CA1048026A - Process of preparing ethers of 3,4-dihydro-1-benzoxepin-5-one oxime - Google Patents
Process of preparing ethers of 3,4-dihydro-1-benzoxepin-5-one oximeInfo
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- CA1048026A CA1048026A CA205,979A CA205979A CA1048026A CA 1048026 A CA1048026 A CA 1048026A CA 205979 A CA205979 A CA 205979A CA 1048026 A CA1048026 A CA 1048026A
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- dihydro
- benzoxepin
- oxime
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
- C07D313/02—Seven-membered rings
- C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
- C07D313/08—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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Abstract
A B S T R A C T
The invention relates to novel compounds of the formula:
wherein:
R represents a halogen atom or a lower alkoxy group;
n is a n integer which has the value 2 or 3;
Z1 and Z2, which may be identical or different, represent each a lower alkyl group or Z1 and Z2 and the nitrogen atom to which they are attached may together form a 5-membered to 7-membered N-heterocyclic group which may contain a second hetero atom consisting of O, N
or S. These compounds have relaxing action on the smooth intestinal muscle fibres and may be used as intestinal regulators.
The invention relates to novel compounds of the formula:
wherein:
R represents a halogen atom or a lower alkoxy group;
n is a n integer which has the value 2 or 3;
Z1 and Z2, which may be identical or different, represent each a lower alkyl group or Z1 and Z2 and the nitrogen atom to which they are attached may together form a 5-membered to 7-membered N-heterocyclic group which may contain a second hetero atom consisting of O, N
or S. These compounds have relaxing action on the smooth intestinal muscle fibres and may be used as intestinal regulators.
Description
~l~48()26 This invention relates to a process for the prepa-ration of novel compounds, ethers of 3,4-dihydro-1-benzoxepin-5-one oxime of the following general formula (I):
R~ (I) N (CH2)n N~ z wherein:
R represents a halogen atom or a lower alkoxy group;
n represents an integer which has the value 2 or 3j Zl and Z2' which may be identical or different, represent each a lower alkyl group or Zl and Z2 and the nitrogen atom to which they are attached may together form a 5 to 7-membered N-heterocyclic group which may contain a second hetero atom in particular N, 0 or S; and the acid addition salts of the free amine function.
Formula (I) represents the two geometric isomers of the oxime, in the cis or ~rans conf;gurat;on relative to the benzene nucleus.
An ether of 3,4-dihydro-1-benzoxepin-5-one oxime of the formula:
CQ ~ 0 ~
N-O-(CH2)2-N(CH3)2,HCQ
and a process for the preparation of this product have already been described (collection Czechoslov Chem. Commun. 37 868-886 (1972)). This product differs from the products obtained according to the invention by the position of substitution in the benzene nucleus and by its properties. The process of 1 _ ~
~2~
preparation described in the said article is also different from the process according to the present invention.
The process according to the present invention com-prises intramolecular acylation of a phenoxybutyric acid which is R-substituted in the para position to yield a 3,4-dihydro-1-benzoxepin-5-one of the formula (II):
R ~ ~II) which is then reacted with a compound of the formula H2N-0-A in which A represents either the group (CH2)n-NZlZ2, in which case an alcoholic solvent is used in an acid medium at the reflux temperature of the solvent, or a hydrogen atom, in which case the reaction is carried out in pyridine or ethanol under reflux, and the intermediate compouncl thus obtained is reacted in a basic medium with a compound of the formula X-(CH2)n-NZlZ2 in which X represents a halogen atom. In the above de-scription, R, n, Zl and Z2 have the same meanin9 as in the general formula (I).
The acid addition salts are prepared by the action of a mineral or organic acid on compounds of formula (I) dissolved in a suitable solvent.
It was found that the products prepared in this way consisted to an extent of 95 to 100% of the geometric isomer of the oxime in the ~s configuration in relation to the benzene nucleus (determined with the aid of nuclear magnetic resonance, infrared spectography and gas phase chromatography). Isolation of this isomer is achieved in excellent yields by successive recrystallizations of the mixture of addition salts of the free amine function with suitably chosen acids. Isolation of its ~ L~48~
~rans homologue, on the other hand, cannot be achieved satis-factorily. It is recommended to carry out partial isomeri-zation after introduction of the oximino function into the heterocyclic group by applying a method known per se, that is to say by the action of a strong anhydrous acid, preferably a hydrohalic acid, in an aprotic solvent. If this operation is carried out on a compound of the formula:
~0~
R
NOH
substitution on the oxygen atom is subsequently carried out by the general method. Isolation of the compound is achieved as in the case of its eis homologue by recrystallization of the acid addition salts, taking into account the fact that the trans isomer is generally more soluble than the eis homologue.
The oxime ethers prepared in this way have in particular a relaxing action on the smooth intestinal muscle fibres and may be used in human therapy as intestinal regu-lators.
The invention is illustrated by the following non-limiting examples:
The melting points indicated were determined on a K~fler bench. Elementary analysis of the novel compounds was carried out and the results correspond to the generally accepted standards (element determined: C, H, N, halogen).
That substitution took place on the oxygen atom and not the nitrogen atom of the oxime could be confirmed by the electronic paramagnetic resonance.
7-chloro-3,4-dihydro-1-benzoxepin-0-(dimethylaminoethyl)-5-one oxime z~
A - 7-chloro-3,4-dihydro-1-benzoxepin-5~one:
30 ml of 85% phosphoric acid (d - 1.71) are poured into 530 ml of anhydrous toluene. 84 9 of phosphoric anhydride are then added slowly with vigorous stirring. The mixture is kept on a boiling water bath for 2 hours, and a tepid solution of 24 9 of e-chlorophenoxy butyric acid(Mp = 123C) in 800 ml of anhydrous toluene is then added~ still at the same tempera-ture, in the course of 2 hours. Heating is continued for 5 hours and the reaction mixture is cooled.
The upper toluene phase is separated, shaken with an equal volume of water and after decantation shaken twice with the same volume of 5% soda. It is then neutralized by washing with water and dried over sodium sulphate. After evaporation of the solvent under reduced pressure, 11.5 9 of a yellow oil are obtained.
The lower phosphoric phase is poured over 3 volumes of crushed ice. This solution is shaken twice with ether at room temperature.
The ethereal phases are shaken in the presence of 5%
soda and, after decantation of the aqueous phase, they are neutralized and dried over sodium sulphate. After evaporation of the solvent under reduced pressure, 5 g of a yellow oil are obtained.
The two oily fractions are combined and distilled under reduced pressure. 12 g of ketone are obtained in the form of a colourless liquid with a boiling point of 105-108C
at 0.02 mm. Hg.
B - 7-chloro-3,4-dihydro-1-benzoxepin-5-one oxime:
A solution of 50 9 of the benzoxepinone previously obtained and 26 g of hyclroxylamine hydrochloride in 200 ml of pyridine is kept at the reflux temperature of pyridine for 5 hours.
The pyridine is then evaporated off under reduced pressure, 300 ml of water are poured over the evaporation residue and the aqueous phase is extracted three times with ether. The organic solutions are washed with water until the wash waters arP neutral and dried over sodium sulphate and then over magnesium sulphate and the solvent is evaporated off under reduced pressure.
The evaporation residue is recrystallized from abso-lute ethanol. 47 g of pure oxime, a white product which meltsat 101-102C, are obtained.
