GB2065105A - Dibenzazepines - Google Patents

Dibenzazepines Download PDF

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GB2065105A
GB2065105A GB8035229A GB8035229A GB2065105A GB 2065105 A GB2065105 A GB 2065105A GB 8035229 A GB8035229 A GB 8035229A GB 8035229 A GB8035229 A GB 8035229A GB 2065105 A GB2065105 A GB 2065105A
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dibenzo
dihydro
azepine
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
    • C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
    • C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
    • C07D223/24—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom
    • C07D223/28—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom having a single bond between positions 10 and 11

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)

Abstract

Diabenzazepines are prepared by the following route: <IMAGE> (R<1-3>=C1-3 alkyl, or NR<2>R<3>=heterocyclic group; n=1-3), optionally followed by salt formation. The products are antiarrhythmic agents.

Description

SPECIFICATION 5-(w-Aminoacyl )-3-carbalkoxyamino-10, 0,11 -dihydrn-5H-dibenzo-[b,f]-azepines, Salts Thereof and Method for Preparing Same The present invention relates to the organic chemistry and, more specifically, it relates to novel compounds, viz. 5-(w-aminoacyl)3-carbalkoxyamino-1 0,11 -dihydro-5H-dibenzo-[b,f]-azepines, salts thereof and a method for preparing same.
These compounds possess an antiarrhythmic activity and can be useful in medicine as active principles of medicated compounds. These compounds 5-(o-aminoacyl)-3-carbalkoxyamino-l 0,1 1 dihydro-5H-dibenzo-[b,f]-azepines and salts thereof are novel substances hitherto unknown in the literature.
According to the present invention, 5-(w-aminoacyl)-3-carbalkoxyamino-1 0,11 -dihydro-5Hdibenzo-[b,f]-azepines have the following general formula:
wherein n is 1 to 3, R' is a straight or branched alkyl radical with 1 to 3 carbon atoms; R2 and R3-lower alkyl radicals the same or different with 1 to 3 carbon atoms, or R2 and R3 along with nitrogen atom form a residue of a cyclic amine such as piperidine, morpholine, N-alkylpiperazine with 1 to 3 atoms of carbon in the N-alkyl group, N-(P-hydroxyethyl)-piperazine or N-1,4-diazobicyclo-[4,m,0]-nonane, -decane, -undecane.
These compounds comprise crystalline substances of white to creamy colour soluble in the majority of organic solvents. Their structure is verified by the data of elemental analysis of salts and bases. These novel compounds are of interest for the treatment of cardio-vascular system diseases, since they have no central stimulant or central sedative effects. Especially promising are the compound! according to the present invention as possible active antiarrythmic agents causing no side effects, thus contributing to a substantial broadening of the range of remedies for the treatment of different types of arrhythmia.
The compounds according to the present invention have been tested experimentally animals.
These experiments have shown that the compounds according to the present invention fali within the range of efficient compounds with antiarrhythmic activity.
The experiments have been carried out both in vivo and in vitro. the activity of the test compounds has been compared to that of typical antiarrhythmic agents such as quinidine, novocainamide (procainamide) and 2-carbethoxyamino-1 0-[p-morpholinopropionyl]phenothiazine hydrochloride.
In experiments on an isolated rabbit's heart auricula the effect of the compounds on the maximum reproducible frequency of contractions at a constant intensity of irritation. The compounds were studied in concentrations within the range of from 4.1 10-7 to 4. 10-6 g/ml. the thus-obtained data are shown in Table 1 hereinbelow. They point to the fact that all the studied compounds possess the ability of lowering the maximum reproducible frequency of contractions and, hence, increasing the effective refractory period of the isolated auricle. The most active, in respect of this test, proved to be compounds I, IV, V, X, Xll.
Arrhythmia of a mixed type (auricle-ventrible) was obtained in experiments on rats upon an intravenous administration of 40-50 yg/kg of aconitine. Electrocardiogram was recorded in the second standard lead. The test compounds were injected intravenously in a dose of from 0.2 to 2.0 mg/kg. For this model of arrhythmia the most efficient were compounds II, V, XIV, XVI, XVII (shown in Table 1).
Therefore, the most efficient, out of the preparations tested for two arrhythmic tests, is compound V. Further experiments have shown that in respect of the ability of lowering the maximum frequency of contractions reproduced by the heart, preparation V is by 5 times more active than quinidine and more than 200 times as active as novocainamide. In the case of aconitine arrhythmia the effective dose producing the prophylactic effect in 50% of the animals (ED50 value) is 0.37 mg/kg for preparation V, 2.3 mg/kg for quinidine and 41 mg/kg for novocainamide.
The test compounds in the above-specified doses do not affect the general condition of the animals and cause no visible toxic phenomena.
