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    • 专利摘要:
    Quinazoline derivatives of the formula …<CHEM>… wherein Ra is hydrogen or alkyl and and q is 2 or 3;… R is hydorgen, hydroxy and alkyl;… Alk is an alkylene chain having from 1 to 4 carbon atoms and Q is a quinazolinyl radical, the 1-, 2-, 3- or 4-position of which is connected with the alkylene side chain, said quinazolinyl radical bearing in one or both of its 2-and 4-positions a carbonyl or thiocarbonyl group, wherein the benzene ring of said quinazolinyl radical is optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halo, alkyl; alkyloxy, trifluoromethyl, nitro and cyano, and wherein the pyrimidino ring of said quinazolinyl radical may be partly or fully saturated, said pyrimidino ring being optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl, aryl and aryl(lower alkyl);… wherein said aryl as used in the definition of said Ar and of said Q is a member selected from the group consisting of phenyl, substituted phenyl, thienyl and pyridinyl, wherein said substituted phenyl has from 1 to 3 substituents each independently selected from the group consisting of halo, lower alkyl, lower alkyloxy, trifluoromethyl and amino. These derivatives are serotonin antagagonists. Further are described compounds of the formula …<CHEM>… (Q, Alk and R have the same meaning as above), R8 and R9 being hydrogen, halogen, alkyl, alkoxy, CF3 and amino, having the same activity.
    公开号:SU1041034A3
    申请号:SU802863403
    申请日:1980-01-07
    公开日:1983-09-07
    发明作者:Ванденберк Ян；Эдмонд Жозефин Кеннис Лудо；Жозеф Мария Катарина Ван Дер Аа Марсель；Хенрикус Мария Терезия Ван Хеертум Альберт
    申请人:Жансен Фармасетика Н.В. (Фирма)；
    IPC主号:
    专利说明:

    R is hydrogen, methyl, phenyl, p-tolyl, fluorophenyl, chlorophenyl, methoxyphenyl, phenylmethyl or pyridinyl;
    one
    R is hydrogen, R is hydrogen, methyl, phenyl p-tolyl, chlorophenyl, or R and H together are oxygen;
    AEK - ethylene, propylene or Tylen;
    R is hydrogen or methyl;
    S.CH
    x- (5o, "l" -sn2-;
    Ar is phenyl, substituted phenyl, having one or two substituents selected from the group: chlorine, bromine, fluorine, methyl, methoxy, trifluoromethyl, amino, or Ar - thienyl or pyridinyl, or their salts with pharmaceutically acceptable acids;
    12.10.79 with R - hydroxyl. .
    This invention relates to a process for the preparation of new piperidinyl alkylquinazoline derivatives of the general formula B5 B7 L -AlK-H- -jL-AT where each R is independently chlorine, fluorine, methyl or methoxy-} n, 0.1 or 2; R is hydrogen, phenyl or methyl, if R and R4 are hydrogen or together are oxygen or sulfur, or R and R together form an additional bond and then R is hydrogen, methyl, phenyl, fi-tolyl, fluorophenyl, chlorophenyl, methoxyphenyl , phenylmethyl or pyridine R5 is hydrogen; H - hydrogen,: methyl, phenyl, p-tolyl, chlorophenyl, sludge R and H together oxygen; ABK - ethylene, propylene or butylene; R is hydrogen, hydroxyl or methyl ftr - phenyl, substituted phenyl, having one or two substituents selected from Echo from the group: chlorine, bromine-flu methyl, methoxy, trifluoromethyl or amino, or Ar - thienyl or pyridium or their salts with pharmaceutically acceptable acids that possess valuable pharmaceutical properties. The interaction of alkyl halides with piperidine derivatives is known. The reaction is carried out in an inert organic solvent medium in the presence of base O. The purpose of the invention is the development, based on a known method. , to obtain new piperidinyl alkylquinazoline derivatives, which can be used in the chemical and pharmaceutical industry, the chemical industry. This goal is achieved by the fact that according to the method of producing piperidinyl alkylquinazoline derivatives of the general formula O) or and: {salts with pharmaceutically acceptable acids, the compound of the general formula, -. t) / B5 B2 where RtH ° and p have the indicated meanings; W is chlorine or bromine, introduced into the reaction with a compound of the general formula where the values R, X, Ar are given above, 5 an inert organic solvent when heated in the presence of a base and the target product is isolated in free form or as a salt with a pharmaceutically acceptable acid. The reaction is carried out in an inert organic solvent medium in the presence of a base with heating. A suitable inert organic solvent can be, for example, a lower alkanol (methanol, ethanol, propanol, butanol, etc.), an aromatic hydrocarbon {benzene, methylbenzene, dimethylbenzene, etc.), simple, 4-dioxane, 1,1-hydroxy - (51 s-propane, etc.), ketone (4-methyl-2-pentanone; S, H-dimethylformamide, nitrobenzene, etc.). To neutralize the acid that is released during the reaction, you can use the appropriate
    the base is a carbonate or acid carbonate of an alkali or alkaline earth metal. As a promoter (a reaction can be used a small amount of the corresponding metal iodide, such as sodium or potassium iodide. To increase the rate of the reaction, elevated temperatures can be used, in a preferred embodiment, the reaction is carried out at the reflux temperature of the reaction mixture.
    Some of the intermediates and the INITIAL substances that are used in the proposed method are known compounds, others can be obtained by known methods.
    The compounds of general formula (I) or their salts with pharmaceutically acceptable acids possess beneficial and pharmacological properties. They are very strong serotonintagonist and as such they can be used to treat many diseases, with KOTOI IX the release of serotinin plays predominantly.
    The activity of the compounds obtained according to the proposed method as serotonintagonists follows from the results obtained during the tests, in which the antagonistic activity of the compounds (I) on the activity of sirotonin is studied.
    And with the ny and e 1. Antagonistic activity on the effect of syrotonin on the rat tail artery.
    The caudal arteries of healthy male rats (210-234 g) are used.
    From each artery receive a spiral band with a length of 5-6 cm and width. 2 mm, which are placed vertically in a 100 ml bath containing Krebs-Henseleit solution enriched with oxygen. Submaximal contractions of the arterial bands are obtained by adding single doses of sirotonin (40. ng / ml) to the baths for
    0 2 min at an interval of 10 min. The amplitude of the contraction is measured before the addition of the preparation and after 5 minutes. after adding the test preparation. After washing, the antagonist is again added three times to establish whether the contraction is restored.
