DE2358470A1 - NEW DERIVATIVE OF L-4-HYDROXYPROLINE, THE PRODUCTION THEREOF AND MEDICAL COMPOSITIONS CONTAINING IT - Google Patents

Description

Dr. F. Zumstein Sr. - Dr. E. Asssmann Dr. R. Koenigsberger - Dipl.-Phys. R. Holzbauer - Dr. F. Zumstein Jun.

PATENT LAWYERS

TELEPHONE: COLLECTIVE NO. 225341

TELEX 529979

TELEGRAMS: ZUMPAT CHECK ACCOUNT; MUNICH 91139

BANK ACCOUNT: BANKHAUS H. AUFHÄUSER

8 MUNICH 2,

BRÄUHAUSSTRASSE 4 / I1I

14 / ge
SC.4176

S.A., Paris / France

New derivative of L-4-hydroxyproline, its production and medicinal compositions containing the same

The invention relates to "the N-propionyl-L-4-hydroxyproline, the corresponds to the general formula

CH, CH _n CO -N: 5 2

HO-

COOH

(I)

its salts, its preparation and medicinal products containing them Compositions.

According to the invention, the new product of the formula (I) can through Implementation of a mixture of propionic anhydride and propionic

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acid with L-Λ-hydroxyproline.

In general, the reaction proceeds by heating to a temperature between 25 and 80 ⁰ C. ■

The new product according to the invention can optionally by physical methods such as crystallization or chromatography or chemical methods, such as the formation of a salt, crystallization of the same and subsequent decomposition in an acidic medium getting cleaned.

• The new product of the formula (i) can be converted into a metal salt or into an addition salt with a nitrogen base can be converted using methods known per se. So can this Salts by the action of an alkali or alkaline earth base, ammonia or an amine on the product of the formula (I) in a suitable solvent such as an alcohol, an ether, a Ketone or water. The formed salt falls optionally after concentrating its solution, and is separated off by filtration or decantation.

The product according to the invention and its salts have interesting pharmacological properties. In particular, they have an anti-inf laminate or i see effect and modify the metabolism of collagen. The product according to the invention and its salts in particular potentialize the effect of classic anti-inflammatory active ingredients that are not steroids, such as those of phenylbutazone, indomethacin, metiazinic acid or ketoprofen, without increasing the ulcerogenic effect of these products, which is a particularly great advantage . In the rat, the product according to the invention in pure form or in the form of its salt by the oral route at doses between 25 and 500 mg / kg is effective as an adjuvant in polyarthritis [according to the technique of F. Delbarre et al., CRSoc. Biol., 162 , p. 58 (1968)] when it comes to these anti-inflammatory

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Active ingredients is attached. .

Purely medical use is made by the. new connection both in the form of the acid and in the form of a pharmaceutically acceptable, i.e. nontoxic at the in-use doses Made use of salt.

As an example of pharmaceutically acceptable salts, the salts with alkali metals such as sodium, potassium, lithium salts or with alkaline earth metals or the ammonium salt.

The following example shows how the invention is put into practice can be.

example

'' S.

110 g of L-4-hydroxyproline in 4-00 cm propionic acid are heated to 50 ° C. with stirring. 119.5 g of propionic anhydride are added over a period of 30 minutes. in solution in 100 cm propionic acid are added and the mixture leaving for 10 hours at 50 ⁰ C.

800 cm ^{y of} diisopropyl ether are added; the product crystalline

. ·. ·. "7. Siert. It is cooled to 15 ° Ό and add a further 300 cnr diisopropylether. The crystals are separated by filtration and washed with 600 cnr diisopropylether. This gives 129 g of a product with a melting point 'of 138 ° C .

Compartment recrystallization from 310 cm ^ acetonitrile gives 118 g N-propionyl-L-4-hydroxyproline with a melting point of "139 ° C>

pn - - ^N

^ ^υ = -114 ° + 1.8 ° (c = 1; water). ,. \

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The. the N-propionyl-L-4-hydroxyproline and / or one of its Pharmaceutical compositions containing salts in pure form or in the presence of a diluent or a coating Settlements that may be present in the company of another pharmacologically active product represent a The present invention further relates to these compositions. These compositions can be administered orally, rectally or parenterally or in the form of pomades.

As solid compositions for oral administration, tablets, pills, powders and granules can be used. In these compositions is the active ingredient according to the invention with one or more inert diluents, such as sucrose, Lactose or starch and optionally mixed with a further pharmacological active ingredient. These compositions may contain substances other than the diluents, for example a lubricant such as magnesium stearate.

The liquid compositions for oral administration can be pharmaceutically acceptable emulsions, suspensions, Solutions, syrups and elixirs that are inert diluents such as water or liquid paraffin. These compositions Substances other than the diluents, for example wetting agents, sweeteners and flavorings, can also be used contain.

The compositions according to the invention for parenteral administration can be aqueous or non-aqueous sterile solutions, Be suspensions or emulsions. As a solvent or carrier one can propylene glycol, polyethylene glycol, vegetable Oils, particularly olive oil, and injectable organic esters, e.g. ethyl oleate, use these compositions can also contain adjuvants, in particular wetting agents, emulsifiers and dispersants. The sterilization can be done in different ways Way, for example with the help of a

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bacteriological filter by incorporating in the composition: sterilizing agents or by irradiation. They \ can also be in sterile solid form. Compositions can be prepared which can be dissolved in sterile water or any other injectable sterile medium at the time of use.

Compositions for rectal administration are suppositories, which, in addition to the active ingredient, can contain excipients such as cocoa butter or soup wax.

In human therapy, the product according to the invention is particularly useful in bheumatology, dermatology and in Healing of wounds useful.

In human therapy, the doses depend on the one desired Effect and the duration of the treatment. they lay generally between 0.2 and 2 g per day when administered orally to an adult. In general, the doctor will Determine the form of administration that he would like to be treated, taking into account age, weight and all others Patients characteristic factors for most suitable holds.

The following example illustrates a composition according to the invention.

example

Tablets are prepared using the usual technique a weight of 500 mg of the following composition:

N-Propionyl-L - ^ - hydroxyproline "..-, .. 250 mg

Strength "." ..... '. 190 mg

Colloidal.es silicon dioxide 50 mg

Magnesium stearate., ..., ... ...., ".... 10 mg

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Claims (3)

Claims N-propionyl-L-4-hydroxyproline and its salts. 2. Process for the production of E-propionyl-L-4 ~ hydroxyproline, characterized in that a mixture of propionic acid and propionic anhydride with L-4-hydroxyproline converts and then optionally the obtained product converted into a metal salt or into an addition salt with a nitrogen base. 3. Medical composition, characterized that they are N-propionyl-L-4-- hydroxyproline together with one or more suitable and pharmaceutically acceptable diluents or adjuvants and optionally contains one or more therapeutically effective products. 409822/1161