DD159426A5 - METHOD FOR PRODUCING AN INHIBITOR FOR ANGIOTENSIN CONVERTING ENZYME - Google Patents

Abstract

The invention relates to a method for producing an inhibitor of angiotensin converting enzyme. The object of the invention is to provide a new inhibitor which can be applied to all patients, regardless of the form of administration and without side effects. According to the invention basic salts of compounds of general formula (I) are prepared wherein R is hydrogen, formyl, acetyl, propanoyl, butanoyl, phenylacetyl, phenylpropanoyl, benzoyl, cyclopentanecarbonyl, tert-butyloxycarbonyl, cyclopentanecarbonyl-L-lysyl, pyro-L-glutamyl -L-lysyl, L-lysyl, L-arginyl or pyro-L-glutamyl, A is phenylalanyl, glycyl, alanyl, tryptophyl, tyrosyl, isoleucyl, leucyl, histidyl or valyl and in this case the alpha-amino group of these radicals to the rest R is linked in amide bond, R deep 1 represents hydrogen or methyl, R deep 2 for L-proline, L-3,4-dehydroproline, D, L-3,4-dehydroproline, L-3-hydroxyproline, L-4- Hydroxyproline, L-thiazolidine-4-carboxylic acid or L-5-oxo-proline stands and in this case the imino group of these radicals is linked in imide bond to the adjacent group and n is zero or 1, where if n is zero, R is 1 deep Methyl stands.

Description

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AP CO7C / 23O 574/1

A method of producing an inhibitor of angiogenic converting enzyme

Field of application of the invention

The invention relates to a method of preparing an inhibitor of angiotensin converting

The compound prepared according to the invention is used as a medicament _f in particular as an antihypertensive agent of the hypertension treatment agent.

The angiotensin converting Enz; ym _s . a designated hereinafter referred to as ACS Peptidyldipeptidhydrolase _s plays in the physiology of hypertension a central role and is capable of _s the amino acid sequence

AspArgValSyrlleHisProPheHis Leu

possessing decapepdid angiotensin I by cleavage of the terminal carboxyl group-containing HisLeu into the octapepdide angiotensin II _e Following, the following symbols are used for the residues of different amino acids and füx ¹ other compounds AIa = I-alanine

Arg s L-arginine

• "Asp i = -. L-Asrfaraginic acid""'''.' .. '' · · ^c . · ..-.- ·.

Boc - t-butyloxycarbonj ⁵ ·!

Glutamic acid <61% pyro-L-glutamic acid (L-5 ~ 0xo ~ proline) Gly - glycine

Hip · Hippuric Acid (Benzoylglycine)

His κ L-Kistidine

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lie = L ~ isoleucine

Leu it L-LeUC in

Phe ~ L ~ phenylalanine

Pro = L, Proline .......

Ρτο s L »3s4 ~ dehydroproline

Ser s L-serine

Tx-Q κ L-! Tryptophan

^r £ yr = L-tyrosine

YaI ~ Ii ȴ alin .. -

ACE s = angiotensin uniwanöelndes Ensyia-. · ......

^? Hepes "S" -2 "H ^- yäroxyäth.ylp.iperazin""l-"2-ä1; hansulfonsäure

Angiotensin I is produced by the action of the enzyme renin _{r on} an endopeptidase found in the liver or other body tissue and in plasma, on c ^ -2 globulin contained in the blood serum. "

The Blutdruck'wird by certain peptides contained in the blood influence One of these peptides ^ the AngiotensinH ₅ eats a potent pressor ₉ so a blood pressure-enhancing substance "That Ifo.napeptid the amino acid sequence ArgProProGlyPh'e-SerProPheArg having bradykinin is a potent depressor, so a blood pressure degrading _'s fabric has addition to direct Pressorwirkimg. the angiotensin IT. also the release of aldosterone '· "" · enhancing .'Wirkung- _9' wherein by the aldosterone .ebenfalls. · The pressure is increased _s aldosterone extracellular salts • and liquids retention «Angiotensin II is detectable in measurable quantities in the blood normal human vision and is showing in the blood of renal hypertension! Patients in increased concentrations

