FR2536397A2 - [4-oxo-4H-1-Benzopyran-8-yl]alkanoic acids, their salts and derivatives, their preparation and medicinal products containing them - Google Patents

[4-oxo-4H-1-Benzopyran-8-yl]alkanoic acids, their salts and derivatives, their preparation and medicinal products containing them Download PDF

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FR2536397A2
FR2536397A2 FR8219640A FR8219640A FR2536397A2 FR 2536397 A2 FR2536397 A2 FR 2536397A2 FR 8219640 A FR8219640 A FR 8219640A FR 8219640 A FR8219640 A FR 8219640A FR 2536397 A2 FR2536397 A2 FR 2536397A2
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radical
phenyl
oxo
hydrogen
benzopyran
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Merck Sante SAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • 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
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
    • 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
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/34—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only
    • C07D311/36—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only not hydrogenated in the hetero ring, e.g. isoflavones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyrane Compounds (AREA)

Abstract

The present improvement relates to [4-oxo-4H-1-benzopyran-8-yl]alkanoic acids represented by the formula: in which AR is hydrogen, a substituted or unsubstituted phenyl radical, or a thienyl, furyl, naphthyl, lower alkyl, cycloalkyl or aralkyl radical; B is a linear or branched lower alkyl radical which is saturated or contains an ethylenic unsaturation; R1 is hydrogen or a phenyl radical; X is hydrogen, a lower alkyl radical or an alkoxy radical and n = 1, as well as their salts, esters, aminoesters and amides. The compounds and their derivatives can be used as medicinal, especially antitumour, products.

Description

Le brevet principal concerne des acides [oxo-4-4H-[1]-oan- zopyran-8-yl] alcanoiques, certains de leurs sels et dérivés, leurs préparations, les composés intermédiaires nécessaires à leur obtention et les médicaments les contenant. The main patent relates to [oxo-4-4H- [1] -oanopyopyran-8-yl] alkanoic acids, some of their salts and derivatives, their preparations, the intermediate compounds necessary for their production and the drugs containing them.

Selon le présent perfectionnement les acides, sels et déri- vés sont représentés par la formule

Figure img00010001

dans laquelle AR est l'hydrogène, un radical phényle, substitué ou non, thényle, furyle, naphtyle, alkyle inférieur, cycloalkyle, aralkyle ;
B est un radical alkyle inférieur linéaire ou ramifié, saturé ou à insaturation éthylénique; R1 est l'hydrogène ou un radical phényle;
X est l'hydrogène ou un radical alkyle inférieur, alkozy et n = 1, ainsi que leurs sels de métaux alcalins, notamment les sels de sodium.According to the present improvement the acids, salts and derivatives are represented by the formula
Figure img00010001

in which AR is hydrogen, a phenyl radical, substituted or not, thenyl, furyl, naphthyl, lower alkyl, cycloalkyl, aralkyl;
B is a linear or branched, saturated or ethylenically unsaturated lower alkyl radical; R1 is hydrogen or a phenyl radical;
X is hydrogen or a lower alkyl radical, alkozy and n = 1, as well as their alkali metal salts, in particular the sodium salts.

Ces acides peuvent se préparer conformément à l'intention selon l'une ou l'autre des méthodes ci-dessous, qui permettent de les obtenir avec de bons rendements. These acids can be prepared according to the intention according to one or other of the methods below, which make it possible to obtain them with good yields.

Quand dans la formule I des acides : n = 1, et 3 X CH2, on prépare les acides en hydrolysant un nitrile, de formule

Figure img00010002

dans laquelle AR, X et R1, ont les mêmes significations que précédem- ment, notamment en milieu acide à chaud. Les nitriles ci-desauz s'obtiennent par traitement d'une bromométhyl-8-bensopyranone-4 de formule
Figure img00010003

dans laquelle X, AR et R1 ont les memes aignifications que précédemment, avec un cyanure alcalin.Ces nitriles sont des composés inter- médiaires nouveaux at à ce titre font partie de l'invention
Dans le cas où AR -H et R1 = phényle, on fait réagir une bromométhyl-8-benzopyraonons -4 de
Figure img00020001

aveo l'hexaméthjylènetétramine, puis procède à la condensation de l'aldéhyde obtenu avec le diéthylaminométhylène diphosphonate de tétraéthyle en présence d'hydrure de sodium. Par hydrolyse on obtient l'acide correspondant. L'[oxo]-4-phényl-3-4H-[1]-benzopyran-8-yl] carboxaldéhyde est nouveau et à ce titre fait partie de l'invention au titre de produit intermédiaire.When in formula I acids: n = 1, and 3 X CH2, the acids are prepared by hydrolyzing a nitrile, of formula
Figure img00010002

in which AR, X and R1, have the same meanings as previously, in particular in hot acid medium. The nitriles below are obtained by treatment of a bromomethyl-8-bensopyranone-4 of formula
Figure img00010003

in which X, AR and R1 have the same meanings as previously, with an alkaline cyanide. These nitriles are new intermediate compounds and as such are part of the invention
In the case where AR -H and R1 = phenyl, a bromomethyl-8-benzopyraonons -4 of
Figure img00020001

with hexamethjylenetetramine, then proceeds to the condensation of the aldehyde obtained with tetraethyl diethylaminomethylene diphosphonate in the presence of sodium hydride. By hydrolysis, the corresponding acid is obtained. [Oxo] -4-phenyl-3-4H- [1] -benzopyran-8-yl] carboxaldehyde is new and as such is part of the invention as an intermediate product.

Lorsque dans la formule (I), n = 1 et B est -CH2-CH2, on fait réagir dans un premier temps une bromométhyl-8-benzopyranone-4 de formule (III) avec le malonate de diéthyle en présence d'un agent basique comme l'hydrure de sodium, un alcoolate de sodium ou le sso- dium et dans un solvant approprié. Le malonate substitué obtenu est ensuite hydrolysé en acide correspondant. When in formula (I), n = 1 and B is -CH2-CH2, a bromomethyl-8-benzopyranone-4 of formula (III) is reacted first with diethyl malonate in the presence of an agent basic like sodium hydride, sodium alcoholate or sodium and in a suitable solvent. The substituted malonate obtained is then hydrolyzed to the corresponding acid.

Les malonates représentes par la formule (V)

Figure img00020002

dans laquelle X, AR et R1 ont les mêmes significations que précédemment, sont des composés intermédiaires nouveau: et à ce titre font partie de l'invention.The malonates represented by the formula (V)
Figure img00020002

in which X, AR and R1 have the same meanings as above, are new intermediate compounds: and as such are part of the invention.

Les sels de métaux alcalins des acides selon l'invention, notamment les sels de sodium s'obtiennent par neutralisation des acides précédents. The alkali metal salts of the acids according to the invention, in particular the sodium salts, are obtained by neutralization of the above acids.

Les dérivés des acides sous forme d'esters de formule

Figure img00020003

dans laquelle AR, 3, X, R1 et n ont les mêmes significations que pré- cédemment, R2 étant un radical alkyle inférieur ou hydroxyalkyle in- férieur se préparent par estérification des acides précédents. Acid derivatives in the form of esters of formula
Figure img00020003

in which AR, 3, X, R1 and n have the same meanings as above, R2 being a lower alkyl or lower hydroxyalkyl radical being prepared by esterification of the above acids.

Les amincesters de formule VI, dans laquelle AR,3,X,R1 et n ont les mêmes significations que précédemment, R2 étant un radical diakyle inférieur aminoalkyle inférieur, ou morpholinoéthyle sont obtenus par condensation des acides précédents avec une halo, de préférence chloroalkyl dialkylamine ou la chloroéthylmorpholine. $R2
Les sels des esters, amincesters avec des acides minéraux ou organiques acceptables en thérapeutique humaine sont d'un accès facile et d'une utilisation aisée.The amincesters of formula VI, in which AR, 3, X, R1 and n have the same meanings as previously, R2 being a lower diakyl radical lower aminoalkyl, or morpholinoethyl are obtained by condensation of the above acids with a halo, preferably chloroalkyl dialkylamine or chloroethylmorpholine. $ R2
The salts of esters, amincesters with mineral or organic acids acceptable in human therapy are easy to access and easy to use.

Les acides et leurs dérivés selon l'invention ont montré d'intéressantes propriétés pharmacologiques dans le domaine antitumoral. Les tests pharmacologiques, dans les conditions décrites dans le brevet principal, ont été effectués sur plusieurs types de tumeurs en particulier la leucémie lymphodytique P 388 et le caroinome 38 du colon. Les résultats obtenus avec les composés du perfectionnement sont comparables avec ceux obtenus pour les composés du brevet principal. The acids and their derivatives according to the invention have shown interesting pharmacological properties in the anti-tumor field. The pharmacological tests, under the conditions described in the main patent, were carried out on several types of tumors, in particular P 388 lymphodytic leukemia and caroinoma 38 of the colon. The results obtained with the compounds of the improvement are comparable with those obtained for the compounds of the main patent.

Il est donné ci après des exemples qui illustrent l'inven- tion à titre non limitatif. Examples are given below which illustrate the invention without implied limitation.

Exemple 1 : [(Méthoxy-3-phényl)-2-oxo-4-4H-[1]-benzopyran-8-yl] acétonitrile
C18H13NO3 (formule 1). PM = 291,31. Example 1: [(Methoxy-3-phenyl) -2-oxo-4-4H- [1] -benzopyran-8-yl] acetonitrile
C18H13NO3 (formula 1). MW = 291.31.

Préparé selon l'exemple 1 du brevet principal, à partir de 23,9 g (0,066 mole) de (bromométhyl)-8-(méthoxy-3-phényl)-2-4H-[1]-benzopy- ranone-4 et de 9,1g de cyanure de potassium, on obtient 9,3 g de produit aveo 46% de rendement, PFD = 170 C. IR : @ c = O = 1650 cm
RMN (IMSO), 3 K à 3,9 (singulet) 2 H à 4,5 (singulet) 8 H de 6,9 à 8,2 (multiplet).Prepared according to Example 1 of the main patent, from 23.9 g (0.066 mole) of (bromomethyl) -8- (methoxy-3-phenyl) -2-4H- [1] -benzopyrananone-4 and 9.1 g of potassium cyanide, 9.3 g of product are obtained with 46% yield, PFD = 170 C. IR: @ c = O = 1650 cm
NMR (IMSO), 3 K to 3.9 (singlet) 2 H to 4.5 (singlet) 8 H from 6.9 to 8.2 (multiplet).

