FR2608924A1 - THERAPEUTIC COMPOSITIONS CONTAINING SULFUR DERIVATIVES OF PROSTAGLANDINS, NOVEL SULFUR DERIVATIVES AND THEIR PREPARATION METHOD - Google Patents

THERAPEUTIC COMPOSITIONS CONTAINING SULFUR DERIVATIVES OF PROSTAGLANDINS, NOVEL SULFUR DERIVATIVES AND THEIR PREPARATION METHOD Download PDF

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FR2608924A1
FR2608924A1 FR8618297A FR8618297A FR2608924A1 FR 2608924 A1 FR2608924 A1 FR 2608924A1 FR 8618297 A FR8618297 A FR 8618297A FR 8618297 A FR8618297 A FR 8618297A FR 2608924 A1 FR2608924 A1 FR 2608924A1
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pga1
cys
formula
gly
prostaglandins
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FR2608924B1 (en
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Fernand Dray
Brigitte Vuilliez Le Normand
Alain Gouyette
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Institut Pasteur de Lille
Institut National de la Sante et de la Recherche Medicale INSERM
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Institut National de la Sante et de la Recherche Medicale INSERM
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Priority to EP88900574A priority patent/EP0295284A1/en
Priority to JP88500743A priority patent/JPH01502117A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
    • C07C405/0033—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing sulfur
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
    • C07C405/0041—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing nitrogen

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Abstract

Therapeutical compositions containing products obtained from the addition of thiols to prostaglandines or analogues of prostaglandines. These compositions have an antitumoral activity.

Description

La présente invention concerne une composition thérapeutique contenant à titre de principe actif un dérive de prostaglandine ou d'un analogue de prostaglandine, ayant notamment une activité antitumorale. The present invention relates to a therapeutic composition containing, as active ingredient, a derivative of prostaglandin or of a prostaglandin analog, having in particular an antitumor activity.

On a déjà décrit des prostaglandines ayant une activité antitumorale. Ainsi Masanori Fukushima et
Taketoshi Ratio ont décrit l'activité antitumorale de prostaglandines et notamment de PGA1,a7PGA1, 12 epi
A7PGA1, PGJ2, h12PGJ2 etc12, 14PGJ2 (Icosanoids and
Cancer, H. Thaler-Dao et al, Raven Press N.Y.; Cancer
Research 46, 35-38, 19861 ainsi que de clavulones et de punaglandines (Advance in Prostaglandin, Thromboxane and Leukotriene Research Vol. 15 O. Hayarshi et
S. Yamomoto Raven Press New York). Ces auteurs ont considéré que l'activité antitumorale était liée à l'insaturationa 3, ss dans le noyau cyclopentènone de ces composés.Prostaglandins with anti-tumor activity have already been described. So Masanori Fukushima and
Taketoshi Ratio described the anti-tumor activity of prostaglandins and in particular of PGA1, a7PGA1, 12 epi
A7PGA1, PGJ2, h12PGJ2 etc12, 14PGJ2 (Icosanoids and
Cancer, H. Thaler-Dao et al, Raven Press NY; Cancer
Research 46, 35-38, 19861 as well as clavulones and punaglandins (Advance in Prostaglandin, Thromboxane and Leukotriene Research Vol. 15 O. Hayarshi and
S. Yamomoto Raven Press New York). These authors considered that the antitumor activity was linked to the unsaturationa 3, ss in the cyclopentenone nucleus of these compounds.

On a maintenant trouvé que des produits d'addition de thiols sur des prostaglandines ou des analogues de prostaglandines ayant un noyau cyclopen tène ont une activité antitumorale. It has now been found that thiol adducts on prostaglandins or prostaglandin analogs having a cyclopen tene ring have anti-tumor activity.