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The activity of the AGE is present in normal human as well as in people suffering from excessive blood pressure, usually in an amount greater than that required to maintain the observed levels of angiotensin II. However, Ee was found to be present at high blood pressure patients by treating the same with ACE inhibitors, the blood pressure greatly abge «. can be lowered / Gavras, I _{0 s} et al, "New Engl" Je Me cU 291, 817 (197417)

ACE is a pepididyl dipeptide hydrolase and catalyzes the hydrolysis of the penultimate peptide junction at the terminal end of various acylated tripeptides and larger, non-blocked "S-carboxy group-containing polypeptides". Under the action of ACE, the penultimate peptide bond is terminated at the carboxy terminus cleaved off by hydrolysis to give a dipeptide and the ent of the original peptide as reaction products,

The reactivity of the enzyme strongly depends on the substrate from _e At least one of Peptiabindungen formed by the nitrogen of the Proline is not hydrolyzed ".Offensichtlich varies the Michaelis constant (K _m) from substrate to substrate over several orders of magnitude * General information on kinetic parameters by enzymes · katalysierten'Reaktionen are ~ 157 in Lehninger ,, JU, Biochemistry, Worth Publishers, Inc _it, Hew York, 197O _see pages 153 |> specified Many of the peptides identified as inhibitors of ensyraatisehe conversion of angiotensin I to angiotensin II are last Finally, only substrates with a lower K than angiotensin I are more appropriate than competitive substrates.

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* draw examples of such competing substrates include bradykinin and also called SQ2O475 and the amino acid sequence <GluLys ^f £ rpAlaPro possessing peptide BEP - _a ·

Ondetti has reported in U.S. Patent 3,832,337 numerous synthetic peptide derivatives useful as inhibitors.

The role of AGE in the pathogenesis of hypertension has led to look for inhibitors of this enzyme? which are useful as anti-hypertensive agents (see, for example, U.S. Patent Nos. 3,891,616, 3,947,575, 4,052,511, and 4,053,651.) An extremely potent and high-bioactivity inhibitor of oral administration is that disclosed in US-A -PS 4,046,889 indicated and SQI4225 called J> -3-mercapto "" 2 "iaethylpropanoyX ~ L = proline _s what _s ascend also from C us D" Where et al _"p in Biochemistry 16, 5484. (1977) and by Ondetti, IU et al., in Science -196, 441 (1977) and has an If-Q = value of 2 _? 3β10 molar _β The I ^Q reported by Cuehman et al., in the above-mentioned reference represents ^ ene inhibitor concentration d £ _s ir which required a ist5in the substrate in a substantially lying above K concentration containing .normierten encryption '.. search system to inhibit the enzyme zu'50% *. the obtained

Qe are then directly comparable if all the essential factors influencing the reaction, such as the enzyme source and its purity _9, the substrate used and its concentration and the composition of the buffer used in the experimental system are constant. _E All the values given below for I _{P. Q} were in the same

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Experimental system and using the same enzyme (ACE from human urine) and at a concentration of about 1/2 K of the substrate and are therefore directly comparable with each other, although deviations from data provided by other authors are possible, "Such deviations are done unknown reasons in the literature ascertainable, as for example. , from the of "Cushman, D" W., et al. _is in Experientia 2% in 1032 (1973) and by Dorer, F "V specified 429 $ 220 E _e9 et alo _S in Biochim * Biophys" Acta (1976) / rs for I _rQ of BPP _5n yields »

The mechanism of action of SQI4225 was based on a model of the action center of ACE developed in analogy to the better known related enzyme Garboxypeptide & se A. It was assumed that this entrainment center has a cationic region which binds the terminal carboxyl group of the substrate and a pocket or cleft which contains the side chain A similar pocket or cleft was also presupposed for the penultimate amino acid residue, and due to published data, a rather severe steric requirement would have to be met because the D-form of the inhibitor, much more effective. is. as its stereoisomer or its 3-methyl derivative and unsubitituted analogues The sulfhydryl group present in the inhibitor and presumably located at the catalytic site near the catalytic site plays a central role in the inactivation of the enzyme by the zinc radical, which is known to be essential for the catalytic action Rolle, "present at the sulfhydryl

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Substituents such as a methyl group or an S-acetyl group considerably reduced the effectiveness of the inhibitor (cf., Cushman, D _e Y / _ej et al., Biochemistry, supra).

