intermediate paper size commonly used in B1 National Standard (CNS) A4 specification (210X297 mm) ) A 7 B7 4 18 " V. Description of the invention (14) Compound 7) ° h) The intermediate compound (7) (10 g) was dissolved in methanol (200 ml) at room temperature (2-bar Pressure; Parr device), Raney nickel (10 g) was used as catalyst, and tritiated for 2 hours. After the radon gas (3 equivalents) was absorbed, the catalyst was filtered, and the filtrate was evaporated to produce theoretically 9.3 g (- )-(A) -4-[(3-Gasphenyl) [2- (methylthio) -1Η-amidazol-1-yl] methyl] -2-phenylenediamine (Intermediate 8) ° i ) The compound (8) (9.3 g) of methaneimine ammonium acetate (8.4 g) in methanol (200 ml) Mix and stir for 3 hours. The solvent was evaporated and the residue was dissolved in dichloromethane. The organic solution was washed with a 10% NaHC03 solution, dried (MgS04), filtered and the solvent was evaporated. The oily residue (10 g) was purified by column chromatography on silica gel (eluent · CH2C12 / CH30H 95/5). Fractions of rhenium were collected and the solvent was evaporated, yielding 6.2 g (65%) of (-)-(A) -5-[(3-aerophenyl) [2- (methyloxy) -1Η-imidazol-1-yl ] Methyl hlH-phenylhydrazone miso (Intermediate 9>. Example a) (±) _4-[(3-Gaphenyl) -1hydrazine-amizol-1-ylpingyl] -2-nitroaniline (500 g) (+)-(15) -7,7-dimethyl-2-oxo-bicyclo [2.2.1] heptane-1-methanesulfonic acid (353.3 g) in 2-acetone ( 2000 ml), stir the mixture at 2 (TC until it becomes homogeneous. Quickly cause crystallization. Add water (100 ml), and heat the mud mixture to 38eC. This mixture becomes Homogeneous, with crystal hips as seed crystals. This compound crystallized out during 20 hours of stirring at 2 ° C, and then stirred at 0 ° C for 2 hours. The precipitate was filtered, and 2-acetone / Wash with 95/5 (250 ml) water, then _ 16-This paper size applies to Chinese National Standard (CNS) A4 specifications (2) × 297 mm 4 idZO 3 A 7 B7 Central Standard of the Ministry of Economics 印 Printed by employee consumer cooperatives V. Description of the invention (15) Drying (50 ° C) yields 288.90 g (33.86%; 67.7% is related to palmar foreign matter) (-)-(A)- 4-[(3-Chlorophenyl) -1Η-amizol-1-ylmethyl] -2-nitroaniline (lS) -7,7-dimethyl-2-oxobicyclo [2.2.1] Heptane-1-methanesulfonic acid; melting point 158.8eC; [0) ^ =-22.70 ° (c = 0.5% in pingol > (Intermediate 10). B) The intermediate (10) (167.7 g ) The conjugation between Jiamei (615ml) and formazan / ammonia (30,7ml), using platinum / activated carbon (5%) (12.3g) as catalyst at 20-25 ° (:) In the presence of stilbene (0.5 g), argonization was performed. After argon (3 equivalents) was absorbed; the catalyst was filtered and washed with 2-propanol (30 ml). At < 301, stilbene A solution of acid in 2-propionase (487 ml) was added to the mash. This slurry was stirred at 20X: for 18 hours, and then at VC for 3 hours. When the precipitate formed by filtration was filtered, Methanol (100 ml) was washed and dried (50 * €) to produce 180.40 g of product (86.7%). The mother liquor was evaporated to produce 25.12 g (12.1%) of product. The total yield was 205.52 g (98.8%) (- )-(Gray) -4-[(3-chlorophenyl) -111-imidazol-1-ylmethyl] -1,2-benzyltriazine (intermediate 11). B. Table! Compounds Spirit Qun mace 3 A mixture of intermediate (9) (6.2 g) in ethanol (100 ml) of compound Guo, Li stirred and refluxed for 24 hours, Ranejr nickel (6 g) as a catalyst. The admixture was stirred and flowed for 5 days, and other amounts of Raney nickel (6 g / addition) were added daily. Then, the catalyst was filtered, and the filter residue was washed with dichloromethane. The filtrate was evaporated. The residue (4 g) was purified by column chromatography on