C - 7-chloro-3,4-dihydro-1-benzoxepin-0-(dimethylaminoethyl)-5-one oxime 7.1 9 of the oxime previously obtained are introduced into 30 ml of a solution of sodium ethylate in ethanol (pre-pared with 0.9 9 of sodium). The reaction mixture is heated at the reflux temperature of the solvent for 1 hour. 50 ml of anhydrous dimethylformamide are then introduced and the ethanol is evaporated off under reduced pressure. 4 g of (2-chloro)-ethyl dimethylamine are added and the mixture is kept at 80Cfor 6 hours. It i5 then cooled, the mineral salts are filtered and the solvent is evaporated under reduced pressure.
The residue is dissolved in a normal aqueous solution of hydrochloric acid and, after extraction with ether, the solution is made alkaline by the addition of a normal soda solution. The oxime ether is then extracted in methylene chloride, and the solvent is evaporated off after drying.
The oily residue is dissolved in ether and the amine hydrochloride is precipitated from the resulting solution by the addition of hydrochloric acid. The hydrochloride is recrystallized from a mixture of ethyl acetate and isopropanol (75 : 25). It melts at 180C.
~04~8~;26 The yield of this stage is 40%.
7-chloro-3,4-dihydro-1-benzoxepin-0-(diethylaminoethyl)-5-one oxime: isomer with the c~s configuration in relation to the benzene nucleus.
1.2 g of 50% sodium hydride are added slowly with stirring and slight cooling to a solution of 5 g of 7-chloro-3,4-dihydro-1-benzoxepin-5-one oxime in 25 ml of anhydrous dimethyl-formamide. This sodium salt may also be prepared by reaction with sodium ethylate in ethanol followed by dissolving in dimethylformamide.
After one hour's stirring at room temperature, 3.1 9 of (2-chloro)-ethyl diethylamine are introduced into the reaction mixture in the course of 15 minutes. One hour later, 200 ml of water are added and the final reaction product is extracted with ether. It is then extracted from the ether with a 5% solution of acetic acid. The aqueous phase is made alka-line by the addition of K2C03 and the amine is again extracted with ether.
After drying of the organic solution, the solvent is evaporated and the oily residue is distilled under reduced pressure.
The boiling point of the basic oxime ether finally obtained is 137C at 2 x 10 2 mm. Hg.
The yield of distilled amine is 60%.
Its hydrochloride prepared in ether is recrystallized from a mixture of isopropyl ether and l,2-dichloroethane (60 : 40). It melts at 115 - 116C.
This salt also can be recrystallized from ethyl acetate but, if it is subjected to prolonged heating in the course of this operation, another crystalline form of the product appears, which has a melting point of 132C.
~L~14~216i The geometric isomer of this oxime ether, which has the ~s configuration in relation to the benzene nucleus, may advantageously be separated from traces of its trans homologue in the form of its acid addition salt with hydrobromic acid by recrystallisation from isopropanol. The hydrobromide melts at ll~C
7-chloro-3,4-dihydro-1-benzoxepin-0-(diethylaminoethyl)-5-one oxime: tYans isomer A solution of 50 9 of 7-chloro-3,4-dihydro-1-benz-oxepin-5-one oxime in 800 cc of anhydrous chloroform is satu-rated with anhydrous hydrochloric acid and the mixture is continuously stirred at 20C for about 24 hours. The precipi-tate formed is then isolated and the filtrate is twice brought into contact with a saturated aqueous sodium bicarbonate solution and then with water until neutral. The organic phase is dehydrated with sodium sulphate and the solvent is evapo-rated under reduced pressure. The evaporation residue is recrystallised from cyclohexane. 40 9 of a product melting in the region of 95C are obtained. The product consists of a mixture of nearly equivalent proportions of the two geometric isomers of the oxime.
The geometric isomer which has the trans configur-ation in relation to the benzene nucleus can be separated from its homologue by subjecting the mixture to chromatography on a silica column, using diethyl ether as the eluent. The trans isomer melts at 150C after recrystallisation from isopropanol.
0-alkylation of the 50/50 mixture of the two isomers is carried out in dimethylformamide, using the method described in example 2. The crude amine obtained consists of nearly the same proportions of isomers as the starting material.
The hemifumarate of the amine function is then pre-pared as follows: 11.45 9 of the oil obtained are dissolved in 50 ml of ethanol, and 4.3 9 of fumaric acld are added. The solution is heated at reflux for 1/4 of an hour and then conled, and one volume of diethyl ether is added. The precipi-tate obtained is isolated. It consists to an extent of at least 90% of the isomer which has the eis configuration in relation to the benzene nucleus. The filtrate is made alkaline by the addition of sodium carbonate. The ethanol is then evaporated off under reduced pressure and the desired product is obtained in the form of the amine by extraction with diethyl ether. After drying of the solutiong the amine hydrochloride is prepared by the addition of anhydrous hydrochloric acid.
The precipitate is filtered and dried. It is then purified by preparing solutions of this hydrochloride in a solvent at 25C, preferably ethanol, and then reprecipitating the product by the addition of diethyl ether. 1.5 9 of the hydrochloride of the t~ans isomer of 7-chloro-3,4-dihydro-1-benzoxepin-0-(diethyl-aminoethyl)-5-one oxime is thereby obtained, which melts at 144C.
Examples 4 and 5 illustrate two other methods of preparation of the product described in example 2.
Preparation of 7-chloro-3,4-dihydro-1-benzoxepin-0-(diethyl-aminoethyl)-5-one oxime from 7-chloro-3,4-dihydro-1-benzoxepin-5-one and 0-(diethylaminoethyl)-hydroxylamine:
10.25 9 of the dihydrochloride of 0-(diethylamino-ethyl)-hydroxylamine are added to a solution of 19.65 9 of 7-chloro-3,4-dihydro-1-benzoxepin-5-one in 100 ml of absolute ethanol, and the reaction mixture is heated to the reflux temperature of the solvent for 5 hours. After 11 hours under reflux, a further 10.25 9 of the dihydrochloride of 0-(diethyl-~.~48~26 aminoethyl)-hydroxylamine are added to the reaction mixture.
The solvent is then evaporated under reduced pressure and a dilute solution of hydrochloric acid is poured over the residue. The aqueous phase obtained is washed with ether and then made alkaline by the addition of sodium carbonate.
The final product is extracted with ether. The organic phase is dried over sodium sulphate and the magnesium sulphate and the solvent is evapora~ed under reduced pressure.
13.9 9 of oil are obtained.
The hydrochloride of the end product is prepared in ether by the action of gaseous hydrochloric acid. After recrystallisation from a mixture of isopropyl ether and 1,2-dichloroethane (60: 40) in the presence of animal charcoal, 10.5 g of the hydrochloride of the desired product are obtained in the form of white crystals melting at 115 - 116C.
The hemifumarate of the end product is prepared in ethanol by adding an equimolecular proportion of fu~aric acid to the amine solution, and is precipitated from this reaction medium by the addition of petroleum ether. After recrystalli-20 sation, from a mixture of isopropanol and isopropyl ether(50: 50), the pure hemifumarate melts at 98C.
Preparation of 7-chloro-3,4-dihydro-1-benzoxepin-0-(diethyl-aminoethyl)-5-one oxime from 7-chloro-3,4-dihydro-1-benzoxepin-5-one oxime: _ _ A mixture of 5.3 g of 7-chloro-3,4-dihydro-1-benz-oxepin-5-one oxime, 4~3 g of the hydrochloride of (2-chloro)-ethyl diethylamine, 10.7 g of potassium carbonate and 50 ml of benzene is kept at the reflux temperature of the solvent for 30 15 hours. The mineral precipitate is then filtered and the benzene phase is washed with a normal aqueous soda solution and the end product is extracted with a normal aqueous solution of ~al4~Z6 hydrochloric acid. After washing with ether, the aqueous phase is made alkaline by the addition of sodium carbonate and the end product is extracted with ether. After dehydration of the solution and evaporation of the solver,t, 7.8 9 of a yellow oil are obtained from which 6.3 9 of the desired hydrochloride of the basic oxime ether are prepared. Melting point of the hydrochloride: 115 - 116C.
