• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Compounds are provided having the structure <IMAGE> wherein R1 and R2 may be the same or different and R1 is hydrogen, alkyl of 1-3 carbons, phenyl optionally substituted by R4 or <IMAGE> R2 is <IMAGE> hydrogen, lower alkyl or phenyl optionally substituted by R4 with the proviso that at lest one of R1 and R2 is <IMAGE> R3 is hydrogen, lower alkyl, benzyl or phenyl optionally substituted by R4; and R4 and R5 are the same or different and represent hydrogen, lower alkyl, lower alkoxy, alkanoyloxy, benzyloxy, hydroxy, halogen (C1, Br and F), nitro, and trifluoromethyl; R6 is hydrogen, lower alkyl, alkanoyl, aroyl, aralkanoyl, aralkyl or phenyl; and R7, R8, m and n are as defined hereinafter.
    公开号:SU730306A3
    申请号:SU772499601
    申请日:1977-07-01
    公开日:1980-04-25
    发明作者:Вогт Б.Ричард
    申请人:Е.Р.Сквибб Энд Санз, Инк (Фирма)；
    IPC主号:
    专利说明:

    where R.J, R4 and Rg have the indicated meanings,
    subjected to interaction with acetylene of the General formula
    R - - Rj,, (3) where one of the substituents from among R, and RO is a group
    7 -iH2) „1-С - (CH2) rt-0"
    RB
    followed by isolation of the desired product as a base or salt or by acylation in dp to prepare a compound of formula I, where R is said alkanoyl or aroyl,
    or by isolating the desired product by alkylation to form a compound of formula I, wherein Rg is said alkyl,
    The reaction may be carried out in excess of an acetylene compound of formula 3 or in a solvent inert under the reaction conditions. Examples of such solvents are aliphatic hydrocarbons such as pentane, hexane, octane and others, aromatic hydrocarbons such as benzene, toluene, xylenes and others; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, ethylene dichloride, chlorobenzene, bromobenzene, and the like; ethers, such as diethyl ether, diisopropyl ether, methyl butyl ether, tetrahydrofuran, 1,4-dioxane and others, aliphatic esters such as methyl acetate, ethyl acetate, butyl acetate, dimethylacetamide, dimesulfoxide, and. etc. Preferred are aromatic hydrocarbons, such as benzene or toluene, and chlorinated hydrocarbons, such as methylene chloride. The amount of solvent used should be sufficient to allow mixing. Typically, the ratio (weight-volume) of reagents to solvent is 1: 2-1: 3, although large volumes of solvent can be used if desired. The molar ratio of substituted acetylene to 3-diazoindole-2 (3N) -one of formula 2 can vary from 1: 1 to 1: 100. Usually, a molar ratio of 1: 1 to 1:40 is used. The reaction time may vary from 15 minutes to 48 hours, usually the reaction time ranges from 15 minutes to 30 hours. The reaction is carried out at elevated temperatures, e.g., 40-150 seconds, more often at the boiling point of the solvent. Commonly used are reaction temperatures of 70-120 ° C. The isolation of compounds of formula 1 is carried out by standard methods. In preferably used solvents, Pyrazolo 1,5-c quinazolin-5 (bN-one is slightly soluble at room temperature
    temperature or at lower temperatures, so the selection of the target product is carried out by cooling the reaction mixture and filtering the precipitate.
    In the absence of a solvent, an excess of substituted acetylene can be removed by distillation in vacuo, the product is isolated by thoroughly triturating the residue with a solvent, followed by filtration of the precipitate.
    The substituted acetylenes of the formula 3 are generally commercially available or readily prepared by well-known methods.
    The 3-diazoindole-2 (3N) -ones used in formula 2 are usually obtained from the corresponding isatin compounds. N-3-Substituted isatin can be obtained in two ways, depending on whether the N-substituent is alkyl or aralkyl or aryl. When the nitrogen substituent in the target isatin is alkyl or aralkyl, the isatin compound is prepared by N-alkylation with alkyl or; aralkyl halide in the presence of a strong base such as sodium hydride. When the aryl substituent on the nitrogen atom of the isatinic compound is desired, the desired N-arylisatin is obtained by direct cyclization of oxalyl chloride and substituted diarylamine.
    The compounds of formula 1 can form acid addition salts or base addition salts with inorganic and organic acids or alkali or alkaline earth metal bases such as sodium hydroxide and calcium hydroxide. Such salts are often a convenient way to isolate products from the reaction mixture by forming a salt in an environment in which it is insoluble. The free base can then be obtained by neutralizing, for example, the base with an acid. Then, any other salt from the free base and the appropriate neoorganic acid can be obtained again. Examples are hydrohalides, especially preferred are hydrochloric acid and hydrobromic salts, sulfates, nitrates, phosphates, oxalates, tartrates, maleates, fumarates, citrates, succinates, methanesulfonates, benzenesulfonates, toluene sulfonates, and the like.
    The compounds of formula 1 and their salts are useful in the treatment of various allergic diseases in mammals by administering them in amounts from 1 to 500 mg / kg of animal weight. The compounds can be used for prophylaxis. Or for the treatment of various allergic and immunological disorders, in particular for the treatment of certain
    types of asthma, hay fever and rhinitis. A preferred dosage is from 3 to 200 mg / kg per day with a single or multiple administration.
    The compounds of formula 1 and their salts are anti-allergens that inhibit antigen-antibody and X2 reactions. Especially strongly inhibit the release of mediators such as histamine. The antiallergenic activity of these compounds was determined using reagent antibodies induced by a passive anaphylactic skin reaction in rats.