    Table 1 presents the values of 4 EODO. (Ng / ml) for the corresponding two numbers of the compound of formula (1) used in test 1 / {. ED 50 values are the minimum concentrations for HBaefttix drugs
    5 which reduce the amplitude of the reduction by at least 50% of its Normal value), as well as for some compounds of the formula 1) dose (mg / kg body weight)
    0
    with KOTORVS fully OTCyTCTBSnOT
    gastric swelling and lesions of gland-containing areas in 50% (RATs participating in the test (value) are also presented; 5 for some compounds of formula (1) doses (mg / kg of animal)) for which cyanosis is completely absent ears and limbs in 50% of the tested rats (EDjo - value),
    " AND I
    (
    to it)
    sc
    8 I t t

    to
    sh

    sh
    about
    No

     D, d Test 2. Tests related to gastric disease. a) Diseases caused by compound 48/80. Compound 48/80 (a mixture of oligomers of the resulting condensed 4-methoxy-K-methylbenzeneethane amine and formaldehyde) is a potent stimulator of the release of amines acting on the vascular system from endogenous glands, such as, for example, histamine and serotonin. In rats that were injected with compound 48/80, significant changes in blood circulation in various parts of the vascular system were observed: clearly pronounced cyanosis of the ears and limbs less than 5 minutes after the injection of soybean: dineneum; rats died from shock within 30 min. Shock and subsequent death of animals can be avoided if the rats are pretreated with the classic H 1 antagonist. However, the stimulatory effects on the gastric secretions remain unsuppressed, therefore, in rats that were injected with 48/80 and were protected from shock by the antagonist H 1, one can observe all signs of intensive activity of the gastric glands: at full dissection, swollen stomachs with abnormal contents and uneven light red spots were found throughout the mucous membrane, respectively. localized glands. Several well-known serotonin antagonists, such as, for example, metisergid,. cyprogertadine, cyananserin, mianzerin, pipamperon ,. spiperone, pizotifen and metergolin, completely prevent cyanosis of stumps and limbs, as well as damage to areas, containing glands, gastric mucosa and abnormal distension of the stomach. b) Method. Males of Wistar rats weighing 220-250 g are kept starving during the night; rats have free access to water. Test compounds are orally administered as a solution or suspension in an aqueous medium. A control rat and a pure rat are also treated with the test compound. After an hour, 5,4- (diphenylmethyl) -1-piperazinylmethyl-1-methyl-1H. -Benzimidazol-2-methanol with a vine 2.5 mg / kg is injected under the skin of all rats. . After 2 hours after the oral administration of the test compound, an intravenous injection is made to all rats, containing 48/80, which is dissolved in water at a concentration of 25 mg Alp (at a dose of 1 mg / kg) before use; the last compound is not administered to a clean rat. Five minutes after the injection, the intensity of blueing (cyanosis) of the extremities was investigated on the (blue no) scale: (light blue) and ++ (intense blue). Four hours after the intravenous administration of the 48/80 compound, the rats are decapitated and the stomachs are removed, examined for swelling and content (blood, liquid, food) and thoroughly washed. Macroscopic lesions of the mucous membrane are recorded according to the following scale: O, - + -I- +, it corresponds to the full extent of any lesions, and a high indicator corresponds to the appearance of reddish rough scars on most of the surface containing glands. The compounds listed in Table 1 serve only as an example of the useful pharmacological activity of all compounds, which are represented by formula (1). For comparison, compound 34.009 (milenperon) ij was chosen as the closest structural analogue of the present compounds, since it differs only in the replacement of the quinazoline group by the benzimidazoline group. The advantage of the present compounds is not so much the TB of their superior activity, as in the absence of effects on the central nervous system (CNS). A good assessment of the effect on the CNS is provided by the ATN test on rats. While millenperon is extremely active in this test, no activity of the proposed compounds is observed. Since these compounds are not intended for use in disorders of the CNS, but are used in peripheral disorders (cardiovascular, gastrointestinal, etc.), the effect on the CNS is an undesirable side effect under certain circumstances. The compounds of formula (I) completely prevent gastric lesions, which cause excessive serotonin release and, in addition, block serotonin-induced contractions of bronchial tissues and blood vessels, arteries, and veins, therefore, the proposed compounds can be used in the treatment of gastrointestinal ulcers, bronchial spasms, hemorrhoids and other similar diseases caused by various kinds of spasms. G. Preparation of intermediate compounds. Prime, pi. K5h, magnesium supplemented with 2.38 h | 1,2-dibromoethane and a small amount of iodine to initiate the reaction. Then drop by drop; a solution of 28 parts of 4-chloro-1methylpiperidine in 180 parts of tetrahydrofuran is added, and the mixture is heated to. After cooling, a solution of 14 parts of 3-methylbenonitrile is added dropwise in 90 hours; tetrahydrofuran. After the addition is complete, stirring is continued for 1 hour at the temperature of reflux. The reaction mixture is cooled and poured into a solution of 75 parts of ammonium chloride in water. The product is extracted using 2,2-oxy-Suc-propane. The extract is washed with water, dried, filtered and evaporated, resulting in the formation of 35 F1 (3-methylphenyl) - (1-methyl-4-pip ridnyl) -methanone as an oily residue. . According to a similar procedure, using equivalent amounts of appropriately substituted benzonitrides and 4-chloro-1-methylpiperidine, (4-bromophenyl) - (1-methyl-4-piperidinyl) -methanone is obtained as a residue and {2-chlorophenyl) - (1-methyl-4-piperidinyl) -methanone as an oily residue. Example2. K7 part of magnesium is added dropwise solution of 50 parts of 1 gbrom-2-methybenzene in 140 hours, 1,1-hydroxy-8, and C-ethane, while the mixture is kept at the temperature of dehydration. The whole mass is stirred for 15 minutes at this temperature. The Grignard complex is cooled to 10 ° C and a solution of 30 parts of 1- (fenshetil) -p-pyridinecarbenitrile is added dropwise in 70 parts of 1,1-hydroxy 6g / C-ethane. After completion, stirring is added for 4 hours at room temperature. The reaction mixture decomposes e with a solution of 40 parts of ammonium chloride in 400. The organic phase is separated, dried, filtered and evaporated, yielding 31 parts of (2-methylphenyl) -1- (phenylmethyl) -4-piperylnyl-methanone as an oily residue. ) Approximately 35 parts of (3-methylphenyl) - (1-methyl-4-piperidinyl) - (methanone, 1 part of sodium carbonate 225 parts of dimethylbenzene are added dropwise to the stirred mixture for 22 hours at 20 ° C, after The completion of the stirring is continued for 6 hours at reflux temperature. The reaction mixture is evaporated, resulting in 12 parts of ethyl 4- (3-methylbenzoyl) -1-piperidinecarboxylate as an oily residue. Similarly, also starting from the corresponding phenyl - (1-methyl- or 1-phenylmethyl-4-piperidinyl) -methanone these -4- (4-bromo | benzoyl) -1-piperidinecarboxylate as a residue, ethyl 4- (2-chlorobenzoyl) -1-piperidinecarboxylate as an oily residue, and ethyl 2- (2-methylbenzoyl) -1-pygeridinecarboxylate in the form of an oily residue. EXAMPLE 4 A mixture of 12 parts ethyl 4- (3-methylbenzoyl) -1-piperidinecarboxylate and 225 parts hydrobromic acid (48% solution in water) is stirred and boiled in for 3 hours. The reaction mixture is evaporated and the residue crystallizes from 2.