Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
  • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
  • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
  • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/275—Nitriles; Isonitriles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
  • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
  • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
  • C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
  • C07C323/40—Y being a hydrogen or a carbon atom
  • C07C323/41—Y being a hydrogen or an acyclic carbon atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
  • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane

Definitions

• the present invention relates to new sulfur derivatives comprising a retroamide bond, their preparation process, the new intermediates obtained, their application as medicaments, the pharmaceutical compositions containing them and the new use of such derivatives.
• R. ⁇ represents a phenyl or biphenyl radical optionally substituted by one or more radicals chosen from halogen atoms, optionally protected hydroxyl radicals, linear or branched alkoxy containing at most 4 carbon atoms, cyano, free carboxy, salified, esterified or amidified, benzyloxy and the dioxol radical, ni and n2, identical or different, represent the whole 0 or 1,
• R 2 represents a hydrogen atom or a methyl radical substituted by a phenyl, phenylthio or indolyl radical and optionally by a second phenyl radical, these phenyl, phenylthio and indolyl radicals being optionally substituted by one or more radicals chosen from halogen atoms, optionally protected hydroxyl radicals, linear or branched alkoxy containing at most 4 carbon atoms, cyano, carboxy free, salified, esterified or amidi ⁇ fied,
• linear or branched alkyl radical designates the methyl, ethyl, propyl, isopropyl, butyl, isobu ⁇ tyle, sec-butyl, tert-butyl, pentyl, isopentyl radicals , hexyl, isohexyl and also heptyl, octyl, nonyl and decyl as well as their linear or branched position isomers
• linear or branched alkoxy radical designates the methoxy, ethoxy, propoxy, isopropoxy, linear butoxy, secondary or tertiary, pentoxy radicals or hexoxy as well as their linear or branched position isomers
• halogen atom preferably designates the chlorine atom, but can also represent a fluorine, bromine or iodine atom.
• the hydroxyl radical may in particular be in the form of a trifluoromethylsulfonyloxy radical.
• the carboxy radical (s) of the products of formula (I) can be salified or esterified by various groups known to those skilled in the art, among which there may be mentioned, for example: - among the salification compounds, mineral bases those which, for example, an equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium or organic bases such as, for example, methylamine, propylamine, trimethylamine, diethylamine, tri- ethylamine, N, N-dimethylethanolamine, tris (hydroxy-methyl) amino methane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, N-methyl-glucamine.
• the sodium or potassium salts are preferred,
• the alkyl radicals to form alkoxy carbonyl or arylalkoxycarbonyl groups such as, for example, methoxycarbonyl, ethoxycarbonyl, n-propoxy- and isopropoxy-carbonyl, n-butoxy-, isobutoxy- and tert-butoxycarbonyl or benzyloxycarbonyl, these alkyl radicals being able to be substituted by radicals chosen for example from halogen atoms, hydroxyl, alkoxy, acyl, acyloxy, alkylthio, amino or aryl radicals as, for example, in chloromethyl, hydroxypropyl, methoxymethyl, propionyloxymethyl, methylthiomethyl, dimethylaminoethyl, benzyl or phenethyl groups.
• radicals formed with easily cleavable ester residues such as the methoxymethyl, ethoxymethyl radicals; acyloxyalkyl radicals such as pival ⁇ yloxymethyl, pivaloyloxyethyl, acetoxy-methyl or acetoxyethyl; alkylalkylcarbonyloxyalkyl radicals such as methoxycarbonyloxy methyl or ethyl radicals, isopropyloxycarbonyloxy methyl or ethyl radicals.
• ester radicals can be found, for example, in European patent EP 0 034 536.
• Amidified carboxy means groups of the type -CON (Rg) (R 7 ) in which the radicals R 6 and R 7 are identical or different represent a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl radicals.
• R 6 and R 7 represent a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl radicals.
• the radical -N (Rg) (R 7 ) represents the amino, mono or dimethylamino radical are preferred.
• the radical N (Rg) (R 7 ) can also represent a heterocycle which may or may not contain an additional heteroatom. Mention may be made of the pyrrolyl, imidazolyl, indolyl, piperidino, morpholino, piperazinyl radicals. The piperidino or morpholino radicals are preferred.
• the addition salts with mineral or organic acids of the products of formula (I) can be, for example, the salts formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, propionic, acetic or formic acids, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, ascorbic, alkylmonosulphonic acids such as for example methanesulphonic acid, ethanesulphonic acid, propanesulphonic acid, such as alkylsulphonic acids example methanedisulfonic acid, alpha acid, beta-ethanedisulfonic acid, arylmonosulfonic acids such as benzenesulfonic acid and aryldisulfonic acids.
• hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, propionic, acetic or formic acids benzoic
• stereoisomerism can be defined in its broad sense as the isomerism of compounds having the same developed formulas, but whose different groups are arranged differently in space.
• the products of formula (I) have in particular two centers (T) and (2).
• T) being asymmetrical
• (g) being asymmetrical
• the subject of the present invention is in particular the products of formula (I) in which the first asymmetrical center ⁇ p) is preferably in R form, the second center
• (2) can be in racemic form or R or S enantiomer.
• the present invention particularly relates to the products of formula (I) as defined above, in which R ⁇ , R 2 , and n2 have the meanings indicated above, nor represents the integer 1, and A represents the free, salified, esterified or amidified carboxy radical or an alkyl radical containing at most 10 carbon atoms and substituted by a radical chosen from free, salified, esterified or amidified carboxy radicals, optionally protected hydroxyl radicals, alkoxy containing plus 4 carbon atoms and phenoxy, said products of formula (I) being in all the racemic isomeric, enantiomeric and diastereoisomeric forms possible, as well as the addition salts with mineral and organic acids or with mineral bases and organic of said products of formula (I).
• the present invention more particularly relates to the products of formula (I) as defined above, in which R ⁇ represents a phenyl or biphenyl radical, optionally substituted by a halogen atom, or by a hydroxyl radical optionally in the form of a trifluoromethylsulfonyloxy radical, or represents the integer 1, n2 represents the integer 0,
• R 2 represents a hydrogen atom or a methyl radical substituted by a phenyl radical, itself optionally substituted by a thienyl or phenyl radical itself itself optionally substituted by a cyano radical,
• A represents the free, salified, esterified or amidified carboxy radical or an alkyl radical containing at most 10 carbon atoms substituted by a phenoxy radical, said products of formula (I) being in all the racemic isomeric, enantiomeric and diastereoisomeric forms possi ⁇ wheat, as well as the addition salts with mineral and organic bases of the said products of formula (I).
• R- ⁇ may represent a phenyl or biphenyl radical, optionally substituted by a bromine atom.
• the present invention particularly relates to the products of formula (I) as defined above, the names of which follow:
• Another subject of the present invention is the process for preparing the products of formula (I), as defined above, characterized in that a product of formula (II) is subjected:
• R ' 2 has the meaning indicated above for R 2 in which the possible reactive functions are optionally protected, and R represents an alkyl or arylalkyl radical, to obtain the product of formula (IV):
• the process described above can be carried out as follows: above with the product of formula (III) as defined above is preferably carried out with a coupling agent such as for example EDC in methylene chloride or else BOP in methyl cyanide in presence of triethylamine, or DDC,
• a coupling agent such as for example EDC in methylene chloride or else BOP in methyl cyanide in presence of triethylamine, or DDC
• the reaction of the product of formula (II) as defined above with the product of formula (V) as defined above is preferably carried out in methylene chloride in the presence of pyridine.
• the halogen atom is preferably a chlorine atom.
• the products of formulas (IV) and (VI) constitute or not products of formula (I) and can give products of formula (I), or be transformed into other products of formula (I) by being subjected to one or more of the reactions indicated above which can be carried out, for example, as indicated below.
• hydroxyl groups can be protected for example by alkyl radicals such as tert-butyl, trimethylsilyl, tert-butyldimethylsilyl, methoxymethyl, tetrahydropyrannyl, benzyl or acetyl.
• alkyl radicals such as tert-butyl, trimethylsilyl, tert-butyldimethylsilyl, methoxymethyl, tetrahydropyrannyl, benzyl or acetyl.
• the acid functions of the products described above can be, if desired, amidified with a primary or secondary amine, for example in methylene chloride in presence, for example, of 1-ethyl-3- (dimethylaminopropyl) carbodiimide hydrochloride at room temperature.
• the acid functions can be protected, for example, in the form of esters formed with easily cleavable esters such as benzyl or tert-butyl esters or esters known in the chemistry of peptides.
• ester function according to acid function of the products described above can be, if desired, carried out under the usual conditions known to those skilled in the art, in particular by acid or alkaline hydrolysis, for example with sodium hydroxide or potash in an alcoholic medium such as, for example, in methanol or also with hydrochloric acid or sulfuri ⁇ that.
• the possible cyano functions of the products described above can, if desired, be transformed into an acid function under the usual conditions known to those skilled in the art, for example by double hydrolysis carried out in an acid medium such as, for example, in a mixture of sulfuric acid, glacial acetic acid and water, these three compounds preferably being in equal proportions, or alternatively in a mixture of soda, ethanol and water at reflux.
• the acid functions can be transformed into tetrazole as indicated in the publication Bio. Med. Chem. Leh. 1995, 145.