La présente invention a en conséquence pour objet des compositions thérapeutiques caractérisées en ce qu'elles contiennent à titre de principe actif un composé choisi parmi les composés de formule

Figure img00010001
The present invention therefore relates to therapeutic compositions characterized in that they contain, as active principle, a compound chosen from the compounds of formula
Figure img00010001

Figure img00020001

dans lesquelles Z1 et Z2 sont deux chaines appartenant aux channes des prostaglandines ou des analogues de prostaglandines,
R est un groupe hydrocarboné éventuellement substitué par un ou plusieurs groupes NH2, ou un groupe de formule
Figure img00020002

dans laquelle n = 1 ou 2 est un atome d'hydrogène, un résidu d'acide aminé ou un résidu dérivant d'un enchaînement d'acides aminés,
W2 est un groupe hydroxy, un résidu d'acide aminé ou un résidu dérivant d'un enchaînement d'acide aminé,
R1 est un atome d'hydrogène, un groupe hydrocarboné ou un atome halogène, R2 est un atome d'hydrogène, un groupe hydroxy ou un groupe acyloxy.
Figure img00020001

in which Z1 and Z2 are two chains belonging to the chains of prostaglandins or prostaglandin analogues,
R is a hydrocarbon group optionally substituted by one or more NH2 groups, or a group of formula
Figure img00020002

in which n = 1 or 2 is a hydrogen atom, an amino acid residue or a residue derived from a chain of amino acids,
W2 is a hydroxy group, an amino acid residue or a residue derived from an amino acid chain,
R1 is a hydrogen atom, a hydrocarbon group or a halogen atom, R2 is a hydrogen atom, a hydroxy group or an acyloxy group.

La chaine Z1 peut être notamment une chaîne de formule

Figure img00030001

correspondant à la chaîne Z1 de PGA1 ou PGJ1 correspondant à la chaîne Z1 de PGA2 ou PGJ2
Figure img00030002
The chain Z1 can in particular be a chain of formula
Figure img00030001

corresponding to the Z1 chain of PGA1 or PGJ1 corresponding to the Z1 chain of PGA2 or PGJ2
Figure img00030002

La chai ne Z2 peut être notamment une chai ne de formule

Figure img00030003

correspondant à la chaîne Z de PGA ou de PGJ ainsi que les chaînes cétoniques correspondantes. The chain Z2 can in particular be a chain of formula
Figure img00030003

corresponding to the Z chain of PGA or PGJ as well as the corresponding ketone chains.

Il peut s'agir également de chaînes qui correspondent au raccoursissement de ces chaînes, ou de chaînes obtenues par des réactions de réduction ou d'oxydation. Comme exemples de telles chaînes on peut citer pour Z2 les chalnes de formule

Figure img00040001
It can also be chains which correspond to the shortening of these chains, or chains obtained by reduction or oxidation reactions. Examples of such chains include for Z2 the chalnes of formula
Figure img00040001

Les chaînes Z1 et Z2 comprennent également celles présentées dans les clavulones et les punaglandines (voir article dans Advance in Prostaglandins déjà cité). The Z1 and Z2 chains also include those presented in clavulones and punaglandins (see article in Advance in Prostaglandins already cited).

Certains composés de formule I et II sont connus. C'est ainsi que E.A. Ham et coll. (Prostaglandins 10, 217, 1975) ont mentionné le produit d'addition de la cysteine et du glutathion sur PGA1. Cajen et coll. (J. Biol. Chem. 251, 6550, 1976) ont en outre décrit le produit de réduction du produit d'addition du glutathion avec PGA1. Certain compounds of formulas I and II are known. This is how E.A. Ham et al. (Prostaglandins 10, 217, 1975) mentioned the adduct of cysteine and glutathione on PGA1. Cajen et al. (J. Biol. Chem. 251, 6550, 1976) have further described the product for reducing the adduct of glutathione with PGA1.