    The proposed compounds may also be useful as anti-inflammatory agents, as determined by a test for reversible passive arthritis, they are effective in preventing and inhibiting the formation of granulomas in warm-blooded animals, and can be used, for example, like phenylbutazone or indomethacin. They effectively reduce joint tumors, pain, pain and ossification (lack of flexibility) in dogs and monkeys with rheumatoid arthritis.
    In addition, these compounds are useful as inhibitors of 3,5-cyclic phosphodiesterase and 3,5-cyclic guanosine phosphodiesterase, and also as an exciting agent in doses of 12-100 mg / kg per day, as inhibitors of platelet aggregation and, therefore, for potential use in the treatment of thrombosis.
    Example 1. 1- (Oxymethyl) -2-phenylpyrazolo 1, 5-with quinazolin-5 (6H) -one.
    A. 5, 6-Dihydro-5-oxo-2-phenylpyrazolo 1, 5-c hina | Zolin-1-carboxaldehyde.
    4.8 g (0, OSO mol) of 3-diazooxoindole are suspended in 350 ml of benzene and 3.9 g (0.30 mol) of phenylpropargyl aldehyde are added. The reaction mixture is refluxed under nitrogen for 48 hours.
    Then the reaction mixture is evaporated, to obtain a residue of 7.0 g, which is chromatographed on a column with 200 g of dry silica gel, 1.5 l of chloroform / ether (3: 2) are eluted. By evaporation of the eluate, 2.5 g (29%) of a solid product is obtained, which crystallizes twice from chloroform / methanol (4: 1), to obtain 1.67 g of product with mp. 347-350 ° C (with decomposition).
    .B. 1- (hydroxymethyl) -2-phenylpyrazolo (1,5-c quinazolin-5 (6H) -one.
    To a suspension of 4.0 g (0.0139 mol) of 5,6-dagidro-5-oxo-2-phenylpyrazolo G1.5-c quinazoline-1-carboxaldehyde
    in 300 ml of methanol (at 0 ° C), adding 2.5 g (0.066 mol) of sodium borohydride. The suspension is stirred at 15 minutes and then overnight, at room temperature. Another 2.5 g of borohydride is added, and after 6 hours another 2.5 g is added, stirring is continued all night. The reaction mixture is treated with 200 ml of water, methanol is distilled off, 3.7 g of solid product is filtered off and dried.
    0 This product is suspended in 500 ml of absolute ethanol, the mixture is cooled to 0 ° C, treated with 2.5 g of sodium borohydride, stirred for 5 hours at room temperature. The suspension is treated with 250 gl of water and distilled to a minimum volume. The precipitate is filtered off, washed with water and dried (weight 2.5 g). After recrystallization from absolute ethanol containing 2% benzene, 2.1 g of product containing 1 liter of hydration water are obtained, m.p. 267-270 ° C (decomposition).
    Example 2. 2- (Oxymethyl) pyrazolo 1, 5-with quinazolin-5 (6H) -one.
    five
    A. Ethyl ester of 5, .6-dihydro-5-oxopyrazolo 1, 5-c quinazoline 2-carboxylic acid.
    A solution of 48 g (0.30 mol) of W-diabooxindole and 38.7 g (0.39 mol) of ethyl propiolate in 2 liters of benzene is refluxed overnight. The reaction mixture is cooled to room temperature and filtered, giving 60 g of product. Crystallization from absolute ethanol gives 54 g of the product with so pl. 242-244 C (with decomposition).
    An analytical sample is obtained.
    0 by recrystallization from absolute ethanol three times isolated 3.92 g of product, m.p. 253-254 ° С (with decomposition).
    B. 2- (Oxymethyl) pyrazolo I, 5-s
    5 quinazolin-5 (6H) -one.
    A suspension of 3.84 g (0.015 mol) of ethyl 5,6-dihydro-5-oxopyrazolo 1, 5-c quinazoline-2-carboxylic acid ethyl ester is stirred in 150 ml
    0 tetrahydrofuran in a nitrogen atmosphere at room temperature. 24 ml (0.034 mol) of a 20% solution of diisobutyl aluminum hydride in hexane are added and stirred for 1 hour, at room temperature, after
    5 then add 50 ml of methanol and boil the reaction mixture under reflux for 1 hour. The precipitate of aluminum alkoxide is filtered off, air-dried and for 48 hours
    0 is extracted in Soxhlet apparatus with boiling methanol. The extract was combined with the filtrate obtained earlier and evaporated, 3.2 g of a white solid were isolated (quantitative).
    5 By recrystallization from methanol, 2.1 g of the pure desired product are obtained, mp 285-287 s.
    Example 3. 2- (1-Hydroxyethyl) pyrazolo 1, Ef-c hinaeolin-5 (bN) -one.
    A. 2-Acetylpiraeolo 1,5-c quinazolin-5 (6H) -one
    A solution of 19.0 g (0.119 mol) of 3-diazoxoindole and 10 g (0 (147 mol) of 3-6 utin-2-ol in 800 ml of benzene is boiled overnight under reflux. The reaction mixture is cooled to room temperature and filtered product (3.1 g). After recrystallization from a mixture of chloroform and methanol, 18.0 g of product are obtained with a melting point of 296-299 ° C. (decomposition). Further recrystallization from glacial acetic acid results in 14.2 g of pure product. with mp 306-308 ° С (decomposition) ...