Table 1
Compound of the formula: Extended duration of the refractory Prevention of \ NH I period aconite arrhythmia tO(CH2),R -C-oR1 I concen CO(CH2)nR tradon Compound wherein: of the % of the Dose, % of the No. n R' R compounds effect mglkg effect 1 2 3 4 5 6 7 8 Th 2 2 QH6 -N O 2.10-7 15 0.2 17 MY II 2 C2H5 4 2. 10-7 4 0.2 50 lil 2 C2Hs ' 2.10- 4 0.2 7 NJ IV 2 QH -N IICH2CH20H 2. 10-' 18 0.2 0 V 2 C2H5 -N(C,H,), 2.10-7 10 0.2 25 VI 2 QH6 -N(CH3)2 210-7 8 0.2 0 VII I C2H5 -N(CH3)2 210-7 7 0.2 0 H VIII I C2H5 -N O 2.10-' 0 0.2 14 IX 3 C,H,N: \o H IX 3 C2H5 -N B X 2 CH3 11 2. 10-7 11 17 X 2 CH, -N, XI 2 OH3 poorly soluble XII 2 CH3 -N(C2H5)2 2.10-7 10 0.2 8 XIII 2 CH3 -N(CH3)2 2.10-7 6 0.2 0 XIV 2 CH3 4 2.10-7 0 0.2 40 -NJ XV 2 i-C3H7 -N 2.10-' 0 0.2 10 H XVI 2 i-QH7 -N O 2. 10-' 0 0.2 50 XVII 2 i-C3H7 -N(C2H5)2 2.10-7 0 0.2 50 XVIII 2 i-QH, -N(CH3)2 2.10-' 0 0.2 0 H XIX 2 i-C3H7 -N NCH2EH20H 2.10-' 0 0.2 0 Upon a lasting intravenous injection of G-strophanthin to narcotized guinea pigs at a constant rate in the dose of 20 Lg/kg/min, the arrhythmogenic dose of strophanthin, i.e. the dose at which supraventricular and ventricular extrasystoles appear, is usually 183+30.9 yg/kg. Death of the animals is observed at the dose of strophanthin of 375+73.7 Hg/kg. The test compounds are administered along the strophanthin.In the case of their positive effect, the time of appearance of the heart rhythm disturbances and death of the animals and, hence, the total dose of strophanthin, are increased. Upon administration of compound V in the doses of 40, 100 and 200,ug/kg the dose of strophanthin causing disturbances of the ventricle rhythm is increased from 1 83 iug/kg to 1 87, 228 and 242,ug/kg respectively. The lethal dose of strophanthin is increased from 375 Mg/kg to 405, 428 and 397 yg/kg respectively.
In the case of a two-step ligation of the descending branch of the left coronary in dogs clearly pronounced disturbances of the ventricle rhythm are observed after 24 hours. The preparation is evaluated as efficient if it stops this arrhythmia for 10 minutes and longer. Compound V in the dose of 1 mg/kg intravenously normalizes the heart rhythm. The effect duration is 1 0-12 minutes.
The effect of the compounds on the central nervous system is investigated using appropriate screening methods. It has been found that the test compounds possess no tranquilizing, or analgetic and myoreiaxant effects.
The acute toxicity of the compounds is determined by way of intraperitoneal or perosal administration of the preparation to white mice weighing 1 8-20 g. The LD50 is calculated according to Litchfield, Wilcoxon. For compounds l, III, IX and XII the LD50 upon intraperitoneal administration is 100, 125, 1 5 and 50 mg/kg respectively. For compound V the LDso upon peroral administration is 58 mg/kg.
As compared to the prior art arrhythmic agent-2-carbethoxyamino-1 0-(- morpholinopropionyl)phenothiazine hydrochloride, the compounds according to the present invention possess, in addition to loss of the sedative effect inherent in the known agent, also the advantage that they contain no sulphur atom in the tricyclic system which, as it is known from the data on metabolism of phenothiazine derivatives, is rapidly oxidized to sulphoxide with weakening or total loss of its activity.
The object of the present invention is also accomplished by the method for preparing the abovespecified compounds.
The method for preparing 5-(w-aminoacyl)-3-carbalkoxyamino-l 10,11 -dihydro-5H-dibenzo-[b,fj- azepines and salts thereof according to the present invention comprises reacting 3-amino-1 0,11- dihydro-5H-dibenzo-[b, < -azepine with an alkylchloroformate of the formula:
wherein R' is a straight or branched alkyl radical with 1 to 3 carbon atoms in an organic solvent medium, treating the resulting 3-(carbalkoxyamino)-1 0,11 -dihydro-5 H-dibenzo-[b,f]-azepine with a chloroanhydride of co-chlorocarboxylic acid of the formula: CiCO(CH9)nCI wherein n is 1 to 3 in an organic solvent: reacting the resulting 1 0, 11 -dihydro-5H-dibenzo-[b,f]-azepine with a secondary amine of the general formula:
wherein R2 and R3 are lower alkyl radicals the same or different with 1 to 3 carbon atoms or R2 and R3 along with nitrogen atom form a residue of a cyclic amine such as piperidine, morpholine, Nalkylpiperazine with 1 to 3 carbon atoms in the N-aikyl group, N-(/3-hydroxyethyl)-piperazine or N-1,4- diazobicyclo-[4,m,0]-nonane, -decane or -undecane in an organic solvent medium, followed by isolatior of the desired product.
It is advisable that the reaction of 3-amino-1 0,1 1-dihydro-5H-dibenzo-[b,f]-azepine with the alkylchloroformate be conducted at a temperature of from --5 to +1 50C. As the organic solvent use can be made of any suitable solvent; it is preferable to use ethanol or acetone in the presence of an acceptor of hydrogen chloride.
The resulting 3-(carbalkoxyamino)-1 0,11 -dihydro-5H-dibenzo-[b,fj-azepine should be preferably treated with the chloroanhydride of w-chlorocarboxylic acids at the boiling temperature of the organic solvent. As the organic solvent use should be preferably made of benzene and toluene. The resulting 5 (o-chloroacyl)-3-carbalkoxyamino-l 0,11 -dihydro-SH-dibenzo-[b;f]-azepine should be preferably reacted with secondary amines at the boiling temperature of the organic solvent. It is desirable to use, as the latter, benzene, toluene, acetone.
