• 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:
    The invention relates to new quinazoline derivatives of the formula (I) wherein (R)n represents 6,7-di(lower alkoxy) or 6,7,8-tri(lower alkoxy); m is 1 or 2; X represents -CHR1- or -CH2CH2-; each R1, which may be the same or different, represents hydrogen or lower alkyl; and R2 and R3, which may be the same or different, each represent hydrogen, lower alkyl, lower alkoxy, halogen, lower alkanoyl, lower alkoxycarbonyl or a group of the formula-CONR4R5 or -SO2NR4R5 wherein R4 and R5, which may be the same or different, each represent hydrogen or lower alkyl; and the pharmaceutically acceptable acid addition salts thereof. Two processes for preparing these derivatives are also described. The new quinazolines are useful as regulators of the cardiovascular system, in particular for the treatment of hypertension.
    公开号:SU816403A3
    申请号:SU782679598
    申请日:1978-10-31
    公开日:1981-03-23
    发明作者:Фрейзер Кэмпбелл Саймон
    申请人:Пфайзер Корпорейшн Панама (Фирма)；
    IPC主号:
    专利说明:

    hydrate, sulfate or bisulfate, phosphate or acidic phosphate, acetate, maleate, fumarate, succinate, lactate, tartrate, citrate, gluconate, saharat or I-toluenesulfonate. NH + -Cf Target products possess anti-hypertanic activity and can be used as medicinal preparations either by dental or intravenous methods. Moreover, in the case of dental use, the dosage is from about 1 to 20 mg / day for a patient with an average. weight (70 kg); this dose is taken either at one time or divided into three separate doses. For intravenous administration, it is assumed that the dose should be between 1/5 and 1/10 of the daily dose for dental administration. Preparation 1. N- (1,4-benzo-dioxane-2-carboxyl) piperazine H / v NH + ce-C; + nse Suspension pipeoazin (11.88 g) and sodium acetate {20.30 g) in a mixture of water (70 ml) and acetone (95 g) is stirred at, and then concentrated hydrochloric acid (about 35 ml) is added until the pH reaches 1.5. Then, 1,4-benzodioxane-2-carbonyl chloride (31.0 g) and sodium hydroxide (5N, about 45 ml) are added dropwise, while keeping the temperature at 10-15 ° C, using sodium hydroxide The pH is maintained at 1.7-2.2. After the addition process is complete, the pH is adjusted to 2.0 with sodium hydroxide, and then the suspension is stirred for another 30 minutes. Water is then added to it until a homogeneous solution is obtained, the acetone is removed under vacuum, and the aqueous residue is extracted with chloroform (3 x 200 ml). The basic phase of the aqueous phase is then adjusted to pH 8-9 with sodium hydroxide (5N solution), again extracted with scoroform (3x200 ml) and the extracts. Washed with water, dried over sodium sulfate and evaporated under vacuum. The oily residue is dissolved in ethyl acetate, treated with a solution of hydrogen chloride in ether, evaporated under vacuum, and the solid residue is triturated with SIMPLE ETHER, then V The starting compounds of general formulas II or 11I are prepared using known methods, for example, intermediate compounds of general formula III are obtained according to the scheme - 77 W VCk ( .,) P Recrystallized from methanol to give N- (1,4-benzodioxan-2-carbonyl) piperazine hydrochloride (4.85 g) with a melting point of 2–5-267 ° C. Found,%: C54.6, H 5.5, N 9.7. . Calculated: C 54.8, H 6.0, N 9.8. Example 1. 4-Amino-2-G4 (1,4-benzodioxan-2-carbonyl) piperazin-1-yl-b, 7-dimethoxyquinazoline hydrochloride. 