AT365574B - METHOD FOR PRODUCING NEW ALKYLENE IMINE DERIVATIVES AND THEIR SALTS - Google Patents

Description

  

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   The invention relates to a process for the preparation of new alkyleneimine derivatives of the general formula
 EMI1.1
 in which mean:
R hydroxy or low. Alkoxy; R, and R each wet, low. Alkyl, phenyl or phenyl-nied. alkyl;
R3 is hydrogen, hydroxy or low. Alkyl; m = 1 to 3 and n = 1 or 2 and their basic salts.
 EMI1.2
 is.



   In the broadest sense, preference is given to compounds of the formula (I) in which:
R hydroxy or low. Alkoxy; R, hydrogen or low. Alkyl; R 3 and R4 are both hydrogen; m = 2, n = 1 or 2, especially 1.



   The compounds of the general formula are particularly preferred
 EMI1.3
 in which mean:
R hydroxy or low. Alkoxy and R, hydrogen or low. Alkyl; especially methyl.



   It should be noted that combinations of the above-mentioned substituents are among the preferred groups.



   The stereoisomers in which the proline is in the L form are particularly preferred.



   The alkyl groups represented by the symbols above include straight or branched hydrocarbon radicals from methyl to heptyl, e.g. B. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert. Butyl, pentyl, isopentyl. The cute Alkoxy groups are of the same type and have 1 to 7 oxygen-bonded carbons, e.g. B. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert. Butoxy. The C1-C4 representatives, in particular the Cl and C2 representatives of both types, are preferred. Phenylmethyl is the preferred phenyl-nied. alkyl group.



   The process according to the invention is characterized in that a compound of the general formula
 EMI1.4
 wherein
R, R, and m are as defined above,

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 with a compound of the formula
 EMI2.1
 wherein R, R and n are as defined above, and, if desired, convert a compound of formula (I) obtained into its salt.



   As compound (VIII) z. B. ss-propiothiolactone or a-methyl-ss-propiothiolactone can be used.



   Products of formula (I) have one or more asymmetric carbon atoms. If R, R or Ra is not hydrogen, then the carbon atom to which this residue is attached is asymmetric. These carbon atoms are identified by an asterisk in formula (I).



  These compounds accordingly exist in stereoisomeric forms or as their racemic mixtures. The manufacture of all of these forms falls within the scope of the invention. The synthesis described above can start from the racemate or one of the enantiomers as a starting material. If the racemic starting material is used, the stereoisomers present in the product obtained can be separated by customary methods of chromatography or fractional crystallization. In general, this is the preferred isomeric form for the carbon of the amino acid L'Isomer. The D-isomer with respect to the a-carbon in the acyl side chain (i.e., the R bearing carbon) is also preferred.



   The compounds which can be prepared according to the invention form basic salts with various inorganic and organic bases, the preparation of which likewise falls within the scope of the invention. Such salts are e.g. B. ammonium salt, alkali metal salt such as sodium and potassium salts (which are preferred), alkaline earth metal salts such as the calcium and magnesium salts, salts with organic bases, e.g. B. salts with dicyclohexylamine, benzathine, N-methyl-D-glucamine, hydrabamine, salts with amino acids such as arginine, lysine and the like. The non-toxic physiologically acceptable salts are preferred, although other salts are also useful; e.g. B. for isolation or purification of the product, as illustrated in the examples for the case of the dicyclohexylamine salt.



   The salts are prepared in a conventional manner by reacting the product in the form of the free acid with one or more equivalents of a suitable base which provides the desired cation in a solvent or medium in which the salt is insoluble or in water and then removing the water formed by freeze drying. By neutralizing the salt with an insoluble acid such as a cation exchanger in the hydrogen form (e.g. Po-
 EMI2.2
 



   Additional experimental details can be found in the examples, which represent preferred embodiments and also serve as models for the production of other representatives of the group.



