FR2554347A1 - Pressinic acid, its substituted amino acid derivatives and homologues of D configuration as well as the N- and C-terminal-substituted derivatives and their applications in the therapeutic, biological or immunological fields - Google Patents

Pressinic acid, its substituted amino acid derivatives and homologues of D configuration as well as the N- and C-terminal-substituted derivatives and their applications in the therapeutic, biological or immunological fields Download PDF

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FR2554347A1
FR2554347A1 FR8317768A FR8317768A FR2554347A1 FR 2554347 A1 FR2554347 A1 FR 2554347A1 FR 8317768 A FR8317768 A FR 8317768A FR 8317768 A FR8317768 A FR 8317768A FR 2554347 A1 FR2554347 A1 FR 2554347A1
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pressinic
acid
derivatives
radioactive
agents
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FR2554347B1 (en
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Jacques Chauveau
Michel Delaage
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Immunotech SAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/16—Oxytocins; Vasopressins; Related peptides
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/531—Production of immunochemical test materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

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  • Proteomics, Peptides & Aminoacids (AREA)
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Abstract

The invention relates, as active agents in the therapeutic, biological and immunological fields, and in the field of immunoassays, to pressinic acid, its derivatives which are substituted in at least one of the positions 2, 3, 4 and 5 by natural amino acids and their homologues of D configuration, the acylated derivatives at the N-terminal side of pressinic acid, the amide and ester derivatives at the C-terminal side and the radioactive derivatives of these agents.

Description

La présente invention concerne l'acide pressinique ou pres5inolque, ses dérivés substitués en 1 'une ou plus~evers des positions 2, 3, 4 et 5 par des aminoacides naturels et leurs homologues de configuration D ainsi que les dérivés acylés sur le côté N-terminal de l'acide pressinique et leurs applications dans les domaines thérapeutique, biologique, ou immunologique. The present invention relates to pressinic or pres5inolque acid, its derivatives substituted in 1 'one or more ~ towards positions 2, 3, 4 and 5 by natural amino acids and their homologs of configuration D as well as the acylated derivatives on the N side. -terminal of pressinic acid and their applications in the therapeutic, biological, or immunological fields.

Qn sait que la diurèse, et plus généralement, les échanges hydriques chez l'homme et les animaux supérieurs jouent un rôle très important. De mauvais échanges hydriques peuvent être à l'origine de maladies graves pouvant entraîner la mort. C'est le cas, par exemple, du "diabète insipide" caractérisé par l'incapacité du sujet à retenir l'eau ; la diurèse est très abondante et, par contrecoup, la soif est permanente (potomanie). I1 est alors difficile de compenser ou d'équilibrer les sujets qui en sont atteints.Des résultats plus ou moins satisfaisants peuvent être obtenus en faisant appel à des anti-diurétiques auxquels,dans certains cas, on reconnaît une efficacité mais à faible dose, d'où une action fugace et,dans d'autres cas, parce qu'utilisés à de plus fortes doses, une action "pressique" toxique. We know that diuresis, and more generally, water exchanges in humans and higher animals play a very important role. Poor water exchange can cause serious illness that can lead to death. This is the case, for example, with "diabetes insipidus" characterized by the subject's inability to retain water; diuresis is very abundant and, as a result, thirst is permanent (potomania). It is therefore difficult to compensate or balance the subjects who are affected. More or less satisfactory results can be obtained by using anti-diuretics which, in some cases, are recognized to be effective but at low doses, d 'where a fleeting action and, in other cases, because used in higher doses, a toxic "press" action.

Le besoin d'agents actifs ne présentant pas ces inconvénients se fait donc de plus en plus sentir, bien que, récemment, on ait vu apparaître des médicaments dérivés de la vasopressine (D.D.A.V.P.) présentant une durée d'action relativement longue pour un seuil de toxicité relativement acceptable. The need for active agents not having these drawbacks is therefore becoming more and more felt, although, recently, there have been emerging drugs derived from vasopressin (DDAVP) having a relatively long duration of action for a threshold of relatively acceptable toxicity.