The process proceeds according to the following scheme:
The starting compound, i.e. 3-amino-i 0,11 -dihydro-5H-dibenzo-[b,f]-azepine is reacted with an alkylchloroformate. The reaction proceeds quite rapidly with a high yield even at room temperature or at temperatures close thereto. The evolving hydrogen chloride is combined by the addition of HCIacceptors such as pyridine, triethylamine, sodium or potassium carbonate and the like. It is also possible to use an excess of 3-amino-10,11 -dihydro-5H-dibenzo-[b,f]-azepine so that HCI is combined with the excessive amount of the amine.For a better control of the reaction, it is advisable to carry it out at a temperature within the range of from --5 to +1 15 C in such solvents as benzene, toluene, chloroform and the like. It is preferable to use acetone or ethanol and to add the alkylchloroformate to the reaction mixture either continuously or portion-wise. The resulting 3-carbalkoxyamino-1 0,11 dihydro-5H-dibenzo-[b,f]-azepine can be readily purified by recrystallization, for example from ethanol or aqueous ethanol.
The thus-prepared 3-carbalkoxyamino-10,1 -dihydro-5H-dibenzo-[b,f]-azepine is treated with a chloroanhydride of w-chlorncarboxylic acids.
This reaction should be preferably carried out in indifferent solvents such as benzene, toluene, chloroform and carbon tetrachloride at the boiling temperature of these solvents. This results in a high yield of 5-(o-chloroacyi)-3-carbalkoxyamino-l 0,1 1 -dihydro-SH-dibenzo-[b.f]-azepine: If required, it can be purified, for example, by recrystallization from ethanol, isopropanol, ethylacetate or acetone, or it can be delivered to the successive stage without any additional purification.
The thus-obtained 5-(Gs-chloroacyl)-3-carbalkoxyamino-10,11 -dihydro-SHdibenzo-[b,fj-azepine is reacted with secondary amines of the above-given general formula. This reaction should be preferably conducted in indifferent solvents such as benzene, toluene, acetone, ethanol, isopropanol or propanol at the boiling temperature of the solvent or slightly lower. Hydrogen chloride evolving in the reaction can be combined with the addition of HCI-acceptors such as pyridine, triethylamine, soda, potash or an excess of the secondary amine taken for the reaction.
5-(w-Aminoacyl)-3-carbalkoxyamino-1 0,11 -dihydro-5H-dibenzo-[b,fj-azepines which can be converted to corresponding salts by the reaction with inorganic or organic acids in any suitable organic solvent. These salts are well crystallizable and can be employed for purification of the desired compounds.
For a better understanding of the present invention, some specific examples illustrating preparation of the compounds of this invention are given hereinbelow.
Example 1 To a solution of 12.6 g (0.06 mol) of 3-amino-10,11 -dihydro-5H-dibenzo-[b,f]-azepine in 50 ml of ethanol at a temperature of 5 to 70C there are gradually added 8.68 g (0.08 mol) of ethyichloroformate (the addition is effected in two portions). Simultaneously with the addition of the second portion of ethylchloroformate there is added a solution of 4.24 g (0.04 mol) of sodium carbonate in 5 ml of water. Then the reaction mass is stirred at the same temperature for one hour, added with 30 ml of water and stirred for additional 30 minutes.The residue is filtered off, washed with water and dried to give 1 5 g (88.5%) of 3-carbethoxyamino-10,11 -dihydro-5H-dibenzo-[b,fl-azepine melting at 119--1210C(from aqueous isopropanol). Rf 0.90 ("Silufol", chloroform-methanol, 9:1).
Found, % C 72.03; H 6.38; N 9.84. C"H,8N202 Calculated, %: C 72.31; H 6.42; N 9.92.
5.6 g (0.02 mol) of the resulting 3-carbethoxyamino-10,1 -dihydro-5 H-dibenzo-[b,f]-azepine are mixed with 3.4 g (0.03 mol) of chloracetylchloride in 30 ml of toluene and the mixture is refluxed for 4 hours. The solvent and the excess of chloracetylchloride are distilled-off and the residue is crystallized from isopropanol. There are obtained 6.0 g (83.6%) of 5-(chloroacetyl)-3-carbethoxyamino-10,1 1dihydro-5H-dibenzo-[b,f]-azepine melting at 1 69-1 700C.
Found, % Cl 9.72; N 7.72; C 1sH1sClN2O3.
Calculated, % Cl 9.79; N 7.83.
A mixture of 5.74 g (0.016 mol) of 5-(&alpha;-chloracetyl)-3-carbethoxyamino-10,1 1-dihydro-5H- dibenzo-[b,f]-azepine in 30 ml of benzene is stirred at room temperature for 4 hours and then heated for 2 hours at reflux. The solvents are distilled, the residue is dissolved in toluene and after treatment with an ethanolic solution of hydrogen chloride there are obtained 4.95 g (75%) of 5-(- dimethylaminoacetyl)-3-carbethoxyamino-l 0,11 -dihydro-5H-dibenzo-[b,fj-azepine melting at 220 2240C (decomposition, from acetone).
Found, % C 60.21, H 6.73; CI 8.40; H20 2.77. C21H26CN303.
Calculated, % C 61.08; H 6.58; Cl 8.58; H20 2.17.