-pronanol (7.5 parts) (3-methylphenyl) (4-piperidinyl) -methanone hydrobromide is formed. According to a similar hydrolysis procedure, (4-bromophenyl) - (4-piperidinyl) -methanone bromohydrate, (2-chlorophenyl) - (4-piperidinyl) -methanone bromohydrate (melting point), and (2-methylphenyl) - ( 4-piperidinyl) -methanone hydrobromide. EXAMPLE 5 A mixture of 25 parts of 2-chloropropanenitrile, 61 parts of (4-fluorophenyl) l (4-piperidinyl) -methanone hydrochloride, 63 parts of sodium carbonate and 160 parts of acetonitrile are stirred and bitumen (100 ° C) during the night. The reaction mixture is cooled, water is added and the layers are separated. The aqueous phase is extracted with 4-methyl-2-pentanone. The combined organic phases are dried, filtered and evaporated. The residue is purified by chromatography on silica gel using a mixture of three chloromethane, hexane and methanol (50: 49: 1, volumes) as eluent. Pure fractions of coz are collected and the eluent is evaporated. The solid residue is crystallized from 2,2-hydroxy-Bis-propane. The product is isolated by filtration and dried, resulting in .17 parts of 4- (4-fluorobenzoyl) -o-methyl-1-piperidineacetonitrile, melting point 12b, 7c. .. A mixture of 32 parts of 4- (4-fluorobenzoyl) -hymethyl-1-piperidineacetonitrile and 400 parts of methanol, saturated with ammonia, is subjected to hydrogenation in a Parr apparatus at 25 ° C with 5 parts of Raine's nickel catalyst. After the calculated amount of hydrogen is added, the catalyst is separated by filtration and the filter is evaporated. The residue is placed in methylbenzene and the latter is evaporated again. The residue is dissolved in 2,2oxy-5ac-propane, and the solution is filtered until it becomes clear. The solvent is evaporated off, with the result that 32 parts (100%) of l- (2-amino-l-methylethyl) -4-piperidinylJ (4-fluorophenyl) methanone are obtained in the form of oily o (; p 6. A mixture of 4.5 parts of 1-chloro-3,3-diethoxypropane, 12, 15 (4-fluorophenyl) - (4-piperidinyl) -methanone hydrochloride, 10.6 parts of sodium carbonate and 120 hours. 4- methyl 2-pentanone is stirred and boiled overnight. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered off by evaporation. The residue is purified on a chromatography column over silica gel using a mixture richloromethane and methanol (95: 5, volumes) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of methyl benzene and 2,2-hydroxy-5-propane, resulting in 9 h. (53.%) l - (3,3-diethoxy-propyl) 4-piperidinyl J. (4-fluorophenyl) methane. P and me. A mixture of 50 parts 2-and 3.5-dichlorobenzoic acid and 240 hours of ethanol is saturated with gaseous hydrogen chloride. All permixed for 10 h. The reaction mixture is allowed to cool, the solvent is evaporated. Water and sodium hydroxide are added to the solid residue. The precipitated product is filtered off and dried, resulting in 25 hours of ethyl 2-amino-3,5-dichlorobenzoate B and a stirred mixture of 25 parts of ethyl 2-amino-3,5-dichlorobenzoate and 180 hours. dimethylbenzene is added dropwise to 30 parts of propionic acid chloride. After the addition is complete, stirring is continued for 8 hours at reflux temperature. The reaction mixture is evaporated and the residue is recrystallized from petroleum ether. The product is filtered and dried, resulting in 30 parts of ethyl-3,5-dichloro-2- (ethoxycarbonyl) amino benzoate. EXAMPLE 8: A mixture of 40 parts of ethyl chloro-2- (ethoxycarbonyl) amino-benzoate and 10 hours, 2-amino-ethanol is stirred and heated to 160–1010 ° C, and ethanol is distilled off. After stirring for about 30 minutes, the mixture is cooled and 2-propanol is added. The solid product is isolated by filtration and dried, whereby it forms, with 23 parts (64%), 7-chloro-3- (2-hydroxyethyl) -2,4- (1H, 3N) -quinazolinedione. In accordance with the analogous cyclization process, using equivalent amounts of appropriately substituted 2- (ethoxycarbonyl) aMHHoJ benzoates and 2-aminoethanol, 3- (2-hydroxyethyl) -1-methyl-2,4- (1H, 3H ) -hina- "lozindione; 6-chloro-3g {2-hydroxyethyl) 2, 4- (1H, 3N) -quinazolinedione; 6,8-dichloro-3-T2-oxyethyl) -2,4- (1H, 3N) nazolindione and 3- (2-hydroxyethyl) -6-methyl 2,4- (1H, 3N) -quinazolinedione. PRI me R 9. A mixture of 14 h. 6-chloro 3,4-dihydro-3- (2-hydroxyethyl) -4-phenyl2- (1H) -quinazolinedione, 5-h. sodium acetate and 200 h-methanol are subjected to hydrogenation at normal pressure and at room temperature; a round with 2 parts of palladium deposited on charcoal (10%) as a catalyst. After the release of the calculated amount of hydrogen, the catalyst is determined by filtration, and the filtrate is evaporated. The residue is stirred at 2.2 hydroxy-C-propane. The solid product is recovered by filtration and stirred in 200 parts of water. Then, it collapses and collapses, resulting in 1}, 2 parts (91%) of 3,4-dihydro-3- (2-hydroxyethyl) -4-phenyl-2-Tsn) quinazolinone, melting point 141 ° C. . Example 10. A mixture of 23 parts of 7-hl.or-3- (2-hydroxyethyl) -2.4- (1H, 3N), quinazolinedione, 32 hours of thionyl chloride and X50 parts of trichloromethane is stirred and boiled for .4 hours The reaction mixture is cooled. The precipitated product was filtered, washed with trichloromethane and petroleum ether and dried, yielding 22 hours (88%) of 7-chloro-3- (2-chloroethyl), 4- (1H, 3N) -Hinazolindio. . Similarly, 3- (2-chloroethyl) -1-methyl-2,4- (1H, 3N) quinazolinedione; 3- (2-chloroethyl) -3,4 dihydro-4-phenyl-2- (1H) -quinazolinone with a melting point of 179.5 ° C; b-chloro 3- (2-chloroethyl) -3,4-dihydro-4-phenyl 2- (1H) -quinazolinone; 6-chloro-3- (2chloroethnl) -2,4- (1H, 3N) -quinazolinedione; 6,8-dichloro-3- (2-chloroethyl) -2,4- (1H, 3N) -quinazolinedione (melting point 207 ° C) and 3- (2-chloroethyl) -6-methyl-2, 4- ( 1H, 3N) -quinazolindione. Example I. A mixture of 13.6 hours 2 aminobenzamide; 31.5 parts of 1-bromo-Zchloropropane, 21 parts of sodium carbonate and 200 parts of ethanol are stirred and boiled for two days. The reaction mixture is filtered and the filtrate is evaporated. The oily residue is stirred in methylbenzene. The mixture is filtered until it is clear and the solvent is evaporated. The oily residue is purified on a silica gel chromatography column using a mixture of trichloromethane and ethanol (95: 5, volumes) as eluent. The pure fractions are combined and the eluent is evaporated. The solid residue is transferred to 2,2-hydroxy-5ac-propane. The product is filtered and dried, resulting in 7 parts (33%) of 2- | (3-chloropropyl) amino benzamide, melting point 4: 100 ° C.
    EXAMPLE 12 A mixture of 10 parts of (3-chloropropyl) amino-benzamide, 15 parts of 2-propanone, 1 part of 4-methylbenzenesulfonic acid, and 40 parts of ethanol is stirred and boiled overnight. The reaction mixture was triturated and the oily residue was stirred in 2,2-hydroxy-Ct-propane. The product is filtered and dried, resulting in 10 parts of 1- (3-chloropropyl) -2,3-dihydro-2,2-dimethyl-H (1H-quinazolinone.
    Example 13. In a solution of aeNMft and a cooled solution (ice on a bath of 27.5 parts of 2-bromoethanamine bromhydrate in 200 hours, a solution of 28.9 hours of 4-methocry-2-nitrobenzoyl chloride is added to 63 parts of benzene at 5-100 s With vigorous stirring, a solution of 10.8 parts of sodium hydroxide in 250 parts of water is added dropwise at 5-10 ° C. After the addition is complete, stirring continues at the same temperature for 2 hours. and the oily residue is stirred in 2-propanol. The product is isolated by filtration and dried, resulting in 27.5 hours (68%) B - (2-bromoethyl) 4-methoxy-2-nitrobenzamide with a melting point of T. SZ, 8 S. ...)
    Example 14. In the first mixed and cooled mixture of 25 parts of 2-amino ethanol and 135 parts of methylbenol, a solution of 29 parts of 4-fluoro-2-nitrobenzoyl chloride in methyl benzene is added dropwise. After completion of the addition, stirring is continued for 30 minutes at room temperature. The precipitated product is filtered off, placed
    into the water and. extracted with
    4-methyl-2-pentanoia. Extract Su-. 1Sh1ts, filtered and evaporated, resulting in 28 hours (64%) of 4-fluoro-L- (2-hydroxyethyl) -2-nitrobenzamide as a residue,
    A mixture of 28h. 4-fluoro-N- (2-hydroxy-. Ethyl) -2-nitrobenzamide, 40 parts of thionyl chloride and 150 parts of trichloromethane are stirred and refluxed for 2 hours. After cooling, the precipitated product is isolated by filtration and dried, resulting in 24.5 hours (83%) of N- (2-chloroethyl-4-fluoro-2-nitrobenzamide.