Experiments on the reaction carried out in ^ itro «. mechanisraus ^ about which SQ14225 and its analogues inhibit the AGE * were somewhat disturbed by the instability of these molecules under ambient conditions. "For example, it was found that a freshly prepared aqueous solution. of SQ14225? which contains, for example, 1 mg of this compound per ml, at a pH of about 8 on standing during -30 minutes loses much activity and that the activity of this solution with prolonged standing still continues to decrease "It is believed that this loss of activity mainly is due to a dimerization of the SQ14225 at the terminal sulfhydryl groups and hiex ^ arises in a largely ineffective as an inhibitor disulfide © Since the free sulfhydryl group is highly reactive and can be easily oxidized to polar acid residues such as a sulfone group or a sulfoxide group _r . For example, the inactive activity loss of aqueous solutions of SQ14225 during standing may be considered, to some extent, as a consequence of at least one such oxidation reaction. as .Inhibitor for.- ^: AGE essentially ineffective SuIfon or SuIfoxid arises "

Currently available clinical trial reports on SQ14225 ₅ which appears in some of these reports under! Far "Captopril""give reason isu assuming _f that this material in the normal gastrointestinal tract of

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most patients is sufficiently stable _? to be effective as an inhibitor for ACE when administered orally _0, but it is not yet clear whether SQ14225 in some patients remains essentially _c Because of the high reactivity of the free -Sulfhydrylgruppen ineffective can SQ14225 readily with serum · »or cell proteins or peptides or with other substances present in the gastrointestinal tract and having a free sulfhydryl group, form mixed disulfides and additionally form dimers in the course of an oxigenic degradation. A mixed disulfide formed by reaction with a protein could have an antigenic effect and the emergence Such substances are reasonably likely, as allergic reactions have occasionally been observed with clinical use (cf., Gavras, et al., ITew England J ₆ Med 298 _S 991 (1978).) Optionally, disulfides and degradation products of SQ14225 are considered as Inhibitors largely ineffective It can therefore be assumed that in Ab In addition, undesirable side effects and difficulties in maintaining an effective level of inhibitor in the body may occur in at least some patients. "

Thioesters are considered to be extremely 'reactive' in that as the thioester bond is readily cleaved, resulting in a sulfhydryl compound and a carboxylic acid, thioesters are often used as intermediates in acylation under mild conditions such as the acetylthio group Therefore, already in accordance with the 'US Patents 3,832,337 and

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4 046 889 It is further assumed that thioesters also occur in the biosynthesis of cyclic peptides, such as B ₉ syroeidine or gramicidin S, as intermediates (compare Lipmann, P _e in Accounts Ghem ₀ Res., 6, 361 (19735 *

Thioesters which strongly inhibit ACE and have an antihypertensive action when administered orally * have already been described in application APA 61. K / 215 * 457

Compounds which are related to compound SQ14225 have already been described in US Pat. Nos. 4,046,889, 4,052,511, 4,053,651, 4,113,715 and 4,154,840. Of special interest are the analogues of the compound SQi4225o, which have the 4-membered or 6-membered ring instead of the 5-membered heterocyclic proline ring. The inhibitory effect of such analogues, however, is not compared with that of the compound SQI4225. It is reported that by exchanging the L ~ Prolins vs. D-Prölin the inhibitory effect of. 3-mercaptopropanoyl amino acids is drastically reduced. (Cushran ₉ D _e W _ej > et al _e> above) ©

The effect of exchanging the proline residue for the remainder of the L-3j4-dehydroproline has already been investigated in various systems _{; o} When in the 7-position of bradykinin _; L ™ 3_ _S 4 »4Pro. is introduced "a 'Bradykininderivat results significantly reduced physiological effect (see _e I? Isher _s 6" H _{it (et} al _{e s} Arch _e Biochem "Biophys _o 81 (197S) ₆ On the other hand during insertion \ ^r on 4- ^ Pro in the 3-, 5 _»s 8- or 9-position, the ACE inhibitor BPPG _a its inhibitory effect is increased (cf. ₀ Pisher, GH, et al," FEBS Letters 107, 273 (1979) "the Pa» tentinhaberin has in the earlier Application A 5962/79 already