7-chloro-3,4-dihydro-1-benzoxepin-0-(morpholinoethyl)-5-one oxime 11 g of this compound are obtained from 7.6 9 of 7-chloro-3,4-dihydro-1-benzoxepin-5-one oxime and 6 g of N-(2-chloroethyl)-morpholine by the method of preparation described in example 1.
The hydrochloride prepared in hydrochloric ether and recrystallised from ethyl acetate melts at 140C.
7-chloro-3,4-dihydro-1-benzoxepin-0-(1-pyrrolidinyl-ethyl)-5-one oxime __ 16.3 9 of the dihydrochloride of 0-(1-pyrrolidinyl-ethyl)-hydroxylamine (Mp = 150C) and a few drops of concen-trated hydrochloric acid are added to 15.7 9 of 7-chloro-3,4-dihydro-l-benzoxepin-5-one dissolved in 100 ml of 95% ethanol, and the reaction mixture is heated at the reflux temperature of the solvent for 6 hours.
The solvent is evaporated off under reduced pressure and the residue is taken up with normal hydrochloric acid, unreacted ketone is extracted with ether, the aqueous phase is made alkaline by the addition of sodium carbonate, and the amine end product is extracted with benzene.
The solution in benzene is copiously washed with water and then dried over magnesium sulphate and the solvent is 1(D4~3~)Z~i evaporated off under reduced pressure.
The hydrochloride of the amine is prepared in hydro-chloric ether and then recrystallised from isopropanol. It melts at 154 - 155C. The yield based on the ketone is 45%.
7-chloro-3,4-dihydro-1-benzoxepin-0-(dimethylaminopropyl)-5-one oxime -Applying the method of preparation described in example 1 and reacting 7.6 9 of oxime and 4.9 9 of (3-chloro)-10 propyl dimethylamine at stage (C), 7 9 of crude end product areobtained in the form of an oil.
The hydrochloride prepared in hydrochloric ether melts at 166C after recrystallisation from isopropanol.
7-methoxy-3,4 dihydro-1-benzoxepin-0--(dimethylaminoethyl)-5-one oxime -A - 7-methoxy-3,4-dihydro-1-benzoxepin-5-one 40 ml of concentrated phosphoric acid (d - 1.71) are added to 300 ml of anhydrous toluene. 70 9 of phosphorus 20 pentoxide are then slowly added with vigorous stirring. The mixture is kept on a boiling water bath for 2 hours. A tepid solution of 20 9 of p-methoxyphenoxybutyric acid (Mp = 104C) in 1 litre of anhydrous toluene is then added at this temper-ature in the course of 2 hours. The mixture is kept on the boiling water bath for a further 3 hours and then cooled. The upper toluene phase is decanted and the lower phase is poured over 2 volumes of crushed ice. When the whole mixture has ad-justed to room temperature, the organic products are extracted with ethyl acetate. After washing this phase with water and 30 then with a solution of sodium bicarbonate and neutralising, it is dried over magnesium sulphate and the solvent is evaporated under reduced pressure. 15.4 9 of an oil are obtained which ~48~Z6 after distillation yields 12 9 of 7-methoxy-3,4-dihydro-1-benz-oxepin-5-one which has a boiling point of 110C at 0.02 mm. Hg.
B - 7-methoxy-3,4-dihydro-1-benzoxepin-5-one oxime 6.95 g of hydroxylamine hydrochloride dissolved in 15 ml of water and 5.3 9 of sodium carbonate are added to a solution of 19.2 9 of 7-methoxy-3,4-dihydro-1-benzoxepin-5-one in 45 ml of ethanol. The mixture is stirred for 24 hours at room temperature. 100 ml of water are then added and the alco-hol is evaporated. The aqueous solution is made alkaline by the addition of soda, and unreacted benzoxepinone is extracted with ether. The aqueous phase is neutralised and the desired oxime is extracted with ether. After drying the organic solution and evaporating the solvent under reduced pressure, a white solid is obtained which when recrystallised from cyclo-hexane yields 17 9 of the desired product in the pure form which has a melting point of 103 - 104C.
C - 7-methoxy-3,4-dihydro-1-benzoxepin-0-(dimethylaminoethyl)-5-one oxime 5.84 g of the oxime prepared as indicated above are added to 30 ml of a solution of sodium ethylate prepared from 0.8 9 of sodium, and the mixture is heated on a boiling water bath for 1 hour. 30 ml of anhydrous dimethylformamide are then added and the alcohol is evaporated under reduced pressure.
3.2 9 of (2-chloro)-ethyl dimethylamine are added and the reaction mixture is kept on a boiling water bath -For 1 hour.
The solvent is evaporated under reduced pressure and the residue is taken up with an aqueous 10% hydrochloric acid solution. This phase is washed once with ether and made alka-line by the addition of 10% soda.
The end product is extracted with methylene chloride,the organic phase is dried and the solvent is evaporated under h8~
reduced pressure. The oil obtain d is distilled. Boiling point: 160C at 0.5 mm. Hg.
4.1 9 of the amine end product are obtained. The hydrochloride prepared in hydrochloric ether and recrystallised from isopropanol melts at 178C.
7-methoxy-3,4-dihydro-1-benzoxepin-0-(diethylaminoethyl)-5-one oxime Applying the method of preparation described in example 9 and reacting 7.25 9 of oxime and 6.8 9 of (2-chloro)-ethyl diethylamine at stage (C), 7 9 of the crude amine end product are obtained.
The hydrochloride prepared in hydrochloric ether melts at 180C after recrystallisation from ethyl acetate.
7-methoxy-3,4-dihydro-1-benzoxepin-0-(dimethylaminopropyl)-5-one oxime Applying the method of preparation described in example 9 and reacting 5.85 9 of oxime and 4 9 of (3-chloro)-propyl dimethylamine at stage (C), 6.2 9 of the amine end product are obtained in the form of a yellow oil.
The hemioxalate of the amine is prepared in ethanol by reacting the amine and acid in equimolecular proportions.
After recrystallisation from ethanol, the pure hemioxalate melts at 130C.
7-bromo-3,4-dihydro-1-benzoxepin-0-(diethylaminoethyl)-5-one oxime -A - 7-bromo-3,4-dihydro-1-benzoxepin-5~one:
This heterocyclic ketone is prepared with a 40% yield from p-bromophenoxy butyric acid (Mp - 132C) by the method described in example 1 (A). Its boiling point is 105C at 0.06 8~
mm. Hg.
B - 7-bromo-3,4-dihydro-1-benzoxepin-0-(diethylaminoethyl)-5-one oxime The amine is prepared by reacting the benzoxepinone previously obtained with the dihydrochloride of 0-(diethyl-aminoethyl) hydroxylamine by the method of operation described in example 4. 4.5 g of end product are obtained in the form of an oil from 7 g of 7-bromo-3,4-dihydro-1-benzoxepin-5-one.
The hydrochloride of this amine is prepared in ether by the action of gaseous hydrochloric acid and purified by dis-solving it in ethanol and then reprecipitating it by the addition of ethyl ether. It melts at 138C.
The yield of hydrochloride from the ketone is 50%.
Toxicological and pharmacological studies of the products of the invention demonstrated the originality of their activity compared with known products. The tests were carried out on acid addition salts of the amines of the general formula.
