CH528538A - 11-(8-alkyl-3-nortropanyloxy)-6,11-dihydro-dibenzo(b,3) thiepin - derivs - used for treatment of stomach ulcers - Google Patents

Abstract

11-(8-Alkyl-3-nortropanyloxy)-6,11-dihydro-dibenzo b,e thiepin derivs - used for treatment of stomach ulcers. Novel title cpds. of formula: (where R = lower alkyl n = 0, 1 or 2 with the exception of the case where n = 0, and R = methyl) and their salts are prepared by reaction of a 6,11-dehydro-debenzo b,e -thiepen deriv. contg. an active gp. in the 11-position with an N-alkyl-nortropine. The cpds. where n = 1, may be obtained by oxidising cpds. where n = 0 in neutral or weakly acid condition pref. at 0-50 degrees C. Cpds. where n = 2, are obtained by oxidation in acid soln. pref. at 50-150 degrees C..

Description

  

  
 



  Process for the preparation of new dibenzothiepine derivatives
The invention relates to a process for the preparation of new dibenzothiepine derivatives of the formula I, in which R stands for an alkyl group having 2 to 4 carbon atoms, and their acid addition salts.



   According to the invention, the new compounds of the formula I are obtained by reacting compounds of the formula II in which X is the acid radical of a reactive ester with compounds of the formula III in which R has the above meaning and, if desired, the compounds of the formula I obtained in their acid addition salts transferred.



   The process can, for example, be carried out as follows: A solution of a compound of the formula II, in which X is preferably chlorine, bromine, iodine, fluorine or the residue of an organic sulfonic acid, is allowed in a solvent which is inert under the reaction conditions, e.g. B. in an aromatic hydrocarbon such as abs. Toluene or abs. Benzene, at elevated temperature, e.g. B. at the boiling point of the reaction mixture, optionally in the presence of an acid-binding agent, e.g. B. an alkali metal carbonate such as sodium or potassium carbonate, or a tertiary organic base such as triethylamine, to a solution of a nortropine or pseudonortropine alkyl derivative (nortropan-3 a-ol, or nortropan-3ss-older derivative) in the same solvent.

  After the reaction has ended, the reaction product is isolated and, if necessary, purified by known methods.



   In the present reaction, the steric configuration remains unchanged, so that when using nortropan-3a-ol derivatives, the corresponding 11- (8-alkyl-3 a-nortropanyloxy) -6, 1 1-dihydrodibenzo- [b, e] thiepin derivatives.



   The compounds of the formula I can be converted into their acid addition salts and vice versa.



   The compounds of the formula I and their pharmacologically acceptable acid addition salts have interesting pharmacodynamic properties with low toxicity and can therefore be used as medicaments. In particular, they are suitable for the preventive and curative treatment of gastric ulcers, as shown by the results of the acetylcholine and histamine toxicity tests in guinea pigs, the mydriase effect in mice and the inhibition of phenylbutazone-induced ulcer formation in rats.



   The doses to be used naturally vary depending on the type of administration and the condition to be treated. In general, however, satisfactory results are obtained in test animals at a dose of 0.05 to 10 mg / kg body weight; if necessary, this dose can be administered in 2 to 3 portions or as a sustained-release form. For larger mammals, the daily dose is around 2 to 10 mg. For oral administration, the partial doses contain about 0.3 to 5 mg of the compounds of the formula I in addition to solid or liquid carrier substances.



   The compounds of the formula I or their physiologically tolerable acid addition salts can be administered as medicaments alone or in a suitable medicinal form with pharmacologically inert auxiliaries.



   The compounds of formula II can be prepared by esterifying the compound of formula IV in a manner known per se, e.g. B.



   a) for the preparation of compounds of the formula IIa, in which XI stands for the radical of an organic sulfonic acid, the compound of the formula IV is reacted with an organic sulfonic acid halide in a solvent which is inert under the reaction conditions, or b) for the preparation of compounds of the formula IIb, in which XII is chlorine, bromine or iodine, introduces chlorine, bromine or hydrogen iodide into the solution of the compound of the formula IV in a solvent which is inert under the reaction conditions, or c) for the preparation of the compound of the formula IIc compounds of the formula IId, wherein XIII stands for bromine or chlorine, treated with metal fluorides,

   or d) for the preparation of compounds of the formula IIb, the compound of the formula IV is reacted with thionyl or phosphorus halides.



   In process a), an organic basic solvent is preferably used as the inert solvent under the reaction conditions, e.g. B. pyridine or a lower trialkylamine such as triethylamine, or the reaction is carried out in an inert organic solvent under the reaction conditions with the addition of pyridine or a lower trialkylamine.



   As a solvent in process b), for. B. an anhydrous aromatic hydrocarbon such as benzene can be used.



   The 11-iodine derivative can also be prepared from the 11-bromine derivative by reacting it with sodium iodide in acetone.



   In process d), as thionyl halide, for. B.



  Thionyl chloride or bromide, as a phosphorus halide z. B. phosphorus trichloride, tribromide or pentachloride can be used.



   If the preparation of the starting compounds is not described, they are known or can be prepared by processes known per se or analogously to those described here or analogously to processes known per se.



   In the following examples, which explain the invention in more detail but are not intended to restrict its scope in any way, all temperatures are given in degrees Celsius and are uncorrected.



   Example 1: 1 1- (8-Ethyl-3 a -nortropanyloxy) -6, 1 1-dihydro dibenzo [b, e] thiepin
To 22.7 g of 6,11-dihydrodibenzo [b, e] thiepin-11-ol in 50 ml of abs. Benzene is passed in hydrogen chloride for 15 minutes while cooling with ice. The solution is then completely concentrated, and the residue is dissolved in 50 ml of abs. Dissolved benzene, dried over magnesium sulfate and completely concentrated again. The residue is then abs in 80 ml. Dissolved xylene and this solution to a boiling solution of 15.5 g of N-ethylnortropine in 50 ml of abs. Xylene was added dropwise within 15 minutes.

  The reaction mixture is then refluxed for 1 hour, then cooled to room temperature, diluted with 100 ml of diethyl ether and extracted twice with 50 ml of 2N hydrochloric acid each time.



  The aqueous extract is made alkaline with 2N sodium hydroxide solution, extracted three times with 100 ml of ether each time, the combined ether extracts are dried over magnesium sulfate, cleaned with animal charcoal and the solvent is completely distilled off. The oily residue, the compound named in the title, is converted into the methanesulfonate, which, after recrystallization from ethanol, melts at 198-2000.

  

   The following compounds of the formula I can also be obtained analogously to that described in Example 1 (Examples 2 to 4):
Example 2: 6,1 1-Dihydro-11 - (8-n-propyl-3 a -nortropanyloxy) dibenzo [b, e] thiepin
Hydrogen Fumarate: 203-2050.



   Example 3: 6,1 1-dihydro-11 - (8-isopropyl-3 a -nortropanyloxy) dibenzo [b, ejthiepin
M.p. 126-1270.



   Example 4: 1 1- (8-butyl-3 a -nortropanyloxy) -6, 1 1-dihydro-dibenzo [b, e] thiepin
M.p. of hydrogen fumarate: 230 (dec.).
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Claims (1)

PATENT CLAIM Process for the preparation of new dibenzothiepine derivatives of the formula I, in which R stands for an alkyl group having 2 to 4 carbon atoms, and their acid addition salts, characterized in that compounds of the formula II in which X stands for the acid radical of a reactive ester, with compounds of Formula III, in which R has the above meaning, is reacted and the compounds of the formula I obtained are, if desired, converted into their acid addition salts.