Exemple 2 : (Méthoxy-6-oxo-4-phényl-2-4H-[1]-benzopyran-8-yl) acétonitrile
C18H13NO3, (formule 2). PM = 291,31.Example 2: (Methoxy-6-oxo-4-phenyl-2-4H- [1] -benzopyran-8-yl) acetonitrile
C18H13NO3, (formula 2). MW = 291.31.

Préparé selon l'exemple 1 du brevet principal à partir de 30 g (0087 mole) de bromométhyl-8-méthoxy-6-phényl-2-4H-[1]-benzopyranone-4 et 11,9 g de cyanure de potassium. Le produit étant insoluble à chaud, on ne filtre pas à chaud, mais on refroidit, filtre à froid, lave à l'eau sèche. Poids obtenu : 15,9 (RDT : 62 %). PFK = 270 C. IR : ic = O =
1635 cm-1. Le produit est trop peu soluble pour obtenir un spectre de
Exemple 3 :
[(Diméthoxy-3,4-phényl)-2-oxo-4-4H-[1]-benzopyran-8-yl]acétonitrile
C19h15NO4, (formule 3). PM = 321,34. Prepared according to Example 1 of the main patent from 30 g (0087 mole) of bromomethyl-8-methoxy-6-phenyl-2-4H- [1] -benzopyranone-4 and 11.9 g of potassium cyanide. The product being insoluble when hot, it is not filtered hot, but cooled, filtered cold, washed with dry water. Weight obtained: 15.9 (RDT: 62%). PFK = 270 C. IR: ic = O =
1635 cm-1. The product is too poorly soluble to obtain a spectrum of
Example 3:
[(Dimethoxy-3,4-phenyl) -2-oxo-4-4H- [1] -benzopyran-8-yl] acetonitrile
C19h15NO4, (formula 3). MW = 321.34.

Préparé selon l'exemple 1 du brevet principal à partir de 30 g (0,080
mole) de (bromométhyl)-8-(diméthoxy-3,4-phényl)-2-4H-[1]-benzopyranone-4 et de Il g de cyanure de potassium. Poids obtenu : 10,5 g (Rdt : 40 %)
PFK = 226 C. IR : @ c = O (pyrone) =1650 cm-1; @ c = N = 2260 cm-1.Prepared according to Example 1 of the main patent from 30 g (0.080
mole) of (bromomethyl) -8- (dimethoxy-3,4-phenyl) -2-4H- [1] -benzopyranone-4 and II g of potassium cyanide. Weight obtained: 10.5 g (Yield: 40%)
PFK = 226 C. IR: @ c = O (pyrone) = 1650 cm-1; @ c = N = 2260 cm-1.

Le produit est trop peu soluble pour obtenir un spectre de RMN.The product is too sparingly soluble to obtain an NMR spectrum.

Exemple 4 :
Acide [(méthoxy-3-phényl)-2-oxo-4-4H-[1]-benzopyran-8-yl] acétique
C18H14O5, (formule 4). PM = 310,31.Example 4:
Acetic [(methoxy-3-phenyl) -2-oxo-4-4H- [1] -benzopyran-8-yl] acetic acid
C18H14O5, (formula 4). MW = 310.31.

Préparé selon l'exemple 2 du brevet principal à partir de 9,1 g (0,031 mole) de [(méthoxy-3-phényl)-2-oxo-4-4H-[1]-benzopyran-8-yl]-acétoui trile. Poids obtenu : 2,2 g. PFG= 238-241 C (MiBK). IR : @ c = O (py- rone) = 1635 cm-1; @c = O (acide) = 1710 cm-1. RMN (DMSO), 1 H à 3,4
(échangeable avec D2O), 3 H à 3,9 (singulet) 2 E à 4,02 (singulet),
1 R à 7,1 (singulet), 7 E de 7,1 à 8,1 (multiplet).Prepared according to Example 2 of the main patent from 9.1 g (0.031 mole) of [(methoxy-3-phenyl) -2-oxo-4-4H- [1] -benzopyran-8-yl] -acétoui trile. Weight obtained: 2.2 g. PFG = 238-241 C (MiBK). IR: @ c = O (pyron) = 1635 cm-1; @c = O (acid) = 1710 cm-1. NMR (DMSO), 1 H at 3.4
(exchangeable with D2O), 3 H at 3.9 (singlet) 2 E at 4.02 (singlet),
1 R to 7.1 (singlet), 7 E from 7.1 to 8.1 (multiplet).

Analyse pondérale C % E % 0 %
Calculée 69,67 4,55 25,78
Trouvée 69,91 4,61
Exemple 5 :
Acide (méthoxy-6-oxo-4-phényl-2-4H-[1]-benzopyran-8-yl) acétique
C18H14O5, (formule 5). PM = 310,31. Weight analysis C% E% 0%
Calculated 69.67 4.55 25.78
Found 69.91 4.61
Example 5:
Acetic acid (methoxy-6-oxo-4-phenyl-2-4H- [1] -benzopyran-8-yl) acetic
C18H14O5, (formula 5). MW = 310.31.

Préparé selon l'exemple 2 du brevet principal à partir de 8 g (0,027 mole) de (méthoxy-6-oxo-4-phényl-2-4H-[1]-benzopyran-8-yl)acétonitrile.Prepared according to Example 2 of the main patent from 8 g (0.027 mole) of (methoxy-6-oxo-4-phenyl-2-4H- [1] -benzopyran-8-yl) acetonitrile.


Poids obtenu : 3,7 g. IR : @ c = O (pyrone) = 1630 cm-1 ; @ c = O (acide) = 1720 cm-1, @ OH = 2400 à 3500 cm-1, la RMN montre qu'on a un mélange
du produit du titre et de l'acide (hydroxy-6-oxo-4-phényl-2-4H-[1]benzopyran-8-yl) acétique. (formule 6). Ce mélange est utilisé tel quel
dans l'exemple 8.
Weight obtained: 3.7 g. IR: @ c = O (pyrone) = 1630 cm-1; @ c = O (acid) = 1720 cm-1, @ OH = 2400 to 3500 cm-1, the NMR shows that we have a mixture
of the title product and of (hydroxy-6-oxo-4-phenyl-2-4H- [1] benzopyran-8-yl) acetic acid. (formula 6). This mixture is used as is
in example 8.

Exemple 6 :
Acide [(diméthoxy-3,4-phényl)-2-oxo-4-4H-[1]-benzopyran-8-yl] acétique
C19H16O6. (formule 7). PM = 340,34.Example 6:
Acetic [(dimethoxy-3,4-phenyl) -2-oxo-4-4H- [1] -benzopyran-8-yl] acetic acid
C19H16O6. (formula 7). MW = 340.34.

Préparé selon ltexemple 2 du brevet principal à partir de 10,2 g
(0,032 mole) de [(diméthoxy-3,4-phényl)-2-oxo-4-4H-[1]-benzopyran-8-yl] acétonitrile. Poids obtenu : 3,9 g. PFG = 250-254 C (AcOH). IR : @ c =
O (pyrone) = 1645 cm-1 ; @ c = O (acide) =1720 cm-1. RMN (DMSO), 3 H à
3,83 (singulet), 3 H à 3,9 (singulet) 2 H à 4,03 (singulet), 7 E de
6,8 à 8,1 (multiplet), t H à 12 (échangeable avec D2O).Prepared according to example 2 of the main patent from 10.2 g
(0.032 mole) of [(dimethoxy-3,4-phenyl) -2-oxo-4-4H- [1] -benzopyran-8-yl] acetonitrile. Weight obtained: 3.9 g. PFG = 250-254 C (AcOH). IR: @ c =
O (pyrone) = 1645 cm-1; @ c = O (acid) = 1720 cm-1. NMR (DMSO), 3 H to
3.83 (singlet), 3 H to 3.9 (singlet) 2 H to 4.03 (singlet), 7 E of
6.8 to 8.1 (multiplet), t H to 12 (exchangeable with D2O).

Analyse pondérale C % H % O %
Calculée 67,05 4,74 28,21
Trouvée 67,16 4,68
Exemple 7 : (Méthyl-6-oxo-4-phényl-2-4H-[1]-benzopyran-8-yl) acétate de (N,Ndiéthylamino)-2-éthyle C24H27N04 (formule 8). PM = 393,49.Weight analysis C% H% O%
Calculated 67.05 4.74 28.21
Found 67.16 4.68
Example 7: (Methyl-6-oxo-4-phenyl-2-4H- [1] -benzopyran-8-yl) acetate of (N, Ndiethylamino) -2-ethyl C24H27N04 (formula 8). MW = 393.49.

Préparé selon l'exemple 3 du brevet principal, à partir de 8,5 g (0,029 mole) d'acide (méthyl-6-oxo-4-phényl-2-4H-[1]-benzopyran-8-yl) acétique et de 4,73 g (0,035 mole) de chloro-2-N,N-diéthyléthylamine en remplaçant l'acétone par le IMF et en chauffant 2h30 à 80 . Après évaporation du DMF, on reprend le résidu au chloroforme, lave à la soude N, puis à l'eau, sèche, évapore sous vide et recristellise dans un mélange hezane-toluène. Poids obtenu s 8,8 g (Rdt : 77 %). PFK = 120 c. IR : @ C = O (pyrone) = 1655 cm-1; @ c = O (ester) = 1750 cm-1
RMN (CDCl3), 6 E à 0s92 (triplet, J = 7 Hz), 9 H de 2,3 à 2,9 (multiplet), 2 H à 3,97 (singulet), 2 H à 4,2 (triplet, J = 6 Hz), 1 H à 6,8 (singulet) 7 E de 7,2 à 8,1 (multiplet).Prepared according to Example 3 of the main patent, from 8.5 g (0.029 mole) of (methyl-6-oxo-4-phenyl-2-4H- [1] -benzopyran-8-yl) acetic acid and 4.73 g (0.035 mole) of chloro-2-N, N-diethylethylamine, replacing acetone with the IMF and heating 2:30 to 80. After evaporation of the DMF, the residue is taken up in chloroform, washed with sodium hydroxide, then with water, dried, evaporated under vacuum and recrystallized from a hezane-toluene mixture. Weight obtained s 8.8 g (YId: 77%). PFK = 120 c. IR: @ C = O (pyrone) = 1655 cm-1; @ c = O (ester) = 1750 cm-1
NMR (CDCl3), 6 E at 0s92 (triplet, J = 7 Hz), 9 H from 2.3 to 2.9 (multiplet), 2 H to 3.97 (singlet), 2 H to 4.2 (triplet , J = 6 Hz), 1 H at 6.8 (singlet) 7 E from 7.2 to 8.1 (multiplet).