Les composés de formules I et III peuvent être obtenus à partir des cyclopentènones correspondantes de formule

Figure img00050001

par une réaction avec des thiols de formule
RSH VII
La réaction peut etre effectuée en milieu aqueux au voisinage de la neutralité (par exemple tampon Tris, HC1, PH 7.4).The compounds of formulas I and III can be obtained from the corresponding cyclopentenones of formula
Figure img00050001

by a reaction with thiols of formula
RSH VII
The reaction can be carried out in an aqueous medium in the vicinity of neutrality (for example Tris buffer, HCl, PH 7.4).

Comme exemple de thiols utilisables on peut citer notamment la cysteine de formule

Figure img00050002

la cysteinylglycine de formule
Figure img00060001

le glutathion de formule
Figure img00060002

la cysteamine de formule
HS-CH2-CH2-NH2
Les composés de formule II et IV peuvent etre obtenus par réduction respectivement des composés de formule I et III, notamment par le borohydrure de sodium.As an example of thiols which can be used, there may be mentioned in particular the cysteine of formula
Figure img00050002

cysteinylglycine of formula
Figure img00060001

the formula glutathione
Figure img00060002

the cysteamine of formula
HS-CH2-CH2-NH2
The compounds of formula II and IV can be obtained by reduction respectively of the compounds of formula I and III, in particular by sodium borohydride.

En variante, un certain nombre de composés de formule II peuvent être obtenus invitro. C'est ainsi que les composés 9-hydroxy-11-cysteinyl-PGA, et 9-hydroxy-1 1-cysteinylglycyl-PGA1 peuvent être obtenus par incubation de la prostaglandine PGA1 avec des cellules tumorales de rat, notamment des neuroblastomes B 104 et des gliomes C6-, et séparation des métabolites. Alternatively, a number of compounds of formula II can be obtained invitro. Thus, the compounds 9-hydroxy-11-cysteinyl-PGA, and 9-hydroxy-1 1-cysteinylglycyl-PGA1 can be obtained by incubation of prostaglandin PGA1 with rat tumor cells, in particular neuroblastomas B 104 and C6- gliomas, and separation of metabolites.

Les exemples suivants illustrent la préparation des composés utilisés dans la présente invention.  The following examples illustrate the preparation of the compounds used in the present invention.

ExemPle 1
Obtention in vitro de produits d'addition de cystéine etde cystéinylglycine sur la 9-hydroxy-PGA1.EXAMPLE 1
Obtaining in vitro cysteine and cysteinylglycine adducts on 9-hydroxy-PGA1.

a) On ensemence 2.104 cellules de neuroblastomes B104 et on les fait incuber pendant 24 h dans un milieu complet (2ml) constitué par un mélange 1/1 milieu de Eagle modifié par Dulbecco (DMEM) et tamponné par du bicarbonate/milieu F12 de Ham complété par du sérum de foetus de veau inactivé par la chaleur (FCS, 2,55) et du sérum de cheval (HS, 50), 15 mM de Hepes, 100 U/ml de pénicilline, 50 micro g/ml de streptomycine et 0,25 micro g/ml de fungizone.Puis on effectue une culture à 37 C dans un incubateur humidifié à 5% de C02 sur un milieu comprenant les mêmes ingrédients que le milieu complet précédent, à l'exception du sérum qui est remplacé par 5 pg/ml d'insuline, 100 gug/ml de transférine, 20 nM de progestérone, 100 luM de putrescine et 30 nM de séleniure de sodium. a) 2.104 neuroblastoma B104 cells are seeded and incubated for 24 h in complete medium (2 ml) consisting of a 1/1 mixture of Eagle medium modified by Dulbecco (DMEM) and buffered with bicarbonate / Ham medium F12 supplemented with heat-inactivated fetal calf serum (FCS, 2.55) and horse serum (HS, 50), 15 mM Hepes, 100 U / ml penicillin, 50 micro g / ml streptomycin and 0.25 micro g / ml of fungizone. Then a culture is carried out at 37 ° C. in an incubator humidified with 5% CO 2 on a medium comprising the same ingredients as the preceding complete medium, except for the serum which is replaced by 5 µg / ml insulin, 100 gug / ml transferin, 20 nM progesterone, 100 µM putrescine and 30 nM sodium selenide.