Or, la Demanderesse a trouvé de façon tout à fait inattendue que l'aciae pressinique lui-même présentait des propriétés anti-diurétiques majeures . Cette propriété est d'autant plus inattendue que ce peptide synthétisé depuis de nombreuses années et répondant à la formule

Figure img00020001

(dans laquelle
- l'ensemble Cys(l-6f représente le motif cystine
- Tyr représente le résidu tyrosine
- Phe représente le résidu de phénylalanine
- Gln représente le résidu de glutamine
- Asn représente le résidu dàsparagine,
tous ces amino-acides étant de configuration L) n'a jamais été décrit comme ayant une propriété thérapeutique
En effet, l'acide pressinique injecté à un lapin ou à un rat, à raison de 0,1 ng/kg, provoque un freinage de la diurèse ; à 1 ng/kg, l'effet est maximal (32 minutes chez le rat) et, à 50 ng/kg, l'effet est toujours maximal avec manifestation d'un léger effet presseur mais sans toxicité.Now, the Applicant has found, quite unexpectedly, that the pressinic steel itself has major anti-diuretic properties. This property is all the more unexpected since this peptide synthesized for many years and corresponding to the formula
Figure img00020001

(in which
- the Cys group (l-6f represents the cystine motif
- Tyr represents the tyrosine residue
- Phe represents the phenylalanine residue
- Gln represents the residue of glutamine
- Asn represents the residue of asparagine,
all these amino acids being of configuration L) has never been described as having a therapeutic property
Indeed, the pressinic acid injected into a rabbit or a rat, at a rate of 0.1 ng / kg, causes braking of the diuresis; at 1 ng / kg, the effect is maximum (32 minutes in rats) and, at 50 ng / kg, the effect is always maximum with manifestation of a slight pressing effect but without toxicity.

Si on le compare a un agent anti-diurétique connu comme, par exemple, la vasopressine, on constate que cette dernière manifeste une activité à partir de 2 ng/kg. Toutefoîs, à 30 ng/kg, une toxicité importante de cet agent se manifeste à cause d'un important effet presseur entraînant la mort des animaux.If we compare it to a known anti-diuretic agent such as, for example, vasopressin, we see that the latter manifests activity from 2 ng / kg. However, at 30 ng / kg, a significant toxicity of this agent manifests itself due to a significant pressure effect resulting in the death of the animals.

L'invention couvre donc, à titre de médicament nouveau, notamment anti-diurétique ne présentant pas les inconvénients dus aux agents anti-diurétiques connus, toute composition à base d'acide pressinique. The invention therefore covers, as a new drug, in particular an anti-diuretic which does not have the drawbacks due to known anti-diuretic agents, any composition based on pressinic acid.

La présente invention couvre également, en tant qu'agents actifs convenant dans le domaine thérapeutique, notamment en tant qu'agents anti-diurétiques, les dérivés de l'acide pressinique substitués en au moins une des positions 2, 3, 4 et 5 par des aminoacides naturels et leurs homologues de configuration D ainsi que les dérivés acylés sur le côté
N-terminal de cet acide et les dérivés amides et esters sur le côté C-terminal. The present invention also covers, as active agents suitable in the therapeutic field, in particular as anti-diuretic agents, derivatives of pressinic acid substituted in at least one of positions 2, 3, 4 and 5 by natural amino acids and their D-configuration counterparts as well as the acylated derivatives on the side
N-terminal of this acid and the amide and ester derivatives on the C-terminal side.

Comme exemples de tels dérivés, on peut citer - l'acide N-acétyl-pressinique - l'acide N-succinyl-pressinique - l'acide (Ileu3) pressinique - l'acide N-acétyl(Ileu3) pressinique - l'acide N-succinyl lIleu3) pressinique ainsi que les dérivés amides et esters à chaîne courte correspondants. Examples of such derivatives include - N-acetyl-pressinic acid - N-succinyl-pressinic acid - (Ileu3) pressinic acid - N-acetyl (Ileu3) pressinic acid - acid N-succinyl lIleu3) pressinique as well as the corresponding amide derivatives and short chain esters.