Chlorhydrate C24H28ClNO4. PM = 429,95. PFG = 188-190 C (éthanoléther).C24H28ClNO4 hydrochloride. MW = 429.95. PFG = 188-190 C (ethanol ether).

Analyse pondérale C % H % Cl % N % O %
Calculée 64,07 6,56 8,25 3,26 14,89
Trouvée 64,34 6,35 8,27 3246
Exemple 8 : (Méthoxy-6-oxo-4-phényl-2-4H-[1]-benzopyran-8-yl) acétate de (N,Ndiéthylamino)-2-éthyl C24H27NO5 (formule 9) PM = 409,49.Weight analysis C% H% Cl% N% O%
Calculated 64.07 6.56 8.25 3.26 14.89
Found 64.34 6.35 8.27 3,246
Example 8: (Methoxy-6-oxo-4-phenyl-2-4H- [1] -benzopyran-8-yl) acetate of (N, Ndiethylamino) -2-ethyl C24H27NO5 (formula 9) MW = 409.49.

Préparé selon l'exemple 3 du brevet principal à partir de 3,5 g du me lange d'acides de l'exemple 5 et de 1,84 g (0,013 mole) de chloro-2-
N,N-diéthyléthylamine, en remplaçant l'acétone par le DMF, et en chauffant 2h30 à 800C. Après évaporation, on reprend avec CH2Cl2, lave à la soude N, puis à l'eau, sèche, évapore sous vide. Poide obtenu 1,4g
RMN (CDCl3), 6 H à Q,95 (triplet, J = 7 Hz), 6 H de 2,3 à 2,8 (multi- plet), 3 E à 3,9 (singulet) 2 H à 3,96 (singulet) 2 H à 4,2 (tri plet, J = 6 Hz), 1 H à 6,8 (singulet) 7 E de 7,1 à 8,1 (multiplet).Prepared according to Example 3 of the main patent from 3.5 g of the mixture of acids of Example 5 and 1.84 g (0.013 mole) of chloro-2-
N, N-diethylethylamine, replacing acetone with DMF, and heating 2:30 at 800C. After evaporation, the residue is taken up with CH2Cl2, washed with sodium hydroxide N, then with water, dried, evaporated in vacuo. Weight obtained 1.4g
NMR (CDCl3), 6 H at Q, 95 (triplet, J = 7 Hz), 6 H from 2.3 to 2.8 (multi-ply), 3 E to 3.9 (singlet) 2 H to 3, 96 (singlet) 2 H at 4.2 (triplet, J = 6 Hz), 1 H at 6.8 (singlet) 7 E from 7.1 to 8.1 (multiplet).

Exemple 9 : [oxo-4-(thényl-2)-2-4H-[1]-benzopyran-8-yl] acétate de (N,N diéthylamino)-2-éthyle. C21H23NO4S, (formule 10), PM = 385,45.Example 9: [oxo-4- (thényl-2) -2-4H- [1] -benzopyran-8-yl] acetate of (N, N diethylamino) -2-ethyl. C21H23NO4S, (formula 10), PM = 385.45.

Préparé selon l'exemple 3 du brevet principal à partir de 9,6 g (0,036 mole) d'acide [Oxo-4-(thényl-2)-2-4H-[1]-benzopyran-8-yl] acétique, 2,2 g (0,033 mole) de potasse et 5 g (0,033 mole) de chloro-2-N,N-dié- thyléthylamine. Après traitement on obtient une huile. Poids obtenu 12 g (Rdt : 88 %).Prepared according to Example 3 of the main patent from 9.6 g (0.036 mole) of [Oxo-4- (2-thényl) -2-4H- [1] -benzopyran-8-yl] acetic acid, 2.2 g (0.033 mole) of potassium hydroxide and 5 g (0.033 mole) of chloro-2-N, N-diethylethylamine. After treatment, an oil is obtained. Weight obtained 12 g (Yield: 88%).

Chlorhydrate C21H24ClNO4S PM = 421,92. PFG = 210-213 C (éthanol)
IR : @NR # = 2800-2400 cm-1, 2 c = O (ester) = 1760 cm-1, @ c = O (pyrone) = 1640 cm-1, RMN (CDCl3) @ en ppm par rapport au TMS, 6 H à1,15
(triplet, J = 7 Hz), 6 H de 2,7 à 3,5 (multiplet) 2 H à 4,1 (singulet), 2 H à 4045 (triplet, J = 6 Hz), 1 R à 6,9 (singulet), 6 H de 7,1 à 8 (multiplet) 1 H à 10,6 (échangeable avec
Analyse C % H % Cl % N % O % S %
Calculée 59,80 5,73 8,40 3,31 15,16 7s60
Trouvée 59s85 5ss79 3,35 7,67
Exemple 10 : [Oxo-4-phényl-2-4H-[1]-benzopyran-8-yl]-2-propionate de (N,N-diéthyllamino)-2-éthyle C24H27NO4 (formyle 11). PM = 393,46.Hydrochloride C21H24ClNO4S PM = 421.92. PFG = 210-213 C (ethanol)
IR: @NR # = 2800-2400 cm-1, 2 c = O (ester) = 1760 cm-1, @ c = O (pyrone) = 1640 cm-1, NMR (CDCl3) @ in ppm compared to TMS , 6 H at 1.15
(triplet, J = 7 Hz), 6 H from 2.7 to 3.5 (multiplet) 2 H to 4.1 (singlet), 2 H to 4045 (triplet, J = 6 Hz), 1 R to 6, 9 (singlet), 6 H from 7.1 to 8 (multiplet) 1 H to 10.6 (exchangeable with
Analysis C% H% Cl% N% O% S%
Calculated 59.80 5.73 8.40 3.31 15.16 7s60
Found 59s85 5ss79 3.35 7.67
Example 10: [Oxo-4-phenyl-2-4H- [1] -benzopyran-8-yl] -2-propionate from (N, N-diethyllamino) -2-ethyl C24H27NO4 (formyl 11). MW = 393.46.

Préparé selon l'exemple 3 du brevet principal à partir de 3,6 g (0,012 mole) d'acide [oxo-4-phényl-2-4H-[1]-benzopyran-8-yl]-2-propionique, 0,8 g ( 0,012 mole) de potasse et 1,82 g (0,012 mole) de chloro-2-N,N- diéthyléthylamine. On obtient une huile.Prepared according to Example 3 of the main patent from 3.6 g (0.012 mole) of [oxo-4-phenyl-2-4H- [1] -benzopyran-8-yl] -2-propionic acid, 0 , 8 g (0.012 mole) of potassium hydroxide and 1.82 g (0.012 mole) of chloro-2-N, N-diethylethylamine. An oil is obtained.

Chlorhydrate C24H28ClNO4. PM = 429,91. PFG = 261-3 C (éthanol).C24H28ClNO4 hydrochloride. MW = 429.91. PFG = 261-3 C (ethanol).

IR : @ NH # = 2400-2800 cm-1, @ c = O (ester) = 1745 cm-1. @ c = O (pyrone) = 1660 cm-1. RMN (CDCl3) & @ en ppm par rapport au TMS, 6 K à 1,2 (triplet J = 7 Hz), 3 H à 1,8 (doublet J - 8 Hz), 6 E de 2,4 à 3,3 (multiplet), 3 H de 3,4 à 3,8 (multiplet) 1 K à 6,9 (singulet) 8 H de 7,2 à 8,4 (multiplet), 1 E à 12,7 (échangeable avee D2O). IR: @ NH # = 2400-2800 cm-1, @ c = O (ester) = 1745 cm-1. @ c = O (pyrone) = 1660 cm-1. NMR (CDCl3) & @ in ppm relative to TMS, 6 K to 1.2 (triplet J = 7 Hz), 3 H to 1.8 (doublet J - 8 Hz), 6 E from 2.4 to 3, 3 (multiplet), 3 H from 3.4 to 3.8 (multiplet) 1 K to 6.9 (singlet) 8 H from 7.2 to 8.4 (multiplet), 1 E to 12.7 (exchangeable with D2O).

Analyse C % H % Cl % N % O %
Calculée 67,04 6,56 8,25 3,26 14,89
Trouvée 66,88 6,52 3,20
Exemple 11: [(Oxo-4-phényl-2-4H-[1]-benzopyran-8-yl]méthyl]-2-propanedioate de diéthyle C23H22O6 (formule 12). PM = 390,24.Analysis C% H% Cl% N% O%
Calculated 67.04 6.56 8.25 3.26 14.89
Found 66.88 6.52 3.20
Example 11: [(Oxo-4-phenyl-2-4H- [1] -benzopyran-8-yl] methyl] -2-diethyl propanedioate C23H22O6 (formula 12). MW = 390.24.

A une suspension de 2,3g (0,1 mole) de sodium en bille dans 100 ml de benzène anhydre, on ajoute à température ambiante 15,6 g (0,1 mole) de propanedioate de diéthyle et on porte 5 heures à reflux, puis on laie se sous agitation 12 heures à température ambiante. On ajoute ensuite une solution de 31,5 g (0,1 mole) de bromométhyl-8-phényl-2-4H-[1] benzopyranone-4 dans 300 ml de benzène. Le milieu est porte 7 heures à reflux. Après filtration et évaporation du solvant on isole un solide blanc que l'on reoristallise. Poids obtenu : 26 g (Rdt : 66 ). To a suspension of 2.3 g (0.1 mole) of sodium ball in 100 ml of anhydrous benzene, 15.6 g (0.1 mole) of diethyl propanedioate are added at room temperature and the mixture is brought to reflux for 5 hours. , then it is stirred for 12 hours at room temperature. A solution of 31.5 g (0.1 mole) of bromomethyl-8-phenyl-2-4H- [1] benzopyranone-4 in 300 ml of benzene is then added. The medium is brought to reflux for 7 hours. After filtration and evaporation of the solvent, a white solid is isolated which is re-crystallized. Weight obtained: 26 g (Yield: 66).