The acute toxicity was determined on male mice of the strain Swiss C.D weighing on average 20 grammes, after oral administration (P.0) and intravenous administration (I.V).
The relaxant action at the level of the smooth intestinal muscle fibre was demonstrated in vitro on the isolated organ and in vivo on the anaesthetised dog by applying the following techniques:
For the tests on the isolated organ: an organ fragment of rat duodenum or guinea pig ileum is kept alive in 50 ml of an oxygenated and thermostatically controlled (37C) tyrode solution. The activity of the compounds is tested on the spontaneous movement of the organ and on the contractions produced by the addition of a solution of barium chloride or acetyl choline to the bath. The movements were recorded on a DMP 4A Roucaire physiograph.
For the in vivo tests: a small balloon is introduced at the level of the terminal part of the duodenum in the chloralosed animal and the intestinal movements are recorded on a Beckman polygraph with the aid of a Statham PM 97 gauge.
The results relating to the acute toxicity and to the relaxant activity in vi~ro are shown in table 1.
The in vivo tests showed that the products of the invention and in particular those of examples 1, 2, 7, 8 and 12 administered intravenously in a dose of 2 mg/kg had an effect which was comparable with or even superior to that of atropine administered in a dose of 50 mg/kg as regards the reduction in intestinal tone and peristalsis. In contrast to atropine, however, this relaxant activity is produced without any anti-cholinergic or vagolytic activity.
Pharmaceutical compositions containing as active ingredient at least one product according to the invention may be presented, for example, in the form of tablets or injection solutionsO
The tablets may contain about 75 mg of active ingredient and known excipients such as microcrystalline cellu-lose, carboxymethyl starch, talcum and magnesium stearate.
The injection ampoules may contain about 25 mg. of active ingredient and a sufficient quantity of glycine to render the product isotonic.
TABLE I
C O M P O U N D TOXICITY in miceISOLATED ORGANS:
LD = (mg/kg)Minimum active dose of 50 Concentration in mcg/ml ______ _ __ _ __ ___ __ example P.O I.V DECONTRACTION ANTI-ACETYL
(rat duodenum) C~IOLINE
(guinea pig 1150 32 0.06 5.5 10 (hydrochloride) 2420 37 0.1 (hydrochloride) 6> 1000 120 0.15 5.5 (hydrochloride) 7450 35 1.5 1.3 (hydrochloride) 8500 60 0.12 3.5 (hydrochloride) 9500 35 0.12 1.5 20 (hydrochloride) .
10450 45 0.5 0.5 (hydrochloride) 11> 1000 _ 0.3 2.0 (hemioxalate) 12250 40 0.1 (hydrochloride) _ ATROPINE 600 90 inactive 0.006 (sulphate) _
R~ (I) N (CH2)n N~ z wherein:
R represents a halogen atom or a lower alkoxy group;
n represents an integer which has the value 2 or 3j Zl and Z2' which may be identical or different, represent each a lower alkyl group or Zl and Z2 and the nitrogen atom to which they are attached may together form a 5 to 7-membered N-heterocyclic group which may contain a second hetero atom in particular N, 0 or S; and the acid addition salts of the free amine function.
Formula (I) represents the two geometric isomers of the oxime, in the cis or ~rans conf;gurat;on relative to the benzene nucleus.
An ether of 3,4-dihydro-1-benzoxepin-5-one oxime of the formula:
CQ ~ 0 ~
N-O-(CH2)2-N(CH3)2,HCQ
and a process for the preparation of this product have already been described (collection Czechoslov Chem. Commun. 37 868-886 (1972)). This product differs from the products obtained according to the invention by the position of substitution in the benzene nucleus and by its properties. The process of 1 _ ~
~2~
preparation described in the said article is also different from the process according to the present invention.
The process according to the present invention com-prises intramolecular acylation of a phenoxybutyric acid which is R-substituted in the para position to yield a 3,4-dihydro-1-benzoxepin-5-one of the formula (II):
R ~ ~II) which is then reacted with a compound of the formula H2N-0-A in which A represents either the group (CH2)n-NZlZ2, in which case an alcoholic solvent is used in an acid medium at the reflux temperature of the solvent, or a hydrogen atom, in which case the reaction is carried out in pyridine or ethanol under reflux, and the intermediate compouncl thus obtained is reacted in a basic medium with a compound of the formula X-(CH2)n-NZlZ2 in which X represents a halogen atom. In the above de-scription, R, n, Zl and Z2 have the same meanin9 as in the general formula (I).
The acid addition salts are prepared by the action of a mineral or organic acid on compounds of formula (I) dissolved in a suitable solvent.
It was found that the products prepared in this way consisted to an extent of 95 to 100% of the geometric isomer of the oxime in the ~s configuration in relation to the benzene nucleus (determined with the aid of nuclear magnetic resonance, infrared spectography and gas phase chromatography). Isolation of this isomer is achieved in excellent yields by successive recrystallizations of the mixture of addition salts of the free amine function with suitably chosen acids. Isolation of its ~ L~48~
~rans homologue, on the other hand, cannot be achieved satis-factorily. It is recommended to carry out partial isomeri-zation after introduction of the oximino function into the heterocyclic group by applying a method known per se, that is to say by the action of a strong anhydrous acid, preferably a hydrohalic acid, in an aprotic solvent. If this operation is carried out on a compound of the formula:
~0~
R
NOH
substitution on the oxygen atom is subsequently carried out by the general method. Isolation of the compound is achieved as in the case of its eis homologue by recrystallization of the acid addition salts, taking into account the fact that the trans isomer is generally more soluble than the eis homologue.
The oxime ethers prepared in this way have in particular a relaxing action on the smooth intestinal muscle fibres and may be used in human therapy as intestinal regu-lators.
The invention is illustrated by the following non-limiting examples:
The melting points indicated were determined on a K~fler bench. Elementary analysis of the novel compounds was carried out and the results correspond to the generally accepted standards (element determined: C, H, N, halogen).
That substitution took place on the oxygen atom and not the nitrogen atom of the oxime could be confirmed by the electronic paramagnetic resonance.
7-chloro-3,4-dihydro-1-benzoxepin-0-(dimethylaminoethyl)-5-one oxime z~
A - 7-chloro-3,4-dihydro-1-benzoxepin-5~one:
30 ml of 85% phosphoric acid (d - 1.71) are poured into 530 ml of anhydrous toluene. 84 9 of phosphoric anhydride are then added slowly with vigorous stirring. The mixture is kept on a boiling water bath for 2 hours, and a tepid solution of 24 9 of e-chlorophenoxy butyric acid(Mp = 123C) in 800 ml of anhydrous toluene is then added~ still at the same tempera-ture, in the course of 2 hours. Heating is continued for 5 hours and the reaction mixture is cooled.
The upper toluene phase is separated, shaken with an equal volume of water and after decantation shaken twice with the same volume of 5% soda. It is then neutralized by washing with water and dried over sodium sulphate. After evaporation of the solvent under reduced pressure, 11.5 9 of a yellow oil are obtained.
The lower phosphoric phase is poured over 3 volumes of crushed ice. This solution is shaken twice with ether at room temperature.
The ethereal phases are shaken in the presence of 5%
soda and, after decantation of the aqueous phase, they are neutralized and dried over sodium sulphate. After evaporation of the solvent under reduced pressure, 5 g of a yellow oil are obtained.
The two oily fractions are combined and distilled under reduced pressure. 12 g of ketone are obtained in the form of a colourless liquid with a boiling point of 105-108C
at 0.02 mm. Hg.