    Example 15. A mixture of 14.4 parts of N- (3-bromopropyl) -2-nitrobenzamide, 12.2 parts of (4-fluorophenyl) - (4-piperidinyl) -methanone hydrochloride, 16 parts of sodium carbonate and 200 parts of 4-methyl2 The pentanone is stirred and boiled for 3 hours using a water separator. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The oily residue is purified by chromatography on silica gel using a mixture of trichloromethane and methanol (90:10, volumes) as eluent. The pure fractions are collected and the eluent is evaporated, resulting in 18 parts (87%) (4-fluorobenzoyl) -1-piperidinyl saw-2 -2-Nitrobenzamide as an oily residue.
    Similarly, using equivalent amounts of (4-fluorophenyl) (4piperidinyl) methanone hydrochloride and suitably substituted: 2-nitrobenzamide can be obtained. N- (2- (4-fluorobenzoyl) -1-piperidine ethyl) g2-nitrobenzamip melting point 4-fluoro-N- 21 4- (4-fluorobenzoyl) -G-piperidinium ethyl -2-nitrobenzamide, melting point 163.50 s and (4-fluorobenzoyl) -1-piperidinyl ethyl -4-methoxy2-nitrobenzamide, melting point ± 134 ° C.
    PRI me R 16. For 1 h; a solution of 2 hours, thiophene in 40 parts of ethanol is added 1.8 parts of .4- (4-fluorobenzoyl) -1-piperidinyl propyl -2-nitrobeneamide and 200 parts of methanol. The mixture is subjected to hydrogenation at normal pressure and at room temperature with 2 parts of platinum, / deposited on a wood charcoal (5%) - as a catalyst. After separation of the calculated amount of hydrogen, the catalyst is separated by filtration, and the filtrate is evaporated. The oily residue is purified by chromatography on silica gel &amp; using a mixture of trichloromethane and methanol (90 .: 10, volumes) as elvdent. The pure fractions are collected and the eluent is evaporated. The oily residue is crystallized from 2-propanol. The product is isolated by filtration and dried, resulting in 7.5, h (45%) of 2-amino-N- (3-4- (4-fluorobenzoyl) -1-piperidinylylpropylbenzamide, melting point 113 ,.
    The mother liquor is evaporated, giving a second fraction of 6 parts (36%) of 2-aMHHO-N- | 3- (14- (4-fluorobenzoyl) -1-piperidinyl propylZbenzamide as an oily residue.
    According to the same procedure, 2-amino-H-2 4- {4-fluoro-benzoyl) -l-pyheridinyl J ethyl 3 benamide with a melting point of 142, 2-aMHrfo. 4-0Top-N-2-l4 (4- fluorobenzoyl) -1-piperidinyl ethyl benamide with a melting point of 124.1 ° C and 2-amino-M- 2-4- (4-fluorobenzoyl) -1-piperidinyl ethylT-4-methoxybenzamide with a melting point of 168 ,.
    Example 17. A mixture of 7 ,, 2-7 4-hLor-1-oxobu5Gyl) amino amide 7.3 parts of (4-fluorophenyl) - (4-pyperidinyl) methanone hydrochloride, 10.1 parts Y, K- diethylethanamine and 120 hours of acetonitrile are stirred and boiled for 24 hours. The reaction mixture is evaporated and water is added to the residue obtained. The oily product is extracted with trichloromethane. The extract is dried, filtered and evaporated, resulting in 10 parts (81%) (amine-box), phenyl 2 -4- (4-fluorobenzoyl) -1-piperidine butanamide as a residue. . PRI me R 18.
    A. In a stirred mixture of 250 parts of pyridine and 39 parts of b-fluoro-1H-indole, 42 parts of benzoyl (chloride at 22e) are added dropwise. After the addition is complete, stirring is continued for 2 hours at room temperature. The reaction mixture diluted with water and a 2N hydrochloric acid solution is added. The product is extracted twice with: p 350 part 1, l-hydroxy-51 C-ethane. Among the extracts, dried, filtered and evaporated. The residue is purified by chromatographic silica gel columns using a mixture of trichloromethane and methane ol (95: 5, volumes)
    as eluent. The pure fractions are collected and the eluent is evaporated, resulting in 95 parts of 1-benzoyl-4- (6-fluoro-1H-inol-3-yl) 1, 4-dihydropyridine as an oily residue.
    B. A mixture of 95 parts of 1-benzoyl-4- (6fluoro-1H-indol-3-yl) -1.4 dihydropyridine and 540 hours K, N-dimethylacetamide is subjected to hydrogenation in a Parr unit with 5 parts of palladium, at lifeceHHoro on charcoal (10%)
    as a catalyst. After separation of the calculated amount of hydrogen, the catalyst is filtered by a filtration of Hiflo, and the filtrate is drained into water with stirring. The oil is suspended in a solid. The upper aqueous phase is drained and the residual oil is washed with water. The oily product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is washed successively.
    a mixture of petroleum ether and 2,2-oxy-6c-propane, 2 n. with hydrochloric acid and water, and then dissolved in trichloromethane. The latter is washed with 1N. sodium hydroxide solution and water, and then dried, filtered and evaporated. The residue is heated in a small amount of M, N-dimethylacetamide at 80 ° C and then kept for two days. The solid product is isolated by filtration, washed with a mixture of water and ethanol, and then dried under vacuum at 80, resulting in 25 parts of 1-benzoyl-4- (6-fluoro-1H-indole-3-yl) piperidine with melting point 220C
    C. A mixture of 24 parts of 1-benzoyl-4- (6fluoro-1H-indol-3-yl) -piperidine, 70 parts of potassium hydroxide, 495 parts
    1,2-ethanediol and 80 parts of water are stirred and refluxed for 6 hours. The reaction mixture is cooled and 500 hours is added to it with stirring; water. The precipitated product is isolated by filtration, washed with water and petroleum ether, and then dried under vacuum at 80 ° C, resulting in 16 parts of 6-fluoro-3- (4-piperidinyl) -1H-indole with a melt point -, laziness 224 ° C.
    D. A mixture of 7.5 parts of 3- (2-chloroethyl) -, 2,4- (1H, 3N) -quinazolinedione; 6.8 hours
    I6-fluoro-3- (4-piperidinyl) -1H-indole; 10 parts sodium carbonate; 0.1 parts potassium iodide and 240 parts 4-methyl-2-pentanone is stirred and refluxed in those
    Teaching night. Water is added and the layers are separated. The aqueous phase is removed. The organic phase is dried, filtered and evaporated. The solid residue is boiled in 2-propanol. The product is isolated by filtration and dried, resulting in a first fractal of 4 parts of 3- (2-C4- (6fluoro-1H-indole-3-yl) -1-yiperidinyl} etyl | -2,4- (1H , HH) - quinazolindione. From the aqueous phase, the solid product is isolated by filtration and boiled in 2-propanol. The product is isolated by filtration and dried, resulting in a second fraction of 3 parts 3- {2-4- {b-fluorine -1H-indol-3-yl) 1-piperidinyl, 4- (1H., 3N) quinazolinedione: with a melting point of 300.6 ° C.