silica gel (eluent: CH2C12 / CH30H 95/5 and CH2C12 / CH30H / NH40H 80/20 / -17) This paper is in accordance with China Standards for Households (CNS) A4 Specifications (2IOX 297, please read it first, fill in the blank, write this page, and bind this page 418203 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (16) 3). Collect the soluble fractions and evaporate the solvent. The residue (2.58 g free state test) was dissolved in 2-propanine and converted to its acidic acid (1: 1) by using HC1 / ethyl. By adding methyl ethyl anion, it caused crystallization. 0 will precipitate Extinction and drying yielded 2: 3 g (38%) of (-)-(A) -5-[(3-chlorophenyl) -1Η-amidazole-1 · ylmethyl] -1H-phenylhydrazone Imidazole monohydrochloride: melting point 27.7 ° C; [iH ^ =-42.43e (c = 1% in methanol) (compound 1). Example 4 The intermediate (11) (177.35 g) was dissolved in water (491 Ml >, the admixture of acid (277 ml) and formic acid (70.6 ml), heated to 50-55 eC. The reaction mixture was stirred at 55 ° C for 3 hours. The mixture was cooled to 20 ° C. Add digas methane (1173 ml). Allow to cool Add ammonium ammonium oxide (700 ml > (pH > 9). This mixture is stirred for 30 minutes at 201. The organic layer is separated, washed with water (500 ml), dried, filtered and filtered at 45- 5 (The solvent was evaporated at TC, yielding 134.16 g (100% > (-)-(4) -5-[(3-Gaphenyl) -1H-Miso-1-ylmethyl] -1H-phenylhydrazone Izodazole; melting point 132.7 * 0; [from, in methanol] (Compound 2) 0-Example 5 The washed compound of compound (2) (2.66 g) in ethanol (28.5 ml) was stirred at 20 ° C Until it became homogeneous. After adding (E) -2-succinic acid (2 g) "after 10 minutes, the light compound became homogeneous. Within 20 hours, the product crystallized out. The material was filtered, washed with ethyl acetate (5 ml) and dried, yielding 1.72 g (41.4%) of (-)-(A) -5-[(3-Gaphenyl) -1H-imidazole-1- Methyl] -1H-benzimidazole (E > -2-butanedioic acid; melting point 116.7C, [a?] D = _29.20 (c-0.5% in methanol)) ( Huahe-18-This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm)

A \ 3203 B7 V. Description of the invention (17) 物 3). Tube Example 6 Compound (2) (114.5 g) was dissolved in 2-butanone (1854 ml). At 20 ° C :, a mixture of hydrochloric acid in 2-propane (68.5 ml) and 2-butane (556 ml) was added over a period of 2 hours. The reaction mixture was stirred at 20 ° C for 16 hours. Hours. The precipitate was filtered, washed with 2-butanone (185 ml) and dried (empty; 80 ° C). 122.6 g (99'5%) (-)-(person) -5-[(3- Phenyl) -1Η-amidazole-1-ylmethyl] -1H-benzimidazole monohydrochloride; melting point 216.4 ° C; (c = 1% in nail eye) (Compound 1). C. The following formulations are exemplified by a typical pharmaceutical composition for systemic or topical administration to animal and human patients according to the invention's combination. The " active ingredient " (AI ), Which is about the compound of formula (I) or a pharmaceutically acceptable acid addition elk. 宭 Example 7: Oral administration at 60-80eC, 500 grams of AI is dissolved in 0.5 liter of 2-fluorenylpropionic acid and 1.5 Liters of polyethylene glycol. After cooling to 30-40eC, add 35 liters of polyethylene glycol and stir the mixture thoroughly. Then add a solution of 1750 g of sodium saccharin and 2.5 liters of pure water, and add 2.5 while stirring. Cocoa And a sufficient amount of polyethylene glycol to 50 liters of hip volume, an oral drip solution containing 10 mg / ml AI is obtained. The formed solution is filled into a container of falcon. F Example 8: 9 g 4-Glycidyl benzoate 1 g 4-Glycidyl benzoate "soluble in 4 -19-This paper size applies to China's 0 standard (CNS) A4 specification (210 X 297 mm) A7 B7 