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* that the compounds described in this application and having the rest of ZL Pro have a high inhibitory action and also have antihypertensive activity, but at present no reason can be given for why pro's produce different effects by pro's, " Similarly, there is still no clear picture of the influence of other sites of ACE inhibitors on the presence of other residues of other proline derivatives or analogues

So far, the influence of the on the .Line side of the sulfur atom of standing in the mentioned earlier application described thioester compounds standing amino acid has not yet been determined. If this is true, it would be expected that a compound containing an amino acid residue at this point would be a better inhibitor, _e

Object of the invention

The object of the invention is to provide a novel inhibitor of angicidin converting enzyme which can be administered "for the treatment of hypertension" for all patients, irrespective of the form of administration and undesirable side effects. '

The invention has for its object to find new compounds, the ale inhibitors for An.giotensln converting enzyme having the desired properties and processes for their preparation

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The Applicant has found that numerous amino acids, substituted amino acids or analogous compounds for the radical A can be used in compounds of the general formula (I) given below and effective antihypertensive agents and effective inhibitors for .ACE are obtained here. The Applicant has furthermore found that hydroxyproline. Proline, L-, and ' _s L-3 »4 ~ dehydroproline _p thiazolidines 4-» carboxylic acid and L-5-oxo-proline derivatives give consistently effective antihypertensive and strong inhibitors for general conditions «

For example, in the earlier application APA 61K / 215e457, the patentee has indicated that compounds of general formula (I) below are potent antihypertensive agents and highly inhibitory to AOE, but the Applicant has not tested salts of such compounds at this time The Applicant has now established salts of these compounds and found that these salts are potent antihypertensives and potent inhibitors of ACE ©

Accordingly, the invention relates to a process for the preparation of novel basic salts of compounds of the general formula. '

I! R - A - S - (<3H ₂ ) _n --CH - C - R ₂ , (I).

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in which. , .......

R is hydrogen, formyl, acetyl _$ propanoyl, butanoyl _s phenylacetyl, phenylpropanoyl, benzoyl, cyclopentane-carbonyl, tert-Butylosycarbonyl, Cyclop entanoarbony 1-L-IySyI ₅ Pyro "L-glutamyl-L-lysyl, L-lysyl _s L-arginyl or pyro-ifglutamyl. stands, . ... ....

A phenyl any al I _{5, 9} Glycyi alanyl, tryptophyl, ÜJyrosyl, iso leucyl ~ "means Leuoyl, histidyl, or valyl, and in this case the amino group o £ ~ dieeer residues at aen radical R is linked in amide linkage"

R _{1 represents} hydrogen or methyl ₉ -.

Rp for-1-proline, L »3> 4-dehydroproline _il D _i L ~ 3s.4 ^ra dehydroproline _s L» 3 »hydroxyproline, L-4 = hydrosyproline _> L-thiazolidine ~ 4-carboxylic acid or L-5" 0xo ~ proline and here the imino group of these radicals in imide bond to the adjacent group

Il

is linked and -

η is zero or 1 ^ wherein _s if η is equal FAIL ₉ R. methyl constituted Dei * rest of the amino acid A may be present in optically active Porin, d ₀ h _6? that A is in L, D or 'kaim _e '"'. ·

All of the above compounds are inhibitors of AOE and are orally administered antihypertensives ₀

Basic salts of the type indicated above are prepared according to the invention by converting a compound of general formula (I) into a salt

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Compounds of general formula (I) form, with various inorganic and organic bases basic SaIiZe ₉ Such salts are, for example .Ammoniumsalze, Alkalimetallsalse _{s 9} alkaline earth salts with organic bases. Salts with amino acids U ₁₅ like © Examples of alkali metal salts are Fatriumsalze or potassium salts, "examples of alkaline earth metal salts are Kalsiumsal & e or magnesium salts,""Beispiele.für salts with organic bases are those with Benzath-in U-methyl-D-glucamine or hydrabamine ₀ Examples for salts with amino acids are those with arginine or lysine. Potassium salts or lysine salts are preferred "slugs" - toxic physiologically acceptable salts are also preferred. "

The salts v / ground according to the invention is preferably prepared by _t that a compound of general Pormel (I) in which the resulting salt is insoluble in the form of the free acid with one equivalent of the desired cation-providing base in a solvent or in a medium _f or in water, wherein water is removed by freeze-drying when using water