   The compounds obtainable according to the invention inhibit the conversion of the decapeptide angiotensin I to angiotensin II and are therefore suitable for reducing or alleviating hypertension in connection with angiotensin. Angiotensin I is produced by the action of the enzyme renin on angiotensinogen, a pseudoglobulin in the blood plasma. Angiotensin I is converted to angiotensin II by angiotensin converting enzyme (ACE). The latter is an active pressure-increasing substance that is the cause of various forms of hypertension in
 EMI2.3
 

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 reduce or suppress the substance angiotensin II.

   The administration of an agent which contains one or more compounds of the formula (I) or their physiologically tolerable salts therefore leads to a reduction in angiotensin-dependent hypertension in mammals.



  A single dose, preferably divided into two to four daily doses (based on approximately 0.1 to 100 mg, preferably approximately 1 to 50 mg / kg and day), is indicated for reducing the blood pressure according to the information on the model tests Animals
 EMI3.1
 cutaneous, intramuscular, intravenous or intraperitoneal.



   The compounds which can be prepared according to the invention can be used to lower blood pressure in the form of preparations such as tablets, capsules or elixirs for oral administration or in sterile solutions or suspensions for parenteral administration. Approximately 10 to 500 mg of a compound or mixture of compounds of formula (I) or their physiologically acceptable salts are processed with a physiologically acceptable carrier, excipient, binder, preservative, stabilizer, flavoring agent, etc. into a unit dosage form according to recognized pharmaceutical practice. The amount of active substance present in these preparations or preparations is such that a suitable dosage is obtained within the range specified above.



   Examples of additives for tablets, capsules and. The like. are: a binder such as tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegrant such as corn starch, potato starch, alginic acid and the like. the like; a lubricant such as magnesium stearate; a sweetener such as sucrose, lactose or saccharin; a flavoring such as peppermint oil, wintergreen oil or cherry oil. A dosage unit in the form of a capsule may contain, in addition to substances of the above type, a liquid carrier, e.g. B. contain a solid oil. Various other materials can be present as a coating or for other modification of the physical form of the dosage unit. For example, tablets can be coated with shellac, sugar, or both.

   A syrup or elixir may contain the active compound, sucrose as a sweetener, methyl and propyl paraben as a preservative, a color and a flavoring such as cherry or orange flavor. Sterile injectables can be obtained in a conventional manner by dissolving or suspending the active compound in a carrier such as water, a natural vegetable oil such as sesame oil, coconut oil, peanut oil, cottonseed oil etc. or a synthetic fatty carrier such as ethyl oleate or the like. Buffers, preservatives, antioxidants and the like Like. Can be added as needed.



   The following example illustrates the invention and represents a particularly preferred embodiment.
 EMI3.2
 Hydrofuran (10 ml) is mixed with propiothiolactone (1.76 g). After standing in an ice bath for 5 minutes and 3 hours at room temperature, the reaction mixture is diluted with ethyl acetate (200 ml) and washed with 5% potassium bisulfite and water. The organic layer is dried over magnesium sulfate and evaporated to dryness in vacuo. The residue, the title compound, is crystallized from ether-hexane, yield 3.7 g, mp. 57 to 58OC.

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Claims (1)

  PATENT CLAIMS: 1. Process for the preparation of new alkyleneimine derivatives of the general formula  EMI3.3    <Desc / Clms Page number 4>  in which mean: R hydroxy or low. Alkoxy; R, and R are each hydrogen, low. Alkyl, phenyl or phenyl-nied. alkyl; R3 is hydrogen, hydroxy or low. Alkyl; m = 1 to 3 and n = 1 or 2, and of their basic salts, characterized in that a compound of the general formula  EMI4.1  wherein R, R3 and m are as defined above, with a thiolactone of the formula  EMI4.2  where Rt, R 4 and n are as defined above,  EMI4.3   2nd  A method according to claim 1, characterized in that starting compounds are used, wherein R = hydroxy, m = 2, n = 1 and R1, R3 and Rt are as defined in claim 1.  3. The method according to claim 1, characterized in that starting compounds are used in which R = hydroxy, R: and R4 is each hydrogen, m = 2 and n = 1 and R, as defined in claim 1.