V. Invention Note (18) liters of boiling pure water. In 3 liters of this solution, firstly dissolve 10 grams of 2,3-dihydroxysuccinic acid, and then dissolve 20 grams of AI. Combine the solution described below with the rest of the former solution And add 12 liters of 1,2,3-propanetriazole and 3 liters of calyx 70% solution. Dissolve 40 grams of saccharin sodium in 0.5 liters of water, then add 2 ml of red lotus root and 2 ml of vinegar Combine the solution described below with the former, add enough water to 20 liters of hip volume, and obtain an oral solution containing 5 mg of AI per teaspoon (5 ml). Fill the resulting solution into an appropriate container. FExample 9: Stir together 20 grams of A. 〖, 6 grams of sodium lauryl sodium breaking acid, 56 grams of "powder, 56 grams of lactose, 0.8 grams of colloidal silicon dioxide, and 1.2 grams of magnesium stearate, and stir vigorously together. Fill the resulting mixture into 1,000 逋 Dang hard gelatin capsules, each containing 20 mg of active ingredient. 宥 Example 10: Infiltration tablets 刽 Tablets 刽 心 heart 100% AI, 570 grams of milk rust and 200 g of mash powder was thoroughly mixed and then filled with a solution of 5 g of dodecyl sodium peroxoate, 10 g of polyvinyl tetrapyrrolidone (Kollidon-Jt 90®) and about 200 ml of water. This moist powder mixture was subjected to a filtration, dried and filtered again. Then add 1 g of microcrystalline cellulose (Avice) ® and 15 g of tritiated vegetable oil (Sterotex®) to fully mix the whole tt, and then press into tablets to obtain 10,000 tablets * each Contains 10 mg of active ingredient. To a solution of 10 grams of Methocel 60 HG® and 75 ml of denatured ethanol, add 5 grams of Ethocel 22 cps ® and -20-This paper size applies to Chinese National Standards (CNS ) A4 specifications (210 > < 297 mm) (Please read the notes on the back before writing this page) -β D printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A 7 B7 418 2u 3 V. Description of the invention ( 19) 150 ml of digas methane solution. Then 75 ml of digas methane and 2.5 ml of 1,2,3-propanetriol were added. 10 g of polyethylene glycol was melted and dissolved in 75 ml of dichloro Tane. The solution described below was added to the former, and then 2.5 g of magnesium octadecanoate, 5 g of polyvinyl tetrapyrrole, and 30 ml of concentrated coloring solution (Opaspray K-1-2109®) were added, and the whole was homogenized. In a coating apparatus, the core of the tablet was coated with the thus obtained slime. Example 11: Note: Setting: 1. 8 g of 4-lethylbenzoate and 0.2 g of 4-hydroxybenzene Propionate T acid is dissolved in about 0.5 liters of boiled water for injection. After cooling to about 50 eC, 4 g of lactic acid, 0.05 g of malon yeast, and 4 g of A.I. were added thereto, while stirring. The solution was cooled to room temperature, and a sufficient amount of water for injection was collected to 1 liter of hip volume to obtain a solution containing 4 mg / ml A.I. This solution is sterilized by filtration (US Pharmacopoeia XVII, page 811 >) and filled into a sterile container. 眚 Example 12: 3 3 grams of A. I · dissolved in 3 grams of 2,3-diphenylbutane In acid 25 ml of a solution of polyethylene glycol 400. Melt 12 g of the surfactant (SPAN⑧) triglyceride (Witepsol 555®) to 300 g. Melt the mixture described below and the solution thoroughly. . At 37-38 ° C, pour the mixture thus obtained into a mold to make 100 suppositories, each containing 30 mg of active ingredient. 