Example 2 The process is carried out in a manner similar to that described in Example 1. From 25.2 g (0.12 moi) of 3-amino-1 0,11 -dihydro-5H-dibenzo-[b,f]-azepine, 1 3.2 g (0.14 mol) of methylchloroformate, 8.48 g (0.08 mol) of sodium carbonate in 100 ml of ethanol there are obtained 24.0 g (74.5%) of 3 carbethoxiamino-1 0,11 -dihydro-SH-dibenzo-[b,-i]-azepine melting at 165--1660C (from aqueous ethanol). Rf=0.45 ("silufol", chloroform-ethanol, 9:1).
Found, % Cl 9.71; N 8.05. C19H19CIN203.
Calculated, % Cl 9.88; N 7.80.
A mixture of 7.2 g (0.02 mol) of 5-(ss-chloropropional)-3-carbomethoxyamino-10,1 1-dihydro-5H dibenzo-[b,f]-azepine, 4 g (0.046 mol) of morpholine in 100 ml of toluene is heated at reflux for 4 hours. The reaction mass is cooled to the temperature of 300C and the precipitated morpholine hydrochloride is fiitered-off. After cooling, from the filtrate there are precipitated 6.6 g (80%) of 5-(ss- morpholinopropionyl)-3-carbomethoxyamino 0,11 -dihydro-5H-dibenzo-[b,f]-azepine melting at 179--1810C (from toluene).
Found, % C 67.88; H 6.36; N 9.98. C23H2,N304.
Calculated, %: C 67.46; H 6.64; N 10.26.
The resulting base is dissolved in toluene and, by the treatment with an ethanolic solution of hydrogen chloride, 5-(ss-morphoxinopropionyl)-3-carbomethoxyamino 10,11 -dihydro-5H-dibenzo-[b,f]- azepine hydrochloride melting at 217--2200C (decomp., from ethanol) is isolated.
Found, % C 61.61; H 6.53; Cl 7.74. C23H28CIN304.
Calculated, %: C 61.94; H 6.32; Cl 7.95.
Example 3 Under the conditions similar to those described in Example 1,from 25.2 g (0.12 mol) of 3-amino10,1 1-dihydro-5H-dibenzo-[b,f]-azepine, 17.1 g (0.14 mol) of isopropylchloroformate, 8.48 g (0.08 mol) of sodium carbonate in 100 ml of ethanol there are obtained 28.05 g (78.8%) of 3 carboisopropoxyamino- 10,11 -dihydro-5H- dibenzo-[b,fj-azepine melting at 1421430C.
Found, % C 72.68; H 6.73; C,8H20N202.
Calculated, % C 72.94; H 6.80.
From 59.3 g (0.2 mol) of 3-carboisopropoxyamino-1 0,1 1-dihydro-5H-dibenzo-[b,f]-azepine, 30.5 g (0.24 mol) of ss-chloropropionylchloride in a manner similar to that described in the foregoing Example 1 there are obtained 47.5 g (61.4%) of 5-(p-chloropropional)-3-carboisopropoxyamino- 10,1 1-dihydro-5H-dibenzo-[b,f]-azepine melting at 139-141 C (from ethylacetate).
Found, % C 65.02; H 5.86; CI 8.74. C21H23CIN203.
Calculated, %: C 65.19; H 5.99; Cl 9.16.
From 11.6 g (0.03 mol) of 5-(,B-chloropropionyl)-3-carboisopropoxyamino-10,1 1-dihydro-5Hdibenzo-[b,f]-azepine, 5.9, (0.068 mol) of morpholine in 100 ml of toluene under the conditions similar to those described in Example 2 hereinbefore there are obtained 10.75 g (75.7%) of 5-(ss- morpholinopropionyl)-3-carboisopropoxyamino- 10,11 -dihydro-5H-dibenzo-[b,f]-azepine hydrochloride melting at 219--2210C (from ethanol).
Found, % C 63.00; H 6.93; Cl. 7.93; N 8.72. C25H32CIN304.
Calculated, %: C 63.34; H 6.80; Cl 7.48; N 8.86.
Example 4 Likewise in Example 1 hereinbefore, 3-carbethoxy amino-I 0,1 1-dihydro-5H-a'ibenzo-[b,f]- azepine is prepared.
From 56.5 g (0.2 mol) of 3-carboethoxyamino-10,1 1-dihydro-5H-dibenzo-[b,f]-azepine, 28.0 g (0.22 mol) of ss-chloropropionyichloride after crystallization from aqueous isopropanol there are obtained 53.0 g of 5-(ss-chloropropionyl)-3-carbethoxyamino-10,11 -dihydrc-SH-dibenzo-[b,f]-azepine melting at 134-135 C.
Found, %: Cl 9.21; N 7.73. C20H2,CIN203 Calculated, %: Cl. 9.51; N 7.51.
From 14.9 g (0.04 mol of 5-(ss-chloropropional)-3-carbethoxyamino-10,11 -dihydro-5H-dibenzo- [b,f]-azepine, 5.4 g (0.12 mol) of dimethylamine in benzene there are obtained 11 g (72.1%) of 5-(ss- dimethylaminopropionyl)-3-carbethoxyamino-1 0,11 -dihydro-5 H-dibenzo-[b,f]-azepi ne melting at 103-104 C.
Found, %: C 69.07; H 7.00; N 11.11. C22H2,N303.
Calculated, %: C 69.26: H 7.13; N 11.01.
Hydrochloride of this compound is prepared in a manner similar to that described in Example 1; M.p. 1950C (decomp., from isopropanol).
Found, % C 61.86; H 6.78; Cl 8.20; N 9.82; H20 2.05. Q2H26ClN303.-21 H20.
Calculated, % C 61.88; H 6.84; CI 8.30; N 9.84; H202.10.