4 Amino-2-chloro-6, 7-dimethoxyquinazoline (140 g) and N- (1,4-benzodioxan-2-carbonyl) piperazine (150 g) are stirred at boiling point in n-butanol (2 l) for 3 , 5 h. The mixture is cooled to, the solid is filtered, washed with cold n-butanol (2x250 ml) and dried. The crude product is dissolved in hot (80 ° C) dimethylformamide (530 ml) and water (130 ml), filtered, concentrated under vacuum to a volume of about 300 ml, then cooled and ether (1.8 L) is added. The precipitate obtained is filtered and washed with ether, whereby 4-amino-2-4-Cl, 4-benzodioxan-2-carbonyl) piperizin-1-yl-6,7-dimethoxyquinazoline hydrochloride (215 g) is obtained, melting point 289290 WITH . Found,%: C 56.9, H 5.4, N 14.4. С2зН25 "5 ° 5Calculated,%: C 56.5, H 5.4, N 14.4. Example 2. 4-Amino-2- 4- - (1,4-benzodioxan-2-carbonyl) piperaZIN-1-ylJ-6, 7,8-trimethoxyquinazoline. 4-Amin6-2-chloro-6,7,8-trimethoxyquinazoline (1 g) and N- (1,4-benzodioxan-2-carbonyl) piperazine (1.168 g) are heated to boil in n-butanol (67 ml ) with triethylamine (1.87 g); this temperature is maintained for 24 hours. Next, N- (1,4-benzodioxane-2-carbonyl) piperase (0.026 g) is added to the mixture and the mixture is boiled for another 30 hours. Then the butanol is distilled off under vacuum, and an aqueous solution of sodium carbonate and chloroform are added to the residue. The combined chloroform extracts are washed with water, dried (N32504) and evaporated under vacuum to form a solid residue (3.4 g), which is dissolved in the minimum amount of dimethylformamide, and then incubated for 12 hours at OC. Ether is then added to the mixture and the turbid solution is cooled, resulting in 4-amino-2- 4- (1,4-benzodkoxan-2-carbonyl) piperaein-1-yl-6,7,8-trimethoxyquinaeoline ( 0.58 g), melting point 269-271 ° C. Found:; C 59.3, H 5.6, N 14.1. 6 Calculated,%: C 59.9, H 5.7, N 14.6. Example 3. 4-AMINO-2- 4- (1,4-benzodioxan-2-carbonyl) piperazin-1-ylZ-6, 7-diethoxyquinazoline. 4-amino-2-chloro-6,7-diethoxyquinazoline (0.33 g) and N- (1,4-benzodioxan-2-carbonyl) piperazine (0.32) are heated at the boil in n-butanol (30 mp) within 12 hours. The solvent is then distilled off under vacuum, and sodium carbonate solution and chloroform are added to the resulting precipitate. The combined chloroform extracts are punctured with water, dried over sodium sulfate, evaporated under vacuum, and the residue is chromatographed on silica gel (70 g) using chloroform / methanol (0.5%) as eluent. The same fractions are combined, evaporated under vacuum, then again dissolved in a mixture of chloroform / methanol and treated with an ethereal solution of hydrogen chloride. Further, the solution is evaporated under vacuum, and the residue is extracted from isopropanol, resulting in 4-amino-2- 4- (1,4-benzodioxan-2 carbonyl ) piperazin-1-yl-6,7-di1ethoxyuinazoline hydrochloride 2.5 hydates (0.19 g), melting point IbO184 C (par. .. Results. Found: C, 53.3, H, 5.5, N12, 2. 2.1 / 2 HgO Calculated,%: with 53.5, H 6.3, 12.5. Example 4. 4-amino-2- 4- (1,4-benzodioxan-g-car-1-carbonyl) homopiperazine 1-yl-6, 7-dimethoxyquinazoline, 4-amino-2-chloro-6,7-dimethoxyquinazoline (1.58 g) and M- (1,4-benzodioxan-2-car6onyl) homopiperazine (2.0 g) boil a n-butanol (114 mp) for 60 h. Next, the mixture is cooled, butanol is distilled off under vacuum, the solid residue is triturated with ether, dissolved in hot methanol, filtered and cooled. The solid product is filtered, the remaining solution is evaporated under vacuum, the solid residue is dissolved in hot isopropanol, the solution is cooled, the precipitate is filtered, and the filtrate is again evaporated under vacuum. The resulting precipitate is combined with the original solid, treated with cold methanol and recrystallized from ethanol to give 4-amino-2- 4- (1,4-benzodioxan-2-carbonyl) homopiperazin-1-yl-6,7- Dimethoxyquinazoline hydrochloride (0.57 g) at 250-251 ° C. The results of the analysis. Found,%: C 57.2, H 5.4, N 13.8. .Hc. Calculated,%: C 57.4, H 5.6, N 14.0. Analogously to Example 1, the compounds listed in the table are prepared.
