CH624379A5 - Process for the preparation of new 2-hydroxymethyl-2-phenyl-1,3-indanedione esters - Google Patents
Process for the preparation of new 2-hydroxymethyl-2-phenyl-1,3-indanedione esters Download PDFInfo
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- CH624379A5 CH624379A5 CH1163477A CH1163477A CH624379A5 CH 624379 A5 CH624379 A5 CH 624379A5 CH 1163477 A CH1163477 A CH 1163477A CH 1163477 A CH1163477 A CH 1163477A CH 624379 A5 CH624379 A5 CH 624379A5
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
- C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
- C07D311/72—3,4-Dihydro derivatives having in position 2 at least one methyl radical and in position 6 one oxygen atom, e.g. tocopherols
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
Description
La présente invention concerne le procédé de préparation de 55 nouveaux esters de 2-hydroxyméthyl-2-phényl-l,3-indanedione. Ces nouveaux produits sont utiles en thérapeutique notamment comme agents anticoagulants pour la prévention et le traitement des thromboses. The present invention relates to the process for the preparation of 55 new esters of 2-hydroxymethyl-2-phenyl-1,3-indanedione. These new products are useful in therapy, in particular as anticoagulant agents for the prevention and treatment of thromboses.
On sait que la pindione (qui répond à la nomenclature systé-60 matique de 2-phényl-l,3-indanedione) et que son dérivé 2-hydroxyméthyle (à savoir la 2-hydroxyméthyl-2-phényl-l ,3-indanedione) sont des agents anticoagulants qui ont déjà été préconisés en thérapeutique. On sait que la pindione et son dérivé 2-hydroxyméthyle présentent l'inconvénient d'avoir des effets 65 secondaires gênants tels que: hémorragie, agranulocytose et hépatite. We know that pindione (which corresponds to the systematic nomenclature of 2-phenyl-1,3-indanedione) and that its derivative 2-hydroxymethyl (namely 2-hydroxymethyl-2-phenyl-1,3-indanedione ) are anticoagulant agents which have already been recommended in therapy. It is known that pindione and its 2-hydroxymethyl derivative have the drawback of having annoying side effects such as: hemorrhage, agranulocytosis and hepatitis.
Un des buts de l'invention est de proposer de nouveaux produits appartenant à la famille de la 2-phényl-l,3-indanedione pour One of the aims of the invention is to propose new products belonging to the family of 2-phenyl-1,3-indanedione for
3 3
624 379 624,379
lesquels les effets secondaires et notamment l'effet hépatotoxique sont soit atténués, soit supprimés. which side effects and in particular the hepatotoxic effect are either reduced or eliminated.
Les nouveaux produits sont des esters de 2-hydroxyméthyl-2-phényl-l,3-indanedione caractérisés en ce qu'ils répondent à la formule générale I The new products are esters of 2-hydroxymethyl-2-phenyl-1,3-indanedione, characterized in that they correspond to the general formula I
0 S 0 S
CHm-0-C-R (I) CHm-0-C-R (I)
dans laquelle R est un groupe choisi parmi l'ensemble constitué par: in which R is a group chosen from the group consisting of:
a) un groupe phényle éventuellement mono- ou polysubstitué; a) an optionally mono- or polysubstituted phenyl group;
b) un groupe phénylalkyle de formule: b) a phenylalkyl group of formula:
-J/ V -J / V
où A est défini comme ci-dessus et le groupe phényle est éventuellement mono- ou polysubstitué; where A is defined as above and the phenyl group is optionally mono- or polysubstituted;
d) un groupe hétérocyclique éventuellement mono- ou polysubstitué; d) an optionally mono- or polysubstituted heterocyclic group;
e) un groupe hétérocyclique-alkyle de formule : e) a heterocyclic-alkyl group of formula:
-A-Het où A est défini comme ci-dessus et Het représente un groupe hétérocyclique éventuellement mono- ou polysubstitué; et f) un groupe de formule : -A-Het where A is defined as above and Het represents an optionally mono- or polysubstituted heterocyclic group; and f) a group of formula:
CH2CH2-C-OR' CH2CH2-C-OR '
II II
O O
où R' est H, phényle, phényle substitué, Het, A — Het où A et Het sont définis comme ci-dessus. where R 'is H, phenyl, substituted phenyl, Het, A - Het where A and Het are defined as above.