B - 7-chloro-3,4-dihydro-1-benzoxepin-5-one oxime:
A solution of 50 9 of the benzoxepinone previously obtained and 26 g of hyclroxylamine hydrochloride in 200 ml of pyridine is kept at the reflux temperature of pyridine for 5 hours.
The pyridine is then evaporated off under reduced pressure, 300 ml of water are poured over the evaporation residue and the aqueous phase is extracted three times with ether. The organic solutions are washed with water until the wash waters arP neutral and dried over sodium sulphate and then over magnesium sulphate and the solvent is evaporated off under reduced pressure.
The evaporation residue is recrystallized from abso-lute ethanol. 47 g of pure oxime, a white product which meltsat 101-102C, are obtained.
C - 7-chloro-3,4-dihydro-1-benzoxepin-0-(dimethylaminoethyl)-5-one oxime 7.1 9 of the oxime previously obtained are introduced into 30 ml of a solution of sodium ethylate in ethanol (pre-pared with 0.9 9 of sodium). The reaction mixture is heated at the reflux temperature of the solvent for 1 hour. 50 ml of anhydrous dimethylformamide are then introduced and the ethanol is evaporated off under reduced pressure. 4 g of (2-chloro)-ethyl dimethylamine are added and the mixture is kept at 80Cfor 6 hours. It i5 then cooled, the mineral salts are filtered and the solvent is evaporated under reduced pressure.
The residue is dissolved in a normal aqueous solution of hydrochloric acid and, after extraction with ether, the solution is made alkaline by the addition of a normal soda solution. The oxime ether is then extracted in methylene chloride, and the solvent is evaporated off after drying.
The oily residue is dissolved in ether and the amine hydrochloride is precipitated from the resulting solution by the addition of hydrochloric acid. The hydrochloride is recrystallized from a mixture of ethyl acetate and isopropanol (75 : 25). It melts at 180C.
~04~8~;26 The yield of this stage is 40%.
7-chloro-3,4-dihydro-1-benzoxepin-0-(diethylaminoethyl)-5-one oxime: isomer with the c~s configuration in relation to the benzene nucleus.
1.2 g of 50% sodium hydride are added slowly with stirring and slight cooling to a solution of 5 g of 7-chloro-3,4-dihydro-1-benzoxepin-5-one oxime in 25 ml of anhydrous dimethyl-formamide. This sodium salt may also be prepared by reaction with sodium ethylate in ethanol followed by dissolving in dimethylformamide.
After one hour's stirring at room temperature, 3.1 9 of (2-chloro)-ethyl diethylamine are introduced into the reaction mixture in the course of 15 minutes. One hour later, 200 ml of water are added and the final reaction product is extracted with ether. It is then extracted from the ether with a 5% solution of acetic acid. The aqueous phase is made alka-line by the addition of K2C03 and the amine is again extracted with ether.
After drying of the organic solution, the solvent is evaporated and the oily residue is distilled under reduced pressure.
The boiling point of the basic oxime ether finally obtained is 137C at 2 x 10 2 mm. Hg.
The yield of distilled amine is 60%.
Its hydrochloride prepared in ether is recrystallized from a mixture of isopropyl ether and l,2-dichloroethane (60 : 40). It melts at 115 - 116C.
This salt also can be recrystallized from ethyl acetate but, if it is subjected to prolonged heating in the course of this operation, another crystalline form of the product appears, which has a melting point of 132C.
~L~14~216i The geometric isomer of this oxime ether, which has the ~s configuration in relation to the benzene nucleus, may advantageously be separated from traces of its trans homologue in the form of its acid addition salt with hydrobromic acid by recrystallisation from isopropanol. The hydrobromide melts at ll~C
7-chloro-3,4-dihydro-1-benzoxepin-0-(diethylaminoethyl)-5-one oxime: tYans isomer A solution of 50 9 of 7-chloro-3,4-dihydro-1-benz-oxepin-5-one oxime in 800 cc of anhydrous chloroform is satu-rated with anhydrous hydrochloric acid and the mixture is continuously stirred at 20C for about 24 hours. The precipi-tate formed is then isolated and the filtrate is twice brought into contact with a saturated aqueous sodium bicarbonate solution and then with water until neutral. The organic phase is dehydrated with sodium sulphate and the solvent is evapo-rated under reduced pressure. The evaporation residue is recrystallised from cyclohexane. 40 9 of a product melting in the region of 95C are obtained. The product consists of a mixture of nearly equivalent proportions of the two geometric isomers of the oxime.
The geometric isomer which has the trans configur-ation in relation to the benzene nucleus can be separated from its homologue by subjecting the mixture to chromatography on a silica column, using diethyl ether as the eluent. The trans isomer melts at 150C after recrystallisation from isopropanol.
0-alkylation of the 50/50 mixture of the two isomers is carried out in dimethylformamide, using the method described in example 2. The crude amine obtained consists of nearly the same proportions of isomers as the starting material.
The hemifumarate of the amine function is then pre-pared as follows: 11.45 9 of the oil obtained are dissolved in 50 ml of ethanol, and 4.3 9 of fumaric acld are added. The solution is heated at reflux for 1/4 of an hour and then conled, and one volume of diethyl ether is added. The precipi-tate obtained is isolated. It consists to an extent of at least 90% of the isomer which has the eis configuration in relation to the benzene nucleus. The filtrate is made alkaline by the addition of sodium carbonate. The ethanol is then evaporated off under reduced pressure and the desired product is obtained in the form of the amine by extraction with diethyl ether. After drying of the solutiong the amine hydrochloride is prepared by the addition of anhydrous hydrochloric acid.
The precipitate is filtered and dried. It is then purified by preparing solutions of this hydrochloride in a solvent at 25C, preferably ethanol, and then reprecipitating the product by the addition of diethyl ether. 1.5 9 of the hydrochloride of the t~ans isomer of 7-chloro-3,4-dihydro-1-benzoxepin-0-(diethyl-aminoethyl)-5-one oxime is thereby obtained, which melts at 144C.
Examples 4 and 5 illustrate two other methods of preparation of the product described in example 2.
Preparation of 7-chloro-3,4-dihydro-1-benzoxepin-0-(diethyl-aminoethyl)-5-one oxime from 7-chloro-3,4-dihydro-1-benzoxepin-5-one and 0-(diethylaminoethyl)-hydroxylamine:
10.25 9 of the dihydrochloride of 0-(diethylamino-ethyl)-hydroxylamine are added to a solution of 19.65 9 of 7-chloro-3,4-dihydro-1-benzoxepin-5-one in 100 ml of absolute ethanol, and the reaction mixture is heated to the reflux temperature of the solvent for 5 hours. After 11 hours under reflux, a further 10.25 9 of the dihydrochloride of 0-(diethyl-~.~48~26 aminoethyl)-hydroxylamine are added to the reaction mixture.
The solvent is then evaporated under reduced pressure and a dilute solution of hydrochloric acid is poured over the residue. The aqueous phase obtained is washed with ether and then made alkaline by the addition of sodium carbonate.
The final product is extracted with ether. The organic phase is dried over sodium sulphate and the magnesium sulphate and the solvent is evapora~ed under reduced pressure.
13.9 9 of oil are obtained.
The hydrochloride of the end product is prepared in ether by the action of gaseous hydrochloric acid. After recrystallisation from a mixture of isopropyl ether and 1,2-dichloroethane (60: 40) in the presence of animal charcoal, 10.5 g of the hydrochloride of the desired product are obtained in the form of white crystals melting at 115 - 116C.