    B. 2- (1-Hydroxyethyl) pyrazolo 1,5-c quinazolin-5SbN) -one.
    A suspension of 3.3 g (0.0146 mol) of acetylpyrazolo 1.5-c quinazolin-5 (6H) -one in 300 ml of absolute ethanol is cooled to and added 2.22 g (0.0584 mol) of sodium borohydride. Continue stirring at 0 ° C for 15 minutes and then 2 hours at room temperature. The reaction mixture is treated with 150 ml of water, the solution is evaporated to 100 ml, saturated with solid sodium chloride and adjusted to pH 6.0 (indicator paper) with diluted (1N) hydrochloric acid. The precipitate is filtered off and dried, and 3.1 g of product is obtained (94% with T.PL. 242-245 0. Recrystallization from a mixture of chloroform and methanol gives 3.0 g of the desired product with mp 250-252 ° C.
    Example 4. 2- (1-Hydroxyethyl) -6-methylpyrazolo 1, 5-c) quinazolin-5 (6H) -one.
    A. 2-Acetyl-6-methylpyrazolo 1,5-c quinazolin-5 (6H) -one,
    To a solution of 5; O g (0.0288 mol) of 1-methyl-3-diazooxoindole in 200 ml of benzene was added 2.38 g (0.035 mol of 3-butyn-2-one) and refluxed overnight. .
    The reaction mixture is cooled to room temperature and the precipitate is filtered off, washed with ether, to obtain 4.5 g of substance with so pl. 250-251 ° C. Recrystallization from a mixture of chloroform and methanol gives 4.0 g of pure product with a melting point of 250-251 ° C.
    B, 2- (1-Hydroxyethyl) -6-methylpyrazolo U, 5-c) quinazolin-5 (6H) -one.
    6.4 g (0.02669 mol) of 2-acetyl-6-methylpyrazolo 1,5-c quinazolin-5 (6H) -one in 325 MP of methanol are suspended and cooled in an ice bath. 4.85 g (0.128 mol of sodium borohydride) is added thereto in portions. The mixture is stirred for 15 minutes in an ice bath (a clear solution is formed during this time), and then stirred for 30 minutes at room temperature.
    The solution is treated with 100 ml of water and methanol is distilled off. The aqueous solution is extracted three times (100 ml each time) with methylene chloride. The combined organic phases are washed twice (75 ml each time) with a saturated solution of sodium chloride, dried with anhydrous sodium sulfate and evaporated to give 6.5 g of residue (quantitative). The residue is poured over with pentane and left overnight with the resulting sticky solid product filtered off and dissolved in boiling acetone. Concentrate the solution on a water bath and filter while cooling, to obtain 4.4 g of an analytically pure desired product with mp 169-172 ° C.
    Example 5. 2- (Oxyphenylmethyl) pyrazolo 1,5-c quinazolin-5 (6H) -one.
    A, Phenylethyl ethyl ketone, A solution of 34.2 g of 1-phenyl-2-propyn-1-ol. In 50 ml of acetone is cooled to 0 ° C, stirred in a stream of nitrogen and treated, adding dropwise a solution of 17.5 over 3 hours g of chromic acid in 50 ml of water and 14.8 ml of concentrated sulfuric acid, keeping the temperature below 5 ° C all the time. At the end of the addition, the mixture was stirred for 1 hour at. Then the reaction mass is diluted with water (100 ml) and extracted (in two portions of 250 mp) with ether. Combine the organic extracts, dry with anhydrous sodium sulfate, filter, evaporate, and obtain a yellow product. A small amount, dried on a porous plate, gives a product with so pl. 45-47 ° C.
    B. 2-Benzoylpyrazolo 1,5-c quinazolin-5 (6H) -one.
    8.23 g (0.039 mol) of diazoskssindol and 6.6 g (0.051 mol or 1.3 equivalents) of phenylethynyl ketone dried on a porous plate before weighing are suspended in 275 ml of benzene and the mixture is heated under reflux in a nitrogen atmosphere for 19 The reaction mass is cooled and the precipitate formed is filtered, washed well with anhydrous ether (150 ml) and dried in a vacuum. oven at 70 ° C for 1.5 hours. Yield 10.3 g, so pl. 308-311 ° C. Additionally, 400 mg of product is obtained by boiling the filtrate for 24 hours under reflux. The total yield of the crude product is 94.4%.
    The crude product is purified by dissolving it in 400 ml of dimethylforma1id, concentrating the solution to 300 mp, and then pouring it into 1.5 l of ice water. After stirring for 30 minutes, a beige color of the precipitate is filtered off and dried with 8 () ° C,
    B. 2- (Oxyphenylmethyl) piraeolo 11, L-cj quinazolin-5 (6H) -one,
    1.65 g (0.0057 mol) of 2-benzoylpyrazolo 11,5-cj quinazolin-5 (bN) -one with 80 mg (4 equivalents) of sodium borohydride in 125 ml of absolute ethanol at room temperature for .i h. Are mixed. the mixture is evaporated to dryness and the resulting solid product is suspended in 40 ml of water, cooled to 0 ° C and treated dropwise with 25 ml of 1N. hydrochloric acid. The mixture is stirred for 30 minutes, diluted with 40 ml of water and stirred for another 10 minutes. A white precipitate is filtered off, washed well with water and dried overnight in a vacuum oven at 70 ° C to obtain 1.6 g of product.
    200 mg of the product from another experiment was added to the crude product and recrystallized, dissolved in 100 ml of 95% ethanol, filtered hot and the clear filtrate was concentrated to a volume of 25 ml. After cooling, the precipitate is filtered off and washed with several milliliters of 95% ethanol. The product is dried in a vacuum oven for 1.5 hours at 70 ° C. The output of 1.47 g, so pl. 231-233 C.
