• 专利附录
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  • 权利要求
  • 类似技术
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    • 专利摘要:

    公开号:SU900808A3
    申请号:SU792843107
    申请日:1979-11-16
    公开日:1982-01-23
    发明作者:Франке Альбрехт；Ленке Дитер；Грис Йосеф；Дитер Леманн Ханс
    申请人:Басф Аг (Фирма)；
    IPC主号:
    专利说明:

    in appropriate cases when alarming to the specified limits. The starting compounds can be reacted directly i. E. without the addition of diluents or solvents. However, it is advisable to carry out the reaction in the presence of an inert diluent or solvent, for example, a lower alcohol with lk carbon atoms, methanol, ethanol or propanol, preferably isopropanol or ethanol, a simple lower saturated dialkyl ether, a dialkyl glycol ether, or a cyclic ether, such as diethyl ether , 152-dimethoxyethane, getra hydrofuran or dioxane, benzene hydrochloride, such as benzene, or an alkyl benol, for example toluene or xylene, or an aliphatic hydrocarbon, on for example, hexane, heptane or octane, a lower aliphatic ketone, for example acetone, methyl ethyl ketone or methyl isobutyl ketone, dialkyl formamide, for example dimethyl or diethyl formamide, dimethyl sulfone or in the presence of water or in a mixture with the named solvents. An amine of the formula HjN-R used in an excess amount is also suitable, as appropriate, as a diluent or as a diluent. Preferred solvents for the reaction of 6- (2-3 epoxy-ppoxy) -2,3,, 5-tetrahydro-1H-1-benzazepin-2-one with the amine R-NHa. are lower alcohols, mainly ethanol or isopropanol, and the reaction is carried out at 50-100 ° and at normal pressure. The resulting compounds of the formula I have a center of chirality at the second carbon atom of the aliphatic side chain and are obtained as retomites that can be split into optically active antipodes by known methods, for example by forming diastereomeric salts with optically active auxiliary acids, dibenzoyl tartaric acid, camphor -10-sulfonic acid, di-toluenic acid or Zbrom-camphor-3-sulfonic acid, 8 in the corresponding case, the resulting compounds are salified with physiological compatible acid As usual physiologically compatible organic or inorganic acids can be used, for example, hydrochloric, hydrobromic, phosphoric or sulfuric acids, and organic acids such as oxalic, maleic, fumaric, dairy, tartaric, block, citric, salicylic, adipic or benzoic acids Salts with acids are usually prepared in a known manner by mixing the free base or its solutions with the corresponding acids or their solutions in an organic solvent, for example lower alcohol, such as methanol, ethanol or propanol, or a lower ketone, such as acetone, methyl ethyl keto .n or methyl isobutyl ketone, or an ether, such as diethyl ether, tetrahydrofuran or dioxane. Mixtures of the named solvents can also be used to better isolate the crystals. In addition, pharmaceutically compatible aqueous solutions of acid addition compounds of aminopropanol derivatives of general formula (O can be obtained by dissolving the free bases of general formula (I) in an aqueous acid solution. Preparation of the starting compounds. Example 1 a. B-Oxy-2, 3, 5 -tetrahydro-1H-1-benzazepin-2-one (A C E5 / dimethylformamide cleavage). To 5 ml of anhydrous aluminum chloride, 10 ml of DMF are added with vigorous stirring and possible cooling. To the melt that is added is added in portions m {0.07 mol) 6-methoxy-2,3t 5 tetrahydro-1H -} - benzazepin-2-one and then the contents of the flask are heated to llO-l iO C, kept at this temperature for 10 minutes and then stirred for another 10 minutes without further heating. The contents of the flask are poured onto ice water, the precipitate formed is sucked off, the filtrate is extracted several times with ether, the ether phases are purified, dried and rotated. The combined residues are recrystallized with the addition of animal carbon from acetone (cyclohexane) acetic ester. 6.3 g of -oxy-2, 3, +, 5-tetrahydro-1H-1-P, -nzazepin-2-one are obtained, m.p. . 