    8 where (R) j | - 6,7-di- (lower alkoxy) OR 6,7, - three - (lower alkoxy) / m is 1 or 2, X - means the group -CHR, in which R is a hydrogen atom or methyl; R and R are the same or different and are denoted by each hydrogen atom or chlorine atom, or their pharmaceutically acceptable salts with acids, characterized in that quinazoline of the general formula / (P) where the values for (R) M are given above, Q. - chlorine atoms, bromine or iodine, is reacted with piperazine or homopiperazine of the general formula X-OxX Mv-tv iri: o - R O where the values of RR x and m are given above, and the target product is taken in a free form or as a pharmaceutically acceptable salt with an acid . Sources of information taken into account in the examination 1. Heterocyclic compounds. Ed. R. Elderfield, M., 1960, v.6, p. 349.
    权利要求:
    Claims (1)
    [1]
    Claim
    A method of obtaining derivatives of 4-amino-2- (piperazin-1-yl) - or 4-amino-2- (homopiperazin-1-yl) quinazoline of the general formula where (R) ^ - 6,7-di- (lower alkoxy) OR 6,7, -8 - three - (lower alkoxy), m is 1 or 2, X - means the group -CHR *, in which R 'is a hydrogen atom or methyl; R c and R 5 are the same or different and represent each atom of water
    kind or atom of chlorine, or their pharmaceutically acceptable salts with acid different I'm the one that quinazoline of the general formula (C)
    where the values of (R) n are given above, Q.- the atoms of chlorine, bromine or iodine, interact with piperazine or homopiperazine of the general formula <and "And he 4 where the values of R ^ -, R 3 χ and m are given above, and the target isolating the product in free form or in the form of Pharmacy 1 and cally acceptable acid addition salt.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US3635979A|1969-09-29|1972-01-18|Pfizer|Certain 6- and/or 7-alkoxy-substituted-2 4-bis quinazolines|
    US3669968A|1970-05-21|1972-06-13|Pfizer|Trialkoxy quinazolines|WO1985002617A1|1983-12-14|1985-06-20|Takeda Chemical Industries. Ltd.|1,5-benzoxathiepin derivatives and process for their preparation|
    WO1985004658A1|1984-04-04|1985-10-24|Takeda Chemical Industries, Ltd.|1,5-benzoxathiepine derivatives and their preparation|
    WO1986002644A1|1984-11-01|1986-05-09|Takeda Chemical Industries, Ltd.|1,5-benzoxathiepin derivatives and process for their preparation|
    EP0849265A1|1996-12-20|1998-06-24|HEUMANN PHARMA GmbH|Novel polymorphic form of doxazosin mesylate |
    EP0849264A1|1996-12-20|1998-06-24|HEUMANN PHARMA GmbH|Novel polymorphic form of doxazosin mesylate |
    AT353892T|1996-12-20|2007-03-15|Heumann Pharma Gmbh & Co|NEW POLYMORPHIC FORM OF DOXAZOSINMESYLATE |
    TW448155B|1999-03-29|2001-08-01|Dev Center Biotechnology|Method for producing amide compounds and quinazolin derivatives|
    EP1403263B1|2002-09-27|2005-06-22|Council of Scientific and Industrial Research|Process for the preparation of N- piperazine|
    法律状态:
    优先权:
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