    Example 6. 2- (acetyloxymethyl) pyrazolo U, 5-c quinazolin-5 (6H) -o
    With reflux, 3.0 g (0.014 mol) of 2- (hydroxymethyl) pyrazolo 1, 5-c quinazolin-5 (bN) -one is boiled in 250 ml of glacial acetic acid for 20 hours under a nitrogen atmosphere. The solution is cooled and evaporated to give a solid residue, which is dissolved in a mixture of ethyl acetate and absolute ethanol. The mixture was partially evaporated and the concentrated solution was left at. The precipitate is filtered off to obtain 3.5 g of product. By recrystallization from ethyl acetate / absolute ethanol, 3.1 g of analytically pure desired product are obtained, m.p. 177 179 ° C.
    Example 7. 2- (Oxymethyl) -6-methylpyrazolo P, 5-with quinazolin-5 (6H) -one.
    A suspension of 5.35 g (0.025 mol) of 2- (hydroxymethyl) pyrazolo 1,5-c quinazolin-5 (6H) - in 250 ml of dimethoxyethane. (DME) is treated with 690 mg (0.029 mol) of OTfiHToro from hydride oil sodium, then a solution of 3.3 ml (0.053 mol) of methyl iodide in 20 ml of hexamethylphosphoric triamide is added. After stirring for 1 h, 6, b ml (0.106 mol) of methyl iodide are added and the suspension is stirred overnight.
    Stir the reaction mixture with 200 ml of 1N. aqueous hydrochloric acid and 400 ml of methylene chloride are added. The organic phase is separated and washed successively with water, with an aqueous solution of sodium thiosulfate, g, finally, with water, and evaporated to obtain a solid product (b). Purification was carried out by thin layer preparative chromatography using silica gel (Merck) and methanol (9: 1). Elute the target product from the adsorbent with a mixture of methylene chloride / / methanol (4g1), to obtain 1.1 g (19%)
    0 target product. After recrystallization from methanol, an analytical sample (945 mg) is obtained, mp. 183184 C.
    Example 8. 2- (Methoxymethyl) 5 b-methylpyrazolo 1,5-c quinazolin-5 (6H) -one.
    To a suspension of 32 mg (0.013 mol) of sodium hydride freed from oil in 25 ml of glyme is added
    0 227 mg (0.001 mol) of 2- (hydroxymethyl) -5-methylpyrazolo 1, 5-c quinazolin-5 (bN) -one. The suspension is stirred for 15 minutes and then a solution of 0.66 ml (0.0107 mol) of methyl iodide in 2 ml of hexamethylphosphoric triamide is added.
    5 The reaction mixture is stirred at room temperature for 18 hours. The solution is filtered and the filtrate is evaporated to give an oil, which is distributed between methylene chloride and aqueous
    Sodium thiosulfate solution. The organic phase is washed with water and evaporated to an oil, which is dissolved in acetone and applied to a silica gel plate (Merck, 20 cm x 20 cm x
    5 2 mm) in the system chloroform methanol (9: 1) and the product is eluted with acetone. After evaporation of the acetone, an oil is obtained which crystallizes on standing in pentane at. The yield of the crude product is 100 mg (41%), m.p. 98-1СрОС.
    EXAMPLE 9. 2- (Formyloxymethyl) pyrazolo 1,5-c quinazolin-5 (6H) -one.
    3.3 g (0.0153 mol) of 2- (hydroxymethyl) pyrazolo tl, 5-c quinazo-5 lin-5 (bN) -one in 250 MP of 97-100% formic acid are suspended and refluxed in nitrogen atmosphere overnight. The solution is evaporated to dryness and recrystallized.
    0 solid dioxane product, obtaining 2.8 g (75%) of analytically pure desired product with m.p. 190-192 - s.
    Example 10. 2- (Propionyloxymethyl) pyrazolo 1,5-c quinazolin-5 (bK) 5 -one.
    3.0 g (0.0193 mol) of 2- (hydroxymethyl) pyrazolo 1,5-c quinazolin-5 (bN) -one is suspended in 250 MP of propionic
    The acid and the mixture was refluxed under nitrogen overnight. The resulting solution is evaporated to a solid and the solid product-i is recrystallized from absolute ethanol to give 2.6 g.