59 found, 68.5; H 7, 1; N 7.2 С, о1п N02 (177.2) Calculated,%: С 68.7; H 7.3; N 7.3; Example 16. b-Oxy-2, 3g, 5-tetrahydro-1H-1-benzazepin-2-one (splitting of pyridinium chloride). 3.8 g (0.02 mol) of 6-methoxy-2,3, k, 5-tetrahydro 1H-1-ben-azepin-2-one and 10 g of pyridinium chloride are heated to 200-220С over 2 hours. The liquor is cooled, poured onto water, acidified with 2 N, HjSOi, and extracted several times with ether. The organic phase is dried, concentrated and the residue supplemented with animal charcoal is recrystallized from acetone (cyclohexane) of acetic ester. 1.6 g of 6-hydroxy-2,3, 5 tetrahydro-1H-1-6enazazepin-2-one are obtained with a melting point of 2-2-2 ° C. Example 2. 6-Methoxy-2,3, 5-tetrahydro-, 1H-1-benzazepin-2-one. 9.7 g (0.029 mol) of 5-methoxy-tetralon-1-hydroxy6-benzenesulfonate are kept in a water bath in 800-900 ml of acetic acid until completely dissolved (approximately 60 minutes). Then diluted with twice the amount of water and extracted several times with ether . The combined ether extracts are washed first with an aqueous solution of bicarbonate, then several times with water, dried and concentrated. The remaining residue is crystallized by aging (it is pure, which is established by analysis). A, 2 g of 6-methoxy-2, 3, +, 5 tetrahydro-1H-1-benzozepin-2-one is obtained (yield 75.7%}, mp. Found,%: C, 68.8; H 6.9; N 7.2. Cu H, NOj (131.2) Calculated D: C 6E, 0; .H 6.8; N 7.3 Example 3. 5-Methoxy-tetralone-1-hydroxybenzenesulfonate. 10 g (0 mol) tetralon-1-oxime is dissolved in 80 ml of anhydrous pyridine. 10.8 g of benzenesulfonic acid chloride is added dropwise at room temperature over 15 minutes and the solution is kept for 12 hours. Then 5 ml of water are added , after which the solution is poured into 300 m of ice-cold N. N. HC R. The precipitate formed is filtered off, dried and recrystallized from Alone: 13.6 g (yield: 92.8%) of 5-methoxy-tetralone-1-hydroxybenzene sulfonate with mp, k ° C was found:% C, 61.7, And 5.3, N k, 3; S 9.7. C "H, -, MOts5 (331) Calculated,%: C 61.6; H 5.2; N C, 2; S 9.6. Example. 5-Methoxy-tetralon-1 -oxime. 17.7 g (0.1 mol) of commercial 5-methoxy-1-tetralone (manufactured by Aid rich) are kept together with 18.4 g (0.2 bmol) of amine hydrochloride and 22.6 g of sodium bicarbonate (o, 26 mol) in ml of methanol and 80 ml of water for 36 hours at the defleimation temperature. The solvent is then removed using a rotary evaporator, the residue is stirred with water and the precipitate is sucked off, dried and recrystallized from toluene. 15.2 g of 5-methoxy-1-tetralone-oxime are obtained, m.p. 158159С (yield 79.6%). Found,%: S b9,1; H 6.6; N7.1. С „HjjNOj (191.2) Calculated: С 69.0; H 6.8; N7.3. Example 5. 6- (2,3, -Epoxypropoxy -2, 3, 5-tetrahydro-1H-1-benzazepin-2-one. 5.3 (0.03 mol) 6-OXI-2, 3, 5-tetrahydro-1H-1-benzazepin-2-it is kept at reflux temperature with 5 ml of epibromohydrin and 5 g of potassium carbonate in 250 ml of methyl isobutyl ketone for 48 hours. After cooling, it is filtered and the filtrate is concentrated on a rotary evaporator under reduced pressure. The residue is recrystallized from cyclohexane using animal charcoal to give 4.2 g of 6- (2, 3-epoxypropoxy) -2, 3, t, 5 tetrahydro-1H-1-benzazepin-2-one (yield 60%), mp 121-123 ° C. Found , 1: C 66.6; H 6.6; N 5.8. C. jH.yNO, (233) Calculated,%: C 66.9; H 6.5; N6.0. Obtaining the desired products. Example 1. 6- (2-Oxy-3-isopropylaminopropoxy) -2, 3,, 5-etrahydro-1H-1-benzazepin-2-one. 3, 3 g (0, mol) 6- (2,3-epoxypropoxy ) -2, 3, 4, 5 tetrahydro-1H-1-benzazepin-2-it is dissolved in 400 ml of n-propanol, 3 g of isopropylamine are added and kept in a water bath for an hour. Then the solvent and excess amine are distilled on a rotary evaporator, dissolved twice with methanol and again distilled off. The residue is chromatographed on a silica gel column (methanol as solvent). Get 1, B5 g of 6- (2-hydroxy-3-isopropylaminopropoxy) -2,3, k, 5-tetrahydro-1H-1-benzazepin-2-one with so pl, 143-143C, 39.9% yield . Found,%: C 65; H 8.4; 14 9, C, bN24 “Oz (292) Calculated: C 65.7 H 8.3 M 9.6 Example 2. 