0 13: Printed by 200 mg of propionate at the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Add 20 mg of AI to the solution of kilu-cyclodextrin and pure water while stirring. Add panic acid until it is completely dissolved, and then add sodium oxide to pH 6.0. Add this solution to 10 mg of deer -21-This paper size is applicable to China National Standard (CNS) A4 size plOX 297 mm) A7 B7 V. Description of the invention (2G) Carrageenan PJ and 50 mg of propylene glycol in a suspension at the same time. At this time, the adduct is heated to 5 ° C and allowed to cool to about 35 ° C. When adding 50 mg of ethanol 95% (v / v). Add the remaining pure water, a sufficient amount to 1 g, and mix the mixture to homogeneity. 15: Shock. Dissolve a) In 0.1 g of hydroxypropyl / 5-ring Dextrin (MS = 0.43) was added to 0.7 ml of a solution of steamed stuffing water, and 730 μg of a 0.1 N hydrochloric acid solution and 2.5 mg of AI were added. After mixing at room temperature for 10 minutes, add 0.1 N of a solution of sodium gasified sodium, The pH of the solution thus obtained was adjusted to pH 5.5. Then, 4 mg of sodium chloride and 0.15 mg of phenylmercury acetate were added to the dragonfly, and the whole hip was stirred to produce complete dissolution. Then distilled water was added to 1.0 Hip volume in milliliters. The whole is filled into a stack of glass bottles. This glass iodine bottle is sealed with a stack of mechanical pumps, and 0.1 milliliter of each blasting wheel is delivered during drug administration. B) 0.1 g of dimethyl jS-ring To a solution of dextrin and 0.7 ml of distilled water, 600 micrograms of a 0.1N calic acid solution and 2 milligrams of AI were added. After stirring at room temperature for 10 minutes, 10 mg of polyvinyl alcohol was dissolved in the mixture, and the pH value of the solution thus obtained was adjusted to pH 5.5 by adding 0.1N sodium hydroxide solution. 4 mg of sodium fluoride and 2 mg of phenylethanol were continuously added thereto, and the whole hip was stirred to produce complete dissolution. Steamed water was added to produce 1.0 ml of tt product, which was filled into a broken glass bottle. This glass bottle was closed with a mechanical pump, and 0.1 ml was delivered each time when it was administered. (Please read the precautions on the reverse side before writing this page) Packaging · Printed by a member of the Central Standards Bureau of the Ministry of Economic Affairs and printed by a consumer cooperative • 22-This paper size applies to the National Standard (CNS) A4 (210 X 297 mm)

Claims (1)

Scope of patent application Patent Application No. 84101154 Patent Appln. No. 84101154 Patent Application B Chinese text "Pieces (1) d Claiiis in Chinese-EncL (Π (September '86), said!) (Submitted on Septenber f , 1997) Amended l modified by fiOC — a left-handed compound of the formula ([) (I) Cl printed by the Central Bureau of the Ministry of Economy of the People's Republic of China, or its pharmaceutically acceptable acid addition basket. 2 * The compound according to item 1 of the patent application paragraph, wherein the compound is (-)-5- [3-nitrophenyl] -p-imidazol-1-ylmethyl] -111-benzimidazole hydrochloride Salt (1: 1). 3. The compound according to item 1 of the applied patent garden, wherein the compound is (-) j- [3-aerophenyl] -1H-imidazol-1-ylmethyl: HH-benzimidazole (E)- 2-butenedioate (3: 2). 4. A medical incontinence composition for treating epithelial swelling, comprising a scientifically acceptable agent and a therapeutically effective amount of a compound according to any one of items 1 to 3 of the patent application park . 5. The medically prohibited composition according to item 4 of the patent application group, wherein the composition is in a form suitable for systemic administration. 