The hemifumarate of the end product is prepared in ethanol by adding an equimolecular proportion of fu~aric acid to the amine solution, and is precipitated from this reaction medium by the addition of petroleum ether. After recrystalli-20 sation, from a mixture of isopropanol and isopropyl ether(50: 50), the pure hemifumarate melts at 98C.
Preparation of 7-chloro-3,4-dihydro-1-benzoxepin-0-(diethyl-aminoethyl)-5-one oxime from 7-chloro-3,4-dihydro-1-benzoxepin-5-one oxime: _ _ A mixture of 5.3 g of 7-chloro-3,4-dihydro-1-benz-oxepin-5-one oxime, 4~3 g of the hydrochloride of (2-chloro)-ethyl diethylamine, 10.7 g of potassium carbonate and 50 ml of benzene is kept at the reflux temperature of the solvent for 30 15 hours. The mineral precipitate is then filtered and the benzene phase is washed with a normal aqueous soda solution and the end product is extracted with a normal aqueous solution of ~al4~Z6 hydrochloric acid. After washing with ether, the aqueous phase is made alkaline by the addition of sodium carbonate and the end product is extracted with ether. After dehydration of the solution and evaporation of the solver,t, 7.8 9 of a yellow oil are obtained from which 6.3 9 of the desired hydrochloride of the basic oxime ether are prepared. Melting point of the hydrochloride: 115 - 116C.
7-chloro-3,4-dihydro-1-benzoxepin-0-(morpholinoethyl)-5-one oxime 11 g of this compound are obtained from 7.6 9 of 7-chloro-3,4-dihydro-1-benzoxepin-5-one oxime and 6 g of N-(2-chloroethyl)-morpholine by the method of preparation described in example 1.
The hydrochloride prepared in hydrochloric ether and recrystallised from ethyl acetate melts at 140C.
7-chloro-3,4-dihydro-1-benzoxepin-0-(1-pyrrolidinyl-ethyl)-5-one oxime __ 16.3 9 of the dihydrochloride of 0-(1-pyrrolidinyl-ethyl)-hydroxylamine (Mp = 150C) and a few drops of concen-trated hydrochloric acid are added to 15.7 9 of 7-chloro-3,4-dihydro-l-benzoxepin-5-one dissolved in 100 ml of 95% ethanol, and the reaction mixture is heated at the reflux temperature of the solvent for 6 hours.
The solvent is evaporated off under reduced pressure and the residue is taken up with normal hydrochloric acid, unreacted ketone is extracted with ether, the aqueous phase is made alkaline by the addition of sodium carbonate, and the amine end product is extracted with benzene.
The solution in benzene is copiously washed with water and then dried over magnesium sulphate and the solvent is 1(D4~3~)Z~i evaporated off under reduced pressure.
The hydrochloride of the amine is prepared in hydro-chloric ether and then recrystallised from isopropanol. It melts at 154 - 155C. The yield based on the ketone is 45%.
7-chloro-3,4-dihydro-1-benzoxepin-0-(dimethylaminopropyl)-5-one oxime -Applying the method of preparation described in example 1 and reacting 7.6 9 of oxime and 4.9 9 of (3-chloro)-10 propyl dimethylamine at stage (C), 7 9 of crude end product areobtained in the form of an oil.
The hydrochloride prepared in hydrochloric ether melts at 166C after recrystallisation from isopropanol.
7-methoxy-3,4 dihydro-1-benzoxepin-0--(dimethylaminoethyl)-5-one oxime -A - 7-methoxy-3,4-dihydro-1-benzoxepin-5-one 40 ml of concentrated phosphoric acid (d - 1.71) are added to 300 ml of anhydrous toluene. 70 9 of phosphorus 20 pentoxide are then slowly added with vigorous stirring. The mixture is kept on a boiling water bath for 2 hours. A tepid solution of 20 9 of p-methoxyphenoxybutyric acid (Mp = 104C) in 1 litre of anhydrous toluene is then added at this temper-ature in the course of 2 hours. The mixture is kept on the boiling water bath for a further 3 hours and then cooled. The upper toluene phase is decanted and the lower phase is poured over 2 volumes of crushed ice. When the whole mixture has ad-justed to room temperature, the organic products are extracted with ethyl acetate. After washing this phase with water and 30 then with a solution of sodium bicarbonate and neutralising, it is dried over magnesium sulphate and the solvent is evaporated under reduced pressure. 15.4 9 of an oil are obtained which ~48~Z6 after distillation yields 12 9 of 7-methoxy-3,4-dihydro-1-benz-oxepin-5-one which has a boiling point of 110C at 0.02 mm. Hg.
B - 7-methoxy-3,4-dihydro-1-benzoxepin-5-one oxime 6.95 g of hydroxylamine hydrochloride dissolved in 15 ml of water and 5.3 9 of sodium carbonate are added to a solution of 19.2 9 of 7-methoxy-3,4-dihydro-1-benzoxepin-5-one in 45 ml of ethanol. The mixture is stirred for 24 hours at room temperature. 100 ml of water are then added and the alco-hol is evaporated. The aqueous solution is made alkaline by the addition of soda, and unreacted benzoxepinone is extracted with ether. The aqueous phase is neutralised and the desired oxime is extracted with ether. After drying the organic solution and evaporating the solvent under reduced pressure, a white solid is obtained which when recrystallised from cyclo-hexane yields 17 9 of the desired product in the pure form which has a melting point of 103 - 104C.
C - 7-methoxy-3,4-dihydro-1-benzoxepin-0-(dimethylaminoethyl)-5-one oxime 5.84 g of the oxime prepared as indicated above are added to 30 ml of a solution of sodium ethylate prepared from 0.8 9 of sodium, and the mixture is heated on a boiling water bath for 1 hour. 30 ml of anhydrous dimethylformamide are then added and the alcohol is evaporated under reduced pressure.
3.2 9 of (2-chloro)-ethyl dimethylamine are added and the reaction mixture is kept on a boiling water bath -For 1 hour.
The solvent is evaporated under reduced pressure and the residue is taken up with an aqueous 10% hydrochloric acid solution. This phase is washed once with ether and made alka-line by the addition of 10% soda.
The end product is extracted with methylene chloride,the organic phase is dried and the solvent is evaporated under h8~
reduced pressure. The oil obtain d is distilled. Boiling point: 160C at 0.5 mm. Hg.
4.1 9 of the amine end product are obtained. The hydrochloride prepared in hydrochloric ether and recrystallised from isopropanol melts at 178C.
7-methoxy-3,4-dihydro-1-benzoxepin-0-(diethylaminoethyl)-5-one oxime Applying the method of preparation described in example 9 and reacting 7.25 9 of oxime and 6.8 9 of (2-chloro)-ethyl diethylamine at stage (C), 7 9 of the crude amine end product are obtained.
The hydrochloride prepared in hydrochloric ether melts at 180C after recrystallisation from ethyl acetate.
7-methoxy-3,4-dihydro-1-benzoxepin-0-(dimethylaminopropyl)-5-one oxime Applying the method of preparation described in example 9 and reacting 5.85 9 of oxime and 4 9 of (3-chloro)-propyl dimethylamine at stage (C), 6.2 9 of the amine end product are obtained in the form of a yellow oil.
The hemioxalate of the amine is prepared in ethanol by reacting the amine and acid in equimolecular proportions.
After recrystallisation from ethanol, the pure hemioxalate melts at 130C.
7-bromo-3,4-dihydro-1-benzoxepin-0-(diethylaminoethyl)-5-one oxime -A - 7-bromo-3,4-dihydro-1-benzoxepin-5~one:
This heterocyclic ketone is prepared with a 40% yield from p-bromophenoxy butyric acid (Mp - 132C) by the method described in example 1 (A). Its boiling point is 105C at 0.06 8~
mm. Hg.