• Any alkoxy functions such as in particular methoxy of the products described above can be, if desired, transformed into a hydroxyl function under the usual conditions known to those skilled in the art, for example by boron tribromide in a solvent such as for example methylene chloride, with pyridine hydrobromide or hydrochloride or also with hydrobromic or hydrochloric acid in water or trifluoro acetic acid at reflux.
• protective groups such as, for example, those indicated above can be carried out under the usual conditions known to those skilled in the art, in particular by acid hydrolysis carried out with an acid such as hydrochloric acid, benzene sulfonic or para- toluene sulfonic, f ⁇ rmic or trifluoroacetic or by catalytic hydrogenation.
• the phthalimido group can be eliminated by hydrazine.
• a list of different protective groups can be found, for example, in patent BF 2,499,995.
• the products of formula (I) of the present invention have been found to have an inhibiting activity of the endothelin converting enzyme which makes it possible to obtain from Big Endothelin, endothelin itself, which is therefore an extremely powerful vasoconstrictor.
• the products of formula (I) of the present invention may therefore be useful in the treatment of conditions resulting from abnormally high amounts of endothelin.
• the compounds of formula (I) as defined above as well as their addition salts as defined above have interesting pharmacological properties.
• the products of formula (I) as defined above, endowed with inhibitory properties of the endothelin converting enzyme, can thus in particular reduce the quantities and thus the effects of endothelin, in particular vasoconstrictor and hypertensive effects. induced by endothelin. There is in particular an antiischemic effect.
• the products of formula (I) thus also have the effect of reducing the stimulating effects of endothelin at the level of all cell types, in particular smooth muscle cells, fibroblasts, neuronal cells and bone cells.
• R- ⁇ represents a phenyl or biphenyl radical, optionally substituted by a halogen atom, nor represents the integer 1, n2 represents the integer 0,
• R 2 represents a hydrogen atom or a methyl radical substituted by a phenyl radical, itself optionally substituted by a thienyl or phenyl radical itself optionally substituted by a cyano radical,
• A represents the free, salified, esterified or amidified carboxy radical or an alkyl radical containing at most 10 carbon atoms substituted by a phenoxy radical, said products of formula (I) being in all the isomeric, racemic or optically active forms, thus as addition salts with mineral and organic acids or with pharmaceutically acceptable mineral and organic bases of said products of formula (I).
• the subject of the invention is very particularly, as medicaments, the products described below in the examples and in particular the products of formula (I) as defined above, the names of which follow: - [S- (R *, S *)] N- [1- (mercaptomethyl) -2-phenylethyl] -alpha- [[(phenylmethoxy) carbonyl] amino] -IH-indole-3-propanamide,
• the drugs which are the subject of the invention thus find their use in the treatment, by the use of an agent inhibiting the endothelin-converting enzyme, of conditions such as, for example, vascular spasms, vasospasm following cerebral hemorrhage, coronary spasms, peripheral vascular spasms as well as renal failure.
• agents such as, for example, vascular spasms, vasospasm following cerebral hemorrhage, coronary spasms, peripheral vascular spasms as well as renal failure.
• These drugs can also be used in the treatment of myocardial infarction, congestive heart failure, in the prevention of post-angioplasty restenosis, cardiac and vascular fibrosis, in the treatment of atherosclerosis, certain forms of hypertension such as pulmonary hypertension, as well as in the treatment of asthma.
• the drugs which are the subject of the invention can also find application in the treatment of osteoporosis, prostatic hypertrophy and as neuronal protectors.
• the invention extends to pharmaceutical compositions containing, as active principle, at least one of the medicaments as defined above.
• compositions can be administered by the oral, rectal, parenteral or local route by topical application to the skin and the mucous membranes or by injection by intravenous or intramuscular route.
• compositions can be solid or liquid and can be presented in all the pharmaceutical forms commonly used in human medicine such as, for example, simple or coated tablets, capsules, granules, suppositories, injections, ointments, creams, gels and aerosol preparations; they are prepared according to the usual methods.
• the active principle can be incorporated therein into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not, fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.
• the usual dosage which varies according to the product used, the subject treated and the condition in question, can be, for example, from 1 to 300 mg per day in adults, orally or from 1 to 100 mg per day. intravenously.
• Certain starting materials of formulas (II), (III) and (V) are known, can be commercial or prepared according to the usual methods known to a person skilled in the art or for example as indicated in European patent EP 0465369. may also in particular prepare certain products of formula (II) from other products of formula (II) for example by subjecting them to one or more of the reactions described above, carried out under the conditions also described above. Preparations of compounds of formula (II) are indicated in the examples described below.