    E. Ozonized oxygen is bubbled through a stirred mixture of 6 parts 3 - ((6-fluoro-1H-indole-3-yl) 1-piperidinyl, 4- (1H, 3N) quinazolinedione and 100 parts of acetic acid until the solution will not become clear. Then 200 parts of crushed ice and 100 hours of water are added and the mixture is alkalinized with sodium hydroxide solution. The product is extracted with yomoshi
    trichloromethane and a small amount of ethanol. The extract is dried, filtered and evaporated, resulting in 2.3 parts of N-f2-tl2- (1,4-DIHIDRO-2, 4-dioxy-3- (2H) quinazolinyl) -ethyl -4-piperidinylcarbonyl -5 -fluorophenyl formamide as a residue.
    Take p19. A mixture of 13.5 parts of 1- (2-aminophenyl) ethanone; 12.1 parts of N, N-diethylethanes A and 7.2 parts of benzene is stirred and cooled to 5-10 ° C. Then a solution of 18.2 parts of trichloroacetyl chloride in 36 parts of benzene is added dropwise while cooling the mixture to 1-10 ° C. After the addition is complete, stirring at this temperature is continued for 30 minutes. The reaction mixture is filtered, the filtrate in the form of a cake is washed with benzene, and the filtrate is evaporated. The solid residue is boiled in methanol. After cooling, the product is filtered off and dried, c. as a result, with 19 parts (68%) of N- (2-acetylphenyl) 2, 2,2-trichloroacetamide with a melting point of 112.7 ° C.
    A mixture of 60 parts of N-G2-acetylphenyl) 2, 2, 2-trichloroacetamide, 14 hours, 2-aminoethanol, and 200 parts of ethanol peremog. First, it is sewed for 5.50 hours at 1 at reflux temperature, and then overnight at room temperature. The precipitate formed is filtered. The product is washed with 2,2-oxy-5 and C-propane and dried under vacuum, resulting in 40 parts (59%) of 2,2,2-trichloro-N- (2 I (2-hydroxyethyl) imino ethyl phenylacetamide) with a dot melting point 182 ° C.
    To 135 parts of N, N-dimethylformamide is added first 16.2 parts of 2,2,2-trichloro-2-2 (1-hydroxyethyl) imino ethyl phenylacetamide and then in small portions 5.7 hours. sodium borohydride f last addition is carried out with stirring (the reaction is exothermic). After the addition is complete, stirring at room temperature continues for a while. The reaction mixture is poured into water and the product is extracted with trichlorome. tang. The extract is dried, filtered and evaporated. The residue is purified by chromatography on silica gel using a mixture of trichloromethane and methanol (V: 10, volumes) as eluent. The pure fractions are collected and the eluent is evaporated, resulting in 8.5 parts of 3,4-dihydro-3- (2oxyethyl) -4-methyl-2- (1H) -quinazodino
    in the form of a solid residue.
    A mixture of 8 parts of thionyl chloride and 90 parts of trichloromethane is stirred and boiled for 1.5 hours. The reaction mixture is evaporated. The residue is purified by chromatography on silica gel using a mixture of trichloromethane and methanol (95: 5, volumes) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is stirred in 2, 2-oxy-8c-propane. The product is filtered off and dried, resulting in 6.6 parts of 3- (2-chloroethyl) -3,4-dihydro-4-methyl-2- (1H) -quinazolinone with a melting point of 126.4 ° C. .
    Example 20 To a stirred mixture of 10 parts of methyl 2- (2-hydroxy-ethyl) -amino benzate and 100 parts of acetic acid is added dropwise a solution of 4.5 parts of potassium cyanate in 25 parts of water. After the addition is complete, stirring at room temperature continues overnight. The reaction mixture is evaporated. The solid residue is stirred with water. The product is isolated by filtration, washed with water and ethanol, and then dried, resulting in S parts (48%) of 1- (2-hydroxyethyl) -2,4- (1H, 3N) -quinazolindione with a melting point of 273 ,.
    A mixture of 3.6 parts of 1- (2-oxyethyl) 2, 4- (lH, 3H) -xinazolindione and 40 hours, thionyl chloride is stirred at reflux overnight. The reaction mixture is allowed to cool to room temperature. The precipitated product is isolated by filtration, washed with 2,2-hydroxy-bis-propane and dried, resulting in 3.4 parts (86%) of 1- (2-chloroethyl) -2.4 (1H, 3N) quinazolindione with a melting point of 215 ,.
    Similarly, using the equivalent qualities of the corresponding starting materials, it is also possible to obtain 1- (3-hydroxypropyl) -2,4- (1H, 3N) quinazolinedione with a melting point. 240C "1- (3-chloropropyl) -2,4- (1H, 3N quinazolinedione with a melting point of 187 ,.
    Example 21. To a stirred mixture of 18 parts of 2-phenyl-4- (3N) -quinazo in Linone and 225 parts of N, N-dimethylformamide, is added in small portions at room temperature to 3.2 parts of 60% sodium hydroxide dispersion (exothermic reaction: the temperature rises to). After the addition is complete, the mixture is stirred for 10 minutes and then. 12.4 parts of 2-br ethanol (mild exotherm) is added dropwise. After the addition is complete, stirring is continued. First for 1 hour at room temperature, then for 2 hours at, then overnight again at room temperature. The reaction mixture is cooled, poured into water and the solid product is recovered. It is washed with water and 2,2-hydroxy-Bis-propane and dried under vacuum, with, as a result, 15 parts of 3- (2oxyethyl) -2-phenyl-4- (3N) -quinazlone are obtained. To the stirred mixture 15 parts of 3- (2oxyethyl) -2-phenyl-4- (3N) quinazolinone and 375 parts of trichloromethane are added dropwise 24 parts of thionyl chloride at room temperature. After the addition is complete, stirring is continued for 2 hours at that; Perratura reflux. The reaction mixture is evaporated. Water is added to the residue and the mixture is neutralized with a solution of sodium hydrogencarbonate. The product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue crystallizes from a mixture of 2,2-hydroxy-5-propane and petroleum ether. The product is isolated by filtration and dried, resulting in 11.6 parts of 3- (2-chloroethyl) -2-phenyl4- (3H) -quinazolinone. A mixture of 5.5 parts of 3- (2-chloroethyl) -2-phenyl-4- (3N) -quinazolinone; 3.2 parts of 3- (4-piperidinyl) -1H-indoles 7h. sodium carbonate; 0.1 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone are stirred and boiled for 22 hours. The reaction mixture is filtered over. Xiflo and the filtrate is evaporated. The residue is purified by chromatography on silica gel using a mixture of trichloromethane and methanol (92: 8, volumes) as eluent. The pure fractions are collected and the eluent is evaporated. The residue crystallizes from a mixture of ethanol and 1,1-hydroxy &amp; UC-3Taifa, resulting in 5 hours. (1H-indol-3-yl) 1-piperidinyl ethyl 2-phenyl-4- (3N) quinazolinone with a melting point of 191.3 ° C. Example 22: 50 parts of 2-thiopheneacetonitrile are added successively to a stirred mixture of 80 parts of sodium methoxide and 160 hours of methanol, then 66 parts of 1- (phenylmethyl) -4-piperidinone are added dropwise. After the addition is complete, the mixture is heated to reflux and stirred at that temperature for 1 hour. The reaction mixture is cooled and evaporated. The residue is subjected to distillation in a molecular distillation unit, resulting in about 70 parts of vol.