PFG = 87-90 C (éthanol). IR : @ c = O (ester) = 1740 cm-1, @ c = O (pyrone) = 1650 cm-1.PFG = 87-90 C (ethanol). IR: @ c = O (ester) = 1740 cm-1, @ c = O (pyrone) = 1650 cm-1.

Exemple 12
Acide [oxo-4-phényl-2-4H-[1]-benzopyran-8-yl]-3-propionique C18H14O4
(formule 13). PM = 294,29.Example 12
[Oxo-4-phenyl-2-4H- [1] -benzopyran-8-yl] -3-propionic acid C18H14O4
(formula 13). MW = 294.29.

On porte au reflux 7 heures une solution de 26 g (0,066 mole) d'[[oxo
-4-phényl-2-4H-[1]-benzopyran-8-yl] méthyl]-2-propanedioate de diéthyle dans 93 ml d'acide acétique et 46 ml d'acide chlorhydrique concentré. On verse le milieu-réactionnel dana 800 mi d'eau, après filtra- tion, traitement par le bicarbonate de sodium à 5 % on isole 10,5 g
(Rdt 53 %). PFG =201-202 C (acétone/éthanol). IR : @OH (acide) = 2800 -3300 cm ',@ c c = O (acide) = 1740 om ', @c c = O (pyrone) = 1640 cm-1.A solution of 26 g (0.066 mole) of [[oxo] is brought to reflux for 7 hours.
-4-phenyl-2-4H- [1] -benzopyran-8-yl] methyl] -2-diethyl propanedioate in 93 ml of acetic acid and 46 ml of concentrated hydrochloric acid. The reaction medium is poured into 800 ml of water, after filtration, treatment with 5% sodium bicarbonate, 10.5 g are isolated.
(Yield 53%). PFG = 201-202 C (acetone / ethanol). IR: @OH (acid) = 2800 -3300 cm ', @ cc = O (acid) = 1740 om', @cc = O (pyrone) = 1640 cm-1.

RMN (CDCl3) @ en ppm par rapport an TMS, 2 H à 2,6 (tripolet J = 7 Hz), 2 E à 3,2 (triplet J = 7 Hz), 1 H à 7 (singulet), 8 H de 7,2 à 8,2
(multiplet), 1 H à 12,1 (échangeable avec D2O).NMR (CDCl3) @ in ppm relative to TMS, 2 H at 2.6 (tripolet J = 7 Hz), 2 E at 3.2 (triplet J = 7 Hz), 1 H at 7 (singlet), 8 H from 7.2 to 8.2
(multiplet), 1 H at 12.1 (exchangeable with D2O).

Analyse C % H % O %
Calculée 73,46 4,80 21,74
Trouvée 73,52 4,55
Exemple 13 [(Furyl-2)-2-oxo-4-4H-[1]-benaopyran-8-yl] acétonitrile C15H9NO3
(formule 14) PM = .251,22. Analysis C% H% O%
Calculated 73.46 4.80 21.74
Found 73.52 4.55
Example 13 [(Furyl-2) -2-oxo-4-4H- [1] -benaopyran-8-yl] acetonitrile C15H9NO3
(formula 14) PM = .251.22.

Préparé selon l'exemple 1 du brevet principal à partir de 23,4 g
(0,077 mole) de bromométhyl-8-(furyl-2)-2-4H-[1]-benzopyranone-4 et 10 g (0,154 mole) de cyanure de potassium. Poids obtenu : 15,5 g
(Rdt : 83 %). PFK = 195 C (éthanol). IR : @ c = N = 2250 cm-1, @c = O
(pyrone) : 1650 cm-1.Prepared according to Example 1 of the main patent from 23.4 g
(0.077 mole) bromomethyl-8- (furyl-2) -2-4H- [1] -benzopyranone-4 and 10 g (0.154 mole) of potassium cyanide. Weight obtained: 15.5 g
(YId: 83%). PFK = 195 C (ethanol). IR: @ c = N = 2250 cm-1, @c = O
(pyrone): 1650 cm-1.

Exemple 14 :
Acide [(furyl-2)-2-oxo-4-4H-[1]-benzopyran-8-yl]-acétique C15H1
(formule 15) PM = 270,23.Example 14:
Acid [(furyl-2) -2-oxo-4-4H- [1] -benzopyran-8-yl] -acetic C15H1
(formula 15) PM = 270.23.

Préparé selon l'exemple 2 du brevet principal à partir de 16 g (0,063 mole) de [(furyl-2)-2-oxo-4-4H-[1]-benzopyran-8-yl] acétonitrile.Prepared according to Example 2 of the main patent from 16 g (0.063 mole) of [(furyl-2) -2-oxo-4-4H- [1] -benzopyran-8-yl] acetonitrile.

Poids obtenu : 8,5 g (Rdt : 49 %). PFG = 240-2 C. IR : @ OH = 2800- 3200 cm-1, @ c = O (acide) = 1720 cm-1, @ c = O (pyrone) = 1650 cm-1.  Weight obtained: 8.5 g (Yield: 49%). PFG = 240-2 C. IR: @ OH = 2800- 3200 cm-1, @ c = O (acid) = 1720 cm-1, @ c = O (pyrone) = 1650 cm-1.

EN (DMSO) E en ppm par rapport au TMS, 2 E à 4 (singuiet), 9 H à 6,7
(singulet) 1 H de 6,8 à 7 (multiplet) 5 H de 7,3 à 8,1 (multiplet)
1 E à 12,6 (échangeable aveo D2O).EN (DMSO) E in ppm compared to TMS, 2 E to 4 (singuiet), 9 H to 6.7
(singlet) 1 H from 6.8 to 7 (multiplet) 5 H from 7.3 to 8.1 (multiplet)
1 E at 12.6 (exchangeable with D2O).

Analyse C % E % O%
Calculée 66,67 3,73 29,60
Trouvée 66,81 3,74
Exemple 15 :
[(Méthyl-4-phényl)-2-oxo-4-4H-[1]-benzopyran-8-yl]acétonitrile
C18H13NO2 (formule 16) PM = 215,30.Analysis C% E% O%
Calculated 66.67 3.73 29.60
Found 66.81 3.74
Example 15:
[(Methyl-4-phenyl) -2-oxo-4-4H- [1] -benzopyran-8-yl] acetonitrile
C18H13NO2 (formula 16) PM = 215.30.

Préparé selon l'exemple 1 du brevet principal à partir de 33g (0,1 mole) de bromométhyl-8-(méthyl-4-phényl)-2-4H-[1]-benzopyranone-4 et 13g
(0,2 mole) de cyanure de potassium. Poids obtenu : 23,5 g (Rdt : 85,5 %). PFK = 190 C. IR : @ c = N = 2160 cm-1, @ c = O (pyrone) = 1640 cm-1.Prepared according to Example 1 of the main patent from 33g (0.1 mole) of bromomethyl-8- (methyl-4-phenyl) -2-4H- [1] -benzopyranone-4 and 13g
(0.2 mole) of potassium cyanide. Weight obtained: 23.5 g (Yield: 85.5%). PFK = 190 C. IR: @ c = N = 2160 cm-1, @ c = O (pyrone) = 1640 cm-1.

Exemple 16 :
Acide [(méthyl-4-phényl-)-2-oxo-4-4H-[1]-benzonyran-8-yl] acétique
C18H14O4. (formule 17). PM = 294,29. Example 16:
[(Methyl-4-phenyl -) - 2-oxo-4-4H- [1] -benzonyran-8-yl] acetic acid
C18H14O4. (formula 17). MW = 294.29.

Préparé selon l'exemple 2 du brevet principal à part-r de 23f5 g (0,085 mole) de [(méthyl-4-phényl)-2-oxo-4-4H-[1]-benzopyran-8-yl] acétonitrile. Après traitement au bicarbonate et recristallisation dans l'acide acétique on obtient 15 g (Rdt : 59 %). PFG t 250-252 C.Prepared according to Example 2 of the main patent apart from r of 23 f5 g (0.085 mole) of [(methyl-4-phenyl) -2-oxo-4-4H- [1] -benzopyran-8-yl] acetonitrile. After treatment with bicarbonate and recrystallization from acetic acid, 15 g are obtained (Yield: 59%). PFG t 250-252 C.

IR : @ OH = 2800-3200 cm-1,@ c = O (acide) = 1720 cm-1, @ c = O (pyrone) = 1630 cm-1. RMN (DMSO) 6 en ppm par rapport au TMS, 3 H à 2,2 (singulet) 2 H à 4 (singulet) 1 H à 7 (singulet) 7 H de 7,2 à 8,1 (multiplet), 1 E à12,7 (échangeable avec D2O).IR: @ OH = 2800-3200 cm-1, @ c = O (acid) = 1720 cm-1, @ c = O (pyrone) = 1630 cm-1. NMR (DMSO) 6 in ppm relative to TMS, 3 H to 2.2 (singlet) 2 H to 4 (singlet) 1 H to 7 (singlet) 7 H from 7.2 to 8.1 (multiplet), 1 E at 12.7 (exchangeable with D2O).

Analyse C % H % O %
Calculée 73,46 4,80 21,74
Trouvée 73,77 4,94
Exemple 17 : [(Méthyl-4-phényl)-2-oxo-4-4H-[1]-benzopyren-8-yl] acétate de N ,N- diéthylaino)-2 éthyle C24H27NO4 (formule 18). PM = 393,46.Analysis C% H% O%
Calculated 73.46 4.80 21.74
Found 73.77 4.94
Example 17: [(Methyl-4-phenyl) -2-oxo-4-4H- [1] -benzopyren-8-yl] acetate of N, N-diethylaino) -2 ethyl C24H27NO4 (formula 18). MW = 393.46.

Préparé selon l'exemple 3 du brevet prinoipal à partir de 16,4 g (0,0557 mole) d'acide [(méthyl-4-phényl)-2-oxo-4-4H-[1]-benzopyran-8yl] acétique, 3,67 g (0,0557 mole) de potasse et 8,27 g (0,061 mole) de chloro-2-N,N-diéthyléthylamine. On obtient 15 g (Rdt s 70 %) d'un solide blanc PFG = 87-890C (diisopropylether). Prepared according to Example 3 of the prinoipal patent from 16.4 g (0.0557 mole) of [(methyl-4-phenyl) -2-oxo-4-4H- [1] -benzopyran-8yl] acid acetic acid, 3.67 g (0.0557 mole) of potassium hydroxide and 8.27 g (0.061 mole) of chloro-2-N, N-diethylethylamine. 15 g (yield 70%) of a white solid are obtained PFG = 87-890C (diisopropylether).