On ajoute un mélange de prostaglandine PGA1 à la dose de 10 6M et de (3H)PGA1 utilisé comme traceur et on laisse incuber. A mixture of prostaglandin PGA1 is added at a dose of 10 6M and (3H) PGA1 used as a tracer and the mixture is left to incubate.

On élimine les cellules par centrifugation et on dépose le surnageant sur une cartouche Sep Pak
C18 (Water) préalablement lavée avec 2 ml de méthanol et 10 ml d'eau.The cells are removed by centrifugation and the supernatant is deposited on a Sep Pak cartridge.
C18 (Water) previously washed with 2 ml of methanol and 10 ml of water.

On lave l'échantillon avec 10 ml d'eau puis on élue avec 6 ml de méthanol. The sample is washed with 10 ml of water and then eluted with 6 ml of methanol.

On amène à sec les fractions méthanoliques et on les redissout dans un tampon phosphate 10 2M pH 7,4 et on introduit sur une colonne de Sephadex G10 (1,8 x 25 cm). On élue avec le même tampon. The methanolic fractions are brought to dryness and redissolved in a phosphate buffer 2M pH 7.4 and introduced onto a column of Sephadex G10 (1.8 x 25 cm). Eluted with the same buffer.

On effectue une élimination de sel sur cartouche Sep Pak C18, puis on réalise une chromatogra phie liquide haute performance à phase inversée (rp
HPLC) sur une colonne de Nucleosil C18. On élue à un débit de 1 ml/mn avec un mélange de deux solvants : A (eau contenant 0,28 d'acide acétique) et B (méthanol) comme suit : un gradient linéaire pendant 10 mn de 47 à 57% de B; 57% de B pendant 40 mn; gradient linéaire pendant 20 mn de 57 à 80% de B.Salt removal is carried out on a Sep Pak C18 cartridge, then a reverse phase high performance liquid chromatography is carried out (rp
HPLC) on a column of Nucleosil C18. Eluted at a flow rate of 1 ml / min with a mixture of two solvents: A (water containing 0.28 acetic acid) and B (methanol) as follows: a linear gradient for 10 min from 47 to 57% B ; 57% B for 40 min; linear gradient for 20 min from 57 to 80% of B.

On analyse les fractions recueillies par comptage par scintigraphie. The fractions collected are analyzed by counting by scintigraphy.

Les résultats sont reportés sur la Fig. 1 qui fait apparaître 4 pics de radioactivité correspondant à 4 métabolites de PGA1. The results are reported in FIG. 1 which shows 4 peaks of radioactivity corresponding to 4 metabolites of PGA1.

A titre de contrôle PGA1 ajouté au même milieu pendant 3 jours à 37*C, en l'absence de cellules a été purifié par la même méthode chromatographique. On observe seulement un pic de rétention à 71 minutes. As a control, PGA1 added to the same medium for 3 days at 37 ° C., in the absence of cells, was purified by the same chromatographic method. We only observe a retention peak at 71 minutes.

b) On opère comme en a) mais en utilisant des cellules gliomes C6 et en utilisant le milieu de culture suivant : DMEM complété avec 10% de FCS, 100
U/ml de pénicilline et 50 micro g/ml de streptomycine.b) The procedure is as in a) but using C6 glioma cells and using the following culture medium: DMEM supplemented with 10% FCS, 100
U / ml of penicillin and 50 micro g / ml of streptomycin.

Les résultats sont reportés sur la Fig. 2 qui met en évidence également 4 pics. The results are reported in FIG. 2 which also highlights 4 peaks.

c) Détermination des produits obtenus par spectrométrie de masse (Technique FAB). c) Determination of the products obtained by mass spectrometry (FAB technique).