Parmi les dérivés acylés, on citera plus particulièrement le composé répondant à la formule
CH2-CO-NH-Gly-Tyr
CH2-CO-NH-acide pressinique et les conjugués acide pressinique-support macromoléculaire (comme une protéine) dans lesquels l'acide pressinique est lié par une liaison amide entre son extrémité N-terminale et une fonction carboxylique portée par la macromolécule.Among the acylated derivatives, mention will be made more particularly of the compound corresponding to the formula
CH2-CO-NH-Gly-Tyr
CH2-CO-NH-pressinic acid and pressinic acid-macromolecular support conjugates (such as a protein) in which pressinic acid is linked by an amide bond between its N-terminal end and a carboxylic function carried by the macromolecule.

En dehors de leur application comme agents anti-diurétiques, l'acide pressinique et ses ddrivés peuvent être utilisés dans le domaine de l'immunologie, de la biologie, de l'analyse immunologique. Apart from their application as anti-diuretic agents, pressinic acid and its derivatives can be used in the field of immunology, biology, immunological analysis.

C'est ainsi que, par injection de conjugués entre l'acide pressinique et un support macromoléculaire (protéine en particulier), il se forme des anti-corps entraînant un important effet diurétique. Ces dérivés trouvent ainsi une application thérapeutique supplémentaire, notamment dans le domaine de la vaccination et de la sérothérapie. Thus, by injection of conjugates between pressinic acid and a macromolecular support (protein in particular), anti-bodies are formed, leading to a significant diuretic effect. These derivatives thus find an additional therapeutic application, in particular in the field of vaccination and serotherapy.

Ils présentent aussi de l'intérêt comme réactifs immunologiques pour le dosage de l'acide pressinique
En effet, ces mêmes anti-corps utilisés in vitro, en associa- tion avec un traceur radioactif comprenant un analogue de l'acide pressinique selon l'invention, permettent le dosage de l'acide pressinique notamment dans les liquides biologiques. They are also of interest as immunological reagents for the determination of pressinic acid
In fact, these same antibodies used in vitro, in combination with a radioactive tracer comprising an analog of pressinic acid according to the invention, make it possible to assay pressinic acid in particular in biological liquids.

Ces analogues radioactifs de l'acide pressinique entrant dans le cadre de la présente invention peuvent aisément être obtenus par des procédés bien connus - soit par substitution d'un aminoacide par un analogue tritié radioactif - soit par iodation radioactive de la tyrosine 2 de 1 'acide pressinique
ou d'un dérivé N-acylé - soit par greffe d'un peptide iodé radioactif à l'extrémité
N-terminale de l'acide pressinique - soit par greffe d'un composé iodé radioactif (tel le
réactif de Bolton-Hunter) à l'extrémité N-terminale de
l'acide pressinique.These radioactive analogs of pressinic acid falling within the scope of the present invention can easily be obtained by well known methods - either by substitution of an amino acid with a radioactive tritiated analog - or by radioactive iodization of tyrosine 2 of 1 ' pressinic acid
or an N-acylated derivative - either by grafting an iodized radioactive peptide at the end
N-terminal pressinic acid - either by grafting a radioactive iodine compound (such as
Bolton-Hunter reagent) at the N-terminus of
pressinic acid.

Quant à l'acide pressinique lui-même, il peut être obtenu par les procédés de synthèse bien connus n'entrant pas dans le cadre de la présente invention. As for the pressinic acid itself, it can be obtained by well-known synthetic methods not falling within the scope of the present invention.