Chlorhydrate C24H28ClNO4, PM = 429,91, PFG = 175-77 C (éthanol). IR :
# NH # = 2400-2800 cm-1, @ c = O (ester) = 1750 cm-1, @ c = O (pyrone) = 1640 cm-1. RMN (CDCl3) 6 en ppm par rapport au TMS, 6 H à 1,3 (triplet J = 7 Ez), 3 H à 2,5 (singulet) 6 K de 2,7 à 3,4 (multiplet) 2 E à 4,2 (singulet), 2 H à 4,7 (triplet, J = 6 Hz), 1 K à 6,8 (singulet), 7 H de 7,2 à 8,4 (multiplet), 1 K à 12,7 (échangeable avec D20)
Analyse C % H % Cl % H % O %
Calculée 67,04 6,56 8,25 3,26 14,89
Trouvée 67,30 6,67 3,36
Exemple 18 : [(Naphtyl-2)-2-oxo-4-4H-[1]-benzopyran-8-yl] acétonitrile C21H13NO2
(formule 19) PM = 311,31.Hydrochloride C24H28ClNO4, PM = 429.91, PFG = 175-77 C (ethanol). IR:
# NH # = 2400-2800 cm-1, @ c = O (ester) = 1750 cm-1, @ c = O (pyrone) = 1640 cm-1. NMR (CDCl3) 6 in ppm relative to TMS, 6 H at 1.3 (triplet J = 7 Ez), 3 H at 2.5 (singlet) 6 K from 2.7 to 3.4 (multiplet) 2 E at 4.2 (singlet), 2 H at 4.7 (triplet, J = 6 Hz), 1 K at 6.8 (singlet), 7 H from 7.2 to 8.4 (multiplet), 1 K at 12.7 (exchangeable with D20)
Analysis C% H% Cl% H% O%
Calculated 67.04 6.56 8.25 3.26 14.89
Found 67.30 6.67 3.36
Example 18: [(Naphtyl-2) -2-oxo-4-4H- [1] -benzopyran-8-yl] acetonitrile C21H13NO2
(formula 19) PM = 311.31.

Préparé selon l'exemple 1 du brevet principal à partir de 61 g (0,167 mole) de bromométhyl-8-(naphtyl-2)-2-4H-[1]-benzopyranone-4 et 21,8 g
(0,334 mole) de cyanure de potassium. On obtient 43 g (Rdt : 84 %).Prepared according to Example 1 of the main patent from 61 g (0.167 mole) of bromomethyl-8- (naphthyl-2) -2-4H- [1] -benzopyranone-4 and 21.8 g
(0.334 mole) of potassium cyanide. 43 g are obtained (Yield: 84%).


PFK = 189 C (éthanol). IR : @ c = N = 2260 cm-1, @ c = O (pyrone) =
1660 cm-1.
PFK = 189 C (ethanol). IR: @ c = N = 2260 cm-1, @ c = O (pyrone) =
1660 cm-1.

Exemple 19 :
Acide [(naphtyl-2)-2-oxo-4-4H-[1]-benzopyran-8-yl] acétique C21H14O4
(formule 20) . PM = 330,32. Example 19:
[(Naphthyl-2) -2-oxo-4-4H- [1] -benzopyran-8-yl] acetic acid C21H14O4
(formula 20). MW = 330.32.

Préparé selon l'exemple 2 du brevet principal à partir de 43,5 g
(0,14 mole) de [(naphtyl-2)-2-oxo-4-4H-[1]-benzopyran-8yl] acétonitrile. Par recristallisation dans l'acide acétique on obtient 29 g
(Rdt : 62,7 %). PFG = 225-228 C. IR : @ OH = 2400-2800 cm-1,@ c = O
(acide) = 1720 cm-1, @ c = O (pyrone) = 1640 cm-1. RMN (DMSO) # en ppm par rapport au TMS, 2 H à 4 (singulet), 1 H à 7,1 (singulet), 10 H de 7,2 à 8,2 (multiplet) 1 H à 12,6 (échangeable avec D2O) Analyse C % E 5s Calculée 76,35 4,27 19938
Trouvée 76,25 4,15
Exemple 20 : [(Méthoxy-4-phényl)-2-oxo-4-4H-[1]-b
C18H13NO3 (formule 21). PM = 291,29.Prepared according to Example 2 of the main patent from 43.5 g
(0.14 mole) of [(naphthyl-2) -2-oxo-4-4H- [1] -benzopyran-8yl] acetonitrile. By recrystallization from acetic acid, 29 g are obtained.
(YId: 62.7%). PFG = 225-228 C. IR: @ OH = 2400-2800 cm-1, @ c = O
(acid) = 1720 cm-1, @ c = O (pyrone) = 1640 cm-1. NMR (DMSO) # in ppm relative to TMS, 2 H to 4 (singlet), 1 H to 7.1 (singlet), 10 H from 7.2 to 8.2 (multiplet) 1 H to 12.6 ( exchangeable with D2O) Analysis C% E 5s Calculated 76.35 4.27 19938
Found 76.25 4.15
Example 20: [(Methoxy-4-phenyl) -2-oxo-4-4H- [1] -b
C18H13NO3 (formula 21). MW = 291.29.

Prépare selon l'exemple 1 du brevet principal à partir de 34,5 g
(0,1 mole) de bromométhyl-8-(méthoxy-4-phényl)-2-4H-[1]-benzopyranone 4 et 13 g (0,2 mole) de cyanure de potassium. On obtient 25,3 g (Rdt 87 %). PFK = 190 C (éthenol), IR : @ c = N =2250 cm-1, @ c = O (pyrone) = 1640 cm-1. Prepares according to Example 1 of the main patent from 34.5 g
(0.1 mole) of bromomethyl-8- (methoxy-4-phenyl) -2-4H- [1] -benzopyranone 4 and 13 g (0.2 mole) of potassium cyanide. 25.3 g are obtained (yield 87%). PFK = 190 C (ethenol), IR: @ c = N = 2250 cm-1, @ c = O (pyrone) = 1640 cm-1.

Exemple 21
Acide [(méthoxy-4-phényl-)2-oxo-4-4H-[1]-benzopyran-8-yl] acétique
C18H14O5 (formule 22) PM = 310,29.Example 21
Acetic [(methoxy-4-phenyl-) 2-oxo-4-4H- [1] -benzopyran-8-yl] acetic acid
C18H14O5 (formula 22) PM = 310.29.

Préparé selon l'exemple 2 du brevet principal à partir de 25,3 g
(0,087 mole) de [(méthoxy-4-phényl)-2-oxo-4-4H-[1]-benzopyran-8-yl] acétonitrile. Poids obtenu : 23,6 g (Rdt : 8724 %). PFK = 228-232 C
(acide acétique). IR :ZOH = 2400-2800 cm-1, Je = O (acide) = 1720 cm-1
c = O (pyrone) = 1640 cm-1. RMN (DMSO) # en ppm par rapport au TMs 3 H à 3,9 (singulet) 2 E à 4,1 (singulet), 8 H de 7 à 8,3 (multiplet)
1 E à 12,7 (échangeable avec D2O),
Analyse C % H % O %
Calculée 69,67 4s55 25,78
Trouvée 69,64 4,58
Exemple 22 :
[(Méthoxy-4-phényl)-2-oxo-4-4H-[1]-benzopyran-8-yl] acétate de (N,N diéthylamino)-2-éthyle. C24H27NO5. (formyule 23). PM = 409,46.Prepared according to Example 2 of the main patent from 25.3 g
(0.087 mole) of [(methoxy-4-phenyl) -2-oxo-4-4H- [1] -benzopyran-8-yl] acetonitrile. Weight obtained: 23.6 g (Yield: 8724%). PFK = 228-232 C
(acetic acid). IR: ZOH = 2400-2800 cm-1, Je = O (acid) = 1720 cm-1
c = O (pyrone) = 1640 cm-1. NMR (DMSO) # in ppm relative to TMs 3 H at 3.9 (singlet) 2 E at 4.1 (singlet), 8 H from 7 to 8.3 (multiplet)
1 E at 12.7 (exchangeable with D2O),
Analysis C% H% O%
Calculated 69.67 4s55 25.78
Found 69.64 4.58
Example 22:
[(Methoxy-4-phenyl) -2-oxo-4-4H- [1] -benzopyran-8-yl] acetate of (N, N diethylamino) -2-ethyl. C24H27NO5. (formula 23). MW = 409.46.

Préparé selon l'exemple 3 du brevet principal à partir de 17,3 g
(0,0557 mole) d'acide [(méthoxy-4-phényl)-2-oxo-4-4H-[1]-benzopyran8-yl]-acétique, 3,67 g (0,0557 mole) de potasse et 8,27 g (0,061 mole) de chloro-2-N,N-diéthylétnylamine. Après traitement on obtient un solide que l'on recristallise dans le diisopropyléther. Poids obtenu : 16 g (Rdt : 70 %). PFK = 110 C.Prepared according to Example 3 of the main patent from 17.3 g
(0.0557 mole) [(methoxy-4-phenyl) -2-oxo-4-4H- [1] -benzopyran8-yl] -acetic acid, 3.67 g (0.0557 mole) of potassium hydroxide and 8.27 g (0.061 mole) of chloro-2-N, N-diethylethylamine. After treatment, a solid is obtained which is recrystallized from diisopropyl ether. Weight obtained: 16 g (Yield: 70%). PFK = 110 C.