The salts prepared according to the invention inhibit the conversion of the decapeptide angiotensin I into angiotensin II and are therefore useful for reducing or eliminating:; increased blood pressure produced by angiotensin © Under the action of the enzyme renin on angiotensin gene in blood plasma Pseudoglobulin, angiotensin I ", which is converted by the angiotensin converting enzyme (ACE) into angiotensin II *, which in turn is a potent preaseor (has an effect of increasing blood pressure) and that in various mammals such as rats and

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Huge blood pressure-producing active substance has been recognized by dogs. The compounds which can be prepared according to the invention are now effective. in the reaction sequence

(Renin) (AGE) Angiotensinogen - »Angiotensin I $ · Angiotensin II

by. Inhibiting angiotensin converting enzyme and reducing or preventing the emergence of angiotensin H ₀ as a pressor. By administering a preparation containing one of the candidate salts of compounds of general formula (I) or a combination of such salts is described in U.S. Pat Upon administration of about 0 _s, 1 to 100 mg / kg · d, preferably about 1 to 50 mg / kg · d, of compounds which can be prepared according to the invention in the form of a single dose or preferably divided into 2 or 4 single doses the blood pressure in a by one of S ₀ L ₀ angels T _e R "Schaeffer _? , M _e H »Waugh and B _e Rubin, P ^ ijCe ^ Soc ^ Jxßi ^ Bjulejaied ^ 143? Be reduced animal experiments described 483 (1973) determinable amount, "The active ingredient is preferably administered orally but verabreich ^ may also be administered parenterally, for example subcutaneously, intramuscularly, intravenously or intraperitoneally administered to be" _e ·. ·

Salts of compounds of general formula (I) can be processed into orally administrable preparations such as tablets, capsules or elixirs or parenterally administrable preparations such as sterile solutions and suspensions, where about 10 to 500 mg of a salt or a mixture of compounds of the general formula ( I) with a physiological

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acceptable vehicle, vehicle _s . Excipients, excipients, preservatives, stabilizers, flavorings USW ₀ can be introduced into a unit dose corresponding to the pharmaceutical practice "The amount of active ingredient in such preparations corresponds to a dosage in the range indicated above *

Examples of in tablets, capsules and the like * * usable excipients are binders such as tragacanth, acacia, gelatin Maisstärke.oder ^ an excipient such as dicalcium phosphate, ein.zerfallsfördernder.Stoff such as corn starch, potato starch, alginic acid and the like _e ", a lubricant such as magnesium stearate, a sweetener such as sucrose, lactose or saccharin; and a flavoring such as peppermint, wintergreen oil, or cherry flavor. "If the unit dose is capsule, it may contain, in addition to the above! Substances, a liquid carrier such as a vegetable oil be included _e Various other materials may be present in the form of coatings, but the physical appearance of the unit dose can be modified in other ways ^ For example, tablets with shellac, sugar or both of these substances are coated " , On. Syrup or an elixir may contain, in addition to the active substance ρ sucrose as sweetener, methyl and propylparaben as K'Onservierungsmittel, · -e.inen'Farbstoff and a taste additive such as cherry or orange flavoring contained '

Sterile injectables suitable for injection can usually be used in the pharmaceutical industry by dissolving or suspending the active ingredient in a vehicle such as water for injections, a natural plant

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Oil like sesame oil, coconut oil, peanut oil, cottonseed oil etc. or a synthetic fat like. Äthyloleat o, dgl «, be prepared« If necessary, buffers, preservatives and the like »can be incorporated«

The invention is further illustrated in the _{8-folgenden.durch} embodiments of the preparation of salts of compounds of general formula (I) .and the applicability and the effect of these salts explain "These embodiments do not limit the subject invention a _e

Preparation of the sodium salt of .H ^ phenylalanylthio) -2-D ~ iiiethylpropanoyl7-Ir-proline