Les métabolites obtenus selon a) et b) sont les mêmes
Métabolites I et II
masse moléculaire 516
composition élémentaire C25H44 N207S
Deux isomères correspondant au produit d'"addition" de la cysteinyl glycine sur la 9-hydroxy
PGA1, par abbréviation 9-OH-PGA1-Cys-Gly, de formule

Figure img00090001
The metabolites obtained according to a) and b) are the same
Metabolites I and II
molecular mass 516
elementary composition C25H44 N207S
Two isomers corresponding to the "addition" product of cysteinyl glycine on 9-hydroxy
PGA1, by the abbreviation 9-OH-PGA1-Cys-Gly, of formula
Figure img00090001

Métabolites III et IV
masse moléculaire 459
composition élémentaire C23 H41 NO6S
Ces métabolites correspondent à deux isomères du produit d'"addition" de la cystéine sur la 9-hydrox-y-PGA1, par abçréviation 9-OH-PGA1-Cys de formule

Figure img00090002
Metabolites III and IV
molecular weight 459
elementary composition C23 H41 NO6S
These metabolites correspond to two isomers of the “addition” product of cysteine on 9-hydrox-y-PGA1, by the abbreviation 9-OH-PGA1-Cys of formula
Figure img00090002

Exemple 2
On fait réagir 1 mmole de PGA1 et 1 mmole de cystéine dans du tampon 0,2 M Tris HCl pH 7,4 pendant une heure à 37-C. Example 2
1 mmol of PGA1 and 1 mmol of cysteine are reacted in 0.2 M Tris HCl pH 7.4 buffer for one hour at 37 ° C.

On obtient un produit d'addition PGA1-Cys. A PGA1-Cys adduct is obtained.

Exemple 3
On opère comme à l'exemple 2 en utilisant comme thiol la cystéinylglycine.Example 3
The procedure is as in Example 2, using cysteinylglycine as the thiol.

On obtient un produit d'addition PGA1-Cys
Gly de formule

Figure img00100001
A PGA1-Cys adduct is obtained
Formula Gly
Figure img00100001

Exemple 4
On opère comme à l'exemple 2 en utilisant comme thiol le glutathion (par ab.réviation GSH).Example 4
The procedure is as in Example 2, using glutathione as thiol (by abbreviation GSH).

On obtient un produit d'addition PGA1-SG. A PGA1-SG adduct is obtained.

Exemple 5
On ajoute à la solution obtenue à l'exemple 2 du borohydrure de sodium. Puis on ajuste le pH à 3,5 avec de l'acide formique. On extrait à l'acétate d'éthyle. On effectue un passage sur une cartouche Sep
Pack C18 puis une chromatographie en phase liquide sur colonne Nucleosil C18 comme à l'exemple 1.Example 5
Sodium borohydride is added to the solution obtained in Example 2. Then the pH is adjusted to 3.5 with formic acid. Extraction is carried out with ethyl acetate. Passing through a Sep cartridge
Pack C18 then liquid phase chromatography on a Nucleosil C18 column as in Example 1.

On sépare ainsi deux isomères de 9-OH-PGA1 -
Cys.Two isomers of 9-OH-PGA1 are thus separated.
Cys.

ExemDlç 6
On opère comme à l'exemple 5 avec la solution de l'exemple 3.Example 6
The procedure is as in Example 5 with the solution of Example 3.

On sépare finalement deux isomères 9-OH PGA1 -CYS-Gly.  Finally, two isomers 9-OH PGA1 -CYS-Gly are separated.

Le's essais suivants mettent en évidence l'activité antitumorale des composés. The following tests demonstrate the anti-tumor activity of the compounds.

On a mesuré l'inhibition de la prolifération de neuroblastomes B104 dans le même milieu qu'à l'exemple la avec une concentration initiale de 2.104 cellules/ml après addition du produit à tester. On a réalisé une incubation pendant 24 h et on a mesuré le nombre de cellules au bout de 24 h à l'aide d'un comp teur Coulter. On a calculé le pourcentage d'inhibition par rapport à une culture témoin. The inhibition of the proliferation of neuroblastomas B104 was measured in the same medium as in example la with an initial concentration of 2.104 cells / ml after addition of the product to be tested. An incubation was carried out for 24 h and the number of cells was measured after 24 h using a Coulter counter. The percentage of inhibition was calculated relative to a control culture.