Chlorhydrate C24H28ClNO5. PM = 445,91. PFG = 161-163 C. IR : @ NH # = 2400-2800 cm-1, @c = O (cator) = 1750 cm-1, @ c= O (pyrone) = 1640 cm-1
RMN (CDCl3) s en ppm par rapport au TMS, 6 H à 1,3 (triplet J = 7 Hz), 6 H de 2,8 à 3,4 (multiplet), 3 H à 3,95 (singulet), 2 H à 4,2 (singulet), 2 H 7 4,65 (triplet, J = 6 Hz), 1 H à 6,8 (singulet), 7 H de 7 à 8,2 (multiplet), 1 H à 12,7 (échangeable avec D2O).
C24H28ClNO5 hydrochloride. MW = 445.91. PFG = 161-163 C. IR: @ NH # = 2400-2800 cm-1, @c = O (cator) = 1750 cm-1, @ c = O (pyrone) = 1640 cm-1
NMR (CDCl3) s in ppm relative to TMS, 6 H at 1.3 (triplet J = 7 Hz), 6 H from 2.8 to 3.4 (multiplet), 3 H at 3.95 (singlet), 2 H at 4.2 (singlet), 2 H 7 4.65 (triplet, J = 6 Hz), 1 H at 6.8 (singlet), 7 H from 7 to 8.2 (multiplet), 1 H at 12.7 (exchangeable with D2O).

Analyse C % H % Cl ss N % O %
Caloulée 64,64 6,33 7,95 3,14 17,94
Trouvée 64,50 6,41 3,02
Exemple 23 : (Cyclohexyl-2-oxo-4-4H-[1]-benzopyran-6-yl) acétontitrile C17H17NO2 (formule 24). PM = 267,33.Analysis C% H% Cl ss N% O%
Caloulée 64.64 6.33 7.95 3.14 17.94
Found 64.50 6.41 3.02
Example 23: (Cyclohexyl-2-oxo-4-4H- [1] -benzopyran-6-yl) acetontitrile C17H17NO2 (formula 24). MW = 267.33.

Préparé selon l'exemple 1 du brevet principal à partir de 15,2 g (0,047 mole) de bromométhyl-8-cyclohexyl-2-4H-[1]-benzopyranone-4 et de 6,2 g (0,095 mole) de cyanure de potassium. A la fin de la réaction, on évapore sous vide, reprend à l'eau, extrait au chloroforme, sèche et évapore sous vide. Poids obtenu : 12,4 g (Rdt : 98 %). Huile. Prepared according to Example 1 of the main patent from 15.2 g (0.047 mole) of bromomethyl-8-cyclohexyl-2-4H- [1] -benzopyranone-4 and 6.2 g (0.095 mole) of cyanide potassium. At the end of the reaction, the mixture is evaporated in vacuo, taken up in water, extracted with chloroform, dried and evaporated in vacuo. Weight obtained: 12.4 g (Yield: 98%). Oil.

IR : @ c=N =2240 cm-1, @ c = O (pyrone) = 1650 cm-1. RMN (CDCl3), 11 H de 1,0 à 3,0 (multiplet), 2 H à 3,95 (singulet) 1 H à 6,2 (sing- let), 2 H de 7,2 à 7,9 (muitiplet), 1 H à 8,15 (doublet de doublet, J1 = 8 Hz, J2 = 2 Hz). IR: @ c = N = 2240 cm-1, @ c = O (pyrone) = 1650 cm-1. NMR (CDCl3), 11 H from 1.0 to 3.0 (multiplet), 2 H to 3.95 (singlet) 1 H to 6.2 (singlet), 2 H from 7.2 to 7.9 (muitiplet), 1 H at 8.15 (doublet of doublet, J1 = 8 Hz, J2 = 2 Hz).

Exemple 24 : [Oxo-4-(phénylméthyl)-2-4H-[1]-benzopyran-8yl] acétonitrile C18H13NO2 (formule 25). PM = 275,31.Example 24: [Oxo-4- (phenylmethyl) -2-4H- [1] -benzopyran-8yl] acetonitrile C18H13NO2 (formula 25). MW = 275.31.

Préparé selon l'exemple 1 du brevet principal à partir de 47 g (0,143 mole) de bromométhyl-8-(phénylméthyl)-2-4H-[1]-benzopyranone-4 et de 18,5 g (0,284 mole) de cyanure de potassium. Après filtration à chaud, on évapore, soue vide on recristallise dans un mélange éthanol-eau. Prepared according to Example 1 of the main patent from 47 g (0.143 mole) of bromomethyl-8- (phenylmethyl) -2-4H- [1] -benzopyranone-4 and 18.5 g (0.284 mole) of cyanide potassium. After hot filtration, the mixture is evaporated, vacuum dried and recrystallized from an ethanol-water mixture.

Poide obtenu : 7,1 g (Rdt : 18 %). PFK = 100 C. IR : @ c = N =2240 cm-1
2 c = O (pyrone) = 1640 cm-1. RMN (CDCl3), 2 H à 3,83 (singulet), 2 H à 3,97 (singulet), 1 H à 6,2 (singuiet), 7 E de 7,2 à 7,8 (multiplet), 1 H à 8,2 (doublet de doublet, J1 = 8 Hz ; J2 = 2 Hz). Weight obtained: 7.1 g (Yield: 18%). PFK = 100 C. IR: @ c = N = 2240 cm-1
2 c = O (pyrone) = 1640 cm-1. NMR (CDCl3), 2 H at 3.83 (singlet), 2 H at 3.97 (singlet), 1 H at 6.2 (singuiet), 7 E from 7.2 to 7.8 (multiplet), 1 H to 8.2 (doublet of doublet, J1 = 8 Hz; J2 = 2 Hz).

Exemple 25 :
Oxo-4-phényl-3-4H-[1]-benzopyran carboxyaldéhyde-8 C16H10O3 (formule 26) PM = 250,26.Example 25:
Oxo-4-phenyl-3-4H- [1] -benzopyran carboxyaldehyde-8 C16H10O3 (formula 26) PM = 250.26.

Préparé selon l'exemple 21 du brevet principal à partir de 88,2 g (0,28 mole) de bromométhyl-8-phényl-3-4H-[1] benzopyranone-4 avec la variante suivante ; après l'addition de l'acide chlorhydrique, on ne chauffe pas, mais on agite une nuit à température ambiante, puis on filtre un insoluble, on dilue le filtrat à l'eau et on filtre le préoipitéobtenu. Poids obtenu : 52,4 g (Rdt : 74 %). PFK = 162 C (AcOEt) IR ; @ c = O (pyrone) =1650 cm-1;@c = O (aldéhyde) = 1700 cm-1.Prepared according to Example 21 of the main patent from 88.2 g (0.28 mole) of bromomethyl-8-phenyl-3-4H- [1] benzopyranone-4 with the following variant; after the addition of hydrochloric acid, the mixture is not heated, but stirred overnight at room temperature, then an insoluble material is filtered, the filtrate is diluted with water and the preoipite obtained is filtered. Weight obtained: 52.4 g (Yield: 74%). PFK = 162 C (AcOEt) IR; @ c = O (pyrone) = 1650 cm-1; @c = O (aldehyde) = 1700 cm-1.

RMN (CDCl3) 6 H de 7,2 à 7,8 (multiplet) 1 H à 8,12 (singulet), 1 H à 8,3 (doublet de doublet, J1 = 8 Hz ; ;2 = 2 Hz), 1 H à 8,6 (doublet de doublet, J1 = 8 Hz @ J2 = 2 Hz), 1 K à 10,7 (singulet).NMR (CDCl3) 6 H from 7.2 to 7.8 (multiplet) 1 H to 8.12 (singlet), 1 H to 8.3 (doublet of doublet, J1 = 8 Hz;; 2 = 2 Hz), 1 H at 8.6 (doublet of doublet, J1 = 8 Hz @ J2 = 2 Hz), 1 K at 10.7 (singlet).

Exemple 26 :
Acide (cyclohexyl-2-oxo-4-4H-[1]-benzopyran-8-yl) acétique C17H18O4 (formule 27). PM = 286,33. Example 26:
Acid (cyclohexyl-2-oxo-4-4H- [1] -benzopyran-8-yl) acetic C17H18O4 (formula 27). MW = 286.33.

Préparé selon l'exemple 2 du brevet principal à partir de 12,4 g (0,046 mole) de cyclohexyl-2-oxo-4-4H-[1]-benzopyran-8-yl) acétonitrile. Après dilution à l'eau, on extrait au chloroforme, lave à l'eau évapore sous vide, dissout dans une solution aqueuse de bicarbonate de sodium à 5 %, filtre un insoluble, refroidit, acidifie, filtre et recristallise dans le toluène. Poids obtenu : 3,4 g (Rdt : 25 %).Prepared according to Example 2 of the main patent from 12.4 g (0.046 mole) of cyclohexyl-2-oxo-4-4H- [1] -benzopyran-8-yl) acetonitrile. After dilution with water, extraction is carried out with chloroform, washing with water evaporates under vacuum, dissolved in an aqueous solution of sodium bicarbonate at 5%, filters an insoluble material, cools, acidifies, filters and recrystallizes from toluene. Weight obtained: 3.4 g (Yield: 25%).

PFG = 180-182 C IR : @ c = O (pyrone) = 1645 cm-1; @c = O (acide) = 1700 cm-1. RMN (DMSO) 11 H de 1,0 à 3,0 (multiplet), 2 H à 3,87 (singulet), 1 H à 6,2 (singulet) 1 H à 7,4 (triplet, J = 8 Hz), 1 H à 7,72 (doublet de doublet, J1 = 8 Hz, J2 = 2 Hz), 1 E à 7,97 (doublet de doublet, J1 = 8 Hz, J2 = 2 Hz). PFG = 180-182 C IR: @ c = O (pyrone) = 1645 cm-1; @c = O (acid) = 1700 cm-1. NMR (DMSO) 11 H from 1.0 to 3.0 (multiplet), 2 H to 3.87 (singlet), 1 H to 6.2 (singlet) 1 H to 7.4 (triplet, J = 8 Hz ), 1 H at 7.72 (doublet doublet, J1 = 8 Hz, J2 = 2 Hz), 1 E at 7.97 (doublet doublet, J1 = 8 Hz, J2 = 2 Hz).

Analyse pondérale C % H % O %
Calculée 71,31 6,34 22,35
Trouvée 71,48 6,35
Exemple 27 :
Acide (oxo-4-phényl-3-4H-[1]-benzopyran-8-yl) acétique C17H12O4 (formule 28) PM = 280,28.Weight analysis C% H% O%
Calculated 71.31 6.34 22.35
Found 71.48 6.35
Example 27:
Acetic acid (oxo-4-phenyl-3-4H- [1] -benzopyran-8-yl) C17H12O4 (formula 28) MW = 280.28.