6. The medical incontinence composition according to item 5 of the patent application group, wherein the composition also contains an effective amount of a retinoic acid, a derivative thereof or a stereochemically isomeric form thereof. The compound of any one of items 1 to 3, which is used in -23 paper sizes, "National Rate (CNS > Α4ΛGrid (210X2M)) (Please read the precautions on the back before filling this page ) Order 4 ^ 6203 The scope of patent application is for the manufacture of drugs for the treatment of epithelial tumors. 8. The compound according to any one of claims 1 to 3 of the patent application park, which is used for the manufacture of a medicament for treating a prostate tumor. 9 isomerically pure intermediates of the formula (Α)-(Π) ηία: Please. Read 注 Note on the back side I ci or its acid addition blue. A method for preparing a compound according to item 1 of the patent application, which is characterized by a) using a para-isomeric pure para-palmitic acid, such as 7,7-dimethyl- 2-oxobicyclo [2 · 2 · 1] heptane-j_methanesulfonic acid, analytical formula ([[[>intermediate; b) reduction of the thus obtained formula (A)-(ΠΙ) para-isomer Intermediate on the pure; order printed by Zhengong Consumer Cooperative, Central Standards Bureau, Ministry of Economic Affairs (Am Ο cyclizes a pure intermediate of the isomer of formula (A)-(ιι) with methaneimide, formic acid, and its functional derivatives to produce a structurally pure compound of formula (j); -24 This paper waves again selected China _ housekeeping rate (CNS) A4 specifications (210X297 mm)% A8 B8 C8 D8 a 『% Patent application scope Η / > N and if necessary, use appropriate acid treatment to convert the compound of formula (I) into its pharmaceutically acceptable acid addition salt form, or vice versa, use a base to convert this acid addition salt Into its free base form. (Please read the notes on the back before filling out this page) Printed by the Ministry of Economic Affairs of the Provincial Bureau of Procurement Bureau, Consumer Consumption Cooperative -25 Officer J vh Jin Lian 丨 Teacher's Department j In the use of this paper size «β home rubbing rate (CNS) A4ft grid (210X297 mm) Scope of patent application Patent Application No. 84101154 Patent Appln. No. 84101154 Patent Application B Chinese text "Pieces (1) d Claiiis in Chinese-EncL (Π (September '86), said!) (Submitted on Septenber f , 1997) Amended l modified by fiOC — a left-handed compound of the formula ([) (I) Cl printed by the Central Bureau of the Ministry of Economy of the People's Republic of China, or its pharmaceutically acceptable acid addition basket. 2 * The compound according to item 1 of the patent application paragraph, wherein the compound is (-)-5- [3-nitrophenyl] -p-imidazol-1-ylmethyl] -111-benzimidazole hydrochloride Salt (1: 1). 3. The compound according to item 1 of the applied patent garden, wherein the compound is (-) j- [3-aerophenyl] -1H-imidazol-1-ylmethyl: HH-benzimidazole (E)- 2-butenedioate (3: 2). 4. A medical incontinence composition for treating epithelial swelling, comprising a scientifically acceptable agent and a therapeutically effective amount of a compound according to any one of items 1 to 3 of the patent application park . 5. The medically prohibited composition according to item 4 of the patent application group, wherein the composition is in a form suitable for systemic administration. 6. The medical incontinence composition according to item 5 of the patent application group, wherein the composition also contains an effective amount of a retinoic acid, a derivative thereof or a stereochemically isomeric form thereof. The compound of any one of items 1 to 3, which is used in -23 paper sizes, "National Rate (CNS > Α4ΛGrid (210X2M)) (Please read the precautions on the back before filling this page ) Order