FI67694C - FRAMEWORK FOR THE FRAMEWORK OF THERAPEUTIC ANALYSIS OF BI-PROLINDERIVAT - Google Patents

Description

1 67694

A process for the preparation of therapeutically useful bis-proline derivatives

Divided apart from patent application 770437 5

The invention relates to a process for the preparation of therapeutically useful bis-proline derivatives of the formula

HOOC-N-CO-CH-CH2-S-S-CH2-CH-CO-N - * - COOH

15 wherein the symbols R are the same and denote a hydrogen atom or a lower alkyl group.

The invention is characterized in that the compound of formula 20

H-S-CH2-CH-CO-N-L COOH

25 is oxidized with iodine. This starting compound can be prepared by the method disclosed in parent application 770437.

The compounds of the invention form basic salts with various inorganic and organic bases and are also within the scope of the invention. Such salts include ammonium salts, alkali metal salts such as 2,6794 sodium and potassium salts (which are preferred), alkaline earth metal salts such as calcium and magnesium salts, salts with inorganic bases, e.g. dicyclohexylamine salts, benzazine, N-methyl-D-glucin-D-methyl , 5 hydrabamine salts, salts with amino acids such as arginine and lysine. Non-toxic, physiologically acceptable salts are preferred, although other salts are also useful, e.g., in isolating or purifying the product as described in connection with the dicyclo-10-hexylamine salt in the working examples.

Salts are formed in a manner known per se by reacting the free acid form of the product with an equivalent of a base to give the desired cation, in a solvent or medium in which the salt is soluble, or in water and then removing the water by freeze-drying. On neutralization of the salt with an insoluble acid such as a cation exchange resin in hydrogen form (e.g. polystyrenesulfonic acid resin. Such as Dowex 50), or with an aqueous acid and extraction with an organic solvent, e.g. ethyl acetate, dichloromethane or the like, the free acid can be obtained.

The compounds of the invention inhibit the conversion of decapeptide angiotensin I to angiotensin II and are therefore useful in alleviating or relieving angiotensin-induced hypertension. The effect of the enzyme renin on angiotensinogen, a pseudoglobulin in the plasma, produces angiotensin I. Angiotensin I is converted to angiotensin II by the angiotensin-producing enzyme (ACE). The latter is an active antihypertensive agent that has been found to cause various forms of hypertension in various mammals, e.g., rats and dogs. The compounds of the invention act on a series of changes in angiotensin 35 I -> angiotensin II by inhibiting the action of an angiotensin converting enzyme and reducing or eliminating the formation of angiotensin II which causes pressure.

Thus, administration of a composition comprising one or more compounds of formula I, or a physiologically acceptable salt thereof, improves angiotensin-dependent hypertension in mammals. A single dose, or preferably 2-4 divided daily doses in an amount of about 0.1 to 100 mg per kg per day, preferably about 1 to 50 mg per kg per day, is suitable for lowering water pressure, as demonstrated by animal experiments described in: S.L. Engel, T.R. Schaeffer, M.H. Waugh and B. Rubib, Proc. Soc. Exp. Biol. Med. 143, 483 (1973). The agent is preferably administered orally, but parenteral administration, such as intravenous, intramuscular, subcutaneous or intraperitoneal administration, may also be used.

The novel compounds can be used to lower blood pressure by formulating compositions such as tablets, capsules or liquids for oral administration or sterile solutions or suspensions for parenteral administration. About 10-500 mg of formula I.

or a mixture of the compounds or a physiologically acceptable salt thereof is combined with a physiologically acceptable medium, carrier, additive, binder, preservative, stabilizer, flavoring agent, etc. in unit dosage form according to accepted pharmaceutical practice.The amount of active ingredient in these compositions or preparations is such that an appropriate amount of substance in the range shown.

Suitable excipients which may be used in connection with tablet-30, capsules and the like include: a binder such as tragacanth, acacia, corn starch or gelatin; additive such as dicalcium phosphate: disintegrant such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; a flavoring agent such as peppermint, 4 67694 Wintergreen oil or cherry. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Various other agents may be present as coatings or to modify the physical form of the 5 unit dose. For example, tablets may be coated with shell lacquer, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propyl paraben as a preservative, a coloring agent and a sweetening agent such as cherry or pomegranate essence.

Suitable compositions for injection are obtained in accordance with standard pharmaceutical practice by dissolving or suspending the active ingredient in a medium such as water for injection, natural vegetable oils such as sesame oil, peanut oil, coconut oil or cauliflower oil, cottonseed oil, etc. or the like. Buffers, preservatives, antioxidants and the like may be added as needed.

The following examples illustrate the method according to the invention and particularly preferred embodiments.

All temperatures are in degrees Celsius.

Example 1 1,1'-Dithiobis (3-propanoyl) -bis-L-proline 3-Mercaptoropanoyl-L-proline (0.95 g) is dissolved in water (20 ml) and the pH is adjusted to 6.5 using 1N sodium hydroxide. The ethanolic solution of iodine is added dropwise while maintaining the pH at 6.5 by careful addition of 1N sodium hydroxide. When a permanent yellow color is obtained, the addition of iodine is stopped and the color is removed with a small amount of sodium thiosulfate. The reaction mixture is acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water, dried and concentrated to dryness with 1,1 '- / dithiobis (3-

II

5,676,94 to give propanoyl) -7-bis-L-proline. The dicyclohexylammonium salt is prepared by adding dicyclohexylamine to a solution of the free acid in acetonitrile, m.p. 179-180 °.

Example 2 1,1 '- / Dithiobis (2-D-methyl-3-propanoyl) γ-bis-L-proline The 3-mercapto-2-D-methylpropanoyl-L-proline used in the process of Example 1 3- instead of mer-10 captopropanoyl-L-proline, 1,1'- / dithiobis (2-D-methyl-3-propanoyl) -7-bis-L-proline is obtained, mp 236-237 °.

Claims (2)

6 67694 A process for the preparation of therapeutically useful bis-proline derivatives of the formula Ri 1 * HOOC-ft-CO-CH-CH 2 SSO 2 -CH-CO-N-'-COOH 10 wherein the symbols are the same and mean hydrogen atom or lower alkyl group, characterized in that the compound of formula Hn-S-CH2-CH-CO N-1 -COOH is oxidized with iodine. Process according to Claim 1, characterized in that a compound is prepared in which R 1 is methyl. Il