    5 (69%) analytically pure target product, so pl. 184-186 0. Example 11. 2- (n-Butyloxime, Tyl) pyrazolo 1,5-c quinazolin-5 (bN) -one. 3.0 g, (0.0193 mol) of 2- (hydroxymethyl) pyrazolo 1,5-c quinazolin-5 (6H) -one in 250 MP n-butyric acid are suspended and refluxed under nitrogen atmosphere in a over night The resulting solution was evaporated to a solid and crystallized from a mixture of ethyladetate and absolute ethanol to obtain 2.8 g of product (71%), mp. 170-172 ° C. An analytical sample was obtained by recrystallization of the indicated product from a mixture of ethyl acetate and absolute ethanol (1: 4), 2.5 g of the pure desired product were isolated, m.p. 17 PRI m e. R 12.. 2- (Benzoyloxymethyl) pyrazolo 1,5-c quin zolin-5 (bN-one. A mixture of 3.0 g (0.014 mol) 2- (hydroxy methyl) pyrazolo 1,5-c quinazolin-5 (bN-it and 100 g of benzoic acid is heated to melting temperature (140-l45-c, silicone oil) in a nitrogen sphere for 18 h, using a magnetic stirrer for stirring. The melt is poured into a well-mixed sodium bicarbonate solution (1 M), insoluble solid is filtered off , the product is washed with water and dried to give 3.8 g (85%) of the desired product, mp 262265 ° C. An analytical sample is obtained by recrystallization of 0.5 g of this material. and from a mixture of dioxane and diisopropyl ether, mp 270-272 ° C. Example 13. 10-Chloro-7-labels si-2- (oxymethyl) pyrazolo, 5 - with quinazolin-5 (bN) -on. A 4-Chloro-7-methoxyisatin-3-p-toluenesulfonyl hydrazone 25.0 g (0.118 mol) of 4-chloro-7-methoxyisatin are dissolved in 500 ml of methanol at 60 ° C and added in parts of 23.8 g 97% p-toluenesulfonyl hydrazine (23.1 g or 1.05 equivalents). The mixture is kept for 15 minutes and then stirred at room temperature for 20 hours. The reaction mixture was concentrated to half its initial volume and the precipitate was filtered, dried in vacuo for 1 h, 37.5 g —X85%) of crude product was obtained, mp. 210-211 ° C. The raw material is dissolved in 1.0 l of dioxane, the dark red solution is concentrated to 400 m and cooled. The resulting yellow precipitate is filtered off and dried overnight in vacuo, at which 27.73 g of product are obtained, mp 217218 ° C. The filtrate is concentrated to about 200 ml and cooled. The precipitate is filtered and dried, 4.4 g of product are obtained, mp. 213-214 ° C. B. 4-Chloro-7-methoxy-3-diazooxo and n dol. 30.0 g (0.079 mol) of isatin-3-p-toluenesulfonylhydrazone are suspended in 900 ml 0.2 n. sodium hydroxide solution and slowly heated for 30 minutes. The mixture is stirred for 22 hours at room temperature with a layer of methylene chloride (300 ml), the methylene chloride is evaporated and the aqueous phase is saturated with carbon dioxide using dry ice. The peach-colored precipitate is filtered off, washed with a small amount of water and dried in vacuo at 45 ° C for 1.5 h, 19.2 g of the expected product are obtained. The crude product is dissolved in 1.8 L of methanol and the clear light red solution is concentrated to a volume of 500 ml, cooled, filtered and the precipitate is dried overnight in vacuo at room temperature. The yield of the target product is 15.2 g, so pl. 206-207 C, light orange crystals. B. 10-Chloro-7-methoxy-2- (oxymethyl) pyrazolo 1,5-c1-quinazolin-5 (6H) -one. Under argon, 2.0 g (0.0089. Mole) of 4-chloro-7-methoxy-8-diazooxindole and 10.3 g of 97% propargyl alcohol are boiled under reflux for 4 hours and cooled. The reaction mixture is diluted with 200 ml of ethyl ether and stirred for 20 minutes, and a creamy precipitate is filtered off. The output of 2.53 g (quantitative), so pl. 221-222 ° C. This crude product is dissolved in 200 ml of absolute ethanol, filtered and the clear solution is hot, the filtrate is concentrated to a volume of 50 ml and cooled. The precipitate obtained is filtered off and dried in vacuo at 45 ° C for several days. Obtain 1, 59 g of the target product, so pl. 230-232 ° C. Example 14. 9-HLOR-2- (hydroxymethyl) pyrazolo 1,5-c quinazolin-5 (bN) -one. 2 g of 5-chlordiazooxoindole (0.01033 mol) and 13 ml (0.22 mol or 21.5 equivalents) are refluxed under nitrogen atmosphere. propargyl alcohol for 4.5 h and cooled. The mixture is diluted with 200 ml of ethyl ether and stirred for 30 minutes. The precipitate obtained is filtered and washed thoroughly with ethyl ether, to obtain 2.41 g (93.4%) of crude product. The crude product is dissolved in 800 ml of absolute ethanol and 300 ml of chloroform, treated with an activated angle for 10 minutes in a hot state, filtered through a layer of zeolite and the clear filtrate is concentrated to a volume of 300 ml, to give 1.0 g of the desired product. the precipitation is filtered off, so pl. 316-
    3l8 ° C. The filtrate is concentrated again to a volume of 150 ml and cooled, another 310 mg of product is obtained, mp. 311-331 ° C.
    Example 15. 2- (1-Oxycyclohexyl) pyrazolo LlI5-c quinazolin-5 (bN) -one. Under reflux in a nitrogen atmosphere, 1.6 g (0.01 mol) of 3-diazooxindole and 12.4 g (0.1 mol of ethynylcyclohexanol for 4.5 h
    The cooled mixture is diluted with 50 m of ethyl ether, stirred for 20 minutes, the precipitate is filtered off and washed thoroughly with ethyl ether, to obtain 2.22 g of product, m.p. 245-251 ° C.
    The crude product is dissolved in 150 ml of absolute ethanol, filtered hot, the clear filtrate is concentrated to a volume of 50 ml and cooled. The precipitate is filtered off, 1.65 g of the desired product are obtained, mp. 253254 S.
    Example 16. 2- (Oxymethyl) pyrazolo 1,5-c quinazolin-5 (6H) -one.
    2.0 g (0.0126 mol) of 3-diazooxindole is dissolved in 22 ml (0.378 mol of propargyl alcohol and refluxed under nitrogen for 3 hours. The reaction mixture is cooled to room temperature and diluted with 10 volumes of ethyl ether. The solid product is filtered off, washed with ethyl ether and dried, and 2.0 g of product (75%) are obtained. After recrystallization from methanol, 1.5 g of the desired product is isolated, mp 2-2C 688 ° C (decomposition) .
    Example 17. 2- (Oxymethyl) pyrazolo 11,5-cj quinazolin-5 (6H) -one.