A un mélange de 4,8 g (0,1 mole) d'une suspension d'hydrure de sodium à 50~% dans l'huile, et de 120 ml de dioxane anhydre, on ajoute gout- te à goutte une solution de 33,1 g (0,1 mole) de diméthylaminométhy- lène diphosphonate de tétraéthyle (C.R. DEGENHARDT, Synth. Commun 1982 12 415) dans 120 ml de dioxane. On agite 1 h à 250C puis on ajoute goutte à goutte une solution de 25 g (0,1 mole) d'oxo-4-phényl-3-4H -[1]-benzopyranobarboxaldéhyde-8 dans 120 ml de dioxane. On chauffe 1 H à 50 c puis on évapore sous vide, reprend à l'eau, extrait au chloroforme, et évapore sous vide. Le résidu est repris avec 1,5 1 d'acide chlorhydrique concentré et chauffé 30 minutes à reflux. On refroidit, dilue à lteau glacée extrait au chloroforme, lave à l'eau, sèche et évapore sous vide.Le résidu est repris avec 300 ml d'une solution aqueuse de bioarbonate de sodium à 5 do à reflux, filtré, le filtrat est refroidi et acidifié (HCl 6 N). Le précipité pâteux obtenu est extrait au chloroforme, séché et évaporé sous vide. Le résidu est purifié par chromatographie (sio2, C6H6-AcOH-MeOH-45 z 8 : 8) puis recristallisé dans le toluène. Poids obtenu : 1,1 g. PFG = 137139 C. IR : @ c = O (pyrone) = 1640 cm-1; @ c = O (acide) = 1730 cm-1.To a mixture of 4.8 g (0.1 mole) of a suspension of sodium hydride at 50 ~% in oil, and 120 ml of anhydrous dioxane, a solution of 33.1 g (0.1 mol) of tetraethyl dimethylaminomethylene diphosphonate (CR DEGENHARDT, Synth. Commun 1982 12 415) in 120 ml of dioxane. The mixture is stirred for 1 hour at 250 ° C. and then a solution of 25 g (0.1 mole) of oxo-4-phenyl-3-4H - [1] -benzopyranobarboxaldehyde-8 in 120 ml of dioxane is added dropwise. It is heated for 1 hour at 50 ° C. then evaporated under vacuum, taken up in water, extracted with chloroform, and evaporated under vacuum. The residue is taken up with 1.5 l of concentrated hydrochloric acid and heated for 30 minutes at reflux. The mixture is cooled, diluted with ice water extracted with chloroform, washed with water, dried and evaporated under vacuum. The residue is taken up in 300 ml of an aqueous solution of sodium bioarbonate at 5 do at reflux, filtered, the filtrate is cooled and acidified (HCl 6 N). The pasty precipitate obtained is extracted with chloroform, dried and evaporated in vacuo. The residue is purified by chromatography (sio2, C6H6-AcOH-MeOH-45 z 8: 8) and then recrystallized from toluene. Weight obtained: 1.1 g. PFG = 137139 C. IR: @ c = O (pyrone) = 1640 cm-1; @ c = O (acid) = 1730 cm-1.

RMN (CDCl3) 2 E à 3s97 (singulet), 7 H de 7,1 à 7,8 (multiplet), 1 E à 8,05 (singulet) 1 H à 8,3 (doublet de doublet, J1 = 8 Hz, J2 = 2
Hz), 1 H à 8,8 (échangeable avec D2O).NMR (CDCl3) 2 E at 3s97 (singlet), 7 H from 7.1 to 7.8 (multiplet), 1 E at 8.05 (singlet) 1 H at 8.3 (doublet of doublet, D1 = 8 Hz , J2 = 2
Hz), 1 H at 8.8 (exchangeable with D2O).

Analyse pondérale C % E % O %
Calculée 72,85 4,32 22,83
Trouvée 72,83 4,50
Exemple 28 :
Acide [oxo-4-(phénylméthyl)-2-4H-[1]-benzopyran-8-yl] acétique
C18H14O4 (formule 29) PM =294,31.Weight analysis C% E% O%
Calculated 72.85 4.32 22.83
Found 72.83 4.50
Example 28:
[Oxo-4- (phenylmethyl) -2-4H- [1] -benzopyran-8-yl] acetic acid
C18H14O4 (formula 29) PM = 294.31.

Préparé selon l'exemple 2 du brevet principal à partir de 7g (0,025 mole) d'[oxo-4-(phénylméthyl)-2-4H-[1]-benzopyran-8-yl] acétonitrile
Poids obtenu : 2,7 g (Rdt : 36%). PFg = 143-145 C (tolluéne). IR : @ c = O (pyrone) = 1640 cm-1 ; @ c = O (acide) = 1720 cm-1. RMN (CDCl3), 2 H à 3S87 (singulet) 2 H à 3,93 (singulet), 1 H à 6,27 (singulet) 9 E de 7,0 à 8,3 (multiplet).Prepared according to Example 2 of the main patent from 7g (0.025 mole) of [oxo-4- (phenylmethyl) -2-4H- [1] -benzopyran-8-yl] acetonitrile
Weight obtained: 2.7 g (Yield: 36%). PFg = 143-145 C (tolluene). IR: @ c = O (pyrone) = 1640 cm-1; @ c = O (acid) = 1720 cm-1. NMR (CDCl3), 2 H at 3S87 (singlet) 2 H at 3.93 (singlet), 1 H at 6.27 (singlet) 9 E from 7.0 to 8.3 (multiplet).

Analyse pondérale C % H % O %
Caloulée 73,46 4,79 21,75
Trouvée 73,40 4,82
Exemple 29 : (Diphényl-2,3-oxo-4-4H-[1]-benzopyran-8-yl) acétonitrile C23H15NO2 (formule 30) PM = 337,38. Weight analysis C% H% O%
Caloulée 73.46 4.79 21.75
Found 73.40 4.82
Example 29: (Diphenyl-2,3-oxo-4-4H- [1] -benzopyran-8-yl) acetonitrile C23H15NO2 (formula 30) PM = 337.38.

Préparé selon l'exemple 1 du brevet principal à partir de 22,5 g
(0,057 mole) de bromométhyl-8-diphényl-2,3-4H-[1]-benzopyranone-4 et de 7,6 g de cyanure de potassium. Poids obtenu : 7,1 g (Rdt : 36 %).Prepared according to Example 1 of the main patent from 22.5 g
(0.057 mole) of bromomethyl-8-diphenyl-2,3-4H- [1] -benzopyranone-4 and 7.6 g of potassium cyanide. Weight obtained: 7.1 g (Yield: 36%).

PFK = 185 C. TR : @ c (pyrone) = 1630 cm-1. RMN (CDCl3) 2 H à 4,0 (singulet), 12 H de 7,0 à 8,0 (multiplet) 1 E à 8,3 (doublet de doublet
J1 =8 Hz, J2 = 2 Hz). PFK = 185 C. TR: @ c (pyrone) = 1630 cm-1. NMR (CDCl3) 2 H to 4.0 (singlet), 12 H from 7.0 to 8.0 (multiplet) 1 E to 8.3 (doublet of doublet
J1 = 8 Hz, J2 = 2 Hz).

Exemple 30 :
Acide (diphényl-2,3-oxo-4-4H-[1]-benzopyran-8-yl) acétique C23H16O4 (formule 31) PM = 256,38.Example 30:
Acid (2,3-diphenyl-oxo-4-4H- [1] -benzopyran-8-yl) acetic C23H16O4 (formula 31) MW = 256.38.

Préparé selon l'exemple 2 du brevet principal à partir de 7,1 g (0,02 mole) de (diphényl-2,3-oxo-4-4H-[1]-benzopyran-8-yl) acétonitrile.Prepared according to Example 2 of the main patent from 7.1 g (0.02 mole) of (2,3-diphenyl-oxo-4-4H- [1] -benzopyran-8-yl) acetonitrile.

Poids obtenu : 2,4 g , PFG = 220-224 C. IR s c = O (acide) = 1730cm-1
O (pyrone) = 1630 cm-1, @OH = 2900 à 3600 cm-1. RMN (DMSO), 1H à 3,5 (échangeable avec D20), 2 H à 490 (singulet), 13 H de 7,0 à 8,3 (multiplet).Weight obtained: 2.4 g, PFG = 220-224 C. IR sc = O (acid) = 1730cm-1
O (pyrone) = 1630 cm-1, @OH = 2900 to 3600 cm-1. NMR (DMSO), 1H to 3.5 (exchangeable with D20), 2H to 490 (singlet), 13H from 7.0 to 8.3 (multiplet).

Analyse pondérale C % H % O %
Calculée 77551 4,53 17,96
Trouvée 77,29 4,51
Exemple 31 : (Méthyl-2-oxo-4-4H-[1]-benzopyran-8-yl)acétonitrila C12H9NO2 (formule 32). PM = 199,21.Weight analysis C% H% O%
Calculated 77,551 4.53 17.96
Found 77.29 4.51
Example 31: (Methyl-2-oxo-4-4H- [1] -benzopyran-8-yl) acetonitrila C12H9NO2 (formula 32). MW = 199.21.

Préparé selon l'exemple 1 du brevet principal à partir de 8,8 g (4034 mole) de bromométhyl-8-méthyl-2-4H-[1]-benzopyranone-4. Poids obtenu : 5,1 g. IR : @c =N =2250 cm-1, @ c = O (pyrone) - 1650 cm-1 . RMN (CDCl3) 3 H à 2,4 (singulet), 2 H à 3,97 (singulet), 9 H à 6,2 (singulet) 1 H à 7,4 (triplet, J = 8 Hz), 1 H à 7,7 (doublet de doublet, J1= 8 Hz, J2 = 2 Hz), 1 H à 8,2 (doublet de doublet, J1 = 8 Hz, J2 = 2 Hz).Prepared according to Example 1 of the main patent from 8.8 g (4034 mole) of bromomethyl-8-methyl-2-4H- [1] -benzopyranone-4. Weight obtained: 5.1 g. IR: @c = N = 2250 cm-1, @ c = O (pyrone) - 1650 cm-1. NMR (CDCl3) 3 H at 2.4 (singlet), 2 H at 3.97 (singlet), 9 H at 6.2 (singlet) 1 H at 7.4 (triplet, J = 8 Hz), 1 H at 7.7 (doublet doublet, J1 = 8 Hz, J2 = 2 Hz), 1 H at 8.2 (doublet doublet, J1 = 8 Hz, J2 = 2 Hz).