Parmi les substituants des groupes phényle entrant dans la définition de R, on peut notamment citer les atomes d'halogène, les groupes alkyle inférieur, OH, acyloxy. Mention may in particular be made, among the substituents of the phenyl groups falling within the definition of R, of halogen atoms, lower alkyl, OH and acyloxy groups.
Parmi les groupes hétérocycliques inclus dans la définition R, conviennent notamment les groupes 2-, 3- et 4-pyridyle, 1-théo-brominyle, 7-théophyllinyle, tocophéryle et les groupes qui sont homologues à ce dernier et notamment décrits dans la demande de brevet français N° 75/19267 du 19 juin 1975. Among the heterocyclic groups included in the definition R, the groups 2-, 3- and 4-pyridyle, 1-theo-brominyl, 7-theophyllinyl, tocopheryl and the groups which are homologous to the latter and especially described in the application are particularly suitable. French Patent No. 75/19267 of June 19, 1975.
D'une manière générale le groupe tocophéryle et les groupes qui lui sont homologues peuvent être représentés par la formule In general, the tocopheryl group and the groups which are homologous to it can be represented by the formula
(ch2CH2Y)3CH3 (Ia) (ch2CH2Y) 3CH3 (Ia)
dans laquelle R'i, R'2 et R'3 identiques ou différents représentent chacun H ou CH3 et Y représente CH2CH(CH3) ou CH=C(CH3), et où la liaison est réalisée en position 6. Dans la formule (la) sont inclus les restes des tocols et a-, ß-, y-, 8-, e-, Çi--, 5 Ç2- et t|-tocophérols. in which R'i, R'2 and R'3, which are identical or different, each represent H or CH3 and Y represents CH2CH (CH3) or CH = C (CH3), and where the bonding is carried out in position 6. In the formula ( la) are included the remains of the tocols and a-, ß-, y-, 8-, e-, Çi--, 5 Ç2- and t | -tocopherols.
Selon l'invention sont notamment inclus dans la définition de R les groupes : According to the invention are notably included in the definition of R the groups:
ch„ ch „
ococh„ ococh „
où A est un reste hydrocarboné aliphatique en C1-C5 à chaîne linéaire ou ramifiée et où le groupe phényle est éventuellement mono- ou polysubstitué; where A is a C1-C5 aliphatic hydrocarbon residue with a straight or branched chain and where the phenyl group is optionally mono- or polysubstituted;
c) un groupe phénoxyalkyle de formule : c) a phenoxyalkyl group of formula:
hooc-ch2-ch2-3 hooc-ch2-ch2-3
n-ch - n-ch -
ch-o-co-ch2-ch2-, ch-o-co-ch2-ch2-,
35 35
(ch2ch2y)3ch3 (ch2ch2y) 3ch3
Le procédé selon l'invention consiste à estérifier la 2-hydroxy-méthyl-2-phényl-l,3-indanedione avec un chlorure d'acide ou un 45 anhydride d'acide notamment dans un solvant organique tel que notamment le dioxanne, l'éther, le benzène, le chlorure de méthylène, en présence d'une base organique tertiaire ou de tout accepteur d'acide. The process according to the invention consists in esterifying 2-hydroxy-methyl-2-phenyl-1,3-indanedione with an acid chloride or an acid anhydride in particular in an organic solvent such as in particular dioxane, l ether, benzene, methylene chloride, in the presence of a tertiary organic base or any acid acceptor.
Une composition thérapeutique peut renfermer en association 50 avec un excipient physiologiquement acceptable au moins un composé de formule (I). A therapeutic composition may contain in association with a physiologically acceptable excipient at least one compound of formula (I).