-1- (phenylmethyl) -4-piperid1L1idene-2-thiopheneacetonitrile as a residue. A mixture of 70 parts of et - 1- (phenylmutil) 4-piperidinylidene3 -2-thiopheneacetonitrile in 800 parts of methanol. It is hydrogenated under normal pressure and at room temperature with 10 parts of palladium on charcoal (10%) as a catalyst. After separation of the calculated amount of hydrogen, the catalyst is separated by filtration and the filtrate is evaporated, resulting in 70 parts of 1- (phenylmethyl) -b, - (2-benzyl) 4-piperidineacetonitrile as a residue. Into a stirred mixture, 29.6 parts of 1- (phenylmethyl) -ob- (2-thienyl) -4-piperidineacetonitrile per 100 parts. Dimethyl sulfooxide and dimethyl are added in small portions 4 parts to 60% sodium hydride dispersion. After the addition is complete, stirring is continued overnight. The reaction mixture is poured into water. The precipitated product is recovered and extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue crystallizes from 2,2-hydroxy- &amp; 6C-propane, resulting in 10 parts (35%) of t- (phenylmethylV 4-piperidinyl - (2-thienyl) -methanone, melting point 1.0 0.5 ° C. In a stirred mixture of 15 parts of LI- (phenylmethyl) -4-piperidyl2- (2-thienyl) methanone, in 120 parts of benzene, 8 parts of carbonchloride are added dropwise. After the addition is complete, the mixture is heated to reflux temperature and stirred for 6 hours at this temperature. The reaction mixture is cooled, filtered and evaporated, resulting in 13 hours of ethyl 4- (2-thienylcarbonyl) -1-piperi dinocarboxylate as a residue. A mixture of 20 parts of ethyl 4- (2-thienylcarbonyl) -1-piperidinecarboxylate and 120 parts (48%) of a solution of hydrobromic acid in water is stirred and refluxed for 2 hours. The reaction mixture is cooled and the precipitated product is filtered off, washed with 2-propanol and dried, resulting in 17 4 (85%) (4-piperidinyl) (2-thienyl) -methanone hydrobromide. I. Preparation of the final compounds. Example 23. A mixture of 4.5 parts of 3- (2-chloroethyl) -2,4- (1H, 3N) -quinazolinedione; 4.9 parts (4-fluorophenyl) - (4-piperidinyl) -methanone hydrochloride, 8h. sodium carbonate and 80 parts of 4-methyl-2 pentanone are stirred and refluxed overnight. The reaction mixture is cooled and water is added. The precipitated product is isolated by filtration and crystallizes from 4-methyl-2-pentanone, resulting in 2.2 hours (27%) after drying (4-fluorobenzoyl 1-piperidinyl 2 ethyl 3-2,4- (1H, 3H) quinazolindir with a melting point of 23,221-235 C. Yield 27%. According to the same procedure, using equivalent amounts of 10 410 3424 of the corresponding starting materials, the compounds shown in Table 2 can also be obtained. Table 2
    Example 24. A mixture of 6 hours 3- (2- (4 piper} chinyl) -methanone and 48 hours
    chloroethyl) -1-phenyl-2 | 4 - (1H, 3N) -Hin. ethane is stirred and boiled,
    Aeolindione; 8.3 parts (4 fluorophenyl) at a reflux temperature of 5 h, H-dimethylformamide until all solid material has gone into solution. Stirring is continued at reflux overnight. The reaction mixture is volatile. The residue was purified twice using silica gel column chromatography, using first a mixture of trichloromethane and methanol (95: 5 o.volumes), and then a mixture of trichloromethane and methanol (96: 2, volumes) as eluents. The pure fractions are collected and the eluent is evaporated. The residue crystallizes from 2-propanol, resulting in 2.2 parts (23%) of (4-fluorobenzoyl) -1-piperidinyl ethyl | -1-phenyl-2, 4- () quinazolinedione with a melting point of 1bb, 1s. Yield 23%. .
    Example 25. A mixture of 5.8 parts of b-chloro-3- (2-chloroethyl) -3,4-hydro-4phenyl-2- (1H) -quinazolinone; 7.4 parts of (4-fluorophenyl) - (4-piperidinyl) methanone and 56 parts of ethanol is stirred and boiled for. The reaction mixture is evaporated. The residue is purified on a chromytographic column on silica gel using a mixture of trichloromethane and methanol (96: 5, volumes) as eluent. The pure fractions are collected together and the eluent is evaporated. The oily residue solidifies upon grinding in 2.2 o.xy-1 &lt; -C-propane. The product is isolated by filtration and dried, resulting in 5h (57%) 6-chloro-3- 2- 4- (4g-fluorobenzoyl) -1-piperidinylJ, 4-dihydro-4-phenyl-2- (1H) - melting point quinazolinone. Yield 57%.
    Similarly, 4-54-fluorobenzoyl) -1-piperidyl NILE ethyl-3,4-dihydro-4-feunyl-27 GnO-quinazolinone with a melting point of 173, and (4-fluorobenzoyl) -1-piperidinyl ethyl 3, 4 -dihydro-4-methyl-2- (1H) -quinazolinone with a melt point, sloth 172s. The output, respectively (51 and 35%.
    Example 26; A mixture of 3.6 hours, 1- (3-chloropropyl) -2,4- (1H, 3N) -quinazolinedione; 3.02 parts (4-fluorophenide) (4-piperidinyl) methane hydrochloride, 3.7 parts sodium carbonate; 0.1 hour {potassium odide and 120 parts of 4-methyl-2-pentanone is stirred and boiled overnight using a water separator. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and concentrated to a small volume. After the concentrate has cooled, the precipitated product is isolated by filtration and crystallizes from 2-propanol, resulting in 1.3 hours (ljB, 5%) 1- {3- 4- (4-fluorobenzosh) -1-piperidinyl propyl -2 , 4- (1Н, ЗН) -хинзолиндиона, melting point 19.2,
    In accordance with the same procedure and starting from 1- (2-chloroethyl) 2, 4- (1H, 3N) -quinazolinedione. (4-Fluorobenzoyl) -1-piperidinyl ethyl -2,4, 4- (1H, ZN) -quinazoline was also obtained with a melting point of 21.9.
    Example 27. A mixture of 5.6 parts of 1- (3-chloropropyl) -2, 3-dihydro-2,2-dimethyl-4- (1H) -quinazolinone; 4.9 parts of (4-fluorophenyl) - (4-piperidinyl) methane hydrochloride; 10 parts sodium carbonate; 0.1 parts of potassium iodide and 200 hours of 4-methyl-2-pentanone are stirred overnight using a water separator. The reaction mixture is cooled, water is added and the layers are separated. The 4-methyl-2-propanone phase is dried, filtered and evaporated. The solid residue is purified by silica gel column chromatography using a mixture of trichloromethane and methanol (95: 5, volumes) as eluent. The pure fractions are collected and the eluent is evaporated. The solid residue is stirred in 2,2-hydroxy-8x4C-propane. The product is filtered and dried, resulting in 6.6 parts (78%) of 1- {3 (4- (4-fluorobenzoyl) -1-piperidinyl) propyl -2, 3-dihydro-2,2-dimethyl 4 (1H) -quinazolinone with melting point 185 ,.
    At m 28; Mixture of 5.5 parts of 3- (2-chloroethyl) -2-phenyl-4- (3N) -quinazolinone; 4 parts (4-fluorophenyl) - (4piperidinyl) -methanone hydrochloride; 7 parts sodium carbonate; 0.1 parts of potassium iodide and 200 parts of 4-methyl-2-pentane are stirred and boiled for 24 hours using a water separator. The reaction mixture is filtered hot. The filter is evaporated. The residue is purified by silica gel chromatography using a mixture of trichloromethane and methanol (95: 5, volumes) as eluent. The pure fractions are collected and the eluent is evaporated. The residue crystallizes from an ethano mixture. la and 1,1-oxy-5 | C-ethane. The product is filtered and dried, resulting in 5 hours. D (69%) 3- 2- .4- (4-fluorobenzoyl) -1-pi; peridinyl-2ethyl -2-phenyl-4- (3N) -quinazolinone m.p. 143.8 Yield 69%.