    4.8 g (0.03 mol) of 3-diazooxindole are suspended in 500 ml of benzene and 1.96 g (0.033 mol) of propargyl alcohol is added. The reaction mixture was heated under reflux overnight in a nitrogen atmosphere, after which 19.6 g (0.33 mol) of propargyl alcohol was added and the reaction mixture was continued to boil (48 hours). The resulting reddish-brown solid was filtered, yielding 1.5 g of substance (yield 23%), m.p. 272-275 ° C (decomposition) .- After recrystallization and methanol, crystals of the desired compound are obtained, m.p. 286-288 ° C (expansion).
    Example 18. 2- (Hydroxyethyl) -9-methoxy-6-methylpyrazolo 1, 5-c quinazolin-5 (6H) -one.
    Work according to the method of example 7, but replacing the 9-hydroxy-2- (oxystil) pyrazolo 1,5-with quinazolin-5 (6H) -one 2- (hydroxymethyl) pyrazole 1,5-with quinazolin-5 (6H) -one from example 7 and using double the amount of other reagents and solvents used in example 7, get the target product.
    Example 19. 2- (Oxymethyl) .. -7- (trifluoromethyl) pyrazolo 1, 5-c quinazolin-5 (6H) -one.
    A.7- (Trifluoromethyl) isatin-3-toeyl hydrazone.
    10.0 g (0.0465 mol) of 7- (trifluoromethyl) isatin and 9.4 g (1.5 equivalents) of 97% p-toluenesulfonyl hydrazine in 250 ml of methanol are stirred for 15 minutes with weak heating and then night at
    0 room temperature. The reaction mixture is concentrated to half its original volume and the resulting yellow precipitate is filtered off and washed with a small amount.
    15 of methanol and dried under vacuum at room temperature for 3 hours. Yield 13.4 g (75.8%).
    The crude product is dissolved in 450 ml of methanol and the clear concentrate is concentrated.
    0 solution to a volume of 100 ml. The solution is cooled and the yellow product is filtered off, washed with a small volume of methanol and dried in vacuo at room temperature for 48 hours and 24 hours at 75 ° C, yielding 11.6 g of the indicated tosyl hydrazone.
    B. 7- (Trifluoromethyl) -3-diazooxindole.
    11.5 g (0.03 mol of 7- (trifluoromethyl) isatintosylhydrazone) are suspended.
    0 to 345 ml 0.2 n. sodium hydroxide and stirred under gentle heating for 1 hour and overnight at room temperature. The reaction mixture is saturated with carbon dioxide (dry ice is used) is stirred for 30 minutes and the precipitate is filtered off, washed with a small amount of water and then dried under vacuum for 3 hours at. Raw product
    0 is dissolved in methanol (200 ml), concentrated to a volume of 20 ml. The output of 3.68 g, so pl. 173-175 C, light orange needles. The product is dried under vacuum at 50 seconds for 2 hours.
    B.2- (Oxymethyl) -6- (trifluoromethyl)
    5 pyrazolo 11,5-c quinazolin-5 (6H) -one.
    2.0 g (0.0088 mol) of 7- (trifluoromethyl) -3-diazooxindole and 10.2 g (0.176 mol or 20 equivalents) of 97% propargyl alcohol are boiled under nitrogen at reflux under nitrogen for 4 The mixture is cooled, diluted with 200 ml of ether and stirred for 30 minutes. The light pink product formed is filtered off.
    5 1.3 g (52.2%).
    The product is dissolved in 150 ml of absolute ethanol, treated with activated carbon, filtered through
    0 a layer of celite a and rot the layer of 25 ml of hot absolute ethanol. Combine the diluted filtrates to a volume of 10 ml, cool, filter the precipitated precipitate and dry it. howl product, so pl. 230-232 ° C.
    5 Example 20. 10-Chloro-2- (hydroxymethyl) pyrazole I, 5-c quinazolin-5 (6H) -one. A. 4-Chlorisatin-Z-tosylhydrazone. 10.0 g (0.055 mol) of 4-chlorozatin and 11.1 g (1.05 equivalent) of 97% p-toluenesulfonyl hydrazide are stirred in 235 ml of methanol. With gentle heating for 15 minutes and 21 hours at room temperature. The reaction mixture is concentrated to half its original volume and the resulting bright yellow precipitate is filtered off and dried in vacuo at room temperature for 3 hours. The yield of the crude product is 18.15 g (94%). Mp. 195-196 e. The crude product is dissolved in 400 MP dioxane and concentrated to a volume of 100 ml. The solution is cooled and the yellow product is filtered off, washed with a small amount of methanol and dried under vacuum for 48 hours at room temperature and at 75 ° C for 24 hours. Exit 15.15 g, so pl. 203 204 ° C. B, 4-Chloro-3-di.azooxindol. 15.0 g (0.043 mol) of 4-chlorois-atintosylhydrazone is dissolved in 480 ml 0.2 n. Sodium hydroxide under gentle heating for 1 hour. Add 200 ml of chloromethylene and continue stirring at room temperature for another 24 hours, evaporate the organic layer on a rotary evaporator and saturate the remaining aqueous phase with carbon dioxide. The reaction. The mixture was stirred for 30 minutes and filtered golden, the precipitate was washed with water and dried in a vacuum. 