6- (2-hydroxy-3-tert.-butylaminopropoxy) hydrochloride -2, 3, 5 tetrahydro-G -1- € enzazepia, Analogously to example 1, to g (0, mol) 6- (2, 3-epoxypropoxy), 3, 5 tetrahydro-1H-Nbenzepin-2-it is added with tert-butylamine. The compound is obtained in the form of hydrochloride from ethanol / acetone with ethereal HC, which is recrystallized from ethanol / acetone / ether. 3.6 g of 6- {2-hydroxy-3-tert are obtained. -butylaminoproxy) -2, 3 k, 5, -tetrahydro-1H-1-benzazepin-2-one with so pl. , yield 26.2. Found: C 59.6; H 8.2; N7.6; eg to, b (, 5). Calculated: C 59.6; H 7,; 2; CE 10.4. Example 3- 6- (2-hydroxy-3 sec-butylaminopropoxy) -2, 3, 4, 5-tetrahydro-1H-1-benzazepin-2-one hydrochloride. From 1.7 g (0.007 mol) of 6- (2,3-epoxypropoxy) 2, 3, 4.5 tetrahydro-tH-1-benzazepin-2-one and 2.5 g of aminobutane as in Example 1 and in the form of hydrochloride as in Example 2, 1.05 g of 6- (2-hydroxy-3 sec-butylaminopropoxy) -2, 3, 4,5-tetrahydro-1H-1-benzazepin-2-one with m.p. 177C, yield 42. Found: C 59.3; And 8.1; N,; CE 10.2. CE (342,5) Calculated: С 59.6; H 7.9; M8.2; CE 10, 4. Example 4. Hydrochloride 6- (2-hydroxy-3- (3-methyl-1-butyl-3-ylamino) -PROPOXY / -2, 3, 4, 5-tetrahydro-1H-1- Benzazepin-2-one. From 1.7 g (O, 007 mol) 6- (2,3-zpoxypropoxy) -2.3, 4, 5-tetrahydro-1H-1-benzazepin-2-one and 1.25 g 3 amino-3-methyl-1-butine according to example 1 get 0.85 f hydrochloride 6-1 2-hydroxy-3- (3-methyl-1-butyl-3-ylamino) propoxy / -2, 3, 4,5-tetrahydro-1H-1 -GeHsasenHH-Z-OHa with t, area TUUS, yield 33%. Found: C 61.2; H 7, 3; N 7.7; CE 10.3. CjgH sNaOjCt (352.5) Calculated: C 61.3; And 7, N7.9; C 10.1. The compounds of formula (I) thus obtained and their physiologically compatible salts with acids end up with valuable pharmacological These properties are 4i and can be used for heart diseases (a and cardiovascular system a. On the basis of their | 5-sympatholytic action, they are particularly suitable for the treatment of diseases of the coronary circulation, heart rhythm disturbances and hypertension. Their high sympatolytic activity significantly exceeds, for example, the one of the known compound, Prologsolla. This resultant is surprising because isomeric to compounds of the formula () 7/2-hydroxy-3-alkylaminopropoxy (-2,3, 4,5, -tetrahydro-L-t-benzazepin-1-ones, t . Compounds in which the (2-hydroxy-3-alki-a 1t-junction) -group is at position 7 and at the same time still in the benzazepine ring of the NH- group and changed positions, are very similar D-sympatholytic agents. And pooled compounds of the formula (O 5/2 hydroxy-3 alkyl amino-proxy / 3 4-dihydrocarbostyrol do not achieve the activity of the proposed compounds. -Sympatolytic effect was studied in cats and dogs. The sympatolytic agent, proprance, was used as a comparative substance. For The studies used “delta tachycardia caused by isog orerenol. Isoproterenol (1 µg / kg intravenously) causes non-pedigreed cats (females and males weighing 1.7 4.0 kg) to increase the heart rate by an average of 612, 4 beats / min on narcotopic drugs with hexacabital (200 mg / kg intramuscularly). - Sympatholytics have a inhibitory effect on this tachycardia. Isoproterenol is injected before and 10 minutes after the intravenous injection or 30 minutes after the intraduodenal administration of the test substance. Install
    9900
    doses inhibiting tachycardia caused by isoproterenol on.
    On a non-narcotized dog, isoprotenerol (1 µg / kg intravenously) causes an increase in heart rate to approximately 100 beats / min. - Sympatholytic agents inhibit t such tachycardia. Isoproterenol is injected before and 10 minutes after intravenous administration by examining the ego substance.
    There are linear ratios between the logarithms of injected doses of the tested substances and the inhibition of tachycardia caused by isoproterenol. For these ratios, those that tachycardia caused by protenol are inhibited by 50% as ED 5b%.