Example 5 3-carbethoxyamino-1 0,11 -dihydro-SH-dibenzo-[b,f]-azepine is prepared in a manner similar to that described in Example 1 hereinbefore.
From 5.6 g (0.02 mol) of 3-carbethoxyamine-1 0,1 1-dihydro-5H-dibenzo-[b,f]-azepine,4.23 g (0.03 mol) of chloroanhydride of w-chlorobutyric acid there are obtained 6.2 g (80%) of 5-(ychlorobutyryl)-3-carbethoxyamino-10,1 1-dihydro-5H-dibenzo-[b,fj-azepine melting at 155-156 C (from isopropanol). Rf 0.61 ("Silufol", chloroform-methanol, 9:1).
Found,%: C 65.10; H 63.1; Cl 8.83. C2,H23N203CI.
Calculated, %: C 65.19; H 5.96; Cl 9.20.
From 7.72 g (0.02 mol) of 5-(ychlorobutyryl)-3-carbethoxyamino-1 0,1 1-dihydro-5H-dibenzo [b,fl-azepine, 3.75 g (0.043 mole) of morpholine in 50 ml of toluene under the conditions similar to those described in Example 2 there are obtained 4 g (40.7%) of hydrochloride melting at 148-150 C (decomp., from acetone).
Found, % C 60.64; H 7.06; N 8.74; H20 2.75. C25H32CIN304.H20.
Calculated, %: C 61.02; H 6.96;N 8.54; H203.65.
Example 6 Following the procedure similar to that of Example 4, there is obtained 5-(ss-chloropropionyl)-3- carbethoxyamino- 10,11 -dihydro-5H-dibenzo-[b,f]-azepine.
A mixture of 4.1 g (0.011 mol) of 5-(-chloropropionyI)-3-carbethoxyamino-10,1 1-dihydro-5H dibenzo-[b,fl-azepine, 2.2 g (0.025 mol) of morpholine in 40 ml of toluene is heated at reflux for 4 hours. The reaction mass is cooled to 30 C and the precipitated morpholine hydrochloride is filteredoff; after cooling from the hydrochioride there are precipitated 3.53 g (76%) of 5-(p- morpholinopropionyl)-3-carbethoxyamino-1 0,11 -dihydro-5H-dibenzo-[b,f]-azepine melting at 128 1300C, Rf 0.16 ("Silufol", chloroform ethylacetate, 9:1).
Found, %: C 68.05; H 6.83. C24H2sN304.
Calculated, %: C 68.06; H 6.90.
Hydrochloride of this compound is obtained as described in Example 2; M.p. of the product is 208-210 C (from isopropanol).
Found, /O: C 62.93; H 6.76; N 9.1 5. C24H30CIN304.
Calculated, %: C 62.66; H 6.57; N 9.13.
Example 7 5-(ss-Chloropropionyl)-3-carbethoxyam ino- 10,11 -dihydro-5 H-dibenzo-[b,fl-azepine is prepared following the procedure similar to that described in Example 4 hereinbefore.
From 18.64 g (0.05 mol) of 5-(-chloropropional)-3-carbethoxyamino-10,11 1-dihydro-5H- dibenzo-[b,f]-azepine, 9.4 g (0.11 mol) of piperidine in 200 ml of acetone there are obtained 17 g (80.7%) of 5-(ss-piperidinopropionyl)-3-carbethoxyamino-10,1 -dihydro-5 H-dibenzo-[b,fj-azepine melting at 139-140 C (from aqueous alcohol).
Found, %:C70.96;H7.46; C25H 3N303.
Calculated, %: C71.23; 7.42.
Hydrochloride of this compound is produced in a manner similar to that described in Example 2; M.p. of the product is 198-200 C (from acetone).
Found, % C 65.58; H 7.00; Cl 7.72; N 8.87; C25H32CIN303.
Calculated, %: C 65.56; H 7.04; CI 7.74; N 9.18.
Example 8 5-(ss-Chloropropionyl)-3-carbethoxyamino-10,11 -dihydro-5H-dibenzo-[b,fj-azepine is prepared as in Example 4.
From 9.3 g (0.025 mol) of 5-(P-chloropropionyl)-3-carbethoxya mino-l 0,1 1-dihydro-5H-dibenzo [b,f]-azepine, 6.3 g (0.05 mol) of 1 .4-diazobicyclo-/4,m,O/-nonane in 100 ml of toluene (after distilling off the solvent) there are obtained 7.75 g (67%) of 5-IP-[1 ,4-diazobicyclo-(4,m,0)-nonanyl-41- propional)-3-carbethoxyamino-10,11 1-dihydro-5H-dibenzo-[b,f]-azepine melting at 146148 C (from aqueous acetone).
Found, %:C70.29;H7.54; N 11.27;C2,H34N403.
Calculated, %: C 70.12; H 7.38: N 12.12.
Dihydrochloride of this compound is prepared in a manner similar to that described in Example 2, melting point of the product is 1 80--1850C (decomp.).
Found, %: C 55.85; H 7.52; Cl 11.98; N 9.68; H20 8.27. C2,HCl2N403 2.5H20.
Calculated, %: C 55.85; H 7.12; Cl 12.23; N 9.65; H20 7.75.
Example 9 5-(ss-chloropropionyl)-3-carbethoxyamino-10,11 -dihydro-5H-dibenzo-[b,f]-azepine is prepared in a manner similar to that described in Example 4.