Exemple 32 :
Acide (méthyl-2-oxo-4-4H-[1]-benzopyran-8-yl) acétique C12H10O4
(formule 33). PM = 218,21.Example 32:
(Methyl-2-oxo-4-4H- [1] -benzopyran-8-yl) acetic acid C12H10O4
(formula 33). MW = 218.21.

Préparé selon l'exemple 2 du brevet principal à partir de 5 g (0,025 mole) de (méthyl-2-oxo-4-4H-[1]-benzopyran-8-yl) acétonitrile. Après traitement au bicarbonate et acidification, le produit est purifié par chromatographie (SiO2, C6H6-CH3-COOR-MeOH, 45 o 8 : 8) puis reori- tallisé dans un mélange eau-acide acétique. Poids obtenu 0,6 g.Prepared according to Example 2 of the main patent from 5 g (0.025 mole) of (methyl-2-oxo-4-4H- [1] -benzopyran-8-yl) acetonitrile. After treatment with bicarbonate and acidification, the product is purified by chromatography (SiO2, C6H6-CH3-COOR-MeOH, 45 or 8: 8) and then re-crystallized in a water-acetic acid mixture. Weight obtained 0.6 g.

PFG = 230-233 C. IR : @ c = O (acide) = 1720 cm-1, @ c = O (pyrone) = 1635 cm-1, @ c = O (pyrone) = 2300 à 3300 cm-1. RMN (DMSO), 3 H à 2,36 (singulet), 1 H à 3,4 (échangeable avec D2O), 2 H à 3,83 (singulet), 1 H à 6,25 (singulet), 1 H à 7,4 (triplet, J = 8 Hz), 1 H à 7,7 (doublet de doublet,J1 = 8 Hz, J2 = 2 Hz), 1 H à 7,9 (doublet de doublet,
J1 = 8 Hz, J2 = 2 Hz).PFG = 230-233 C. IR: @ c = O (acid) = 1720 cm-1, @ c = O (pyrone) = 1635 cm-1, @ c = O (pyrone) = 2300 to 3300 cm-1. NMR (DMSO), 3 H at 2.36 (singlet), 1 H at 3.4 (exchangeable with D2O), 2 H at 3.83 (singlet), 1 H at 6.25 (singlet), 1 H at 7.4 (triplet, J = 8 Hz), 1 H to 7.7 (doublet of doublet, J1 = 8 Hz, J2 = 2 Hz), 1 H to 7.9 (doublet of doublet,
J1 = 8 Hz, J2 = 2 Hz).

Analyse powdérale C % H % O %
calculée 66,05 4,62 2o,33
trouvée 66,14 4,75 General analysis C% H% O%
calculated 66.05 4.62 2o, 33
found 66.14 4.75

Claims (9)

REVENDICATIONS 1. Acides [oxo-4-4H-[1]-benzopyran-8-yl] aloanoiques, selon le brevet principal, caracterisés par la formule 1. [oxo-4-4H- [1] -benzopyran-8-yl] aloanoic acids, according to the main patent, characterized by the formula
Figure img00140001
Figure img00140001
 dana laquelle AR est l'hydrogène, un radical phényle substitué ou non ou thényle, furyle, naphtyle, alkyle inférieur, cycloalkyle, aralkyle; in which AR is hydrogen, a substituted or unsubstituted phenyl or thényl, furyl, naphthyl, lower alkyl, cycloalkyl, aralkyl radical; B est un radical allyle inférieur linéaire ou ramifié, saturé ou à insaturation éthylénique, R1 est l'hydrogène ou un radical phényles B is a linear or branched, saturated or ethylenically unsaturated lower allyl radical, R1 is hydrogen or a phenyl radical X est l'hydrogène ou un radical allyle inférieur, alkozy et n = 1, ainsi que leurs sels de métaux alcalins.X is hydrogen or a lower allyl radical, alkozy and n = 1, as well as their alkali metal salts. 2. Esters et aminoesters des composés selon la revendication 1 caractérisés par la 2. Esters and aminoesters of the compounds according to claim 1, characterized by the
Figure img00140002
Figure img00140002
 dans laquelle AR, B, R1, X et n ont les mêmes significations que précédemment, R2 est un radical alkyle inférieur, hydroxyalkyle inférieur,dialkyl inférieur aminoalkyle inférieur, ou morpholinoéthyle ainsi que leurs sels avec dés acides minéraux ou organiques aocepta- bles en thérapeutique humaine. in which AR, B, R1, X and n have the same meanings as previously, R2 is a lower alkyl, lower hydroxyalkyl, lower dialkyl lower aminoalkyl, or morpholinoethyl radical as well as their salts with mineral or organic acids acceptable in therapy human. 3. Procédé de préparation des acides selon la revendication 1, quand B = CH2, caractérisé en ce que l'on procède à l'hydrolyse des nitriles correspondants 9 les dits nitriles étant obtenus par traitement du bromométhyl-8 benzopyranone-4 correspondant avec un cyanure alcalin. 3. A process for the preparation of acids according to claim 1, when B = CH2, characterized in that the corresponding nitriles are hydrolyzed 9, the said nitriles being obtained by treatment of the corresponding 8-bromomethyl-benzopyranone-4 with a alkaline cyanide. 4. Procédé de préparation des acides selon la revendication 1, quand AR = H et R1 = phényle, caractérisé en ce qu'on met en réaction la bromométhyl-8 benzopyranone-4 correspondante avec l'hexaméthylànetétramine, puis on procède à la condensation de l'aldéhyde obtenu avec le diéthylaminométhylène diphosphonate de tétraéthyle en présence d'hydrure de sodium, et hydrolyse en vue de l'obtention de l'acide. 4. Process for the preparation of acids according to claim 1, when AR = H and R1 = phenyl, characterized in that the corresponding 8-bromomethyl-benzopyranone-4 is reacted with hexamethylanetetramine, then the condensation of the aldehyde obtained with tetraethyl diethylaminomethylene diphosphonate in the presence of sodium hydride, and hydrolysis with a view to obtaining the acid. 5. Procédé de préparation des acides selon la revendication 1, quand B est - CE2 - CH2, caractérisé en ce qu'on soumet à une hydrolyse le malonate correspondant. 5. Process for the preparation of acids according to claim 1, when B is - CE2 - CH2, characterized in that the corresponding malonate is subjected to hydrolysis. 6. Nitriles utilisables dans la préparation des acides selon la revendication 3, quand B = CH2, caractérisés par la formule. 6. Nitriles which can be used in the preparation of acids according to claim 3, when B = CH2, characterized by the formula.
Figure img00150001
Figure img00150001
 dans laquelle AR est un radical phényle substitué ou non ou thényle, furyle, naphtyle, alkyle inférieur, cycloalkyle, aralkyle, X est l'hydrogène ou un radical alkyle inférieur, alkoxyS R1 est l'hydrogène ou un radical phényle.in which AR is a substituted or unsubstituted phenyl radical or thényl, furyl, naphthyl, lower alkyl, cycloalkyl, aralkyl, X is hydrogen or a lower alkyl radical, alkoxyS R1 is hydrogen or a phenyl radical. 7. Malonates utilisables dans la préparation des acides selon la revendication 5, quand B est un radical alkylène, en particulier -CH2-CH2 et n = 1, caractérisés par la formule 7. Malonates which can be used in the preparation of acids according to claim 5, when B is an alkylene radical, in particular -CH2-CH2 and n = 1, characterized by the formula
Figure img00150002
Figure img00150002
 dans laquelle AR est un radical phényle et X est l'hydrogène ou un radical alkyle inférieur, R1 a la même signification que précédemment in which AR is a phenyl radical and X is hydrogen or a lower alkyl radical, R1 has the same meaning as above 8. [oxo-4-phényl-3-4H-[1]-benzopyran-8-yl] carboxaldéhyde utilisable dans la préparation des acides selon la revendication 4, quand AR est l'hydrogène et R1 est phényle. 8. [oxo-4-phenyl-3-4H- [1] -benzopyran-8-yl] carboxaldehyde usable in the preparation of acids according to claim 4, when AR is hydrogen and R1 is phenyl. 9. Médicament contenant comme principe actif un acide selon la revendication 1, de formule 9. Medicament containing as active principle an acid according to claim 1, of formula
Figure img00150003
Figure img00150003
 dans laquelle AR est un radical phényle substitué ou non, ou thényle, furyle, naphtyle, alkyle inférieur, cycloalkyle, aralkyle ; B est un radical alkyle inférieur linéaire ou ramifié 3 R1 est l'hydrogène ou un radical phényle X in est l'hydrogène ou un radical alkyle inférieur alcoxy et n = 1, ainsi que leurs sels, notamment de sodium, ainsi que leurs esters et aminoesters selon la revendication 2.  in which AR is a substituted or unsubstituted phenyl radical, or thenyl, furyl, naphthyl, lower alkyl, cycloalkyl, aralkyl; B is a linear or branched lower alkyl radical 3 R1 is hydrogen or a phenyl radical X in is hydrogen or an alkoxy lower alkyl radical and n = 1, as well as their salts, especially sodium, as well as their esters and aminoesters according to claim 2.
FR8219640A 1981-11-25 1982-11-24 [4-oxo-4H-1-Benzopyran-8-yl]alkanoic acids, their salts and derivatives, their preparation and medicinal products containing them Granted FR2536397A2 (en)

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US5116954A (en) * 1988-04-06 1992-05-26 Lipha, Lyonnaise Industrielle Pharmaceutique Pharmaceutically useful flavonoic compounds containing at least one substituent on the benzopyranone ring moiety

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FR2516922A1 (en) * 1981-11-25 1983-05-27 Lipha ACIDS (OXO-4-4H- (1) -BENZOPYRAN-8-YL) ALKANOIC, SALTS AND DERIVATIVES, PREPARATION AND DRUG CONTAINING THEM

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FR2516922A1 (en) * 1981-11-25 1983-05-27 Lipha ACIDS (OXO-4-4H- (1) -BENZOPYRAN-8-YL) ALKANOIC, SALTS AND DERIVATIVES, PREPARATION AND DRUG CONTAINING THEM

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5116954A (en) * 1988-04-06 1992-05-26 Lipha, Lyonnaise Industrielle Pharmaceutique Pharmaceutically useful flavonoic compounds containing at least one substituent on the benzopyranone ring moiety

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