De façon générale, les enchaînements d'acides aminés peuvent être obtenus par la synthèse de Merrifield en phase solide ou par les procédés bien connus en phase homogène. Les dérivés N-acylés peuvent être obtenus par réaction avec les anhydrides correspondants (anhydride acétique, anhydride succinique, anhydrides mixtes et analogues), soit en milieu anhydre (alcool, diméthylformamide, etc), soit en milieu aqueux à pH légèrement alcalin.In general, the amino acid sequences can be obtained by the synthesis of Merrifield in the solid phase or by the well-known methods in the homogeneous phase. The N-acylated derivatives can be obtained by reaction with the corresponding anhydrides (acetic anhydride, succinic anhydride, mixed anhydrides and the like), either in an anhydrous medium (alcohol, dimethylformamide, etc.), or in an aqueous medium at a slightly alkaline pH.

Pour leur administration en tant que médicament, les agents actifs selon l'invention sont conditionnés au poids médicinal dans tout véhicule, excipient ou support approprié. Ils peuvent se présenter sous forme liquide (solution ou suspension) ou solide (poudres, comprimés, dragées, cachets, etc) et être administrés par voie orale, parentérale, nasale (poudre à priser) ou rectale (suppositoires) etc.  For their administration as a medicament, the active agents according to the invention are conditioned to the medicinal weight in any suitable vehicle, excipient or support. They can be in liquid (solution or suspension) or solid (powders, tablets, dragees, cachets, etc.) form and can be administered by oral, parenteral, nasal (snuff) or rectal (suppositories) etc.

La posologie est éminemment variable d'un sujet à l'autre et laissée à l'appréciation du praticien suivant la gravité du cas à traiter. En tout état' due cause, cette posologie est de l'ordre d'au moins 1 ng/kg par jour
Il va de soi que la présente invention n'a été décrite qu'à titre purement explicatif et nullement limitatif et que toute modification utile pourra y être apportée sans sortir de son cadre. The dosage is eminently variable from one subject to another and left to the discretion of the practitioner according to the gravity of the case to be treated. In any case, this dosage is of the order of at least 1 ng / kg per day
It goes without saying that the present invention has been described for purely explanatory and in no way limitative and that any useful modification may be made without departing from its scope.

Claims (6)