B - 7-bromo-3,4-dihydro-1-benzoxepin-0-(diethylaminoethyl)-5-one oxime The amine is prepared by reacting the benzoxepinone previously obtained with the dihydrochloride of 0-(diethyl-aminoethyl) hydroxylamine by the method of operation described in example 4. 4.5 g of end product are obtained in the form of an oil from 7 g of 7-bromo-3,4-dihydro-1-benzoxepin-5-one.
The hydrochloride of this amine is prepared in ether by the action of gaseous hydrochloric acid and purified by dis-solving it in ethanol and then reprecipitating it by the addition of ethyl ether. It melts at 138C.
The yield of hydrochloride from the ketone is 50%.
Toxicological and pharmacological studies of the products of the invention demonstrated the originality of their activity compared with known products. The tests were carried out on acid addition salts of the amines of the general formula.
The acute toxicity was determined on male mice of the strain Swiss C.D weighing on average 20 grammes, after oral administration (P.0) and intravenous administration (I.V).
The relaxant action at the level of the smooth intestinal muscle fibre was demonstrated in vitro on the isolated organ and in vivo on the anaesthetised dog by applying the following techniques:
For the tests on the isolated organ: an organ fragment of rat duodenum or guinea pig ileum is kept alive in 50 ml of an oxygenated and thermostatically controlled (37C) tyrode solution. The activity of the compounds is tested on the spontaneous movement of the organ and on the contractions produced by the addition of a solution of barium chloride or acetyl choline to the bath. The movements were recorded on a DMP 4A Roucaire physiograph.
For the in vivo tests: a small balloon is introduced at the level of the terminal part of the duodenum in the chloralosed animal and the intestinal movements are recorded on a Beckman polygraph with the aid of a Statham PM 97 gauge.
The results relating to the acute toxicity and to the relaxant activity in vi~ro are shown in table 1.
The in vivo tests showed that the products of the invention and in particular those of examples 1, 2, 7, 8 and 12 administered intravenously in a dose of 2 mg/kg had an effect which was comparable with or even superior to that of atropine administered in a dose of 50 mg/kg as regards the reduction in intestinal tone and peristalsis. In contrast to atropine, however, this relaxant activity is produced without any anti-cholinergic or vagolytic activity.
Pharmaceutical compositions containing as active ingredient at least one product according to the invention may be presented, for example, in the form of tablets or injection solutionsO
The tablets may contain about 75 mg of active ingredient and known excipients such as microcrystalline cellu-lose, carboxymethyl starch, talcum and magnesium stearate.
The injection ampoules may contain about 25 mg. of active ingredient and a sufficient quantity of glycine to render the product isotonic.
TABLE I
C O M P O U N D TOXICITY in miceISOLATED ORGANS:
LD = (mg/kg)Minimum active dose of 50 Concentration in mcg/ml ______ _ __ _ __ ___ __ example P.O I.V DECONTRACTION ANTI-ACETYL
(rat duodenum) C~IOLINE
(guinea pig 1150 32 0.06 5.5 10 (hydrochloride) 2420 37 0.1 (hydrochloride) 6> 1000 120 0.15 5.5 (hydrochloride) 7450 35 1.5 1.3 (hydrochloride) 8500 60 0.12 3.5 (hydrochloride) 9500 35 0.12 1.5 20 (hydrochloride) .
10450 45 0.5 0.5 (hydrochloride) 11> 1000 _ 0.3 2.0 (hemioxalate) 12250 40 0.1 (hydrochloride) _ ATROPINE 600 90 inactive 0.006 (sulphate) _
Claims (24)
1. A process for preparing a compound of the formula:
wherein:
R represents a halogen atom or a lower alkoxy group;
n is an integer which has the value 2 or 3;
Z1 and Z2' which may be identical or different, represent each a lower alkyl group or Z1 and Z2 and the nitrogen atom to which they are attached may together form a heterocyclic ring selected from morpholinyl and pyrrol-idinyl;
which comprises:
A) reacting a 3,4-dihydro-1-benzoxepin-5-one-oxime of the formula:
with a compound of the formula X-(CH2)n-NZ1Z2 in the presence of a base, X being halo, R, n, Z1 and Z2 being as previously defined; or B) reacting a 3,4-dihydro-1-benzoxepin-5-one of the formula:
with a compound of the formula H2N-O-(CH2)n-NZ1Z2, R, n, Z1 and Z2 being as previously defined, and if desired treating the amine thus obtained with an acid to form the amine acid addition salt suitable for separation of the two oxide isomers by crystallization.
wherein:
R represents a halogen atom or a lower alkoxy group;
n is an integer which has the value 2 or 3;
Z1 and Z2' which may be identical or different, represent each a lower alkyl group or Z1 and Z2 and the nitrogen atom to which they are attached may together form a heterocyclic ring selected from morpholinyl and pyrrol-idinyl;
which comprises:
A) reacting a 3,4-dihydro-1-benzoxepin-5-one-oxime of the formula:
with a compound of the formula X-(CH2)n-NZ1Z2 in the presence of a base, X being halo, R, n, Z1 and Z2 being as previously defined; or B) reacting a 3,4-dihydro-1-benzoxepin-5-one of the formula:
with a compound of the formula H2N-O-(CH2)n-NZ1Z2, R, n, Z1 and Z2 being as previously defined, and if desired treating the amine thus obtained with an acid to form the amine acid addition salt suitable for separation of the two oxide isomers by crystallization.
2. A process according to Claim 1, wherein a 3,4-dihydro-1-benzoxepin-5-one oxime of the formula:
is reacted in the presence of a base with a compound of the formula X-(CH2)n-NZ1Z2, R, n, Z1 and Z2 are as defined in Claim 1 and X is halo, and if desired treating the amine thus obtained with an acid to form the amine acid addition salt suitable for separation of the two oxime isomers by crystalli-zation.
is reacted in the presence of a base with a compound of the formula X-(CH2)n-NZ1Z2, R, n, Z1 and Z2 are as defined in Claim 1 and X is halo, and if desired treating the amine thus obtained with an acid to form the amine acid addition salt suitable for separation of the two oxime isomers by crystalli-zation.
3. A process according to Claim 1, wherein a 3,4-dihydro-1-benzoxepin-5-one of the formula:
is reacted with a compound of the formula H2N-O-(CH2)n-NZ1Z2, R, n, Z1 and Z2 being as defined in Claim 1, and if desired treating the amine thus obtained with an acid to form the amine acid addition salt suitable for separation of the two oxime isomers by crystallization.
is reacted with a compound of the formula H2N-O-(CH2)n-NZ1Z2, R, n, Z1 and Z2 being as defined in Claim 1, and if desired treating the amine thus obtained with an acid to form the amine acid addition salt suitable for separation of the two oxime isomers by crystallization.
4. The process of Claim 2, wherein 7-chloro-3,4-dihydro-1-benzoxepin-5-one oxime is reacted with (2-chloro)-ethyl dimethylamine to form the 7-chloro-3,4-dihydro-1-benzoxepin-O-(dimethylamino)-5-one oxime.
5. The process of Claim 3, wherein 7-chloro-3,4-dihydro-1-benzoxepin-5-one is reacted with O-(diethylamino-ethyl)-hydroxylamine to form the 7-chloro-3,4-dihydro-1-benzoxepin-O-(diethylaminoethyl)-5-one oxime.