D'autres avantages et caractéristiques de l'invention seront mieux compris à la lecture qui va suivre d'exemples de préparation nullement limitatifs, mais donnés à titre d'illustration. Other advantages and characteristics of the invention will be better understood on reading which will follow examples of preparation which are in no way limiting, but given by way of illustration.
55 55
Exemple 1 : Example 1:
2- (4-chlorophénoxy ) -2-méthylpropionate de 2- (2-phényl-1,3- 2- (2-phenyl-1,3-) 2- (4-chlorophenoxy) -2-methylpropionate
dioxo-indanyl)-méthyle dioxo-indanyl) -methyl
G G
- Cl - Cl
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4 4
Dans un ballon à trois tubulures muni d'un agitateur, d'un réfrigérant et d'une ampoule, on introduit (en atmosphère anhydre) 0,1 mol de 2-hydroxyméthyl-2-phényl-l,3-indanedione dans du chlorure de méthylène et 0,11 mol de triéthylamine anhydre. On ajoute lentement 0,11 mol de chlorure de 2-(p-chlo-rophénoxy)-2-méthylpropionyle dans du chlorure de méthylène. On chauffe 1 h au reflux. 0.1 mol of 2-hydroxymethyl-2-phenyl-1,3-indanedione in chloride is introduced (in an anhydrous atmosphere) into a three-tube flask fitted with an agitator, a condenser and a bulb of methylene and 0.11 mol of anhydrous triethylamine. 0.11 mol of 2- (p-chlo-rophenoxy) -2-methylpropionyl chloride in methylene chloride is added slowly. It is heated for 1 hour at reflux.
Après refroidissement, on reprend par de l'eau, décante la solution, sèche sur sulfate de sodium, évapore le solvant et recristallise le solide obtenu dans l'éthanol. After cooling, the residue is taken up in water, the solution is decanted, dried over sodium sulfate, the solvent is evaporated and the solid obtained is recrystallized from ethanol.
On obtient des cristaux blancs crème. F = 85°C. Creamy white crystals are obtained. Mp 85 ° C.
Rendement: 65%. Yield: 65%.
Exemple 2: Example 2:
2-acétylsalicylate de 2-(2-phényl-l ,3-dioxo-indanyl) -méthyle 0 0 2- (2-Phenyl-1,3-dioxo-indanyl) -methyl 2-acetylsalicylate 0 0
-ol/\ -ol / \
o-coch, o-coch,
Dans un ballon muni d'un réfrigérant, on introduit 0,5 mol de 2-hydroxyméthyl-2-phényl-l,3-indanedione. On ajoute du benzène anhydre et 0,5 mol de pyridine anhydre. On verse ensuite une solution de 0,5 mol de chlorure de l'acide 2-acétylsalicylique dans du benzène. On chauffe à 40° C pendant 2 h puis on laisse refroidir, on filtre le chlorhydrate de pyridine obtenu, puis on évapore le benzène sous vide. 0.5 mol of 2-hydroxymethyl-2-phenyl-1,3-indanedione is introduced into a flask fitted with a condenser. Anhydrous benzene and 0.5 mol of anhydrous pyridine are added. A solution of 0.5 mol of 2-acetylsalicylic acid chloride in benzene is then poured. The mixture is heated at 40 ° C. for 2 h and then allowed to cool, the pyridine hydrochloride obtained is filtered, then the benzene is evaporated under vacuum.
On obtient une huile qui triturée avec de l'isopropanol donne des cristaux que l'on recristallise dans l'éthanol. F= 146°C. Rendement: 78%. An oil is obtained which triturated with isopropanol gives crystals which are recrystallized from ethanol. Mp 146 ° C. Yield: 78%.
Exemple 3: Example 3:
Nicotinate de 2- (2-phényl-l ,3-dioxo-indanyl)-méthyle 2- (2-Phenyl-1,3-dioxo-indanyl) -methyl nicotinate
P 9 /r-N. P 9 / r-N.