3 h: at 60-70 C. The yield of crude product is 8.2 g (98.6%), so pl. 214-215 ° The crude product is dissolved in 600 m of methanol, the reddish-brown solution is concentrated to a volume of 200 ml, cooled and the brown-orange product is filtered off, dried overnight in a vacuum at 60-70 s, yield 7.5 g m.p. 216-217 C. B.10-Chloro-2- (hydroxymethyl) pyrazolo U, 5-CJ quinazolin-5 (6H) -one. 2.0 g (0.0103 mol of 4-chloro-3-diazooxindole and 11.95 g (0.207 mol) or 20 equivalents) of 97% propargyl alcohol in 4 hours are boiled under reflux under nitrogen atmosphere, - - The reaction mixture is cooled, diluted with 200 ml of ether and stirred for 20 min.; Filtering off the creamy precipitate: washed with ether and dried under vacuum for two days at. Yield 2.44 g (94.9%) t, mp, 295-296 0. The crude product is dissolved in absolute ethanol, filtered hot and the filtrate is concentrated to a volume of 150 ml. The solution is cooled and the precipitate is filtered off and washed with ether. and dried in vacuo at room temperature for 24 hours, obtain 1.4 g of the intended product, mp, 309-311 C. Example 21. 9-Fluoro-2- (hydroxymethyl) pyrazolo 1,5-c quinazolin-5 (6H) -one, A, p-Toluenesulfonylhydrazone-5-fluorizatin. 10 g (0.06 / 1 mol) of 5-fluoroisatin is dissolved in 280 ml of methanol at--and added in portions of Г 2.3 g of 97% toluenesulfonyl hydrazine (1.05 equivalents or 0.064 mol). The mixture is stirred at room temperature for 15–20 minutes and then at room temperature for 20 hours under a nitrogen atmosphere. The reaction mixture is concentrated to half its original volume, brilliant yellow crystals are filtered and dried in vacuum for 1.5 h at 45 s, Yield 16.3 g (80%), t, mp, 205-20 ° C. The crude product is dissolved in 500 ml of dioxane and the resulting solution is concentrated to a volume of 150 ml. The solution is cooled, the yellow precipitate is filtered off and rotted with a small amount of methanol. The product is dried in vacuum at 55 ° C for 20 h, 13.6 g of the desired product are obtained, mp: 210-211 ° C, B, 5-Fluoro-3-diazooxindol, 12.0 g (0.036 mol) of the obtained tosyl hydrazone is dissolved in 410 ml of 0.2 N, sodium hydroxide under gentle heating for 1 hour and then stirred. at room temperature for 20 hours. Then the reaction mixture is saturated with carbon dioxide (using dry ice), stirred for 30 minutes and filtered light orange precipitate, which is dried in vacuum at 45 ° C for 3 h, yield 6.2 g (97%), t, Ø1, 209-210 ° C. The crude product is a solution from 300 ml of methanol and the clear red solution is concentrated to a volume of 100 ml. The red precipitate is filtered off and dried in vacuo overnight at 55 ° C, B. 9-FTOR-2- (oxymethyl) pyrazolo 1,5-s Quinazolin-5- (6H) -one. 2.0 g (0.0113 mol) of 5-fluoro-3-diazooxindole and 13.1 g (0.226 mol or 20 equivalents) of 97% propargyl alcohol are refluxed under argon for 4 hours; The reaction mixture was cooled, diluted with ether (200 ml) and stirred for 15 minutes. A beige precipitate is filtered off and dried in vacuo overnight, yield 2.3 g (87.5%), mp, 295-297 ° C. The product is dissolved in 500 ml of absolute ethanol, treated with activated carbon, filtered through a layer of zeolite, the layer is washed with 50 ml of hot ethanol. The clear filtrate is concentrated to a volume of
    100 ml and cool. A white precipitate is filtered off and dried in vacuo at 60 ° C. 1.16 g of the expected product are obtained, mp. 303-304 S.
    权利要求:
    Claims (1)
    [1]
    1. US patent 3897434, cl. 260-256.4, pub. 1975.
    类似技术:
    公开号 | 公开日 | 专利标题
    US5686457A|1997-11-11|Pyrrolopyrimidine derivatives having pharmacological activity
    US3592895A|1971-07-13|Pyrimidine derivatives as anti-inflammatory,analgesic and antipyretic agents
    SU730306A3|1980-04-25|Method of preparing derivatives of pyrazolo-/1,5-c/quinazoline or salts
    JP2001509805A|2001-07-24|Pyrido [2,3-D] pyrimidine and 4-aminopyrimidine as cell growth inhibitors
    JPH05140167A|1993-06-08|Substituted pyrazolopyrimidine and imidazopyridazine as angiotensin ii antagonist
    US6124285A|2000-09-26|Indole-2,3-dione-3-oxime derivatives
    DK165409B|1992-11-23|3-AMINOPYRAZOLOOE3,4-DAAPYRIMIDINE DERIVATIVES
    Bertelli et al.2000|Substituted 1, 2, 3-triazolo [1, 5-a] quinazolines: synthesis and binding to benzodiazepine and adenosine receptors
    JPH05163240A|1993-06-29|Substituted diaminophthalimide and homologue
    US3963736A|1976-06-15|Preparation of 1-|-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acids
    CA1203801A|1986-04-29|Piperazine derivatives, their production andpharmaceutical compositions containing them
    Chen et al.1983|Synthesis of 7‐phenylpyrimido [5, 4‐d][1] benzazepin‐2‐ones