From 9.3 g (0.025 mol) of 5-(-chlornprnpionyl)-3-carbethoxyamino-1 0,11 -dihydro-5H-dibenzo- [b,f]-azepine, 6.5 g (0.05 mol) of ss-hydroxyethylpiperazine in 100 ml of toluene under conditions similar to those of Example 2 there are obtained 8 g (60%) of 5-(P-[N-(2- hydroxyethylpiperazi nyl)jpropionyl 1-3-carbethoxyamino- 10,11 -dihyd ro-5H-dibenzo-[b,f] -azepi ne dihydrochloride; after drying in vacuum at the temperature of 1 00 C the product has melting point of 185-187 C (from ethanol).
Found, % C 57.05; H 6.86; C28H36Cl2N404.
Calculated, %: C 57.87; H 6.72.
Example 10 5-(&alpha;-Chloroacetyl)-3-carbethoxyamino-10,1 1-dihydro-5H-dibenzo-[b,f]-azepine is prepared as in Example 1.
From 7.2 g (0.02 mol) of 5-(&alpha;-chloroacetyl)-3-carbethoxyamino-10,11 -dihydro-5H-dibenzo-b,f- azepine, 3.8 g (0.044 mol) of morpholine there are obtained 7 g (71.4%) of 5-(-morpholinoacetyl )-3 carbethoxyamino-10,1 1-dihydro-5H-dibenzo-[b,f]-azepine melting at 174-175 C (from ethylacetate).
Found, %: C 67.11; H 6.62; C23H2,N304.
Calculated, %: C 67.46; H 6.64, Hydrochloride is obtained as described in Example 2; the product melting point is 205 C (from isopropanol).
Found, %: C 62.35; H 6.32; Cl 7.83; N 9.18. C23H28CIN304.
Calculated, %: C 61.94; H 6.32; 7.95; N 9.42.
Example 11 5-(ss-Chloropropionyl)-3-carbomethoxyamino-10,1 1-dihydro-5H-dibenzo-[b,fl-azepine is prepared similarly to the procedure of Example 2.
From 7.2 g (0.02 mol) of 5-(ss-chloropropionyl)-3-carbomethoxyamino-10,1 1-dihydro-5H dibenzo-[b,fl-azepine, 3.8 g (0.045 mol) of piperidine in 100 ml of toluene there are prepared 6.8 g (83.5%)of 5-(ss-piperidinopropionyl)-3-carbomethoxyamino-10,11-dihydro-5H-dibenzo-[b,fl-azepine melting at 176-178 C (from toluene).
Found, %: C 70.96; H 7.36; N 10.24. C24H29N303.
Calculated, %: C 70.73; H 7.17; N 10.31.
Hydrochloride of this compound is prepared in a manner similar to that described in Example 2 hereinbefore; the product has melting point of 21 5-21 7 C (from ethanol).
Found, %: C 65.25; H 6.97; Cl 7.70; N 9.46; C24H30CIN303 Calculated, %: C 64.92; H 6.81; Cl 7.98; N 9.46.
Example 12 5-(ss-Chloropropionyl)-3-carbomethoxyamino-10,11 -di hyd rb-5 H-dibenzo-[b,f]-azepi ne is prepared as in Example 2.
From 7.2 g (0.02 mol) of 5-(ss-chloropropionyl)-3-carbomethoxyamino-10,11 1-dihydro-5H- dibenzo-[b,f]-azepine, 3.3 g (0.045 mol) of diethylamine there are obtained 7 g (88.5%) of 5-(p- diethylaminopropionyl-3-carbomethoxyamino-1 0,11 -dihydro-5H-dibenzo-[b,f]-azepine melting at 119-121 0C (from ethylacetate).
Found, %: C 69.70, H 7.1 1; N 10.26.C23H29N303.
Calculated, %: C 69.84; H 7.39; N 10.62.
Hydrochloride of this compound is obtained in a manner similar to that described in Example 2; the product has its melting point of 162-166 C (decomp., from ethanol).
Found, %: C 63.50; H 7.05; Cl 7.97; N 9.70. C23H30CIN303.
Calculated, %: C 63.95; H 7.00; Cl 8.20; N 9.72.
Example 13 5-(-Chlornpropionyl-3-carbomethoxyamino-10,11 1-dihydro-5H-dibenzo-[b,f]-azepine is prepared as described in Example 2 hereinbefore.
From 8.97 g (0.025 mol) of 5-(ss-chloropropionyl)-3-carbomethoxyamino-10,1 1-dihydro-5H- dibenzo-[b,fj-azepine and an excessive amount of dimethylamine in benzene there are obtained 6.8 g (74%) of 5-(ss-dimethylaminopropional)-3-carbomethoxy amino-1 0,11 -dihydro-5H-dibenzo-[b.f]- azepine melting at 137-138 C.
Found, %: C 68.98; H 6.84; N 11.61. C21H26N303.
Calculated, %: C 68.64; H 6.85; N 11.43.
Hydrochloride of this compound is prepared following the procedure similar to that of Example 2; melting point of the product is 198-201 C (decomp., from a mixture of methanolethylacetate 1 :4).
Found, %: C 60.84; H 6.84; Cl 8.62; N 10.07 H20 1.92. C2tH26ClN303.2 H20.
Calculated, %: C 61.08; H 6.58; Cl 8.58; N 10.17; H20 2.18.
Example 14 5-(ss-chloropropionyl)-3-carbomethoxyamino-10,11-dihydro-5H-dibenzo-[b,f]-azepine is prepared as in Example 2.