Dans un ballon muni d'un agitateur, d'un réfrigérant et d'une ampoule (en atmosphère anhydre), on introduit 1 mol de 2-hydroxyméthyl-2-phényl-l,3-indanedione et 1,1 mol de chlorure de l'acide nicotinique sous forme de chlorhydrate. On ajoute environ 11 de chlorure de méthylène. On obtient une pâte sur laquelle on verse goutte à goutte environ 3 mol de pyridine. La pâte devient jaune citron et se solubilise au reflux du chlorure de méthylène avec formation de chlorhydrate de pyridine, en maintenant le reflux pendant 30 à 60 mn. On laisse refroidir, on filtre le chlorhydrate de pyridine. Après évaporation du filtrat, on obtient un résidu que l'on recristallise dans l'alcool isopropylique. 1 mol of 2-hydroxymethyl-2-phenyl-1,3-indanedione and 1.1 mol of chloride are introduced into a flask fitted with an agitator, a condenser and a bulb (in an anhydrous atmosphere). nicotinic acid as hydrochloride. About 11 of methylene chloride are added. A paste is obtained onto which about 3 mol of pyridine is poured dropwise. The paste becomes lemon yellow and dissolves at the reflux of methylene chloride with the formation of pyridine hydrochloride, maintaining the reflux for 30 to 60 minutes. The mixture is allowed to cool and the pyridine hydrochloride is filtered. After evaporation of the filtrate, a residue is obtained which is recrystallized from isopropyl alcohol.
On obtient des cristaux blancs. F= 131°C. Rendement: 80%. White crystals are obtained. M = 131 ° C. Yield: 80%.
Exemple 4: Example 4:
Picolinate de 2-( 2-phényl-l ,3-dioxo-indanyl)-méthyle n 2- (2-Phenyl-1,3-dioxo-indanyl) -methyl picolinate n
Dans un ballon, on introduit (en atmosphère anhydre) 0,10 mol de 2-hydroxyméthyl-2-phényl-l,3-indanedione et 0,11 mol de chlorhydrate de chlorure de l'acide picolinique. On ajoute ensuite du dioxanne anhydre et 0,25 mol de pyridine. On 5 chauffe pendant 3 h à 60° C. On filtre à froid le chlorhydrate de pyridine obtenu. Après évaporation du filtrat, on obtient un résidu que l'on reprend par de l'isopropanol et que l'on recristallise ensuite dans l'éthanol. 0.10 mol of 2-hydroxymethyl-2-phenyl-1,3-indanedione and 0.11 mol of picolinic acid chloride hydrochloride are introduced into a flask (in an anhydrous atmosphere). Anhydrous dioxane and 0.25 mol of pyridine are then added. The mixture is heated for 3 h at 60 ° C. The pyridine hydrochloride obtained is filtered cold. After evaporation of the filtrate, a residue is obtained which is taken up in isopropanol and which is then recrystallized from ethanol.
On obtient ainsi des cristaux blancs. F= 143°C. Rendement: io 75%. White crystals are thus obtained. Mp 143 ° C. Yield: 75%.
Exemple 5: Example 5:
7-théophyllinylacétate de 2-(2-phényl-l,3-dioxo-indanyl)-méthyle 2- (2-Phenyl-1,3-dioxo-indanyl) -methyl 7-theophyllinylacetate
15 0 0 15 0 0
ir ch„-0-c-ch„—n ir ch „-0-c-ch„ —n
" \A, " \AT,
Dans un ballon à trois tubulures, on introduit 0,10 mol de 2-25 hydroxyméthyl-2-phényl-l,3-indanedione dissous dans du chlorure de méthylène sec. On ajoute ensuite 0,11 mol de pyridine anhydre, puis 0,12 mol de chlorure de l'acide 7-théophyllinylacé-tique dans du chlorure de méthylène sur 30 mn et on chauffe au reflux pendant 2 h 30 mn. Après évaporation du solvant on 30 obtient une pâte. On ajoute de l'isopropanol et on obtient ainsi des cristaux blancs que l'on recristallise dans le propanol. F= 177°C. Rendement: 70%. 0.10 mol of 2-25 hydroxymethyl-2-phenyl-1,3-indanedione dissolved in dry methylene chloride is introduced into a three-tube flask. 0.11 mol of anhydrous pyridine is then added, then 0.12 mol of 7-theophyllinylacetic acid chloride in methylene chloride over 30 min and the mixture is heated at reflux for 2 h 30 min. After evaporation of the solvent, a paste is obtained. Isopropanol is added and white crystals are thus obtained which are recrystallized from propanol. Mp 177 ° C. Yield: 70%.