    In addition)} - the sympatolytic effect was determined to be acutely toxic in 10 female mice of the type NMP1 weighing 22-27 g, when administered intraperitoneally. In this case, the LO 50 value recognized the dose at which 50% of animals die within 2k a (probit analysis).
    ten
    The compounds of formula (I) have a high p-sympatholytic effect. The table shows that the doses of neobhodikad for the inhibition of tachycardia caused by isoproterenol, at 50-60, with pharmaco-therapeutically important intestinal (intraduoden 1 (Nalnoe) introduction cats 2 times (example 1} or 4.7 times (example 2) below, When administered intravenously, the required dose is t, 7 times lower (example 2) or 2 times higher (example 1) than propranolol.
    High-sympatholytic activity in example 2 can also be installed on the dog. Here, the value of ED, 00t3 mg / kg was established. Thus, the substance is 2 times more active than propranolol (ED 50% O, 10 mg / kg).
    The toxicity of example 2 is weaker than the toxicity of propranol, the intraperitoneal LD50 mouse is 237 mg / kg, and the propranol 108 mg / kg.
     -Sympatholytic effect on the cat is given in the table.
    10,21559
    20.021557 Propranolol 0.1 52
    Thus, the invention also relates to therapeutic agents or preparations that, in addition to conventional carriers and diluents, contain a compound of formula (I) as an active principle, as well as the use of new compounds for therapeutic purposes.
    Examples of drugs that can be obtained by known methods.
    Tablets mg:
    a) Active ingredient of the formula (I) 5
    56 52
    57
    Lactose
    Methylcellulose a
    Corn starch
    Talc
    Magnesium stearate
    b) The active principle of the formula (I) Lactose Aviiel Polivosk 6000 Magnesium stearate
    权利要求:
    Claims (1)
    [1]
    c) A compound of formula (I) Polivinilpirrolydon (mean 210 mol.molyu 25000) Polyethylene glycol (average mol, 4.000 mol) and hydroxypropylmethylcellulose akQ Talkk Magnesium stearate 2 The active ingredient is wetted with a saline solution 0% polyvinylpyrrolidone, passed through a screen with a large lattice in 1.0 mm and dried at. This granulate is mixed with polyethylene glycol (average mol.mol), Hydroxypropyl methylcellulose with talc and magnesium stearate and pressed into tablets of 280 g each. Dragee, mg: Compound form / hell (I) 2,5 Lactose90 5 Corn starch Polyvinylpyrrolidone6 Magnesium stearate 1 The mixture of active principle with lactose and cornstarch is granulated with an 8% aqueous solution of polyvinylpyrrolidone through a 1.5 mm sieve at 50 ° C dried and again rubbed through a 1.0 mm sieve. The resulting 1st granulate is mixed with magnesium stearate and pressed into a dragee. The resulting dragee cores are coated with known processes, which mainly consist of sugar and talc. Capsule, mg: Compound of formula (1) 5.0 Magnesium stearate 2.0 Milk sugar19 3 Solution for injection, mg: Compound of formula (I) 1.0. 2 Sodium chloride 9 Distilled water Up to 10 Claims of Invention The method of producing aminopropanol derivatives of 6-OXII-2, 3, 5 tetrahydro-1H-1-benzazepin-2-one of the general formula I - € Hf-f n K; where R is an alkyl residue with 3 carbon atoms or a 3-methyl-1-butynyl residue, or salts thereof, characterized in that 2,3, 5-tetrahydro-1H-1-benzazipen-2-ones of the general formula. , is reacted with an amine of the formula, V HgN - R g R has the above values, in an organic solvent, followed by isolation of the target product in free form or as a salt. Sources of Information Received Attention in Examination 1. Buper K., Pearson D. Organic Synthesis. M., Mir, 1973, m.1, p.530.
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    引用文献:
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    DE3119874A1|1981-05-19|1982-12-09|Dr. Karl Thomae Gmbh, 7950 Biberach|"BENZAZEPINE DERIVATIVES, THEIR PRODUCTION AND THEIR USE AS MEDICINAL PRODUCTS"|
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    DE3434271A1|1984-09-19|1986-03-20|Beiersdorf Ag, 2000 Hamburg|SUBSTITUTED 3,4-DIHYDRO-CHINOLIN-2-ONE METHODS FOR THE PRODUCTION AND USE THEREOF AND PREPARATIONS CONTAINING THESE COMPOUNDS|
    US4774239A|1987-08-26|1988-09-27|E. R. Squibb & Sons, Inc.|Benzazepine derivatives|
    ES2323217T3|1999-11-30|2009-07-09|Electric Power Research Institute|METHOD FOR THE PHOTOMETRIC DETECTION OF IONS USED IN CAPILLARY ELECTROPHORESIS PROBES, MANUFACTURING PROCEDURE AND USE OF THESE PROBES.|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE19782850078|DE2850078A1|1978-11-18|1978-11-18|AMINOPROPANOL DERIVATIVES OF 6-HYDROXY-2,3,4,5-TETRAHYDRO-1H-1-BENZAZEPIN-2-ONS|
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