    US5250521A|1993-10-05|Substituted pyrazolopyrimidines as angiotensin II antagonists
    Cain et al.1976|Potential antitumor agents. 19. Multiply substituted 4'-| methanesulfonanilides
    SU999973A3|1983-02-23|Process for producing derivatives of pyrido|pyrimidine or their pharmaceutically acceptable salts or their optically active isomers
    US3993650A|1976-11-23|Pyrrolo [3,4-d] pyrimidines
    FI57105B|1980-02-29|FREQUENCY REFRIGERATION FOR NEW S-TRIAZOLO | EQUIPMENT WITH BEARING CONDITIONS
    EP1066037B1|2004-12-29|Use of indole-2,3-dione-3-oxime derivatives as ampa antagonists
    US5260285A|1993-11-09|Substituted imidazopyridazines as angiotensin II antagonists
    US4053600A|1977-10-11|Tricyclic 1,2,4-triazolo-quinazolines
    US4183932A|1980-01-15|Fused quinazolinones and preparation thereof
    US4495187A|1985-01-22|Method of using [1,2,4]triazolo[4,3-a]quinoxaline-4-amine derivatives as antidepressant and antifatigue agents
    US3850932A|1974-11-26|5-|-1,2,4-triazolo-quinazolines
    SU725563A3|1980-03-30|Method of preparing imidazo-| diazepine derivatives or their salts
    EP0313288A1|1989-04-26|Imidazole derivatives, process for their preparation and their use as alpha 2-adreno-receptor antagonists
    同族专利:
    公开号 | 公开日
    AU512177B2|1980-09-25|
    GB1585681A|1981-03-11|
    PL106659B1|1980-01-31|
    DE2726389A1|1978-01-12|
    CA1097347A|1981-03-10|
    NL7707086A|1978-01-04|
    FR2356650A1|1978-01-27|
    AT361487B|1981-03-10|
    US4076818A|1978-02-28|
    ATA424077A|1980-08-15|
    FR2356650B1|1981-08-28|
    HU173531B|1979-06-28|
    BE856386A|1978-01-02|
    ZA773319B|1978-04-26|
    PL199270A1|1978-09-11|
    JPS5312894A|1978-02-04|
    US4112096A|1978-09-05|
    AU2583077A|1978-12-07|
    PH12768A|1979-08-17|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    DE1111505B|1960-02-11|1961-07-20|Agfa Ag|Process for the production of colored photographic reflective or transparent images by the color development process|
    US3313815A|1964-05-04|1967-04-11|Sterling Drug Inc|8-chloropyrazolo-[1, 5-c]quinazoline derivatives and methods of preparing same|
    US3531482A|1966-10-13|1970-09-29|Sandoz Ag|Pyrazoloquinazolines|
    DE2058501A1|1970-11-27|1972-05-31|Bayer Ag|Process for the production of new N-bridged bicyclic heteroaromatics|
    JPS50116498A|1974-02-27|1975-09-11|
    US3890324A|1974-04-12|1975-06-17|Lilly Co Eli|1h-pyrazoloquinol-4-one-3-carboxylic acids|
    US3897434A|1974-04-12|1975-07-29|Lilly Co Eli|Pyrazolo{8 1,5-c{9 quinazolin-5-ones|
    US3899508A|1974-04-12|1975-08-12|Lilly Co Eli|5-pyrazole-3-carboxylic acids and esters thereof|
    US3903106A|1974-04-12|1975-09-02|Lilly Co Eli|Pyrazole-3-carboxylic acids|
    US3895027A|1974-04-12|1975-07-15|Lilly Co Eli|Process for preparing pyrazole-3-carboxylic acids|US4128644A|1977-07-29|1978-12-05|E. R. Squibb & Sons, Inc.|Pyrazoloquinazoline derivatives and related compounds|
    US4282226A|1978-04-26|1981-08-04|E. R. Squibb & Sons, Inc.|Thioxopyrazolo[1,5-c]quinazoline derivatives, anti-allergic compositions and methods for treating allergic conditions by parenteral administration, aerosol or insufflation|
    CA1111033A|1978-04-26|1981-10-20|Berthold R. Vogt|Thioxopyrazolo[1,5-c]quinazoline derivatives and related compounds|
    US4239896A|1978-12-13|1980-12-16|E. R. Squibb & Sons, Inc.|5--1H-pyrazole-3-methanol|
    US4198412A|1978-12-13|1980-04-15|E. R. Squibb & Sons, Inc.|Pyrazolo [1,5-C] quinazoline derivatives and their use in treating allergic conditions|
    HU178523B|1979-05-18|1982-05-28|Egyt Gyogyszervegyeszeti Gyar|Process for preparing new pyrazolo-quinazoline derivatives|
    US4312870A|1979-06-21|1982-01-26|Ciba-Geigy Corporation|Pyrazoloquinolines|
    US4252945A|1979-07-11|1981-02-24|E. R. Squibb & Sons, Inc.|Process for preparing pyrazolo[1,5-c]-quinazoline derivatives and novel intermediates|
    US4307099A|1980-06-25|1981-12-22|E. R. Squibb & Sons, Inc.|Reaction products of pyrazolo[1,5-c]quinazoline derivatives and proline derivatives and methods for reducing blood pressure while inhibiting allergic reactions with them|
    US4459298A|1982-09-28|1984-07-10|Ciba-Geigy Corporation|Method of suppressing appetite|
    US4713383A|1984-10-01|1987-12-15|Ciba-Geigy Corporation|Triazoloquinazoline compounds, and their methods of preparation, pharmaceutical compositions, and uses|
    US4831013A|1986-03-20|1989-05-16|Ciba-Geigy Corporation|2-substituted-e-fused-[1,2,4]triazolo[1,5-c]pyrimidines, pharmaceutical compositions, and uses thereof|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US05/702,364|US4076818A|1976-07-02|1976-07-02|Pyrazolo [1,5-C]quinazoline derivatives and related compounds|
    [返回顶部]