A solution of 234-3 mg (0 _s 5 mmol) of 1-alanylthio) ~ 2-D ~ metb.ylpropanoy_l7-'3> -pr-oline in 1 ml absolute ethanol was added under stirring with 0.5 mmol of UaHCOo in Porm 1m solution in Y / asser added ₉ whereupon the solvent was evaporated from the reaction mixture by means of a rotary evaporator at a temperature of about 35 ⁰ C and the resulting oily residue was taken up in fresh ethanol and finally the solvent was evaporated again by means of the 'rotating evaporator "This procedure was again carried out with absolute ethanol and then twice with benzene. The resulting white residue was dried in a vacuum desiccator over ΡρΟς and then recrystallized from 95- / Sigein ethanol and benzene, which with a yield of 55. 1 % 135 mg of white crystals with a decomposition point of 185 to 186 ⁰ G (Erv, ^r eichungspuiikt

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at 153 ⁰ G), the infrared absorption spectrum determined in a KBr tablet was found to be zwitterionic at 1398 and. at 1600 cm "and a thioester band at 1682 cm" * The paper electrophoresis performed at pH 2 and 5 and the thin layer chromatography on silica gel plates using three different solvents showed reacting with phenazine methosulfate reagent only a single spot recognizable in the short-wave W *

Analyzes',. ,

calculated for C ₂₅ H ₂₇ I ₂ SIaO ₅₀ 2K ₂ Os 57.02 % 0 _f 5 * 93 % H _s

5.32 % IS, -6 _s O9 % S.

found 56.37 % G ₉ 5 * 59 % H,

5.30 % M _s 5 _S 99 % S

2.

Preparation of the potassium salt of H ^ -Zl- (1-B-phenylalanylthio) -2-D-methylpropanoy3.7-L-proline

The potassium hydroxide of this compound was prepared according to the procedure set forth in Example 1 using Im-KHCOo solution instead of the im-UaHCO 4 solution. Recrystallization was carried out on 70 mg of a white solid having a decomposition point of 132-134 '. ⁰ C receive, "in .the · determination of the infrared absorption spectrum in the paper electrophoresis and thin-layer chromatography, the same values were obtained as for the one prepared in example 1 sodium salt"

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Preparation of the L-lysine salt of the H ^of phenylalanylthio 2-D-methylpropanoyl 7 ° Ii ~ proline

A solution of 234 "3 mg (0.5 mmol) N ^ - D _} Ir-» phe] .iylalanylthio) ~ 2- »D->meth5'-l-propanoyl7-L- = proliji in 1 ml of absolute alcohol was washed with a solution of 1 73 mg (Ο * 5 mmol) of this in the form of the free base L -? Lysihs ₅ 3 ml of demineralized water are added in O dropwise and stirring, and then evaporated from Reaktionsgem.isch the solvent by a rotary evaporator. were the residue was taken up in fresh absolute ethanol _e., whereupon the solvent was again evaporated by a rotary evaporator * This procedure was still 2 times carried out with absolute alcohol and then 2- = times with benzene of the obtained by drying this Residue in a vacuum desiccator over P ₂ Oc were obtained 0 _f 292 g of a substance having a decomposition point of 152 to 154j4 ° C, which on recrystallization from absolute water mixed with a few drops of water and Benaol 141 mg of a white Ni with a decomposition point of. 162.5 to 163 ", 5 ⁰ C (softening point at 160 ^° C.) provided * The infrared absorption spectrum determined in a KBr tablet showed zwitterionic

-1

AEEN at 1389 and 1620 cm _s showed a carbonyl of an amide group .for 1641. cm and a · Thioesterbande 'at 1678 -era ν · The processing performed at a pH value of 5 by paper and carried out using three different solvent systems on silica gel plates Dünnschichtchroraatographie the presence of lysine and said compound ", using bases other than the bases used in Examples 1-3

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o or lysine can be prepared according to the information in these examples, other physiologically acceptable.Salze * Obswar according to Examples 1 to 3 salts of I ⁰⁰ - / 3- (N ^ -BeIiZOyI-D, L-phenylalanylthio) -2-I> of course, physiologically acceptable salts of any other compound of general formula (I) can also be prepared in the same way,

Game 4 ·

Efficacy in oral administration of the sodium salt · of the H ^ ^ / J (ET ^ benzoyl-D, L-phenylalanylthio) -2-D »methylpro-. panoyl7 ~ ~ L proline