Exemple 6: Example 6:
35 Hémisuccinate de 2-(2-phényl-l,3-dioxo-indanyl)-méthyle 35 2- (2-Phenyl-1,3-dioxo-indanyl) -methyl hemisuccinate
0 0 0 0
ch2-o-c-ch2ch2-cooh ch2-o-c-ch2ch2-cooh
45 Dans un ballon, on introduit de la 2-hydroxyméthyl-2-phényl-1,3-indanedione et un grand excès d'anhydride succinique. On ajoute une petite quantité de 4-diméthylaminopyridine et du chlorure de méthylène anhydre. 45 A 2-hydroxymethyl-2-phenyl-1,3-indanedione and a large excess of succinic anhydride are introduced into a flask. A small amount of 4-dimethylaminopyridine and anhydrous methylene chloride are added.
On chauffe au reflux du chlorure de méthylène pendant 12 h. 50 Après traitement, on recristallise le solide obtenu dans de l'isopropanol. F= 137°C. Rendement: quantitatif. The methylene chloride is heated to reflux for 12 h. After treatment, the solid obtained is recrystallized from isopropanol. Mp 137 ° C. Yield: quantitative.
Exemple 7: Example 7:
Succhiate de 3-pyridylméthyle et de 2-(2-phényl-l,3-dioxo-inda-55 nyl) -méthyle ch2-o-c-ch2-ch2-c-o-ch2 3-pyridylmethyl and 2- (2-phenyl-1,3-dioxo-inda-55 nyl) -methyl ch2-o-c-ch2-ch2-c-o-ch2
V \ V \
a) On prépare en premier lieu le chlorure d'acide du produit de l'exemple 6. Dans un ballon rodé muni d'un réfrigérant, on introduit 7 g (0,02 mol) d'hémisuccinate de 2-(2-phényl-l,3-dioxo- a) The acid chloride of the product of Example 6 is first prepared -l, 3-dioxo-
5 5
624 379 624,379
indanyl)-méthyle en solution dans du chlorure de méthylène. On ajoute 20 ml de chlorure de thionyle et on chauffe jusqu'à cessation du dégagement de vapeurs acides. On évapore ensuite le solvant et le chlorure de thionyle en excès et recristallise le solide obtenu dans du benzène. F = 115°C. Rendement: 94%. indanyl) -methyl in solution in methylene chloride. 20 ml of thionyl chloride are added and the mixture is heated until the evolution of acid vapors is stopped. The solvent and the excess thionyl chloride are then evaporated off and the solid obtained is recrystallized from benzene. Mp 115 ° C. Yield: 94%.
Selon un autre mode de synthèse en remplaçant le chlorure de méthylène par le benzène, on peut éviter l'évaporation du solvant et le produit souhaité précipite dans le benzène après refroidissement. According to another mode of synthesis, by replacing methylene chloride with benzene, it is possible to avoid evaporation of the solvent and the desired product precipitates in benzene after cooling.