From 7.2 9 (0.02 mol) of 5-(P-chloropropionyl-3-carbomethoxyam ino-l0,1 l-dihydro-SH- dibenzo-[b,f]-azepine, 5 g (.04 mol) of 1 ,4-diazobicyclo-4(4,m,0)-nonane in 100 ml of toluene under the conditions similar to those of Example 2 there are obtained 8.2 g (77.3%) of 5-(I3-[1 4- diazabicyclo-(4,m,O)-nonanyl-4]-propionyl}-3-carbomethoxyamino-1 0-1 -dihydro-5H-dibenzo-tb,fj- - azepine dihydrochloride melting at 198202 C (decomp. from isopropanol).
Found, %: C 58.44; H 6.69; Cl13.55; N 10.47; H 20 2.56. C26H34C12N403- 2 H20.
Calculated, %: C 58.88; H 6.65; Cl13.36; N 10.561 H20 1.69.
Example 15 5-(ss-Chloropropionyl)-3-carbisopropoxyamino-10,11 -dihydro-5H-dibenzo-[b,f]-azepine is prepared in a manner similar to that described in Example 3.
From 1 1.6 g (0.03 mol) of 5-(ss-chloropropionyl)-3-carboisopropoxyamino-10,11 -dihydro-5H- dibenzo-[b,fl-azepine, 5.78 g (0.068 mol) of piperidine in 100 ml of toluene under the conditions similar to those described in Example 2 there are prepared 10.6 g (75%) of 5-(ss-peridinopropionyl)- 3-carboisopropoxyamino- 10,11 -dihydro-5H-dibenzo-[b,f]-azepine hydrochloride melting at 198200 C (from acetone).
Found, %: C 66.18; H 7.21; Cl 7.34; N 8.98; C26H34CIN303.
Calculated, %: C 66.15; H 7.26: CI 7.52; N 8.90.
Example 16 5-(ss-Chloropropionyl)-3-carboisopropoxyamino-10,1 -dihydro-5H-dibenzo-[b,f]-azepine is prepared similarly to the procedure described in Example 3.
From 11.6 g (0.03 mol) of 5-(ss-chloropropionyl)-3-carboisopropoxyamino-10,1 1-dihydro-5H- dibenzo-[b,f]-azepine, 4.9 g (0.067 mol) of diethylamine in 100 ml of toluene under the conditions similar to those described in Example 2 there are prepared 9.5 g (69%) of 5-(P-diethylaminopropionyl)- 3-carboisopropoxyamino-1 0,11 1-dihydro-5H-dibenzo-[b,f]-azepine hydrochloride melting at 161 - 16300 (from acetone).
Found, %: C 65.50; H 7.44; Cl 7.74. C2sH34CIN303.
Calculated, %: C 65.27; H 7.44; CI 7.70.
Example 17 5-(ss-Chloropropionyl)-3-carboisopropoxya mino-10,11-dihydro-5H-dibenzo-[b,f]-azepine is prepared in a manner similar to Example 3.
From 27.1 g (0.07 mole) of 5-(ss-chloropropionyl)-3-carboisopropoxyamino-10-1 1-dihydro-5H dibenzo-[b,f]-azepine and an excess of dimethylamine in benzene under the conditions similar to those of Example 1 there are prepared 25 g (81%) of 5-(ss-dimethylaminopropionyl)-3- carboisopropoxyamino-1 0-11 -dihydro-5H-dibenzo-[b,f]-azepine hydrochloride melting at 148 15100 (decomp., from methylethylketone).
Found, %: C 62.51 H 7.19; Cl 7.85; H20 2.24. 023H300IN3O3. 2 H20 Calculated, %: C 62.64; H 7.08; Cl 8.04; H20 2.04.
Example 18 5-(ss-Chloropropionyl)-3-carboisopropoxyamino-10,1 -dihydro-5H-dibenzo-[b,f]-azepine is prepared in a manner similar to that described in Example 3.
From 1 1.6 g (0.03 mol) of 5-(ss-chloropropionyl)-3-carboisopropoxyamino-10,1 -dihydro-5H- dibenzo-[b,f]-azepine, 8.5 g (0.065 mol) of N-(ss-hydroxyethyi)-piperazine in 100 ml of toluene under conditions similar to those of Example 2 there are prepared 12.5 g (73%) of dihydrochloride of 5-(ss-N-/2-hydroxyethylpiperazinyl-1 /propionyl)-3-carboisopropoxyamino- 10,11 -dihydro-5H-dibenzo [b,f]-azepine melting at 180--1840C (decomposition, from isopropanol).
Found, %: C 56.99: H 7.26; Cl 12.13; N 9.67; H20 3.50. C2TH38C12N404.H20.
Calculated, %: C 56.73; H 7.05; Cl 12.40; N 9.80; H20 3.14.
Example 19 5-(Chlornprnpionyl)-3-carboethoxyamino- 10,11 -dihydro-5 H-dibenzo-[b,f]-azepine is prepared in a manner similar to that described in Example 4 hereinbefore.
From 9.3 g (0.025 mol) of 5-(ss-chloropropionyl)-3-carboethoxyamino-10,1 -dihydro-5H- dibenzo-{b,f]-azepine, 3.6 g (0.05 mol) of diethylamine under conditions similar to those described in Example 2 there are prepared 8.5 g (76.2%) of 5-(ss-diethylaminopropionyl)-3-carboethoxyamino- 10,11-dihydro-5H-dibenzo-[b,fl-azepine hydrochloride melting at 164-165 C (from acetone).
Found, %: C 64.86; H 7.41; Cl 8.09. C24H32CI N303.
Calculated, %: C 64.63; H 7.23; CI 7.93.