• the compound of formula (II) in which ni represents the integer 1 and R ' ⁇ represents the phenyl radical can be prepared as indicated in preparation IE of EP 0465369, either from the amino acid L-phenylalamine to give the product of formula (II) of form S, either from the amino acid D-phenylalamine to give the product of formula (II) of form R, or from a mixture of the amino acids L- and D-phenyl - alamine to give the product of formula (II) of racemic form: these compounds of formula (II) thus obtained give respectively, after reaction with the compound of formula (III), a product of formula (IV) which will be respecti ⁇ vely in (Jp) in form S (example 1), in form R (example-
• ni represents the integer 0
• Other compounds of formula (II), in which ni represents the integer 0 can be prepared from the corresponding acid to give, by a Curtius reaction described in the literature, the desired amine.
• the compounds of formula (III) represent amino acids which can be substituted on nitrogen: such compounds of formula (III) can be commercial or prepared according to the usual methods known to those skilled in the art.
• the compounds of formula (V) are preferably acid chlorides prepared from the corresponding acid itself commercial or prepared according to the usual methods known to those skilled in the art, such as by condensation of an alkyl halide on a malonate.
• the present invention finally relates, by way of new industrial products, to the compounds of formulas (IV) and (VI) as defined above.
• a particular subject of the invention is the use of the products of formula (I) as defined above, for the preparation of an agent inhibiting the endothelin conversion enzyme.
• the invention therefore particularly relates to the use of the products of formula (I) as defined above, for the preparation of pharmaceutical compositions intended for treatment, by inhibition of the enzyme of conversion of the endothelin, of conditions such as in particular hypertension induced by endothelin, vascular spasms, the consequences of a cerebral hemorrhage, renal insufficiency, myocardial infarction, heart failure as well as prevention of post-angioplasty restenosis and cardiac and vascular fibrosis.
• N-CBZ-tryptophan N-carbobenzyloxy-Trp.
• EP 0465368 (example 49).
• the solution is stirred 1 h at 0 ° C and 3 h at room temperature, then acidified with IN hydrochloric acid to pH ⁇ 2. Then extracted with ethyl acetate and dried. After chromatography on silica with ethyl acetate - cyclohexane: 25-75 as eluent, 400 mg of an oil is obtained which is taken up in 10 ml of methylene chloride. 10 ml of trifluoro acetic acid are added and the mixture is left for 3 h at room temperature and then evaporated. The oily residue is taken up in 10 ml of thionyl chloride and left stirring overnight. After evaporation of the thionyl chloride, the expected acid chloride is obtained, used as it is in the following stage.
• reaction is then acidified by adding IN hydrochloric acid to pH z 2, then, after adding 5 ml of H 2 O, it is extracted three times with methylene chloride +
• STAGE 1 alpha- (ethoxycarbonyl) -benzenepropanoyl chloride
• the procedure is carried out as in stage 1 of Example 4 using instead of 4 '- (bromo-methyl) (1,1 * -biphenyl) 2-carbonitrile, benzyl bromide (commercial) and thus obtains the expected product.
• Example 4 The procedure is as in Example 4, taking as starting material, instead of the amine hydrochloride in which R- represents phenyl, the amine hydrochloride in which R-, represents biphenyl, prepared using as starting material the product (R) - a- [[(1,1-dimethylethoxy) carbonyl] amino] [1,1 '-biphenyl] -4-propanoic acid, which is here in the form R and which is prepared as its S-form enantiomer, the preparation of which is described in the following reference: Journal of Medecinal Chemistry, 1995, Vol. 38, 1689, then by preparing the corresponding hydrochloride as indicated in stage D of EP 0465369. The product of Example 7 thus obtained is thus obtained.
• Tablets corresponding to the following formula were prepared: Product of Example 4 50 mg Excipient for a tablet terminated at 200 mg
• the toluene is evaporated until a solution of
• Elution is carried out with a flow rate of 0.8 ml / min by a gradient of 0 to 20% acetonitrile in 20 min then 20 to 35% in 50 min.
• Analyzes The analysis of the fractions is carried out by counting the tritium on the liquid scintillation counter (1 ⁇ l in 5 ml of HiSafe3 scintillant) for 60 seconds.
• reaction is initiated by adding 10 ⁇ l of (2,3- 3 H) propionyl-b-ET-1 (19-35) prepared as indicated above in a), at the final concentration of 1.8 ⁇ 10 ⁇ 12 Mr.
• reaction After one hour of incubation at 37 ° C, the reaction is stopped by adding 600 ⁇ l of ethyl acetate and the (2,3- 3 H) propionyl-b-ET-1 (19-21) is extracted by mechanical agitation for 2 minutes.
• the blank is made from the solution obtained without enzyme.
• the test was validated by its application to known inhibitors, ie Pl which is phosphoramidon and P2 which is N- (phenylethylphosphonyl) -Leu-Trp (TAKEDA).
• Pl which is phosphoramidon
• P2 which is N- (phenylethylphosphonyl) -Leu-Trp

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