b) Dans un ballon à trois tubulures, on introduit 2 mol de 3-pyridineméthanol dissous dans du chlorure de méthylène et on ajoute goutte à goutte à cette solution le chlorure d'acide obtenu en a) (1 mol) dissous également dans du chlorure de méthylène. La réaction est exothermique; il se forme un précipité. On chauffe encore pendant quelques minutes pour terminer la réaction, puis on refroidit, on filtre le précipité obtenu, on évapore le solvant, on lave le solide obtenu et on sèche. F= 130-131°C. Rendement: 77%. b) In a three-necked flask, 2 mol of 3-pyridinemethanol dissolved in methylene chloride are introduced and the acid chloride obtained in a) (1 mol) also dissolved in chloride is added dropwise to this solution methylene. The reaction is exothermic; a precipitate is formed. It is further heated for a few minutes to complete the reaction, then cooled, the precipitate obtained is filtered, the solvent is evaporated, the solid obtained is washed and dried. Mp 130-131 ° C. Yield: 77%.
Exemple 8: Example 8:
Succinate de tocophéryle et de 2-(2-phényl-l ,3-dioxo-indanyl)-méthyle ch2-o-c-ch2ch2 Tocopheryl and 2- (2-phenyl-1,3-dioxo-indanyl) -methyl ch2-o-c-ch2ch2 succinate
V CiH3 V CiH3
lh3 ch, lh3 ch,
I I
(CH2CH2CH2CH)3 CH3 (CH2CH2CH2CH) 3 CH3
On prépare en premier lieu le chlorure d'acide de l'hémisucci-nate de tocophéryle en faisant réagir dans l'éther anhydre l'hémi-succinate de tocophéryle avec le chlorure de thionyle, ce dernier réactif étant introduit goutte à goutte dans le milieu réactionnel; on chauffe ensuite au reflux jusqu'à cessation du dégagement des vapeurs acides ; on évapore et on lave plusieurs fois pour obtenir ledit chlorure d'acide qui se présente sous la forme d'une huile et que l'on additionne à la 2-hydroxyméthyl-2-phényl-l,3-indane-dione en présence de pyridine dans le benzène. On chauffe au reflux pendant 2 h, on laisse refroidir, on filtre le chlorhydrate de pyridine, on lave plusieurs fois à l'eau et on évapore le benzène. On obtient une huile jaune que l'on lave plusieurs fois au métha-nol à chaud. The acid chloride of tocopheryl hemisuccinate is first prepared by reacting in anhydrous ether tocopheryl hemi succinate with thionyl chloride, the latter reagent being introduced dropwise into the medium. reactive; then heated to reflux until the evolution of acid vapors ceases; it is evaporated and washed several times to obtain the said acid chloride which is in the form of an oil and which is added to the 2-hydroxymethyl-2-phenyl-1,3-indane-dione in the presence of pyridine in benzene. The mixture is heated at reflux for 2 h, allowed to cool, the pyridine hydrochloride is filtered, washed several times with water and the benzene is evaporated. A yellow oil is obtained which is washed several times with hot methanol.
Le produit de l'exemple 8 peut encore être préparé à partir du chlorure d'acide de l'exemple 7a) et du tocophérol en présence de 25 pyridine. The product of Example 8 can also be prepared from the acid chloride of Example 7a) and tocopherol in the presence of pyridine.
On a résumé ci-après une partie des essais pharmacologiques qui ont été entrepris chez le lapin avec les produits selon l'invention et des substances de référence : la pindione et la 2-hydroxy-méthyl-2-phényl-l,3-indanedione, afin de déterminer: 30 — Q, le temps de quick (en secondes); A summary of the pharmacological tests which have been carried out in rabbits with the products according to the invention and reference substances are summarized below: pindione and 2-hydroxy-methyl-2-phenyl-1,3-indanedione , to determine: 30 - Q, the quick time (in seconds);
— TCK, le temps de céphaline kaolin (en secondes); - TCK, the kaolin partial thromboplastin time (in seconds);
— II, le facteur II (taux de prothrombine); - II, factor II (prothrombin level);
— VII-X, et X (où VII et X représentent le taux de proconvertine et le facteur de Stuart). - VII-X, and X (where VII and X represent the level of proconvertine and the Stuart factor).