Les résultats figurent dans le tableau ci-après
TABLEAU I
Concentration
Produit 10-6M 10-7
Métabolite I 28 t 3 26 t 2
Métabolite II 49 t 1 41 + 3
Métabolite III 19 + 9 17 + 3
Métabolite IV 13 + 10 10 + 4
PGA1-GSH 23 - 11 13 - 10
PGA1-Cys 51 + 10 43+ 8
PGA1-Cys-Gly 46 t 10 18 # 19 9-OH-PGA1-Cys (isomère 1) 24 # 8 9-OH-PGA1-Cys (isomère 2) 34 # 8 26 - 1 9-OH-PGA1-Cys-Gly (isomère 1) 54 # 23 26 # 23 9-OH-PGA1-Cys-Gly (isomère 2) 49 t 6 30 # 12
Les compositions thérapeutiques selon l'invention peuvent être administrées à l'homme par voie orale ou parentérale. Compte tenu de la solubilité élevée dans l'eau des composés utilisés, on peut généralement les administrer sous forme de solutions aqueuses.The results are shown in the table below
TABLE I
Concentration
Product 10-6M 10-7
Metabolite I 28 t 3 26 t 2
Metabolite II 49 t 1 41 + 3
Metabolite III 19 + 9 17 + 3
Metabolite IV 13 + 10 10 + 4
PGA1-GSH 23 - 11 13 - 10
PGA1-Cys 51 + 10 43+ 8
PGA1-Cys-Gly 46 t 10 18 # 19 9-OH-PGA1-Cys (isomer 1) 24 # 8 9-OH-PGA1-Cys (isomer 2) 34 # 8 26 - 1 9-OH-PGA1-Cys- Gly (isomer 1) 54 # 23 26 # 23 9-OH-PGA1-Cys-Gly (isomer 2) 49 t 6 30 # 12
The therapeutic compositions according to the invention can be administered to humans by the oral or parenteral route. In view of the high solubility in water of the compounds used, they can generally be administered in the form of aqueous solutions.

La quantité de principe utilisée dépend généralement du patient et de la sévérité de la maladie. The amount of principle used generally depends on the patient and the severity of the disease.

Chez l'homme de 70 kg on peut généralement administrer de 50 à 500 mg/jour par voie parentérale.In men weighing 70 kg, it can generally be administered from 50 to 500 mg / day parenterally.

Les compositions peuvent en outre contenir plusieurs principes actifs de formule I à IV ainsi que d'autres composés à activité antitumorale.  The compositions can also contain several active principles of formula I to IV as well as other compounds with anti-tumor activity.

Claims (10)