    Example 29. A mixture of 5h. 3- (2-chloroethyl) -2,4- (1H, 3N) -quinazolyidione, b hp c6 - (4-fluorophenyl) -4 piperidine methanol acetate (ester) hydrochloride, 8 parts sodium carbonate and 280 parts 4-methyl The -2-pentanone is stirred and baked overnight. Reaction mixture
    filtered and the filtrate evaporated. The oily residue is purified on a silica gel chromatography column using a mixture of trichloromethane and methanol (95: 5, volumes) as eluent. The pure fractions are collected and the eluent is evaporated. The residue crystallizes with 4-methyl-2-pentanone, yielding 2.3. including (1,4-digilro-2,4-dioxo-3- (2H) quinazolinyl etyl-L- (4-fluorophenyl) -4 piperidine methanol acetate (ester1 with a melting point of 185 ,.
    Example 30. In accordance with the procedure described in Example 25, using equivalent amounts of the corresponding starting materials, 3,4-dihydro-ZG2-4- (4-fluorobenzoyl) -1-piperidinyl ethyl-2 lH) -quinazoline with melting point 182 ,,
    Example 31. In accordance with the procedure described in Example 23, using equivalent amounts of the corresponding starting materials, 3-f2-4- (3-pyridinylcarb6nyl) -1-piperidinyl ethyl 2, 4- (1H, 3H) quinzblindione can also be obtained.
     At measure 32, In accordance with the procedure described in Example 18, using equivalent amounts of the corresponding starting materials, it is possible5 to obtain 3-2-t4- (lHindol-3-yl) -1-piperidinyl ethyl 2, 4- (1H, 3N ) - quinazolinedione with a melting point of 291.2 ° C.
    . Example 33. Mixture 5.8 parts of compound A; 3.6 parts of compound B 8 parts of compound C and 120 parts of compound-. Neither D is stirred and refluxed overnight using a water separator. The reaction mixture is cooled and water is added. The precipitate formed is filtered off and crystallized from 96 parts of isopropanol to give 3 parts of compound -R 51449, mp. 169 ,.
    A: (R 51448): 3- (2-Bromoethyl) -2 (3-Chlorophenyl) -4- (3N) -Hiazolinone; B: (4-fluorophenyl) - (4-piperidinyl) methanone hydrochloride;
    C: sodium carbonate; D: 4-methyl-2-pentanone;
    R 51449: 2- (3-chlorophenyl) (4-fluorobenzoyl) -PiperidinylJ ethyl} -4- (3N) -quinazolinone.
    The following compounds were prepared in a similar manner: 46,538 3-G2 4- (4-fluorobenzoyl) -1-piperidinyl Jethyl -2, 3-dihydro-4- (1H) -quinazolines m.p. 203.4 ° C, yield 29%.
    46,539 .4- (4-Fluorobenzoyl) 1-piperidinyl ethyl-4- (3N) -quinazolinone, m.p. 139 ,, yield 26%. 46.63b 3- (4-fluoro-benzoyl) -1-piperidinyl) propyl-4- (3N) -quinazolinone (E) -2-butendnoate (1: 1), m.p. 201 ,, yield 23%. 46.694 3- 3-C4- (4-fluorobenzoyl) -1-piperidinyl propyl -2, 3-dihydro-2thioxo-4- (1H) -quinazolinone, m.p. 200.2 ° C, yield 11%.
    46.700 (4-fluorobenzoyl) 1-piperidinyl ethyl -2, 3-dihydro-2thioxo-4- (1H) -quinazolinone, m.p. 225.5 ° C, yield 13%.
    46.780 .4- (4-fluorobenzoyl) -1-piperidinyl ethyl -2-methyl4- (3N) -quinazolinone, mp. 164, .9 ° C, yield 22%.
    46.808 (2-amine-4fluorobenzoyl) -1-piperidinyl ethyl 2, 4- (1H, 3N) -quinazolinedione, m.p. 269.5 ° C, yield 17%.
    47.280 7-fluoro-3-1 2-4- (4fluorobenzoyl) -1-piperidinyl ethyl 2, 4- (1N.ZH) -quinazolinedione, m.p. , yield 20%.
    47,288 (4-fluorobenzoyl) 1-piperidinyl ethyl-7-methoxy-2, 4 (1H, 3N) quinazolinedione, m.p. 245, yield 19%.
    48.909 (4-Fluorobenzoyl) 1-piperidinyl, 4-dihydro-2 (1H) -quinazolinin, mp. 182.1 ° C, yield 16%.
       (4-fluorophenyl) (1,4-dihydro 2-thioxo 3 (2H) -quinazolinyl) ethyl-4-piperidinyl methanone, m.p. 169.7 ° C, yield 21%.
    49.722 4- (4-chlorophenyl) (4-fluorobenzoyl) -1-piperidinyl, 4-DIHIDRO-2- (1H) -quinazolinone, m.p. 19lc, yield 18%.
    46.704 (4-fluorobenzoyl) 1-piperidinyl propyl) -2,3-dihydro4- (1H) -quinazolinone (E) -2-butandioate (1: 1), m.p. 188.2 ° C, yield 27%.
    49.885 3- (2-L4- (4-fluorobenzoyl) l-piperidinyl i-ethyl-3, 4-dihydro, 4- (4-methylphenyl) -2- (1H) -quinazolinone, mp. 159, lG , yield 17%.
    49.976 ((4-chlorophenyl) 1,4-dihydro-2-thioxo-3- (2H) -quinazolinyl ethyl-4-piperidinyl) (4-fluorophenyl j-methanone monohydrochloride, mp. 172.2 ° C, yield 25 %
    50.274 (4-fluorobenzoyl) 4-methyl-1-piperidinyl-methyl 5-2.4 (1H, 3H) -quinazolinedione m.p. 189, yield 43%.
    50.944 3- 2- | 14- (3,4-dimetoibenzoyl) -1-piperidinylZ-ethyl -2,4 (1H, 3N) -quinazolinedione, m.p. 217.8 With an exit of 15%.
    51.378 3 - ((4-fluorobenzoyl) 1-piperidinyl ethyl -2- (4-fluorophenyl) 4- (3N) -quinazolinone, mp 131, yield 41% ..