A body weight of 150 to 19Og rats was fasted overnight and then anesthetized by intraperitoneal administration of pentobarbital 50 to 60 mg / kg, followed by tracheostomy in the rats and then mechanical ventilation of the rats for injection of angiotensin I. another cannula was inserted into a carotid artery to prevent coagulation. "1000 units of heparin were delivered via the pemorvene. The blood pressure was measured by means of a clamp connected to a vascular funnel Pressure transmitter measured. The rats were on the injection paths 400 ng / kg angiotensin I in 20 / ul Oj, _e 9 wt -% strength dissolved HACL solution administered _s? d _G h _ö that the · administered amount of angiotensin I was sufficient "to increase the mean arterial blood pressure to 60 mbar _e after the response of each rat to angiotensin I was administered, the above-mentioned connects _s to be tested

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in an amount of 10 / umol / kg dissolved in 0.15 ml HgO and 10 / Ul in-liaHGO solution via a gastric tube. The influence of the angiotensin I administered in an amount of 400 ng / kg on the mean arterial blood pressure was measured at certain time intervals. The results obtained were the following j

Time after oral administration Response of blood (in minutes) pressure to 400 ng / kg

Angiotensin I (in % of the same value)

-5 100 (60 mbar)

+5 82

10 33

15 24

20 27

30 27

40 22

50 24

60 27

.90 36

44

: '150 .62

"'60'

, , 210 · 71

'' '··' 240 '·. 73 ·' ''

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LX

Y / irkung of the potassium salt of. U ^ - ^ - dr ^ -Benzoyl-D, L-phenylaianylthio) »2-D-methylpropanoyl7 ~ L-proline · when administered intravenously.

The efficacy of this compound on intravenous administration was determined as described in Example 4 _. however, the test compound was administered intravenously in an amount of 1 μmol / kg · The results obtained were as follows

Time after intravenous blood pressure response Administration to 400 ng / kg angiotensin I (in

(in minutes) % of the comparison value)

~ 5 100 (72 inbar) +5. 46

10 37

15 41

20 37

30 44

40 50

50 33

60 46

SO 52

120 59

Without departing from the scope of the invention, numerous modifications of the illustrated embodiments can be made.

Claims (1)

I - 21 - Berlin, 17 * 11.81 ⁴ 59 298 12 A process for producing an inhibitor of angiotensin converting enzyme, characterized by containing a compound of the general formula 0 Il "* Jx ~ * tJ - V. vjilp J ·" VyIl ~ O · "Jxn, VL / R ₁ R is hydrogen, pormyl, acetyl, propanoyl, butanoyl, phenylacetyl, phenylpropanoyl, benzoyl, cyclopentane · carbonyl, tert-butyloxycarbonyl, cyclopentanecarbonyl-L-lysyl, pyro-L-glutamyl-L-lysyl, L-lysyl, L-arginyl or pyro ~ L ~ glutamyl,. - A phenylalanyl, G-lycyl, Al is any 1, tryptophyl, tyrosyl, isoleucyl, leucyl, histidyl or valyl and in this case the οό-amino group of these radicals is attached to the radical R in amide bond, R _{1 represents} hydrogen or methyl, Rp for L-proline, L ~ 3 »4-dehy ^ roproline ,. _D> L-3 ^"4-I> ehydroprolin.j L '3 ~ Hydro ^ proline, L-4 ~ hydroxyproline, L-thia" zolidin ~ 4-carboxylic acid or L "5" 0XO-proline has stopped and • in this case the Imino group of these radicals in Imidbin'dung to the adjacent group 0 is knotted and. , ' η Hull or 1, where, if η is Hull, R _{1 is} methyl, is reacted with a base to form a salt - 22 - Berlin, the 17,11 «81 59 298 12 2e method according to item 1, characterized in that the • sodium », potassium = * calcium, magnesium ·», benzathine, hydrabamine, H-methyl ^ D-glucamiri, arginine or lysine salt is prepared « Process according to item 1 or 2 _8, characterized in that a salt of a compound of general formula (I) is prepared * in which A is phenylalanyl, R _{1 is} methyl and Rp is L-proline and η is 1 ''. Process according to one of the items 1 _S 2 or 3 *, characterized in that the free acid of the general formula (I) is reacted with 1 equivalent of the base yielding the desired cation, expediently being carried out in a solvent or in a medium for the resulting salt is worked and when using water as a solvent, the water is preferably driven off by freeze-drying »