REVENDICATIONS 1. Composition thérapeutique caractérisée en ce qu'elle contient à titre de principe actif un composé choisi parmi les composés de formule 1. Therapeutic composition characterized in that it contains, as active principle, a compound chosen from the compounds of formula
Figure img00130001
Figure img00130001
 dans lesquelles Z1 et Z2 sont deux chaînes appartenant aux chaînes des prostaglandines ou des analogues de prostaglandines. in which Z1 and Z2 are two chains belonging to the chains of prostaglandins or prostaglandin analogs. R2 est un atome d'hydrogène, un groupe hydroxy ou un groupe acyloxy.R2 is a hydrogen atom, a hydroxy group or an acyloxy group. R1 est un atome d'hydrogène, un groupe hydrocarboné ou un atome halogène,R1 is a hydrogen atom, a hydrocarbon group or a halogen atom, W2 est un groupe hydroxy, un résidu d'acide aminé ou un résidu dérivant d'un enchaînement d'acide aminé,W2 is a hydroxy group, an amino acid residue or a residue derived from an amino acid chain, W1 est un atome d'hydrogène, un résidu d'acide aminé ou un résidu dérivant a d'un enchaînement d'acides ami- nés,W1 is a hydrogen atom, an amino acid residue or a residue derived from a chain of amino acids, dans laquelle n = 1 ou 2 where n = 1 or 2
Figure img00140001
Figure img00140001
 R est un groupe hydrocarboné éventuellement substitué par un ou plusieurs groupes NH2, ou un groupe de formule R is a hydrocarbon group optionally substituted by one or more NH2 groups, or a group of formula 2. Composition selon la revendication 1, caractérisée en ce qu'elle contient une 9-OH-PGA1-Cys de formule 2. Composition according to claim 1, characterized in that it contains a 9-OH-PGA1-Cys of formula
Figure img00140002
Figure img00140002
 3. Composition selon la revendication 1, caractérisée en ce qu'elle contient une 9-OH-PGA1 -  3. Composition according to claim 1, characterized in that it contains a 9-OH-PGA1 - Cys-Gly de formuleCys-Gly formula
Figure img00140003
Figure img00140003
 4. Composition selon la revendication 1, caractérisée en ce qu'elle contient une PGA1-Cys. 4. Composition according to claim 1, characterized in that it contains a PGA1-Cys. 5. Composition selon la revendication 1, caractérisée en ce qu'elle contient une PGA1-Cys-Gly. 5. Composition according to claim 1, characterized in that it contains a PGA1-Cys-Gly. 6. 9-OH-PGA1-Cys de formule 6. 9-OH-PGA1-Cys of formula
Figure img00150001
Figure img00150001
 7. 9-OH-PGA1-Cys-Gly de formule 7. 9-OH-PGA1-Cys-Gly of formula
Figure img00150002
Figure img00150002
 8. Procédé de préparation de 9-OH-PGA1-Cys et de 9-OH-PGA1-Cys-Gly, caractérisé en ce que l'on fait incuber la prostaglandine PGA1 avec des cellules tumorales de rat et l'on sépare les métabolites. 8. Process for the preparation of 9-OH-PGA1-Cys and of 9-OH-PGA1-Cys-Gly, characterized in that prostaglandin PGA1 is incubated with rat tumor cells and the metabolites are separated . 9. Procédé selon la revendication 8, caractérisé en ce que les cellules tumorales de rat sont des neuroblastomes B104 ou des gliomes C6.  9. Method according to claim 8, characterized in that the rat tumor cells are neuroblastomas B104 or gliomas C6. 10. Une PGA1-Cys-Gly de formule10. A PGA1-Cys-Gly of formula
Figure img00160001
Figure img00160001
FR8618297A 1986-12-29 1986-12-29 THERAPEUTIC COMPOSITIONS CONTAINING SULFUR DERIVATIVES OF PROSTAGLANDINS, NOVEL SULFUR DERIVATIVES AND THEIR PREPARATION METHOD Expired - Lifetime FR2608924B1 (en)

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PCT/FR1987/000518 WO1988005042A1 (en) 1986-12-29 1987-12-29 Compositions containing sulphur prostaglandines
EP88900574A EP0295284A1 (en) 1986-12-29 1987-12-29 Compositions containing sulphur prostaglandines
JP88500743A JPH01502117A (en) 1986-12-29 1987-12-29 Therapeutic compositions containing sulfurized derivatives of prostaglandins, novel sulfurized derivatives and methods for producing them

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CN111658628B (en) * 2019-03-08 2022-03-01 中国科学院动物研究所 Application of GLI2 inhibitor and screening method of compound inhibiting GLI2

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WO2006101244A3 (en) * 2005-03-21 2007-02-08 Sucampo Ag Method and composition for treating mucosal disorders
EP2384790A3 (en) * 2005-03-21 2011-12-28 Sucampo AG Method and composition for treating mucosal disorders

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