6. The process of Claim 29 wherein 7-chloro-3,4-dihydro-1-benzoxepin-5-one oxime is reacted with (2-chloro)-ethyl diethylamine to form the 7-chloro-3,4-dihydro-1-benzoxepin-O-(diethylaminoethy1)-5-one oxime.
7. The process of Claim 2, wherein 7-chloro-3,4-dihydro-1-benzoxepin-5-one oxime is reacted with N-(2-chloro-ethyl)-morpholine to form the 7-chloro-3,4-dihydro-1-benzoxepin-O-(morpholinoethyl)-5-one oxime.
8. The process of Claim 3, wherein 7-chloro-3,4-dihydro-1-benzoxepin-5-one is reacted with O-(1-pyrrolidinyl-ethyl)-hydroxylamine to form the 7-chloro-3,4-dihydro-1-benzoxepin-O-(1-pyrrolidinyl-ethyl)-5-one oxime.
9. The process of Claim 2, wherein 7-chloro-3,4-dihydro-1-benzoxepin-5-one oxime is reacted with (3-chloro)-propyl dimethylamine to form the 7-chloro-3,4-dihydro-1-benzoxepin-O-(dimethylaminopropyl)-5-one oxime.
10. The process of Claim 2, wherein 7-methoxy-3,4-dihydro-1-benzoxepin-5-one oxime is reacted with (2-chloro)-ethyl dimethylamine to form the 7-methoxy-3,4-dihydro-1-benzoxepin-O-(dimethylaminoethyl)-5-one oxime.
11. The process of Claim 2, wherein 7-methoxy-3,4-dihydro-1-benzoxepin-5-one oxime is reacted with (2-chloro)-ethyl diethylamine to form the 7-methoxy-3,4-dihydro-1-benzoxepin-O-(diethylaminoethyl)-5-one oxime.
12. The process of Claim 2, wherein 7-methoxy-3,4-dihydro-1-benzoxepin-5-one oxime is reacted with (3-chloro)-propyl dimethylamine to form the 7-methoxy-3,4-dihydro-1-benzoxepin-O-(dimethylaminopropyl)-5-one oxime.
13. The process of Claim 3, wherein 7-bromo-3,4-dihydro-1-benzoxepin-5-one is reacted with O-(diethylamino-ethyl)-hydroxylamine to form the 7-bromo-3,4-dihydro-1-benzoxepin-O-(diethylaminoethyl)-5-one oxime.
14. A compound of the formula:
wherein:
R represents a halogen atom or a lower alkoxy group;
n is an integer which has the value 2 or 3;
Z1 and Z2' which may be identical or different, represent each a lower alkyl group or Z1 and Z2 and the nitrogen atom to which they are attached may together form a heterocyclic ring selected from morpholinyl and pyrrol-idinyl;
when prepared by the process defined in Claims 1, 2 or 3 or by an obvious chemical equivalent.
wherein:
R represents a halogen atom or a lower alkoxy group;
n is an integer which has the value 2 or 3;
Z1 and Z2' which may be identical or different, represent each a lower alkyl group or Z1 and Z2 and the nitrogen atom to which they are attached may together form a heterocyclic ring selected from morpholinyl and pyrrol-idinyl;
when prepared by the process defined in Claims 1, 2 or 3 or by an obvious chemical equivalent.
15. The 7-chloro-3,4-dihydro-1-benzoxepin-O-(dimethylamino)-5-one oxime, when prepared by the process defined in Claim 4 or by an obvious chemical equivalent.
16. The 7-chloro-3,4-dihydro-1-benzoxepin-O-(diethyl-aminoethyl)-5-one oxime, when prepared by the process defined in Claim 5 or by an obvious chemical equivalent.
17. The 7-chloro-3,4-dihydro-1-benzoxepin-O-(diethyl-aminoethyl)-5-one oxime, when prepared by the process defined in Claim 6 or by an obvious chemical equivalent.
18. The 7-chloro-3,4-dihydro-1-benzoxepin-O-(morpholinoethyl)-5-one oxime, when prepared by the process defined in Claim 7 or by an obvious chemical equivalent.
19. The 7-chloro-3,4-dihydro-1-benzoxepin-O-(1-pyrrolidinyl-ethyl)-5-one oxime, when prepared by the process defined in Claim 8 or by an obvious chemical equivalent.
20. The 7-chloro-3,4-dihydro-1-benzoxepin-O-(dimethylaminopropyl)-5-one oxime, when prepared by the process defined in Claim 9 or by an obvious chemical equivalent.
21. The 7-methoxy-3,4-dihydro-1-benzoxepin-O-(dimethylaminoethyl)-5-one oxime, when prepared by the process defined in Claim 10 or by an obvious chemical equivalent.
22. The 7-methoxy-3,4-dihydro-1-benzoxepin-O-(diethylaminoethyl)-5-one oxime, when prepared by the process defined in Claim 11 or by an obvious chemical equivalent.
23. The 7-methoxy-3,4-dihydro-1-benzoxepin-O-(dimethylaminopropyl)-5-one oxime, when prepared by the process defined in Claim 12 or by an obvious chemical equivalent.
24. The 7-bromo-3,4-dihydro-1-benzoxepin-O-(diethyl-aminoethyl)-5-one oxime, when prepared by the process defined in Claim 13 or by an obvious chemical equivalent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7328038A FR2244491A1 (en) | 1973-07-31 | 1973-07-31 | 3,4-Dihydro-1-benzoxepine-5-one oxime ethers - as intestinal regulators |
| FR7417976A FR2271812A2 (en) | 1974-05-22 | 1974-05-22 | 3,4-Dihydro-1-benzoxepine-5-one oxime ethers - as intestinal regulators |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1048026A true CA1048026A (en) | 1979-02-06 |
Family
ID=26217870
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA205,979A Expired CA1048026A (en) | 1973-07-31 | 1974-07-30 | Process of preparing ethers of 3,4-dihydro-1-benzoxepin-5-one oxime |
Country Status (9)
| Country | Link |
|---|---|
| JP (1) | JPS5041883A (en) |
| CA (1) | CA1048026A (en) |
| CH (1) | CH592077A5 (en) |
| DD (1) | DD116033A5 (en) |
| DE (1) | DE2436075A1 (en) |
| ES (1) | ES428422A1 (en) |
| GB (1) | GB1449406A (en) |
| IL (1) | IL45340A (en) |
| NL (1) | NL7408676A (en) |
-
1974
- 1974-06-27 NL NL7408676A patent/NL7408676A/en not_active Application Discontinuation
- 1974-07-02 CH CH906574A patent/CH592077A5/xx not_active IP Right Cessation
- 1974-07-19 ES ES428422A patent/ES428422A1/en not_active Expired
- 1974-07-24 IL IL45340A patent/IL45340A/en unknown
- 1974-07-26 DE DE2436075A patent/DE2436075A1/en active Pending
- 1974-07-29 DD DD180176A patent/DD116033A5/xx unknown
- 1974-07-30 CA CA205,979A patent/CA1048026A/en not_active Expired
- 1974-07-31 GB GB3375074A patent/GB1449406A/en not_active Expired
- 1974-07-31 JP JP49087124A patent/JPS5041883A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| IL45340A (en) | 1977-12-30 |
| DE2436075A1 (en) | 1975-02-13 |
| CH592077A5 (en) | 1977-10-14 |
| DD116033A5 (en) | 1975-11-05 |
| GB1449406A (en) | 1976-09-15 |
| ES428422A1 (en) | 1976-12-01 |
| NL7408676A (en) | 1975-02-04 |
| JPS5041883A (en) | 1975-04-16 |
| IL45340A0 (en) | 1974-10-22 |
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