REVENDICATIONS 1. En tant qu'agents actifs dans les domaines thérapeutique, biologique, immunologique, et du dosage immunologique, acide pressinique, ses dérivés substitués en l'une au moins des positions 2, 3, 4 et 5 par des aminoacides naturels et leurs homologues de configuration D, les dérivés acylés sur le côté N-terminal de l'acide pressinique, les dérivés amides et esters sur le côté C-terminal et les dérivés radioactifs de ces agents. 1. As active agents in the therapeutic, biological, immunological and immunological assay fields, pressinic acid, its derivatives substituted in at least one of positions 2, 3, 4 and 5 by natural amino acids and their counterparts of configuration D, the acylated derivatives on the N-terminal side of pressinic acid, the amide and ester derivatives on the C-terminal side and the radioactive derivatives of these agents. 2. Agents actifs selon la revendication 1, caractériséspar le fait que ce sont outre l'acide pressinique, 1 'acide N-acétyl-pressinique, 1 'acide N-succinyl-pressinique, l'acide (Ileu3) pressinique, l'acide N-acétyl(Ileu3) pressinique, l'acide N-succinyl(Ileu3) pressinique, les conjugués acide pressinique-support macromoléculaire (du type protéine) dans lesquels l'acide pressinique est lié par une liaison amide entre son extrémité N-terminale et une fonction carboxylique portée par la macromolécule, ainsi que les analogues radioactifs obtenus, soit par substitution d'un aminoacide par un analogue tritié radioactif, soit par une iodation radioactive de la tyrosine 2 de l'acide pressinique ou d'un dérivé N-acylé, soit par greffe d'un peptide iodé radioactif à l'extrémité N-terminale de l'acide pressinique, soit par greffe d'un composé iodé radioactif (tel que le réactif de Bolton-Hunter) à l'extrémité N-terminale de l'acide pressinique. 2. Active agents according to claim 1, characterized in that they are, in addition to pressinic acid, 1 N-acetyl-pressinic acid, 1 N-succinyl-pressinic acid, (Ileu3) pressinic acid, acid N-acetyl (Ileu3) pressinic, N-succinyl (Ileu3) pressinic, pressinic acid-macromolecular support conjugates (of the protein type) in which pressinic acid is linked by an amide bond between its N-terminal end and a carboxylic function carried by the macromolecule, as well as the radioactive analogues obtained, either by substitution of an amino acid by a radioactive tritiated analog, or by a radioactive iodization of tyrosine 2 of pressinic acid or of an N-acylated derivative , either by grafting a radioactive iodized peptide at the N-terminal end of pressinic acid, or by grafting a radioactive iodized compound (such as the Bolton-Hunter reagent) at the N-terminal end of pressinic acid. 3. Application des agents selon l'une des revendications 1 ou 2, en thérapeutique en tant qu'agents ayant un effet sur la diurèse. 3. Application of the agents according to one of claims 1 or 2, in therapy as agents having an effect on diuresis. 4. Application des agents selon l'une des revendications 1 à 3 pour l'induction d'anti-corps ayant un effet sur la diurèse et utilisables en vaccination ou pour la sérothérapie.  4. Application of the agents according to one of claims 1 to 3 for the induction of antibodies having an effect on diuresis and usable in vaccination or for serotherapy. 5. Application des agents selon l'une des revendications 1 à 3 en immunologie pour induire la formation d'anti.-corps permettant le dosage de l'acide pressinique ou de ses analogues. 5. Application of the agents according to one of claims 1 to 3 in immunology to induce the formation of anti-bodies allowing the determination of pressinic acid or its analogs. 6. Application des agents radioactifs selon l'une des revendications 1, 2 ou 5 en tant qu'agents traceurs pour le dosage in vitro de l'acide pressinique.  6. Application of the radioactive agents according to one of claims 1, 2 or 5 as tracer agents for the in vitro determination of pressinic acid.
FR8317768A 1983-11-07 1983-11-07 PRESSINIC ACID, ITS SUBSTITUTED AMINOACID DERIVATIVES AND HOMOLOGATED CONFIGURATION AS WELL AS THE N- AND C- TERMINAL-SUBSTITUTED DERIVATIVES AND THEIR APPLICATIONS IN THE THERAPEUTIC, BIOLOGICAL OR IMMUNOLOGICAL FIELDS Expired FR2554347B1 (en)

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FR8317768A FR2554347B1 (en) 1983-11-07 1983-11-07 PRESSINIC ACID, ITS SUBSTITUTED AMINOACID DERIVATIVES AND HOMOLOGATED CONFIGURATION AS WELL AS THE N- AND C- TERMINAL-SUBSTITUTED DERIVATIVES AND THEIR APPLICATIONS IN THE THERAPEUTIC, BIOLOGICAL OR IMMUNOLOGICAL FIELDS

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0029579A1 (en) * 1979-11-27 1981-06-03 Sandoz Ag Polypeptides, processes for their production, pharmaceutical compositions comprising said polypeptides and their use
US4282143A (en) * 1980-06-13 1981-08-04 American Home Products Corporation Octapeptides lowering growth hormone
US4328135A (en) * 1980-06-13 1982-05-04 American Home Products Corporation Octapeptides lowering growth hormone

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0029579A1 (en) * 1979-11-27 1981-06-03 Sandoz Ag Polypeptides, processes for their production, pharmaceutical compositions comprising said polypeptides and their use
US4282143A (en) * 1980-06-13 1981-08-04 American Home Products Corporation Octapeptides lowering growth hormone
US4328135A (en) * 1980-06-13 1982-05-04 American Home Products Corporation Octapeptides lowering growth hormone

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 79, no. 17, 29 octobre 1973, réf. no. 100857j, page 58, Columbus Ohio (US); *
UNLISTED DRUGS, vol. 31, no. 11, novembre 1979, page 169m *

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