Claims (9)

Claims
1. 5-(#-Aminoacyl)-3-carbalkoxyamino-10,1 -dihydro-5H-dibenzo-[b,f]-azepines of the general formula:
and salts thereof with inorganic and organic acids, wherein n is 1 to 3, R' is a straight or branched alkyl radical with 1 to 3 carbon atoms, R2 and R3 are lower alkyl radicals the same or different with 1 to 3 carbon atoms or R2 and R3 with nitrogen form a residue of a cyclic amine such as piperidine, morphollne, a N-alkylpiperazine with 1 to 3 carbon atoms in the N-alkyl group, N-(P-hydroxyethyl)- piperazine or N-I ,4-diazobicyclo-[4,m,OJnonane -decane or -undecane.
2. A method for preparing 5-(w-aminoacyl)-3-carbalkoxyamino-1 0,11 -dihydro-5H-dibenzo-[b,f]- azepines and salts thereof according to Claim 1, comprising reacting 3-amino-1 0,11 -dihydro-5H dibenzo-[b,fl-azepine with an alkylchloroformate of the general formula:
wherein R' is a straight or branched alkyl radical with 1 to 3 carbon atoms in an organic solvent, treating the resulting 3-carbalkoxyamino-1 0,11 -dihydro-5H-dibenzo-[b,f]-azepine with a chloroanhydride of co-chlorocarvoxylic acids of the general formula:CICO CH2)nCI, wherein n is 1 to 3, in an organic solvent, reacting the resulting 5-(w-chloroacyl)3-carbalkoxya mino- 10,11 -dihydro-5 H- dibenzo-[b,f]-azepine with a secondary amine of the formula:
wherein R2 and R3 are lower alkyl radicals the same or different with 1 to 3 carbon atoms or R2 and R3 together with nitrogen form a residue of a cyclic amine such as piperidine, morpholine, a Nalkylpiperazine with 1 to 3 carbon atoms in the N-alkyl group, N-(ss-hydroxyethyl)-piperazine or N-1,4- diazobicyclo-[4,m,O]-nonane, -decane, or -undecane in an organic solvent, followed by isolation of the desired product.
3. A method according to Claim 2, wherein the reaction of 3-amino-1 0,11 -dihydro-5H-dibenzo- [b,fl-azepine with the alkylchloroformate is carried out at a temperature within the range of from -5 to +1500.
4. A method according to Claims 2 and 3, wherein as the organic solvent use is made of ethanol, acetone in the presence of a hydrogen-chloride acceptor.
5. A method according to Claim 2, wherein the resulting 3-carbalkoxyamino-10,1 1-dihydro-5H- dibenzo-Eb,fj-azepine is treated with a chloroanhydride of cs-chlorocarboxylic acids at the boiling point of the organic solvent
6. A method according to Claims 2 and 5, wherein as the organic solvent use is made of benzene and toluene.
7. A method according to Claim 2, wherein the resulting 5-(wchloracyl)-3-carbalkoxyamlno- 10,11 -dlhydro-5H-dibenzo-[b,fl-azepine is reacted with secondary amines at the boiling point of the organic solvent
8. A method according to Claims 2 and 7, wherein as the organic solvent use is made of benzene, toluene, acetone, ethanol, isopropanol, propanoi.
9. A method according to the foregoing Claims 2 to 8, substantially as desclosed In the Specification and Examples set forth hereinbefore.
GB8035229A 1979-11-05 1980-11-03 Dibenzazepines Expired GB2065105B (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0405254A2 (en) * 1989-06-30 1991-01-02 ARZNEIMITTELWERK DRESDEN GmbH 3-Carbalkoxyamino-5-(alpha-aminopropionyl)-5H-dibenzo(b,f)-azepines, their preparation and their use
EP0405255A2 (en) * 1989-06-30 1991-01-02 ARZNEIMITTELWERK DRESDEN GmbH 3-Carbalkoxyamino-5-aminoacyl-5H-dibenzo[b,f]-azepines, their salts and process for their preparation

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JPS61159986U (en) * 1985-03-25 1986-10-03

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AR205239A1 (en) * 1974-07-29 1976-04-12 Searle & Co PROCEDURE FOR THE PREPARATION OF A GROUP OF N- (OMEGA-HEXAMETHYLENIMINE-ALKYLEN C2-C6) -5H-BENZO (B, F) -AZEPINE-5-CARBOZAMIDES

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0405254A2 (en) * 1989-06-30 1991-01-02 ARZNEIMITTELWERK DRESDEN GmbH 3-Carbalkoxyamino-5-(alpha-aminopropionyl)-5H-dibenzo(b,f)-azepines, their preparation and their use
EP0405255A2 (en) * 1989-06-30 1991-01-02 ARZNEIMITTELWERK DRESDEN GmbH 3-Carbalkoxyamino-5-aminoacyl-5H-dibenzo[b,f]-azepines, their salts and process for their preparation
EP0405255A3 (en) * 1989-06-30 1991-08-07 Veb Arzneimittelwerk Dresden 3-carbalkoxyamino-5-aminoacyl-5h-dibenzo(b,f)-azepines, their salts and process for their preparation
EP0405254A3 (en) * 1989-06-30 1991-08-07 Veb Arzneimittelwerk Dresden 3-carbalkoxyamino-5-(alpha-aminopropionyl)-5h-dibenzo(b,f)-azepines, their preparation and their use

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DE3040085A1 (en) 1981-06-04
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GB2065105B (en) 1984-01-25
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JPS5690062A (en) 1981-07-21

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