35 La dose administrée est équivalente, en fonction du poids moléculaire de chaque produit, à 26,4 mg/kg de pindione. Les résultats ont été consignés dans le tableau ci-après dans lequel les pourcentages sont exprimés par rapport à un plasma témoin. The dose administered is equivalent, depending on the molecular weight of each product, to 26.4 mg / kg of pindione. The results have been recorded in the table below in which the percentages are expressed relative to a control plasma.
Produit et dose Product and dose
Q* Q *
TCK TCK
II II
VII-X VII-X
X X
Pindione Pindione
26,4 mg/kg 26.4 mg / kg
26 s 26s
55 s 55s
15% 15%
12% 12%
41% 41%
2-Hydroxyméthyl-2 2-Hydroxymethyl-2
-phényl-1,3 indanedione -1,3-phenyl indanedione
30 mg/kg 30 mg / kg
24 s 24s
60s 60s
13% 13%
15% 15%
40% 40%
Exemple 1 Example 1
53 mg/kg 53 mg / kg
27 s 27s
50 s 50s
11% 11%
9% 9%
47% 47%
Exemple 2 Example 2
50 mg/kg 50 mg / kg
26 s 26s
51 s 51s
20% 20%
18% 18%
54% 54%
Exemple 3 Example 3
42 mg/kg 42 mg / kg
34 s 34s
52 s 52s
5% 5%
5% 5%
25% 25%
Exemple 4 Example 4
42 mg/kg 42 mg / kg
37 s 37s
85 s 85s
6% 6%
3% 3%
17% 17%
Note: * Temps de quick après dilution au 'A. Note: * Quick time after dilution at 'A.
D'une manière générale les composés de formule I présentent une activité anticoagulante particulèrement intéressante et sont par suite utiles pour la prévention et le traitement de la maladie thrombo-embolique. In general, the compounds of formula I exhibit a particularly interesting anticoagulant activity and are therefore useful for the prevention and treatment of thromboembolic disease.
Les essais cliniques ont permis de déterminer que la dose quo-55 tidienne varie entre 25 et 200 mg/j, le mode d'administration étant la voie orale. Au cours de ces essais le produit de l'exemple 8 s'est avéré très efficace. Clinical trials have determined that the daily dose varies between 25 and 200 mg / day, the mode of administration being the oral route. During these tests the product of Example 8 proved to be very effective.
R R
Claims (6)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7631284A FR2367489A1 (en) | 1976-10-18 | 1976-10-18 | NEW ESTERS OF 2-HYDROXYMETHYL-2-PHENYL-1,3-INDANEDIONE |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH624379A5 true CH624379A5 (en) | 1981-07-31 |
Family
ID=9178872
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1163477A CH624379A5 (en) | 1976-10-18 | 1977-09-23 | Process for the preparation of new 2-hydroxymethyl-2-phenyl-1,3-indanedione esters |
Country Status (5)
| Country | Link |
|---|---|
| BE (1) | BE859783A (en) |
| CH (1) | CH624379A5 (en) |
| DE (1) | DE2744809A1 (en) |
| ES (1) | ES463298A1 (en) |
| FR (1) | FR2367489A1 (en) |
-
1976
- 1976-10-18 FR FR7631284A patent/FR2367489A1/en active Granted
-
1977
- 1977-09-23 CH CH1163477A patent/CH624379A5/en not_active IP Right Cessation
- 1977-10-05 DE DE19772744809 patent/DE2744809A1/en not_active Withdrawn
- 1977-10-17 BE BE2056343A patent/BE859783A/en unknown
- 1977-10-17 ES ES463298A patent/ES463298A1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| FR2367489B1 (en) | 1979-03-02 |
| FR2367489A1 (en) | 1978-05-12 |
| ES463298A1 (en) | 1978-07-16 |
| BE859783A (en) | 1978-04-17 |
| DE2744809A1 (en) | 1978-04-20 |
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