    51.478 "(2-Fluorobenzoyl) 1-piperidinylZethyl -2- (4-methylphenyl) 4- (ZN) -quinazolinone, mp. 143.5С, yield 36%. 51.484 (4-fluorobenzoyl 1-piperidinyl ethyl -2, 3-dihydro-2 (3-pyridinyl) -4- (1H) -quinazolinone, mp 126.3 ° C, 27% yield. 51.716 (4-fluorobenzoyl ) 1-pip.eridinyl, 3-dihydro-2 (4-methoxyphenyl) -4- (1H) -quinazolinone, mp 154.8 ° C, yield 23%. 51.S80 3- (4-fluorobenzoyl) 1 piperidinyl | ethyl -2- {4-methoxyfencl) -4- (3N) -quinazolinone, m.p. 151.4 ° C, yield 36%. 52.047 3- {2- 4- (2-fluoro-4-methoxybenzoyl) -1-piperidinyl ethyl 2, 4- (1H, 3N) -hinazolindisn, t. Pl. 197.5 ° C, yield 11%. 53.343 (4-fluorobenzoyl) 1-piperidinyl buty7 2,3-dihydro-2thioxo-4- (1H) -quinazolinone, m.p. 174.7 ° C, yield 12%. 51.558 2- (2-chlorophenyl) {4-fluorobenzoyl) -1-piperidinyl ethyl 4- (3N) -quinazolinone (E) -2-butanedioate. (Itl), m.p. 199.2 C, yield 39%. 51.754 2- (4-chlorophenyl) (4-fluorobenzoyl) -1-piperidinyl ethyl 4- (3N) -quinazolinone (E) -2-butandioate (1: 1), mp. 225.6 ° C, yield 45%. 51.797 3 - ((4-fluorobenzoyl) 1-piperidinyl (phenylmethyl) 4- (3N) -quinazolinone (E) -2-butandioate (1: 1), mp. 226 ° C, yield 51%. P p and meper 34. According to the procedure of Example 23, the following compounds are also obtained: 49.238 (3-pyridinylcar bonyl) -1-piperidinyl ethyl -2.4-. (1H, 3N) -quinazolinedione, mp 216.4 50.274 ( 4-fluorobenzoyl) 5-methyl-1-piperidinyl ethyl J-2,4 (1H, 3N) -5 Synazolindione, mp 189.1 50.94- (3,4-dimethoxy benzoyl) -l-piperidinylJ ETHIL -2 -2, 4 (1H, ZN) -quinazolindione, so pl. 217.8 51.378 (article) (4-fluorobenzoyl) -1-piperidinyl ethyl32- (4fluorophenyl) -4- (3N) -quinazolinone, mp 131, 51.4449 2- (3-chlorophenyl) -3 -1 2 -14 (4-fluorobenzoyl) -1-piperidinyl (3N) -quina-zolinone, mp. 169, in ° C; 51.478. 3 - ((4-fluorobenzoyl) 1-piperidinyl-ethyl 2- (4-methylphenyl) 4- (3N) -quinazolinone, mp. 143.5 ° C. The compounds of the formula (|) have basic properties and can to convert therapeutically active non-toxic added acid salts into acid by treatment with appropriate acids, such as, for example, inorganic acids (hydrochloric acids, for example hydrochloric acid, hydrobromic acid, etc., and sulfuric acid, nitric acid, phosphoric acid. acid, etc.) or organic acids (acetic acid, propanoic acid, oxyacetic , 2-hydroxypropanoic acid, 2-oxooropan, propandionic, butandnonic, (Z) -2-6ytenedione, (E) - 2-butenedionic, 2-hydroxybutanedioic, 2,3-dioxibu, tamdionova, 2-oxy-1, 2,3-propaytricarboxylic, benzoic, 3-phenyl-3-propenova, ob-benzene benzene, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfamic, - 2-hydroxybenzoic, 4-amino-2-2-2-hydroxybenzoate, 4-methylbenzenesulfonic acid, cyclohexanesulfamic, Salt can be converted by treatment with alkali into a free base. The proposed new derivatives of piperidinyl alkyl quinazoline or their salts with pharmaceutically acceptable acids can be used in medicine as anti-spasmodic agents.
    权利要求:
    Claims (1)
    [1]
    A method of obtaining piperidinylalkylquinazoline derivatives of the general * formula ^ · r6 to 5 in 2 where each R * is independently chlorine ,. fluorine, methyl or methoxy;
    P = 0.1 or 2;
    R 2 is hydrogen, phenyl or methyl, if R 'and r4 are hydrogen either together are oxygen or sulfur, or R 2 and R ^ together form an additional bond and then
    R 4 is hydrogen, methyl, phenyl,. P-tolyl, fluorophenyl, chlorophenyl, methoxyphenyl, phenylmethyl or pyridinyl;
    R - hydrogen, R 6 is hydrogen, methyl phenyl, I-tolyl, chlorophenyl, or R ^ and R 6 together are oxygen;
    And K - ethylene, propylene or buttslen;
    R7 is hydrogen, HYDROXYL OR OR 'methyl;
    X-CO, I ___ | silt-snu;
    Ag is phenyl, substituted phenyl having one or two substituents selected from the group: chloro, bromo, fluoro methyl, methoxy, trifluoromethyl, or amino, or Ag is thienyl or pyridinyl, or their salts with pharmaceutically acceptable acids, characterized by with i ^ that the compound of the general formula AND .SU n . 1041034 And where R * -R 6 IP have the indicated values <';
    ; W is chlorine or bromine, · is reacted with a compound of the general formula β 7 'OLr'!
    where the values of R 7 , X, Ar are given! above, in an inert organic solvent, when heated in the presence of, [the bases and target product are isolated I in free form or as a salt with a pharmaceutically acceptable acid.
    Priority by signs:
    01/08/79 at B 1 - chlorine, fluorine, are oxygen or sulfur, or R 2 and R ^ together form an additional bond and toha methyl or methoxy; P = 0.1 or 2;
    R 2 is hydrogen, phenyl, or methyl, if R 'and R 4 is hydrogen or together
    R "is hydrogen, methyl, phenyl, P-tolyl, fluorophenyl, chlorophenyl, methoxyphenyl, phenylmethyl or pyridinyl;
    R y is hydrogen, R ^ is hydrogen, methyl, phenyl η-tolyl, chlorophenyl, or R ^ and R 6 together are oxygen;
    A6K - ethylene, propylene or bog thylene;
    R 7 is hydrogen or methyl;
    X-CO, ΐ — J “li-CH 2 ~;
    Ag is phenyl, substituted phenyl having one or two substituents selected from the group: chloro, bromo, fluoro, methyl, methoxy, trifluoromethyl, amino, or Ag - thienyl or pyridinyl, or their salts with pharmaceutically acceptable acids;
    10/12/79 at K 7 - hydroxyl. .
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    US4711899A|1987-12-08|2-|-1-phenylalkanol derivatives
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    同族专利:
    公开号 | 公开日
    PL125789B1|1983-06-30|
    CA1132557A|1982-09-28|
    PT70662A|1980-02-01|
    CY1252A|1984-08-31|
    AU536175B2|1984-04-19|
    IE800021L|1980-07-08|
    YU42957B|1989-02-28|
    NO800034L|1980-07-09|
    DK7280A|1980-07-09|
    IE49351B1|1985-09-18|
    KR850000677B1|1985-05-10|
    NL930018I2|1993-09-16|
    JPS6346753B2|1988-09-19|
    FI800047A|1980-07-09|
    MY8700555A|1987-12-31|
    ES487537A0|1980-12-16|
    JPS55105679A|1980-08-13|
    HK76284A|1984-10-19|
    GR67304B|1981-06-29|
    ES8101586A1|1980-12-16|
    NL930018I1|1993-05-03|
    NO155243B|1986-11-24|
    IL59084D0|1980-05-30|
    HU184222B|1984-07-30|
    FI66609B|1984-07-31|
    FI66609C|1984-11-12|
    LU88219I2|1994-02-03|
    PH17114A|1984-06-01|
    DK170669B1|1995-11-27|
    EP0013612B1|1983-11-09|
    KR830001926A|1983-05-19|
    CS223977B2|1983-11-25|
    RO79148A|1982-08-17|
    KR850000683B1|1985-05-14|
    IL59084A|1984-02-29|
    SG48684G|1985-03-29|
    AU5438180A|1980-07-17|
    ZA8082B|1981-08-26|
    US4335127A|1982-06-15|
    DE3065489D1|1983-12-15|
    EP0013612A2|1980-07-23|
    PL221249A1|1980-12-01|
    NZ192551A|1984-07-06|
    KR850000684B1|1985-05-14|
    AT5258T|1983-11-15|
    NO155243C|1987-03-04|
    YU4680A|1983-06-30|
    MA18694A1|1980-10-01|
    EP0013612A3|1980-10-15|
    KR850002015A|1985-04-10|
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    法律状态:
    优先权:
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    US06/084,272|US4335127A|1979-01-08|1979-10-12|Piperidinylalkyl quinazoline compounds, composition and method of use|
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